Clinical Ophthalmic Oncology: Eyelid and Conjunctival Tumors [3rd ed.] 978-3-030-06045-9;978-3-030-06046-6

Table of contents :
Front Matter ....Pages i-xiii
Eyelid Tumors: Examination Techniques (Catherine J. Hwang, Julian D. Perry)....Pages 1-5
Eyelid Tumors: Classification and Differential Diagnosis (Jacob Pe’er, Shahar Frenkel)....Pages 7-13
Benign Eyelid Squamous and Melanocytic Tumors (Lynn Schoenfield, Arun D. Singh)....Pages 15-31
Basal Cell Carcinoma (Mordechai Rosner, Ido Didi Fabian)....Pages 33-43
Squamous Cell Carcinoma (Mordechai Rosner, Ido Didi Fabian)....Pages 45-52
Sebaceous Gland Carcinoma (Mordechai Rosner, Ido Didi Fabian)....Pages 53-62
Eyelid Tumors: Cutaneous Melanoma (Jacob Pe’er, Robert Folberg)....Pages 63-69
Adnexal Tumors (Martina C. Herwig-Carl, Karin U. Loeffler)....Pages 71-81
Stromal Tumors (Geeta K. Vemuganti, Santosh G. Honavar)....Pages 83-96
Surgical Techniques (Andrew J. Rong, Jennifer I. Hui, David T. Tse)....Pages 97-111
Systemic Associations (Matteo Scaramuzzi, Lucy T. Xu, Arun D. Singh, Elias I. Traboulsi)....Pages 113-129
Conjunctival and Corneal Tumors: Examination Techniques (Jacob Pe’er, Shahar Frenkel)....Pages 131-135
Conjunctival and Corneal Tumors: Classification and Differential Diagnosis (Jacob Pe’er, Shahar Frenkel)....Pages 137-141
Conjunctival and Corneal Tumors: Benign Epidermal and Melanocytic Tumors (Jacob Pe’er, Shahar Frenkel)....Pages 143-158
Conjunctival and Corneal Tumors: Ocular Surface Squamous Neoplasia (Jacob Pe’er, Shahar Frenkel, Arun D. Singh)....Pages 159-184
Conjunctival and Corneal Tumors: Primary Acquired Melanosis (Jacob Pe’er, Robert Folberg)....Pages 185-195
Conjunctival and Corneal Tumors: Melanoma (Jacob Pe’er, Robert Folberg)....Pages 197-207
Conjunctival Stromal Tumors (Jacob Pe’er, Shahar Frenkel)....Pages 209-234
Caruncle Tumors (Hans E. Grossniklaus, Daniel R. Capiz-Correa, Jill R. Wells)....Pages 235-243
Pharmacotherapy for Conjunctival Malignancies (Ghada Al Bayyat, Dan Arreaza-Kaufman, Anat Galor, Jacob Pe’er, Carol L. Karp)....Pages 245-259
Sentinel Lymph Node Biopsy for Eyelid and Conjunctival Malignancies (Oded Sagiv, Bita Esmaeli)....Pages 261-277
Surgical Techniques (Anat Galor, Bennie H. Jeng, Arun D. Singh, Carol L. Karp)....Pages 279-285
Radiation Therapy: Conjunctival and Eyelid Tumors (Christopher Fleming, Shlomo Koyfman, Arun D. Singh)....Pages 287-293
Conjunctival and Corneal Tumors: Systemic Associations (Matteo Scaramuzzi, Lucy T. Xu, Arun D. Singh, Elias I. Traboulsi)....Pages 295-306
Back Matter ....Pages 307-320

Citation preview

Clinical Ophthalmic Oncology Eyelid and Conjunctival Tumors Jacob Pe’er Arun D. Singh Bertil E. Damato Editors Third Edition

123

Clinical Ophthalmic Oncology

Jacob Pe’er  •  Arun D. Singh Bertil E. Damato Editors

Clinical Ophthalmic Oncology Eyelid and Conjunctival Tumors Third Edition

Editors Jacob Pe’er Ocular Onocology Service and Ophthalmic Pathology Laboratory Department of Ophthalmology Hadassah - Hebrew University Medical Center Jerusalem Israel

Arun D. Singh Department of Ophthalmic Oncology, Cole Eye Institute, Cleveland Clinic Cleveland, OH USA

Bertil E. Damato Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford UK

ISBN 978-3-030-06045-9    ISBN 978-3-030-06046-6 (eBook) https://doi.org/10.1007/978-3-030-06046-6 Library of Congress Control Number: 2019933401 © Springer Nature Switzerland AG 2019 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Preface

Ophthalmic tumors are rare and diverse so that their diagnosis can be quite complex. Treatment usually requires special expertise and equipment and, in many instances, is controversial. The field is advancing rapidly, because of accelerating progress in tumor biology, pharmacology, and instrumentation. Increasingly, the care of patients with an ocular or adnexal tumor is provided by a multidisciplinary team, consisting of ocular oncologists, general oncologists, radiotherapists, pathologists, psychologists, and other specialists. For all these reasons, we felt that there was a need for the new edition of the textbook providing a balanced view of current clinical practice. Although each section of Clinical Ophthalmic Oncology, 3rd Edition now represents a standalone volume, each chapter has a similar layout with boxes that highlight the key features, tables that provide comparison, and flow diagrams that outline therapeutic approaches. The enormous task of editing a multi-author, multivolume textbook could not have been possible without the support and guidance by the staff at Springer: Caitlin Prim, Melanie Zerah, ArulRonika Pathinathan, and Karthik Rajasekar. Michael D.  Sova kept the pressure to meet the production deadlines. It is our sincere hope that our efforts will meet high expectation of the readers. Jerusalem, Israel Oxford, UK Cleveland, OH, USA

Jacob Pe’er, MD Bertil E. Damato, MD, PhD, FRCOphth Arun D. Singh, MD

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Acknowledgments

To my wife, Edith, and my children, Liron, Neta, and Doron, for years of support and patience. Jacob Pe’er, MD To my family, Frankanne, Erika, Stephen, and Anna. Bertil E. Damato, MD, PhD, FRCOphth To my parents who educated me beyond their means, my wife, Annapurna, and my children, Nakul and Rahul, who make all my efforts worthwhile. Arun D. Singh, MD

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Contents

1 Eyelid Tumors: Examination Techniques��������������������������������������   1 Catherine J. Hwang and Julian D. Perry 2 Eyelid Tumors: Classification and Differential Diagnosis������������   7 Jacob Pe’er and Shahar Frenkel 3 Benign Eyelid Squamous and Melanocytic Tumors���������������������   15 Lynn Schoenfield and Arun D. Singh 4 Basal Cell Carcinoma����������������������������������������������������������������������   33 Mordechai Rosner and Ido Didi Fabian 5 Squamous Cell Carcinoma��������������������������������������������������������������   45 Mordechai Rosner and Ido Didi Fabian 6 Sebaceous Gland Carcinoma����������������������������������������������������������   53 Mordechai Rosner and Ido Didi Fabian 7 Eyelid Tumors: Cutaneous Melanoma������������������������������������������   63 Jacob Pe’er and Robert Folberg 8 Adnexal Tumors ������������������������������������������������������������������������������   71 Martina C. Herwig-Carl and Karin U. Loeffler 9 Stromal Tumors��������������������������������������������������������������������������������   83 Geeta K. Vemuganti and Santosh G. Honavar 10 Surgical Techniques ������������������������������������������������������������������������   97 Andrew J. Rong, Jennifer I. Hui, and David T. Tse 11 Systemic Associations���������������������������������������������������������������������� 113 Matteo Scaramuzzi, Lucy T. Xu, Arun D. Singh, and Elias I. Traboulsi 12 Conjunctival and Corneal Tumors: Examination Techniques ���������������������������������������������������������������� 131 Jacob Pe’er and Shahar Frenkel 13 Conjunctival and Corneal Tumors: Classification and Differential Diagnosis�������������������������������������� 137 Jacob Pe’er and Shahar Frenkel

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14 Conjunctival and Corneal Tumors: Benign Epidermal and Melanocytic Tumors�������������������������������� 143 Jacob Pe’er and Shahar Frenkel 15 Conjunctival and Corneal Tumors: Ocular Surface Squamous Neoplasia �������������������������������������������� 159 Jacob Pe’er, Shahar Frenkel, and Arun D. Singh 16 Conjunctival and Corneal Tumors: Primary Acquired Melanosis���������������������������������������������������������� 185 Jacob Pe’er and Robert Folberg 17 Conjunctival and Corneal Tumors: Melanoma���������������������������� 197 Jacob Pe’er and Robert Folberg 18 Conjunctival Stromal Tumors�������������������������������������������������������� 209 Jacob Pe’er and Shahar Frenkel 19 Caruncle Tumors������������������������������������������������������������������������������ 235 Hans E. Grossniklaus, Daniel R. Capiz-Correa, and Jill R. Wells 20 Pharmacotherapy for Conjunctival Malignancies������������������������ 245 Ghada Al Bayyat, Dan Arreaza-Kaufman, Anat Galor, Jacob Pe’er, and Carol L. Karp 21 Sentinel Lymph Node Biopsy for Eyelid and Conjunctival Malignancies������������������������������������������ 261 Oded Sagiv and Bita Esmaeli 22 Surgical Techniques ������������������������������������������������������������������������ 279 Anat Galor, Bennie H. Jeng, Arun D. Singh, and Carol L. Karp 23 Radiation Therapy: Conjunctival and Eyelid Tumors���������������������������������������������������������������������������������� 287 Christopher Fleming, Shlomo Koyfman, and Arun D. Singh 24 Conjunctival and Corneal Tumors: Systemic Associations���������������������������������������������������������������������� 295 Matteo Scaramuzzi, Lucy T. Xu, Arun D. Singh, and Elias I. Traboulsi Index���������������������������������������������������������������������������������������������������������� 307

Contents

Contributors

Ghada Al Bayyat, MD  Department of Ophthalmology, Bascom Palmer Eye Institute, Miami, FL, USA Dan  Arreaza, MD Department of Ophthalmology, Bascom Palmer Eye Institute, Miami, FL, USA Daniel  R.  Capiz-Correa, MD Department of Orbit and Oculoplastic, Fundacion Hospital Nuestra Senora de la Luz, I.A.P., Mexico City, Mexico Bertil E. Damato, MD, PhD, FRCOphth  Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK Bita Esmaeli, MD, MA  Department of Plastic Surgery, Orbital Oncology and Ophthalmic Plastic Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Ido  Didi  Fabian, MD Department of Ophthalmology, Ocular Oncology Center, Goldschleger Eye Institute, Sheba Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel Christopher  Fleming, MD Department of Radiation Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, USA Robert  Folberg, MD Oakland University William Beaumont School of Medicine, Rochester, MI, USA Shahar  Frenkel, MD, PhD Ocular Oncology Service and Ophthalmic Pathology Laboratory, Department of Ophthalmology, Hadassah - Hebrew University Medical Center, Jerusalem, Israel Anat  Galor, MD Department of Ophthalmology, Bascom Palmer Eye Institute, Miami, FL, USA Hans E. Grossniklaus, MD MBA  Department of Ophthalmology, Emory University School of Medicine/Emory Eye Center, Atlanta, GA, USA Martina  C.  Herwig-Carl, MD, FEBO Department of Ophthalmology, University Clinic Bonn, Bonn, NRW, Germany

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Santosh  G.  Honavar, MD, FACS Department of Ophthalmic Plastic Surgery and Ocular Oncology, Centre for Sight, Hyderabad, Telangana, India Jennifer I. Hui, MD  Oculofacial Plastic Surgery, The Eyelid Institute, Palm Desert, CA, USA Catherine  J.  Hwang, MD Division of Orbital and Oculofacial Plastic Surgery, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA Bennie H. Jeng, MD  Department of Ophthalmology and Visual Sciences, University of Maryland School of Medicine, Baltimore, MD, USA Carol  L.  Karp, MD  Department of Ophthalmology, Bascom Palmer Eye Institute, Miami, FL, USA Shlomo Koyfman, MD  Department of Radiation Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, USA Karin  U.  Loeffler, MD Department of Ophthalmology, Division of Ophthalmic Pathology, University Clinic Bonn, Bonn, NRW, Germany Jacob  Pe’er, MD Ocular Oncology Service and Ophthalmic Pathology Laboratory, Department of Ophthalmology, Hadassah - Hebrew University Medical Center, Jerusalem, Israel Julian D. Perry, MD  Division of Orbital and Oculofacial Plastic Surgery, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA Andrew J. Rong, MD  Department of Oculofacial Plastic Surgery, Bascom Palmer Eye Institute, Miami, FL, USA Mordechai Rosner, MD  Department of Ophthalmology, Eye Histopathology Laboratory, Goldschleger Eye Institute, Sheba Medical Center, Sackler Faculty of Medicine, Tel Aviv university, Tel Aviv, Israel Oded  Sagiv, MD Department of Plastic Surgery, Orbital Oncology and Ophthalmic Plastic Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Matteo  Scaramuzzi, MD Department of Pediatric Ophthalmology and Strabismus, Center for Genetic Eye Diseases, Cole Eye Institute (i-32), Cleveland Clinic, Cleveland, OH, USA Lynn  Schoenfield, MD Department of Pathology, Ohio State University Wexner Medical Center, Columbus, OH, USA Arun  D.  Singh, MD Department of Ophthalmic Oncology, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA Elias  I.  Traboulsi, MD Department of Pediatric Ophthalmology and Strabismus, Center for Genetic Eye Diseases, Cole Eye Institute (i-32), Cleveland Clinic, Cleveland, OH, USA

Contributors

Contributors

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David  T.  Tse, MD Department of Oculofacial Plastic Surgery, Bascom Palmer Eye Institute, Miami, FL, USA Geeta K. Vemuganti, MD, DNB  School of Medical Sciences, University of Hyderabad, Hyderabad, Telangana, India Jill R. Wells, MD  Department of Ophthalmology, Emory University School of Medicine/Emory Eye Center, Atlanta, GA, USA Lucy T. Xu, MD  Department of Ophthalmic Oncology, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA

1

Eyelid Tumors: Examination Techniques Catherine J. Hwang and Julian D. Perry

Introduction

Presenting Symptoms

Neoplasia may develop within any eyelid structure. Examination of the eyelid is thought to be relatively straightforward, given its anterior location and the ability to visualize its anterior and posterior surfaces. However, examination including structure and function is critical to determine the layers of the eyelid involved and if there might be extension posteriorly into the orbit or medially into the lacrimal system. The examination of an eyelid tumor determines the need for any ancillary tests and the surgical plan.

Eyelid neoplasia present with a limited spectrum of symptoms (Box 1.1). Most often, patients notice an abnormal eyelid appearance or asymmetry compared to the contralateral eyelid. The eyelid may harbor a distinct lesion, displaying elevation, ulceration, crusting, bleeding, altered pigmentation, telangiectasia, or other visible cutaneous or conjunctival changes. The patient may complain of loss of eyelashes or an irregularity along the eyelid margin.

History

Box 1.1 Symptoms of Eyelid Neoplasia

The history begins with a description of the symptoms: severity, onset, and rate of progression. A targeted review of systems reveals additional clues to the etiology. The authors of the chapter would like to thank Dr. Bryan R. Costin for his contribution towards previous edition of this chapter. C. J. Hwang (*) · J. D. Perry Division of Orbital and Oculofacial Plastic Surgery, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA e-mail: [email protected]

• Sensory: tenderness, itching, visual changes • Motor: ptosis, lagophthalmos • Structural: visible or palpable lesion, change in symmetry • Functional: keratopathy or tearing • Secondary: pigmentation, lymphadenopathy

© Springer Nature Switzerland AG 2019 J. Pe’er et al. (eds.), Clinical Ophthalmic Oncology, https://doi.org/10.1007/978-3-030-06046-6_1

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Eyelid neoplasia may produce symptoms that occur with or without visible structural changes. Sensory symptoms such as pain, tenderness, itching, or vision symptoms due to keratopathy, induced astigmatism, or obstruction of vision may develop. Motor symptoms, such as blepharoptosis or lagophthalmos, may develop owing to involvement of the eyelid retractors and protractors or indirectly from a mass effect. Functional symptoms develop from mechanical keratoconjunctivitis, exposure keratopathy, or decreased lacrimal outflow.

Rate of Onset Rapidity and progression help characterize the pathology. Most symptoms from eyelid tumors develop over weeks to months, but associated hemorrhage, infection, and inflammation may be acute. Both benign (e.g., angiomas, papillomas) and malignant (e.g., cutaneous malignancies, metastases) eyelid tumors can produce hemorrhage. Any eyelid tumor that blocks lacrimal outflow or causes diminished cutaneous integrity can result in infection. Eyelid tumors may also be associated with a significant inflammatory reactions.

Past Medical History Because the majority of eyelid neoplasms are epidermal in origin, the past medical history should focus on risk factors for epidermal malignancy. Information should be obtained regarding family history of cutaneous malignancy, skin type, freckle density, eye color, hair color, and prior history of skin cancer. Patients

of Celtic or Scandinavian descent with blonde or red hair, blue eyes, and fair skin carry a greater risk for cutaneous malignancy [1, 2]. The history should also include immunosuppression, tobacco use, prior radiotherapy, sun exposure, and similar growths elsewhere on the skin.

Examination The physical examination of an adult with suspected eyelid neoplasia does not end with direct visualization of the lesion. It should include a comprehensive inspection of the eyelid, ocular adnexa and orbit, eye, and other cutaneous lesions described in the history. Underlying conditions that may make reconstruction more challenging should be noted, including prominent globe, midface ptosis, hypoplastic orbital rim, lack of cutaneous or tissue redundancy, previous scarring from cutaneous malignancy repair or other surgery, asymmetry, lymph node enlargement, lagophthalmos, trichiasis, dry eye syndrome, and blepharitis.

Eyelid Examination The patient should point out smaller lesions to the examiner using a hand mirror. The entire face should be evaluated to note Fitzpatrick skin type and any other cutaneous lesions. The eyelid examination should describe the appearance of the lesion, any associated anatomical deformities, and the results of palpation. The dimensions should be measured using a ruler or slit lamp beam. The eyelid examination should focus particularly on signs of malignancy, including telangiectasia, nodularity, pearly

1  Eyelid Tumors: Examination Techniques

a

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b

Fig. 1.1  Photograph of lower eyelid shows a benign eyelid nodule without loss of lashes (a) and loss of eyelid tissue with cilia loss secondary to a malignant tumor (b)

translucency, ulceration, bleeding, crusting, irregularity of the eyelid margin, meibomian gland effacement, misdirection of lashes or trichiasis, and loss of cilia (Fig.1.1; Box 1.2). Palpation results should describe the mobility of the lesion, as well as any fluctuance or associated tenderness. Color changes and irregularities should be noted.

Box 1.2 Signs of Malignant Eyelid Tumor • Telangiectasia • Nodularity, pearly translucency • Ulceration, bleeding, crusting, margin notch • Misdirection of lashes or trichiasis • Loss of cilia • Effacement of meibomian gland orifice

Function of the eyelid including levator excursion, orbicularis function, lagophthalmos, and lid lag in downgaze should be measured and noted. Horizontal eyelid laxity, blepharoptosis, cutaneous insufficiency, and other preexisting eyelid malpositions, scarring, and conditions should be noted, as they may challenge repair and will affect the reconstruction design. In addition, patients that relate these preoperative conditions to eyelid tumor surgery in the follow-up period can be reminded of the preoperative findings.

Ocular Adnexal Examination Eyelid tumors may spread directly to the lacrimal gland, orbit, or lacrimal outflow apparatus. Conversely, primary tumors of these areas may occasionally present with only eyelid signs and symptoms. The structure and function of the orbit and ocular adnexal tissues in proximity to the

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lesion should be evaluated. The examiner should palpate for preauricular, submandibular, cervical and supraclavicular adenopathy. Cranial nerves V and VII should be tested carefully to assess for involvement and possible perineural spread of an eyelid malignancy.

Eye Examination The ocular examination should focus on detecting findings caused by, or associated with, the eyelid lesion. Slit lamp biomicroscopy may reveal signs of mechanical or exposure keratoconjunctivitis, or it may reveal signs of conjunctival spread of sebaceous cell carcinoma or cutaneous malignancy. During the evaluation of a pigmented eyelid lesion, the sclera and episclera should be observed for pigmentary changes as well. Direct intraocular extension of eyelid tumors is extremely rare, but fundoscopy may reveal signs of ocular or orbital involvement (choroidal folds, venous congestion) in suspected cases.

Diagnostic Evaluation  ncillary Laboratory and Imaging A Studies History and physical examination of a suspected eyelid tumor occasionally dictates ancillary testing. In cases of suspected eyelid granulomas, inflammatory labs may be indicated such as antinuclear cytoplasmic antibodies (p-ANCA/c-ANCA) and angiotensin-converting enzyme (ACE) to rule out more specific causes of inflammation. If the examination reveals associated orbital or lacrimal outflow signs, computed tomography (CT) or magnetic resonance imaging (MRI) may help to determine the extent of the lesion. Schirmer testing could be considered to document underlying dry eye disease. Lacrimal probing and irrigation should be performed for peri-punctal lesions, for lesions in proximity to the nasolacrimal drainage system, and for patients with preexisting epiphora. Photodocumenation of the lesion and periorbita should also be performed, especially prior to

biopsy. Marking the lesion and taking a photograph is helpful in  localization if further procedures or monitoring are needed.

Dermatoscopy Dermatoscopy is an in  vivo noninvasive technique that may improve the clinical accuracy in diagnosing melanoma and other pigmented skin lesions [3]. Optical coherence tomography (OCT) may represent a new and promising technique for noninvasive investigation of skin tumors [4]. This modality may not only distinguish tumor tissue from normal tissue but may also visualize the epidermis, the dermoepidermal junction, and the dermis, as well as hair follicles, blood vessels, and sweat glands [5]. Although noninvasive techniques may improve diagnostic accuracy, the clinical diagnosis of eyelid tumors remains imperfect, and biopsy still represents the gold standard.

Biopsy Based on clinical examination, the clinician is accurate in diagnoses in a high percent of patients anywhere from 83.7% to 96.9% [6, 7]. When the lesion is clinically misdiagnosed, it is often thought the lesion is benign but in fact histologically malignant. Malignant lesions can be clinically misdiagnosed as benign, especially when they are small and have nondescript surface features, thereby emphasizing the need for a confirmatory histology via incisional or excisional biopsy [6, 7]. The goal of biopsy is to determine the pathologic nature of the lesion, while minimizing adverse functional and cosmetic consequences. Tumor location and the presumptive clinical diagnosis largely dictate the approach and technique. Shave biopsy or excisional biopsy can be performed of lesions to determine pathology. Biopsy-proven epidermal malignancies require margin-controlled excision and repair, with either frozen section control of Moh’s micrographic surgery. Melanoma, sebaceous cell carcinoma, and Merkel cell carcinoma

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1  Eyelid Tumors: Examination Techniques

require excision with wide margins. Some tumors, such as capillary hemangioma, may resolve spontaneously or require nonsurgical treatment (Chap. 10).

tion results can direct the patient discussion to illuminate surgical risks and realities.

Treatment Planning

A systematic approach to the evaluation of suspected eyelid neoplasia allows the clinician to diagnose and treat these tumors efficiently and effectively. Current clinical diagnostic techniques remain inaccurate, and the threshold for biopsy should remain quite low. In the future, we hope less invasive diagnostic and therapeutic techniques will be available, as well as for improved preventive options and better early detection to limit the morbidity of these common tumors.

Information gathered from the history and eyelid examination determines the initial surgical plan for biopsy. This information also determines whether any special studies on the biopsy specimen are required. Any testing specific for the suspected diagnosis should be communicated to the pathologist in advance. For example, if sebaceous carcinoma is suspected, then the specimen usually is sent fresh for Oil Red O staining; however, it can be evaluated with immunohistochemistry on paraffin section with adipophilin and ­androgen receptor depending on the pathologist’s preference [8]. If suspicion for lymphoproliferative disease exists, a fresh specimen for immunohistochemistry and cytology may be indicated. Such foresight may avoid inconclusive biopsy results, the need for an additional tissue biopsy, and lost time. A detailed eyelid examination may also increase the efficiency of any anticipated surgery by determining the probable extent of tumor burden. For instance, if examination points to a larger, possibly infiltrating lesion rather than a smaller, localized process, the examination may dictate map biopsies to determine the extent of the lesion. Conversely, if examination shows a small, discreet lesion, then it may call for excisional biopsy to minimize the number of surgical interventions. Shave biopy is also widely used and allows for examination of the tissue without significant disruption. The downside of shave biopsy is evaluation of the pathology at the depth of the lesion is sometimes inadequate. The examina-

Conclusion

References 1. Gandini S, Sera F, Cattaruzza MS, et al. Meta-analysis of risk factors for cutaneous melanoma: III.  Family history, actinic damage and phenotypic factors. Eur J Cancer. 2005;41:2040–59. 2. Cook BE, Bartley GB. Epidemiologic characteristics and clinical course of patients with malignant eyelid tumors in an incidence cohort in Olmsted County. Minn Ophthalmol. 1999;106:746–50. 3. Lallas A, Apalla Z, Chaidemenos G.  New trends in dermatoscopy to minimize the risk of missing melanoma. J Skin Cancer. 2012;2012:820474. https://doi. org/10.1155/2012/820474. Epub 2012 Oct 8. 4. Khandwala M, Penmetsa BR, Dey S, et al. Imaging of periocular basal cell carcinoma using en face optical coherence tomography: a pilot study. Br J Ophthalmol. 2010;94:1332–6. 5. Gambichler T, Jaedicke V, Terras S. Optical coherence tomography in dermatology: technical and clinical aspects. Arch Dermatol Res. 2011;303:457–73. 6. Kersten BC, Ewing-Chow D, Kulwin DR, et al. Accuracy of clinical diagnosis of cutaneous eyelid lesions. Ophthalmology. 1997;104:479–84. 7. Margo CE. Eyelid tumors: accuracy of clinical diagnosis. Am J Ophthalmol. 1999;128:635–6. 8. Schmitz EJ, Herwig-Carl MC, Holz RG, et al. Sebaceous gland carcinoma of the ocular adnex – variability in clinical and histological appearance with analysis of immunohistochemical staining patterns. Graefes Arch Clin Exp Ophthalmol. 2017;255(11):2277–85.

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Eyelid Tumors: Classification and Differential Diagnosis Jacob Pe’er and Shahar Frenkel

Introduction

Eyelid Skin

In spite of being a small organ, the eyelids contain numerous histological elements that can be the origin of several types of benign or malignant tumors. In this chapter, we review the basic anatomy of the eyelid, outline a clinically relevant classification of eyelid tumors, and briefly discuss their differential diagnosis.

The eyelid skin, especially the lower eyelid, is among the most sunlight-exposed anatomical structures. The eye and the eyelids are one of the most observed parts of the face, and therefore, eyelid tumors are usually diagnosed at an early stage. The eyelid skin is the thinnest in the body and lacks subcutaneous fat, but otherwise contains all other skin structures. In the pretarsal part, the skin and orbicularis oculi muscle are normally firmly attached to the tarsal plate, whereas in the preseptal part, they are more loosely attached. The skin epithelium is keratinized stratified squamous epithelium, the origin of all types of benign and malignant epidermal tumors. Melanocytes are spread in the basal layer of the epithelium and may give rise to melanocytic cutaneous lesions. The dermis contains also fibrous tissue, blood and lymphatic vessels, and nerves that can give rise to many types of fibrous tissue tumors, fibrohistiocytic tumors, vascular tumors, and neural tumors.

Anatomical Features The eyelids are composed of four layers: skin and subcutaneous tissue, striated muscle (orbicularis oculi), tarsus, and conjunctiva [1]. The rest of the orbital entrance, which clinically may be considered as part of the eyelids, is covered, behind the skin and the orbicularis muscle, by the orbital septum that holds back the orbital fat.

Adnexal Glands J. Pe’er (*) · S. Frenkel Ocular Oncology Service and Ophthalmic Pathology Laboratory, Department of Ophthalmology, Hadassah - Hebrew University Medical Center, Jerusalem, Israel e-mail: [email protected]

The eyelids are rich in glandular tissue that may be the origin of various glandular tumors. Eccrine gland tumors may arise from the sweat glands of the eyelid skin as well as from the accessory lacrimal glands of Krause and

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Wolfring. The glands of Moll can give rise to apocrine tumors. The sebaceous glands of Zeiss and the meibomian gland are the origin of sebaceous gland tumors.

the possible tumors that can originate from this tissue are described elsewhere (Chap. 12).

Orbicularis Oculi The entire orbital entrance is covered by the orbicularis oculi—a striated muscle that is divided into pretarsal and preseptal zones which are part of the eyelids and are involved in the eyelid movements and the orbital zone that is located over the external orbital bones.

The eyelid margin is a flat area on the edge of each eyelid. The anatomical structures that are seen in the margin from the skin backwards are the eyelashes and their lash follicles, the gray line which consists of the tips of the pretarsal orbicularis muscle (the muscle of Riolan), the meibomian gland orifices, and the mucocutaneous junction just posterior to them.

Tarsus

Vascular System

The tarsi are firm plates composed of dense connective tissues that serve as the skeleton of the eyelids. The upper tarsal plates are much larger than the lower ones. The meibomian glands, large sebaceous glands, are embedded in the connective tissue of the tarsal plates. The superior tarsal muscle (Muller’s muscle), a smooth muscle, is attached to the upper margin of the tarsus. A parallel muscle does not exist in the inferior tarsus, but the aponeurosis of the inferior rectus muscle attaches to the inferior edge of the inferior tarsus. The upper and lower orbital septum, a thin sheet of fibrous tissue, arises from the periosteum in the orbital rim and fuses with the levator aponeurosis superiorly and the lower margin of the lower tarsus inferiorly. All these histological structures can give rise to rare fibrous, striated, and smooth muscular and glandular tumors. The orbital fat behind the septum and the fat under the orbital part of the orbicularis oculi can be the origin of rare lipomatous tumors.

The venous and lymphatic drainage is important in understanding the routes of possible eyelid tumor metastases. The eyelid has extensive vascularity that comes from two main sources— the internal carotid and external carotid arteries— with anastomoses between these two systems. The venous drainage is into the angular vein medially, superficial temporal vein laterally, and the orbital veins, anterior facial vein, and the pterygoid plexus posteriorly. The lymphatic drainage of the medial portions of the eyelids is into the submandibular lymph nodes and of the lateral portions into the superficial preauricular nodes and then into the deeper cervical nodes.

Palpebral Conjunctiva The posterior eyelid surface is lined by the conjunctiva—a translucent mucous membrane that is composed of epithelium and subepithelial stroma—the substantia propria. The anatomical and histological features of the conjunctiva and

Eyelid Margin

Nerve Supply The sensory nerve supply to the eyelids is from the fifth cranial nerve, and the motor nerve supply to the striated muscles is from the third and seventh cranial nerves and to the smooth muscles from sympathetic nerves.

Classification of Eyelid Tumors Tumors of the eyelid may be classified, like tumors in other organs, according to their tissue or cell of origin and as benign or malignant. In

2  Eyelid Tumors: Classification and Differential Diagnosis

most groups of tumors, unique histological subtypes behave differently in spite of being of the same cell of origin. The classification of eyelid tumors that appears in this section is based primarily on the second edition of the World Health Organization (WHO) International Histological Classification of Tumors (Table  2.1) [2]. The epithelial tumor classification has been modified and divided into groups according to the tumor cell of origin. Some tumors that are missing from the WHO list have been added from other sources [3–5]. The vast majority of the eyelid tumors, benign and malignant, are of cutaneous origin, mostly epidermal. These tumors are divided into non-­ melanocytic and melanocytic tumors (Table 2.2). Benign epithelial proliferations, basal cell carcinoma, cystic structures, and melanocytic nevi represent about 85% of all eyelid tumors [6, 7]. The squamous cell carcinoma and the melanoma are relatively rare [7]. Tumors arising from adnexal structures (Table  2.3), fibrous tissue, fibrohistiocytic and muscular tumors (Table 2.4), Table 2.1  Major types of eyelid tumors Category Epidermal tumors Adnexal tumors

Stromal tumors

Subtypes Non-melanocytic tumors Melanocytic tumors Sebaceous gland tumors Sweat gland tumors Lacrimal gland tumors Hair follicle tumors Cystic lesions Fibrous tissue tumors Fibrohistiocytic tumors Lipomatous tumors Smooth muscle tumors Skeletal muscle tumors Vascular tumors Perivascular tumors Neural tumors Lymphoid, plasmacytic, and leukemic tumors Cartilage and bone tumors Hamartoma and choristoma Palpebral conjunctival tumors

Secondary tumors Metastatic tumors Inflammatory and infectious lesions that simulate neoplasms

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and other stromal tumors (Tables 2.5 and 2.6) are less frequent. Lymphoid tumors, hamartomas and choristomas, and inflammatory and infectious lesions that simulate neoplasms are listed in Table 2.7.

Differential Diagnosis Various characteristics of the tumor and the patient’s general health are important in making the correct diagnosis. The important features that should be noted in examining the eyelid tumor are the tumor location (upper or lower eyelid, inner or outer canthus); is it on the eyelid margin; the eyelid layer involved (skin, subcutaneous tissue, or palpebral conjunctiva); is the tumor solid or cystic; tumor size; the color of the lesion (pigmented or non-pigmented); skin color (red, pink, yellow, white, or blue); the tumor consistency (hard, soft, or rubbery); its surface (smooth, irregular, papillary, ulcerated, umbilicated, cratered, or keratinized); its shape (flat or raised, pedunculated, papillary); is the tumor thin or thick; is the tumor solitary or are there several or multiple tumors; is there loss of eyelashes; the patient’s race, age, and gender; is the tumor movable with the skin or is it fixed to the subcutaneous layers; the existence of systemic diseases such as genetic diseases (e.g., neurofibromatosis) or systemic malignancies; and the existence of diseases or malignancies in the surrounding structures (the eyeball, conjunctiva, orbit, lacrimal drainage system, and neighboring skin). Certain features of the tumor are suggestive of malignancy [5]. Development of a new lesion or changes in size, shape, color, or surface appearance of an existing lesion is suspicious for malignant conversion. Poorly defined borders, palpable induration beyond visible boundaries, loss of fine cutaneous rhytids, hypervascularity, ulceration, and destruction of the normal eyelid architecture are all worrisome. Lesions that are not freely mobile due to invasion of underlying structures and those associated with regional lymphadenopathy, hypesthesia, paresthesia or pain, indicating

J. Pe’er and S. Frenkel

10 Table 2.2  Classification of epidermal tumors of the eyelid Category Non-melanocytic

Subtypes Benign

Premalignant

Malignant

Melanocytic

Epithelial pigmentation

Benign

Premalignant Malignant

Squamous cell papilloma Seborrheic keratosis Inverted follicular keratosis Reactive hyperplasia (pseudoepitheliomatous hyperplasia) Actinic (solar) keratosis Intraepithelial neoplasia Sebaceous nevus (of Jadassohn) Xeroderma pigmentosum Basal cell carcinoma Squamous cell carcinoma Mucoepidermoid carcinoma Keratoacanthoma Ephelis or freckles Lentigo simplex Solar lentigo Junctional nevus Intradermal nevus Compound nevus Spitz nevus Balloon cell nevus Blue nevus Cellular blue nevus Oculodermal nevus of Ota Congenital dysplastic nevus Lentigo maligna (melanotic freckle of Hutchinson) Melanoma arising from nevi Melanoma arising in lentigo maligna Melanoma arising de novo

Table 2.3  Classification of adnexal and cystic tumors of the eyelid Category Sebaceous gland tumors

Subtypes Benign

Sweat gland and lacrimal gland tumors

Malignant Benign

Malignant

Hair follicle tumors

Benign

Malignant

Sebaceous gland hyperplasia Sebaceous gland adenoma Sebaceous gland carcinoma Syringoma Papillary syringadenoma Eccrine spiradenoma Eccrine acrospiroma Pleomorphic adenoma (benign mixed tumor) Eccrine cylindroma Apocrine adenoma Other benign tumors Sweat gland (eccrine) adenocarcinoma Mucinous sweat gland adenocarcinoma Apocrine gland adenocarcinoma Adenoid cystic carcinoma Porocarcinoma Trichoepithelioma Trichofolliculoma/trichoadenoma Trichilemmoma Pilomatrixoma (calcifying epithelioma of Malherbe) Carcinoma of hair follicles

2  Eyelid Tumors: Classification and Differential Diagnosis

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Table 2.3 (continued) Category Other cystic lesions

Subtypes Benign

Table 2.4  Classification of fibrous, fibrous histiocytic, and muscular tumors of the eyelid Origin Fibrous

Fibrous histiocytic

Smooth muscle Skeletal muscle

Type Benign

Tumor Fibroma Keloid Nodular fasciitis Proliferative fasciitis Fibromatosis Malignant Fibrosarcoma Congenital fibrosarcoma Benign Xanthelasma Xanthoma Dermatofibroma Xanthogranuloma Fibrous histiocytoma Juvenile xanthogranuloma Necrotic xanthogranuloma Reticulohistiocytoma Intermediate Atypical fibroxanthoma Dermatofibrosarcoma protuberans Angiomatoid fibrous histiocytoma Malignant Malignant fibrous histiocytoma Malignant giant cell fibrous histiocytoma Malignant fibroxanthoma Benign Leiomyoma Angiomyoma Malignant Leiomyosarcoma Benign Rhabdomyoma Malignant Rhabdomyosarcoma

l­ymphatic or perineural spread are also suspicious for malignancy. Lesions associated with chronic inflammation that respond partially or temporarily to topical corticosteroids or antibiotics also may harbor malignancies. However, one should keep in mind that on the one hand malignant tumors can appear without any worrisome signs, while totally benign tumors can express some of the abovementioned features.

Epidermal inclusion cyst Sebaceous cyst Retention cyst Eccrine hidrocystoma Apocrine hidrocystoma Trichilemmal cyst Other benign cystic lesion Table 2.5  Classification of vascular and perivascular tumors of the eyelid Category Vascular

Subtypes Benign

Nevus flammeus (port wine stain) Papillary endothelial hyperplasia Capillary hemangioma Cavernous hemangioma Venous hemangioma Epithelioid hemangioma (angiolymphoid hyperplasia) Arteriovenous malformation Lymphangioma Malignant Angiosarcoma Lymphangiosarcoma Kaposi’s sarcoma Perivascular Benign Hemangiopericytoma Glomus tumor Malignant Malignant hemangiopericytoma Malignant glomus tumor Table 2.6  Classification of neural, lipomatous, cartilage, and bone tumors of the eyelid Category Neural

Lipomatous

Cartilage and bone

Subtypes Benign

Traumatic neuroma Neurofibroma Plexiform neurofibroma Schwannoma (neurilemoma) Others, e.g., neuroglial choristoma Malignant Malignant peripheral nerve sheath tumor Merkel cell tumor Benign Lipoma Others, e.g., hibernoma Malignant Lilposarcoma Benign Chondroma Osteoma Malignant Chondrosarcoma Mesenchymal chondrosarcoma Osteosarcoma

J. Pe’er and S. Frenkel

12 Table 2.7  Classification of lymphoid tumors, hamartomas, choristomas, and inflammatory and infectious lesions that simulate neoplasms Category Lymphoid

Subtypes Benign lymphoid hyperplasia Lymphoma Plasmacytoma Leukemic infiltration Hamartomas and Dermoid cyst choristomas Phakomatous choristoma Ectopic lacrimal gland Inflammatory and infectious Chalazion lesions Pyogenic granuloma Verruca vulgaris Molluscum contagiosum Others Others e.g., myxoma

Epidermal Non-melanocytic Tumors The most common benign epithelial tumor is the squamous papilloma that is often sessile or pedunculated with papillary shape and keratinized surface (Table  2.2). Squamous papillomata may be multiple. Other epithelial tumors, including the premalignant actinic keratosis or small squamous cell carcinoma may look similar. Basal cell carcinoma comprises over 90% of all malignant eyelid tumors [7]. Its common location is the lower eyelid and medial canthus; it is usually firm and often has an ulcerated center. Other ulcerated eyelid tumors, such as keratoacanthoma or the more rare papillary syringadenoma, should be differentiated from BCC. Features of keratoacanthoma, such as rapid growth and possible spontaneous regression, can help in its diagnosis. Staging of carcinomas of the eyelid skin and adnexa can be found in the AJCC Cancer Staging Manual [8].

Epidermal Melanocytic Tumors The most common pigmented eyelid lesions are the nevi, which are usually flat or mildly elevated and can appear anywhere in the eyelid in any size, and when appearing on the eyelid margin

can be sessile (Table 2.2). Congenital nevi u­ sually appear at birth and acquired nevi between the ages of 5 and 10 years. Nevi should be differentiated on the one hand from flat epithelial pigmentation such as ephelis or freckles and, on the other hand, from the flat premalignant lentigo maligna or from malignant melanoma that is relatively rare in the eyelids.

Adnexal and Cystic Tumors The eyelid adnexa include many different glands that are the origin of various benign and malignant tumors (Table  2.3). These include cystic lesions such as eccrine and apocrine hidrocystoma that are totally benign and may be transparent or have a distinct color like the blue apocrine hidrocystoma. On the other hand, there are very malignant solid sebaceous gland carcinomas that may resemble chalazion but unlike chalazion cause loss of eyelashes.

Stromal Tumors The stromal eyelid tumors usually have a smooth surface, being under the skin (Tables 2.4, 2.5, and 2.6). The tumor elevation may have normal skin color, but many of the tumors will have a distinct color. Xanthomatous lesions are usually yellow. Most hemangiomas, diffuse or localized, are red. Subcutaneous varix is soft and blue, and Kaposi’s sarcoma is blue or red. Merkel cell tumor is red or violaceous. Eyelid lymphoma can be manifested as a smooth, firm subcutaneous nodule. Sometimes also subcutaneous tumors can be sessile or even ulcerated, so such phenomena, which are usually seen in epidermal tumors, should not exclude them.

Inflammatory and Infective Simulating Conditions In the differential diagnosis of eyelid tumors, we should include lesions that simulate tumors (Table 2.7). The most common simulating lesions

2  Eyelid Tumors: Classification and Differential Diagnosis

are inflammatory lesions such as chalazion or pyogenic granuloma (a misnomer for granulation tissue) or infectious viral lesions such as molluscum contagiosum or verruca vulgaris that is clinically and histologically similar to squamous papilloma. Many dermatological diseases such as amyloidosis and malakoplakia or connective tissue disease and systemic metabolic diseases such as hemachromatosis may, sometimes, simulate eyelid tumors and should be differentiated from them.

References 1. Bedrossian EH. Chapter 5: Embryology and anatomy of the eyelid. In: Tasman W, Jaeger EA, editors. Duane’s foundation of clinical ophthalmology, ocular anatomy, embryology and teratology, vol. 1. Philadelphia: Lippincott Williams & Wilkins; 2004. p. 1–24.

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2. Campbell RJ, Sobin LH.  Tumours of the eyelid. In: Histological typing of tumours of the eye and its adnexa, World Health Organization international histological classification of tumors. 2nd ed. Berlin: Springer; 1998. p. 3–9. 3. Shields JA, Shields CL. Atlas of eyelid and conjunctival tumors. Philadelphia: Lippincott Williams & Wilkins; 1999. p. 3–189. 4. Hassan AS, Nelson CC.  Benign eyelid tumors and skin diseases. Int Ophthalmol Clin. 2002;42:135–49. 5. Soparkar CN, Patrinely JR. Eyelid cancers. Curr Opin Ophthalmol. 1998;9:49–53. 6. Kersten RC, Ewing-Chow D, Kulwin DR, et al. Accuracy of clinical diagnosis of cutaneous eyelid lesions. Ophthalmology. 1997;104:479–84. 7. Cook BE, Bartley GB. Epidemiologic characteristics and clinical course of patients with malignant eyelid tumors in an incidence cohort in Olmsted County. Minn Ophthalmol. 1999;106:746–50. 8. Esmaeli B, Dutton JJ, Graue GF, et  al. Chapter 64: Eyelid carcinoma. In: Amin MB, et al., editors. AJCC Cancer staging manuel. 8th ed. New York: Springer; 2017. p. 779–85.

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Benign Eyelid Squamous and Melanocytic Tumors Lynn Schoenfield and Arun D. Singh

Introduction The eyelid consists of six layers with epidermis externally and palpebral conjunctiva internally. Between these two (from outer to inner) are dermis, loose subcutaneous layer, orbicularis muscle, and tarsal plate. The epithelium consists of squamous cells and melanocytes primarily with smaller numbers of Langerhans cells and Merkel cells. The presence of Langerhans cells is important to recognize, as they, like melanocytes, are positive for the immunohistochemical stain S100. Benign tumors of the eyelid include a variety of nonpigmented and pigmented epidermal tumors, which arise from squamous and melanocytic cells, respectively, adnexal tumors (Chap. 4), stromal tumors (Chap. 5), and benign lymphoid proliferations. Important to note is that not all clinically pigmented lesions are melanocytic, since squamous cell proliferations can include scattered melanocytes or melanin pigment, thus giving a pigmented appearance to a lesion. The benign epidermal tumors of the eyelid are similar to those observed in the other sun-exposed areas

L. Schoenfield (*) Department of Pathology, Ohio State University Wexner Medical Center, Columbus, OH, USA e-mail: [email protected] A. D. Singh Department of Ophthalmic Oncology, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA

of the skin, but they may also include conjunctival tumors as well. Some of these tumors represent manifestations of systemic disease (Chap. 11). A classification of the epidermal eyelid tumors is presented in Table  3.1. Only the description of the most common and frequently observed benign tumors, along with their corresponding premalignant lesions and tumor-like nonneoplastic lesions, is included in this chapter.

Squamous (Non-melanocytic) Tumors Squamous Cell Papilloma Squamous papillomas are the most common benign tumors typically occurring in middle-­ aged or older adults. The clinical appearance is that of a pedunculated or sessile nodular growth with a variably convoluted surface with or without hyperkeratosis. They are often multiple, present at the lid margin, and are skin-colored (Fig. 3.1a) [1]. Microscopically a papilloma consists of benign squamous hyperplastic (acanthotic) epithelium with variable hyperkeratosis or parakeratosis overlying an expanded fingerlike fibrovascular core, which creates the exophytic nodule. They sometimes have overlapping features with seborrheic keratosis (Fig. 3.1b). If symptomatic, surgical excision may be performed.

© Springer Nature Switzerland AG 2019 J. Pe’er et al. (eds.), Clinical Ophthalmic Oncology, https://doi.org/10.1007/978-3-030-06046-6_3

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L. Schoenfield and A. D. Singh

Table 3.1  Classification of epidermal tumors of the eyelid, excluding adnexal tumors Types Non-­ melanocytic

Subtypes Benign

Squamous cell papilloma Seborrheic keratosis Inverted follicular keratosis Molluscum contagiosum Reactive hyperplasia (pseudoepitheliomatous hyperplasia) Actinic (solar) keratosis Intraepithelial neoplasia Sebaceous nevus (of Jadassohn) Basal cell carcinoma Squamous cell carcinoma Ephelis or freckles Lentigo simplex Solar lentigo Junctional nevus Intradermal nevus Compound nevus Spitz nevus Balloon cell nevus Blue nevus and cellular blue nevus Oculodermal nevus of Ota Seborrheic keratosis Congenital dysplastic nevus Lentigo maligna (melanotic freckle of Hutchinson) Melanoma arising from nevi Melanoma arising in lentigo maligna Melanoma arising de novo

Potentially premalignant

Malignant Melanocytic

Benign epithelial pigmentation or hypermelanosis Benign

Potentially premalignant Malignant

a

b

Fig. 3.1  Squamous papilloma. Clinical appearance. (a) Polypoid lesion consisting of benign squamous epithelium with variable acanthosis and hyperkeratosis overly-

ing a fibrovascular core ((b) hematoxylin and eosin; original magnification 4×)

Seborrheic Keratosis

also been referred to as basal cell papilloma, seborrheic wart, and senile verruca. The clinical appearance varies considerably in terms of size (few millimeters to several centimeters) and degree of pigmentation making it sometimes

Seborrheic keratoses are commonly acquired skin lesions which can occur on the eyelid affecting middle-aged and elderly patients. They have

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3  Benign Eyelid Squamous and Melanocytic Tumors

a

b

Fig. 3.2  Seborrheic keratosis. Upper eyelid involvement in a 75-year-old man. (a) Retiform (network-like) pattern of squamous epithelium surrounding islands of connective

tissue and composed of sheets of basaloid cells with keratin-filled horn pseudocysts ((b) hematoxylin and eosin; original magnification 10×)

d­ ifficult to differentiate clinically from nevi, pigmented basal cell carcinomas, and melanoma [1]. They are sharply demarcated warty plaques or dome-shaped growths with a greasy and cerebriform surface, which may become friable with inflamed eczema-like features (Fig. 3.2). Seborrheic keratoses are divided into several histological types according to the predominant histologic features: acanthotic, hyperkeratotic, adenoid (reticulated), clonal, and irritated (Fig.  3.2).The most common type is the acanthotic, in which there is a proliferation of squamous basaloid cells protruding above the skin surface, which is punctuated by horn pseudocysts. Typically, the basal plane of the lesion is in alignment with the surrounding uninvolved squamous epithelium. Hyperpigmentation can occur, which is due to transfer of melanin to the keratinocytes. When a patient experiences a sudden appearance of a seborrheic keratosis or an increase in the number or size of these lesions, this may be associated with an internal malignancy and is referred to as the Leser-Trelat sign [2, 3]. Even in lesions that are large, the growth pattern is superficial with growth predominantly above the epidermal surface. Therefore, deep excision is unnecessary; and these lesions are often removed by shave biopsy.

ant of seborrheic keratosis or verruca vulgaris. It is commonly seen on the face, particularly the cheeks, upper lip, and less often, eyelid [4–7]. It usually occurs in older men and ranges in size from 0.3 to 1.0 cm. Usually a solitary lesion of recent onset (less than 3 months), it may be nodular, papillomatous, or cystic in appearance. Inverted follicular keratosis may recur following incomplete excision and thus be easily mistaken for squamous cell carcinoma [7]. Histopathologically, there are four main growth patterns: papillomatous, keratoacanthoma-­ like, solid nodular form, or cystic type. Usually it consists of an endophytic proliferation of squamous epithelium with squamous eddies, hyperkeratosis, parakeratosis, acantholysis, generally little if any melanin pigment, and dermal chronic inflammation. There may be increased mitoses and apoptosis (Fig.  3.3) [6, 7]. Complete excision should be performed to prevent recurrence.

Inverted Follicular Keratosis Inverted follicular keratosis is a somewhat controversial entity, as some consider it to be a vari-

Molluscum Contagiosum Molluscum contagiosum is an on neoplastic skin infection caused by a virus from the pox virus group. This entity occurs frequently in children but may also occur in adults anywhere on the body except the palms and soles. It appears as papules that are white- or flesh-colored measuring 2–5  mm, often with a central dimple or plug containing cheesy or waxy ­material (Fig. 3.4).

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L. Schoenfield and A. D. Singh

Fig. 3.3  Inverted follicular keratosis. Note endophytic growth pattern with overlying hyperkeratosis and parakeratosis. Flattened concentric epidermal cells within acanthotic areas are called squamous eddies (hematoxylin and eosin; original magnification 10×)

a

b

c

d

Fig. 3.4  Molluscum contagiosum. Clinical appearance. (a) Epidermal crater filled with keratinocytes containing molluscum bodies (intracytoplasmic inclusions). ((b) hematoxylin and eosin; original 40× magnification). (c) The clinical presentation of a conglomerated lesion which

is well-demarcated, white, sessile lesion located on the grey line. (d) A molluscum contagiosum virus under electron microscopy. (c, d): (Reprinted from Rosner and Zloto [8]. With permission from John Wiley & Sons)

3  Benign Eyelid Squamous and Melanocytic Tumors

Molluscum contagiosum is characterized by downward growth of hyperplastic epidermis, sometimes forming multiple lobules. The keratinocytes contain large eosinophilic intracytoplasmic inclusion bodies (“molluscum bodies”), which enlarge as they reach the surface and become more basophilic (Fig.  3.4). The central crater consists of disintegrating cells discharging the molluscum bodies and keratin [8]. These lesions usually resolve over months to years in patients with intact immune systems. However, removal of individual lesions can be done surgically or by scraping, decoring, freezing, or electrosurgery. Medications used for warts may also be used, and cantharidin (“beetle juice”) is the most common solution used. Tretinoin cream is an alternative.

Keratoacanthoma Keratoacanthoma has a complicated history and has been classified both as benign and malignant (self-healing squamous cell carcinoma or squamous cell carcinoma, keratoacanthoma-type). The latter is favored in many countries. However, in some literature, it has been noted to sometimes spontaneously regress and thus considered to be a benign lesion [9–12]. Typically a keratoacanthoma is a solitary-, pink-, or flesh-colored, domeshaped nodule with a central keratin crater, arising on sun-exposed skin of an elderly individual. There may be rapid growth to 1 or 2 cm over the course of 2–10 weeks. This is followed by a stationary period of similar duration and then involution over the course of 8–50 weeks or more. The histologic features needed for a confident diagnosis require assessment of the entire lesion, so as not to miss an infiltrating squamous cell carcinoma at the base. The tumor is cup- or crater-­shaped and consists of centrally proliferating well-differentiated squamous cells with strongly eosinophilic cytoplasm that enlarge in the center of the tumor nests. Often there is a central keratin plug, and there may be neutrophilic abscesses in the epithelium. At the periphery, the epithelium forms symmetrical “lips” or “buttresses” which overhang the crater. The underly-

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ing dermis is usually inflamed but without desmoplasia, unless the lesion is involuting. Deeper sections are recommended in order to rule out the possibility of typical infiltrating squamous cell carcinoma, which may be focal in an otherwise classic picture of keratoacanthoma (thus the term “keratoacanthoma-like squamous cell carcinoma”) [12]. Complete excision should be performed.

Reactive Hyperplasia (Pseudoepitheliomatous Hyperplasia) Squamous epithelial hyperplasia occurs as a reaction to trauma, surgical wound, cryotherapy, burn, radiation, ulcers, or fungal infection [13]. It can also occur in association with tumors such as granular cell tumor and melanocytic lesions. It is not a tumor but rather a reactive process that may clinically be seen as a tumor. Histopathology can be challenging as well. An elevated nodular or ulcerative lesion resembling basal or squamous cell carcinoma. There may be an ulcer. There is squamous hyperplasia with elongated, irregular, and sometimes anastomosing rete pegs (rete ridges) which may resemble invasive tongues or nest of squamous carcinoma. Cellular nests may be contain neutrophilic microabscesses, especially when associated with infection (Fig. 3.5) [14]. The epithelium shows normal maturation without true dysplasia; however, there may be cytologic atypia and even mitoses, further complicating the distinction from carcinoma. Complete excision is recommended when clinically suspicious.

 utaneous Horn or Nonspecific C Keratosis These are nondiagnostic descriptive terms for any hyperkeratotic lesion (benign or malignant) and thus do not imply by themselves predilection for malignant behavior. A protruding keratotic lesion is the presentation (Fig. 3.6). This lesion is

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L. Schoenfield and A. D. Singh

the lesion [15]. Treatment should be determined by the histopathology if possible. If the lesion is clinically suspicious for malignancy, excision is recommended.

Sebaceous Nevus (of Jadassohn)

Fig. 3.5 Reactive hyperplasia (pseudoepitheliomatous hyperplasia). Epidermal (squamous) hyperplasia with elongated and sometimes anastomosing rete ridges, normal maturation of epithelium, and variable hyperkeratosis. Note the absence of atypia in this case (hematoxylin and eosin; original magnification 20×)

Sebaceous nevus syndrome (of Jadassohn), an uncommon congenital lesion, is part of the epidermal nevus syndrome and characterized by cutaneous sebaceous nevi and extracutaneous manifestations. It is a benign hamartoma composed of large sebaceous glands, heterotopic apocrine glands, defective hair follicles, acanthosis, and papillomatosis. These lesions evolve with time. They are most commonly found on the head and neck region and appear as irregular linear lesions with alopecia (Fig. 3.7). In spite of their being benign, there is an increased risk in adulthood for the development of secondary benign (such as syringocystadenoma papilliferum) or malignant skin tumors (most commonly basal cell carcinoma) within the area of these nevi [17–19].

Actinic (Solar) Keratosis Fig. 3.6  Cutaneous horn is a clinically descriptive, nondiagnostic term for a nonspecific keratosis

associated with a variety of benign or malignant lesions. In a study of 48 cases [6] involving the eyelids, 77.1% were associated with found to be benign on histopathology, 14.6% were premalignant, and 8.3% were malignant skin tumors. The most common associated lesions were seborrheic keratosis, actinic keratosis, basal cell carcinoma, and squamous cell carcinoma [15, 16]. There are no specific histopathologic features other than hyperkeratosis, with or without parakeratosis. The keratosis (or horn) by itself is not diagnostic, but rather the features of the squamous epithelium giving rise to the keratosis are the defining factors as to the biologic behavior of

Actinic or solar keratosis is most frequently a result of chronic and cumulative exposure of the epidermal cells of the skin to ultraviolet radiation (UV-B) in the form of sunlight, causing mutations to the p53 gene [20]. Fair-skinned older patients and those with a history of excessive sun exposure are typically affected. However, there is also an increased incidence in renal transplant patients, and thus immunosuppression is a risk factor [21]. There are a variety of clinical presentations, usually characterized by multiple, ­erythematous, scaly lesions with either discrete or diffuse borders [21]. They feel like sandpaper and may be plaque-like on palpation. Actinic keratosis has historically been considered a precursor to squamous cell carcinoma, and most now consider it to represent squamous cell carcinoma in situ or keratinocyte intraepithelial neo-

3  Benign Eyelid Squamous and Melanocytic Tumors

a

b

c

Fig. 3.7  External photo showing tan-colored linear nasal lesion (a); Low magnification (b, 4×) and higher magnification (c, 10×) histopathology of a benign epidermal lesion with presence of acanthosis and hyperkeratosis in association with enlarged gland lobules consistent with nevus sebaceous. (Reprinted from Echegaray et al. [18]. With permission from Taylor & Francis)

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plasia. In a study wherein histopathologic evaluation of 165 cases of resected squamous cell carcinoma was undertaken, 82.4% of cases had concomitant actinic keratosis close to the carcinoma [22]. However, it is not clear what the rate of conversion of an actinic keratosis to squamous cell carcinoma is; and studies have given a wide range of estimates [23]. Histopathology generally shows hyperkeratosis and parakeratosis with varying degrees of squamous dysplasia, characterized by loss of epithelial cell polarity, cytologic atypia, and dysmaturation. The parakeratosis is usually focal and overlies areas of underlying loss of the granular layer of the epidermis. Solar elastosis of varying degrees is present in the dermis, along with a mild chronic inflammatory infiltrate (Fig. 3.8). Subtypes include hypertrophic (characterized by acanthotic epithelium with irregular psoriasiform hyperplasia), proliferative (characterized by fingerlike projections into the dermis), atrophic (atrophic or thin epithelium), acantholytic (characterized by prominent dyscohesion of the basal cells), and lichenoid (when there is a dense band-­like mononuclear cell infiltrate in the upper dermis). The hyperkeratotic or parakeratotic crust may be so thickened as to form a keratotic horn. With severe full thickness dysplasia, the differential is with Bowen’s disease (Fig.  3.9). Management is close observation and excision of

Fig. 3.8  Actinic (solar) keratosis. Note dysmaturation of the squamous epithelium, mitoses, loss of granular layer, and parakeratotic crust (hematoxylin and eosin; original magnification 20×)

22

Fig. 3.9 Squamous intraepithelial neoplasia. Marked squamous dysplasia (Bowen’s disease, also considered a type of squamous carcinoma in situ); also note suggestion of early or superficial invasion (hematoxylin and eosin; original magnification 10×)

more suspicious lesions. Multiple lesions can be treated with topical chemotherapeutic agents or cryotherapy. A meta-analysis of published studies indicates that 3% diclofenac in 2.5% hyaluronan gel is effective in treatment of actinic kertatosis [24]. Topical gel must not be applied to the eyelids as it is not approved for ophthalmic use [25].

 elanocytic Benign Epidermal M Tumors Freckles or Ephelides Freckles are flat brown skin macules measuring 1–2 mm that appear in childhood. Freckles characteristically occur in fair-skinned individuals and darken with sunlight exposure and fade in winters in the absence of sunlight exposure. In contrast, solar lentigines do not fade with cessation of sunlight exposure [26]. The epidermal structure is not altered. There is increased melanin pigment in the basal layers without an increase in melanocytes. The delineation of the lesion with the surrounding skin is distinct.

Lentigo Simplex The lesion of lentigo simplex is flat, brown to black sharply circumscribed macule measuring

L. Schoenfield and A. D. Singh

1–2 mm in diameter. Pigmentation is usually uniform. They are the precursors of junctional nevi and are clinically indistinguishable from them. Similar appearing multiple lesions of the perioral skin, buccal mucosa, and sometimes eyelid may be associated with the autosomal dominant Peutz-Jeghers syndrome of mucocutaneous pigmentation and intestinal polyposis (Chap. 11), Carney syndrome, LEOPARD syndrome, and xeroderma pigmentosum [27]. Histology shows hyperpigmentation of the basal layer with increased number of melanocytes, often with regular elongation of the rete ridges. The papillary dermis may contain a lymphohistiocytic infiltrate and melanophages. If the melanocytic hyperplasia evolves to form early junctional nests (with or without an intradermal component), the lesion is referred to as a lentiginous nevus.

Solar (Senile) Lentigo The lesions of solar lentigo are light to dark brown, slowly expanding macules that develop in chronically sun-exposed areas of the skin, including the eyelids. They occur in middleaged to elderly adults and are considered a hallmark of aged skin. Presenting as small macules 3–5 mm in diameter, the lesions may gradually grow to several centimeters in diameter. They sometimes evolve into the reticulated (adenoid) form of seborrheic keratosis and thus develop a thickened and warty surface. Differentiation from lentigo maligna and lentigo malignant melanoma may be necessary, requiring histopathologic examination. Solar lentigo lesions respond to treatment with topical 0.1% tretinoin, 2% hydroxyanisole, laser therapy, and cryotherapy.

Melanocytic Nevus A melanocytic nevus is considered as a hamartoma or a benign tumor of neural crest-derived melanocytes [28]. An eyelid nevus, as in other areas of the skin, can be acquired (usually) or congenital.

3  Benign Eyelid Squamous and Melanocytic Tumors

Fig. 3.10  Congenital nevus of the eyelid surrounding the puncta

Congenital Nevus Congenital nevi are present in about 1% of newborns (Fig. 3.10) [29, 30]. Congenital nevi may be single or multiple with sharp borders and are usually larger than acquired nevi. They may be light in color in neonates and relatively hairless, and they tend to become darker with papular or nodular change which may be verrucous or cerebriform with age. With age, darkly pigmented hairs may develop. Congenital nevi have been reported to be associated with several developmental abnormalities, including scoliosis, spina bifida, clubfoot, elephantiasis, and cranial bone hypertrophy, as well as syndromes such as neurocutaneous melanocytosis and neurofibromatosis type I [30]. Congenital nevi are classified by their largest diameter as small (20 cm). However other classifications are based on ease of removal, location, and relationship to other anatomic structures, comparison to the size of the patient’s palm, and surface area of the body involved. Proportionate expansion over time is also important in classification [30]. The risk of malignant transformation varies significantly with the size of the lesion. Lifetime risk of developing melanoma in patients with giant congenital nevi has been reported to range from about 2–31%, mostly in the 5–6% range

23

[30]. Despite evidence supporting origin of ­melanoma in small congenital nevi, it is rare in children [30]. Congenital nevi may be junctional, compound, or intradermal; and they show different patterns depending on the age of the individual. In neonates they are usually junctional and show prominent melanocytic hyperplasia in the epidermis and adnexal epithelium. If biopsied during the first year of life, the histologic picture is that of larger nevus cells in the epidermis and just below it with an intervening uninvolved dermal space and small nevus cells in the reticular dermis. Congenital nevi after the postnatal period have a tendency to involve the lower dermis and subcutaneous tissue with single-file permeation of dermal collagen bundles and perineural, perifollicular, and perivascular distribution of nevus cells. There are differences of opinion as to whether or not these features are pathognomonic and sufficient to distinguish from acquired nevi. Like most other melanocytic nevi, except for blue nevi and Spitz nevi, congenital nevi commonly show BRAF mutation [29, 31]. Surgical excision is recommended for giant congenital nevi because they are disfiguring and potentially malignant. Neurocutaneous Melanosis Neurocutaneous melanosis (NCM) is a rare association of multiple and large congenital cutaneous nevi and meningeal melanosis or melanoma [32, 33]. Split Nevus (Kissing Nevus, Divided Nevus) A variant of congenital compound nevus involving both upper and lower eyelids is the kissing nevus, which can be associated with significant cosmetic and functional defect of the eyelids (Fig. 3.11). Such a contiguous involvement suggests that the nevus develops between 9th and 20th week of gestation when the eyelids are fused. There have been reports citing potential for malignant transformation, but a review of 23 articles (149 cases) revealed no documented cases of this occurring. Most were of medium size. Surgical repair involves excision, and numerous methods of reconstruction have been utilized [34, 35].

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Fig. 3.11  Split nevus. A sharply demarcated, brown discoloration, involving the upper and lower eyelids in a 16-year-old Asian female. Nevomelanocytes migrate from the neural crest to the skin after the tenth week in utero but before 24  weeks when splitting of eyelids occurs. Concomitant conjunctival nevus is also present

Blue Nevus The blue nevus arises from dermal dendritic melanocytes that have been arrested in the dermis before reaching the epidermis (Fig.  3.12) [33]. Within the spectrum of types of blue nevi, different clinicopathologic variants are identified: common blue nevus and cellular blue nevus (localized variants), and oculodermal melanocytosis (diffuse variant) [36, 37]. Epithelioid blue nevus is a multicentric familial form that is part of the Carney complex together with cardiac myxoma, endocrine tumors, schwannoma, and other abnormalities [38]. The blue nevus appears as an atypical small dark lesion, the blue color due to the deep location of the melanocytes with absorption of larger wavelengths of light as it passes through the dermis (Tyndall phenomenon).Such eyelid changes can extend to involve adjacent conjunctiva (Chap. 14), orbit, and intracranial cavity. The relationship between blue nevus, blue nevus that has undergone malignant transformation, and melanoma is fraught with classification controversies [39]. Difficulties arise because some metastatic melanomas can resemble blue nevi, spindled sclerotic lesions may be challeng-

L. Schoenfield and A. D. Singh

ing with a differential including scar, dermatofibroma, neurofibroma, and desmoplastic melanoma, and intermediate or hard to classify lesions are often given terms such as atypical or metastasizing nevi, terms which by definition should be avoided [40]. Surgical excision is recommended for cosmesis or to establish a definitive diagnosis. Histologically, the common blue nevus is composed of dendritic (elongated and finely branching) melanocytes confined to the mid- and upper dermis. Melanophages are also present. The cellular blue nevus consists of both dendritic melanocytes and a second population of islands of epithelioid and plump spindle-shaped melanocytes. Blue nevi do not show BRAF and NRAS mutations as found in conventional melanocytic nevi. They do show frequent somatic mutations (83%) in GNAQ, a gene also frequently implicated in uveal melanoma [41, 42]. Nevus of Ota The nevus of Ota (oculodermal melanocytosis) occurs as a diffuse or speckled bluish or brown discoloration of the eyelids and periorbital skin and episclera due to a proliferation of dermal melanocytes. The temple, forehead, malar region, sclera, and mucosa of the nose and mouth may also be involved (Chap. 14). These regions correspond to the ophthalmic and maxillary divisions of the trigeminal nerve. Associated melanocytosis of structures such as uvea, orbit, and ipsilateral meninges may be present but not readily apparent. Nevus of Ota may appear at birth or may develop during the first year of life or during adolescence. It tends to follow the distribution of the first and second divisions of the trigeminal nerve. It may rarely be bilateral. Histopathologically, nevus of Ota is characterized by excess scattered dendritic and plump polyhedral melanocytes in the dermis. Nevus of Ota carries a small risk of development of a uveal melanoma [43]. Possibility of malignant transformation of the cutaneous component is even more remote [44, 45]. Periodic observation including dilated fundus examination is the recommended treatment.

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3  Benign Eyelid Squamous and Melanocytic Tumors

a

b

c

d

e

f

Fig. 3.12 (a) Eyelid margin blue nevus. A 93-year-old Caucasian woman had an irregular, flat, black lesion (arrow) measuring 3 × 4 mm at the left upper eyelid mucocutaneous junction. (b) A full-thickness perpendicular section of the eyelid contains a loose population of pigmented cells mostly located in the dermis (arrows) that has failed to produce any appreciable eyelid thickening. There are no intraepithelial junctional nests. The tarsus (T), Meibomian glands (MG), and orbicularis striated muscle fibers (OR) are overall noninvolved by the tumor cells. The crossed arrow indicates a cilium (hematoxylin-­eosin, X25). (c) The cells in the dermis are a mixture of elongated and polygonal melanocytes. The arrow highlights a small fascicle of nonpigmented cells, depicted to greater advantage in the inset. This feature was regarded as a terminal nerve twig with mild Schwann cell hyperplasia. OR, orbicularis muscle fibers devoid of infiltrating cells (hematoxylin-eosin, X200). (d) Spindled and rounded pigmented cells are intermixed. Despite the density of the cytoplasmic pigmentation, a central round nucleus is discernible as a clear

zone in the center of most of the cells. Note the absence of both inflammatory cells and a prominent vascularity in the background stroma (hematoxylin-eosin, X400). (e) Ki-67 immunostaining for cells in the S-phase signifying active DNA replication demonstrate positive nuclear staining among the basal germinal cells of the epithelium (EP). The arrows point out central clear zones corresponding to non-­ staining melanocytic nuclei in the connective tissue (immunoperoxidase reaction, diaminobenzidine chromogen, X200). (f) Microphthalmia-associated transcription factor immunostains the nuclei of scattered dendritic melanocytes (arrows) within the epithelium (EP) with trail-off on the left within the conjunctiva. There are no visible nuclei among the dendritic dermal melanocytes constituting the tumor, because the immunoproduct of the positively staining nuclei merges imperceptibly with the melanin within the surrounding cytoplasm (immunoperoxidase reaction, diaminobenzidine chromogen, X200). (Reprinted from Kirzhner et al. [37]. With permission from Wolters Kluwer Health, Inc.)

L. Schoenfield and A. D. Singh

26

Acquired Nevus Acquired nevi develop during childhood and adolescence. Mild to moderate sun exposure in early life induces the development of nevi [45]. The acquired nevus appears as a small, flat, or minimally elevated lesion that is light brown in color (Fig.  3.13). They have a limited growth phase, often during adolescence after which they stabilize. Acquired nevi may be located anywhere on the eyelids and frequently involve the eyelid margin and conjunctiva. Surgical excision of large eyelid nevi may necessitate significant tissue loss, so frequent observation rather than routine excision may be warranted in many cases. The nevus cells (melanocytes) are found in discrete nests and consist of oval to cuboidal cells with

clear cytoplasm and variable melanin. Typically the cells become smaller and contain less pigment in the deeper dermal component of the lesion if present. Junctional, compound, and intradermal nevi are differentiated by the location of these nests of nevus cells. There is an evolution of acquired nevi in which the nevus cells are initially located only at the dermoepidermal junction (junctional nevus) (Fig. 3.13), followed later with nests at the dermoepidermal junction and dermis (compound nevus) (Fig. 3.14), and finally in the dermis only (intradermal nevus) (Fig. 3.15). This progression is referred to as the process of nevogenesis [16]. Thus, junctional nevi are most frequent in the first decade, compound nevus in the second decade, and the proportion of dermal nevi increases with age [45].

a

Fig. 3.13  Eyelid compound nevus. Pigmented melanocytic nevus on the margin of the upper eyelid. (a) Compound nevus consisting of melanocytic nests without cytologic

a

b

atypia in the epithelium at the dermoepidermal border as well as nests in the dermis (left half of photograph) ((b) hematoxylin and eosin; original magnification 20×)

b

Fig. 3.14  Junctional nevus. Flat pigmented lesion (a). Junctional nests of melanocytes (at dermoepidermal junction) only (b) (hematoxylin and eosin; original magnification 20×)

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3  Benign Eyelid Squamous and Melanocytic Tumors

a

Fig. 3.15 Eyelid nevus. Nonpigmented intradermal nevus of the eyelid margin. Note that surface epithelium and lashes are intact. (a) Intradermal nevus composed of nevus cells confined to the dermis and arranged in nests,

Spitz Nevus A distinctive type of nevus is the Spitz nevus [46], which is usually reported only in childhood and adolescence. They are found on the face, trunk, or extremities; and they can rarely involve the eyelid (Fig. 3.16) [47, 48]. These lesions are rapidly growing red- or tan-colored lesions that should be differentiated from pyogenic granuloma or hemangioma and, more importantly, from melanoma, which is extremely uncommon in children. They are a type of nevocellular nevus and have been referred to in the past as spindle cell nevus, epithelioid nevus, and benign juvenile melanoma. While some point to controversy over their biologic nature, they are generally considered benign. However, it is recognized that there may be local recurrences following incomplete excision; and several cases have been associated with regional lymph node involvement or rarely metastasis. These unusual cases probably are due to the fact that distinction between some Spitz nevi and melanoma (Spitzoid melanoma) can be difficult; and both melanomas falsely called Spitz nevi and the reverse have occurred. Some authors invoke the term atypical Spitz nevus/tumor in borderline cases. While sometimes worrisome histopathological features are noted, these are not uniformly present [48]. Histologically, Spitz nevi are usually compound in type; however 5–10% are junctional,

b

cords, and singly with maturation (nuclei becoming smaller) in the deeper dermis (b) (hematoxylin and eosin; original magnification 10×)

Fig. 3.16  Spitz nevus: Recurrent eyelid margin Spitz nevus in a 6-year-old girl

and 20% are intradermal. They are composed of either spindle or epithelioid cells, spindle cells being more common. Superficially located mitotic figures tend to be few in number, and they reflect rapid clinical growth but not an indication of malignancy. Atypical mitoses should not be present nor should mitoses deep in the lesion [2, 29]. These nevi are symmetrical, with no lateral extension of junctional activity beyond the intradermal component. There may be aggregates of nevus cells within the epidermis (but not single cells) in what is referred to as transepidermal elimination. Kamino bodies may be present at the dermoepidermal junction. These are eosinophilic globules which stain with PAS and trichrome

28

h­ istochemical stains, and they are an important diagnostic feature [48]. Maturation of the nevus cells toward the base is also seen in most cases. Minor diagnostic criteria include junctional cleavage (separation of the epidermis from the nevus nests in the junctional zone), pseudoepitheliomatous hyperplasia, absence of pleomorphism, dermal edema and telangiectasia, and giant nevus cells [48]. Comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH) can be useful in difficult cases because most melanomas show chromosomal changes, as opposed to Spitz nevi which do not typically. Homozygous deletion of 9p21 (location of CDKN2A/p16) is commonly seen in Spitzoid melanomas but not Spitz nevi [48]. In general, there is genetic similarity between Spitzoid melanoma and conventional melanoma [49]. Because the clinical features of rapid onset are alarming, excision to exclude the possibility of melanoma should be performed.

 typical (Clark’s) or Dysplastic Nevus A Atypical nevi are present in the 2–18% of the population, and they may be associated with an increased risk for malignant melanoma. In addition to educating such patients about dangers of sun exposure, periodic total skin examinations starting at puberty should be recommended. The term “dysplastic nevus” has been controversial with suggestions to not use in the clinical setting [50]. Atypical nevi tend to be larger (≥5  mm), with ill-defined borders, and have variegated colors (tan, brown, and pink). They may be multiple. The characteristic features of dysplastic nevi are lentiginous hyperplasia, random cytologic atypia of the melanocytes, stromal response (lamellar fibroplasia of the papillary dermis), and shouldering or peripheral extension of the junctional component over the intradermal component. Management of dysplastic nevi has been controversial. Options are re-excision of histologically dysplastic nevi (HDN) vs. observation [51]. A recent review of 2673 cases published in 12 articles was performed. Of these cases, 1535 were observed and 1138 re-excised with followup from 2 weeks to 30 years. Nine studies found

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no melanomas. In the few melanomas that did develop in the other studies, 0.39% were in observed lesions and 0.44% in re-excised lesions. While recognizing inherent problems in many of the studies as well as selection bias in determining whether to observe or re-excise (such as family history of melanoma, large burden of HDNs, tanning bed use, or sunburns in childhood), the authors concluded that observation of HDNs may be safe with only minimal risk of subsequent melanoma [52].

 amilial Atypical Mole and Melanoma F Syndrome (Dysplastic Nevus Syndrome) Atypical mole or dysplastic nevus syndrome denotes a specific clinicopathologic entity that is associated with an increased risk for the development of cutaneous melanoma [53]. This syndrome of autosomal dominant predisposition to cutaneous melanoma was originally described by Clark as B-K mole syndrome [54]. FAM-M syndrome is due to mutations of the gene CDKN2A on chromosome 9p21 [55]. Even so, the concept of FAM-M syndrome remains controversial [36]. The association between FAM-M syndrome and uveal nevi and uveal melanoma is discussed elsewhere [56].  entigo Maligna (Melanotic Freckle L of Hutchinson) Lentigo maligna refers to an acquired pigmented macule in the sun-exposed skin of middle-aged or elderly individuals [57]. It was initially described by Hutchinson; hence, it is also called melanotic freckle of Hutchinson [58]. Lentigo maligna is now considered the in situ phase (melanoma in situ) of lentigo maligna melanoma (invasive melanoma). Lentigo maligna is characterized by an atypical melanocytic proliferation (cells occurring singly or in nests) confined to the epidermis (mostly basilar), with features including pleomorphic and enlarged nuclei, increased and eosinophilic cytoplasm, and mitotic activity. Lentigo maligna can slowly enlarge horizontally before entering a vertical growth phase and transforming into lentigo maligna melanoma

3  Benign Eyelid Squamous and Melanocytic Tumors

(invasive melanoma). Overall, it is estimated that the lifetime risk of developing invasive melanoma is approximately 5% [59]. Proposed suitable methods of treatment include surgical excision with mapping, radiotherapy, cryotherapy, topical imiquimod, imiquimod with cryotherapy [60], and a modified Mohs micrographic technique using immunoperoxidase staining with HMB-45 or MART-1 [59].

Summary Benign epidermal tumors of the eyelid are similar to those observed in the other sun-exposed areas of the skin. Some benign eyelid lesions may represent manifestations of systemic disease. They may or may not be pigmented, and with histopathologic examination, they are classified as being melanocytic or non-melanocytic in origin. Once malignancy has been ruled out, they might still have features of a dysplastic or premalignant lesion, warranting closer follow-up or excision. It is at times difficult, if not impossible, to differentiate benign tumors from premalignant tumors especially in early stages of malignant transformation. If malignant, excisional biopsy with suitable margins is the preferred treatment. Melanocytic lesions of the eyelid are similar to such lesions elsewhere. Therefore, management of such patients should be guided by the general principles of dermatology and dermatopathology.

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L. Schoenfield and A. D. Singh 40. Wang Q, Prieto V, Esmaeli B, et al. Cellular blue nevi of the eyelid: a possible diagnostic pitfall. J Am Acad Dermatol. 2008;58(2):257–60. 41. Van Raamsdonk CD, Bezrookove V, Green G, et  al. Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature. 2009;457(7229):599–602. 42. Roh MR, Eliades P, Gupta S, et al. Genetics of melanocytic nevi. Pigment Cell Melanoma Res. 2015;28(6):661–72. 43. Singh AD, De Potter P, Fijal BA, et  al. Lifetime prevalence of uveal melanoma in white patients with oculo(dermal) melanocytosis. Ophthalmology. 1998;105(1):195–8. 44. Patel BC, Egan CA, Lucius RW, et  al. Cutaneous malignant melanoma and oculodermal melanocytosis (nevus of Ota): report of a case and review of the literature. J Am Acad Dermatol. 1998;38(5 Pt 2):862–5. 45. Wiecker TS, Luther H, Buettner P, et al. Moderate sun exposure and nevus counts in parents are associated with development of melanocytic nevi in childhood: a risk factor study in 1,812 kindergarten children. Cancer. 2003;97(3):628–38. 46. Spitz S.  Melanoma of the childhood. Am J Pathol. 1948;24:591–609. 47. Hiscott P, Seitz B, Naumann GO.  Epithelioid cell Spitz nevus of the eyelid. Am J Ophthalmol. 1998;126(5):735–7. 48. Shields PW, Jakobiec FA, Stagner AM, et al. Spitz nevus arising in the eyelid of a teenager. Surv Ophthalmol. 2016;61(2):228–35. 49. Lazova R, Pornputtapong N, Halaban R, et al. Spitz nevi and Spitzoid melanomas: exome sequencing and comparison with conventional melanocytic nevi and melanomas. Mod Pathol. 2017;30(5):640–9. 50. Rosendahl CO, Grant-Kels JM, Que SK.  Dysplastic nevus: fact and fiction. J Am Acad Dermatol. 2015;73(3):507–12. 51. Vuong KT, Walker J, Powell H, et  al. Surgical re-­ excision versus observation for histologically dysplastic nevi: a systematic review of associated clinical outcomes. Br J Dermatol. 2018;179(3):590–8. 52. Kim CC, Swetter SM, Curiel-Lewandrowski C, et al. Addressing the knowledge gap in clinical recommendations for management and complete excision of clinically atypical nevi/dysplastic nevi: pigmented Lesion Subcommittee consensus statement. JAMA Dermatol. 2015;151(2):212–8. 53. Salopek TG.  The dilemma of the dysplastic nevus. Dermatol Clin. 2002;20(4):617–28, viii. 54. Clark WH Jr, Reimer RR, Greene M, et  al. Origin of familial malignant melanomas from heritable melanocytic lesions. The B-K mole syndrome. Arch Dermatol. 1978;114(5):732–8. 55. Soura E, Eliades PJ, Shannon K, et  al. Hereditary melanoma: update on syndromes and management: genetics of familial atypical multiple mole melanoma syndrome. J Am Acad Dermatol. 2016;74(3):395– 407; quiz 8–10. 56. Chen S.  The dysplastic nevus controversy: it is not about the nevus per se but one’s belief in the mul-

3  Benign Eyelid Squamous and Melanocytic Tumors tistep tumorigenesis theory. Am J Dermatopathol. 2010;32(8):858. 57. Stevenson O, Ahmed I.  Lentigo maligna: progno sis and treatment options. Am J Clin Dermatol. 2005;6(3):151–64. 58. Hutchinson J. Notes on the cancerous process and on new growths in general. Arch Surg. 1890;2:83–6.

31 59. Arlette JP, Trotter MJ, Trotter T, et al. Management of lentigo maligna and lentigo maligna melanoma: seminars in surgical oncology. J Surg Oncol. 2004;86(4):179–86. 60. Read T, Noonan C, David M, et  al. A systematic review of non-surgical treatments for lentigo maligna. J Eur Acad Dermatol Venereol. 2016;30(5):748–53.

4

Basal Cell Carcinoma Mordechai Rosner and Ido Didi Fabian

Introduction Basal cell carcinoma (BCC) is a malignant cutaneous neoplasm capable of extensive tissue destruction. It is often observed on the head and neck, and the eyelids are a very common location. BCC was initially described as a distinct entity by Krompecher at the beginning of the twentieth century. Some authorities preferred the term “epithelioma” to carcinoma because of the tumor’s limited capacity to metastasize [1]. While the mortality from BCC is low, the morbidity may be considerable.

Epidemiological Aspects BCC is the most common human malignancy and accounts for nearly 90% of all nonmelanoma skin cancers. It is also the most common skin cancer of the eyelid, accounting for 86–96% of all cases [2]. It seems that geographical and ethnic differences exist in the occurrence of BCC. In M. Rosner (*) Department of Ophthalmology, Eye Histopathology Laboratory, Goldschleger Eye Institute, Sheba Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel I. D. Fabian Department of Ophthalmology, Ocular Oncology Center, Goldschleger Eye Institute, Sheba Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

the USA, the incidence of BCC is more than 500 per 100,000, and in parts of Australia, it reaches 2400 per 100,000 [1, 3, 4]. While increase in frequency was reported during the last century, a possible decreasing trend in the incidence rates was shown in the last decade [5, 6].

Etiology The risk factors for periocular BCC include ultraviolet (UV) irradiation, local and systemic immune dysfunction, previous ionizing radiation, and focal trauma. It is believed that exposure to UV light causes defects in immune function and that this has a role in the pathogenesis of BCC. Other risk factors are fair skin color, inability to tan, and exposure to trivalent inorganic arsenic, such as from medications including arsenical compounds [1]. Genetic or congenital diseases predisposing to BCC are Gorlin–Goltz syndrome, xeroderma pigmentosum, albinism, Basex–Dupré syndrome, Muir–Torre syndrome, Rombo syndrome, linear basocellular hamartoma, and sebaceous hamartoma of Jadassohn [3].

Pathogenesis The origin of BCC is controversial. It could arise from the basal cell of the epidermis, from the infundibular cells of the hair follicle, or from a

© Springer Nature Switzerland AG 2019 J. Pe’er et al. (eds.), Clinical Ophthalmic Oncology, https://doi.org/10.1007/978-3-030-06046-6_4

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pluripotential cell. BCC does not arise from a precursor lesion [1].

Clinical Features Approximately 95% of all BCCs occur in people between 40 and 79 years of age, and the average age at diagnosis for BCC of the eyelid is 60. BCC may occur in young adults and in children who have an inherited predisposition to cutaneous neoplasia. However, rarely, a solitary BCC may arise in an adolescent or young adult who has no known risk factors. Men may be more afflicted than women. In most cases, BCC arises as a solitary lesion on hair-bearing sun-exposed skin, particularly the face. Most periocular BCCs arise on the lower eyelid and medial canthus and least often near the lateral canthus. Tumors are usually present for many months prior to diagnosis [1, 4].

Symptoms and Signs There are several different clinical variants of BCC, including nodular and nodulo-ulcerative, pigmented, cystic, and infiltrating (which is called

a

M. Rosner and I. D. Fabian

also morpheaform or sclerotic) BCC. All the clinical variants are usually accompanied by loss of adnexa (hair and lashes); they are firm to palpation and are painless unless secondarily infected [1].

Nodular The nodular BCC begins as a small papule and slowly enlarges to an irregular, dome-shaped tumor. The epithelial surface of the tumor is usually smooth, often described as pearly, with fine telangiectatic vessels beneath it. Ulceration may develop and is filled with a crusty exudate (Fig. 4.1).

Pigmented The pigmented BCC is usually nodular or nodulo-­ ulcerative, ranging in color from light tan to deep brown.

Cystic The cystic BCC may attain significant dimensions (Fig. 4.2).

b

Fig. 4.1  Nodular BCC of the lower lid margin, presenting as an irregular, pearly dome-shaped tumor (a). Ulcerated lesion with poorly defined margins (b)

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4  Basal Cell Carcinoma

Infiltrating

Histopathologic Features

The infiltrating BCC presents as an indurated, yellowish to tan patch or plaque with occasional focal ulceration and poorly defined margins (Fig. 4.3). Patchy crusts, papules, and nodules are scattered throughout some morpheaform tumors. Infiltration within the eyelid can cause deformities and malpositioning of the lid margin.

BCC is characterized by a proliferation of cells with oval nuclei and scant cytoplasm that form infiltrative nests or strands (Fig.  4.4). The neoplastic cells are relatively uniform in appearance and seldom display significant anaplasia or mitotic figures. At the periphery of the nests, they are usually arranged in a radial pattern called “palisading” (Fig. 4.5): although this is not diagnostic, in its absence, the diagnosis of BCC should be questioned. The nests of tumor cells characteristically retract from the stroma, creating a gap (Fig. 4.5). Initially thought to be a processing artifact, this gap reflects defects in the production of adhesion-like substances by tumor cells. Necrosis is a common finding in BCC, and the necrotic debris eventually calcifies or is replaced by fibrous scar tissue. BCC also demonstrates an inflammatory infiltrate of variable intensity around the nests of tumor cells that consists predominantly of lymphocytes. The junction between the stroma of the neoplasm and normal connective tissue is ill defined [1]. There is no universally accepted histopathologic subclassification of BCC according to ­patterns of growth and cellular differentiation.

Fig. 4.2  Cystic BCC of the upper lid

a

b

Fig. 4.3  Nodulo-ulcerative lesion of the lid margin with loss of lashes (a). External examination reveals lid retraction with linear scars on the upper eyelid due to infiltrative BCC (b)

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M. Rosner and I. D. Fabian

Fig. 4.6  An infiltrative BCC is composed mainly of elongated strands of tumor cells that are several cell layers thick, with no peripheral cellular palisading Fig. 4.4  Histopathologically, BCC is characterized by a proliferation of cells with oval nuclei and scant cytoplasm that form infiltrative nests or strands

Fig. 4.7  In many cases, different growth patterns of BCC occur in the same tumor Fig. 4.5  At the periphery of the nests, the tumor cells are usually arranged in a radial pattern called “palisading” (arrow), and these are characteristically retracted from the stroma, creating a gap (arrowhead)

The two most important growth patterns are the circumscribed and the infiltrative. Circumscribed BCC is characterized by nests and sheets of tumor cells and usually corresponds clinically to a nodular tumor. In contrast, an infiltrative BCC is composed mainly of elongated strands of tumor cells that are several cell layers thick, with no peripheral cellular palisading (Fig.  4.6), and usually corresponds to a morphemic variety. However, in many cases, different growth pat-

terns occur in the same tumor (Fig. 4.7). There is a third important histologic pattern, the superficial BCC, which is presumed to be of multicentric origin and with horizontal spread. Superficial BCC is described mainly on the trunk and extremities [1]. More than 20 types of cellular differentiation or histologic patterns have been described in BCC as signs of sebaceous, apocrine, or eccrine gland, as well as pillar differentiation in an otherwise typical BCC [1, 8]. However, the rare morpheaform, infiltrating and basosquamous subtypes of BCC, are more aggressive. The metatypical (basosquamous) car-

4  Basal Cell Carcinoma

cinomas have an impact on prognosis. Basosquamous carcinoma displays various degrees of squamous differentiation and has been suggested to occupy a conceptual intermediate ground between squamous cell carcinoma and BCC (Box 4.1) [1].

Box 4.1 Salient Diagnostic Findings

• Painless, firm, nodular, or flat skin lesion with smooth, pearly epithelium, and subepithelial telangiectatic vessels, accompanied by loss of adnexa. • Microscopic findings of infiltrative nests, sheets, or strands of cells with oval nuclei and scant cytoplasm, which are arranged at the periphery of the nests in a radial “palisading” pattern. • Presence of a gap between the nests of tumor cells and the stroma.

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highly questionable, otherwise excisional biopsy should be performed.

Exfoliative Cytology Exfoliative cytology has been shown to have a high diagnostic accuracy for BCC but may be considered only occasionally, when the plan is to treat the tumor nonsurgically [9].

Imaging When orbital or intraocular invasion is suspected, imaging is used to evaluate it. T1 contrast-­enhanced fat-suppressed MRI scans are the modality of choice for demonstrating a soft tissue mass or infiltration. Computed tomographic (CT) bone windows with axial and coronal views of the orbit are best for demonstrating bony destruction – which, however, is uncommon in BCC patients [10].

Other Noninvasive Methods The morpheaform BCC showed a high expression of Bcl-2 (an important apoptotic gene) and moderate levels of proliferating cell nuclear antigen (a proliferation-associated marker) in a histological and immunohistochemical study of eyelid BCCs [7]. It was also found that telomere length was shortened and gene expression of Bcl-2 and Ki-67 (correlated with cell proliferation) was increased in BCC samples compared with normal tissues [7].

Diagnostic Evaluation Histopathologic Examination of Excisional or Incisional Biopsy The most important diagnostic evaluation of BCC is histopathologic examination of the excised tissue. Incisional biopsy should be taken only in cases where the clinical diagnosis is

Pulsed ultrasound at 20 MHz has been used for the noninvasive measurement of BCC thickness in order to plan photodynamic therapy (PDT) and to evaluate the rate of tumor regression after treatment. It was found that such measurements can distinguish between skin, fibrosis, and tumor and can even trace recurrences of BCC prior to clinical findings [11]. Near-infrared reflectance-mode confocal scanning laser microscopy is a novel imaging technique for microscopic analysis of skin lesions that may offer a sensitive and specific tool for the noninvasive diagnosis of BCC in vivo [12, 13].

Differential Diagnosis The clinical and histopathologic differential diagnosis is broad. Challenging examples are trichoepithelioma and desmoplastic trichoepithe-

38

lioma, metastatic carcinoma, sebaceous carcinoma, squamous cell carcinoma, and keratoacanthoma. However, as BCC is by far the most common malignant lesion of the periocular skin, most periocular nodular or cystic skin lesions should be treated as suspicious.

Treatment The main treatment modality for BCC is surgical excision of the lesion with microscopic monitoring of its margins or Mohs’ microsurgery [1, 12]. The other surgical and nonsurgical modalities include curettage and electrodessication, cryosurgery, radiotherapy, chemotherapy, photodynamic therapy, and immunotherapy. Selection of the appropriate therapy depends on the patient’s age, anticipated life expectancy, and the location, size, and pattern of growth characteristics of the tumor. However, therapies that are not surgical and do not include microscopic monitoring should be avoided for BCCs when they are not very small, when they are located in the medial canthus, or when the margins are clinically ill defined. The importance of preventing sun exposure needs to be stressed to children and young adults in order to reduce the incidence of BCC in the future [1].

Surgical Excision

M. Rosner and I. D. Fabian

culty, time, and expense of Mohs’ surgery may not be justified in all BCCs of the eyelid, it is usually reserved for deeply infiltrative tumors with a high risk of recurrence [1]. An intermediate technique that incorporates Mohs’ surgery using formalin-fixed, paraffin-embedded sections (slow Mohs) was suggested to offer a histologically superior and cheaper alternative to standard Mohs’ surgery [16]. The carbon dioxide laser has a few advantages over the conventional scalpel in the excision of BCC, including the possibility of bloodless excision of tissue in thin layers for histological examination of the margins and the possibility of obviating electrocautery, which is important for patients taking anticoagulants or who have a cardiac pacemaker [1]. Special reconstructive techniques are used to maintain the functions of the eyelid and to achieve the best cosmetic results after surgical excision of periocular BCC (Chap. 10).

Curettage and Electrodesiccation Curettage and electrodesiccation and, lately, vaporization of the tumor by CO2 laser are commonly used techniques to treat small BCC in areas remote from the eye. As the adequacy of margins is not determined, there is always the risk that residual tumor will escape destruction, especially near embryonic fusion planes. Also, the amount of secondary scarring and contracture with electrodesiccation may be cosmetically unacceptable in the periocular area [1].

Only by surgical excision of the tumor with safe margins it is possible to assess the adequacy of extirpation. However, in cases with deep infiltration into the orbit or in proximity to the eyeball tissues, excision with safe margins is not possi- Cryotherapy ble, and exenteration is inevitable. A variety of ways are used to examine the surgical margins, Cryotherapy is a tissue-sparing modality with no and good results have been reported when frozen-­ control of the adequacy of tumor removal. It has section control is used. Mohs’ micrographic sur- been suggested that cryotherapy of eyelid BCC gery has been considered to be the most reliable with a well-defined border, including tumors method for tumor extirpation or as reliable as larger than 10 mm and tumors in the medial canexcision with frozen-section or permanent-­ thal area, has a high cure rate and is cost-effective section control, with the lowest recurrence rate and well tolerated, with good cosmetic and funcand best cure rate [1, 14, 15]. As the extra diffi- tional outcomes [1, 17–21].

4  Basal Cell Carcinoma

Radiation Therapy The role of radiation therapy in the management of BCC is controversial. It has been found that there is significant recurrence after radiotherapy for BCC [1, 22], and such recurrences, particularly those in the midface, are exceptionally difficult to treat successfully by any means and are at high risk ultimately to cause death [1]. Radiotherapy can be used as an adjuvant therapy to exenteration in cases with orbital invasion by periocular basal cell carcinoma [10].

Chemotherapy and Other Therapies Chemotherapy is used for cases of nonresectable BCC, when for some reason surgery cannot be undertaken, or for rare cases of metastatic BCC. Cisplatinum chemotherapy, used alone or in combination with doxorubicin or with paclitaxel, has been beneficial in case reports [1, 23]. The results of preliminary studies using retinoids (etretinate and isotretinoin) in the management of BCC have been varied [1].

Interferon Over a decade ago, intralesional injection of human recombinant α-interferon was used to treat BCC, with some success [1, 24]. A new class of immune response modifier, represented by topical imiquimod cream, was demonstrated to have the potential to provide topical treatment of BCC, either alone or in combination with retinoids [24, 25]. Photodynamic Therapy Photodynamic therapy (PDT) is a new, noninvasive procedure that produces tumor destruction, and photodynamic therapy with aminolevulinic acid was found to be a promising approach in the therapy of dermal lesions of the eyelids [10, 26]. Imiquimod Topical treatments such as imiquimod cream (IMQ) have the advantage of assisting in the removal of BCC without causing collateral struc-

39

tural damage. IMQ is an immune response modifier that causes eventually production of cytokines such as interferon-a. It was reported to be effective for treatment of eyelid nodular BCCs with good cosmesis and good functional results [27].

Vismodegib Vismodegib (Erivedge) is a molecular inhibitor of the Hedgehog signaling pathway. It was approved by the FDA in January 2012 for the oral therapy of metastatic and locally advanced BCC.  Oral Vismodegib has been shown to be effective in preventing disease progression in patients with metastatic or locally advanced BCC not amenable to surgical excision or radiotherapy [2, 28] (Fig. 4.8). Although new nonsurgical procedures were found to be promising approaches in the therapy of BCC of the eyelids, none of them are yet an acceptable alternative to surgical excision and are reserved for research or for selected patients.

Follow-Up As two-thirds of recurrences appear within 3 years of treatment and 18% appear between 5 and 10 years, long-term clinical follow-up is necessary [1, 3].

Prognosis Prognostic Factors The prognosis of BCC depends mainly on the size of the tumor, its anatomic location, its pattern of infiltrative growth, and the age of the patient [1]. Large tumors and location in the medial canthal region are the most important clinical features predicting recurrence. A high risk for orbital invasion was found for BCC of the medial and lateral canthus [1, 8]. The morpheaform clinical pattern, the histologic finding of an infiltrative growth pattern, or metatypical (basosquamous carcinoma) differentiation have been correlated with deep invasion and

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M. Rosner and I. D. Fabian

a

b

c

d

e

Fig. 4.8  A 67-year-old woman presented with a biopsy proven neglected basal cell carcinoma (over 2.5  years) involving the right side of the face with loss of orbital contents (a, b). She was started on vismodegib 150 mg daily (November 2016). For another 6 months, there was gradual reduction in the nodular and ulcerative surface of the lesion (c), but in February 2018, patient noticed growth over the cheek. MRI also showed slight increased exten-

sion of the residual infiltrating soft tissue skull base mass involving the right orbit, paranasal sinuses, facial soft tissues, and masticator space into the right anterior cranial fossa (d, e). Following discussion in a multidisciplinary treatment group, surgery followed by radiation therapy is also being considered. (Courtesy of Allison Vidimos, MD, Dermatology, Cleveland Clinic)

4  Basal Cell Carcinoma

greater recurrence after treatment [1]. More aggressive tumors and a higher frequency of recurrence was found in patients under 35 years of age [1].

Local Spread The vast majority of BCC grow in a slow but relentless manner. However, localized spontaneous regression has been documented [29]. BCC invades along the paths of least resistance and then destroys adjacent tissues (Fig.  4.8). Destruction of bone, cartilage, and muscle is usually seen only in the very late stages of the d­ isease. Invasion of lymphatics is common but does not correlate with the rarely occurring regional metastasis. Some BCCs follow peripheral nerves and can thereby gain access to deeper tissues. Spread to the central nervous system may occur via cranial nerves, the orbital fissure, and cranial foramina. Intraocular invasion by BCC is rare and usually occurs in advanced cases with orbital invasion. The globe is entered through a sclera emissary canal or an old surgical wound [1].

Recurrence The recurrence rate of treated BCC of the eyelid averages 4.2% in the short term and 8.7% for more than 5 years. This varies according to the therapeutic method used. Tumors that recur tend to be more aggressive and difficult to manage [1, 3, 4].

Metastases and Mortality Metastatic BCC is extremely rare, and its rate has been estimated to be between 0.0028% and 0.01%. The most frequent sites of metastasis are the lymph nodes, lungs, bone, liver, and spleen [1]. Clinical features suggesting a greater probability of metastasis include multiple recurrences, an aggressive histological appearance, perineural invasion, and a history of previous ionizing radiation [23]. Mortality from eyelid and medial canthal BCC is rare, and all deaths recorded were related to intracranial extension [1].

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Staging According to the applied practical review of the American Joint Committee on Cancer (AJCC) seventh edition (Box 4.2) [30], primary BCC 5 mm or less, between 5 and 20 mm in greatest dimension, not invading the tarsal plate or eyelid margin with no involvement of regional lymph nodes and no distant metastasis, were classified as stage I tumors. BCC more than 20  mm in greater dimension or any tumor that invades adjacent ocular or orbital structures were classified as stage II.  Stage III was when tumor complete resection requires enucleation, exenteration, or bone resection, when regional lymph node metastasis is evident, or when the tumor is not resectable due to extensive invasion of ocular, orbital, and craniofacial structures or the brain. Stage IV is the rare cases with distant metastasis. This classification was found to be a practical tool for staging of carcinoma of the eyelids [31]. Box 4.2 AJCC Cancer Staging of Carcinoma of the Eyelids

• Stage I A – primary BCC 5 mm or less in greatest dimension, not invading the tarsal plate or eyelid margin with no involvement of regional lymph nodes and no distant metastasis. • Stage I B – primary BCC between 5 and 10 mm in greatest dimension, not invading the tarsal plate or eyelid margin with no involvement of regional lymph nodes and no distant metastasis. • Stage I C  – primary BCC between 10 and 20  mm in greatest dimension, not invading the tarsal plate or eyelid margin with no involvement of regional lymph nodes and no distant metastasis. • Stage II  – primary BCC more than 20  mm in greater dimension or any tumor that invades adjacent ocular or orbital structures. • Stage III A  – when tumor complete resection requires enucleation, exenteration, or bone resection.

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12. Nori S, Rius-Diaz F, Cuevas J, et al. Sensitivity and specificity of reflectance-mode confocal microscopy for in  vivo diagnosis of basal cell carcinoma: a multicenter study. J Am Acad Dermatol. 2004;51:923–30. 13. Murra DE, Torres A, Schanbacher CF, et al. Detection of residual basal cell carcinoma by in vivo confocal microscopy. Dermatol Surg. 2005;31:538–41. 14. Cook BE Jr, Bartley GB.  Treatment options and future prospects for the management of eyelid malignancies: an evidence-based update. Ophthalmology. 2001;108:2088–98. 15. Malhotra R, Huilgol SC, Huynh NT, et al.  The Australian Mohs Database, Part II.  Periocular basal cell carcinoma outcome at 5-year follow-up. References Ophthalmology. 2004;111:631–6. 16. Morris DS, Elzaridi E, Clarke L, et al.  Periocular 1. Margo CE, Waltz K.  Basal cell carcinoma of the basal cell carcinoma: 5-year outcome following slow eyelid and periocular skin. Surv Ophthalmol. Mohs surgery with formalin-fixed paraffin-embed1993;38:169–92. ded sections and delayed closure. Br J Ophthalmol. 2. Yin VT, Merritt HA, Sniegowski M, et al. Eyelid and 2009;93(4):474–6. ocular surface carcinoma: diagnosis and management. 17. Lindgren G, Larko O. Long-term follow-up of cryoClin Dermatol. 2015;33:159–69. surgery of basal cell carcinoma of the eyelid. J Am 3. Allali J, D’Hermies F, Renard G. Basal cell carcinomas Acad Dermatol. 1997;36:742–6. of the eyelids. Ophthalmologica. 2005;219:57–71. 18. Tuppurainen K. Cryotherapy for eyelid and periocu 4. Malhotra R, Huilgol SC, Huynh NT, et al.  The lar basal cell carcinomas: outcome in 166 cases over Australian Mohs Database, Part I: periocular basal cell an 8-year period. Graefes Arch Clin Exp Ophthalmol. carcinoma. Experience over 7 years. Ophthalmology. 1995;233:205–8. 2004;111:624–30. 19. Kokoszka A, Scheinfeld N. Evidence-based review of 5. Paavilainen V, Tuominen J, Pukkala E, et al. Basal cell the use of cryosurgery in treatment of basal cell carcicarcinoma of the eyelid in Finland during 1953–97. noma. Dermatol Surg. 2003;29:566–71. Acta Ophthalmol Scand. 2005;83:215–20. 20. Jaramillo-Averbe F.  Cryosurgery in difficult to treat 6. Lim VSY, Amrith S.  Declining incidence of eyebasal cell carcinoma. Int J Dermatol. 2000;39:223–9. lid cancers in Singapore over 13 years: population-­ 21. Lindgren G, Larko O. Cryosurgery of eyelid basal cell based data from 1996 to 2008. Br J Ophthalmol. carcinomas including 782 cases treated over 30 years. 2012;96:1462–5. Acta Ophthalmol. 2014;92:787–92. 7. Shi Y, Jia R, Fan X.  Ocular basal cell carcinoma: a 22. Avril MF, Auperin A, Margulis A, et al. Basal cell carbrief literature review of clinical diagnosis and treatcinoma of the face: surgery or radiotherapy? Results ment. Onco Targets Ther. 2017;10:2483–9. https:// of a randomized study. Br J Cancer. 1997;76:100–6. doi.org/10.2147/OTT.S130371.. eCollection 2017. 23. Jefford M, Kiffer JD, Somers G, et al. Metastatic cell Review. carcinoma: rapid symptomatic response to cisplatin 8. Wade TR, Ackerman AB.  The many faces of and paclitaxel. ANZ J Surg. 2004;74:704–5. basal-­ cell carcinoma. J Dermatol Surg Oncol. 24. Wang I, Bauer B, Andersson-Engels S, et  al. 1978;4:23–8. Photodynamic therapy utilising topical delta-­ 9. Bakis S, Irwig L, Wood G, et al. Exfoliative cytology aminolevulinic acid in non-melanoma skin malignancies as a diagnostic test for basal cell carcinoma: a metaof the eyelid and the periocular skin. Acta Ophthalmol analysis. Br J Dermatol. 2004;150:829–36. Scand. 1999;77:182–8. 10. Leibovitch I, McNab A, Sulivan T, et  al. Orbital 25. Ingves C, Jemec GBE.  Combined imiquimod and invasion by periocular basal cell carcinoma. acitretin for non-surgical treatment of basal cell Ophthalmology. 2005;112:717–23. carcinoma. Scand J Plast Reconstr Surg Hand Surg. 11. Allan E, Pye DA, Levine EL, et al. Non-invasive 2003;37:293–5. pulsed ultrasound quantification of the resolution of 26. Rhodes LE, de Rie M, Enström Y, et al. Photodynamic basal cell carcinomas after photodynamic therapy. therapy using topical methyl aminolevulinate vs surLasers Med Sci. 2002;17:230–7. gery for nodular basal cell carcinoma. Results of

• Stage III B – when regional lymph node metastasis is evident. • Stage III C  – when the BCC is not resectable due to extensive invasion of ocular, orbital, and craniofacial structures or the brain. • Stage IV  – primary BCC with distant metastasis.

4  Basal Cell Carcinoma a multicenter randomized prospective trial. Arch Dermatol. 2004;140:17–23. 27. Garcia-Martin E, Gil-Arribas LM, Idoipe M, et al. Comparison of imiquimod 5% cream versus radiotherapy as treatment for eyelid basal cell carcinoma. Br J Ophthalmol. 2011;95:1393–6. 28. Sekulic A, Migden M, Oro A, et al.  Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 2012;366:2171–9.

43 29. Curson C, Weedon D.  Spontaneous regression in basal cell carcinoma. J Cutan Pathol. 1979;6:432–7. 30. Edge SE, Byrd DR, Carducci MA, et al., editors. Carcinoma of the eyelid. In: AJCC cancer staging manual. 7th ed. New York: Springer; 2010. 31. Crawford C, Fernelius C, Young P, et al. Application of the AJCC 7th edition carcinoma of the eyelid staging system: a medical center pathology based, 15-year review. Clin Ophthalmol. 2011;5:1645–8.

5

Squamous Cell Carcinoma Mordechai Rosner and Ido Didi Fabian

Introduction Squamous cell carcinoma (SCC) is an invasive epithelial malignancy that arises from the prickle– squamous cell layers of the epidermis and shows keratinocytic differentiation. It is capable of metastasis to regional lymph nodes and is potentially lethal. SCC was first distinguished from basal cell carcinoma (BCC) by Kompecher in 1902 [1]. The terms “squamous cell epithelioma,” “epidermoid carcinoma,” “epithelioma spinocellular,” “prickle cell epithelioma,” and “spinalioma” have all been used in the literature, but “squamous cell carcinoma” is the preferred terminology.

Epidemiological Aspects The incidence of eyelid SCC varies from 0.9 to 2.42 cases per 100,000 population, with the highest incidence reported from Australia [2–5]. In most populations, SCC is the second most common M. Rosner (*) Department of Ophthalmology, Eye Histopathology Laboratory, Goldschleger Eye Institute, Sheba Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel I. D. Fabian Department of Ophthalmology, Ocular Oncology Center, Goldschleger Eye Institute, Sheba Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

malignant neoplasm of the eyelids after basal cell carcinoma (BCC) comprising 5–10% of all eyelid malignancies [1–3]. However, in India, China, and Japan, the proportion of BCC and sebaceous gland carcinoma (SGC) was found to be almost equal, and more than SCC [6], and in most other countries, the reported incidence of SCC relative to BCC ranges from 1:11 to 1:40 [7, 8].

Etiology Extrinsic risk factors for SCC include ultraviolet light and actinic damage, exposure to arsenic, hydrocarbons, radiation, immunosuppressive drugs, and a high-fat diet. Intrinsic risk factors include immunosuppression, fair skin, albinism, preexisting chronic skin lesions, genetic skin disorders such as xeroderma pigmentosum and epidermodysplasia verruciformis, and infection with human papillomavirus [9–11].

Clinical Features SCC occurs most commonly in fair-skinned elderly individuals who have a history of chronic sun exposure [1, 2, 10, 12]. The majority of patients with SCC are 60  years of age or older [10, 11]. Men are affected two to three times as often as women. It has been suggested that the distinct male predominance may represent

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increased occupational sunlight exposure by males, rather than a genetic predisposition [10]. Periocular SCC occurs most frequently on the lower eyelid, followed by the medial canthus, the upper eyelid, and the lateral canthus, in that order of frequency. The preponderance of lower-lid involvement in SCC is not as pronounced as in BCC [1, 12]. In some series, SCC of the medial canthus has outnumbered those confined to the eyelid. SCC also has a predilection for the eyelid margin [1].

M. Rosner and I. D. Fabian

Box 5.1 Salient Diagnostic Features of Squamous Cell Carcinoma

• Painless nodular, plaque-like, or ulcerated lesions with scaling and fissuring of the skin and irregular, rolled, pearly borders • Microscopic findings of infiltrative neoplasm arising from the epidermis and composed of polygonal cells with abundant acidophilic cytoplasm and prominent, hyperchromatic, pleomorphic nuclei • Presence of dyskeratotic cells with the formation of keratin pearls and intercellular bridges

Symptoms and Signs Although the clinical presentation of SCC varies, most often it appears as a painless, elevated, nodular, or plaque-like lesion with chronic scaling and fissuring of the skin. Pearly irregular borders and a tendency to develop ulceration with irregular rolled edges are also characteristic features (Box 5.1) [1, 12]. In a well-differentiated tumor, keratin gives the lesion a grayish-white, granular appearance (Fig. 5.1). Additional presenting features include a small erythematous scaly patch, a cyst-like lesion, a papillomatous lesion, a cutaneous horn, and a large ulcerated lesion. The edges of the lesion are well circumscribed in some cases and ill defined in others [1, 10, 12].

a

Patients with SCC tend to have other tumors of the skin, including intraepidermal carcinoma (Bowen’s disease), senile keratosis, and basal cell carcinoma [1]. Squamous intraepidermal carcinoma (Bowen’s disease) represents fullthickness involvement of the epidermis by neoplastic cells (carcinoma in situ) with a relatively high risk of progression to invasive SCC [10]. Its clinical manifestation is of a persistent and

b

Fig. 5.1  Squamous cell carcinoma of the upper lid (a) and lower eyelid (b) presenting as an irregular, elevated lesion with masses of keratin

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5  Squamous Cell Carcinoma

slowly enlarging erythematous, scaly, or crusted lesion with a sharp, irregular outline [1, 13].

Histopathologic Features Pathogenesis SCC arises from the epidermal prickle and squamous cells. Although it may develop de novo, actinic keratosis, Bowen’s disease, and radiation dermatoses are all precursors to the development of SCC [10, 12].

Evolution SCC of the eyelid usually begins with an early epithelial phase referred to as actinic keratosis (senile keratosis, solar keratosis), with subtotal replacement of the epidermis by atypical cells (intraepithelial squamous dysplasia). Intraepithelial squamous cell carcinoma or squamous cell carcinoma in situ is diagnosed when there is complete disorganization of the epidermis, with numerous atypical cells that are rounded, large, and with homogeneous, eosinophilic cytoplasm. Invasion of the dermis is the hallmark for the histopathologic diagnosis of invasive SCC (Fig. 5.2) [1].

Fig. 5.2  Invasive well-differentiated squamous cell carcinoma showing invasion of the dermis by tumor polygonal cells that vary in size and staining properties

Light Microscopic Features The invading cells show different degrees of differentiation leading to variable histologic features. In well-differentiated tumors, the cells are polygonal, with abundant acidophilic cytoplasm and prominent hyperchromatic nuclei that vary in size and staining properties. Characteristic findings are of abnormal keratinization with dyskeratotic cells and keratin pearls and intercellular bridges. Poorly differentiated lesions show an increased degree of cellular anaplasia, with irregularly shaped and sized cells, enlarged nuclei, abnormal mitoses, little or no evidence of keratinization, and loss of intercellular bridges (Fig. 5.3).

Diagnostic Evaluation Because of its variable clinical presentation, biopsy and histological examination are required for an accurate diagnosis [1]. Examination of the face or extremities for other types of premalignant lesions may aid in the diagnosis [1, 12]. The diagnosis of perineural spread and orbital invasion may be confirmed with appropriate imaging techniques.

Fig. 5.3  Poorly differentiated squamous cell carcinoma showing cellular anaplasia with irregularly shaped and sized cells, enlarged nuclei, and no evidence of keratinization

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Differential Diagnosis SCC of the eyelid and periocular region typically has no pathognomonic feature that allows its differentiation from other cutaneous lesions, and it may mimic many other types of skin lesion, both benign and malignant [1, 12].

Treatment Preventive Prevention by minimizing sun exposure, especially in childhood and adolescence, remains of prime importance in minimizing the morbidity and mortality associated with SCC.

Therapeutic The main treatment modality used for eyelid SCC is surgical excision, with microscopic monitoring of the margins or Mohs’ microsurgery. A variety of other forms of therapy were suggested, such as radiation therapy, cryotherapy, chemotherapy, curettage with carbon dioxide laser, photodynamic therapy, and treatment with retinoids or α-interferon. When used alone, these therapies have high recurrence rates, which are not acceptable for SCC of the eyelid, where recurrent tumors can be more aggressive and invasive. However, they may be appropriate for patients who cannot tolerate or who decline surgery [12].

Surgery Only surgical excision with monitoring of the margins, using either a frozen-section, or a paraffin-­section control, or Mohs’ micrographic surgery, is an acceptable treatment option for periocular SCC [1, 2, 12, 13]. The treatment of choice for secondary orbital invasion of SCC is orbital exenteration [1, 10].  entinel Lymph Node Biopsy S The presence of regional lymph node metastases is the single most important prognostic factor for most solid neoplasms, and complete lymph node dissection with pathologic examination of a cross

M. Rosner and I. D. Fabian

section of a lymph node is considered the gold standard in staging patients for adjuvant therapy. However, its therapeutic value is questionable, and it may be associated with considerable morbidity [12]. The sentinel lymph node biopsy has been suggested as a potentially useful technique to stage periocular SCC, especially in patients with recurrent, large, or highly invasive lesions or those with perineural invasion (Chap. 21) [12, 14].

Radiation Therapy Radiation therapy has been used in the treatment of eyelid malignancies since the beginning of the twentieth century. SCC is relatively radioresistant and responds even less than BCC to radiation [1]. However, postoperative radiotherapy has been recommended in all patients with microscopic perineural invasion [15], as the role of surgery in the treatment of perineural spread seems to be only palliative [16]. Three-dimensional conformal planning or intensity-modulated radiation therapy is needed to minimize damage to adjacent structures, and synchronous chemotherapy should be considered to potentiate the effectiveness of radiation. It was suggested that primary radiotherapy for SCC of the eyelid may provide high control rates with good function and cosmesis and should be considered an alternative to surgery in selected patients [17]. It was also shown that radical radiotherapy using electron beams for SCC of the eyelid yielded good results and could be a treatment option [18]. Chemotherapy Chemotherapy may be used for patients with systemic disease and for those who cannot tolerate surgical excision or who decline surgery [19]. It is usually used as an adjuvant to surgery and radiotherapy in aggressive infiltrating SCC. Topical Therapy Topical treatments such as with fluorouracil (5-FU) cream and imiquimod cream (IMQ) were found to be effective treatments for SCC of the eyelids in only very small series of patients. Topical 5% 5-FU cream was found to be useful in the treatment of squamous cell carcinoma in situ involving the eyelid, including the eyelid margin

5  Squamous Cell Carcinoma

[20]. Topical 5% IQ treatment was reported as successful in cases with intraepidermal as well as invasive SCC of the eyelids [21].

Photodynamic Therapy Photodynamic therapy (PDT) is emerging as a promising treatment for patients with multiple or large SCC or in whom surgery is not appropriate. In such cases, PDT is associated with reasonable efficacy, good cosmesis, and limited morbidity. However, until prospective-controlled trials are performed, the precise role of PDT in relation to more conventional surgical approaches remains to be defined [22, 23].

Prognosis

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neglected cases of eyelid SCC may spread into the lacrimal passages, the orbit, and the intracranial cavity. SCC is by far the most frequent of the secondary epithelial neoplasms in the orbit [1]. However, orbital invasion is a rare complication that has been reported to occur in 2.5% of all eyelid BCC and SCC [30]. Orbital invasion of eyelid SCC may take years to occur, often preceded by several surgical interventions, irradiations, and recurrences of the tumor. If left unattended, the entire orbital region and a major portion of the face are destroyed in an ulcerating fungating crater [1]. Orbital spread is usually associated with complete ptosis, ophthalmoplegia, and proptosis. Eventually, involvement of the orbital nerves and bones causes severe and constant pain [1, 10].

Prognostic Factors

Perineural Spread

High-risk eyelid SCC lesions are those larger than 2 cm, with poor histological differentiation, deep invasion, and the presence of perineural invasion [24]. Recurrent tumors and tumors developing in scars or in immunocompromised patients also imply a poor prognosis [25, 26]. The histologic variant of adenoid SCC is associated with a better prognosis [1].

Perineural spread of SCC occurs in up to 14% of facial lesions [31]. The perineural infiltration of SCC of the eyelids along branches of the trigeminal nerve, the extraocular motor nerves, and the facial nerve facilitates its spread into the orbit, periorbital structures, and intracranial cavity [32]. Once clinical signs or symptoms of perineural spread have developed, the prognosis is poor, with around 50% recurrence after simple ­excision [31].

Staging According to the applied practical review of the American Joint Committee on Cancer (AJCC) 7th edition [27], primary SCC is classified into stages I, II, III, and IV stages according to size, adjacent invasion, complete resection that requires enucleation, exenteration or bone resection, involvement of regional lymph nodes, extensive invasion making the tumor not resectable, and evidence of distant metastasis. This classification was found to be a practical tool for staging of carcinoma of the eyelids [28, 29].

Local Spread Eyelid SCC is potentially fatal and responsible for considerable morbidity [9]. Aggressive or

Local Recurrence The 5-year local recurrence rate for SCC is about 23%. The 5-year metastatic rates vary between 5% and 45% [25, 33]. The recurrence rate of periocular squamous intraepithelial carcinoma is 5% and 12% for primary and recurrent lesions, respectively [13].

Metastasis Unlike BCC, SCC has a tendency to metastasize to regional lymph nodes and distant sites through hematogenous and lymphatic pathways. The incidence of lymph node metastasis from eyelid SCC has ranged from 0% to as high as 24%, and

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of distant metastasis varies from 1% to 21% [1, 14, 34]. The incidence of metastasis of SCC arising from actinic keratoses is lower than for SCC arising de novo [1].

Mortality The tumor-related mortality rates have been reported to be as high as 40%, and an increased rate is associated with lesions of the upper lid and medial canthus [1]. However, if detected early and treated adequately, the prognosis of SCC is generally excellent, and the risk of death and disability can be minimized [10].

 ariants of SCC Including V Keratoacanthoma Less common histologic variants of SCC include the spindle cell and adenoid (adenoacanthoma or pseudoglandular) squamous cell carcinoma. The adenoid SCC variant is characterized by extensive acantholysis and tubular and pseudoglandular patterns [1]. Keratoacanthoma is indistinguishable from squamous cell carcinoma clinically as well as histopathologically (keratocarcinoma or keratoacanthoma-like squamous cell carcinoma) [35, 36]. However, because keratoacanthoma may regress, it is considered to be a variant of squamous cell carcinoma.

M. Rosner and I. D. Fabian

Epidemiology The annual incidence of cutaneous keratoacanthoma varies according to geographical location and is estimated to be 100–150 cases per 100,000  in sun-exposed areas (e.g., northern parts of Australia). It is considered more prevalent in males and affects patients in their fifth to seventh decades [38]. Clinical Features The lesion begins as a small flesh-colored papule that develops rapidly over 4–8 weeks to a lesion typically 5–25  mm in diameter with a central, keratin-filled crater (Fig. 5.4), followed by a stationary phase of similar duration, and a resolution phase may develop in up to 6 months duration (Fig. 5.5a, b). The keratoacanthoma has smooth borders that merge with the surrounding skin, and some present with erythema surrounding the base of the lesion and with telangiectases running over the surface of the tumor. The macroscopic sequelae are rare, generally only a mildly depressed scar. The tumor is most commonly seen on sun-exposed hair-bearing areas, mainly on the face, forearms, and hands. In the eyelids, it is considered not common [38]. There are several rare variants of keratoacanthoma, which include the giant keratoacanthoma

Keratoacanthoma Keratoacanthoma was first described by Sir Jonathan Hutchinson in 1889 as a crateriform ulcer of the face and was classified for many years as a benign skin lesion [37]. Although there are many variants of the disease, it usually presents as a solitary rapidly growing lesion. The etiology is diverse and remains unknown, ranging from ultraviolet exposure, viral infection by human papilloma virus, immunosuppression, and genetic susceptibility [36].

Fig. 5.4  Keratoacanthoma is a nodular lesion with a central keratin-filled crater

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a

b

Fig. 5.5  Keratoacanthoma (a) with spontaneous resolution 2 weeks later (b)

(>3  cm in diameter), keratoacanthoma centrifugum marginatum, subungual keratoacanthoma (keratoacanthoma of the nail), and mucosal keratoacanthoma. Keratoacanthomas are usually solitary lesions. However, there are a number of syndromes that feature multiple keratoacanthomas, including the Muir–Torre syndrome, a generalized eruptive variant of Grzybowski, and the Ferguson-Smith syndrome.

Histopathologic Features Keratoacanthoma typically has a dome-shaped elevation and thickening of the epidermis, surrounding a central mass of keratin (Fig.  5.6). Microabscesses may be present within islands of squamous epithelium that may show atypia. The dermis shows a polymorphous inflammatory infiltrate [39]. Treatment Some advocate a wait-and-watch strategy for keratoacanthoma, since the tumor can regress spontaneously. However, since tumor excision provides tissue for accurate histological diagnosis, hastens cure, and prevents growth of possible squamous cell carcinoma, surgical excision with margin control using frozen sections or Mohs’

Fig. 5.6  Histologically, variable squamous atypia may be seen at the base of the lesion, and inflammatory infiltrate is present in the dermis

surgery should be considered for such lesions in the periocular area [40]. Alternative treatment modalities described include radiotherapy, cryotherapy, topical or intralesional 5-fluorouracil, and topical application of 5% imiquimod cream.

References 1. Reifler DM, Hornblass A. Squamous cell carcinoma of the eyelid. Surv Ophthalmol. 1986;30(6):349–65. 2. Malhotra R, Huilgol SC, Huynh NT, et al.  The Australian Mohs database: periocular squamous cell carcinoma. Ophthalmology. 2004;111(4):617–23. 3. Cook BE Jr, Bartley GB. Epidemiologic characteristics and clinical course of patients with malignant eyelid tumors in an incidence cohort in Olmsted County, Minnesota. Ophthalmology. 1999;106(4):746–50. 4. Scotto J, Kopf AW, Urbach F.  Non-melanoma skin cancer among Caucasians in four areas of the United States. Cancer. 1974;34(4):1333–8. 5. Green A.  Changing patterns in incidence of non-­ melanoma skin cancer. Epithelial Cell Biol. 1992;1(1):47–51. 6. Lim VS, Amrith S.  Declining incidence of eyelid cancers in Singapore over 13 years: population-­ based data from 1996 to 2008. Br J Ophthalmol. 2012;96(12):1462–5. 7. Kwitko ML, Boniuk M, Zimmerman LE.  Eyelid tumors with reference to lesions confused with

52 s­quamous cell carcinoma. I.  Incidence and errors in diagnosis. Arch Ophthalmol. 1963;69:693–7. 8. Aurora AL, Blodi FC.  Lesions of the eyelids: a clinico-­ pathological study. Surv Ophthalmol. 1970;5:94–104. 9. Maclean H, Dhillon B, Ironside J.  Squamous cell carcinoma of the eyelid and the acquired immunodeficiency syndrome. Am J Ophthalmol. 1996;121(2):219–21. 10. Donaldson MJ, Sullivan TJ, Whitehead KJ, et al. Squamous cell carcinoma of the eyelids. Br J Ophthalmol. 2002;86(10):1161–5. 11. Yin VT, Merritt HA, Sniegowski M, et al. Eyelid and ocular surface carcinoma: diagnosis and management. Clin Dermatol. 2015;33:159–69. 12. Cook BE Jr, Bartley GB.  Treatment options and future prospects for the management of eyelid malignancies: an evidence-based update. Ophthalmology. 2001;108(11):2088–98; quiz 99–100, 121 13. Malhotra R, James CL, Selva D, et  al. The Australian Mohs database: periocular squamous intraepidermal carcinoma. Ophthalmology. 2004;111(10):1925–9. 14. Faustina M, Diba R, Ahmadi MA, et al.  Patterns of regional and distant metastasis in patients with eyelid and periocular squamous cell carcinoma. Ophthalmology. 2004;111(10):1930–2. 15. McNab AA, Francis IC, Benger R, et al.  Perineural spread of cutaneous squamous cell carcinoma via the orbit. Clinical features and outcome in 21 cases. Ophthalmology. 1997;104(9):1457–62. 16. Bowyer JD, Sullivan TJ, Whitehead KJ, et  al. The management of perineural spread of squamous cell carcinoma to the ocular adnexae. Ophthal Plast Reconstr Surg. 2003;19(4):275–81. 17. Petsuksiri J, Frank SJ, Garden AS, et  al. Outcomes after radiotherapy for squamous cell carcinoma of the eyelid. Cancer. 2008;112(1):111–8. 18. Inaba K, Ito Y, Suzuki S, et  al. Results of radical radiotherapy for squamous cell carcinoma of the eyelid. J Radiat Res. 2013;54:1131–7. 19. Luxenberg MN, Guthrie TH Jr. Chemotherapy of basal cell and squamous cell carcinoma of the eyelids and periorbital tissues. Ophthalmology. 1986;93(4):504–10. 20. Couch SM, Custer PL. Topical 5-fluorouracil for the treatment of periocular actinic keratosis and low-­ grade squamous malignancy. Ophthal Plast Reconstr Surg. 2012;28(3):181–3. 21. Ross AH, Kennedy CT, Collins C, et al. The use of imiquimod in the treatment of periocular tumours. Orbit. 2010;29(2):83–7. 22. Marmur ES, Schmults CD, Goldberg DJ. A review of laser and photodynamic therapy for the treatment of nonmelanoma skin cancer. Dermatol Surg. 2004;30(2 Pt 2):264–71. 23. Rossi R, Puccioni M, Mavilia L, et al. Squamous cell carcinoma of the eyelid treated with photodynamic therapy. J Chemother. 2004;16(3):306–9.

M. Rosner and I. D. Fabian 24. Soysal HG, Markoc F.  Invasive squamous cell carcinoma of the eyelids and periorbital region. Br J Ophthalmol. 2007;91(3):325–9. 25. Rowe DE, Carroll RJ, Day CL Jr. Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip. Implications for treatment modality selection. J Am Acad Dermatol. 1992;26(6):976–90. 26. Committee on Guidelines of Care. Task Force on Cutaneous Squamous Cell Carcinoma. Guidelines of care for cutaneous squamous cell carcinoma. J Am Acad Dermatol. 1993;28(4):628–31. 27. Edge SE. Carcinoma of the eyelid. In: Edge SE, Byrd DR, Carducci MA, Compton CA, editors. AJCC cancer staging manual. 7th ed. New York: Springer; 2010. 28. Crawford C, Fernelius C, Young P, et al. Application of the AJCC 7th edition carcinoma of the eyelid staging system: a medical center pathology based, 15-year review. Clin Ophthalmol. 2011;5:1645–8. 29. Sun TM, Andrew NH, O’Donnell B, et al. Periocular squamous cell carcinoma. TNM staging and recurrence. Ophthalmology. 2015;122:1512–6. 30. Howard GR, Nerad JA, Carter KD, et al.  Clinical characteristics associated with orbital invasion of cutaneous basal cell and squamous cell tumors of the eyelid. Am J Ophthalmol. 1992;113(2):123–33. 31. Goepfert H, Dichtel WJ, Medina JE, et al. Perineural invasion in squamous cell skin carcinoma of the head and neck. Am J Surg. 1984;148(4):542–7. 32. Cottel WI. Perineural invasion by squamous-cell carcinoma. J Dermatol Surg Oncol. 1982;8(7):589–600. 33. Petter G, Haustein UF.  Histologic subtyping and malignancy assessment of cutaneous squamous cell carcinoma. Dermatol Surg. 2000;26(6):521–30. 34. Loeffler M, Hornblass A. Characteristics and behavior of eyelid carcinoma (basal cell, squamous cell sebaceous gland, and malignant melanoma). Ophthalmic Surg. 1990;21(7):513–8. 35. Cribier B, Asch P, Grosshans E. Differentiating squamous cell carcinoma from keratoacanthoma using histopathological criteria. Is it possible? A study of 296 cases. Dermatology. 1999;199(3):208–12. 36. Schwartz RA. Keratoacanthoma: a clinico-pathologic enigma. Dermatol Surg. 2004;30(2 Pt 2):326–33; discussion 33 37. Hutchinson J. Morbid growths and tumours. The “crateriform ulcer of the face”, a form of acute epithelial cancer. Trans Pathol Soc Lond. 1889;40:275–81. 38. Donaldson MJ, Sullivan TJ, Whitehead KJ, et al. Periocular keratoacanthoma: clinical features, pathology, and management. Ophthalmology. 2003;110(7):1403–7. 39. Grossniklaus HE, Wojno TH, Yanoff M, et al. Invasive keratoacanthoma of the eyelid and ocular adnexa. Ophthalmology. 1996;103(6):937–41. 40. Leibovitch I, Huilgol SC, James CL, et al. Periocular keratoacanthoma: can we always rely on the clinical diagnosis? Br J Ophthalmol. 2005;89(9):1201–4.

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Sebaceous Gland Carcinoma Mordechai Rosner and Ido Didi Fabian

Introduction

Epidemiological Aspects

Sebaceous gland carcinoma (SGC) is a malignant neoplasm capable of aggressive local behavior and metastasis to regional lymph nodes and distant organs. It originates from cells of the sebaceous glands and occurs most often in the periorbital area, usually in the eyelid [1]. This lesion is considered among the most lethal of all ocular adnexal tumors [2]. Thiersch may have reported the first case of periorbital SGC in 1865, and Baldauf reported another case in 1870. However, Allaire is credited with the first well-documented case of adenocarcinoma of the meibomian gland in 1891, and most of the modern understanding of eyelid SGC was initiated by the review of Straatsma in 1956 [2]. The terms “sebaceous gland carcinoma,” “sebaceous cell carcinoma,” and “sebaceous carcinoma” are all used interchangeably in the literature.

The incidence of SGC varies in different series. In the USA, SGC accounts for only 5% of all malignant eyelid tumors, whereas basal cell carcinoma (BCC) accounts for 90%, and squamous cell carcinoma (SCC) and other tumors including melanoma represent the remaining 5% of cases. The annual incidence of eyelid SGC in the USA is about 0.5 per million in the White population older than 20  years, and the incidence may be increasing [3, 4]. In addition, SGC is more common in Caucasians than in African-Americans [5]. A higher incidence of SGC has been observed in China, India, and other Asian countries, where it may be as prevalent as or even more common than periocular BCC and SCC [1]. This difference is attributed to the relative lack of other tumors like BCC and SCC in Asian population [6].

M. Rosner (*) Department of Ophthalmology, Eye Histopathology Laboratory, Goldschleger Eye Institute, Sheba Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel e-mail: [email protected]

There are no systemic conditions that convincingly predispose to SGC. Ocular or facial irradiation for the treatment of hereditary retinoblastoma, acne, cutaneous hemangioma, and eczema are important risk factors [1]. The relationship between the use of diuretic medications and the development of SGC is not firmly proven [1, 4]. Occasional reports have suggested an association between SGC at a relatively young age and

I. D. Fabian Department of Ophthalmology, Ocular Oncology Center, Goldschleger Eye Institute, Sheba Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

Etiology

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immune dysfunction. A possible relationship between SGC and human papillomavirus (HPV) has also been observed [1].

Clinical Features SGC is generally a disease of older individuals, with a reported median age at diagnosis of 70–73 years [7]. However, it may develop in older children and young adults, particularly after irradiation for retinoblastoma [1]. Reports regarding gender have varied, and while some studies have suggested that men are 1.35–1.4 times as likely as women to have SGC, other studies have found a higher incidence in women [1, 7, 8]. SGC has a marked tendency to arise in the ocular region, but it is estimated that approximately 25% occur in regions other than the head and neck [9]. The majority of SGC arise from the meibomian glands within the tarsus. About 65% occur in the upper eyelid, 25% in the lower eyelid, 5% involve both eyelids [2, 8], and 5% arise in the caruncle [4, 8, 10]. Occasional cases of primary SGC of the conjunctiva and even of the lacrimal gland are reported [1]. Sebaceous carcinoma of the eyelid also has the tendency to exhibit multicentric origins [5] and pagetoid spread, which makes local recurrence a potential problem (Box 6.1) [11]. When patients present with a history of multiple SGCs the possibility of Muir–Torre syndrome, now considered a subtype of hereditary nonpolyposis colonorectal cancer, needs to be considered [7].

Box 6.1 Salient Diagnostic Features of Sebaceous Gland Carcinoma • A unilateral, solitary, and sessile subcutaneous round nodule that is firm, painless, and yellow masquerading as chalazion • Unilateral diffuse thickening of the eyelid and/or the conjunctiva masquerading as blepharoconjunctivitis

• Microscopic findings of an infiltrating mass composed of cells with lipid vacuoles in the cytoplasm, pronounced nuclear pleomorphism, and mitotic activity • Flat superficial involvement of the epithelium—“pagetoid growth pattern” • Positive oil red-O stain for lipid • Immunohistologic expression of HMFG1, EMA, and BRST-1, but not of cytokeratins

Symptoms and Signs Solitary Nodule of the Eyelid The most common clinical variant of SGC is a solitary, firm, painless, sessile subcutaneous round nodule fixed to the tarsus (Fig. 6.1). With thickening of the eyelid, the tumor may assume a yellow color owing to the lipids it contains (Fig.  6.2). However, SGC that arises from the glands of Zeis is located at the eyelid margin and has no firm attachment to the tarsus. The tumor eventually causes loss of cilia, as observed with other eyelid malignant tumors (Fig.  6.1) [1]. Rarely, SGC may become ulcerated.

Diffuse Thickening of the Eyelid Unilateral diffuse thickening of the eyelid is the second most frequent presentation of SGC. The diffuse tumor may extend into the epithelium of the forniceal or bulbar conjunctiva and even the cornea (Fig.  6.3). Rarely, SGC arising from the glands of Zeis can become pedunculated, keratinized, and even appear as a cutaneous horn. When SGC develops in the caruncle, it appears as an irregular yellow mass that usually is not fixed to adjacent structures [1, 12].

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a

b

Fig. 6.1  Sebaceous gland carcinoma arising in left upper eyelid—a firm, round nodule with prominent meibomian gland orifices and intrinsic vessels (a). The tarsoconjunc-

tival origin of the lesion is evident on partial eversion the eyelid (b)

Fig. 6.2  Sebaceous gland carcinoma arising in left lower eyelid—a firm nodule with prominent intrinsic vessels. Note yellow color due to lipid

Fig. 6.3  Diffuse involvement of the lower eyelids by sebaceous gland carcinoma causing loss of liod margin including cilia

Histopathologic Features

the tarsus, glands of Zeis of the cilia, pilosebaceous glands of the caruncle, and from the conjunctival epithelium [1]. It may exhibit multicentric origins [13, 14]. Most SGC appears to arise de novo and not from a preexisting sebaceous adenoma, sebaceous hyperplasia, or sebaceous (organoid) nevus [1].

Pathogenesis Periocular SGC arises from the sebaceous glands in the ocular region, including meibomian glands in

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a

Fig. 6.4  Histopathologically sebaceous gland carcinoma is an unencapsulated infiltrating mass (a, hematoxylin– eosin × 100). The tumor is composed of cells with finely

M. Rosner and I. D. Fabian

b

vacuolated, frothy cytoplasm and pronounced nuclear pleomorphism (b, hematoxylin–eosin × 400)

Light Microscopic Features Histopathologically, SGC is an unencapsulated infiltrating mass composed of cells with finely vacuolated, frothy cytoplasm, pronounced nuclear pleomorphism, and usually high mitotic activity (Fig. 6.4) [1]. The presence of lipid can be demonstrated with the oil red-O stain (Fig.  6.5). This lipid can incite a foreign body giant cell reaction. SGC is associated with a chronic inflammatory response that is less intense than in BCC [1, 14].

Pagetoid Spread SGC exhibits peculiar intraepithelial spread into the eyelid epidermis and the conjunctival epithelium in 44–80% of cases [1, 5, 8]. This flat ­superficial involvement of the epithelium is usually referred to as “pagetoid spread.”

Immunohistochemistry The histopathologic diagnosis of SGC can usually be made readily on routine light microscopy. However, immunohistochemistry replaces the

Fig. 6.5  Accentuation of the lipid using oil red-O stain. The lipid globules have a red color (Frozen section, oil red-O × 250)

need for fat stains on frozen sections and may help to differentiate SGC from basal and squamous cell carcinoma. The central foamy cells of SGC express human milk fat globulin-1 (HMFG1) and epithelial membrane antigen (EMA), but not cytokeratins, whereas the small peripheral basal and duct cells generally express cytokeratin but not HMFG1 or EMA. SGC also expresses Cam 5.2 and BRST-1, whereas BCC expresses neither EMA nor BRST-1, and SCC

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6  Sebaceous Gland Carcinoma Table 6.1 Immunohistochemistry profile of common malignant eyelid tumors

Tumor antibody EMA and BRST-1 EMA and Cam 5.2 EMA and Cam 5.2 Adipophilin Androgen receptor Ber-EP4 P53

Tumor type (% positive cases) Squamous Sebaceous cell gland Basal cell carcinoma carcinoma carcinoma 64 0 36 73

6

0

55

0

0

100 100

0 33

28 0

0 99

100 100

0 100

Modified from Sinard [15] and Mulay et al. [17] EMA anti-epithelial membrane antigen, BRST-1 anti-BCA 225, Cam 5.2 anti-low molecular weight keratin

Fig. 6.6  A papillary growth arising from the lower eyelid tarsal conjunctiva. Note yellow color and prominent meibomian gland orifices (arrow)

expresses EMA but not Cam 5.2 (Table 6.1) [1, 15]. Additional immunohistochemical staining including adipophilin (ADP), androgen receptor (AR), and Ber-EP4 can also help to do the correct diagnosis. AR was found as a sensitive marker for SGC, especially in less differentiated tumors. Along with other markers and morphologic features, AR can be helpful in the diagnosis of SGC and its differentiation from SCC and BCC.  AR was also found to be more specific and reliable in identifying intraepithelial spread of SGC, especially when this component has isolated tumor cells [16, 17].

Comedocarcinoma Pattern A large necrotic central core surrounded by viable cells characterizes the comedocarcinoma pattern.

Histopathological Classification In addition to being well, moderately, or poorly differentiated [1], SGC can be readily classified into one of four patterns: lobular, comedocarcinoma, papillary, and mixed [1].

Lobular Pattern Lobular pattern is the most common and has architecture similar to that of a normal sebaceous gland, with fewer differentiated cells peripherally and more differentiated lipid-producing cells located centrally.

Papillary Pattern Papillary pattern which occurs frequently in small conjunctival lesions is distinguished by papillary projections and areas of sebaceous differentiation (Fig. 6.6). Mixed Pattern Mixed pattern exhibits any combination of these three patterns.

Diagnostic Evaluation Full-thickness excisional or incisional biopsy of the eyelid that contains tarsus and tarsal conjunctiva is the preferred method of confirming the suspected clinical diagnosis of SGC (Fig.  6.7). When diffuse involvement of eyelid and conjunctiva is suspected, multiple conjunctival map biopsies should be performed to determine the extent of the disease [1, 8]. Fine-needle aspiration biopsy and impression cytology have been used in the early diagnosis of SGC [18, 19] and to

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a

M. Rosner and I. D. Fabian

b

Fig. 6.7  Crater like lesions after three tarsoconjunctival biopsies were obtained using a 3.0 mm cylindrical skin punch (a). The histopathology sample shows a tarsal tissue with meibomian gland carcinoma (b)

detect conjunctival spread, but these methods are generally not advisable because of the limited amount of tissue obtained. However, fine-needle biopsy may be acceptable for the diagnosis of regional lymph node metastases [1]. Only in cases with suspected diffuse involvement of the eyelid and conjunctiva is orbital imaging indicated, either before or after the initial biopsy, to rule out posterior extension [1].

Differential Diagnosis SGC is notorious for its variable clinical presentation and its ability to masquerade, both clinically and histopathologically, as common benign or less invasive conditions, resulting in delayed diagnosis and treatment [1, 2, 8].

Chalazion In the early stages, SGC of the eyelids can be very similar to chalazion. However, in contrast to SGC, chalazion generally occurs in younger individuals, is more circumscribed and painful, and is usually not associated with loss of cilia. However, recurrent chalazia, as well as chalazia

in older patients, should undergo a biopsy to rule out SGC.

Inflammatory Conditions Virtually any inflammatory condition of the eyelid and the conjunctiva must be included in the differential diagnosis of SGC. These include unilateral blepharitis, conjunctivitis, meibomitis, superior limbic keratoconjunctivitis, papillary conjunctivitis, cicatricial pemphigoid, conjunctival granuloma, and sarcoidosis. Thus, SGC should be suspected in every middle-aged or older patient with a diagnosis of unilateral blepharitis or other inflammatory conditions that do not respond to usual therapy [1].

Benign and Malignant Tumors Several benign and malignant tumors can have a clinical appearance similar to that of SGC. These include BCC, SCC, melanoma, Merkel cell carcinoma, lymphoma, sweat gland neoplasm, junctional squamous papilloma, hereditary benign intraepithelial dyskeratosis, metastatic carcinoma, and other rare tumors [1].

6  Sebaceous Gland Carcinoma

 asal Cell Carcinoma B The nodular BCC is more common on the lower lid and is white rather than yellow. BCC is also more likely to become ulcerated than SGC.  Although diffuse sclerosing BCC may closely simulate SGC, it very rarely exhibits diffuse invasion of the conjunctiva. Histologically, BCC typically shows peripheral palisading of nuclei and retraction artifact that are not seen in SGC.  quamous Cell Carcinoma S SCC is more superficial and lacks a yellow color. Conjunctival intraepithelial neoplasia can be very similar to diffuse epithelial invasion by SGC, except for eyelid involvement, which is less likely to be present in SGC. Histopathologically, SCC is the lesion most often confused with SGC [8, 20, 21]. Unlike SGC, SCC cells have more abundant eosinophilic cytoplasm, lack lipid ­vacuoles, and demonstrate eddy formation and keratin cysts. Melanoma Nodular or diffuse cutaneous melanoma in the eyelid or conjunctiva can usually be distinguished from SGC by its black or brown pigmentation, but amelanotic melanoma can resemble SGC. Other Tumors Merkel cell carcinoma of the eyelid is distinguished by its red or red-blue color. Lymphoma of the eyelid arises from deeper layers than does SGC, and in the conjunctiva, it has a characteristic “salmon patch” color. Moreover, inflammatory signs that are commonly associated with SGC are lacking in lymphoma.

Treatment Surgery The most acceptable management of periocular SGC is complete surgical removal [22]. Excisional biopsy of a small lesion is recommended even before histopathologic verification of the diagnosis [1]. Either frozen section control

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or Mohs’ microsurgery is usually used at the time of tumor excision, to evaluate the margins, and the resection is continued until the margins are histopathologically clear. However, there is controversy as to which is preferable and whether either technique is better than waiting for permanent sections, because of the difficulty in diagnosing SGC in frozen sections [1, 23, 24]. It has been suggested that wide margins, of at least 5  mm, should be taken in order to prevent recurrence. Orbital exenteration is currently performed less often but is still indicated for advanced and diffuse SGC with orbital invasion in the absence of metastasis [1].

Cryotherapy As the removal of wide margins is not possible in the case of conjunctival lesions, supplemental treatment by double freeze-thaw cycle cryotherapy is indicated. Combination therapy with cryotherapy, topical chemotherapy [25–27], and radiotherapy [28] can also be used in advanced cases [1].

Topical Chemotherapy Topical chemotherapy with mitomycin C drops has been found to be effective as an alternative to complete conjunctivectomy or exenteration in selected cases [25–27].

Sentinel Lymph Node Biopsy The technique of sentinel node biopsy or at least strict regional lymph node surveillance was suggested as a useful method for SGC of the eyelid and conjunctiva [29, 30] especially for patients with eyelid sebaceous carcinoma of 10  mm or more in greatest dimension, tumors that involves full thickness of the eyelid, with invasion of adjacent ocular or orbital structures, with perineural invasion, when enucleation, exenteration, or bone resection is required for its complete resection, or

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when tumor is not respectable (Chap. 10) [31]. Localized regional lymph node metastasis is treated by lymph node dissection or by a combination of chemotherapy and radiotherapy [32].

Regional spread to lymph nodes and hematogenous metastasis to distant organs is treated by chemotherapy [1, 32].

Various factors have been associated with a worse prognosis, including vascular, lymphatic, and orbital invasion; involvement of both upper and lower eyelids; poor differentiation; multicentric origin; duration of symptoms more than 6 months; tumor diameter exceeding 10 mm; a highly infiltrative pattern; pagetoid invasion; and hyperexpression of tumor suppressor gene p53 [1, 36]. According to the applied practical review of the American Joint Committee on Cancer (AJCC) 7th edition [37], primary SGC is classified, like all other carcinomas of the eyelids, into stages I–IV (Box 4.2) according to the various parameters of the primary tumor (T category), regional lymph nodes (N category), and metastases (M category). These include the size of the primary tumor; adjacent invasion; complete resection that requires enucleation, exenteration, or bone resection; involvement of regional lymph nodes; extensive invasion making the tumor not respectable; and evidence of distant metastasis. It was found that the T category correlates well with outcomes in patients with sebaceous carcinoma of the eyelid [31]. All patients with SGC should be followed regularly because of the risk of recurrence as well as the potential for metastasis and mortality.

Targeted Therapy

Local Growth

The Hedgehog signaling pathway was found to be significantly more upregulated in periocular SGC compared to eyelid nodular BCC, a known aberrant Hedgehog pathway tumor. Furthermore, the stroma of the SGC demonstrated Hedgehog upregulation, compared to eyelid nodular BCC.  Thus targeting this pathway may be a potential treatment strategy for SGC as it is for BCC [35].

Regardless of its origin, SGC can show direct local extension beyond its original site and involve the entire eyelid, the adjacent eyelid, and invade the orbital soft tissues, lacrimal secretory system, lacrimal excretory system, and the cranial cavity. Such local growth is more likely to occur in neglected or recurrent cases [1, 5].

Prognosis

Despite radical surgery like orbital exenteration with extended neck dissection, locoregional failure rate may be high, and the 5-year local recurrence rates following wide excision have ranged from 9% to 36% [38]. Adequate disease control must be achieved by combined modality approach

Radiotherapy In the past, irradiation was considered as not highly effective in the management of SGC; it has been advocated only in selected cases [1, 28, 32]. However, newer studies are suggesting that radiation therapy is a safe and effective treatment for patients with sebaceous carcinoma of the eyelid. It appears to contribute to prolonged survival as a result of good tumor control, and it also facilitates functional and cosmetic preservation of the eyelid [33]. Postoperative radiation therapy after radical surgery is suggested for adequate disease control in advanced disease [34].

Systemic Chemotherapy

Prognostic Factors The visual prognosis varies with the extent of the disease and the type of treatment employed [1].

Local Recurrence

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6  Sebaceous Gland Carcinoma Table 6.2  Survival rates with eyelid sebaceous gland carcinoma First author Boniuk Ni Ni Rao Doxanas Zurcher Muqit Esmaeli

Year 1968 1979 1982 1982 1984 1998 2004 2014

Country USA China China USA USA England Scotland USA

Cases 88 100 82 104 40 43 32 50

Mortality rate (%) 30 41 24 22 15 9 3 21

Follow-up (years) 5 5–15 4 5 Not available 3 5 5a

Modified from Muqit et al. [40] and Esmaeli et al. [31] a Disease specific survival rate of 79% at 5 years

of radical surgery followed by postoperative radiation therapy [34].

Metastasis The most common path of metastasis of eyelid SGC is via the lymphatic channels to regional lymph nodes, which occurs in about 30% of cases. From the upper eyelid, it tends to metastasize to preauricular and parotid nodes, which are the most common sites of metastasis, and from the lower lid region, it tends to metastasize to the submandibular and cervical nodes [1]. Advanced cases of eyelid SGC occasionally exhibit distant metastasis, probably by hematogenous spread, mainly to the liver, lung, bone, and brain [1, 4]. Periocular sebaceous carcinomas had a higher incidence of regional or distant metastases at presentation compared with extraocular head and neck sites [30]. Lymph node metastasis was found to be associated with p21 downregulation, and, therefore, it was suggested that p21 immunoreactivity should be used as a tool for prediction of nodal metastasis in sebaceous carcinoma of the eyelid [36]. Patients with AJCC T2 bore more advanced disease had a significantly higher risk of nodal metastasis, and no tumor smaller than 9 mm was associated with nodal metastasis [31].

Mortality The 5-year tumor-related death rate was estimated in the past to be as high as 30% [39] and 50–67%

[34], for patients presenting with lymph nodal metastases. However, increased awareness and earlier aggressive treatment have markedly improved this to less than 10% (Table 6.2) [2, 40].

References 1. Shields JA, Demirci H, Marr BP, et  al. Sebaceous carcinoma of the ocular region: a review. Surv Ophthalmol. 2005;50:103–22. 2. Kass LG, Hornblass A.  Sebaceous carcinoma of the ocular adnexa. Surv Ophthalmol. 1989;33:477–90. 3. Margo CE, Mulla ZD.  Malignant tumors of the eyelid: a population-based study of non-basal cell and non-squamous cell malignant neoplasms. Arch Ophthalmol. 1998;116:195–8. 4. Khan JA, Doane JF, Grove AS. Sebaceous and meibomian carcinomas of the eyelid. Recognition, diagnosis, and management. Ophthalmic Plast Reconstr Surg. 1991;7:61–6. 5. Rao NA, Hiadayat AA, McLean IW, et al. Sebaceous carcinomas of the ocular adnexa: a clinicopathologic study of 104 cases, with five-year follow-up data. Hum Pathol. 1982;13:113–22. 6. Dasgupta T, Wilson LD, Yu JB.  A retrospective review of 1349 cases of sebaceous carcinoma. Cancer. 2009;115:158–65. 7. Yin VT, Merritt HA, Sniegowski M, et al. Eyelid and ocular surface carcinoma: diagnosis and management. Clin Dermatol. 2015;33:159–69. 8. Shields JA, Demirci H, Marr BP, et al. Sebaceous carcinoma of the eyelids. Personal experience with 60 cases. Ophthalmology. 2004;111:2151–7. 9. Wick MR, Goellner JR, Wolfe JT, et al. Adnexal carcinomas of the skin. II. Extraocular sebaceous carcinomas. Cancer. 1985;56:1163–72. 10. Shields CL, Shields JA, White D, et al. Types and frequency of lesions of the caruncle. Am J Ophthalmol. 1986;102:771–8.

62 11. von Below H, Rose GE, McCartney AC, et  al. Multicentric sebaceous gland carcinoma of the lid? Br J Ophthalmol. 1993;77:819–20. 12. Shields JA, Shields CL.  Sebaceous carcinoma of the glands of Zeis. Ophthal Plast Reconstr Surg. 1988;4:11–4. 13. Cavanagh HD, Green WR, Goldberg HK. Multicentric sebaceous adenocarcinoma of the meibomian gland. Am J Ophthalmol. 1974;77:326–32. 14. Herman DC, Chan CC, Bartley GB, et  al. Immunohistochemical staining of sebaceous cell carcinoma of the eyelid. Am J Ophthalmol. 1989;107:127–32. 15. Sinard JH.  Immunohistochemical distinction of ocular sebaceous carcinoma from basal cell and squamous cell carcinoma. Arch Ophthalmol. 1999;117:776–83. 16. Asadi-Amoli F, Khoshnevis F, Haeri H, et al. Comparative examination of androgen receptor reactivity for differential diagnosis of sebaceous carcinoma from squamous cell and basal cell carcinoma. Am J Clin Pathol. 2010;134:22–6. 17. Mulay K, White VA, Shah SJ, et al. Sebceous carcinoma: clinicopathologic features and diagnostic role of immunohistochemistry (including androgen receptor). Can J Ophthalmol. 2014;49:326–33. 18. Arathi CA, Vijaya C.  Scrape cytology in the early diagnosis of eyelid sebaceous carcinoma. J Cytol. 2010;27:140–2. 19. Gill M, Garg S, Kalra R, et al. Sebaceous carcinoma of the eyelid diagnosed on fine needle aspiration cytology. J Cytol. 2012;29:75–6. 20. Kwitko ML, Boniuk M, Zimmerman LE.  Eyelid tumors with reference to lesions confused with squamous cell carcinoma: incidence and errors in diagnosis. Arch Ophthalmol. 1963;69:696–7. 21. Lai TF, Huilgol SC, Selva D, et al. Eyelid sebaceous carcinoma masquerading as in situ squamous cell carcinoma. Dermatol Surg. 2004;30:222–5. 22. Cook BE Jr, Bartley GB.  Treatment options and future prospects for the management of eyelid malignancies: an evidence-based update. Ophthalmology. 2001;108:2088–98. 23. Folberg R, Whitaker DC, Tse DT, et  al. Recurrent and residual sebaceous carcinoma after Mohs’ excision of the primary lesion. Am J Ophthalmol. 1987;103:817–23. 24. Spencer JM, Nossa R, Tse DT, et al. Sebaceous carcinoma of the eyelid treated with Mohs micrographic surgery. J Am Acad Dermatol. 2001;44:1004–9. 25. Shields CL, Naseripour M, Shields JA, et al. Topical mitomycin-C for pagetoid invasion of the conjunctiva by eyelid sebaceous gland carcinoma. Ophthalmology. 2002;109:2129–33. 26. Rosner M, Hadar I, Rosen N.  Successful treatment with mitomycin C eye drops for conjunctival diffuse

M. Rosner and I. D. Fabian intraepithelial neoplasia with sebaceous features. Ophthal Plast Reconstr Surg. 2003;19:477–9. 27. Tumuluri K, Kourt G, Martin P. Mitomycin C in sebaceous gland carcinoma with pagetoid spread. Br J Ophthalmol. 2004;88:718–9. 28. Yen MT, Tse DT, Wu X, et al. Radiation therapy for local control of eyelid sebaceous cell carcinoma: report of two cases and review of the literature. Ophthal Plast Reconstr Surg. 2000;16:211–5. 29. Nijhawan N, Ross MI, Diba R, et al. Experience with sentinel lymph node biopsy for eyelid and conjunctival malignancies at cancer center. Ophthal Plast Reconstr Surg. 2004;20:291–5. 30. Tryggvason G, Bayon RMD, Pagedar NA.  Epidemiology of sebaceous carcinoma of the head and neck: implications for lymph node management. Head Neck. 2012;34:1765–8. 31. Esmaeli B, Nasser QJ, Cruz H, et al. American Joint Committee on Cancer T category for eyelid sebaceous carcinoma correlates with nodal metastasis and survival. Ophthalmology. 2012;119:1078–82. 32. Murthy R, Honavar SG, Burman S, et al. Neoadjuvant chemotherapy in the management of sebaceous gland carcinoma of the eyelid with regional lymph node metastasis. Ophthal Plast Reconstr Surg. 2005;21:307–9. 33. Hata M, Koike I, Omura M, et al.  Noninvasive and curative radiation therapy for sebaceous carcinoma of the eyelid. Int J Radiat Oncol Biol Phys. 2012;82:605–11. 34. Deo SVS, Shukla NK, Singh M, et al.  Locally advanced sebaceous cell carcinoma (T3) of eyelid: incidence and pattern of nodal metastases and combined modality management approach. Orbit. 2012;31:150–4. 35. Bladen JC, Moosajee M, Tracey-White D, et  al. Analysis of hedgehog signaling in periocular sebaceous carcinoma. Graefes Arch Clin Exp Ophthalmol. 2018;256:853–60. 36. Kiyosaki K, Nakada C, Hijiya N, et al. Analysis of p53 mutations and the expression of p53 and p21WAF1/ CIP1 protein in 15 cases of sebaceous carcinoma of the eyelid. Invest Ophthalmol Vis Sci. 2010;51:7–11. 37. Edge SE. Carcinoma of the eyelid. In: Edge SE, Byrd DR, Carducci MA, Compton CA, editors. AJCC cancer staging manual. 7th ed. New York: Springer; 2010. 38. Callahan EF, Appert DL, Roenigk RK, et al. Sebaceous carcinoma of the eyelid: a review of 14 cases. Dermatol Surg. 2004;30:1164–8. 39. Boniuk M, Zimmerman LE.  Sebaceous carcinoma of the eyelid, eyebrow, caruncle, and orbit. Trans Am Acad Ophthalmol Otolaryngol. 1968;72:619–41. 40. Muqit MM, Roberts F, Lee WR, et al. Improved survival rates in sebaceous carcinoma of the eyelid. Eye. 2004;18:49–53.

7

Eyelid Tumors: Cutaneous Melanoma Jacob Pe’er and Robert Folberg

Introduction

Epidemiology

Cutaneous melanoma of the eyelid is a rare tumor, representing fewer than 1% of all malignant neoplasms of the eyelid skin [1], 1% of all skin melanomas [2], and 7% of cutaneous malignant melanomas of the head and neck region [3]. Many primary melanomas of the eyelid involve the mucosal surfaces of the palpebral and bulbar conjunctiva, and in these cases, one must manage not only the eyelid but also the conjunctival component of the lesion. One may argue reasonably that primary conjunctival melanomas may affect the eyelid secondarily. This chapter, therefore, focuses on the rare subset of melanomas confined to the eyelid skin. Our knowledge of such tumors is based on a few case series and some case reports. It is difficult to draw definite conclusions about the epidemiology, etiology, clinical behavior, prognosis, and the appropriate management of these malignancies.

Because of its rarity, there are no data in the literature regarding the incidence of cutaneous melanoma of the eyelid. The vast majority of the reported cases are of white patients from series in North America, Australia, and Europe [4–10], but eyelid skin melanoma is also reported in series of eyelid tumors in Asia [11, 12]. The incidence is similar in men and women [7–9]. The eyelid cutaneous melanomas are tumors of adults and the elderly, with a peak incidence in the sixth and seventh decades of life [7–10].

J. Pe’er (*) Ocular Oncology Service and Ophthalmic Pathology Laboratory, Department of Ophthalmology, Hadassah - Hebrew University Medical Center, Jerusalem, Israel e-mail: [email protected] R. Folberg Oakland University William Beaumont School of Medicine, Rochester, MI, USA

Etiology and Pathogenesis Ultraviolet radiation most likely contributes to the etiology of eyelid melanoma. The appearance of these malignancies mostly in fair-skinned elderly adults, the histological findings of solar elastosis in most cases of cutaneous melanomas, the higher incidence of the tumor in the lower eyelid, and the relatively frequent association with basal cell carcinoma support this pathogenesis [7, 9, 10, 13, 14]. Ten cases of cutaneous melanoma were reported in eyelids and the periorbital region in patients with oculodermal melanocytosis (nevus of Ota) [15]. This is a relatively high incidence of this rare tumor in the relatively rare condition; thus, oculodermal melanocytosis may be

© Springer Nature Switzerland AG 2019 J. Pe’er et al. (eds.), Clinical Ophthalmic Oncology, https://doi.org/10.1007/978-3-030-06046-6_7

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J. Pe’er and R. Folberg

Fig. 7.1  A partially pigmented cutaneous melanoma in the lateral aspect of the lower eyelid of the right eye, near the lateral canthus; the lesion changed in shape before the photograph was taken. (Photograph courtesy of Dr. Peter A. Martin)

Fig. 7.2  High magnification of superficial cutaneous melanoma of the lower eyelid margin without involvement of the palpebral conjunctiva. (Photograph courtesy of Dr. Peter A. Martin)

c­ onsidered a risk factor for the development of eyelid cutaneous melanoma. Preexisting pigmented lesions that show a sudden or gradual increase in size were seen in most patients in one series [9].

the exposed cutaneous surface of elderly patients. It slowly enlarges in size, although some areas may undergo regression. The lesions change shape and size and may change color from tan to brown to black. When there is progression to lentigo maligna melanoma, the invasive areas are usually marked by small nodular formations and are usually dark brown or black, although invasion may occur without any obvious clinical changes. Theoretically, eyelid melanomas may evolve through dysplastic nevi that affect the eyelid or as melanomas of the superficial spreading type. Nodular melanomas are exceptionally rare among these already rare tumors, and small heavily pigmented nodules at the eyelid margin may well represent pigmented basal cell carcinomas. Eyelid melanoma can often involve the eyelid margins (Fig. 7.3). In such cases, the mucocutaneous junction may be breached and the palpebral conjunctiva may be involved. It is often difficult to know whether the melanoma originates in the skin or in the conjunctiva. Such cases have a worse prognosis, and some relate this to the conjunctival involvement that may grow unseen for many years [8].

Clinical Features Eyelid cutaneous melanoma arises most frequently in the lower eyelid (Figs.  7.1 and 7.2), many times from a preexisting longstanding pigmented lesion that increases in size gradually, although a newly acquired pigmented lesion is also common [9]. In one series [7] the three most frequently listed clinical characteristics of the melanoma were pigmentation, documented growth, and ulceration or hemorrhage. Other suspicious signs are irregular borders and variegated shades of brown, red, white, blue, or dark black color. Cutaneous melanoma can be amelanotic. It is likely that most eyelid melanomas evolve through the lentigo maligna precursor lesion [10, 13, 14, 16]. Lentigo maligna is a slowly developing non-palpable pigmented macule, usually on

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7  Eyelid Tumors: Cutaneous Melanoma

Fig. 7.3  Large cutaneous melanoma of right upper eyelid with involvement of the eyelid margin. (Photograph courtesy of Dr. Peter A. Martin)

Diagnosis and Differential Diagnosis The clinical examination of pigmented periocular lesions requires the ophthalmologist to provide an exceptional level of illumination (beyond that typically available in ophthalmic examining lanes that are used for refraction, slit-lamp examination, and funduscopy). One should be prepared to turn the room lights up to maximum level and to cast additional illumination on the affected area by a dedicated light near the examination chair. Magnification may help the ophthalmologist to detect subtle changes in a lesion’s color and texture, and the lens used for indirect ophthalmoscopy may be especially useful in this setting. Ophthalmologists should also not overlook the utility of the slit lamp in examining the eyelids for malignancies of all types, not only pigmented eyelid lesions. The slit lamp provides exceptional magnification and illumination, critical to achieving a focused clinical differential diagnosis. Most nevi of the eyelid margin are nodular, a reflection of the space-occupying characteristics of the intradermal collection of nevus cells.

Lesions that feature a roughened or exaggerated skin texture are more likely to be of epithelial origin, even if pigmented. Thus, melanocytes may generate pigmentation within seborrheic keratosis. These lesions should never be mistaken for melanomas because (a) the precursor lesions of most melanomas in the periocular skin are flat (pigmented seborrheic keratosis are elevated) and (b) seborrheic keratosis features an irregular surface texture, while invasive melanoma typically produces a smooth nodular surface in the context of an otherwise flat precursor lesion in which skin markings are unaffected. As mentioned above, basal cell carcinomas may be pigmented by the generation of excess melanin pigment in an otherwise “mundane” basal cell carcinoma of the nodular type. Such lesions are rare and may be mistaken for malignant melanomas of the nodular type. The treatment of pigmented nodular lesions of the eyelid involves total resection, so the initial treatment of these lesions is identical regardless of the eventual histological diagnosis. Spitz nevi may be confused clinically and histologically for melanomas of the nodular type on and around the eyelid (Chap. 3).

Histopathologic Features Lentigo maligna is remarkable for epidermal atrophy in the context of effacement of the rete and solar elastosis. Upon this background, on may encounter atypical melanocytes populating the basal layers of the epidermis and along adnexal structures such as the pillar units of the eyelash. Ophthalmologists should realize that in the terminology of contemporary dermatopathology, these lesions may be called “melanoma in situ,” meaning that atypical melanocytes are within the epidermis, confined above the epidermal basement membrane. Any breach of the epidermal basement membrane by atypical melanocytes renders the lesion a malignant melanoma. Should the invasive

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c­ omponent arise in the context of an intradermal melanocytic lesion featuring melanocytes in a pagetoid distribution, one might then state that the melanoma is of a superficial spreading type. The type of melanoma (lentigo maligna melanoma or superficial spreading melanoma) ­ does not influence the clinical behavior of the lesion. Clark’s micro-staging of melanoma [17] does not apply to the eyelid skin because in this location, the dermis is not stratified into papillary and reticular zones and there is no subcutaneous fat in the eyelid. If one encounters adipose tissue in the examination of an eyelid biopsy, then the pathologist should conclude that the surgeon violated the orbital septum. The primary prognostic parameter for melanomas of the eyelid skin is the depth of invasion measured by a calibrated ocular micrometer from the top of the granular layer of the epidermis to the point of deepest invasion into the dermis [18]. Other prognostic factors of importance in cutaneous melanoma at different body sites include the presence of ulceration (a poor prognostic sign), which is seldom seen in primary eyelid melanomas. Cell type, so significant among the histological characteristics of uveal melanoma, does not appear to play an independent role in this histological prognosis of eyelid melanomas.

Treatment Excision There is a consensus that complete surgical excision with free surgical margins of healthy skin is the treatment of choice for cutaneous malignant melanoma in general and eyelid melanoma in particular. However, the ideal width of the surgical margins that are necessary in order to prevent recurrences is a matter of controversy. Harris et  al. [19] recommended simple excision for in situ melanoma, 1 cm margins for tumors of 1 mm thickness or less, 2  cm margins for tumors of 1–4 mm depth, and at least 2 cm for more than 4 mm depth. However, because of difficulties in eyelid reconstruction, most studies exclude eye-

J. Pe’er and R. Folberg

lid melanomas from these recommendations. Early diagnosis and treatment are essential in managing eyelid melanomas and especially to attain adequate functional and cosmetic lid reconstruction. In an extensive series of cutaneous eyelid melanoma from Australia, the authors recommended a surgical excision margin of 3  mm for eyelid melanoma ≤1  mm in Breslow thickness and 5  mm for melanomas >1  mm in thickness [20]. Modified “slow” Mohs’ surgery (mapped serial excision) using paraffin sections has been recommended by several experts as the treatment of choice in cases of lentigo maligna and lentigo maligna melanoma [10, 13, 21, 22]. They found that this technique offers a high early cure rate in conjunction with tissue conservation. They also found that the recommendation of 1 cm margins for melanoma of less than 1 mm thick is insufficient for complete excision. Cook and Bartley [1] recommended modified Mohs’ technique using frozen tissue as treatment of choice, but the use of frozen tissue sections for melanoma is controversial because of freeze artifacts that make accurate interpretation difficult. A recent survey of 44 cases did not find that margins of excision have a statistically significant effect on local, regional, or distant recurrence [23]. Resection of periorbital and eyelid melanomas is challenging because of the important anatomic structures in this region [24]. The challenge lies in the need to provide the best functional and aesthetic results and to still resect the primary lesion with the intent of effecting the cure and protecting the eye. The surgeon should not compromise the adequate margins of resection in order to facilitate periorbital reconstruction. The type of reconstruction performed depends on the size of the surgical defect and its location (e.g., primary closure, full-thickness skin grafts, upper lid mucocutaneous flaps, cheek advancement flaps, cervicofacial flaps, inferiorly based nasolabial flaps, transconjunctival flaps, frontalis muscle flaps, and medial transposition Z-plasty) (Chap. 10) [24]. The needs of most patients can be met by one procedure, but in difficult cases, two or more procedures are required. In a large series of eyelid melanoma more than a third of

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the patients require more than one excision to achieve clear margins, supporting delayed reconstruction for eyelid melanoma [25].

has been reported in several cases series, suggesting a biologic interaction between these two methods [29].

Palliative Therapy

Sentinel Lymph Node Biopsy

Primary use of nonsurgical ablation in cutaneous melanoma is not recommended [20]. Methods of treatment such as cryotherapy, radiotherapy, topical treatment with azelaic acid, and curettage electrodissection are associated with high recurrence rates. In addition, these techniques do not provide tissue for histologic assessment of tumor thickness, the single most significant prognostic parameter in the management of melanoma. Cryotherapy and external beam radiation can be used as adjuvant therapy, although according to one study [9] adjuvant radiotherapy did not add at all to cure; thus the use of radiotherapy is at best palliative. One group reported a successful treatment with brachytherapy, using iodine-125 applicator in eyelid malignant melanoma [26]. Recently, treatment of eyelid lentigo maligna melanoma by the use of imiquimod cream was reported to be an effective option as primary adjuvant therapy [27].

The issue of elective lymph node dissection in patients with periocular melanoma is controversial [24, 30]. The procedure is probably not indicated for lesions less than 1.0 mm thick and may offer little advantage for lesions thicker than 4.0 mm (Chap. 21). It is currently recommended to perform elective lymph node dissection for melanomas of “intermediate” thickness (1–4  mm), which may have generated occult nodal metastases. Sentinel lymph node mapping using lymphoscintigram has been advocated in order to locate suspicious involved lymph nodes and prevent unnecessary lymph node dissection. The technique has evolved into intraoperative lymphatic mapping and facilitates selective sentinel lymphadenectomy [31]. When positive, fine-­ needle aspiration biopsy or excision of the node should be performed for histologic confirmation of the metastatic disease. In those patients with histologic confirmation of nodal metastases but no evidence of distant metastases, parotidectomy or modified neck dissection is performed [24] (Chap. 21). Histologic features associated with a positive sentinel lymph node include greater tumor thickness, a greater number of mitotic figures, and ulceration [30].

Chemotherapy and Immunotherapy In advanced metastatic cutaneousmelanoma, chemotherapy has been used recently with limited success, mostly increasing survival but not curing the disease. Immunotherapy has been introduced in recent years for treating metastatic cutaneous melanoma. In recent years, immunotherapy has become a cornerstone in the treatment of advanced cases of melanoma, intending to modulate the host immunity against the tumor [28]. Currently, the leading drugs for immunotherapy for cutaneous melanoma are ipilimumab (Yervoy), pembrolizumab (Keytruda), and nivolumab (Opdivo). Immunotherapy can be used in adjuvant setting after complete surgical excision in patients with high-risk diseases, unrespectable disease, or metastatic disease. A combination of radiation therapy and immunotherapy

Prognosis Prognostic Factors Factors such as age, gender, and histologic type are not of prognostic value [31]. Location of the tumor in the upper or lower lid and in the canthi does not affect prognosis, but location of melanoma in the lid margin involving the mucocutaneous junction is associated with higher mortality [5]. The involvement of the palpebral conjunctiva in such cases may explain this association. The status of the excision margins in cutaneous eyelid

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5. Garner A, Koornneef L, Levene A, et  al. Malignant melanoma of the eyelid skin: histopathology and behaviour. Br J Ophthalmol. 1985;69(3):180–6. 6. Zoltie N, O’Neill TJ. Malignant melanomas of eyelid skin. Plast Reconstr Surg. 1989;83(6):994–6. Recurrence 7. Grossniklaus HE, McLean IW.  Cutaneous melanoma of the eyelid. Clinicopathologic features. Local recurrence of eyelid cutaneous melanoma Ophthalmology. 1991;98(12):1867–73. is very frequent in incompletely excised tumor, 8. Tahery DP, Goldberg R, Moy RL.  Malignant melanoma of the eyelid. A report of eight cases and happening in most of these cases. However, a review of the literature. J Am Acad Dermatol. local recurrence is not rare also when melano1992;27(1):17–21. mas are completely excised [9]. Regional lymph 9. Vaziri M, Buffam FV, Martinka M, et  al. Clinicopathologic features and behavior of node metastases were also reported in patients cutaneous eyelid melanoma. Ophthalmology. with completely excised eyelid melanoma. In 2002;109(5):901–8. large series, local recurrence occurred in 21%, 10. Chan FM, O’Donnell BA, Whitehead K, et  al. nodal metastasis in 11%, and distant metastasis Treatment and outcomes of malignant melanoma of the eyelid: a review of 29 cases in Australia. in 4% [A]. Ophthalmology. 2007;114(1):187–92. 11. Wang JK, Liao SL, Jou JR, et  al. Malignant eyelid tumours in Taiwan. Eye. 2003;17(2):216–20. Mortality 12. Takamura H, Yamashita H. Clinicopathological analysis of malignant eyelid tumor cases at Yamagata University Hospital: statistical comparison of tumor The mortality rate from eyelid cutaneous melaincidence in Japan and in other countries. Jpn J noma varies significantly in various series, rangOphthalmol. 2005;49(5):349–54. ing from 7% to 58% [5, 7, 10]. The wide variation 13. Then SY, Malhotra R, Barlow R, et  al. Early cure rates with narrow-margin slow-Mohs surgery for in the reported mortality may reflect the relative periocular malignant melanoma. Dermatol Surg. rarity of primary melanoma confined to the skin 2009;35(1):17–23. of the eyelid, and the high mortality in a series 14. Kostopoulos E, Champsas G, Konofaos P, et al. Eyelid from a major tertiary cancer center is likely melanoma: our experience a propos of 23 cases. Ann Chir Plast Esthet. 2012;57(2):158–63. explained by a selection bias with more advanced cases treated in this setting [9]. The time from 15. Patel BC, Egan CA, Lucius RW, et  al. Cutaneous malignant melanoma and oculodermal melanocytodiagnosis to death ranges from 8  months to sis (nevus of Ota): report of a case and review of 14 years [31]. The late recurrence in a significant the literature. J Am Acad Dermatol. 1998;38(5 Pt 2):862–5. number of patients reinforces the need for long-­ 16. Demirci H, Johnson TM, Frueh BR, et  al. term follow-up of patients treated for cutaneous Management of periocular cutaneous melanoma eyelid melanoma. with a staged excision technique and permanent sections: the square procedure. Ophthalmology. 2008;115(12):2295–300. 17. Clark WH Jr, From L, Bernardino EA, et al. The hisReferences togenesis and biologic behavior of primary human malignant melanomas of the skin. Cancer Res. 1. Cook BE Jr, Bartley GB.  Treatment options and 1969;29(3):705–27. future prospects for the management of eyelid malig 18. Breslow A. Thickness, cross-sectional areas and depth nancies: an evidence-based update. Ophthalmology. of invasion in the prognosis of cutaneous melanoma. 2001;108(11):2088–100. Ann Surg. 1970;172(5):902–8. 2. Rodriguez-Sains RS, Jakobiec FA, Iwamoto 19. Harris MN, Shapiro RL, Roses DF. Malignant melaT.  Lentigo maligna of the lateral canthal skin. noma. Primary surgical management (excision and Ophthalmology. 1981;88(12):1186–92. node dissection) based on pathology and staging. 3. Batsakis J. Tumors of the head and neck. Baltimore: Cancer. 1995;75(2 Suppl):715–25. Williams and Wilkins; 1974. 20. Harish V, Bond JS, Scolyer RA, et  al. Margins of 4. Naidoff MA, Bernardino VB, Clark WH. Melanocytic excision and prognostic factors for cutaneous eyelesions of the eyelid skin. Am J Ophthalmol. lid melanomas. J Plast Reconstr Aesthet Surg. 1976;82(3):371–82. 2013;66:1066–73.

melanoma is not associated with local, regional, or distant recurrence [24].

7  Eyelid Tumors: Cutaneous Melanoma 21. Malhotra R, Chen C, Huilgol S, et  al. Mapped serial excision for periocular lentigo maligna and lentigo maligna melanoma. Ophthalmology. 2003;110(10):2011–8. 22. Boulos PR, Rubin PA. Cutaneous melanomas of the eyelid. Semin Ophthalmol. 2006;21(3):195–206. 23. Esmaeli B, Youssef A, Naderi A, et  al. Margins of e­xcision for cutaneous melanoma of the eyelid skin: the Collaborative Eyelid Skin Melanoma Group report. Ophthal Plast Reconstr Surg. 2003;19(2):96–101. 24. Glat P, Longaker M, Jelks EB, et al. Periorbital melanocytic lesions: excision and reconstruction in 40 patients. Plast Reconstr Surg. 1998;102(1):19–27. 25. Yin VT, Warneke CL, Merritt HA, et al. Number of excisions required to obtain clear surgical margins and prognostic value of AJCC T category for patients with eyelid melanoma. Br J Ophthalmol. 2014;98:1681–5.

69 26. Stanowsky A, Krey HF, Kopp J, et al. Irradiation of malignant eyelid melanoma with Iodine-125 plaque. Am J Ophthalmol. 1990;110(1):44–8. 27. Elia MD, Lally SE, Hanlon AM, et al. Periocular melanoma in situ treated with imiquimod. Ophthalmic Plast Reconstr Surg. 2016;32:371–3. 28. Sanlorenzo M, Vujic I, Posch C, et  al. Melanoma immunotherapy. Cancer Biol Ther. 2014;15:665–74. 29. Barker CA, Postow MA.  Combinations of radiation therapy and immunotherapy for melanoma: a review of clinical outcomes. Int J Radiat Oncol Biol Phys. 2014;88:986–97. 30. Pfeiffer ML, Ozgur OK, Myers JN, et  al. Sentinel lymph node biopsy for ocular adnexal melanoma. Acta Ophthalmol. 2017;95:e323–8. 31. Esmaeli B, Wang B, Deavers M, et al. Prognostic factors for survival in malignant melanoma of the eyelid skin. Ophthal Plast Reconstr Surg. 2000;16(4):250–7.

8

Adnexal Tumors Martina C. Herwig-Carl and Karin U. Loeffler

Introduction Eyelid adnexal tumors are frequent and comprise a large variety of different entities because the lid is rich in adnexal structures such as hairs (lashes) and glands. Overall, benign adnexal lesions of the eyelids are much more frequent than the malignant lesions [1–3]. In a series of 864 eyelid lesions that were biopsied, 82% were benign [1]. It is reassuring to note that the accuracy of clinically suspected malignant eyelid tumors is reported in the 90% range [1, 2]. Amongst benign lesions of the eyelid, adnexal tumors are frequent and display a variety of clinical as well as histologic features. Most commonly, they originate from sweat glands or hair follicles. Malignant neoplasms are rare but can occur, and excision and histopathologic evaluation are therefore recommended even for less suspicious tumors (Box 8.1).

M. C. Herwig-Carl (*) Department of Ophthalmology, University Clinic Bonn, Bonn, NRW, Germany e-mail: [email protected]

Box 8.1

• Eyelid adnexal tumors are frequent and comprise a large variety of different entities. • Most commonly these lesions arise from sweat glands or hair follicles. • Histology can provide further information with regard to the origin of the lesion and its dignity.

Etiopathogenesis The eyelid adnexal tumors may be classified as cystic lesions as well as benign and malignant tumors arising from sweat glands, hair follicles, sebaceous glands, and accessory lacrimal glands (Table 8.1). All glands can, particularly in cases of duct obstruction, lead to retention cysts. Epidermal inclusion cysts and epidermoid cysts may occur following trauma, surgery, and inflammatory processes. Otherwise, the precise etiology of most adnexal tumors of the eyelids is still unknown.

K. U. Loeffler Department of Ophthalmology, Division of Ophthalmic Pathology, University Clinic Bonn, Bonn, NRW, Germany © Springer Nature Switzerland AG 2019 J. Pe’er et al. (eds.), Clinical Ophthalmic Oncology, https://doi.org/10.1007/978-3-030-06046-6_8

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Table 8.1  Classification of eyelid adnexal tumors Types Cystic lesions

Sweat gland tumors

Subtypes Benign

Benign

Malignant

Hair follicle tumors

Benign

Epidermal inclusion cyst Retention cyst Trichilemmal cyst Apocrine hidrocystoma Eccrine hidrocystoma Syringoma Eccrine spiradenoma Pleomorphic adenoma Syringocystadenoma papilliferum Sweat gland adenocarcinoma Mucinous sweat gland adenocarcinoma Apocrine gland adenocarcinoma Trichoepithelioma Trichofolliculoma Trichoadenoma Trichilemmoma Pilomatrixoma Carcinoma of hair follicles Pilomatrix carcinoma Sebaceous gland hyperplasia Sebaceous gland adenoma Sebaceous epithelioma Nevus sebaceous of Jadassohn Sebaceous epithelioma Sebaceous gland carcinoma

Treatment, Follow-Up, and Prognosis Management is similar in the majority of these tumors; benign lesions are excised for histologic confirmation, and malignant tumors are removed surgically with a tumor-free margin confirmed by histopathologic evaluation. Follow-up and the prognosis depend on the dignity and on the  – extremely rare – development of metastases.

Cystic Lesions  pidermal Inclusion Cysts or E Epidermoid Cysts

Epidermal inclusion cysts or epidermoid cysts usually occur as smooth dome-shaped nodules of varying size (Fig.  8.1a), frequently revealing a Malignant punctum or pore. Occasionally, they appear pigmented. The characteristic feature is a cystic space filled with keratin, lined by regular keratinSebaceous Benign izing stratified squamous epithelium (Fig. 8.1b). gland tumors In the case of keratin extrusion after cyst rupture, a marked inflammatory reaction can develop. Milia are miniature variants of epidermal cysts. Histologically, comedonal cyst is similar to an epidermoid cyst in that the lining consists of Malignant keratinizing stratified squamous epithelium. Clinically, a comedonal cyst is characterized as “blackhead” (comedo with opening onto the surface) or “whitehead” (comedo with blocked opening). Clinical Findings A “sebaceous” cyst is a clinical misnomer, as, Benign lesions usually respect the anatomical despite the yellowish color of many cysts, histostructures and occur as slowly growing, well-­ logic findings do not qualify any of these lesions confined tumors with a smooth surface. As with as sebaceous. Clinically, the term is used most all malignant tumors, clinical symptoms include often for epidermoid or trichilemmal cyst. progressive growth, recurrence after incomplete excision, infiltrative growth, and destruction of adjacent tissue (loss of eyelashes). Ulceration Retention Cysts and hemorrhage can be present in advanced stages. Pain is an uncommon presenting feature Retention cysts can develop from all glands with in this location. the sudoriferous cyst, originating from sweat

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a

Trichilemmal (Pilar) Cysts Trichilemmal (pilar) cysts occur frequently in the scalp and appear as intradermal yellowish-­smooth intradermal swelling. The cyst lining is composed of basophilic cells surrounded by a rim of fibrous tissue. Toward the lumen the cells develop into squamous epithelium with pale and fairly high keratocytes that abruptly turn into keratin without a granular layer. Sometimes calcification occurs, and often cholesterol clefts are seen.

b

Sweat Gland Tumors Benign Tumors

c

Fig. 8.1  Epidermoid cyst. Yellowish dome-shaped lesion at the lower eyelid (a). The cyst is filled with keratin (b) and lined by a keratinized squamous epithelium (c)

glands, as the most frequent type. The typical lining consists of a layer of nonkeratinizing glandular epithelium and a thin layer of myoepithelial cells.

There are two types of sweat glands: eccrine and apocrine. Eccrine sweat glands are widely distributed in the body, and each gland consists of a single duct with a coiled deeper component [4]. By contrast, the apocrine sweat glands are limited to the special regions such as axilla, nipple, external ear, external genitalia, and the eyelids [4]. The apocrine glands and their ductal openings are closely associated with eyelashes [5]. Apocrine hidrocystoma and eccrine hidrocystoma represent the majority of the benign sweat gland tumors. In contrast to apocrine hidrocystoma, the eccrine hidrocystoma does not involve the eyelid margin. This is due to the fact that the eccrine sweat glands are distributed throughout the eyelid skin and are not confined to the eyelid margin unlike the apocrine glands [5].

Apocrine Hidrocystoma Apocrine hidrocystoma (cystadenoma, apocrine tubular adenoma, cyst of Moll) is usually a solitary nodule affecting mostly the head (cheek) or neck in middle-aged people of either sex. It presents as a translucent or bluish-black nodule up to about 1  cm in diameter involving the eyelid m ­ argin (Fig.  8.2a) [6]. In rare instances, it can occur as  multiple lesions [7, 8] and can be a feature of  Schopf-Schulz-Passarge syndrome [8, 9]. Histopathology reveals an unilocular or

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a

b

c

Fig. 8.2  Apocrine hidrocystoma. Note bluish color of the cystic lesion involving the eyelid margin (a). Histology shows cyst lined by a single to double layer of epithelial cells, surrounded by flattened myoepithelial cells. Proliferations of the epithelial lining are characteristic. Typical decapitation secretion is also found (b). Note focal epithelial proliferation (c)

­ ultilocular cystic space (Fig. 8.2b) that is lined m by a single or double layer of epithelial cells,

M. C. Herwig-Carl and K. U. Loeffler

s­ urrounded by an outer layer representing myoepithelial cells, while the inner layer frequently shows the typical decapitation secretion. In some areas, epithelial proliferations can be found (Fig. 8.2c).

Eccrine Hidrocystoma A typical eccrine hidrocystoma of the eyelid manifests in an adult as a solitary clear cystic lesion (Smith and Chernosky type) [10], although cases with simultaneous bilateral involvement (Robinson type) [11] have also been reported (Fig.  8.3a). The tumor is usually located along the medial or lateral aspect of the eyelid. On average, eccrine hidrocystoma measures 4 mm in the largest dimension, and it is rare for them to be larger than 10 mm [12]. Histologically, this tumor probably just represents a markedly dilated sweat gland duct with a presumably functional pathogenesis (Fig.  8.3b). Myoepithelial cells and decapitation secretion are absent (Fig. 8.3c). Syringoma Syringomas are common lesions on the upper eyelids, especially in females. They usually present as multiple small asymptomatic nodules (2–3 mm) but show a wide variety of clinical pictures (Fig. 8.4a) [13]. Histology shows interconnecting eccrine ducts and strands, lined by two layers of flattened cuboidal cells and sometimes giving rise to the characteristic tadpole configuration (Fig.  8.4b). Intracellular glycogen accumulation can cause a clear cell variant. Eccrine Spiradenoma Eccrine spiradenomas are uncommon tumors presenting as a mostly tender or painful subcutaneous nodule of fairly characteristic histology. Sharply demarcated aggregations of basaloid cells without connection to the dermis are arranged in a rosette-like fashion. Two types of tumor cells can be distinguished: the more peripheral small basophilic cells with round and hyperchromatic nuclei and the more central cells with larger oval nuclei and a pale-staining eosinophilic cytoplasm. Due to a rich vascular supply, this tumor can resemble an angioma, hemangiopericytoma, or glomus tumor.

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a

b

c

Fig. 8.3  Eccrine hidrocystoma. Note the gap between the tumor and the eyelid margin (a). There is the absence of papillary projections into the cystic cavity (b). The lining

a

cuboidal epithelium is double layered and the cells lack decapitation (c)

b

Fig. 8.4  Syringoma. Multiple syringomas of the lower eyelid in an older woman (a). The histopathology shows interconnecting eccrine ducts and stands which may present in a comma-shaped fashion (b)

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 leomorphic Adenomas (Benign P Mixed Tumor) Pleomorphic adenomas (benign mixed tumor) usually occur in the lacrimal or salivary glands but can also occur in accessory lacrimal glands of the eyelid. This lesion presents as a slowly growing either firm or cystic subcutaneous nodule, usually solitary and asymptomatic. Histologically, it is multilobulated and composed of a mixture of epithelial glandular elements embedded in myxoid stroma [14]. The stromal component can become very prominent, sometimes exhibiting a chondroid (pseudocartilaginous) and/or hyalinized appearance [15]. Syringocystadenoma Papilliferum Syringocystadenoma papilliferum is usually a solitary lesion that presents as a grey to dark-­brown papillary or warty excrescence which is clinically often mistaken for basal cell carcinoma or cyst [16]. Although it can grow in an endophytic or exophytic fashion, histopathology characteristically shows superficially located papillae communicating with duct-like structures in the deeper aspect. The lining consists of the typical doublelayered epithelium with flattened myoepithelial cells at the outer zone and tall columnar cells at the inner zone [17]. Further entities such as eccrine acrospiroma, eccrine cylindroma, eccrine spiradenocylindromas, and apocrine adenomas exist.

Malignant Tumors  weat Gland Adenocarcinomas S (Malignant Syringoma) Sweat gland adenocarcinomas (malignant syringoma) most frequently affect the nasolabial and periorbital region and present nonspecifically as a slowly growing plaque-like lesion, sometimes associated with hyperkeratosis [18]. Typically, the margins are not well delineated, and sometimes pain can be present due to perineural infiltration. Histology shows various features including small- to medium-sized squamous microcysts, solid strands of cells with ductular lumina, and small solid infiltrative strands, all embedded in a dense fibrous stroma.

M. C. Herwig-Carl and K. U. Loeffler

 ucinous Sweat Gland M Adenocarcinoma Mucinous sweat gland adenocarcinoma is rare and shows a predilection for the eyelid and presents as a slowly growing flesh-colored, erythematous, or bluish nodule [19]. It is locally aggressive and frequently recurs, but distant metastases are uncommon. Histology shows islands of tumor cells embedded in an abundant pool of mucin, separated by fibrous septae. The tumor cells are cuboidal with a pink-staining, sometimes vacuolated cytoplasm and round nuclei. Often a glandular differentiation is present, and sometimes light- and dark-cell forms can be distinguished. Immunohistochemistry supports an eccrine derivation.  pocrine Gland Adenocarcinoma A (Carcinoma of the Glands of Moll) Apocrine gland adenocarcinoma (carcinoma of the glands of Moll) is rare and most documented cases have affected the axilla. Fewer than 10 cases have been described to arise from the glands of Moll in the eyelid [20]. The clinical appearance is of a reddish cystic nodular lesion located at the lid margin with a smooth surface (Fig. 8.5a). The tumor cells reveal a variably glandular, papillary, or diffuse growth, sometimes with cyst formation and necrosis, and decapitation secretion is a typical feature (Fig. 8.5b). Occasionally, intracytoplasmic diastase-­ resistant, periodic acid-Schiff-positive granules, and intracytoplasmic iron can be demonstrated while glycogen is negative. Normal apocrine glands are often found in close proximity to the tumor, and occasionally a preexisting apocrine adenoma may be evident. Since primary cutaneous apocrine carcinoma is indistinguishable from metastatic mammary ductal apocrine carcinoma, a careful breast assessment should be advised especially in cases where the diagnosis is questionable [21].

Hair Follicle Tumors Benign Tumors Trichoepithelioma Trichoepithelioma is a hamartomatous lesion that may be solitary, multiple, or even familial [22].

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a

b

Fig. 8.5  Carcinoma of the glands of Moll in the eyelid. A reddish cystic nodular lesion located at the lid margin (a). Histologically, there is a papillary growth of tumor cells with mitotic figures and atypia (b)

The typical histologic appearance shows numerous horn cysts, partially within nests of basaloid cells that are sometimes difficult to distinguish from basal cell carcinoma. There can be continuity with the epidermis while ulceration is exceedingly rare. In trichoepithelioma, however, the perilobular connective tissue is more conspicuous and is frequently associated with the formation of papillary mesenchymal bodies [23]. Occasionally, a foreign body giant cell reaction to free keratin and calcification is seen. Trichoepithelioma shows less follicular differentiation than trichofolliculoma [24].

Trichofolliculoma Trichofolliculoma is a hamartoma presenting as a single dome-shaped papule with a central pore. Characteristic is the presence of one or more silky white threadlike hairs growing out of this opening [25]. A wide age range is affected, although lesions are very rare in children. Histologically, this tumor consists of a cystic cavity (dilated hair follicle) lined by stratified squamous epithelium usually continuous with the surface epithelium. Arising from its wall are numerous hair follicles. Abortive pilar differentiation, small primitive sebaceous acini, keratocysts, stromal granulomatous inflammation surrounding hair shaft fragments, and focal calcification are additional features. A variant of trichofolliculoma with numerous additional sebaceous glands is called sebaceous trichofol-

liculoma. A trichoepithelioma with prominent desmoplastic stroma is categorized as desmoplastic trichoepithelioma.

Trichoadenoma Trichoadenoma is a rare tumor that occurs as a solitary asymptomatic soft or firm nodule of varying size and yellowish or erythematous color [26]. Under a normal epidermis, there is a well-­ defined fibroepithelial tumor composed of keratinous cysts and a conspicuous fibrovascular stroma. The cysts are lined by keratinizing epithelium including a granular layer. Sometimes solid epithelial islands are also present, but evidence of hair follicle formation is lacking. Trichilemmoma Trichilemmoma may be solitary or multiple and presents as a small warty or smooth skin-colored papule on the face of older adults (Fig. 8.5) [27]. Solitary trichilemmoma represents a proliferation of the follicular outer root sheath with close-­ set lobules connecting with the epidermis. There is usually peripheral nuclear palisading, but pleomorphism and mitoses tend to be absent. Intracellular glycogen can result in a conspicuous clear cell component. Another typical feature is a dense PAS-positive mantle surrounding individual tumor lobules. A variant with marked keratinization, squamous eddies, and surface hyperkeratosis and parakeratosis is called keratinizing trichilemmoma [24]. Associated with the

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presence of multiple trichilemmomas is the rare autosomal dominant condition called Cowden’s (multiple hamartoma) disease [28].

 ilomatrixoma (Calcifying Epithelium P of Malherbe) Pilomatrixoma (calcifying epithelium of Malherbe) usually presents as a solitary lesion but can rarely be part of an autosomal dominantly inherited disorder or a systemic disease such as dystrophia myotonia or Gardner’s syndrome [29]. It is a slowly growing hard nodule of bluish or reddish tint and frequently located subcutaneously beneath the eyebrow (Fig.  8.6a). Most often teenagers and older adults in the sixth and seventh decades are affected [30]. Histology reveals a well-circumscribed tumor consisting of a

two different cell populations: small basophilic basaloid cells and the characteristic and diagnostic pale-pinkish ghost cells (Fig. 8.6b). Frequently, calcification and a foreign body giant cell reaction are encountered, and occasionally melanin pigment is found. Even bone formation and amyloid deposition may be features. Mitoses are seen in early lesions but are not abnormal and simply indicate a rapid growth phase (Fig. 8.7) [31].

Malignant Tumors  arcinoma of Hair Follicles C (Trichilemmal Carcinoma) Carcinoma of hair follicles (trichilemmal carcinoma) is a rare tumor that is found predominantly

b

c

Fig. 8.6  Trichilemmoma of the lower eyelid. A solitary papule is located (clinically suspicious for basal cell carcinoma) at the eyelid margin of an older lady (a). The lesion shows a lobular architecture, peripheral pallisading,

d

and a surrounding hyline membrane. Adjacent to the lesion are hair follicles (b). The cells show a clear cell component (c). Sclerotic stroma is also occasionally present (d)

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a

b

Fig. 8.7  Pilomatrixoma. Bluish-reddish nodule on the upper lid (a). Histology shows an epithelioid island surrounded by pinkish ghost/shadow cells and inflammation (b)

a

b

Fig. 8.8  Sebaceous gland hyperplasia. Yellowish papule with a central umbilication (a). The histologic picture shows conglomerates of regular sebaceous glands (b)

on sun-exposed skin of the elderly. The clinical presentation ranges from papule or a nodule to plaque that often ulcerates. Usually, the lesion is erythematous or flesh colored and measures between 5 and 20 mm in diameter. Despite a histologically worrying picture, recurrences and metastases are absent.

Sebaceous Gland Tumors Benign Tumors

 ebaceous Gland Hyperplasia S Sebaceous gland hyperplasia usually presents as a yellowish umbilicated papule 1–2 mm in size on the face of older adults. Clinically, it can be misPilomatrix Carcinomas taken for basal cell carcinoma. Histopathologically, This rare tumor has been described in middle-­ regular mature but hyperplastic sebaceous glands aged patients [32]. However, only a few cases are seen that are situated rather superficially in the have been observed in the ocular adnexa [33]. dermis while the epidermis is normal (Fig. 8.8).

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 ebaceous Gland Adenoma S Sebaceous gland adenomas are rare and present as tan, yellow, or reddish papules/nodules about 5 mm in diameter, most frequently located on the face of older people (mean age: 60  years). Clinically, they can easily be misdiagnosed as basal cell carcinoma. Sebaceous gland adenoma in a younger person can be an indication for the Muir-Torre syndrome (Chap. 11) [34]. Sebaceous Epithelioma/Sebaceoma Eyelid sebaceous epithelioma, or sebaceoma, is a rare entity [35]. It clinically appears as a nodular tumor, e.g., on the eyelid margin [36]. Histologically basaloid cells and vacuolated sebaceous cells without cellular atypia are found. Cells with sebaceous differentiation can be highlighted immunohistochemilly by adipophilin staining. Sebaceomas can be also associated with Muir-Torre syndrome [37]. Some authors consider this lesion a variant of basal cell carcinoma, i.e., a basal cell carcinoma with sebaceous differentiation [38].  evus Sebaceous of Jadassohn N Nevus sebaceous of Jadassohn is a complex choristoma comprising abnormalities of the hair follicles, sweat glands, sebaceous glands, and epidermis [39]. All of these tissues can proliferate and can constitute the major part of the tumor. Malignant transformation of any of the components is possible, with basal cell carcinoma being the most frequent [40].

Malignant Tumors  ebaceous Gland Carcinoma S Sebaceous gland carcinoma is covered in a separate chapter (Chap. 6).

References 1. Kersten RC, Ewing-Chow D, Kulwin DR, et al. Accuracy of clinical diagnosis of cutaneous eyelid lesions. Ophthalmology. 1997;104(3):479–84. 2. Margo CE. Eyelid tumors: accuracy of clinical diagnosis. Am J Ophthalmol. 1999;128(5):635–6.

M. C. Herwig-Carl and K. U. Loeffler 3. Deprez M, Uffer S.  Clinicopathological features of eyelid skin tumors. A retrospective study of 5504 cases and review of literature. Am J Dermatopathol. 2009;31(3):256–62. 4. Warwick R, Williams PL.  Gray’s anatomy. 35th ed. Edinburgh: Longman Group Ltd; 1973. p. 1168–9. 5. Warwick R.  Eugene Wolf’s anatomy of the and orbit. 7th ed. London: H.K. Lewis & Co. Ltd; 1976. p. 195–7. 6. Smith JD, Chernosky ME.  Apocrine hidrocystoma (cystademnoma). Arch Dermatol. 1974;109(5):700–2. 7. Sacks E, Jakobiec FA, McMillan R, et  al. Multiple bilateral apocrine cystadenomas of the lower eyelids. Light and electron microscopic studies. Ophthalmology. 1987;94(1):65–71. 8. Alessi E, Gianotti R, Coggi A.  Multiple apocrine hidrocystomas of the eyelids. Br J Dermatol. 1997;137(4):642–5. 9. Verplancke P, Driessen L, Wynants P, et al.  The Schopf-Schulz-Passarge syndrome. Dermatology. 1998;196(4):463–6. 10. Smith JD, Chernosky ME.  Hidrocystomas. Arch Dermatol. 1973;108(5):676–9. 11. Robinson R.  Hidrocystoma. J Cutan Genitourinary Dis. 1893;11:293–303. 12. Singh AD, McCloskey L, Andrew Parsons M, et  al. Eccrine hidrocystoma of the eyelid. Eye. 2005;19:77–9. 13. Lee SJ, Cho S, Cho SB. Syringomas versus sebaceous gland prominence of the eyelids. J Cosmet Laser Ther. 2011;13(3):130–1. 14. Alyahya GA, Stenman G, Persson F, et al. Pleomorphic adenoma arising in an accessory lacrimal gland of Wolfring. Ophthalmology. 2006;113(5):879–82. 15. Jordan DR, Nerad JA, Patrinely JR.  Chondroid syringoma of the eyelid. Can J Ophthalmol. 1989;24(1):24–7. 16. Barbarino S, McCormick SA, Lauer SA, et al. Syringocystadenoma papilliferum of the eyelid. Ophthalmic Plast Reconstr Surg. 2009;25(3):185–8. 17. Behera M, Chatterjee S.  A case of syringocystadenoma papilliferum of eyelid with literature review. Indian J Ophthalmol. 2015;63(6):550–1. 18. Esmaeli B, Ramsay JA, Chorneyko KA, et  al. Sclerosing sweat-duct carcinoma (malignant syringoma) of the upper eyelid: a patient report with immunohistochemical and ultrastructural analysis. Ophthal Plast Reconstr Surg. 1998;14(6):441–5. 19. Boynton JR, Markowitch W Jr. Mucinous eccrine carcinoma of the eyelid. Arch Ophthalmol. 1998;116(8):1130–1. 20. Paridaens D, Mooy CM. Apocrine sweat gland carcinoma. Eye (Lond). 2001;15(Pt 2):253–4. 21. Hunold AC, Herwig MC, Holz FG, et al. Pigmented tumour of the eyelid with unexpected findings. Case Rep Pathol. 2012;2012:471368. 22. Aurora AL. Solitary trichoepithelioma of the eyelid. Indian J Ophthalmol. 1974;22(2):32–3. 23. Brooke JD, Fitzpatrick JE, Golitz LE.  Papillary mesenchymal bodies: a histologic finding useful in

8  Adnexal Tumors differentiating trichoepitheliomas from basal cell carcinomas. J Am Acad Dermatol. 1989;21(3 Pt 1):523–8. 24. Tellechea O, Cardoso JC, Reis JP, et al. Benign follicular tumors. An Bras Dermatol. 2015;90(6):780–96; quiz 97–8. 25. Carreras B Jr, Lopez-Marin I Jr, Mellado VG, et al. Trichofolliculoma of the eyelid. Br J Ophthalmol. 1981;65(3):214–5. 26. Shields JA, Shields CL, Eagle RC Jr. Trichoadenoma of the eyelid. Am J Ophthalmol. 1998;126(6):846–8. 27. Hidayat AA, Font RL. Trichilemmoma of eyelid and eyebrow. A clinicopathologic study of 31 cases. Arch Ophthalmol. 1980;98(5):844–7. 28. Bardenstein DS, McLean IW, Nerney J, et al. Cowden’s disease. Ophthalmology. 1988;95(8):1038–41. 29. Boniuk M, Zimmerman LE.  Pilomatrixoma (benign calcifying epithelioma) of the eyelids and eyebrow. Arch Ophthalmol. 1963;70:399–406. 30. Yap EY, Hohberger GG, Bartley GB. Pilomatrixoma of the eyelids and eyebrows in children and adolescents. Ophthalmic Plast Reconstr Surg. 1999;15(3):185–9. 31. Herwig MC, Vogel A, Holz FG, et al. Pilomatrixoma of the ocular adnexae: clinical and histologic analysis (13 cases). Klin Monatsbl Augenheilkd. 2009;226(5):404–8.

81 32. Jones C, Twoon M, Ho W, et  al. Pilomatrix carcinoma: 12-year experience and review of the literature. J Cutan Pathol. 2018;45(1):33–8. 33. Cahill MT, Moriarty PM, Mooney DJ, et al. Pilomatrix carcinoma of the eyelid. Am J Ophthalmol. 1999;127(4):463–4. 34. Singh AD, Mudhar H, Bhola R, et  al. Sebaceous adenoma of the eyelid in Muir-Torre syndrome. Arch Ophthalmol. 2005;123:562–5. 35. Mittal R, Tripathy D. Sebaceoma of the eyelid: a rare entity. Can J Ophthalmol. 2014;49(3):e78–80. 36. Yonekawa Y, Jakobiec FA, Zakka FR, et al. Sebaceoma of the eyelid. Ophthalmology. 2012;119(12):2645 e1–4. 37. Abbas O, Mahalingam M. Cutaneous sebaceous neoplasms as markers of Muir-Torre syndrome: a diagnostic algorithm. J Cutan Pathol. 2009;36(6):613–9. 38. McKee PH. Sebaceous epithelioma pathology of the skin with clinical correlations. London: Mosby; 1996. 39. Traboulsi EI, Zin A, Massicotte SJ, et  al. Posterior scleral choristoma in the organoid nevus syndrome (linear nevus sebaceus of Jadassohn). Ophthalmology. 1999;106(11):2126–30. 40. Cribier B, Scrivener Y, Grosshans E. Tumors arising in nevus sebaceus: a study of 596 cases. J Am Acad Dermatol. 2000;42(2 Pt 1):263–8.

9

Stromal Tumors Geeta K. Vemuganti and Santosh G. Honavar

Fibrous Tissue Tumors Fibrous tissue tumors comprise several benign lesions (fibroma, keloid, nodular fasciitis, and proliferative fasciitis), fibromatosis, and a malignant tumor (fibrosarcoma).

Fibromas Clinical Features Fibromas are rare tumors that could be congenital, developmental, or acquired [1]. Congenital fibroma presents as a diffusely infiltrative lower eyelid nodule that recurs following local excision. The histologic and electron-microscopic features point to the hamartomatous origin of this tumor with partial myofibroblastic differentiation [1]. Developmental fibroma has a propensity for involvement of the infraorbital region and lower eyelid and is diffusely infiltrative. Recurrence often follows local excision [2].

G. K. Vemuganti (*) School of Medical Sciences, University of Hyderabad, Hyderabad, Telangana, India e-mail: [email protected] S. G. Honavar Department of Ophthalmic Plastic Surgery and Ocular Oncology, Centre for Sight, Hyderabad, Telangana, India

Histopathologic Features A typical fibroma is sparsely cellular with prominent collagen bundles separated by compressed fibroblasts. Rarely it can present as multiple lesions in the eyelid and face [3]. A characteristic feature is the lack of inflammation without zonal pattern. Pleomorphic fibroma is a variant with multinucleate giant cells.

Eyelid Keloids Eyelid keloids are hypertrophic cutaneous scars or nodular outgrowths on the surface or the margin of the eyelid that follow surgical intervention or trauma and could occur de novo. Rarely could keloids arise from the tarsus and simulate a tumor [4].

Nodular Fasciitis Nodular fasciitis is, in general, a relatively common benign reactive fibroblastic proliferation of the soft tissues with acute manifestations that progress rapidly.

Clinical Features Nodular fasciitis of the eyelid is rare and only case reports have been published. It presents with a solitary subcutaneous nodule [5]. Although excisional biopsy is curative, the nodules may often resolve spontaneously [5].

© Springer Nature Switzerland AG 2019 J. Pe’er et al. (eds.), Clinical Ophthalmic Oncology, https://doi.org/10.1007/978-3-030-06046-6_9

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Histopathologic Features Nodular fasciitis is an infiltrative lesion consisting of proliferation of immature and activated fibroblasts, with slit-like spaces between the cells. Foci of myxoid change, endothelial proliferation, lipid-laden macrophages, multinucleated giant cells, and acute and chronic inflammatory cell infiltration are also seen. Ultrastructurally, the cells show characteristic features of myofibroblasts. Clinical presentation and histologic appearance of a pleomorphic spindle cell neoplasm with frequent mitotic figures may raise the concern of a malignant neoplasm and lead to unnecessary and overly aggressive therapy. The lesion is therefore called pseudosarcomatous fasciitis.

G. K. Vemuganti and S. G. Honavar

a

b

Fibromatosis Fibromatosis could be juvenile or adult onset. Juvenile fibromatoses are a distinct group of benign fibrous lesions with aggressive clinical behavior and predilection to occur in the lower eyelid and inferior orbit [6]. Infiltration of the local tissues including extraocular muscle and periosteum results in incomplete removal and local recurrence (Fig. 9.1).

Fibrosarcoma Fibrosarcoma is a highly malignant tumor that can be locally destructive and can metastasize.

Clinical Features It manifests as a rapidly progressive poorly circumscribed eyelid nodule or as a second malignant neoplasm in hereditary retinoblastoma survivors with or without prior radiotherapy [7]. Rarely, it could occur in children with local recurrences which could be managed conservatively. Wide surgical excision or orbital exenteration may minimize the risk of local tumor recurrence [7].

Fig. 9.1  Eyelid fibromatosis. A 6-month-old child with a tethering of the eyelid to a deeper firm mass in the superonasal aspect with consequent lagophthalmos (a). Histopathology examination shows infiltrating bundles of spindle cells with lobulated pattern in few areas diagnostic of fibromatosis (b, hematoxylin and eosin, original magnification ×200)

Histopathologic Features The lesion consists of closely packed cells that assume an interlacing woven herringbone pattern. The cells contain a vesicular nucleus with prominent nucleoli, tapering pointed ends with moderate mitotic activity.

Fibrohistiocytic Tumors Fibrohistiocytic tumors could be subclassified as benign (xanthelasma, xanthoma, dermatofibroma, xanthogranuloma, juvenile xanthogranuloma, reticulohistiocytoma), intermediate (atypical

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fibroxanthoma, dermatofibrosarcoma protuberans, angiomatoid fibrous histiocytoma), and malignant (malignant fibrous histiocytoma, malignant fibroxanthoma).

a

Xanthelasma Xanthelasma palpebrarum is a common bilateral subcutaneous lesion of the eyelid seen in normolipemic individuals and in those with primary hyperlipidemia (types II and III) or secondary hyperlipidemia (diabetes mellitus, biliary cirrhosis) [8]. It was found that alteration in apolipoprotein levels in patients with xanthelasma may predispose to cutaneous and systemic depositions of lipids, including atherosclerosis [9].

Clinical Features Xanthelasma manifests as a yellowish-tan soft plaque occurs in the inner canthus in middle-­ aged individuals (Fig.  9.2). Large nodular xanthelasma is called xanthoma or tuberous xanthoma, which has a known association with Erdheim–Chester disease. Acute-onset eruptive xanthoma occurs in patients experiencing a rapid rise in serum triglyceride levels. Management should include systemic evaluation for the causative etiology and excision or laser [10] or radiofrequency-­ assisted vaporization of large cosmetically unacceptable lesions [11].

b

Fig. 9.2 Xanthelasma. Bilateral yellowish placoid lesions clinically diagnostic of xanthelasma (a). Sheets of large, foamy lipid-laden cells on histopathology (b, hematoxylin and eosin, original magnification ×400)

Clinical Features Juvenile xanthogranuloma of the eyelid may be a part of systemic affection seen as multiple fleshy superficial eyelid nodules with or without coexisting conjunctival, iris, and orbital involvement. Histopathologic Features Microscopically, xanthelasma consists of lipid-­ The adult variant may be diffuse and associated laden macrophages in the superficial dermis, with bronchial asthma (Fig.  9.3) [12]. Juvenile xanthogranuloma is known to spontaneously around blood vessels, and adnexa. involute, thus qualifying for observation. Systemic corticosteroids are indicated in recalcitrant juvenile xanthogranuloma and as primary Xanthogranuloma therapy for the adult variant [12]. Extensive, cosXanthogranuloma is an idiopathic inflamma- metically disfiguring, and steroid-resistant tory granuloma with juvenile and adult variants lesions could be excised or treated with systemic chemotherapy or radiotherapy. [12, 13].

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a

recurrent pyogenic granuloma [14, 15]. Dermatofibrosarcoma protuberans, which manifests as a rapidly growing eyelid nodule, is considered an aggressive form of malignant fibrous histiocytoma. It has tendency for local invasion and is known to metastasize. The mainstay of treatment is complete surgical excision with wide margins. Because of risk of recurrence following excision, consideration should be given to histologic margin control and adjuvant radiotherapy [16].

b

Histopathologic Features Malignant fibrous histiocytoma differs from benign variant in exhibiting marked nuclear pleomorphism, high mitotic activity, pericytoma-like areas with foci of xanthoma cells, and multinucleated giant cells.

Lipomatous Tumors Lipoma, lipoma variants, and liposarcoma are the lipomatous tumors affecting the eyelid [17]. Fig. 9.3  Adult-onset xanthogranuloma presenting as a diffuse eyelid mass with a yellowish haze (a). Sheets of foamy histiocytes and classic Touton type of multinucleated giant cells with wreath-like arrangement of the nuclei on histopathology (b, hematoxylin and eosin, original magnification ×250)

Histopathologic Features Xanthogranuloma consists of monomorphic infiltrate of histiocytes, intermixed with lymphocytes and the classic Touton giant cell with a wreath-like arrangement of nuclei and peripheral clear zone.

Malignant Fibrous Histiocytoma Malignant fibrous histiocytoma is a pleomorphic soft tissue sarcoma that occurs rarely in the eyelid.

Clinical Features Malignant fibrous histiocytoma presents as a firm  subcutaneous mass, sometimes mimicking a

Lipoma and Lipoma Variants Lipoma could be congenital or acquired. Nasopalpebral lipoma–coloboma syndrome is an autosomal dominant syndrome characterized by congenital upper eyelid and nasopalpebral lipomas, upper and lower eyelid colobomas, telecanthus, and maxillary hypoplasia [18]. Lipoblastoma is an uncommon benign tumor of adipose tissue that occurs in infants and young children [19]. Intramuscular lipoma of the eyelid manifesting as a slowly growing globular lesion has been described in elderly individuals. Hibernoma is a variant of lipoma that contains embryonal brown fat and is relatively more vascular. If treatment is indicated for cosmetic and functional reasons, complete tumor excision is adequate.

Liposarcoma Primary liposarcoma is a rare orbital tumor that may involve the eyelid by local extension.

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Smooth Muscle Tumors

Nevus Flammeus (Port-Wine Stain)

Smooth muscle tumors of the eyelid are very rare and could be benign (leiomyoma, angiomyoma) [20] or malignant (leiomyosarcoma) [21].

Nevus flammeus is a diffuse congenital vascular malformation of the face, involving the periocular area and eyelid (Chap. 11).

Skeletal Muscle Tumors

Pyogenic Granuloma

Rhabdomyoma and rhabdomyosarcoma are the skeletal muscle tumors of the eyelid.

Papillary endothelial hyperplasia or “pyogenic granuloma” is the most common acquired vascular lesion of the eyelid. It is neither “pyogenic” nor “granuloma.”

Rhabdomyoma Rhabdomyoma is a benign tumor of the skeletal muscle and is seen in two forms. The adult form consists of well-differentiated large rounded or polygonal cells with abundant acidophilic cytoplasm containing lipid and glycogen. Some cells appear like spider cells and some may show cross striations. The fetal form is very cellular and consists of immature skeletal muscle fibers and primitive mesenchymal cells. One case of adult-onset rhabdomyoma attributed to chronic irritation by a prosthetic eye has been reported in the literature [22].

Rhabdomyosarcoma Rhabdomyosarcoma is primarily a malignant orbital tumor with eyelid involvement only in about 3% of cases [23].

Vascular Tumors Benign vascular tumors of the eyelid include nevus flammeus, papillary endothelial hyperplasia, capillary hemangioma, cavernous hemangioma, venous hemangioma, epithelioid hemangioma, arteriovenous malformation, and lymphangioma. Angiosarcoma, lymphangiosarcoma, and Kaposi’s sarcoma are the malignant vascular eyelid tumors.

Clinical Features Pyogenic granuloma occurs anywhere in the eyelid, as a rapidly growing, pedunculated reddish-­ pink mass with or without superficial ulceration and may easily bleed on touch (Fig. 9.4). It usually follows trauma or surgery. Local excision of the lesion is curative [24]. Histopathologic Features Pyogenic granuloma consists of exuberant mass of proliferating radiating capillaries and edematous stroma with mixed inflammatory infiltrates. Intravascular papillary endothelial hyperplasia is a rare form of “pyogenic granuloma” in which the angiomatous proliferation is confined entirely within the lumen of a vessel [25].

Capillary (Infantile) Hemangioma Capillary hemangioma of the eyelid is the most common vascular tumor of the eyelid in children (Fig. 9.5). It is usually congenital in origin and is often sporadic. Occasional reports of acquired capillary hemangiomas have been reported in adults. Newborns of mothers who have undergone amniocentesis and in premature infants are at a risk of developing capillary hemangioma [26]. The pathogenesis of this tumor is not well understood, but the affected infants have an increased urinary level of basic fibroblastic growth factor, a marker of angiogenesis. Familial

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b b

Fig. 9.5  Capillary hemangioma of the upper eyelid manifesting as a bright red, spongy, soft mass causing total ptosis (a). It resolved following treatment with intralesional triamcinolone injection (b)

Fig. 9.4  Pyogenic granuloma. The tarsal conjunctiva of the upper eyelid showing a vascular polypoidal reddish-­ pink mass with superficial ulceration (a). subcutaneous tissue and is bluish or blue-gray in Histopathologically, loose edematous stroma with surface color. necrosis, proliferating blood vessels, and mixed inflammatory infiltrates, characteristic of inflammatory granulation tissue, is present (b, hematoxylin and eosin, original Natural History Congenital capillary hemangioma grows rapidly magnification ×200)

congenital capillary hemangioma with autosomal dominant inheritance with incrimination of chromosome 5q has been reported [27].

Clinical Features Congenital capillary hemangioma usually manifests at birth or within the first months of life. There are two distinct clinical variants – superficial and deep. The superficial variant, better known as strawberry hemangioma, appears as a bright red to deep purple, lobulated, spongy, soft eyelid mass that typically blanches on the application of direct pressure and engorges when the infant cries or strains. Contiguous conjunctival and orbital extension is known to occur. The superficial variant is localized to the epidermis and dermis, whereas the deep variant lies in the

in size and reaches its final size by 6–12 months of age. It then becomes stable and slowly involutes by 4–7 years of age [28]. About 70% regress by the age of 7 years [28].

Histopathologic Features Histologically, capillary hemangioma of the eyelid consists of lobules of capillaries separated by sparse fibrous septae. The morphology of the lesion changes with age. An early immature lesion tends to have obliterated lumen with plump endothelial cells and occasional mitotic figures (Fig.  9.6), while in later stages the lumina increases and the endothelial cells get attenuated, with increasing fibrosis and fat infiltration. The lobular capillary hemangioma show repeating units of various sizes (lobules) consisting of CD34-positive, GLUT-1-negative endothelial cells and SMA-positive pericytes arranged in

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a

b

Fig. 9.6  An older child with a large red vascular mass in the upper eyelid (a) that was excised. Histopathology shows lobulated appearance with vascular channels lined

by plump endothelial cells. Note the presence of a few mitotic figures could be seen in proliferating lesions (b, hematoxylin and eosin, original magnification ×400)

macro- or micro-lobules. Some foci may exhibit ectatic vessels or diffuse nonlobular capillary proliferations [29].

Extensive lesions are treated with oral prednisolone 1–2  mg/kg body weight tapered over 4–6 weeks. Application of topical clobetasol propionate [29] and timolol maleate [30] may help. Intralesional steroid injection (Fig. 9.5) is mainly reserved for eyelid and anterior orbital lesions. Most lesions regress after 1–3 injections of triamcinolone or a combination of dexamethasone and triamcinolone injected at 6–8 weekly intervals [31]. The recommended dosage per injection is 6 mg/kg body weight equivalent of prednisolone. Although uncommon, reported complications of intralesional steroid injection include central retinal artery occlusion, eyelid depigmentation, fat atrophy, eyelid necrosis, and adrenal suppression [31]. Alternative treatment modalities include interferon, laser sclerotherapy, and excision of circumscribed anterior lesions (Fig. 9.6). In recent years several centers have reported the use of systemic β-blockers for the treatment of infantile hemangioma, with very promising results (Fig.  9.7) [32–34]. The dose that has been used is 0.5–2.0  mg/kg/day for several months, with significant reduction in the size of the hemangioma in all babies. Side effects such as bradycardia, hypotension, bronchospasm, hypoglycemia, and electrolyte disturbances have been reported, leading to a reduction in the dose of the drug. Topical timolol maleate 0.5% was also found to be effective [35].

Systemic Association In most instances, congenital capillary hemangioma is a sporadic condition, but approximately 20% of patients may manifest it as multiple tumors involving the cutaneous tissue elsewhere, central nervous system, liver, and gastrointestinal tract [26]. Systemic lesions, especially those found in association with Kasabach–Merritt syndrome, could aggressively proliferate and lead to hemorrhage, platelet consumption, disseminated intravascular coagulation, cardiac failure, and death [26]. Treatment The main ocular complications are amblyopia and strabismus. Amblyopia could be meridional because of induced astigmatism or because of stimulation deprivation secondary to mechanical ptosis. Because most lesions spontaneously regress, observation, refractive correction, and appropriate amblyopia management are the standard treatment. Active intervention is indicated if the lesion extensively involves the face or is ulcerated with episodes of bleeding and if there is mechanical ptosis with obscuration of pupillary axis or induced astigmatism with amblyopia.

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a

both clinical and histopathologic features with angiolymphoid hyperplasia with eosinophilia and may be clinically indistinguishable [38].

b

Histopathologic Features Cavernous hemangioma is composed of large dilated vascular channels filled with blood, hemosiderin-laden macrophages, scattered lymphoplasmacytic infiltrates, and secondary changes such as calcification, phlebolith, and fibrosis.

Arteriovenous Malformations

Fig. 9.7  Capillary hemangioma. A 10-month-old female with history of failed intralesional steroid injection. After pediatric cardiology examination, BP, EKG, and echocardiogram, propranolol was started at 1 mg/kg/day in three divided doses daily (a, 11/11/2010), with a blood glucose level and repeat blood pressure check after the first dose (blood pressure, taken in the left thigh 87/61; pulse 108; glucose 80; about 2 h after the first increased dose). One week later (11/18/2010), the dosage was doubled to 2 mg/ kg/day in three divided doses daily. BP, heart rate, and blood glucose were again checked about 2 h after the first increased dose. No additional testing was performed for increases above 2 mg/kg/day. Her dose was increased to 3 mg/kg/day (12/9/2010). After 3 months of treatment, the infantile hemangioma had shown marked regression (b, 2/10/11). The dose was then tapered to 1.5  mg/kg/day (4/13/2011), 1  mg/kg/day (5/25/2011), 0.5  mg/kg/day (6/15/2011), and finally discontinued on 7/1/2011. No regrowth of infantile hemangioma was observed

Cavernous Hemangioma Cavernous hemangioma of the eyelid is a rare, acquired condition and is generally seen in adults [36]. It may be associated with blue rubber bleb nevus syndrome [37].

Clinical Features The lesions are ill circumscribed and bluish in color and may undergo slow progression. Epithelioid hemangioma also known as angiolymphoid hyperplasia with eosinophilia occurs as a nodular lesion in the eyelid. Kimura disease, which is predominant in Asian population, shares

Arteriovenous malformations, as the name suggests, are communications between arteries and veins that bypass normal capillary beds. In contrast to arteriovenous fistulas, arteriovenous malformations are mainly congenital lesions with multiple large feeding arteries, a central nidus, and numerous dilated draining veins (Fig.  9.8). Rarely, arteriovenous malformations may follow trauma or surgery [39]. While surgical embolization or excision alone may be possible, a combined approach is considered ideal [39].

Lymphangioma Lymphangioma commonly manifests in the orbit rather than in the eyelid. Eyelid lesion generally represents the anterior extension of an orbital lymphangioma [40].

Angiosarcoma Angiosarcoma is an uncommon malignant vascular eyelid tumor. It appears as a raised, reddish-­ purple, or violaceous subcutaneous placoid lesion, tan-colored nodules or a mass that tends to ulcerate and bleed spontaneously or with excessive edema mimicking a Morbihan disease or periorbital hematoma [41–43]. Angiosarcoma most often develops de novo but may arise from preexisting benign vascular tumors such as nevus flammeus or irradiated lymphangioma. It is an

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a

b

Fig. 9.8  Arteriovenous malformation. A lobulated soft compressible upper eyelid lesion (a). Vascular channels of varying sizes including medium-sized feeder vessels on

histopathology (b, hematoxylin and eosin, original magnification ×200)

aggressive tumor that tends to recur locally and disseminate widely with a 5-year survival ranging from 12% to 29% [44], although patients with isolated eyelid involvement have a much better prognosis [45].

abnormally sensitive to high levels of cytokines seen in patients with AIDS [46]. Subsequent proliferation and additional mutation result in clinically apparent disease. Histopathologically, Kaposi’s sarcoma appears as a network of proliferating endothelial cells that forms slit-like spaces surrounded by spindle-shaped mesenchymal cells and collagen [46]. The tumor cells show immunoreactivity to endothelial markers CD31 and ERG (a subfamily of the ETS family transcription factors) and for human herpes virus HHV-8 [50].

Kaposi’s Sarcoma Kaposi’s sarcoma is a malignant vascular tumor that most often presents in the setting of association with acquired immunodeficiency syndrome (AIDS); it is the most common malignancy seen in patients with AIDS [46]. However, it can also occur in immunocompetent elderly males as well [47, 48]. The possibility of occult AIDS should be entertained in a young individual with an atypical hordeolum or avascular eyelid mass as Kaposi’s sarcoma sometimes mimics these ­common lesions and represents the initial presenting sign of AIDS [46, 49].

Clinical Features Kaposi’s sarcoma appears as a solitary or multifocal, circumscribed or diffuse smooth blue subcutaneous lesion. Histopathologic Features Infection by human herpes virus 8 possibly transforms normal mesenchymal cells to become

Treatment Improvement in immunological status and highly active antiretroviral therapy may result in spontaneous regression of Kaposi’s sarcoma. Treatment modalities include local methods such as excision, cryotherapy, and radiotherapy. Systemic chemotherapy is indicated for widespread disease [46]. Second-line paclitaxel given every 2  weeks has been reported to show complete response [51].

Perivascular Tumors Perivascular tumors of the eyelid are very rare and include benign or malignant hemangiopericytoma and glomus tumor.

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Neurogenic Tumors Neurogenic tumors of the eyelid include a variety of benign (neurofibroma, schwannoma, and neuroglial choristoma) and malignant tumors (malignant peripheral nerve sheath tumor and Merkel cell tumor).

Neurofibroma Neurofibroma of the eyelid could be plexiform, multifocal, localized, or solitary and constitute nearly 70% of the peripheral nerve sheath tumors of the oculoadenexal region [52].

Schwannoma Schwannoma (neurilemoma) is one of the common benign peripheral nerve sheath tumors that rarely grow on the eyelid. Clinically it appears as a slow-growing well-defined firm subcutaneous eyelid nodule that could simulate a large chalazion [53]. Solitary schwannoma lacks systemic association. Multiple lesions, however, are associated with neurofibromatosis type 1 [53].

Merkel Cell Tumor First described in 1972, Merkel cell tumor is an aggressive primary cutaneous neuroendocrine malignant neoplasm that arises from Merkel cells, which are specialized neuroendocrine receptors of touch located in the eyelid and conjunctiva [54, 55]. Recent studies have implicated polyomavirus in pathogenesis of Merkel cell carcinoma [56, 57]. A rare occurrence was reported in a patient of chronic rheumatoid arthritis who was treated with tumor necrosis factor (TNF) inhibitor injection (golimumab) for 6 months [58].

Clinical Features Merkel cell tumor is rare, aggressive neuroendocrine malignancy of the skin comprising 50%) • Free tarsal graft + myocutaneous advancement / unipedicle rotational flap • Periosteal strip + myocutaneous advancement flap • Hughes tarsoconjuctival flap + free skin graft or myocutaneous advancement flap

6-0 or 7-0 nylon or silk sutures in the skin. If insufficient anterior lamella remains, a full-­ thickness pentagonal wedge, including the anterior lamellar defect, may be excised with Westcott scissors. The tarsal borders should be sharp and perpendicular to the lid margin. The resulting full-thickness defect may then be closed primarily as described below.

Skin Graft For defects that are too large to close primarily, full-thickness skin grafts from hairless areas may be employed. Possible donor sites include the ipsilateral or contralateral upper eyelid, the preauricular or retroauricular skin, and less commonly the supraclavicular fossa and the upper inner arm. In general, split-thickness skin grafts

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are not recommended in eyelid reconstruction [2]. If a skin graft is obtained from the upper ­eyelid or retroauricular area, it must be thinned of subcutaneous fat and connective tissue. The graft is then trimmed to size and sutured to the edges of the defect with interrupted 7-0 nylon or silk sutures [9].

 llipse Sliding Flap E An elliptical sliding flap may also be used to close some anterior lamellar defects [10]. This flap, however, should not be used to reconstruct anterior lamellar defects near the lid margin because ectropion or retraction may be induced by excessive perpendicular tension. The ellipse should be oriented parallel to the relaxed skin tension lines. The long axis should be four times longer than the short axis, with the ellipse angle at approximately 30°. The flap is secured in two layers.  yocutaneous Advancement Flap M An ideal method to address a large anterior lamellar deficit is the myocutaneous advancement flap because it provides the best tissue match with an independent blood supply (Fig.  10.3). Incision lines should be oriented horizontally and blend within naturally occurring skin creases. Planes of dissection should be determined before the undermining is advanced past the lateral orbital rim [8, 9]. The flap consists of skin and muscle and is designed to advance medially to fill an anterior lamellar defect. The creation of a myocutaneous advancement flap begins with an infralash incision that extends laterally to the canthus and arches superiorly. The key component is a tension-bearing permanent suture (4-0 Prolene) at the zygoma or the lateral orbital rim; the flap is then closed in two layers. This technique provides an anterior lamella replacement with an inherent vascular supply.

Full-Thickness Eyelid Defect Primary Closure For small defects involving less than one-third of the lower eyelid margin, primary closure without lateral cantholysis is the best option. Primary lay-

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ered closure provides the best tissue match, a smooth lid margin, and a continuous eyelash line. If tension is present and precludes proper lid margin reapproximation, a lateral canthotomy with inferior cantholysis may be performed to yield 5–6 mm of medial advancement of the temporal eyelid margin [9, 10]. The first step requires trimming of the eyelid defect edges. The tarsal borders should be sharp and perpendicular to the lid margin. The tissue inferior to the tarsus is cut into a wedge, forming a pentagonal-shaped defect. Direct closure may be utilized if the borders of this defect can be reapproximated without excess tension; otherwise, a lateral cantholysis is needed. To perform a cantholysis, a 4–5 mm horizontal incision through the skin and orbicularis muscle is made from the lateral canthal angle toward the orbital rim. The tip of the Westcott scissors should be used to identify the lateral attachment of the lower lid, and the inferior crus of the lateral canthal tendon is cut by making a vertical incision. The most important step in primary closure of the pentagonal lid margin defect is precise approximation of the tarsal edges. Accurate vertical alignment provides most of the tension-­ bearing support of the wound. Following lid margin reapproximation and repair of the tarsal defect as outlined in Fig.  10.4, the anterior lamella is closed in two layers.

 emicircular Rotational Flap S A lateral semicircular rotational flap may be used to reconstruct up to two-thirds of a central lower lid defect if there is a sufficient temporal tarsal remnant. The temporal tarsal remnant and a myocutaneous flap are moved as a unit [9]. The first step is to outline a semicircle, approximately 20 mm in diameter, starting at the lateral canthal angle. The outline should arc superiorly and temporally, but not pass the lateral extent of the brow. In addition, a lateral canthotomy of the inferior crus is performed with the scissors extending to the inside of the orbital rim. The lateral lower lid and flap are moved medially until the lid margin defect may be covered and closed without tension. Once the defect is closed, the lateral canthus is reformed. Fixation of the lateral edge of the flap is needed to provide posterior and lateral vector

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a

b

c

d

e

Fig. 10.3  Myocutaneous advancement flap. A large anterior lamella deficit may be repaired with a myocutaneous advancement flap because it provides the best tissue match with an independent blood supply (a). A flap of sufficient size that allows for tension-free closure is dissected from the underlying tissue (b). Proper placement of a

tension-bearing permanent suture (4-0 Prolene) at the zygoma or the lateral orbital rim is important in securing the flap into position (c). Closure at the tip of the flap should be devoid of tension (d). The myocutaneous advancement flap with its inherent vascular supply now covers the anterior lamella defect (e)

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A. J. Rong et al. Meibomian Eyelashes gland orifice

Tarsus

Meibomian gland orifice

Tarsus

Meibomian gland orifice

a

b

Orbicularis muscle

c Fig. 10.4  Lid margin repair, full-thickness defect. The eyelid margin defect may be closed primarily if less than one-third of the margin is involved. An important step in primary closure of a full-thickness lid margin defect is the precise approximation of the tarsal edges. Accurate vertical alignment provides the tension-bearing support of the wound. Three interrupted 5-0 Vicryl sutures are placed at partial thickness through the tarsal plate (a). The lid mar-

gin is closed with a vertical mattress suture using 6-0 silk suture which provides proper anteroposterior alignment. A vertical lid margin suture induces puckering of the wound edges to avoid notching after healing (b). Two additional sutures, one posterior and another inferior to the lashes, are placed to align the lid margin. The three 6-0 silk sutures should be left long and secured away from the wound onto the lower lid skin with a suture (c)

forces so that the reconstructed lower eyelid lies in apposition with the globe. The deep edge of the flap is sutured to the inner aspect of the lateral orbital rim inferior to the superior crus using 4-0 Vicryl sutures. Finally, the conjunctival edge previously cut during the canthotomy is advanced superiorly and attached to the skin edge of the lateral lid margin with a running 7-0 Vicryl suture.

contralateral upper eyelid can be used for posterior lamella replacement [10]. The graft provides posterior lamellar support and a mucous membrane lining for the reconstructed lower lid. A myocutaneous advancement flap is then fashioned to provide blood supply to the free graft (Fig.  10.5). This option is most appropriate for patients whose involved eyelid is on the side of the only seeing eye or who would not be able to tolerate closure of the eyelids with a Hughes flap (see below). The harvest of a free autogenous tarsal graft first involves the placement of a 4-0 silk traction

 ree Tarsal Graft and Myocutaneous F Advancement Flap For larger defects where primary closure is not possible, a free tarsal graft from the ipsilateral or

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a

b

c

Fig. 10.5  Free tarsal graft plus myocutaneous advancement flap. A full-thickness lower eyelid defect may be repaired with a free tarsal graft for posterior lamella replacement and an overlying myocutaneous advancement flap to provide vascular support (a). The free tarsal graft harvested from either the ipsilateral or the contralateral upper eyelid provides posterior lamellar replacement (b). The myocutaneous advancement flap, fashioned in the manner of a lower eyelid blepharoplasty, provides an inherent blood supply to the underlying free tarsal graft. This figure demonstrates the key principle that either the reconstructed anterior or posterior lamella must have its own inherent vascular supply (pedicle flap), thus ensuring tissue survival and optimum surgical outcome for the patient (c)

suture through the central upper lid margin. The lid is everted to expose the tarsoconjunctival surface. The inferior edge of the graft is parallel to and 4 mm or more from the lid margin. The supe-

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rior tarsal border determines the vertical height of the graft. The incision is made through the conjunctiva and full-thickness tarsus along the inferior and vertical edges. Dissection is used to separate the levator aponeurosis from the underlying tarsus. Mueller’s muscle and conjunctiva are cut from the superior tarsal border, leaving 2  mm of conjunctiva attached to the graft. The donor site is allowed to heal by secondary intention. The graft is secured into the defect with the conjunctival surface in contact with the globe and the superior edge of the graft, with the conjunctival remnant along the new lid margin. The medial edges are secured with interrupted 5-0 Vicryl sutures passed at partial thickness to avoid ocular irritation. The superior edge is attached to the superior forniceal conjunctiva and the edges of Mueller’s muscle and levator aponeurosis using interrupted 6-0 Vicryl sutures. The graft may subsequently be covered with a vascularized myocutaneous advancement flap (similar to the previously described rotational flap).

 eriosteal Strip and Myocutaneous P Advancement Flap The periosteal strip with myocutaneous advancement flap is an alternative to the free tarsal graft [9]. This method may be used to reconstruct the lower lid when the lateral third of the tarsus is not present. The periosteal strip may also be used in combination with other procedures for larger defects. When fashioning the periosteal strip, the skin overlying the flap is first outlined with a marking pen in a semicircle or as a cheek flap extended 1–2  cm past the lateral commissure. Once the skin–muscle flap is mobilized and reflected, the lateral orbital rim is exposed. A rectangular strip of periosteum based at the inner aspect of the rim is then formed. The strip should be 1 cm wide, angled at 45° to follow the lower lid contour. The distance from the lateral edge of the tarsal defect to the orbital rim determines the length. The fascia is dissected from the temporalis muscle and separated from the bony rim with a periosteal elevator. The strip is reflected nasally to fill the tarsal defect. The anterior periosteum lies against the globe, and the distal end is secured to the lateral border of the remaining tarsus with

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partial-thickness 5-0 Vicryl sutures. The strip thus provides posterior lamellar support for the reconstructed lower eyelid. The myocutaneous advancement flap is then rotated and secured to fill the anterior lamellar defect.

advancement flap may be considered [9]. In this procedure (Fig.  10.7), a tarsoconjunctival flap from the upper eyelid is passed behind the upper eyelid margin remnant and advanced into the posterior lamellar defect of the lower eyelid. The anterior lamella is then recreated with a skin Free Tarsal Graft and Unipedicle Flap advancement flap or a free skin graft from the from the Upper Eyelid preauricular or retroauricular area. The main disA free tarsal graft with a unipedicle flap from the advantage is that the pupil remains covered for upper eyelid is another method used to close full-­ 4–8 weeks by the tarsoconjunctival bridge. This thickness lower eyelid defects. The free tarsal vascularized pedicle is severed and released in a graft is first harvested. Next, a flap is harvested second procedure after the lower eyelid flap is from excess upper lid skin and subcutaneous tis- revascularized. sue, based at the lateral canthus (Fig.  10.6), rotated inferiorly to fill the lower anterior lamellar defect, and then closed in two layers. The unipedicle flap may leave the patient with a lump of tissue at the lateral canthus. If necessary, a second procedure may be undertaken 6–8 weeks later to thin the base of the flap and remove this excess tissue.

 arsoconjunctival (Hughes) Flap T and Free Skin Graft or Myocutaneous Advancement Flap For large defects involving more than 50% of the eyelid margin, a tarsoconjunctival flap (Hughes flap) with a free skin graft or myocutaneous

a

Fig. 10.7  Hughes tarsoconjunctival flap. With the upper eyelid everted over a retractor, a three-sided flap is created in the central tarsal conjunctiva of the upper eyelid. The horizontal incision should be at least 4 mm from the lid margin to avoid entropion, lid margin contour deformity, loss of lashes, and trichiasis. The vertical incisions course up toward the superior fornix perpendicular to the lid mar-

Fig. 10.6  Unipedicle flap. A unipedicle flap from the upper eyelid with an inherent vascular supply is used to replace an anterior lamella defect in the lower eyelid

b

gin. All incisions are made through conjunctiva and tarsus. The Muller’s muscle is dissected off the conjunctiva and remains in the upper eyelid proper (a). The tarsoconjunctival flap is mobilized into the lower lid defect to align the upper lid superior tarsal border with the lower lid margin remnant (b)

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Upper Eyelid Defects (Fig. 10.8)  nterior Lamellar Deficit, A Lid Margin Intact Primary Closure As in the case of the lower eyelid, small defects may be closed primarily if lid distortion will not be induced. If insufficient anterior lamella remains, a full-thickness pentagonal wedge may be used.

Skin Graft For larger defects not involving the lid margin, a free full-thickness skin graft may be employed [8, 9].  llipse Sliding Flap E An elliptical sliding flap is a technique used to close some anterior lamellar defects, as described in the section on lower eyelid defects [9]. The main advantage of this flap is the ability to repair an anterior lamellar defect without sacrificing significant amounts of normal tissue.

Fig. 10.8  Algorithm for the repair of upper eyelid defects

Upper eyelid defects

Anterior lamellar defect, margin intact

• Primary closure ± lateral cantholysis • Semicircular rotational flap • Ellipse sliding flap • Myocutaneous advancement flap

Full-thickness eyelid defect

Small (< 30%) • Primary closure ± lateral cantholysis

Medium (30-50%) • Semicircular rotational flap + myocutaneous advancement flap • Free tarsal graft + myocutaneous advancement flap

Large (> 50%) • Free tarsal graft + myocutaneous advancement flap • Cutler Beard tarsoconjunctival flap + free skin graft or myocutaneous advancement flap

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 yocutaneous Advancement Flap M As with lower lid defects, a myocutaneous advancement flap may also be used. Flaps provide the best tissue match, the best cosmetic result, and an inherent vascular supply.

Full-Thickness Eyelid Defect Primary Closure Central upper lid defects – up to 30% in younger patients and 50% in older patients  – may be closed using the same technique as in the lower lid. The main difference is that the vertical height of the tarsus is two to three times longer than that of the lower lid. Also, the levator aponeurotic attachments should not be disturbed, so as to avoid postoperative ptosis. If necessary, lateral cantholysis may provide 3–5  mm of medial mobilization of the remaining lateral eyelid margin.  emicircular Rotational Flap S Up to half of the medial or central upper lid may be reconstructed with primary closure and a lateral semicircular or myocutaneous flap, similar to that described for the lower lid [9]. The first difference is an inferiorly, not superiorly, arching semicircle flap. The second is that the superior, not inferior, crus of the lateral canthal tendon should be lysed.  ree Tarsal Graft and Myocutaneous F Advancement Flap With larger defects, a free tarsal graft with a myocutaneous advancement flap may be needed [9]. A free tarsoconjunctival graft may be harvested from the contralateral upper eyelid. Once the flap is secured, the conjunctival remnant is advanced anteriorly and secured to the inferior flap skin edge with a running 7-0 Vicryl suture to reestablish the mucocutaneous junction. Finally, the superior eyelid must be immobilized and kept on stretch to minimize postoperative retraction. A temporary 4-0 silk suture is tied over bolsters and placed on inferior traction.

 arsoconjunctival Flap (Cutler–Beard T Flap) and Free Skin Graft or Myocutaneous Advancement Flap The Cutler–Beard procedure is a less commonly used, two-stage method of closing large, full-­ thickness upper eyelid defects involving more than 50% of the lid margin. The procedure is similar to the Hughes flap. It involves the advancement of a lower eyelid flap, consisting of skin and muscle (anterior lamella) and conjunctiva, behind the lower eyelid margin remnant into the defect of the upper eyelid. The main disadvantage of the procedure is the creation of a thick, relatively immobile upper eyelid without tarsal support. Modifications to the Cutler–Beard approach include combining it with a myocutaneous advancement flap, when there are no alternative methods of closing the defect [8, 9].

Special Circumstances (Fig. 10.9) Medial Canthal Defect  edian Forehead Flap M The median forehead flap is a unipedicle flap used to close large anterior lamellar defects of the lower eyelid and medial canthus (Fig. 10.10) [8]. The flap is based on the axis of the contralateral supraorbital neurovascular bundle. Following 120–180° of rotation into the defect, the flap is secured with a two-layered closure. It may be combined with other rotational flaps for very large defects. Glabellar Flap Medial canthal defects may also be repaired with a glabellar flap, which is a modified V–Y rotation flap [8] in the shape of an inverted V, which begins at the midpoint of the glabella just above the brow, with an angle of less than 60°. Following rotation into the defect, the apex is placed at the lateral edge and the point at the inferior tip. Finally, the donor site is sutured in a V–Y closure which may induce a shortening of the interbrow distance. This flap may require secondary debulking.

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Special circumstances

Medial canthal defects

• Glabellar flap • Median forehead flap • Rhombic flap

• • • • •

Insufficient posterior lamella

Insufficient anterior lamella

Insufficient vascularized pedicle

Tarsoconjunctival graft Hard palate graft Nasal cartilage graft Ear cartilage graft Donor sclera

Tissue expansion

• Galeopericranial flap • Pericranial flap

Fig. 10.9  Algorithm for surgical repair in special circumstances

a

b

c

Fig. 10.10  Median forehead flap. This patient has a large forehead and right-sided medial canthal defects following excision of two lesions in these respective areas (a). The medial canthal defect is repaired by rotating a median forehead flap, with its own inherent vascular supply, down

into the area of deficient tissue (b). The large forehead defect is not amenable to primary closure; thus it may be repaired with a free skin graft. This case illustrates the simultaneous use of two reconstructive options to correct two disparate defects (c)

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b

Fig. 10.11  Rhombic flap. First, the defect is made into a rhombus by marking two lines parallel to the lines of maximum extensibility (LME) (a). These LME are oriented perpendicular to the relaxed skin tension lines (RSTL). The first rhombic flap is made by placing two more parallel lines equal in length to and tangential to the defect at either 60° or 120° to the first set of lines while sacrificing the minimal amount of normal tissue possible. Next, a line is drawn from each end of the shorter diagonal that bisects the 120° angle. This line should be equal in length to the

sides of the rhombus. Further lines are marked from the end of the previous mark at a 60° angle parallel to the sides of the rhombic defect. Of the four possible flaps that are designed, only one of the two flaps oriented to close the donor site along LME, which causes the least interference with surrounding structures, should be chosen. With medial rotation, this flap is advanced into the defect so that point B aligns with medial point of the defect and point A is placed in the inferior apex (b)

Rhombic Flap The rhombic flap is a non-transposition flap used in the closure of medial and lateral canthal defects [9]. With minimal sacrifice of normal tissue, most defects may be converted to a rhombic configuration with angles of 60° and 120° and all sides of equal length (Fig. 10.11).

need to avoid the central palatine raphe, the anterior palatine rugae, and the area overlying the greater palatine foramen where the anterior palatine artery exits. Xenogenic spacer grafts made from a porcine collagen matrix have also become increasingly popular in cases of insufficient posterior lamella. In patients who need more posterior lamellar augmentation or have concomitant volume ­deficiency, a dermis fat graft can be harvested from the postauricular area or abdomen. The graft should be oversized to account for postoperative contraction. The dermis is removed with a diamond burr or scalpel once a graft of sufficient thickness is harvested. The end point or dermabrasion is fine pinpoint bleeding of the graft. The graft is then placed into the eyelid defect with the dermis facing the globe. A frost suture or tarsorrhaphy should be used postoperatively to counteract contractile forces [13–15].

Insufficient Posterior Lamella In defects with insufficient posterior lamella, tarsoconjunctival grafts are preferred because they provide a smooth surface over the cornea. If such a graft is not available, nasal or ear cartilage grafts, donor sclera grafts, or dermis fat grafts may be used to reconstruct the deficiency. Hard palate grafts harvested from the gingival surface of the roof of the mouth have been used with greater frequency [11, 12]. The key points are the

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Insufficient Anterior Lamella More extensive defects of the anterior lamella may require more involved methods of repair. The posterior lamella is first replaced with a graft, as described above. If a free graft is used, the anterior lamella must be reconstructed with a vascular flap. Tissue expanders allow for the use of vascularized skin that is similar in appearance, thickness, and texture to that adjacent to the defect without sacrificing normal tissue [16]. Most importantly, tissue expansion seems to enhance the vascularity of the skin flap. Other advantages include the non-hair-bearing nature and pliability of the created tissue. The main disadvantage is the creation of temporary disfigurement. In tissue expansion, skin is recruited from the adjacent skin, such as the forehead, the temporalis and preauricular regions, and the lid proper. Adequate tissue area is created in a staged procedure. A skin incision is made along the hairline, brow, or a preexisting incision line, and a recipient pocket is dissected in the subcutaneous tissue. The expander is soaked in an antibiotic solution, tested for leaks, placed into the recipient pocket, and filled with saline. A remote expander is then placed into the pocket as well and the wound is closed in two layers. Serial expansion is begun 2–3  weeks after placement. A 27-gauge needle is used to inflate the expander with saline percutaneously through the injection port until the expander feels taut. Usually 10–15% of the total expander volume is injected at any one time, and the process is usually repeated twice weekly. Once adequate tissue has been created, the expander is removed, and the newly created skin is ready for use as a local skin flap in eyelid reconstruction. In cases where tissue expansion is not viable, the use of a bioengineered dermal substitute allows for increased wound healing and adequate anterior lamella reconstruction [17]. The dermal substitute is cut to fit over the defect and may be sutured into place using 7-0 Vicryl. As the material incorporates into the surrounding skin, its collagen matrix promotes vascularization and cellular migration into the defect. An overlying

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silicone membrane acts to protect against dessication and provide increased tensile strength and can typically be removed after 2–4 weeks. Once adequate wound integration has occurred, the smaller anterior lamellar defect can undergo a secondary reconstructive procedure. In many cases, use of a dermal substitute can allow for complete closure of the defect without need for further reconstructive techniques.

Insufficient Vascularized Pedicle For large defects with an insufficient vascularized pedicle, galeal and pericranial flaps may be used [18]. They provide an excellent vascular supply for the recipient site and any underlying free tarsoconjunctival or overlying skin grafts. The main difference from a median forehead flap is that skin is not transposed with a galeal or pericranial flap. The thinner nature of these flaps reduces the amount of bunching over the nasal bridge. Although both types of flap may be employed in upper eyelid reconstruction, the galeopericranial flap is thought to be superior to the pericranial flap because of its increased vascularity. In the repair of large upper eyelid defects, the posterior lamella is first reconstructed using one of the previously described grafts. The galeopericranial or pericranial flap is then created to fill the soft tissue defect. A standard bicoronal incision is outlined over the skull vertex. It is important to avoid a transverse incision of the flap two fingerbreadths above the superior orbital rim, as this is the region where the frontalis nerve penetrates into the frontalis muscle. A transcoronal incision is then made to access the pericranium of the forehead. For a galeopericranial flap, the plane of dissection is between the subcutaneous tissue and the galea (for pericranial flaps, the plane is subgaleal, leaving the loose areolar tissue and periosteum adherent to the frontal bone). Dissection is carried toward the supraorbital rim while preserving the supraorbital and supratrochlear vessels. The pericranium and galea are then incised and elevated off the frontal bone. The flap is mobilized, turned down anteriorly through the

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skin defect, and subsequently serves as a well-­ vascularized bed for a skin graft.

Summary (Box 10.1) The treatment of malignant eyelid lesions includes complete excision of the tumor as well as reconstruction to provide optimum function, globe protection, and esthetics. Mohs’ micrographic surgery technique is the preferred method of excision of periocular malignancies, as it allows for clearance of the tumor margin while maximally conserving normal tissues. Repair of the eyelid depends on the size of the defect and whether or not the lid margin is involved. Most importantly, either the reconstructed anterior or the posterior lamella must have its own inherent blood supply (pedicle flap), as this will ensure tissue survival and optimal surgical outcome for the patient.

Box 10.1 Anterior lamella defect upper eyelid, eyelid margin intact 1. Primary closure (a) With lateral cantholysis (b) Without lateral cantholysis 2. Skin graft (of non-hair-bearing skin) (a) Contralateral upper eyelid (b) Preauricular skin graft (c) Retroauricular skin graft (d) Supraclavicular skin graft (e) Upper inner arm skin graft 3. Ellipse sliding flap 4. Myocutaneous advancement flap

Full-thickness eyelid defect lower eyelid 1. Primary closure (a) With lateral cantholysis (b) Without lateral cantholysis

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2. Semicircular rotational flap (a) Temporal tarsal remnant + myocutaneous advancement flap (b) Only feasible if sufficient temporal tarsal remnant 3. Free tarsal graft  +  myocutaneous advancement flap 4. Periosteal strip  +  myocutaneous advancement flap 5. Free tarsal graft + unipedicle rotational flap from the upper eyelid 6. Hughes tarsoconjunctival flap + free skin graft or myocutaneous advancement flap

Anterior lamella defect lower eyelid, eyelid margin intact 1. Primary closure (a) With lateral cantholysis (b) Without lateral cantholysis 2. Skin graft (of non-hair-bearing skin) (a) Ipsilateral upper eyelid (b) Preauricular skin graft (c) Retroauricular skin graft (d) Supraclavicular skin graft (e) Upper inner arm skin graft 3. Ellipse sliding flap 4. Myocutaneous advancement flap

Full-thickness eyelid defect upper eyelid 1. Primary closure (a) With lateral cantholysis (b) Without lateral cantholysis 2. Semicircular rotational flap (a) Temporal tarsal remnant + myocutaneous advancement flap (b) Only feasible if sufficient temporal tarsal remnant 3. Free tarsal graft  +  myocutaneous advancement flap 4. Cutler–Beard tarsoconjunctival flap + free skin graft or myocutaneous advancement flap

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Medial canthal defect 1. Median forehead flap 2. Glabellar flap 3. Rhombic flap

Insufficient anterior lamella 1. Tissue expansion 2. Dermal substitute

Insufficient posterior lamella 1. Tarsoconjunctival graft 2. Hard palate graft 3. Nasal cartilage graft 4. Ear cartilage graft 5. Donor sclera

Insufficient vascularized pedicle 1. Galeopericranial flap 2. Pericranial flap

References 1. Shields JA, Demirci H, Marr BP, et al. Sebaceous carcinoma of the ocular region: a review. Surv Ophthalmol. 2005;50(2):103–22. 2. Cook BE Jr, Bartley GB.  Treatment options and future prospects for the management of eyelid malignancies: an evidence-based update. Ophthalmology. 2001;108:2088–98; quiz 2099–2100, 2121. 3. Tse DT, Gilberg SM.  Malignant eyelid tumors. In: Krachmer JH, Mannis MJ, Holland EJ, editors. Cornea: surgery of the cornea and conjunctiva. 2nd ed. Philadelphia: Mosby; 2005. 4. Esmaeli B, Wang B, Deavers M, et  al. Prognostic factors for survival in malignant melanoma of the eyelid skin. Ophthal Plast Reconstr Surg. 2000;16:250–7. 5. Coleman WP III, Davis RS, Reed RJ, et al. Treatment of lentigo maligna and lentigo maligna melanoma. J Dermatol Surg Oncol. 1980;6:476–9. 6. Zitelli JA, Mohs FE, Larson P, et al. Mohs micrographic surgery for melanoma. Dermatol Clin. 1989;7:833–43. 7. Esmaeli B.  Sentinel lymph node mapping for patients with cutaneous and conjunctival malignant melanoma. Ophthal Plast Reconstr Surg. 2000;16:170–2. 8. Nerad JA. The requisites in ophthalmology oculoplastics surgery: eyelid reconstruction. In: Krachmer JH, editor. Requisites in ophthalmology: oculoplastic surgery. St Louis: Mosby; 2001.

9. Kronish J. Eyelid reconstruction In: Tse DT, editor. Color atlas of ophthalmic surgery: oculoplastic surgery. Philadelphia: JB Lippincott; 1992. 10. Kersten RC, Codére F, Dailet RA, et  al. Basic and clinical science course: section 7, orbit, eyelids, and lacrimal system. San Francisco: American Academy of Ophthalmology; 2003. 11. Bartley GB, Kay PP. Posterior lamellar eyelid reconstruction with a hard palate mucosal graft. Am J Ophthalmol. 1989;107:609–12. 12. Beatty RL, Harris G, Bauman GR, et al. Intraoral palatal mucosal graft harvest. Ophthal Plast Reconstr Surg. 1993;9:120–4. 13. Korn BS, Kikkawa DO, Cohen SR, et al. Treatment of lower eyelid malposition with dermis fat grafting. Ophthalmology. 2008;115:744–751.e2. 14. Brock WD, Bearden W, Tann T 3rd, et al. Autogenous dermis skin grafts in lower eyelid reconstruction. Ophthal Plast Reconstr Surg. 2003;19:394–7. 15. Chang HS, Lee D, Taban M, et al. “En-glove” lysis of lower eyelid retractors with AlloDerm and dermis-fat grafts in lower eyelid retraction surgery. Ophthal Plast Reconstr Surg. 2011;27:137–41. 16. Tse DT, McCafferty LR. Controlled tissue expansion in periocular reconstructive surgery. Ophthalmology. 1993;100:260–8. 17. Chen TA, Ayala-Haedo JA, Blessing NW, et al. Erickson BP.  Bioengineered dermal substitutes for the management of traumatic periocular tissue loss. Orbit. 2018;37(2):115–20. 18. Tse DT, Goodwin WJ, Johnson T, et al. Use of galeal or pericranial flaps for reconstruction or orbital and eyelid defects. Arch Ophthalmol. 1997;115:932–7.

Systemic Associations

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Matteo Scaramuzzi, Lucy T. Xu, Arun D. Singh, and Elias I. Traboulsi

Abbreviations

Introduction

AVM Arteriovenous malformation BCC Basal cell carcinoma CHRPE Congenital hypertrophy of retinal pigment epithelium CM Capillary malformations CNC Carney complex CS Cowden syndrome FDA Food Drug Administration HNPCC Hereditary nonpolyposis colorectal cancer MRI Magnetic resonance imaging MTS Muir-Torre syndrome NBCCS Nevoid basal cell carcinoma syndrome NF1 Neurofibromatosis type 1 PDL Pulsed dye laser PDT Photodynamic therapy RPE Retinal pigment epithelium SWS Sturge-Weber syndrome

Patients with an inherited predisposition for tumors tend to develop these tumors at an earlier age, have multiple tumors with bilateral involvement, and may have a positive family history of similar lesions [1]. The majority of eyelid tumors in the setting of an inherited predisposition are benign, but some malignant tumors can have a syndromic association such as ones that occur (Table  11.1), for example, in the setting of the Gorlin-Goltz syndrome. With eyelid tumors, one of the most important clues to the presence of an associated systemic disease is an unusual histopathologic feature. For example, tumors such as myxomas and sebaceous adenomas of the eyelid are unlikely to occur in the absence of a syndromic association. Eyelid tumors can also be metastatic, but such cases are rare and account for less than 1% of malignant eyelid tumors [2].

M. Scaramuzzi · E. I. Traboulsi (*) Department of Pediatric Ophthalmology and Strabismus, Center for Genetic Eye Diseases, Cole Eye Institute (i-32), Cleveland Clinic Foundation, Cleveland, OH, USA e-mail: [email protected] L. T. Xu · A. D. Singh Department of Ophthalmic Oncology, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA

Neurofibroma in Neurofibromatosis Type 1 Neurofibroma is the hallmark of neurofibromatosis type 1 (NF1). NF1 is inherited in an autosomal-­ dominant fashion in about 50% patients and is sporadic in the remainder [3]. The disease affects 1 out of 3000 persons and is due to mutations in the NF1 gene on chromosome 17q11.2, which encodes the protein neurofibromin [3].

© Springer Nature Switzerland AG 2019 J. Pe’er et al. (eds.), Clinical Ophthalmic Oncology, https://doi.org/10.1007/978-3-030-06046-6_11

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114 Table 11.1  Eyelid tumors that are markers of a syndromic association Entity Neurofibromatosis type 1

Eyelid tumor Neurofibroma

Sturge-Weber Syndrome Gardner syndrome

Gorlin-Goltz syndrome

Diffuse hemangioma Epidermoid cyst Fibroma Orbital osteoma Basal cell carcinoma

Cowden syndrome

Trichilemmoma

Carney complex

Myxoma

Muir-Torre syndrome

Sebaceous adenoma

Associated features Lisch nodules Café au lait spots Pheochromocytoma Leptomeningeal hemangioma CHRPE Colorectal polyps/carcinoma Odontogenic cysts Bifid ribs Palmar pits Ovarian tumor Oral papilloma Breast tumor Thyroid tumor Spotty mucocutaneous pigmentation Schwannoma Endocrine overactivity Testicular tumor Keratoacanthoma Basal cell carcinoma Colorectal adenocarcinoma

Locus/gene 17q NF 1 gene Sporadic 5q21 APC gene 9q 22 PTC gene

10q23 PTEN gene 17q PRKAR1A gene chromosome 2 2p hMLH1, hMSH2

CHRPE congenital hypertrophy of retinal pigment epithelium

The neurofibromas appear as discrete soft been described in literature [6, 7]. Characteristics tumors on the face (including eyelids), hands, of plexiform neurofibromas of the eyelid are and trunk. Previously given different names, they thickening of the upper lid, S-shaped eyelid are now designated as orbital-periorbital-­ deformity, “bag of worms”-like feel on palpation, plexiformal neurofibromas in order to include all and detachment of the lateral [8] or medial canthe locations in which they appear [4]. Cutaneous thal ligaments [9]. The extent of a neurofibroma neurofibromas arise from small nerves or nerve cannot be determined by clinical examination endings and protrude from the surface of the skin, alone, so MRI is necessary [10]. while subcutaneous neurofibromas are firm nodAmblyopia can be caused by these lesions, ules just below the surface of the skin [4]. They mainly as a result of ptosis or anisometropia, so a tend to be small and generally appear in the sec- comprehensive ophthalmologic exam should be ond decade of life, becoming more numerous as performed at every 6  months throughout the the patient ages, with no risk of malignant trans- period of visual development [11]. Debulking of formation. They rarely cause neurologic deficits the tumor mass, ptosis surgery, and canthal fixa[4]. In contrast, plexiform neurofibromas are tion are the treatment surgical modalities in cases complex nerve sheath tumors that follow multi- of plexiform neurofibroma, in order to clear the ple nerve branches, mainly diagnosed in early visual axis and improve appearance [12]. childhood [4]. They are more prone to cause Unfortunately surgery can be challenging and functional and neurologic deficits, and there is a associated with a high risk of complications and risk of malignant transformation [4]. In the eye recurrences, as a result of the tumor’s integration and ocular adnexa, a plexiform pattern is more with the surrounding soft tissue [13]. With frequent [5]. These tumors are usually associated asymptomatic, nonprogressive, and nonobstrucwith other features of NF1. Solitary tumors are tive tumors, monitoring is an option, taking into rare, but tumors masquerading as chalazia have consideration the fact that neurogenic tumors in

11  Systemic Associations

NF1 carry a risk of approximately 10% for malignant transformation [14]. This risk is greater with atypical neurofibromas [15], whole-gene deletion [16], higher numbers of plexiform neurofibromas, larger whole body benign tumor volume, and younger age [17].

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AVMs [18]. It is also important to differentiate port-wine stain from other similar malformations such as infantile hemangiomas, which are associated with different syndromes such as PHACES [25]. A useful diagnostic clue is that the distribution is dermatomal in nevus flammeus and segmental in infantile hemangiomas [26]. Moreover the endothelial cells of port-wine stains do not Nevus Flammeus stain for GLUT-1, which is a specific marker for infantile hemangiomas [18]. Nevus flammeus is also known as capillary malIn general, only about 10% of all patients with formation (CM) or port-wine stain, and is the nevus flammeus or port-wine stain of the eyelid most common type of congenital vascular mal- are associated with Sturge-Weber syndrome formation. It is usually present at birth and per- (SWS) (Fig. 11.1) [27]. SWS occurs in patients sists throughout life, although its appearance or who have hemangiomas in the V1 or V2 areas of color may change [18]. It is initially flat and light distribution of the trigeminal nerve. It is typically red, or violaceous and affects the skin of the face unilateral, present at birth, and does not change in almost all cases (90%), followed by the neck, with age [28]. The size of the nevus flammeus in trunk, leg, arm, and hand [19]. With an incidence SWS has been found to be correlated with neuroof 0.3% in newborns, it usually occurs as a spo- logic severity in patients more than 5 years old radic unifocal lesion, not associated with any [29]. Bilateral port-wine stains of the eyelids underlying disease [18]. have a higher likelihood of being associated with A recently proposed pathophysiologic mecha- SWS than unilateral lesions [27]. In a study of 55 nism for tissue hypertrophy is focal venous patients with SWS, glaucoma was the main ocuhypertension caused by venous dysplasia [20]. lar disease and was related to the extension of the Despite this, a definitive pathogenic mechanism nevus flammeus in the palpebral area [30]. If is still not known. A somatic activating mutation there is involvement of both upper and lower eyein GNAQ has been identified as the cause of lids, the risk of glaucoma is as high as 50%. The Sturge–Weber syndrome and apparently-­glaucoma is almost always ipsilateral to the facial nonsyndromic port-wine stains [21, 22]. Nevus flammeus associated with arteriovenous malformation subtypes have been found to result from dominant RASA-1 gene mutations [22, 23]. Although multiple treatments are available, the gold standard for facial nevus flammeus is the flashlamp-pumped pulsed dye laser (PDL) treatment [24]. However, when there are hypertrophic skin changes, surgical intervention can achieve better results [24]. Nevus flammeus is sometimes associated with certain syndromes, such as Sturge-Weber syndrome, macrocephaly-CM syndrome, CM-arteriovenous malformation (AVM) syndrome, phacomatosis pigmentovascularis, and overgrowth syndromes such as Klippel-­Trenaunay syndrome. It is sometimes difficult to distinguish between Fig. 11.1  Sturge-Weber syndrome. In addition to typical different diseases. Doppler assessment may be diffuse cutaneous involvement, note nodular helpful in differentiating nevus flammeus from hemangioma

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port-wine stain [28]. Patients without nevus flammeus in the palpebral area do not develop glaucoma or choroidal hemangioma [30]. Diffuse choroidal hemangioma is present in about 40–50% of patients with SWS and is usually ipsilateral to the facial port-wine stain. In the setting of phakomatosis pigmentovascularis, port-wine stain can be associated with scleral and uveal hyperpigmentation, predisposing to uveal melanoma, similar to that observed in Nevus of Ota (Volume 5 Chap. 9). Diagnosis of SWS is based on the typical clinical signs, facial appearance, and brain MRI with contrast findings [28]. In the absence of leptomeningeal involvement, patients should only be given a diagnosis of nevus flammeus, port-wine stain, or facial angioma to avoid the stigma associated with a diagnosis of SWS. In infants with nevus flammeus in the distribution of the trigeminal nerve, early referral to a pediatric neurologist is critical, considering that outcomes depend on prompt recognition of neurologic abnormalities and early seizure control [31]. There is no evidence that a presymptomatic Sturge-Weber syndrome diagnosis with magnetic resonance imaging results in better neurodevelopmental outcomes [31]. In SWS nevus flammeus, laser treatment should be performed early for better outcomes; however, its success depends on the location of the lesions: those affecting the central forehead respond better than central facial lesions [32]. Unfortunately, lesions that are left untreated have a tendency to thicken and get darker with time and, in some cases, become nodular [32].

Gardner Syndrome Gardner syndrome was first described by Eldon J. Gardner in 1951 as a autosomal-dominant disorder characterized by the triad of multiple osteomas, colonic polyposis, and benign tumors of the skin and soft tissues [33]. Gardner syndrome is a variant of familial adenomatous polyposis caused by a mutation in the APC gene on chromosome 5q21 [33]. Extracolonic manifestations of Gardner syndrome include jaw anomalies, pigmented ocular fundus lesions that resemble congenital hypertrophy of the retinal pigment

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epithelium, soft tissue tumors, desmoid tumors, and other cancers [34, 35]. Orbital osteoma, soft tissue tumors of the brows or eyelids, and epidermoid cysts of the eyelid may also occur [36–38] .

 evoid Basal Cell Carcinoma N Syndrome (Gorlin-Goltz Syndrome) Nevoid basal cell carcinoma syndrome (NBCCS) is also referred to as basal cell nevus syndrome, Gorlin syndrome, or Gorlin-Goltz syndrome [39, 40]. Its incidence is estimated at 1 in 50,000 with no sex predilection. The median age at diagnosis is 23  years in sporadic cases and 12  years in familial cases [41]. NBCCS is inherited in an autosomal-­dominant fashion with complete penetrance and variable expressivity; however, about 30% of probands have a de novo mutation [40]. The mutation is in the PTCH gene on chromosome 9q22.3 [42, 43]. PTCH sequence alterations can be detected in about 60–85% of cases that meet clinical diagnostic criteria for NBCCS [43]. Studies have shown that the PTCH gene may be inactivated by haploinsufficiency or through dominant-negative isoforms [44]. To date, approximately 448 unique PTCH1 mutations are known [45]. Furthermore, mutations in the SUFU and PTCH2 genes have been detected in patients with signs and symptoms of Gorlin syndrome and no PTCH1 mutations [46, 47]. NBCCS is characterized by the classic clinical triad of multiple basal cell carcinomas, keratocystic odontogenic tumors and bifid ribs; however cutaneous, ophthalmic and neurological abnormalities may also be present [48]. Associated neoplasms are medulloblastoma, astrocytoma, meningioma, and ovarian fibroma [48]. Although basal cell nevi may occur in early childhood, it is the risk for multiple basal cell carcinoma and developmental anomalies that characterizes NBCCS [49]. The tumors tend to be multiple (>5 in a lifetime) and occur before the age of 30 years. They may arise from preexisting basal cell nevi or de novo. In general, about 0.5% of patients with basal cell carcinoma have underlying NBCCS [50]. The proportion is much higher (22%) in patients with basal cell c­ arcinoma

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developing before the age of 20 years [51]. White race, age, sun exposure, and radiation therapy are major risk factors for inducing basal cell carcinoma [52]. Jaw keratocysts and calcification of the falx cerebri are some of the most frequent (90%) manifestations of the NBCCS (Fig.  11.2) [49, 53]. Patients could be characterized by typical facial features that include forehead bossing and macrocephaly [53]. a

A wide variety of ophthalmic manifestations may be present in 26% of patients with NBCCS [49]. Periocular basal cell carcinoma [54, 55], hypertelorism, nystagmus, and cataracts are some of the common features (Fig. 11.2) [49, 54]. The occurrence of microphthalmia [56], coloboma, combined retinal and RPE hamartoma [57], and vitreoretinal abnormalities [58] in the setting of NBCCS implicates the PTCH1 gene in ocular development [56, 58]. Other less common

b

c

Fig. 11.2  External photograph showing multiple facial basal cell carcinoma (a). Orthopantomograph of the right mandible shows odontogenic keratocysts seen as round, well-circumscribed radiolucent areas (b, arrows). Coronal

noncontrast computed tomography scan of the skull showing of falx cerebri (arrow) and large diffuse lesion in the medial orbit (c). (Reprinted from Honavar et al. [54]. With permission from Elsevier)

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f­ eatures include subconjunctival epidermoid cysts [59], congenital orbital teratoma [60], strabismus [61], epiretinal membrane and myelinated nerve fibers [62], bilateral macular holes [63], orbital cysts and congenital blindness [48]. Diagnosis is difficult because of the great phenotypic variation of this disease, with over 100 clinical manifestations in many major organs. Diagnosis is based on the presence of major and minor clinical and radiological criteria (Table 11.2) and confirmed by DNA analysis [49]. If there are no PTCH1 mutations, testing of SUFU and PTCH2 should be considered [41]. The best approach in the diagnosis and management of patients with NBCCS is multidisciplinary, in order to achieve a diagnosis and to optimize care. Basal cell carcinoma is usually treated by surgical excision, with an overall success rate of 94–98% [64]. Other therapies are PDT, cryosurgery and electrocauterization [65]. A recent alternative therapy is Vismodegib, a small-molecule inhibitor of the Hedgehog pathway. It is approved by the United States Food and Drug Administration (FDA) for the treatment of metastatic, and locally advanced basal cell carcinomas [66]. Treatment with Vismodegib reduces the tumor burden and prevents new basal cell carcinomas [66]. Sonidegib is another Hedgehog pathway inhibitor with FDA approval for use in adults with locally advanced recurrent basal cell Table 11.2  Clinical diagnostic criteria for nevoid basal cell nevus syndrome Major criteria

≥2 major and ≥1 minor criteria

Minor criteria

≥1 major and ≥3 minor criteria

Jaw keratocyst Falx calcification Palmar or plantar pits Basal cell carcinoma >5 in a lifetime or before the age of 30 years Affected first-degree relative Macrocephaly Medulloblastoma Lympho-mesenteric or pleural cysts Cleft lip/palate Vertebral anomalies Polydactyly Ovarian/cardiac fibromas Ocular anomalies

Based on data from Ref. [49]

carcinomas after radiation or surgery, and patients who cannot undergo surgery or radiation therapy [67]. Chemoprevention with isotretinoin can be used when existing lesions have been controlled [68]. Patients with NBCCS can have a normal life span if they have adequate multidisciplinary monitoring to check for medulloblastoma and invasive or metastatic BCC, which are the most common, albeit rare, causes of early mortality [69].

 ultiple Hamartoma Syndrome M (Cowden Syndrome) Cowden syndrome was first described in 1963 [70]. Initially considered a predominantly dermatologic disease, the phenotypic spectrum has broadened to include increased cancer risk as well as neurodevelopmental disorders [71]. Cowden syndrome is inherited as an autosomal-­ dominant trait with 90–99% penetrance by the age of 30 years. Ten to 50% of individuals with Cowden syndrome have an affected parent [72]. It has generally been reported that 80% of patients with Cowden syndrome have detectable PTEN (phosphatase and tensin homolog) missense mutations [73]; however, in large cohorts actual mutation rates are reported to occur in 30–35% of patients [74]. PTEN is a tumor suppressor gene located on chromosome 10 that codes for a lipid phosphatase in the PI3K/Akt pathway to arrest the cell in G1 phase and promote apoptosis, also acting as a protein phosphatase in the MAPK pathway that regulates cell survival [75]. PTEN has been hypothesized to play a role in cell migration and adhesion due to its homology to focal adhesion molecules such as tensin and auxilin [75]. As PTEN mutations are also present in closely related clinical entities, Cowden syndrome is now considered to be within the spectrum of the PTEN hamartoma tumor syndrome, which includes Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, and Proteus-like syndrome [76]. As the majority of tumors in this syndrome are hamartomatous malformations, it has also been referred to as multiple hamartoma syndrome [77].

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a

b

Fig. 11.3  Clinical photograph of flesh-colored papular lesions at the eyelid margin (a). High-power photomicrograph of trichilemmoma with basal palisading and bland-­ looking cells with more cytoplasm than basal cell

carcinoma cells (b, H&E original magnification ×200). (Repritned from Bardenstein et al. [79]. With permission from Elsevier)

Patients have greatly increased lifetime risks for breast, thyroid, renal, and endometrial cancers and slightly elevated risks for colorectal cancers and melanoma, without any recognized genotype-phenotype correlations [78]. Eyelid trichilemmomas are hallmark manifestation of Cowden syndrome (Fig. 11.3). The tumors appear as multiple flesh-colored papular lesions of the eyelid [79]. One study found that complete PTEN loss, as determined by immunohistochemistry, occurs in 83% of trichilemmomas associated with Cowden syndrome, but only in 3% of sporadic trichilemmomas [80]. Several other ophthalmic features associated with Cowden syndrome and PTEN mutations have been described, such as anterior stromal and epithelial alterations in the cornea [81], iris ­mammillations [82], uveal ganglioneuroma [83], cataract [84], retinal angioma [85], choroidal pigmented schwannoma [86], proliferative retinopathy [87], and optic nerve head drusen [88]. In addition to the ophthalmic features, mucocutaneous lesions such as trichilemmomas, ­papillomatous papules, acral keratoses, and plantar keratoses are most striking manifestations of Cowden syndrome. More significantly, this syndrome has been found to be associated with a lifetime increased risk for breast tumors (benign 67%, malignant 25–50%) [89], thyroid tumors (benign 75%, malignant 10%) [90], and uterine tumors (benign fibroids and malignant 10%).

Other uncommon hamartomatous manifestations include gastrointestinal polyps and cerebellar dysplastic gangliocytoma (Lhermitte-Duclos ­disease) [76]. In 2013, Pilarski proposed a revision of the PTEN hamartoma tumor syndrome clinical diagnostic criteria (Table 11.3) [74], with a substantial improvement in the specificity of these criteria. Thanks to the Cleveland Clinic PTEN Risk Calculation tool, it is now possible to calculate the percentage risk for PTEN mutation and then decide whether or not to refer the patient for PTEN testing/genetics [91]. This tool is freely available online at http://www.lerner.ccf.org/gmi/ ccscore/. It weights score for each patient’s ­characteristic in order to help decide whether to recommend a genetic test. The presence of three or more trichilemmomas, among other mucocutaneous manifestations, should raise a strong suspicion of Cowden syndrome [74]. The management of Cowden syndrome consists of surveillance for early cancer detection and treatment in the hope of improving survival. All patients should undergo an annual thyroid ultrasound scan and dermatologic evaluation. Women should receive an annual mammogram and breast MRI from the age of 30 years, along with annual transvaginal ultrasound and blind suction endometrial biopsies, while prophylactic mastectomy or prophylactic hysterectomy may also be c­ onsidered

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Table 11.3  Revised PTEN hamartoma tumor syndrome clinical diagnostic criteria Operational diagnosis in an individual (either of the following) 1. Three or more major criteria, but one must include macrocephaly, Lhermitte-Duclos disease, or gastrointestinal hamartomas 2. Two major and three minor criteria Operational diagnosis in a family where one individual meets revised PTEN hamartoma tumor syndrome clinical diagnostic criteria or has a PTEN mutation: 1. Any two major criteria with or without minor criteria 2. One major and two minor criteria 3. Three minor criteria Major Breast cancer Endometrial cancer (epithelial) Thyroid cancer (follicular) Gastrointestinal hamartomas (including ganglioneuromas, but excluding hyperplastic polyps; ≥3) Lhermitte-Duclos disease (adult) Macrocephaly (≥97 percentile: 58 cm for females, 60 cm for males) Macular pigmentation of the glans penis Multiple mucocutaneous lesions (any of the following):  Multiple trichilemmomas (≥3, at least one biopsy proven)  Acral keratoses (≥3 palmoplantar keratotic pits and/or acral hyperkeratotic papules)  Mucocutaneous neuromas (≥3)  Oral papillomas (particularly on tongue and gingiva), multiple (≥3) OR biopsy proven OR dermatologist diagnosed Minor Autism spectrum disorder Colon cancer Esophageal glycogenic acanthosis (≥3) Lipomas (≥ 3) Mental retardation (i.e., IQ ≤ 75) Testicular lipomatosis Thyroid cancer (papillary or follicular variant of papillary) Thyroid structural lesions (eg, adenoma, multinodular goiter) Vascular anomalies (including multiple intracranial developmental venous anomalies) Based on data from Ref. [74]

after appropriate counseling. All adults with CS should have a colonoscopy beginning at the age of 35 years and renal imaging every 2 years, beginning at the age of 40 years [92].

Carney Complex Carney complex (CNC) is a multiple neoplasia syndrome characterized by cutaneous pigmentary abnormalities, myxomas, endocrine tumors, and schwannomas [93, 94]. It has also been designated by descriptive acronyms such as NAME syndrome (nevi, atrial myxomas, ephelides) and LAMB syndrome (lentigines, atrial myxoma, blue nevi). Carney complex should be differentiated from a completely unrelated entity “Carney triad”, which refers to gastric leiomyosarcoma,

pulmonary chondroma, and extra-adrenal paraganglioma [95]. Carney complex is inherited as an autosomal-­ dominant trait [96]. In about 30% of patients, the disease is due to de novo mutations. It is a genetically heterogeneous disease, with >70% patients with CNC carrying mutations of the PRKAR1A gene [97], which encodes the 1-α regulatory subunit of the cAMP-dependent protein kinase A and functions as a tumor suppressor gene [98]. Pathogenic PRKAR1A mutations include single base substitutions, small (≤15 bp) deletions/insertions, combined rearrangements, and large deletions [99]. More than 125 PRKAR1A gene mutations have been identified; however, linking genotype to phenotype has been challenging [100]. Although previous studies have demonstrated associations between specific mutations and CNC

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manifestations, only 3 pathogenic variants (c.82C > T, c.491_492delTG, and c.709–2_709–7 delATTTTT) have been identified in >3 unrelated pedigrees [97]. The other mutations are unique (i.e., present in a single kindred) [101]. Mutations in PRKAR1A appear to be the most common cause of CNC.  Patients carrying PRKAR1A mutations have more severe disease, with earlier presentation and higher frequency of myxomas, thyroid, and gonadal tumors, schwannomas, and lentigines compared with PRKAR1A-­negative patients [97]. However, in most cases, genotype cannot predict phenotype or penetrance [101]. Periocular involvement is frequent, both by pigmentary changes [102] and myxomas [103]. In a study of 63 patients, facial and eyelid lentigines were observed in 70%, conjunctival, caruncular pigmentation in 27%, and eyelid myxomas in 16% of the patients (Fig.  11.4) [103]. Lentigines typically involve the centrofacial area, including the lips, and the conjunctiva [104]. Cutaneous myxomas are usually less than 1 cm in diameter and often affect the eyelids, ears, and nipples but can also be seen on other areas of the face, ears, trunk, and perineum [104]. Myxomas are typically diagnosed during the teenage years and appear as sessile, small papules and large, fingerlike, pedunculated lesions [104]. The median age at diagnosis is 20  years. Cutaneous pigmentary abnormalities are the

most common presenting feature. The brown or black lentigines may be present anywhere in the body and become prominent during puberty. The most common noncutaneous lesions in CNC are cardiac myxomas (affecting 20–40% of patients), which are responsible for >50% of CNC-related mortality [105]. Although cardiac myxomas are typical, myxomas may occur in the skin and other sites. Endocrine tumors and hormonal hypersecretion may manifest as thyroid adenoma (75%), Sertoli cell tumors (33%) in males, Cushing syndrome (25%), and acromegaly (10%) [94]. Psammomatous melanotic schwannoma, a rare variant of schwannoma, is also a manifestation of Carney complex [106]. The diagnosis of CNC is made if two of the main manifestations of the syndrome are present (Table 11.4); these need to be confirmed by histology, biochemical testing, or imaging; alternatively, the diagnosis is made when one of the criteria is present and the patient is a carrier of a known inactivating mutation of the PRKAR1A gene [94]. Clinical and biochemical screening for CNC remain the gold standard for the diagnosis of CNC. Molecular testing for PRKAR1A mutations is not recommended at present for all patients with CNC, but in families with known mutations may be useful for detecting affected patients and avoiding unnecessary medical surveillance of non-carriers [107]. Considering that Carney reported that more than 50% of patients have a significant embolic event in their lifetime related to cardiac myxomas and that the ophthalmic manifestations have been shown to precede embolic events, early identification of ocular myxomas and subsequent screening and monitoring for cardiac myxoma is recommended [108].

Muir-Torre Syndrome

Fig. 11.4  Eyelid myxoma in a patient with Carney complex. Hypocellular myxomatous mass composed of ground substance and collagen fibers (H&E original magnification ×200). (Courtesy of Ralph C. Eagle Jr., MD)

Muir-Torre syndrome is a rare cancer predisposition syndrome characterized by unusual cutaneous tumors and internal malignancy [109]. It is considered to be a subset of the hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome [110]. The cutaneous tumors a­ ssociated

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Table 11.4  Clinical diagnostic criteria for Carney complex Disease manifestation

Any ≥2 present

Supplemental manifestation

≥1 Disease manifestation ≥1 Disease manifestation

Spotty skin pigmentation with a typical distribution (lips, conjunctiva and inner or outer canthi, vaginal and penile mucosa) Myxoma (cutaneous and mucosal) Cardiac myxoma Breast myxomatosis or fat-suppressed magnetic resonance imaging findings suggestive of this diagnosis Primary pigmented nodular adrenocortical disease or paradoxical positive response of urinary glucocorticosteroids to dexamethasone administration during Liddle’s test Acromegaly due to growth hormone-producing adenoma Large-cell calcifying Sertoli cell tumor or characteristic calcification on testicular ultrasonography Thyroid carcinoma or multiple, hypoechoic nodules on thyroid ultrasonography Psammomatous melanotic schwannoma Blue nevus, epithelioid blue nevus (multiple) Breast ductal adenoma (multiple) Osteochondromyxoma of bone Affected first-degree relative Inactivating mutation of the PRKAR1A gene

Based on data from Ref. [94]

with Muir-Torre syndrome include mainly sebaceous gland neoplasms (sebaceous adenoma and sebaceous carcinoma), keratoacanthoma, and basal cell carcinoma [111]. The internal malignancies include upper gastrointestinal, colorectal, endometrial, and urological tumors [112], but in rare cases glioblastoma multiforme has been described [113]. MTS is seen in about 9% of individuals with HNPCC, mainly in Caucasian and men [114]. Malignant tumors appear between 23 and 89 years of age [115]. Although Muir-Torre syndrome is characterized by autosomal-dominant inheritance, sporadic cases do occur. Similar to HNPCC, the majority of MTS cases result from highly penetrant but variably expressed germline mutations in the MSH2 and MLH1 genes, though a disease variant without mismatch repair (MMR) gene defects has also been described [116]. Ninety percent of MTS patients have mutations in MSH2, but rare cases with mutations in MSH6, PMS22 or MLH3 have been described [114]. Sebaceous neoplasms, such as adenomas, epitheliomas and carcinomas, are reported to be so

rare that finding one of these tumors should alert the clinician to the possibility of Muir–Torre syndrome [117]. Solitary or multiple sebaceous adenomas are uncommon. They are benign, yellow flesh-colored nodular tumors, approximately 0.5 cm in diameter, which occasionally ulcerate or bleed, and which grow slowly in older individuals, typically on the face (Fig.  11.5) [111, 118]. The Meibomian and Zeis glands of the eyelids are modified sebaceous glands and can also be the site of origin of sebaceous adenomas [119]. Cystic change within a sebaceous adenoma is indicative of Muir-Torre syndrome because sporadic sebaceous adenomas do not exhibit this feature [120]. Sebaceous epitheliomas are benign, yellowish papulonodules, usually present on the face and scalp, with similar appearance, localization, and age incidence as basal cell carcinomas [118]. They grow slowly and tend not to recur after treatment [118]. Sebaceous carcinomas, occasionally associated with MTS, may arise in the ocular adnexa or at extraocular sites. They clinically appear as painful red nodules, often on the upper eyelid, and

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a

b

c

d e

Fig. 11.5  Sebaceous adenomas on the face in a patient with Muir-Torre syndrome. Note a yellowish pink warty growth arising from anterior lamella of the left upper eyelid (a). Multiple yellow nodular lesions involving the central forehead, nose, and adjacent cheek area (b). Both eyelid and facial biopsies revealed sebaceous adenomas (c, original magnification ×10). Immunohistochemical

staining with an antibody to MSH-2 protein was absent in the sebaceous adenoma (d, magnification ×50). Normal positive nuclear staining of sebaceous lobules adjacent to the sebaceous adenoma serves as an internal control (e, magnification ×50). (Reprinted from Singh et  al. [119]. With permission from American Medical Association)

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may be mistaken for an inflammatory condition, such as chalazion or blepharoconjunctivitis, resulting in a delay in diagnosis [121]. Tumors occurring in the ocular adnexa are more common and account for 1% of all eyelid neoplasms, while extraocular tumors are uncommon and usually located in the head-and-neck region [118]. Although sebaceous gland carcinomas of the eyelid and extraocular sites [122] have been reported in patients with Muir-Torre syndrome, such patients also had sebaceous adenomas [123] . Rarely, keratoacanthomas may be associated with MTS. They are flesh-colored, rapidly growing, dome-shaped nodules with a central keratin plug. They may cause local destruction, especially if they are on the eyelids, and they tend to involute spontaneously after several months [118]. In a review of 120 patients with Muir-Torre syndrome, sebaceous tumors were diagnosed prior to the internal malignancy in almost 40% of patients [111]. Almost half of the patients with Muir-Torre syndrome develop colorectal adenocarcinoma and one-fourth develop genitourinary tumors. Adenocarcinoma of the colon in the setting of Muir-Torre syndrome tends to be multifocal and occurs almost a decade earlier than in sporadic cases [111]. In addition, the proximal colon is more often affected as compared with unifocal involvement of the distal colon in sporadic cases [124]. There are significant variations in the phenotypic manifestations of Muir-Torre syndrome, which in some individuals may resemble those of hereditary nonpolyposis colorectal carcinoma [125]. MTS is rarely encountered by ophthalmologists, who may not consider the systemic ­implications of certain periocular skin tumors. Importantly, these tumors present commonly on the face, and ophthalmologists may receive referrals of patients with these lesions in the periocular region [118]. Of the defining skin lesions, sebaceous adenomas and epitheliomas are the most sensitive markers of the syndrome, whereas sebaceous carcinomas and keratoacanthomas are much less frequently associated [118]. The clinical diagnostic criteria are known as Amsterdam criteria and the Bethesda guidelines,

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the latter being more sensitive; these are used also for the diagnosis of hereditary non-polyposis colorectal cancer [126, 127]. Additional microsatellite instability testing or germline mutation analysis is recommended if all of the Amsterdam criteria or one of the Bethesda guidelines is met [126, 127]. The Mayo MTS risk scoring algorithm may be used to identify patients who should undergo further germline genetic testing [128]. Management is based on screening recommendations and a surveillance program of patients with MTS and their first degree relatives (Table 11.5) [129]. Managing cutaneous MTS is challenging because patients present with multiple and disfiguring tumors. Aggressive surgical treatment usually provides a good outcome with prolonged survival, even in the presence of metastases [121]. Sebaceous adenomas and sebaceous epitheliomas are either excised or treated with cryotherapy. Sebaceous carcinomas should be widely excised. Keratoacanthomas are best treated with excision [118]. Radiation can be considered for recurrence or local metastasis, as can 5-­fluorouracil and cisplatin combination chemotherapy [130]. Table 11.5 Screening recommendations for patients with Muir-Torre syndrome and their first-degree relatives Physical examination yearly including breast examination in women, testicular and prostate examination in men, and laboratory tests including full blood cell count, carbohydrate antigen 125, carcinoembryonic antigen, fecal occult blood, and urinalysis Colonoscopy every 1–2 years from age 25 years or at 5 years before the youngest age at diagnosis of colorectal cancer in family and annually from age 40 years Pelvic examination annually in women with transvaginal ultrasonographic scan and endometrial biopsy in patients with a gene mutation, from age 25 years Consider prophylactic colectomy in patients with a gene mutation Consider gastroscopy every 1–2 years in families with a history of gastric cancer Consider renal ultrasonographic scan every 1–2 years in families with a history of renal tract cancer Based on data from Ref. [129]

11  Systemic Associations

References 1. Ponder B.  Inherited cancer syndromes. In: Carney D, Sikora K, editors. Genes and cancer. New York: John Wiley & Sons; 1990. p. 99–106. 2. Bianciotto C, Demirci H, Shields CL, et al. Metastatic tumors to the eyelid: report of 20 cases and review of the literature. Arch Ophthalmol. 2009;127(8):999–1005. 3. Boyd KP, Korf BR, Theos A.  Neurofibromatosis type 1. J Am Acad Dermatol. 2009;61(1):1–14. 4. Avery RA, Katowitz JA, Fisher MJ, et  al. Orbital/ periorbital plexiform neurofibromas in children with neurofibromatosis type 1: multidisciplinary recommendations for care. Ophthalmology. 2017;124(1):123–32. 5. Zhang ML, Suarez MJ, Bosley TM, et al. Clinicopathological features of peripheral nerve sheath tumors involving the eye and ocular adnexa. Hum Pathol. 2017;63:70–8. 6. Pai HV, Abbagani S, Jaishankar PP. Isolated neurofibroma of the eyelid mimicking recurrent chalazion. Indian J Ophthalmol. 2018;66(3):451–3. 7. Chen N, Hsu Y-H, Lee Y-C. Solitary neurofibroma of eyelid masquerading as chalazion. Int Med Case Rep J. 2017;10:177–9. 8. Savar A, Cestari DM.  Neurofibromatosis type I: genetics and clinical manifestations. Semin Ophthalmol. 2008;23(1):45–51. 9. Jain G, Jain VK, Sharma IK, et al. Neurofibromatosis type 1 presenting with ophthalmic features: a case series. J Clin Diagn Res. 2016;10(11):SR01–3. 10. Hirbe AC, Gutmann DH. Neurofibromatosis type 1: a multidisciplinary approach to care. Lancet Neurol. 2014;13(8):834–43. 11. Avery RA, Dombi E, Hutcheson KA, et  al. Visual outcomes in children with neurofibromatosis type 1 and orbitotemporal plexiform neurofibromas. Am J Ophthalmol. 2013;155(6):1089–1094.e1. 12. Altan-Yaycioglu R, Hintschich C.  Clinical features and surgical management of orbitotemporal neurofibromatosis: a retrospective interventional case series. Orbit. 2010;29(5):232–8. 13. Gandhi NG.  Treatment of neuro-ophthalmic and orbitofacial manifestations of neurofibromatosis type 1. Curr Opin Ophthalmol. 2013;24(5):506–11. 14. Rasmussen SA, Yang Q, Friedman JM. Mortality in neurofibromatosis 1: an analysis using U.S. death certificates. Am J Hum Genet. 2001;68(5):1110–8. 15. Higham CS, Dombi E, Rogiers A, et al. The characteristics of 76 atypical neurofibromas as precursors to neurofibromatosis 1 associated malignant peripheral nerve sheath tumors. Neuro Oncol. 2018; 16. Kehrer-Sawatzki H, Vogt J, Mußotter T, et al. Dissecting the clinical phenotype associated with mosaic type-2 NF1 microdeletions. Neurogenetics. 2012;13(3):229–36.

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11  Systemic Associations 64. Yin VT, Pfeiffer ML, Esmaeli B.  Targeted therapy for orbital and periocular basal cell carcinoma and squamous cell carcinoma. Ophthal Plast Reconstr Surg. 2013;29(2):87–92. 65. Chen JJ, Sartori J, Aakalu VK, et al. Review of ocular manifestations of Nevoid basal cell carcinoma syndrome: what an ophthalmologist needs to know. Middle East Afr J Ophthalmol. 2015;22(4):421–7. 66. Tang JY, Ally MS, Chanana AM, et  al. Inhibition of the hedgehog pathway in patients with basal-cell nevus syndrome: final results from the multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2016;17(12):1720–31. 67. Jain S, Song R, Xie J.  Sonidegib: mechanism of action, pharmacology, and clinical utility for advanced basal cell carcinomas. Onco Targets Ther. 2017;10:1645–53. 68. Bettoli V, Zauli S, Virgili A. Retinoids in the chemoprevention of non-melanoma skin cancers: why, when and how. J Dermatolog Treat. 2013;24(3):235–7. 69. Figueira JA, Batista FR de S, Rosso K, et al. Delayed diagnosis of Gorlin–Goltz syndrome. J Craniofac Surg. 2018;29:e530. 70. Lloyd KM, Dennis M.  Cowden’s disease. A possible new symptom complex with multiple system involvement. Ann Intern Med. 1963;58:136–42. 71. Mester J, Eng C.  Cowden syndrome: recognizing and managing a not-so-rare hereditary cancer syndrome. J Surg Oncol. 2015;111(1):125–30. 72. Schrager CA, Schneider D, Gruener AC, et al. Clinical and pathological features of breast disease in Cowden’s syndrome: an underrecognized syndrome with an increased risk of breast cancer. Hum Pathol. 1998;29(1):47–53. 73. Liaw D, Marsh DJ, Li J, et al. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet. 1997;16(1):64–7. 74. Pilarski R, Burt R, Kohlman W, et al. Cowden Syndrome and the PTEN Hamartoma tumor syndrome: systematic review and revised diagnostic criteria. J Natl Cancer Inst. 2013;105(21):1607–16. 75. Pilarski R. Cowden syndrome: a critical review of the clinical literature. J Genet Couns. 2009;18(1):13–27. 76. Zhou X-P, Marsh DJ, Morrison CD, et al. Germline inactivation of PTEN and dysregulation of the phosphoinositol-3-kinase/Akt pathway cause human Lhermitte-Duclos disease in adults. Am J Hum Genet. 2003;73(5):1191–8. 77. Weary PE, Gorlin RJ, Gentry WC, et al. Multiple hamartoma syndrome (Cowden’s disease). Arch Dermatol. 1972;106(5):682–90. 78. Tan M-H, Mester JL, Ngeow J, et al. Lifetime cancer risks in individuals with germline PTEN mutations. Clin Cancer Res. 2012;18(2):400–7. 79. Bardenstein DS, McLean IW, Nerney J, et al. Cowden’s disease. Ophthalmology. 1988;95(8): 1038–41.

127 80. Al-Zaid T, Ditelberg JS, Prieto VG, et  al. Trichilemmomas show loss of PTEN in Cowden syndrome but only rarely in sporadic tumors. J Cutan Pathol. 2012;39(5):493–9. 81. Sbordone S, Savastano A, Savastano MC, et al. Corneal confocal microscopy anomalies associated with Cowden syndrome: a case report. Case Rep Ophthalmol. 2013;4(2):76–80. 82. Suaiti L, Al-Haseni A, Lee H, et al.  Iris mammillations in a pair of twins with Cowden syndrome. JAAD Case Rep. 2016;2(4):323–5. 83. DeParis SW, Bloomer M, Han Y, et  al. Uveal ganglioneuroma due to germline PTEN mutation (Cowden syndrome) presenting as unilateral infantile glaucoma. Ocul Oncol Pathol. 2017;3(2):122–8. 84. Sellitto C, Li L, Gao J, et  al. AKT activation promotes PTEN hamartoma tumor syndrome– associated cataract development. J Clin Invest. 2013;123(12):5401–9. 85. Gicquel J-J, Vabres P, Bonneau D, et al.  Retinal angioma in a patient with Cowden disease. Am J Ophthalmol. 2003;135(3):400–2. 86. Venturini G, Moulin AP, Deprez M, et  al. Clinicopathologic and molecular analysis of a choroidal pigmented Schwannoma in the context of a PTEN hamartoma tumor syndrome. Ophthalmology. 2012;119(4):857–64. 87. Mansoor Q, Steel DHW.  Proliferative retinopathy in Cowden syndrome. Case Rep. 2012;2012(mar08 1):bcr1120115273. 88. Gama I, Almeida L.  Optic nerve head drusen as a rare manifestation of Cowden syndrome: multimodal imaging. Ophthalmology. 2017;124(8):1164. 89. Brownstein MH, Wolf M, Bikowski JB.  Cowden’s disease: a cutaneous marker of breast cancer. Cancer. 1978;41(6):2393–8. 90. Harach HR, Soubeyran I, Brown A, et al.  Thyroid pathologic findings in patients with Cowden disease. Ann Diagn Pathol. 1999;3(6):331–40. 91. Tan M-H, Mester J, Peterson C, et  al. A clinical scoring system for selection of patients for PTEN mutation testing is proposed on the basis of a prospective study of 3042 probands. Am J Hum Genet. 2011;88(1):42–56. 92. Gosein MA, Narinesingh D, Nixon CA-AC, et al. Multi-organ benign and malignant tumors: recognizing Cowden syndrome: a case report and review of the literature. BMC Res Notes. 2016;9:388. 93. Carney JA, Gordon H, Carpenter PC, et al.  The complex of myxomas, spotty pigmentation, and endocrine overactivity. Medicine (Baltimore). 1985;64(4):270–83. 94. Stratakis CA, Kirschner LS, Carney JA. Clinical and molecular features of the Carney complex: diagnostic criteria and recommendations for patient evaluation. J Clin Endocrinol Metab. 2001;86(9):4041–6. 95. Carney JA. The triad of gastric epithelioid leiomyosarcoma, pulmonary chondroma, and functioning extra-adrenal paraganglioma: a five-year review. Medicine (Baltimore). 1983;62(3):159–69.

128 96. Carney JA, Hruska LS, Beauchamp GD, et al. Dominant inheritance of the complex of myxomas, spotty pigmentation, and endocrine overactivity. Mayo Clin Proc. 1986;61(3):165–72. 97. Bertherat J, Horvath A, Groussin L, et al. Mutations in regulatory subunit type 1A of cyclic adenosine 5′-monophosphate-­ dependent protein kinase (PRKAR1A): phenotype analysis in 353 patients and 80 different genotypes. J Clin Endocrinol Metab. 2009;94(6):2085–91. 98. Stratakis CA, Kirschner LS, Carney JA, et  al. Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex. Nat Genet. 2000;26(1):89–92. 99. Salpea P, Horvath A, London E, et al. Deletions of the PRKAR1A locus at 17q24.2-q24.3  in Carney complex: genotype-­ phenotype correlations and implications for genetic testing. J Clin Endocrinol Metab. 2014;99(1):E183–8. 100. Anselmo J, Medeiros S, Carneiro V, et  al. A large family with carney complex caused by the S147G PRKAR1A mutation shows a unique spectrum of disease including adrenocortical cancer. J Clin Endocrinol Metab. 2012;97(2):351–9. 101. Liu Q, Tong D, Liu G, et al. Carney complex with PRKAR1A gene mutation: a case report and literature review. Medicine (Baltimore). 2017;96(50):e8999. 102. Cohen C, Turner ML, Stratakis CA.  Pigmented lesions of the conjunctiva in Carney’s complex. J Am Acad Dermatol. 2000;42(1 Pt 1):145. 103. Kennedy RH, Waller RR, Carney JA.  Ocular pigmented spots and eyelid myxomas. Am J Ophthalmol. 1987;104(5):533–8. 104. Horvath A, Stratakis CA.  Carney complex and lentiginosis. Pigment Cell Melanoma Res. 2009;22(5):580–7. 105. Boikos SA, Stratakis CA. Carney complex: the first 20 years. Curr Opin Oncol. 2007;19(1):24–9. 106. Carney JA. Psammomatous melanotic schwannoma. A distinctive, heritable tumor with special associations, including cardiac myxoma and the Cushing syndrome. Am J Surg Pathol. 1990;14(3):206–22. 107. Stratakis CA. Carney complex: a familial lentiginosis predisposing to a variety of tumors. Rev Endocr Metab Disord. 2016;17(3):367–71. 108. Carney JA. Carney complex: the complex of myxomas, spotty pigmentation, endocrine overactivity, and schwannomas. Semin Dermatol. 1995;14(2):90–8. 109. Muir EG, Bell AJ, Barlow KA.  Multiple primary carcinomata of the colon, duodenum, and larynx associated with kerato-acanthomata of the face. Br J Surg. 1967;54(3):191–5. 110. Hampel H, Peltomaki P. Hereditary colorectal cancer: risk assessment and management. Clin Genet. 2000;58(2):89–97.

M. Scaramuzzi et al. 111. Cohen PR, Kohn SR, Kurzrock R.  Association of sebaceous gland tumors and internal malignancy: the Muir-Torre syndrome. Am J Med. 1991;90(5):606–13. 112. Ponti G, de Leon MP. Muir-Torre syndrome. Lancet Oncol. 2005;6(12):980–7. 113. Lehrer MD, Lynch H, Glembocki DJ, et al. Glioblastoma multiforme as initial internal malignancy in Muir-Torre syndrome (MTS). JAAD Case Rep. 2015;1(6):381–3. 114. South CD, Hampel H, Comeras I, et al. The frequency of Muir-Torre syndrome among Lynch syndrome families. J Natl Cancer Inst. 2008;100(4):277–81. 115. Ponti G, Pellacani G, Seidenari S, et al.  Cancerassociated genodermatoses: skin neoplasms as clues to hereditary tumor syndromes. Crit Rev Oncol Hematol. 2013;85(3):239–56. 116. John AM, Schwartz RA.  Muir-Torre syndrome (MTS): an update and approach to diagnosis and management. J Am Acad Dermatol. 2016;74(3):558–66. 117. Coldron J, Reid I.  Muir-Torre syndrome. J R Coll Surg Edinb. 2001;46(3):178–9. 118. Tay E, Schofield JB, Rowell NP, et al. Ophthalmic presentation of the Muir Torre syndrome. Ophthalmic Plast Reconstr Surg. 2003;19(5):402–4. 119. Singh AD, Mudhar HS, Bhola R, et al.  Sebaceous adenoma of the eyelid in Muir-Torre syndrome. Arch Ophthalmol. 2005;123(4):562. 120. Burgdorf WH, Pitha J, Fahmy A.  Muir-Torre syndrome. Histologic spectrum of sebaceous proliferations. Am J Dermatopathol. 1986;8(3):202–8. 121. Gauthier A-S, Campolmi N, Tumahai P, et al. Sebaceous carcinoma of the eyelid and Muir-Torre syndrome. JAMA Ophthalmol. 2014;132(8):1025. 122. Propeck PA, Warner T, Scanlan KA.  Sebaceous carcinoma of the breast in a patient with Muir-Torre syndrome. AJR Am J Roentgenol. 2000;174(2):541–2. 123. Mencía-Gutiérrez E, Gutiérrez-Díaz E, Santos-­Briz A, et al. Sebaceous gland carcinoma of the eyelid and palpebral conjunctiva in a patient with Muir-Torre syndrome. Br J Ophthalmol. 2000;84(11):1325–6. 124. Rustgi AK.  Hereditary gastrointestinal polyposis and nonpolyposis syndromes. N Engl J Med. 1994;331(25):1694–702. 125. Kruse R, Rütten A, Lamberti C, et  al. Muir-Torre phenotype has a frequency of DNA mismatchrepair-gene mutations similar to that in hereditary nonpolyposis colorectal cancer families defined by the Amsterdam criteria. Am J Hum Genet. 1998;63(1):63–70. 126. Umar A, Risinger JI, Hawk ET, et al. Testing guidelines for hereditary non-polyposis colorectal cancer. Nat Rev Cancer. 2004;4(2):153–8.

11  Systemic Associations 127. Umar A, Boland CR, Terdiman JP, et  al. Revised bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst. 2004;96(4):261–8. 128. Roberts ME, Riegert-Johnson DL, Thomas BC, et al. A clinical scoring system to identify patients with sebaceous neoplasms at risk for the Muir–Torre variant of Lynch syndrome. Genet Med. 2014;16(9):711–6.

129 129. Jones B, Oh C, Mangold E, et al. Muir-Torre syndrome: diagnostic and screening guidelines. Australas J Dermatol. 2006;47(4):266–9. 130. Le S, Ansari U, Mumtaz A, et al. Lynch syndrome and Muir-Torre syndrome: an update and review on the genetics, epidemiology, and management of two related disorders. Dermatol Online J. 2017;23(11)

Conjunctival and Corneal Tumors: Examination Techniques

12

Jacob Pe’er and Shahar Frenkel

Introduction

External Examination

The conjunctiva is a translucent, vascular mucous membrane [1]. It may be divided into three portions: the bulbar conjunctiva, including the corneo-­ conjunctival limbus, which covers the sclera in the anterior part of the eyeball; the superior, inferior, and lateral conjunctival fornices; and the palpebral conjunctiva, including the mucocutaneous transitional zone in the eyelid margin, which covers the back surface of the upper and lower eyelids. The conjunctiva is movable over the globe and in the fornix, where it is loosely adherent to the sclera, but fixed to the posterior eyelid surface where it is markedly adherent to the tarsal plate. Conjunctival and corneal tumors are usually detected and diagnosed at a relatively early stage. Because many of these tumors have characteristic clinical features, the correct diagnosis can usually be made by an experienced ophthalmologist by clinical examination alone.

Inspection should include the face as well as the eyes, comparing both sides to detect conditions such as anisocoria, iris heterochromia and Nevus of Ota. When malignancy is suspected, it is important to palpate the preauricular (parotid), retro-auricular, and submandibular areas for enlarged lymph nodes, to detect any regional metastases.

J. Pe’er (*) · S. Frenkel Ocular Oncology Service and Ophthalmic Pathology Laboratory, Department of Ophthalmology, Hadassah - Hebrew University Medical Center, Jerusalem, Israel e-mail: [email protected]

Slit-Lamp Examination and Photography The extent of the conjunctival and corneal involvement by any tumor should be accurately defined by slit-lamp examination and documented. This is particularly important if surgery is planned, since it may be difficult to evaluate conjunctival lesions under the diffuse lighting of an operating microscope. Fluorescein, rose bengal, and lissamine green stains can be used for delineating abnormal epithelium and the tumor margins, especially with diffuse lesions. Rose bengal and lissamine green have similar staining patterns, and the latter is better tolerated by the patients [2]. The lesion should be drawn and photographed to document the clinical features and the extent. A system for clinically mapping conjunctival tumor location and extent has been described for staging purposes [3].

© Springer Nature Switzerland AG 2019 J. Pe’er et al. (eds.), Clinical Ophthalmic Oncology, https://doi.org/10.1007/978-3-030-06046-6_12

131

132

It is essential to examine the entire conjunctiva, including the upper and lower fornices, the palpebral conjunctiva, the plica semilunaris and the caruncle. The superior fornix can be visualized by double eversion, using a Desmarres retractor, or by gently pinching the skin of the upper eyelid and pulling the eyelid away from the globe while inspecting the fornix with a loupe or 20D lens. The abnormal bulbar conjunctiva should be gently pushed with a cotton-tipped applicator, to determine whether it moves freely or whether it is tethered to the sclera as a result of fibrosis or scleral invasion.

Ancillary Studies Anterior segment imaging with high-frequency ultrasonography (also known as ultrasound biomicroscopy [UBM]), anterior segment OCT, and confocal microscopy can be useful for measuring tumor thickness, evaluating invasion of adjacent structures and perhaps aiding diagnosis.

J. Pe’er and S. Frenkel

a

b

Fig. 12.1 Recurrent amelanotic melanoma. Clinical ­photograph (a). UBM showing partial thickness scleral extension (b)

a

Ultrasound Biomicroscopy Conjunctival lesions can be assessed by high-­ frequency ultrasonography to determine the tumor thickness and, its extension into the sclera and cornea or rarely, intraocular invasion [4–6] (Fig.  12.1). Low-frequency, posterior segment ultrasonography may detect advanced choroidal and orbital invasion.

b

Anterior Segment OCT Superficial conjunctival and corneal tumors that are not pigmented can be readily identified on high-resolution anterior segment OCT which can provide useful information about the tumors size, extension, shape, and internal features [7–9]. Preliminary observations suggest that OCT ­findings may even assist in differentiating and diagnosing ocular surface squamous neoplasia (Fig.  12.2) from pinguecula (Fig.  12.3) and ­pterygium (Fig. 12.4).

Fig. 12.2  Conjunctival intraepithelial neoplasia. Clinical photograph (a) and optical coherence tomography (b). Note a hyper-reflective and thickened epithelium with an abrupt transition zone from abnormal to normal epithelium, consistent with ocular surface squamous neoplasia

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Confocal Microscopy

a

In vivo confocal microscopy can be a useful tool for structural and cellular analysis of non-­ pigmented and pigmented conjunctival and corneal tumors. It is a noninvasive technique for in  vivo assessment of tissue features with high correlation to histological findings [9–13].

Systemic Imaging Other imaging methods such as computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography/CT (PET-CT) may be necessary to assess extensive local invasion, nodal disease, and systemic spread.

b

Biopsy

Fig. 12.3  Pinguecula. Clinical photograph (a) and optical coherence tomography (b). Note a normal surface epithelium with underlying hyper-reflective, subepithelial mass, consistent with pinguecula

a

The definitive diagnosis of conjunctival and corneal tumors is the histopathologic diagnosis. Nevertheless, benign-looking, asymptomatic tumors, such as nevi with cysts, are often managed by observation, with biopsy only when there is evidence of growth or malignant change. If a

b

Fig. 12.4  Pterygium. Clinical photograph (a) and optical coherence tomography (b). Note a normal surface epithelium with underlying hyper-reflective, subepithelial mass

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small tumor does require biopsy, it is preferable to completely excise the lesion, to avoid seeding of tumor cells if the tumor proves to be malignant. When complete removal of the tumor may severely compromise the ocular surface or when it is impossible to perform total excision of the lesion, it may be appropriate to perform an incisional biopsy, sampling the tumor by wedge biopsy or punch biopsy. Incisional biopsy is also appropriate when complete excision is not usually the treatment of choice (e.g., primary acquired melanosis) and with tumors that are preferably treated by radiotherapy, chemotherapy, and local means such as cryotherapy and topical chemotherapy. Exfoliative cytology has been used for diagnosing conjunctival and corneal tumors [14, 15]. However, this method samples only the superficial layers of the lesion and does not show the invasiveness of the tumor, which is important when planning management. Conjunctival map biopsies have been performed with tumors such as the pagetoid spread of sebaceous adenocarcinoma, to determine the extent of disease [16, 17]. Immunohistochemistry is routine when examining excisional or incisional biopsies of conjunctival tumors. Advanced techniques such as fluorescence in-situ hybridization (FISH), and ex-vivo fluorescence confocal microscopy have also been used [18, 19]. In recent years, genetic tests of excised conjunctiva, such as analysis of multiple DNA copy number alterations, genome-­ wide analysis, microRNA expression profile, and whole exome profiling, have been applied [20–23]. Sentinel lymph node biopsy (SLNB), which is performed in some ophthalmic oncology centers, especially in cases of conjunctival melanoma, is considered to be a safe procedure with minimal complications. However, the relation between SLNB and patient survival and tumor recurrence requires further investigation [24–26] (see Chap. 21 for details).

J. Pe’er and S. Frenkel

References 1. Pepperl JE, Ghuman T, Gill KS, et  al. Chapter 29: Conjunctiva. In: Tasman W, Jaeger EA, Duane’s Foundations of Clinical Ophthalmology, editors. Ocular anatomy, embryology and teratology, vol. 1. Philadelphia: Lippincott Williams & Wilkins; 2004. p. 1–30. 2. Machado LM, Castro RS, Fontes BM.  Staining patterns in dry eye syndrome: rose Bengal versus lissamine green. Cornes. 2009;28:732–4. 3. Damato B, Coupland SE. Clinical mapping of conjunctival melanomas. Br J Opthalmol. 2008;92:1545–9. 4. Conway RM, Chew T, Golchet P, et al.  Ultrasound biomicroscopy: role in diagnosis and management in 130 consecutive patients evaluated for anterior segment tumours. Br J Ophthalmol. 2005;89:950–5. 5. Ho VH, Prager TC, Diwan H, et al.  Ultrasound biomicroscopy for estimation of tumor thickness for conjunctival melanoma. J Clin Ultrasound. 2007;35:533–7. 6. Bianciotto C, Shields CL, Guzman JM, et  al. Assessment of anterior segment tumors with ultrasound biomicroscopy versus anterior segment optical coherence tomography in 200 cases. Ophthalmology. 2011;118:1297–302. 7. Kieval JZ, Karp CL, Abou Shousha M, et  al. Ultra-­ high resolution optical coherence tomography for differentiation of ocular surface squamous neoplasia and pterygia. Ophthalmology. 2012;119(3):481–6. 8. Thomas BJ, Galor A, Nanji AA, et  al. Ultra high-­ resolution anterior segment optical coherence tomography in the diagnosis and management of ocular surface squamous neoplasia. Ocul Surf. 2014;12:46–58. 9. Janssens K, Mertens M, Lauwers N, et al.  To study and determine the role of anterior segment optical coherence tomography and ultrasound biomicroscopy in corneal and conjunctival tumors. J Opthalmol. 2016;(Epub ahead Dec 2016). 10. Messmer EM, Mackert MJ, Zapp DM, et al.  In vivo confocal microscopy of pigmented conjunctival tumors. Graefes Arch Clin Exp Ophthalmol. 2006;244:1437–45. 11. Alomar TS, Nubile M, Lowe J, et al. Corneal intraepithelial neoplasia: in vivo confocal microscopic study with histopathologic correlation. Am J Opthalmol. 2011;151:238–47. 12. Xu Y, Zhou Z, Xu Y, et al. The clinical value of in  vivo confocal microscopy for diagnosis of ocular surface squamous neoplasia. Eye (Lond). 2012;26(6):781–7. 13. Cinotti E, Singer A, Labeille B, et  al. Handheld in  vivo reflectance confocal microscopy for the

12  Conjunctival and Corneal Tumors: Examination Techniques diagnosis of eyelid margin and conjunctival tumors. JAMA Opthalmol. 2017;135:845–51. 14. Semenova EA, Milman T, Finger PT, et al. The diagnostic value of exfoliative cytology vs histopathology for ocular surface squamous neoplasia. Am J Ophthalmol. 2009;148(5):772–8. 15. Kayat KV, Correa Dantas PE, Felberg S, et al. Exfoliative cytology in the diagnosis of ocular surface squamous neoplasms. Cornea. 2017;36:127–30. 16. Putterman AM.  Conjunctival map biopsy to determine pagetoid spread. Am J Ophthalmol. 1986;102:87–90. 17. McConnell LK, Syed NA, Zimmerman MB, et  al. An analysis of conjunctival map biopsies in sebaceous carcinoma. Ophthal Plast Reconstr Surg. 2017;33:17–21. 18. Mudhar HS, Smith K, Talley P, et al. Fluorescence in situ hybridisation (FISH) in histologically challenging conjunctival melanocytic lesions. Br J Ophthalmol. 2013;97:40–6. 19. Iovieno A, Longo C, De Luca M, et al. Fluorescence confocal microscopy for ex  vivo diagnosis of conjunctival tumors: a pilot study. Am J Ophthalmol. 2016;168:207–16. 20. Asnaghi L, Alkatan H, Mahale A, et al. Identification of multiple DNA copy number alterations includ-

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ing frequent 8p11.22 amplification in conjunctival squamous cell carcinoma. Invest Opthalmol Vis Sci. 2014;55:8604–13. 21. Takahashi H, Usui Y, Ueda S, et  al. Genome-wide analysis of ocular adnexal lymphoproliferative disorders using high-resolution single nucleotide polymorphism Array. Invest Opthalmol Vis Sci. 2015;56:4156–65. 22. Larsen AC, Mikkelsen LH, Borup R, et al. MicroRNA expression profile in conjunctival melanoma. Invest Ophthalmol Vis Sci. 2016;57:4205–12. 23. Galor A, Karp CL, Sant D, et  al. Whole exome profiling of ocular surface squamous neoplasia. Ophthalmology. 2016;123:216–7. 24. Maalouf TJ, Dolivet G, Angioi KS, et al. Sentinel lymph node biopsy in patients with conjunctival and eyelid cancers: experience in 17 patients. Ophthalmic Plast Reconst Surg. 2012;28:30–4. 25. Cohen VM, Tsimpida M, Hungerford JL, et al. Prospective study of sentinel lymph node biopsy for conjunctival melanoma. Br J Ophthalmol. 2013;97:1525–9. 26. Pfeiffer ML, Ozgur OK, Myers JN, et  al. Sentinel lymph node biopsy for ocular adnexal melanoma. Acta Ophthalmol. 2017;95:e323–8.

Conjunctival and Corneal Tumors: Classification and Differential Diagnosis

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Jacob Pe’er and Shahar Frenkel

Introduction

Anatomical Features

Many different types of tumor can arise in the conjunctiva, which is composed of a wide variety of cells that form the epithelium and the substantia propria. The bulbar conjunctiva that lies within the palpebral fissure is exposed to sunlight, which may be a factor in the development of some of the tumors. The entire conjunctiva may be affected by a wide variety of chemical, physical, and biological insults that may influence the development of some of the tumors. Most of the conjunctival and corneal tumors are diagnosed early because they are readily visible. Epithelial non-melanocytic and melanocytic tumors of the cornea are very rare and are usually the result of involvement of the cornea in conjunctival tumors. Corneal stromal tumors are almost nonexistent. The conjunctiva may be invaded by tumors from its surrounding structures  – the eyeball, eyelid, and orbit  – and may develop metastases from distant organs.

Epithelium

J. Pe’er (*) · S. Frenkel Ocular Oncology Service and Ophthalmic Pathology Laboratory, Department of Ophthalmology, Hadassah - Hebrew University Medical Center, Jerusalem, Israel e-mail: [email protected]

The conjunctival epithelium near the limbus, where it is continuous with the corneal epithelium, and in the mucocutaneous junction, where it is continuous with the eyelid skin epidermis is a non-keratinized stratified squamous epithelium. The epithelial cells are stratified columnar in the fornix and tend to be cuboidal on the bulbar and tarsal conjunctiva. Goblet cells are present in the middle and superficial layers of the epithelium and most numerous in the lower fornix and close to the plica semilunaris, being almost completely absent in the limbal areas. Melanocytes are scattered in the basal layer of the epithelium.

Stroma The conjunctival stroma is composed of a fibrovascular connective tissue that is thicker in the fornix and thinner over the globe and the posterior surface of the eyelids. It contains collagenous and elastic tissue; vessels including arteries, veins, and lymphatics; nerves; and accessory lacrimal glands of Krause and Wolfring. Like other mucous membranes, the conjunctiva contains associated lymphoid tissue. Numerous lymphocytes, plasma cells, mast cells, and neutrophils are present in the conjunctival stroma.

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Lymphocytes may be aggregated into nodules, but without the formation of follicles.

Specialized Regions Plica Semilunaris The plica semilunaris is a vertical fold of conjunctiva lying lateral to the caruncle. There are eight to ten layers of epithelial cells containing many goblet cells. The loose, highly vascular stroma may have some nonstriated muscle fibers supplied by sympathetic nerves and may contain fatty tissue. Caruncle The caruncle is a fleshy prominence located in the medial canthus. It contains both conjunctival and cutaneous structures. It is covered by nonkeratinized stratified squamous epithelium with many goblet cells and contains hair as well as sebaceous, sweat, and accessory lacrimal glands. Its blood and nerve supply is abundant. Tumors of the caruncle can be of both mucosal and cutaneous origin.

Classification of Conjunctival and Corneal Tumors The classification of the conjunctival tumors, like tumors of other parts of the body, is made according to two major lines: the tissue or cell of origin of the tumor and its being benign or malignant. In groups of tumors, there may be subtypes of tumors that, due to special histological structures, features, and location of the tumor cells, can appear or behave differently in spite of being of the same cell of origin. Most conjunctival tumors are of epithelial and melanocytic origin. The remainder arise from various elements of the conjunctival stroma and include vascular, fibrous, neural, histiocytic, myogenic, myxoid, lipomatous, and lymphoproliferative tumors. Three unique groups of conjunctival tumors are the hamartomas and choristomas, the caruncular tumors, and metastatic and secondary tumors.

The classification of conjunctival and corneal tumors that appear in this section is based primarily on the second edition of the World Health Organization (WHO) International Histological Classification of Tumors, in its volume on histological typing of tumors of the eye and its adnexa [1]. Since this classification does not include all conjunctival tumors, the list has been completed by using some other major series of conjunctival and corneal tumors [2–4]. The following list of tumors (Tables 13.1, 13.2, and 13.3) includes both common and rare, sometimes very rare, tumors, so as to familiarize the reader with the current terminology.

Differential Diagnosis Most conjunctival tumors are benign; malignant tumors are relatively rare. When considering the differential diagnosis, it is important to take account of the patient’s general health as well as the clinical features of the lesion. The more important diagnostic clues are the color of the lesion (i.e., pigmented, non-pigmented, red, pink, blue, white, or yellow); consistency (i.e., hard, soft, rubbery, gelatinous); solid or cystic nature; size; number (i.e., solitary or multiple); surface (i.e., smooth, irregular, granular, papillary, ulcerated or umbilicated, with or without keratin); Table 13.1  Major types of conjunctival tumor Epidermal Stromal

Congenital Caruncular Metastatic Secondary Simulating lesions

Non-melanocytic Melanocytic Vascular Neural Myxoid Lipomatous Melanocytic Fibrous tissue Histiocytic Myogenic Lymphoproliferative Hamartoma Choristoma

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Table 13.2  Classification of epidermal tumors of the conjunctiva Types Non-melanocytic

Subtypes Benign

Premalignant and malignant

Melanocytic

Benign

Premalignant and malignant

Squamous papilloma Keratotic plaque Keratoacanthoma Reactive hyperplasia (pseudoepitheliomatous hyperplasia) Inverted follicular keratosis Hereditary intraepithelial dyskeratosis Oncocytoma Dacryoadenoma Actinic (solar) keratosis Conjunctival intraepithelial neoplasia (CIN) Xeroderma pigmentosum Squamous cell carcinoma Mucoepidermoid carcinoma Spindle cell carcinoma Sebaceous gland carcinoma (pagetoid spread) Basal cell carcinoma Junctional nevus Compound nevus Spitz nevus Blue nevus PAM without atypia Congenital melanosis Racial melanosis PAM with atypia Melanoma arising from nevi Melanoma arising in PAM Melanoma arising de novo

shape (i.e., flat or raised, pedunculated, papillary); thickness; location (i.e., bulbar, palpebral, forniceal, caruncular); layer (i.e., epithelial or stromal); growth rate; and adherence to underlying structures, such as the sclera. Other diagnostic clues include the patient’s race, age, gender; as well as any present or previous systemic diseases, such as metabolic disease or malignancy, particularly in adjacent tissues (e.g., lacrimal drainage system, eyelids, globe, orbit).

Epidermal Epidermal tumors are usually classified into melanocytic and non-melanocytic tumors, based on the clinical presence or absence of brown-­ black pigmentation and histological evidence of melanocytes, although non-melanocytic tumors (e.g., squamous cell carcinoma) can rarely be pigmented.

Melanocytic Lesions Melanocytic lesions include nevi, primary acquired melanosis (PAM) without or with atypia, and melanomas. While melanosis is purely epithelial, nevi and melanomas also involve the stroma. While in bulbar conjunctival melanosis the lesions are movable with the conjunctiva, in melanoma, the tumor may be fixed to the underlying sclera. Staging of conjunctival melanoma can be found in the AJCC Cancer Staging Manual [5]. Non-Melanocytic Lesions Non-melanocytic lesions are usually epithelial. Epithelial tumors, such as papilloma and carcinoma, usually have irregular, granular, or papillary surface and may be leukoplakic (white, because they are covered by keratin). Sometimes they may be gelatinous in appearance. They may be superficial and thin or thick and fleshy. Conjunctival car-

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140 Table 13.3 Classification of stromal tumors of the conjunctiva Types Vascular

Subtypes Capillary hemangioma Varix Hemangiopericytoma Kaposi’s sarcoma Malignant hemangioendothelioma Cavernous hemangioma Racemose malformation Lymphangiectasia Lymphangioma Fibrous Nodular fasciitis Benign fibrous histiocytoma Fibroma Malignant fibrous histiocytoma Neural Neurofibroma (localized) Schwannoma (neurilemmoma) Neurofibroma (diffuse) Granular cell tumor Histiocytic Xanthoma Reticulohistiocytoma Juvenile xanthogranuloma Myxoid Myxoma Myogenic Rhabdomyosarcoma Lipomatous Lipoma Liposarcoma Herniated orbital fat Lymphoproliferative Benign reactive lymphoid hyperplasia Leukemic infiltrates Lymphoma

cinoma can invade the orbit, the eyelid, and the globe. Staging of conjunctival carcinoma can be found in the AJCC Cancer Staging Manual [6].

Stromal Tumors Stromal tumors, including secondary tumors and metastasis have a smooth surface, being under the conjunctival surface. The color of the tumor can be very helpful in the diagnosis. Most vascular tumors are red, pink, or sometimes blue. Fibrous tumors are white but may be pink. Neural, histiocytic, and lipomatous tumors are yellow, and lymphoid tumors and leukemic ­infiltrates are pink, similar to smoked salmon, and thus are termed “salmon patch.”

Congenital Tumors Congenital tumors diagnosed in infancy and childhood are usually hamartomatous or choristomatous lesions.

Caruncular Tumors Caruncular tumors present a special challenge of differential diagnosis of both conjunctival and cutaneous tumors (see Chap. 19).

Metastatic and Secondary Tumors In the case of metastatic tumors, there is usually a history of primary malignancy elsewhere in the body. In secondary involvement of the conjunctiva by tumors in surrounding structures, the primary tumor is usually well known, except for many cases of pagetoid spread of sebaceous gland carcinoma of the eyelid in which the presentation of the malignancy can be in the conjunctiva.

Simulating Lesions It is interesting to note that the WHO histological classification of conjunctival tumors includes lesions that simulate tumors such as pinguecula and pterygium. These most common conjunctival lesions are not real neoplasms but sometimes can be confused with real tumors when they are covered by keratin plaque or have a gelatinous appearance. Keloid is also included in this classification. Among conditions that may simulate pigmented conjunctival tumors, we have to consider drug and metallic deposits, mascara deposits, foreign body, post-inflammatory melanosis, and systemic conditions with flat pigmentary patches such as in Addison’s disease [7]. Inflammatory and infectious lesions such as lepromatous and sarcoidal nodules and, more commonly, allergic and granulomatous nodules should be included in the differential diagnosis of conjunctival tumors.

13  Conjunctival and Corneal Tumors: Classification and Differential Diagnosis

References 1. Campbell RJ, Sobin LH. Tumors of the conjunctiva and caruncle. In: Histological typing of tumours of the eye and its adnexa, World Health Organization International Histological Classification of Tumours. 2nd ed. Berlin: Springer; 1998. p. 9–15. 2. Shields CL, Shields JA. Tumors of the conjunctiva and cornea. Surv Ophthalmol. 2004;49:3–24. 3. Grossniklaus HE, Green WR, Luckenbach M, et al.  Conjunctival lesions in adults. A clinical and histopathologic review. Cornea. 1987;6:78–116. 4. Elsas FJ, Green WR. Epibulbar tumors in childhood. Am J Ophthalmol. 1975;79:1001–7.

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5. Conway RM, Graue GF, Pelayes D, et  al. Chapter 65: Conjunctival carcinoma. In: Amin MB, et al., editors. AJCC cancer staging manual. 8th ed. New York: Springer; 2017. p. 787–93. 6. Coupland SE, Barnhill R, Conway RM, et al. Chapter 66: Conjunctival melanoma. In: Amin MB, et al., editors. AJCC cancer staging manual. 8th ed. New York: Springer; 2017. p. 795–803. 7. Folberg R, Jakobiec FA, Bernardino VB, et al. Benign conjunctival melanocytic lesions. Clinicopathologic features. Ophthalmology. 1989;96:436–501.

Conjunctival and Corneal Tumors: Benign Epidermal and Melanocytic Tumors

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Jacob Pe’er and Shahar Frenkel

Introduction

Squamous Cell Papilloma

Benign tumors of the conjunctiva are much more common than malignant tumors of the conjunctiva. In this chapter, benign tumors of epithelial and melanocytic origin, which comprise the majority of the conjunctival tumors, are described. Benign conjunctival tumors of stromal origin are described in Chap. 17.

Conjunctival squamous papilloma is a benign and common epithelial tumor that can be seen at almost any age, although more commonly occurs in young adults [1–4]. More males than females develop conjunctival papilloma [4]. Conjunctival squamous papillomas are often located in the inferior fornix or bulbar conjunctiva but may appear in any part of the conjunctiva including the palpebral conjunctiva, lid margin, caruncle, and plica semilunaris. According to one study, most of the papillomas are located medially and inferiorly, a fact that is explained by the direction of the tear flow [4].

Benign Tumors of the Epithelium Abnormal cellular proliferation and differentiation that is confined to the conjunctival epithelium may cause thickening, papillary or nodular focal elevation of the conjunctiva, and sometimes plaque-like opacification (leukoplakia). Such lesions rarely progress to malignancy.

J. Pe’er (*) · S. Frenkel Ocular Oncology Service and Ophthalmic Pathology Laboratory, Department of Ophthalmology, Hadassah - Hebrew University Medical Center, Jerusalem, Israel e-mail: [email protected]

Clinical Features Childhood Papilloma In children, the papillomas have been documented to be associated with human papilloma virus (HPV) (mostly types 6, 11, and 16) infection of the conjunctiva. The papilloma appears as sessile or pedunculated pink/red fleshy fronds of tissue or finger-like projections with an irregular surface that sometimes resembles a cauliflower (Fig. 14.1a). They are often asymptomatic, without associated inflammatory reaction. However, large and more pedunculated lesions are usually symptomatic and may cause foreign body sensation, mucous secretion, hemorrhagic tears, incomplete eyelid closure, and poor cosmetic

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Fig. 14.1  Solitary sessile squamous papilloma of the bulbar conjunctiva. Clinical appearance (a). Histopathology shows papillomatous fronds of acanthotic

nonkeratinized squamous epithelium with central fibrovascular cores (b; hematoxylin and eosin, original magnification ×4)

appearance. They are usually solitary but can be bilateral and multiple and may become confluent.

goblet cells were more frequently associated with HPV infection [7]. In adults, the squamous papilloma usually has a broader base, and its acanthotic epithelium may show varying degree of epithelial pleomorphism, and even dysplasia can occur, albeit generally mild. Although the lesions are usually nonkeratinized, moderate keratinization may be present. The basement membrane is typically intact.

Adulthood Papilloma In adults, conjunctival squamous papilloma usually appears as single and unilateral lesions, commonly arising close to the limbal area or bulbar conjunctiva. They are usually flat with a broad base, may be large and cover a large area of the conjunctiva, and may cover the cornea and interfere with vision. Sometimes it may be difficult to differentiate them clinically from squamous cell carcinoma.

Histopathologic Features Histologically, the squamous papilloma of childhood is composed of epithelial projections covered by nonkeratinized acanthotic stratified squamous epithelium, which may have goblet cells, and have a fibrovascular core in which acute and chronic inflammatory cells are often found (Fig.  14.1b). The basement membrane is always intact. Various types of HPV, the most common are HPV-6 and HPV-11, have been demonstrated in these papillomas by various immunohistochemical and molecular techniques [5–7]. Some clinical and histopathological features such as extralimbal location and presence of

Treatment Small papilloma in children can be observed, as there usually is a slow spontaneous resolution. However, larger papillomas should be treated by complete surgical excision, where some prefer the use of the “no-touch technique” to avoid spreading the papilloma-related virus [3]. Others find that this spread has already occurred through the tears, and through hemorrhage at the time of the surgery and therefore do not use this technique, and opt for adjuvant topical chemotherapy, if needed. Cryotherapy is often used in conjunction with the “no-touch” surgical technique, either to the conjunctiva around the excised lesion or to the lesion itself that is then excised in a frozen state. Sometimes cryotherapy may be performed without excision, letting the lesion slough off the conjunctival ­surface later.

14  Conjunctival and Corneal Tumors: Benign Epidermal and Melanocytic Tumors

Conjunctival papillomas tend to recur often, usually when multiple lesions are caused by papillomavirus. Such lesions may be treated by adjuvant interferon alpha-2B locally or systemically [8, 9] or topical mitomycin C [10]. Others have used carbon dioxide laser vaporization [11], photodynamic therapy [12], scanning laser photocoagulation [13], or oral cimetidine [12, 14]. Papilloma recurrence is more common in children and adolescents than in adults [12]. In one study, the recurrence after surgical excision was associated with epithelial atypia [15].

I nverted Papilloma (Inverted Follicular Keratosis) The lesions derive their name from the propensity to invaginate inward into the underlying conjunctival substantia propria, instead of growing in an exophytic manner outward like the other conjunctival papillomas. Some of the lesions may show a mixed inverted-exophytic papilloma [16].

Clinical Features These are rare lesions that appear as solid or cystic solitary nodules in the conjunctiva, although they may present as papillary sessile lesion [16, 17]. They have been reported to appear in the limbal area, plica semilunaris, and tarsal conjunctiva. Histopathologic Features Lobules of proliferating epithelium without keratinization or inflammation invaginate the underlying connective tissue. Mucus-producing goblet cells are scattered throughout the lesions, and mucoid material, when it exists, is found in the wall of the cyst. Lesions without goblet cells at all were also reported [15]. Unlike inverted papillomas in other sites, such as the nose, paranasal sinuses, and lacrimal sac, conjunctival inverted papilloma does not exhibit locally aggressive behavior, does not involve extensive segments of the conjunctival epithelium, and does not display diffuse spread or multicentricity. Therefore, it is suggested that a clear

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distinction is made from inverted squamous papillomas of the nasal cavity and sinuses [18]. However, complete removal of these lesions is still recommended.

Seborrheic Keratosis Seborrheic keratosis of the conjunctiva is extremely rare, and only a very few case reports are found in the medical literature [19]. They mostly appear as a pigmented conjunctival lesion and may be misdiagnosed clinically as conjunctival melanoma. The typical basaloid cell acanthosis and keratin-filled pseudocysts confirm the diagnosis.

 eactive Epithelial Hyperplasia R (Pseudoepitheliomatous Hyperplasia and Pseudocarcinomatous Hyperplasia) This conjunctival lesion is secondary to irritation by concurrent or preexisting stromal inflammation [1–3].

Clinical Features It appears as an elevated leukoplakic pink lesion in the limbal area. Histopathologic Features Acanthosis, hyperkeratosis or parakeratosis, and subepithelial inflammation are observed. Mitotic figures may be present, but cytologic atypia is generally lacking. Due to the possible clinical and histological difficulty in differentiating such lesions from conjunctival squamous cell carcinoma, it should be completely excised, and additional cryotherapy may be considered.

Keratoacanthoma This is a variant of conjunctival reactive epithelial hyperplasia that does not show spontaneous regression [1, 3, 20].

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Clinical Features Keratoacanthoma appears as a benign, solitary, gelatinous, or leukoplakic rapidly growing nodule on the bulbar conjunctiva surrounded by dilated blood vessels [1, 3, 20, 21]. In some cases, an umbilicated center is observed (Fig. 14.2a). Histopathologic Features The lesion shows marked invasive acanthotic epithelium with keratin-filled pseudocysts, hyperkeratosis, and parakeratosis (Fig. 14.2b). Usually there is minimal cytologic atypia. In cases with a marked degree of atypia, it may be difficult to distinguish the lesion from well-differentiated squamous cell carcinoma. Treatment Therefore, conjunctival keratoacanthoma should be treated by complete excision, and additional cryotherapy should be considered.

 ereditary Benign Intraepithelial H Dyskeratosis (HBID) HBID is an autosomal dominant disorder with a high degree of penetrance occurring in descendants of an inbred isolate of European, African-­ American, and Native American (Haliwa Indian) origin in northeastern North Carolina. HBID has been subsequently detected in other parts of the

a

United States. Using genetic linkage analysis, the HBID gene was localized to chromosome 4 (4q35) [22].

Clinical Features HBID is characterized by bilateral elevated fleshy plaques on the nasal or temporal perilimbal bulbar conjunctiva, with dilated conjunctival vessels around it, causing the eye to appear red [1, 3] (Fig.  14.3a). In mild cases, the patients are asymptomatic, but in severe cases, most of the bulbar conjunctiva and cornea are involved, causing corneal opacification and vascularization leading to loss of vision. Patients may complain of foreign body sensation, photophobia, and tearing, especially in the spring. Similar lesions may occur in the buccal mucosa. Histopathologic Features The lesions are characterized by acanthosis, prominent dyskeratosis in the surface and deep epithelium, and severe chronic inflammation in the stroma (Fig. 14.3b). The basement membrane is intact. The lesions do not have malignant potential. Treatment HBID usually does not require aggressive treatment. Mild cases can be treated by ocular lubricants, and, if needed, by topical corticosteroids. Larger lesions can be treated by local excision.

b

Fig. 14.2  A rapidly growing keratoacanthoma of the bulbar conjunctiva at the limbus. Clinical appearance ­ (a). Histopathology of the lesion demonstrates squamous epithelium with invasive acanthosis and hyperkeratosis

(b; hematoxylin and eosin, original magnification ×2). (Reprinted from Munro et al. [20]. With permission from Elsevier)

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b

Fig. 14.3  Hereditary benign intraepithelial dyskeratosis. Typical clinical appearance is of a white lesion of the temporal conjunctiva with dilated conjunctival vessels around it (a). Histopathology showing acanthosis, hyperkeratosis,

dyskeratosis, and marked chronic inflammation in the stroma beneath the intact basement membrane (b; hematoxylin and eosin, original magnification ×20). (Courtesy of Gordon Klintworth, MD)

Mucous membrane grafting can be used when the excision is wide. Recurrence of HBID lesions is common.

lesion in older individuals, mostly women [2, 24, 25]. Histologically, large cells with eosinophilic granular cytoplasm are arranged in nests, cords, or sheets and may form glandular or ductal structures. Ultrastructurally, the cytoplasm is laden with mitochondria. The lesion is treated by simple excision. Rarely, the tumor may undergo carcinomatous transformation.

Dacryoadenoma Dacryoadenoma is a rare conjunctival tumor that occurs in children and young adults. It appears as a translucent pink lesion in the bulbar, forniceal, or palpebral conjunctiva [3]. It is uncertain whether the lesion is congenital or acquired. Histologically, it is a benign epithelioid cell proliferation forming glandular lobules, similar to the lacrimal gland. In one reported case, scattered myoepithelial cells were associated with acinar-­ type epithelium, and goblet cells were intermixed [23]. The lesions are treated by simple excision.

Oncocytoma Oncocytoma, known also as oxyphilic cell adenoma, is a rather common lesion of the lacrimal gland. It often arises in the caruncle or adjacent plica semilunaris and canthal conjunctiva as a slowly-growing benign yellow-tan or reddish

Epithelial Cysts Conjunctival cysts are common and may be congenital or acquired. The acquired cysts are more common and are mostly epithelial inclusion cysts that can occur spontaneously or following surgical or nonsurgical trauma [1, 3, 26] (Fig. 14.4). Other common cysts are ductal cysts, usually of accessory lacrimal gland origin (Fig. 14.5).

Clinical Features The conjunctival cyst is a smooth translucent lesion that contains clear fluid, although the fluid may be turbid (Fig.  14.6) or contain epithelial debris in the lumen that is layered like pseudohypopyon (Fig. 14.7). In dark-skinned patients, the cyst can be pigmented.

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Fig. 14.4  Epithelial inclusion cyst. Multiple cysts in the inferior fornix (a). A large conjunctival cyst in the nasal bulbar conjunctiva that occurred after strabismus surgery (b)

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Fig. 14.5  Ductal cyst. Bluish cyst in the temporal bulbar conjunctiva. Posterior margin of the cyst cannot be visualized (a). The cyst lined by two cell layers, with luminal cells showing apical snouts, consistent with apocrine differentiation. The double cell lining is consistent with a

ductal-type cyst, possibly from an accessory lacrimal gland. Apocrine differentiation may be metaplastic (b,  hematoxylin and eosin stain, 40× magnification). (Reprinted with permission from Bryn Mawr Communications. Aponte et al. [51])

Histopathologic Features The epithelial inclusion cyst is lined by conjunctival epithelium. The lumen can be clear or it can contain mucinous material, epithelial debris, and occasionally keratin. Ductal cysts are lined by two layers of epithelium and may contain PAS-­ positive material.

Treatment The cyst can be stable and asymptomatic or can enlarge and become symptomatic, necessitating excision. In most cases, over the long-term follow-­up, the cyst eventually undergoes spontaneous resolution. Successful removal of conjunctival cysts with high-frequency radio-wave electrosurgery was reported [27].

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Fig. 14.6  Conjunctival epithelial cyst with lipid contents (a). Anterior segment OCT reveals fat filled content (b, droplets)

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Fig. 14.7  Conjunctival epithelial cyst with layered contents (a). Anterior segment OCT reveals multiple levels within cysts (b)

Keratotic Plaque

Actinic Keratosis

This is a leukoplakic lesion that may develop in the limbal or bulbar conjunctiva, usually in the interpalpebral region (Fig.  14.8) [1, 2]. Histologically, there is a focal thickening of keratin and epithelial layer, characterized mainly by acanthosis, hyperkeratosis, or parakeratosis. No dyskeratosis is seen. These lesions have little or no potential for carcinomatous changes.

Actinic keratosis of the conjunctiva is a rarely-­ diagnosed focal leukoplakic lesion occurring at the intrapalpebral limbus, usually located over a chronically inflamed pinguecula or pterygium [2, 3, 28]. Rare cases of tarsal conjunctival involvement were reported [29]. Actinic Keratosis is classified among precancerous lesions, and it is also referred to as conjunctival dysplasia, actinic

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Fig. 14.8 Keratotic plaque. Clinical appearance (a). Conjunctiva with loss of goblet cells, hyperkeratotic epithelium, and Underlying stroma with basophilic elastotic

degeneration (b, Hematoxylin & Eosin ×20). (Courtesy of Gabreilla Yeaney, MD, Cleveland, Ohio)

keratosis variety. Histologically, the epithelium exhibits acanthosis, hyperkeratosis, and ­occasionally parakeratosis. The degree of dysplasia is minimal. Due to suspicion of a squamous cell carcinoma, these lesions are usually excised. Treatment by topical Imiquimod was successful in one reported case [30].

It appears in all races, although it is more common in Caucasians. Many ophthalmic oncologists and pathologists will consider nevi that appear at birth or within the first 6 months of life as congenital nevi, and those that appear more than 6  months after birth to be acquired. Most acquired conjunctival nevi will appear during the first two decades of life. Melanocytic conjunctival lesions that appear later in life should be suspicious for PAM or melanoma (Box 14.1).

Benign Melanocytic Tumors Conjunctival nevi are the most common conjunctival lesions. The various types of nevi are discussed herein, together with other benign melanocytic lesions of the conjunctiva, the episclera and sclera, such as complexion-associated melanosis, ocular melanocytosis, and primary acquired melanosis (PAM) without atypia. There are many other pigmented conjunctival lesions that are not of melanocytic origin and should always be included in the differential diagnosis of melanocytic conjunctival lesions (see Chap. 15).

Conjunctival Nevus Introduction The circumscribed nevus is the most common melanocytic conjunctival tumor [31, 32].

Box 14.1. Clinical Features of Conjunctival Nevus that Are Suspicious for Melanoma

• • • •

Onset in adulthood Recent growth of the nevus Recent color change of the nevus Location other than bulbar conjunctiva, plica semilunaris, or caruncle • Prominent feeder vessels • Recurrence of excised lesion

Clinical Features Conjunctival nevi are typically located in the interpalpebral bulbar conjunctiva, commonly near the limbus, and rarely involve the cornea

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[32]. The finding of melanocytic tumors in locations other than bulbar conjunctiva, plica ­semilunaris, and caruncle is rare and should raise the suspicion for PAM or malignant melanoma. Clinically, conjunctival nevus is a discrete, variably pigmented, slightly elevated sessile lesion, which in most cases contains cystic structures that can be seen by the naked eye, slit-lamp biomicroscopy (Fig.  14.9), or anterior segment OCT (Fig. 14.10). Conjunctival nevi may vary in size from tiny lesions to ones that occupy large parts of the bulbar conjunctiva (Fig. 14.11) [33]. a

Nevi may become darker or lighter but usually will not change in size and color after adolescence. Changes in adulthood should raise the suspicion for malignant transformation. The overall risk of malignant transformation is about 1% [32]. The presence of cystic structures can help in differentiating nevi from other possible amelanotic conjunctival lesions. In childhood and adolescence, conjunctival nevi may become more pink and congested, due to inflammatory infiltration. These inflamed nevi will be discussed separately.

b

Fig. 14.9 A typical partially pigmented compound conjunctival nevus with cystic elements, in an atypi­ cal location in the upper bulbar conjunctiva at the limbus

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(a). Histopathology of a compound nevus of the conjunctiva with cystic structures lined by conjunctival epithelium (b; hematoxylin and eosin, original magnification ×10)

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Fig. 14.10  A partially pigmented conjunctival nevus. Intrinsic cysts are not readily identified (a). Anterior segment OCT reveals multiple cysts within the nevus (b)

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Fig. 14.11  Large conjunctival nevus. Clinical appearance (a). Histopathology revealed a compound nevus with cystic structures lined by conjunctival epithelium (b; hematoxylin and eosin, original magnification ×10)

Histopathologic Features Conjunctival nevi range from junctional through compound to subepithelial nevi and reflect stages in the evolution of the nevus. Most excised nevi that are examined in the ophthalmic pathology laboratories are compound nevi. Two distinctive types of nevus cells were described in the conjunctiva, balloon cells and spindle cells [34, 35], and they usually appear in otherwise typical conjunctival nevus. About half of the conjunctival nevi express BRAF and NRAS mutations [36]. Junctional Nevus The junctional nevi usually appear as focal, flat, well-circumscribed lesions with various amounts of pigmentation. They are found only early in life and shows nests of nevus cells along the interface of the epithelium and the substantia propria. The cells in the junctional nevus can be round to oval, plump, epithelioid, cuboidal, or lymphocyte-like cells. They can form single, confluent, or irregular nests anterior to the epithelial basement membrane which is in general intact. The epithelium overlying the nests is commonly reduced to a thin rim. These lesions may be confused with primary acquired melanosis; the latter usually appears in adults.

Compound Nevus Compound conjunctival nevi represent an intermediate stage between the early junctional and late subepithelial nevus stage. They usually appear as elevated, well-circumscribed, pigmented lesions. Nests of nevus cells are found in the substantia propria in addition to the junctional area and have less cytoplasm, which may reflect maturation. Solid nests of epithelium and ­epithelial cysts are very common within a compound nevus and may confuse the pathologist who is not familiar with conjunctival nevi (Fig. 14.11). Subepithelial Nevus Subepithelial nevi are believed to represent the last stage of conjunctival nevus, characterized by migration of intraepithelial nevus cells into the substantia propria, followed by the disappearance of the junctional component. They appear as elevated, well-circumscribed, pigmented lesions. Microscopically, these nevi typically appear as a symmetrically arranged intrastromal proliferation of predominantly small lymphocytoid melanocytes, often organized in large nests. Cystic and solid nests of conjunctival epithelium entrapped in melanocytic proliferation are seen in about half of the lesions [31].

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Clinicopathologic Variants Spitz Nevus A more distinctive type of conjunctival nevus is the Spitz nevus, which has been reported only in childhood and adolescence [37]. Clinically, these lesions are rapidly growing non-pigmented lesions that should be differentiated from granulation tissue (“pyogenic granuloma”) and, more importantly, from melanoma, which is extremely uncommon in children. Histologically, conjunctival Spitz nevi feature fascicles of spindle nevus cells that are usually oriented perpendicular to

the epithelial surface and are uniformly and symmetrically arranged, unlike spindle cells in typical conjunctival nevi that are oriented parallel to the surface. Mitotic figures reflect the rapid clinical growth and do not indicate malignancy [31]. Blue Nevus Blue and cellular blue nevi are rare conjunctival lesions that arise from neural crest cells, are situated in the deep conjunctival substantia propria, and do not reach the surface epithelium (Fig. 14.12). Clinically, they appear brown or black and have a benign clinical course [31, 38, 39]. They can be

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Fig. 14.12  Conjunctival blue nevus. The nevus is located under the conjunctival stroma (a) confirmed by anterior segment OCT (b). Appearance following excision that involved partial thickness scleral dissection, requiring scleral graft (c). Histopathology showing flat collection of densely pigmented spindle melanocytes and melanophages on scleral surface (d, Hematoxylin & Eosin ×20). Bleached

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stain reveals abundant cytoplasm, bland nuclei and inconspicuous nucleoli (e, ×40). Immunohistochemistry for SOX10 highlights the melanocytic nuclei, (f, ×40 red chromogen) HMB45 the melanocytic cytoplasm (g, ×40 red chromogen), and CD163 highlights admixed macrophages (h, ×40 red chromogen). (Courtesy of Gabreilla Yeaney, MD, Cleveland, Ohio)

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Fig. 14.12 (continued)

located in any part of the conjunctiva although most commonly in the bulbar conjunctiva [39]. Histologically, the blue nevus is composed of spindle-shaped cells with uniform melanin pigmentation. Elements of a blue nevus may be present in a typical conjunctival nevus. Such lesions have been termed “mixed nevus.” In cellular blue nevi, the fascicles of spindle-shaped cells are admixed with fibrillar collagen. There has been only one report of conjunctival melanoma arising from a blue nevus [40]. Inflamed Juvenile Conjunctival Nevus Inflamed juvenile conjunctival nevus (IJCN) is a benign, juxta-limbal nevus that appears in children and adolescents, can grow rapidly, shows

lesional redness, often shows cystic structures, and can be surrounded by vascular congestion [41]. Therefore, these lesions are frequently approached with undue concern by patients and clinicians, usually suspecting malignancy. More than half of these nevi are amelanotic, and changes in the pigmentation of amelanotic lesions have been documented (Fig. 14.13a). Histologically, these rapidly growing lesions do not differ from simple compound conjunctival nevi in their benign histopathological features [41]. Cystic and solid epithelial elements are found in most of these nevi. In all lesions, there is significant polyclonal lymphocytic infiltration in and around the nevus, and significant infiltration of eosinophils is found in areas in most of these

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Fig. 14.13  Amelanotic inflamed juvenile conjunctival nevus in the temporal conjunctiva with cystic elements and dilated vessels around it (a) Histopathology showing

nevus nests with marked chronic inflammation around it and a remarkable number of eosinophils (b; hematoxylin and eosin, original magnification ×40)

nevi (Fig.  14.13b) [41, 42]. Periods of rapid growth of inflamed nevi represent inflammatory infiltration and cystic enlargement, rather than malignant proliferation. IJCNs are almost always associated with symptomatic allergic conjunctivitis or asymptomatic conjunctival papillary reaction. Increased expression of nerve growth factor (NGF), eosinophils, and mast cells in IJCN and modulation of eosinophil properties by lesion fibroblasts partly through NGF suggest a possible association between IJCN and allergic inflammation [43]. Typical cases of IJCN can be differentiated on clinical grounds from conjunctival melanoma. IJCN should also be differentiated from “salmon patch” lesions of conjunctival lymphoma, which is exceedingly rare in childhood, and the polyclonality of the lymphoid infiltrate that rule out the diagnosis of lymphoma [42]. The patient’s young age and the cystic nature of typical lesions are indicators of a benign lesion.

local excision of the lesion should be considered [32]. In general, incisional biopsy is contraindicated in lesions that can be resected entirely. Some of the indications for excisional biopsy of conjunctival nevi include the recent growth of the nevus, recent color change of the nevus, cosmetic concerns, recurrence of the excised lesion, and clinical suspicion of malignant melanoma. Parts of the lesion can be amelanotic, which may lead to an incomplete surgical resection. At the time of excision, the entire mass is removed, and if adherent to the globe, a thin lamella of underlying sclera is also removed with the lesion. Excision of wide margins and cryotherapy to the tumor bed and the resection margins are employed by some surgeons to prevent recurrence, as the majority of cases that are excised are due to suspicion for malignant transformation. Laser photoablation of conjunctival nevi has been shown to be a safe and effective treatment [44, 45]. In cases of typical IJCN, observation alone may suffice, although excisional biopsy is recommended in atypical lesions or whenever the clinician cannot make a definite diagnosis of IJCN. Similarly, lesions causing functional problems, such as dellen, interference with contact lens wear, or a significant cosmetic blemish, should be excised.

Treatment Most conjunctival nevi do not require excision, since most patients relate that the lesion has been present and stable for many years, often since childhood or adolescence. The best management is usually periodic observation with a photographic comparison. If growth is documented,

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Complexion-Associated Conjunctival Pigmentation (Racial Melanosis) Complexion-associated conjunctival pigmentation, also known as racial pigmentation, is a common, bilateral condition of flat conjunctival pigmentation found in individuals with a dark complextion [3, 31]. However, distribution of pigmentation may be asymmetric.

Clinical Features The pigmentation is commonly present at the limbus, often for 360°, and may involve the adjacent cornea and limbal conjunctiva. Uncommonly, pigmentation may involve the fornix and rarely the palpebral conjunctiva. Histopathologic Features The basal layer of the conjunctival epithelium appears hyperpigmented due to benign melanocytes located in this layer. Treatment As malignant transformation is extremely rare in complexion-associated melanosis, apart from observation, there is no need for surgical treatment.

J. Pe’er and S. Frenkel

Clinical Features The surface of the eye appears slate gray or blue and not brown or black as seen in conjunctival melanocytic lesions, due to the Tyndall effect of the pigmented melanin that is seen through the layers of the episclera and sclera (Fig. 14.14). Histopathologic Features Since the pigmentation is due to dendritic melanocytes that are present within the episcleral and scleral tissue, it does not move with the bulbar conjunctiva. Treatment Conjunctival melanoma has not been described in melanosis oculi. However, the risk of uveal melanoma is 1:400. Therefore, affected patients should be followed regularly for the development of uveal melanoma [47].

 rimary Acquired Melanosis (PAM) P Without Atypia Primary acquired melanosis appears as a flat, variably brown, and usually monocular lesion. Histologically, PAM lesions are flat, intraepithe-

 ongenital Melanosis Oculi C (Congenital Ocular Melanocytosis) Congenital melanosis oculi is a pigmentary condition of the sclera and uvea that can be associated with periocular skin, orbit, meninges, and soft palate pigmentation [3, 31]. In this condition, the conjunctiva is usually not pigmented; it is included here because it is often considered in the clinical differential diagnosis of a conjunctival pigmented lesion. Due to its diffuse pattern, congenital melanosis oculi is often confused with conjunctival primary acquired melanosis. When the periocular skin is involved, the condition is called “oculodermal melanocytosis” or “nevus of Ota” [46] (Fig. 14.8).

Fig. 14.14  Congenital melanosis oculi with gray-blue pigmentation of the sclera

14  Conjunctival and Corneal Tumors: Benign Epidermal and Melanocytic Tumors

lial melanocytic lesions and divided into two major groups: PAM without atypia and PAM with atypia. Both types of PAM are discussed in Chap. 15.

Tumors of the Caruncle The caruncle contains both conjunctival and cutaneous elements. Consequently, any tumor of the conjunctiva and skin may occur in the caruncle. In large series of caruncular lesions [48–50], the vast majority were benign lesions, led by nevi and squamous papillomas. The caruncle is the most common site for oncocytoma [24, 25]. Only about 5% of the lesions in these series were premalignant and malignant tumors (for details, see Chap. 19).

References 1. Spencer WH.  Chapter 2, Conjunctiva. In: Spencer WH, editor. Ophthalmic pathology, an atlas and textbook. 4th ed. Philadelphia: Saunders; 1996. p. 106–25. 2. Campbell RJ, Sobin LH.  Tumors of the conjunctiva and caruncle. In: Histological typing of tumours of the eye and its adnexa, World Health Organization histological classification of tumours. 2nd ed. Berlin: Springer; 1998. p. 9–15. 3. Shields CL, Shields JA.  Tumors of the conjunctiva and cornea. Surv Ophthalmol. 2004;49:3–24. 4. Sjo N, Heegaard S, Prause JU.  Conjunctival papilloma. A histopathologically based retrospective study. Acta Ophthalmol Scand. 2000;78:663–6. 5. Lass JH, Jenson AB, Papale JJ, et al. Papillomavirus in human conjunctival papillomas. Am J Ophthalmol. 1983;95:364–8. 6. Sjo NC, von Buchwald D, Cassonnet P, et al. Human papillomavirus in normal conjunctival tissue and in conjunctival papilloma: types and frequencies in a large series. Br J Ophthalmol. 2007;91:1014–5. 7. Mlakar J, Kocjan BJ, Hošnjak L, et al. Morphological characteristics of conjunctival squamous papillomas in relation to human papillomavirus infection. Br J Ophthalmol. 2015;99:431–6. 8. Schechter BA, Rand WJ, Velazquez GE, et  al. Treatment of conjunctival papillomata with topical interferon Alfa-2b. Am J Ophthalmol. 2002;134:268–70.

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9. Lass JH, Foster CS, Grove AS, et al. Interferon-alpha therapy of recurrent conjunctival papillomas. Am J Ophthalmol. 1987;103:294–301. 10. Hawkins AS, Yu J, Hamming NA, et al. Treatment of recurrent conjunctival papillomatosis with mitomycin C. Am J Ophthalmol. 1999;128:638–40. 11. Bosniak SL, Novick NL, Sachs ME.  Treatment of recurrent squamous papillomata of the conjunctiva by carbon dioxide laser vaporization. Ophthalmology. 1986;93:1078–82. 12. Kaliki S, Arepalli S, Shields CL, et al. Conjunctival papilloma: features and outcomes based on age at initial examination. JAMA Ophthalmol. 2013;131:585–93. 13. Belfort RN, Isenberg J, Castillejos AG, et al.  Novel treatment of papillomatous conjunctival lesions using pattern scanning laserphotocoagulation: 1-Year results. Ocul Surf. 2018;16:337. 14. Shields CL, Lally MR, Singh AD, et al. Oral cimetidine (Tagamet) for recalcitrant, diffuse conjunctival papillomatosis. Am J Ophthalmol. 1999;128:362–4. 15. Yazu H, Dogru M, Miyauchi J, et al. Association of epithelial atypia with recurrence after surgical excision in conjunctival papilloma. Eye Contact Lens. 2017:1. https://doi.org/10.1097/ICL.0000000000000330. 16. Streeten BW, Carrillo R, Jamison R, et  al. Inverted papilloma of the conjunctiva. Am J Ophthalmol. 1979;88:1062–6. 17. Stagner AM, Jakobiec FA, Chi A, et al. Conjunctival inverted squamous papilloma: a case report with immunohistochemical analysis and review of the literature. Surv Ophthalmol. 2015;60:263–8. 18. Jakobiec FA, Harrison W, Aronian D. Inverted mucoepidermoid papillomas of the epibulbar conjunctiva. Ophthalmology. 1987;94:283–7. 19. Tseng SH, Chen YT, Huang FC, et  al. Seborrheic keratosis of conjunctiva simulating a malignant melanoma: an immunocytochemical study with impression cytology. Ophthalmology. 1999;106:1516–20. 20. Munro S, Brownstein S, Liddy B. Conjunctival keratoacanthoma. Am J Ophthalmol. 1993;116:654–5. 21. Oellers P, Karp CL, Shah RR, et al. Conjunctival keratoacanthoma. Br J Ophthalmol. 2014;98:275–6. 22. Allingham RR, Seo B, Rampersaud E, et al. A duplication in chromosome 4q35 is associated with hereditary benign intraepithelial dyskeratosis. Am J Hum Genet. 2001;68:491–4. 23. Jakobiec FA, Perry HD, Harrison W, et  al. Dacryoadenoma. A unique tumor of the conjunctival epithelium. Ophthalmology. 1989;96:1014–20. 24. Say EA, Shields CL, Bianciotto C, et  al. Oncocytic lesions (oncocytoma) of the ocular adnexa: report of 15 cases and review of literature. Ophthal Plast Reconstr Surg. 2012;28:14–21. 25. Østergaard J, Prause JU, Heegaard S.  Oncocytic lesions of the ophthalmic region: a clinicopathologi-

158 cal study with emphasis on cytokeratin expression. Acta Ophthalmol. 2011;89:263–7. 26. Kalantzis GK, Verity DH, Rose GE.  Periocular implantation cysts: a late complication of ophthalmic surgery. Eye (Lond). 2014;28:1004–7. 27. Park J, Lee S, Suh E.  Removal of conjunctival cyst with high-frequency radio-wave electrosurgery. Can J Ophthalmol. 2015;50:378–83. 28. Mauriello JA Jr, Napolitano J, McLean I.  Actinic keratosis and dysplasia of the conjunctiva: a clinicopathological study of 45 cases. Can J Ophthalmol. 1995;30:312–6. 29. Khan S, Chak M. A rare presentation of actinic keratosis affecting the tarsal conjunctiva and review of the literature. Case Rep Ophthalmol Med. 2018;12:4375354. 30. Rowlands MA, Giacometti JN, Servat J, et al. Topical imiquimod in the treatment of conjunctival actinic heratosis. Ophthalmic Plast Reconstr Surg. 2017; 33:e21–3. 31. Folberg R.  Chapter 2, Melanocytic lesions of the conjunctiva. In: Spencer WH, editor. Ophthalmic pathology, an atlas and textbook. 4th ed. Philadelphia: Saunders; 1996. p. 125–55. 32. Shields CL, Fasiudden AF, Mashayekhi A, et  al. Conjunctival nevi: clinical features and natural course in 410 consecutive patients. Arch Ophthalmol. 2004;122:167–75. 33. Shields CL, Regillo AC, Mellen PL, et al. Giant conjunctival nevus: clinical features and natural course in 32 cases. JAMA Ophthalmol. 2013;131:857–63. 34. Thompson JM, Bermudez-Magner JA, Barker NH, et al.  Balloon cell nevi of the conjunctiva: Clinico­ pathologic correlation and literature review. Surv Ophthalmol. 2015;60:481–5. 35. Seregard S.  Pigmented spindle cell naevus of reed presenting in the conjunctiva. Acta Ophthalmol Scand. 2000;78:104–6. 36. Francis JH, Grossniklaus HE, Habib LA, et al. BRAF, NRAS, and GNAQ Mutations in Conjunctival Melanocytic Nevi. Invest Ophthalmol Vis Sci. 2018; 59:117–21. 37. Kantelip B, Boccard R, Nores JM, et al. A case of conjunctival Spitz nevus: review of literature and comparison with cutaneous locations. Ann Ophthalmol. 1989;21:176–9.

J. Pe’er and S. Frenkel 38. Blicker JA, Rootman J, White VA. Cellular blue nevus of the conjunctiva. Ophthalmology. 1992;99:1714–7. 39. Sayed-Ahmed I, Murillo JC, Monsalve P, et  al. Blue Nevi of the ocular surface: clinical characteristics, pathologic features, and clinical course. Ophthalmology. 2018;125(8):1189–98. 40. Demirci H, Shields CL, Shields JA, et al. Malignant melanoma arising from unusual conjunctival blue nevus. Arch Ophthalmol. 2000;118:1581–4. 41. Zamir E, Mechoulam H, Micera A, et  al. Inflamed juvenile conjunctival naevus: clinicopathological characterisation. Br J Ophthalmol. 2002;86:28–30. 42. Choi EK, Chévez-Barrios P.  Inflamed conjunctival nevi: histopathological criteria. Arch Pathol Lab Med. 2014;138:1242–6. 43. Levi-Schaffer F, Micera A, Zamir E, et  al. Nerve growth factor and eosinophils in inflamed juvenile conjunctival nevus. Invest Ophthalmol Vis Sci. 2002;43:1850–6. 44. Shin KH, Hwang JH, Kwon JW. Argon laser photoablation of superficial conjunctival nevus: results of a 3-year study. Am J Ophthalmol. 2013;15:823–8. 45. Park YM, Lee JE, Lee JS.  Efficacy of Pattern Scan Laser photocoagulation for superficial conjunctival nevi ablation. Lasers Med Sci. 2016l;31:1037–9. 46. Plateroti AM, Scavella V, Abdolrahimzadeh B, et al.  An update on oculodermal melanocytosis and rare associated conditions. Semin Ophthalmol. 2017;32: 524–8. 47. Singh AD, De Potter P, Fijal BA, et  al. Lifetime prevalence of uveal melanoma in white patients with ocula (dermal) melanocytosis. Ophthalmology. 1998;105:195–8. 48. Santos A, Gomez-Leal A. Lesions of the lacrimal caruncle. Clinicopathologic features. Ophthalmology. 1994;101:943–9. 49. Ostergaard J, Prause JU, Heegaard S.  Caruncular lesions in Denmark 1978–2002: a histopathological study with correlation to clinical referral diagnosis. Acta Ophthalmol Scand. 2006;84:130–6. 50. Kaeser PF, Uffer S, Zografos L, et  al. Tumors of the caruncle: a clinicopathologic correlation. Am J Ophthalmol. 2006;142:448–55. 51. Aponte EP, Schoenfield L, Stern RM, et al. A ductal cyst of lacrimal origin. Adv Ocul Care. 2010:29–30.

Conjunctival and Corneal Tumors: Ocular Surface Squamous Neoplasia

15

Jacob Pe’er, Shahar Frenkel, and Arun D. Singh

Introduction Ocular surface squamous neoplasia (OSSN) is a term used for the precancerous and cancerous epithelial lesions of the conjunctiva and cornea [1, 2]. It includes dysplasia, carcinoma in situ (CIS), and invasive squamous cell carcinoma (SCC). The most common previously used names for the intraepithelial lesions are “intraepithelial epithelioma,” “Bowen’s disease” of the conjunctiva, or “Bowenoid epithelioma.” Because of differences in histology of conjunctiva and skin, the term Bowen’s disease should be reserved only for cutaneous lesions. Other terms for the intraepithelial ocular surface neoplasia are conjunctival intraepithelial neoplasia [3], corneal intraepithelial neoplasia (CIN), or both corneal and conjunctival intraepithelial neoplasia (CCIN). Since

J. Pe’er (*) · S. Frenkel Ocular Oncology Service and Ophthalmic Pathology Laboratory, Department of Ophthalmology, Hadassah - Hebrew University Medical Center, Jerusalem, Israel e-mail: [email protected] A. D. Singh Department of Ophthalmic Oncology, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA

the term OSSN does not distinguish between premalignant squamous epithelial dysplasia including carcinoma in situ from invasive SCC, it should not be used in surgical pathology reports to avoid mismanagement and can be used only clinically [4].

Epidemiological Aspects OSSN is found in all races. It is uncommon in Northern countries but common in countries that are closer to the equator and where exposure to sunlight is greater. In an NIH study, the incidence of OSSN was 0.3 per million in the United States [5]. In a study that was performed in Uganda, the incidence of OSSN was 1.3 per million, and in Australia, the incidence is reported to be as high as 19 per million population [1]. OSSN occurs predominantly in adults, although a few cases in children have been reported, especially in those with xeroderma pigmentosum [6]. In most series, OSSN is more common in men [5], an occurrence which is explained by their greater exposure to sunlight. In one large series, men also showed higher-grade lesions [7]. According to some studies, patients with CIN are younger by 5–9 years than those with invasive SCC, a fact that implies the precancerous nature of the CIN [8].

© Springer Nature Switzerland AG 2019 J. Pe’er et al. (eds.), Clinical Ophthalmic Oncology, https://doi.org/10.1007/978-3-030-06046-6_15

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Etiology and Associated Diseases

Human Papillomavirus

There are several possible factors and mechanisms that may explain or are associated with the development of OSSN. The most important ones are exposure to solar ultraviolet radiation, human papillomavirus, AIDS, and the stem cell theory.

In recent years, human papillomavirus (HPV), mainly type 16, has been demonstrated in tissues of OSSN [13]. DNA of HPV was found in fresh tissue of OSSN, using amplification with PCR and sequencing of the DNA, in ocular surface swabs of patients with OSSN and in studies of formalin-fixed paraffin-embedded tissue, using immunostaining. However, HPV was also detected in uninvolved eyes with apparently healthy conjunctiva and in cases of persistence of infection many years after successful eradication of OSSN lesions. In one study, where evidence for HPV was analyzed by immunohistochemistry and multiplex polymerase chain reaction (PCR), no HPV was detected in OSSN lesions [14]. Another study showed no statistically significant association between anti-HPV antibody status and the risk of conjunctival neoplasia [15]. These facts lead to the assumption that HPV alone may be incapable of causing OSSN [16], and that other factors in conjunction with HPV are involved in causation of OSSN.  According to a study from India, HPV was a predictor of better survival in OSSN patients [17].

Sunlight Exposure

Exposure to solar ultraviolet radiation has been identified in many studies as a major etiologic factor in the development of OSSN [3, 8]. The rarity of OSSN in Europe and North America and its higher incidence in sub-Saharan African countries and in Australia [1], where people are more exposed to sunlight, suggests an important role for solar ultraviolet light in the development of OSSN. Lee and Hirst [1] observed a relationship between lifetime exposure to solar ultraviolet light and the risk of developing OSSN. Newton et al. [9] noted that the incidence of ocular SCC increases by 29% per unit increase in ambient solar ultraviolet light exposure, corresponding to a 49% increase in incidence with each 10° decline in latitude. A history of actinic skin lesions such as solar keratoses and SCC is also strongly associated Acquired Immunodeficiency with the development of OSSN. It is well known Syndrome (AIDS) that ultraviolet B rays cause damage to DNA in human epithelial cells. Failure of DNA repair, as The incidence of OSSN has increased signifioccurs in xeroderma pigmentosum, leads to cantly since the eruption of the AIDS epidemic, somatic mutations and the development of can- especially in sub-Saharan African countries [18]. cerous cells of OSSN.  According to a study on In studies from Rwanda, Uganda, Congo, the pathophysiology of OSSN [10], UV radiation Kinshasa, and Zimbabwe, HIV infection was damages DNA and produces pyrimidine dimers strongly associated with an apparent increase in in the DNA chain. Specific CC -- > TT base pair the incidence of OSSN. In a study from Kenya, dimer transformations of the p53 tumor-­ 74% of patients with OSSN were HIV positive suppressor gene occur in OSSN, allowing cells [19]. In these countries, the OSSN occurs at a with damaged DNA past the G1-S cell cycle younger age than was previously reported and the checkpoint. In recent years, several studies dem- disease tends to be aggressive (Fig.  15.1). onstrated that ultraviolet light-signature  – the Although HIV infection seems to be an obvious telomerase reverse transcriptase (TERT) pro- risk factor by itself, its interaction with ultraviomoter – mutations are common in OSSN lesions, let light and HPV, which are also prevalent in supporting UV induction as the major source of African countries, can accelerate the developmutagenesis in these lesions [11, 12]. ment of OSSN.

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Fig. 15.1  A 52-year-old African woman was diagnosed with HIV, with a CD4 count of 56  ×  106/mm3 and viral load >100,000 copies/mL. At presentation, a fleshy conjunctival growth extending onto the cornea was initially diagnosed as a pterygium (a). The ocular symptoms worsened with enlargement of the mass, which on CT scan revealed extension into the medial rectus muscle insertion. Conjunctival biopsy confirmed diffusely infiltrating invasive, moderately differentiated squamous cell carcinoma. The patient declined lid-sparing exenteration.

In  the interim she was started on antiretroviral therapy (zidovudine, lamivudine, and efavirenz). Over the next several months her symptoms improved. At 12  months, CD4 count was 221 × 106/mm3 and the viral load undetectable. The conjunctival mass had completely resolved (b). In the setting of HIV, even Kaposi’s sarcoma and nonHodgkin’s lymphoma are recognized as responding to highly active antiretroviral therapy via immune restoration. (Reprinted from Holkar et al. [81]. With permission from Sage Publications)

Post Transplantation and Immunosuppression

nucleotide excision repair genes related to Bloom syndrome, Nijmegen breakage, and other DNA repair disorders (Fig. 15.3). Patients with XP have severe sun sensitivity and are prone to develop skin cancers including basal cell, skin SCC, and melanoma (Fig.  15.4) [26]. Patients with XP require multidisciplinary care monitoring for ocular manifestations [27]. Cornea undergoes progressive scarring, vascularization, pannus formation due to limbal stem cell deficiency and even endothelial loss [28, 29], The conjunctival and corneal neoplasms tend to occur in early age with bilateral, multiple, recurrent, aggressive, and invasive behavior and are difficult to manage (Fig. 15.5) [30].

Solid organ transplantation and consequent immunosuppression is an important risk factor for development of squamous cell carcinoma, basal cell carcinoma, melanoma, and lymphoma [20–22]. The incidence of squamous cell carcinoma varies with the type, intensity, and duration of the immunosuppressive treatment [23]. OSSN have also been observed in the setting of immunosuppression [24]. Such tumors tend to be bilateral, aggressive, and non-responsive to topical interferon therapy [25] (Fig. 15.2).

Xerodermatic Pigmentosum and Other DNA Repair Disorders Xerodermatic pigmentosa (XP) is caused by Autosomal Recessive inheritance of defective

Stem Cell Theory Because of the tendency for OSSN to arise in the limbal area, where the stem cells for the corneal and conjunctival epithelium are located, Lee and

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Fig. 15.2  A 55-year-old male s/p simultaneous liver kidney transplant about 10 years prior with nodular thickening left lower eyelid (basal cell carcinoma) and biopsy proven CIN right eye (a). The lesion was adherent to underlying sclera. UBM excluded deep scleral extension (b). He was treated with six subconjunctival injections of

Hirst [1] proposed the limbal transition zone/ stem cell theory for the development of OSSN.  Based on Tseng’s concept of the ­long-­living and high proliferation rate of stem cells in the limbal area, they postulated that alterations in this anatomical site influenced by other factors cause abnormal maturation of the conjunctival and corneal epithelium resulting in the formation of OSSN.  It has been postulated that limbal epithelial stem cells are the possible progenitor cells in OSSN [10].

interferon alpha-2b (3million units/0.5  ml) given at 1–2  weeks interval. Response is evident after second injection. Note subconjunctival hemorrhage (c). There was total resolution after the sixth injection. The patient has remained recurrence-free at 6  months after last ­injection (d)

Clinical Features Symptoms In addition to the presence of the lesion on the ocular surface, other symptoms include ocular redness and irritation. Visual acuity is usually not reduced, unless the center of the cornea is affected [31]. OSSN may grow within weeks to years; in most cases, the history is of several months.

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15  Conjunctival and Corneal Tumors: Ocular Surface Squamous Neoplasia GGR DNA damage Recognition

XPC

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DNA damage CSA

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XPD TTDA TFIIH XPB

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Excision and synthesis

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Fig. 15.3  Overview of the NER system as the genetic basis for XP and related disorders. TCR removes damaged DNA from genes that are actively transcribed, while GGR works in the remaining genome. In GGR, the DNA damage by UV radiation leads to the formation of cyclobutane pyrimidine dimers (CPDs) or 6–4 photoproducts (PPs), which are recognized by XPC proteins. Meanwhile in TCR, DNA damage blocks RNA poly-

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Fig. 15.4  A 33-year-old Asian female with xeroderma pigmentosum. Note pterygium like changes in the left eye (a) and peripheral corneal opacification and vascularization of the right cornea attributed to limbal stem cell defi-

merase II function. Pathways overlap after initial damage recognition, in a process involving XPB, XPG, XPA, and replication protein A (RPA). Finally, XPF and XPG remove the damaged regions by making incisions of ∼30 nucleotides, followed by DNA synthesis to fill the gaps. (Reprinted from Suarez et al. [30] With permission from S. Karger AG, Basel © 2016)

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ciency (b). OCT at 6 o’clock position (c) showing thickened corneal epithelium indicating CIN within the corneal pannus (d)

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Fig. 15.4 (continued)

Signs

Differential Diagnosis

Clinically, it may be difficult to distinguish between conjunctival epithelial dysplasia, carcinoma in situ, and invasive squamous cell carcinoma, although suspicion towards one of these three lesions may exist. These lesions arise commonly within the interpalpebral fissure, mostly at the limbus (Figs.  15.6 and 15.7). OSSN may appear gelatinous with superficial vessels; papilliform when it has a papillary appearance (Fig. 15.8); or leukoplakic, with a white keratin plaque covering the lesion [3] (Fig. 15.9). It may also appear as a nodular lesion (Fig. 15.10), especially when it is invasive SCC, or as a diffuse lesion masquerading as chronic conjunctivitis. OSSN may rarely occur in tarsal or forniceal conjunctiva (Fig. 15.11). The limbal component may be inconspicuous with predominant corneal extension (Fig. 15.12). Usually, OSSN appears as a nonpigmented lesion, although pigmented conjunctival SCC has been reported (Fig.  15.13). According to one study, clinical characteristics that may predict high-grade lesions are temporal and superior location, papillomatous and nodular-­ appearing lesions, and size of lesional area [6].

The main lesions in the differential diagnosis of OSSN are pinguecula (Fig.  15.14), pterygium (Fig.  15.15), and squamous papilloma (Fig. 15.16) [3].

Diagnostic Evaluation It may be difficult to clinically distinguish between intraepithelial and invasive squamous neoplasia and between these and other lesions such as pinguecula and pterygium, especially with leukoplakia and squamous papilloma.

Staining Patterns In our experience, the use of fluorescein staining can help in the diagnosis, emphasizing the papillary or granular surface of part of the OSSN lesion and delineating its borders (Fig.  15.17) [31, 32]. Others have used rose bengal, lissamine green [33, 34], or 1% toluidine blue eye drops [35].

15  Conjunctival and Corneal Tumors: Ocular Surface Squamous Neoplasia Fig. 15.5  Spectrum of differentiation of squamous neoplasia in XP. XP patients develop a variety of squamous lesions, including CIN with variable dysplasia (a, b) and well-­ differentiated, highly keratinized eyelid SCCs (patient 3; c, d). A subset of tumors may be less differentiated and demonstrate increased pleomorphism (e, f). (Reprinted from Suarez et al. [30]. With permission from S. Karger AG, Basel © 2016)

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Imaging Techniques Recent publications have described the use of high-frequency ultrasound in the diagnosis of OSSN and particularly in estimating the depth of invasion [36]. Others have used confocal microscopy [37] or ultrahigh-resolution optical coherence tomography [38] even with coexisting ocular surface diseases (Figs.  15.12, 15.13, 15.14, 15.15, and 15.16) [39] (Chap. 12

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“Conjunctival and Corneal Tumors: Examination Techniques”). However, the definitive diagnosis must be a histological one.

Diagnostic Cytology Preoperative cytologic diagnosis may be of value in planning surgery in order to prevent unnecessary removal of large areas of normal conjunctiva

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Fig. 15.6 Papillomatous ocular surface squamous neoplasia

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Fig. 15.7  Papillary conjunctival SCC invading into the upper half of the cornea

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Fig. 15.8  Papillomatous limbal CIN with prominent intrinsic and feeder vessels (a). Note subtle corneal extension (b, arrows) visualized by OCT as abruptly (c, small arrow) thickened hyperreflective epithelium (c, large arrow)

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in the case of a benign lesion and to prevent partial excision of malignant lesions.

Exfoliative Cytology Cells from the conjunctival surface are obtained with a platinum spatula, brush, or cotton-wool tip. The cells are then smeared onto slides and fixed in 90% alcohol. Papanicolaou and Giemsa stains are used to examine the specimen [40, 41]. The advantages of this technique are the ability to obtain prospective cytologic information on the nature of the lesion, mainly in differentiating between benign and malignant lesions, and in the

Fig. 15.9  Leucoplakic CIN

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ability to sample multiple sites, also simplifying follow-up evaluation after treatment. The major disadvantage is that only superficial cells are obtained with this technique. Sometimes only keratinized cells are obtained. Exfoliative cytology does not provide information on the degree of the tumor invasion, which may be crucial in the overall management.

Impression Cytology Another method of obtaining cells from the surface of the conjunctival lesion is by impression cytology [42]. With this technique several types of

Fig. 15.11  CIN originating in the inferior fornix

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Fig. 15.10  Nodular CIN (a). UBM excluded deep scleral or intraocular extension (b)

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Fig. 15.12  CIN presenting as limbal/ peripheral corneal opacity (a). Small area of leukoplakia offers the diagnostic clue (b, arrow). OCT reveals abruptly (c, small arrow) thickened and hyperreflective epithelium (c, large arrow)

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Fig. 15.13  Invasive conjunctival squamous carcinoma in an Indian man. The lesion is pigmented, resembling conjunctival melanoma (a). Anterior segment OCT indicates

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superficial epithelial involvement with shadowing due to pigmentation (b)

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Fig. 15.14  Faint yellow white lesion of conjunctiva resembling pinguecula (a, encircled by dots). OCT reveals abruptly thickened and hyperreflective epithelium (b, arrow)

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Fig. 15.15  Pterygium with nodular thickening mimicking CIN (a). OCT reveals normal corneal epithelium over a stromal nodular change both in the transervse (b, arrow) and longitudinal scan (c, arrow)

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Fig. 15.16  Squamous papilloma. Lesion with limbal involvement from 11 to 4 o’ clock, with corneal and conjunctival extension (a). Histopathology demonstrated a papillary squamoproliferative lesion characterized by acanthotic squamous epithelium and fibrovascular cores.

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Fig. 15.17  Diffuse corneal involvement by CIN showing hazy and irregular corneal surface (a). Staining with fluorescein shows the granular surface of the involved cornea

filter paper, such as cellulose acetate filter paper, millipore filter paper, or biopore membrane device, are gently placed in contact with the ocular surface, sampling the most superficial cells. These are fixed and stained with Papanicolaou stain. The advantages and disadvantages of exfoliation cytology also apply to impression cytology.

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No goblet cells were present within the lesion. Features of high-grade dysplasia such as full thickness basaloid population lacking orderly maturation were not identified. (Hematoxylin and eosin, 100×). (Reprinted from Ganapathy et al. [82]. With permission from Elsevier)

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and clearly delineates the border between the affected and nonaffected areas (b)

Histopathologic Features Only histological evaluation of excised lesions, either from incisional or excisional biopsy, can differentiate between the three lesions in the spectrum of OSSN [1, 2].

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Fig. 15.18  Histological picture of acanthotic conjunctival epithelium with dysplastic changes involving most of the epithelial thickness. The epithelium lost its normal cellular polarity. Normal conjunctival epithelium is seen

on the right side (a, hematoxylin and eosin, original magnification × ~ 100). Note deep invasion of tumor cell islands of well-differentiated conjunctival SCC (b, hematoxylin and eosin, original magnification × ~ 100)

Dysplasia

Invasive Squamous Cell Carcinoma

Dysplastic lesions exhibit mild, moderate, or severe degrees of cellular atypia that may involve various thicknesses of the epithelium, starting from the basal layer outwards (Fig 15.18a). These lesions show modification of epithelial cell organization with various degrees of loss of the normal cellular polarity. Usually the most superficial layers are uninvolved. In cases with severe dysplastic changes, it may be difficult to distinguish the lesion from carcinoma in situ.

Invasive squamous cell carcinoma shows features similar to carcinoma in situ, but the basement membrane of the epithelium is breached and the subepithelial tissue of the conjunctiva is invaded (Fig. 15.18b). Most conjunctival SCCs are well-­ differentiated, and they often show surface keratinization. The tumor may show various degrees of cellular pleomorphism. In examining such lesions, hyperplastic and hyperchromatic cells, individually keratinized cells (dyskeratosis), concentric collections of keratinized cells (horn pearls), loss of cellular cohesiveness, and atypical mitotic figures may be observed. The subepithelial tissue in invasive SCC is usually inflamed and contains islands of atypical epithelial cells. In pigmented individuals, OSSN can be pigmented due to abnormal proliferation of melanocytes in the lesions. Genetic studies of OSSN tumors found multiple chromosomal alterations, losses and gains, which may be important in tumor formation and growth [43]. Another study showed differential expression of stem cell markers in OSSN tumors, which can indicate the

Carcinoma In Situ Carcinoma in situ may show all the histological features of SCC; however, it usually is confined to the epithelium, respecting the basement membrane. Carcinoma in situ usually shows a total loss of normal cellular maturation and affects the full thickness of the epithelium. The cells are large and usually elongated. Keratinized cells may be identified and mitotic figures can be present in all layers.

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important role that stem cells, especially limbal epithelium stem cells, play in the genesis of OSSN [44].

Staging In the recent editions of the American Joint Committee on Cancer (AJCC) staging system, the primary OSSN tumors are classified according to the degree of depth of invasion, as found in histopathological evaluation; the size of the lesions; and the involvement of neighboring structures (Table  15.1) [45, 46]. The OSSN lesions are divided into carcinoma in situ  – Tis  – and four stages of invasive SCC: T1 for tumors ≤5 mm in greatest dimension, T2 for tumors >5  mm in greatest dimension, T3 for tumors invading adjacent structures (excluding the orbit), and T4 for Table 15.1  AJCC (8th ed.) Definition of primary tumor (T) [45, 46] T category TX T0 Tis T1

T2

T3 T4 T4a T4b T4c T4d

T criteria Primary tumor cannot be assessed No evidence of primary tumor Carcinoma in situ Tumor (5 mm in greatest dimension) invades through the conjunctival basement membrane without invasion of adjacent structures Tumor invades adjacent structures (excluding the orbit) Tumor invades the orbit with or without further extension Tumor invades orbital soft tissue without bone invasion Tumor invades bone Tumor invades adjacent paranasal sinuses Tumor invades brain

Used with permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original and primary source for this information is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer Science+Business Media. & Used with permission of the American College of Surgeons, Chicago, Illinois. The original and primary source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing

tumors invading the orbit with or without further extension, divided to four sub-staging, T4a, T4b, T4c, and T4d. The intraepithelial neoplasia which is not subdivided in the AJCC staging has been catergorized by others as mild dysplasia (grade 1/3), moderate dysplasia (grade 2/3), and severe dysplasia (grade 3/3 or carcinoma in situ) [47]. While some studies found that the AJCC category of OSSN is a reliable predictor of clinical outcome [48], others did not find this staging a useful guide for initial management, and these authors suggest a partial reclassification [47].

Histopathologic and Clinical Variants Several types of invasive conjunctival SCC with rather aggressive behavior have been reported [2]. Because of the aggressiveness of these variants, which often invade the eyeball and the orbital tissue and which even metastasize to lymphatics and distant sites, they should be histopathologically differentiated from less aggressive, conventional SCC.

 pindle Cell Squamous Carcinoma S Spindle cell variant of SCC exhibits spindle-­ shaped cells, which may be difficult to distinguish from fibroblasts. Mucoepidermoid Carcinoma Mucoepidermoid carcinoma is a variant of conjunctival SCC that shows, besides the squamous cells, mucus-secreting cells that are positively stained for mucopolysaccharides.  denoid Squamous Cell Carcinoma A Another aggressive variant of conjunctival SCC is the adenoid squamous carcinoma, which histologically shows extracellular hyaluronic acid but no intracellular mucin.  quamous Cell Carcinoma of Cornea S OSSN arising in the corneal epithelium is rare [8, 49]. There is controversy about its origin. Some authors support the possible potential of the corneal epithelium to undergo dysplastic and ­ cancerous changes, while others believe that the

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Fig. 15.19  Squamous cell carcinoma of cornea resembling filamentary keratitis (a). Examination of the limbus reveals small area of conjunctival thickening with fine intrinsic vascularity (b)

origin of corneal OSSN is at the limbus (Fig.  15.19) histologically, the corneal intraepithelial neoplasia is similar to that in the limbal region and conjunctiva. Usually, the Bowman’s layer is intact. Corneal intraepithelial neoplasia has a tendency to recur because of inadequate scraping, but with current methods of treatment (topical therapy), this rarely occurs (Fig. 15.20) [31, 32].

 quamous Cell Carcinoma S in Anophthalmic Socket Review of nine published cases indicates a long interval between enucleation and the diagnosis of SCC (mean, 45  years), predominant diffuse involvement of the upper eyelid, advanced stage at diagnosis, and tendency for metastases (Fig. 15.21). It is speculated that the presence of prosthesis-induced chronic inflammation may be a factor in initiating and masking the signs and symptoms of OSSN [50].

Treatment Surgery Surgical excision of the OSSN lesion is the traditional method of treatment (Chap. 22). Its success depends on the involvement of the peripheral

and deep surgical margins. In order to avoid recurrence, it is recommended to excise the tumor tissue with wide surgical margins of 2–3 mm [3, 51] (Fig. 15.22). When the deep cornea or sclera is involved, deep lamellar keratectomy or sclerectomy is performed. Recurrence rates following excision of OSSN alone range from 15% to 52%, with an average of 30% [1]. Erie et al. [8] found 5% recurrence when the surgical margins were free and 53% recurrence when they were involved. Similarly, Pizzarello and Jakobiec found 69% recurrence when dysplastic tissues were left at the surgical margins [3]. Therefore, techniques to ensure clear surgical margins have been applied. Frozen sections were used by Char et al. to assess the surgical margins [52]. However, there was a disparity between the apparently free surgical margins and recurrence of the OSSN.  Buus et  al. have used a modified Mohs’ micrographic technique that was developed for cutaneous tumors, to ensure clear surgical margins [53]. No recurrences were documented in their series of 19 patients. Excision with large margins, especially when cryotherapy is applied to the tumor bed and the margins, may necessitate the use of an amniotic membrane graft to close the surgical wound. Two cases of OSSN with intraocular involvement were managed by local excision. Char et al. [52] reported a successful iridocyclochoroidectomy

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Fig. 15.20  Corneal CIN. Patient treated for nonspecific keratitis with topical steroids for several months (a). Note superficial corneal opacity on transillumination (b). OCT reveals abruptly (C, small arrow) thickened and hyperreflective epithelium (c, large arrow). Diagnostic biopsy

shows strips of thickened epithelium with nuclei that are large, hyperchromatic, and are haphazardly arranged suggestive of CIN (d). Topical treatment interferon alpha-2b (one million units/ml) led to total resolution within 3 months (e)

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Fig. 15.21  Recurrent squamous cell carcinoma in the superior nasal aspect of tarsal conjunctiva of the upper lid in anophthalmic socket (a). Poorly differentiated invasive carcinoma without keratinization was associated with an overlying squamous carcinoma in situ. Although some

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areas were suggestive of sebaceous differentiation, oil red O and immunostaining for androgen receptor were both negative (b, 40× magnification, hematoxylin and eosin). (Reprinted from Espana et al. [50]. With permission from Elsevier)

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Fig. 15.22  CIN Local excision. Pretreatment appearance (a). Following excision with 2 mm clear margins alcohol epitheliectomy double freeze thaw cryotherapy application and primary closure (b)

with adjunctive cryotherapy. Most eyes with intraocular invasion of OSSN are enucleated [54], and in cases with orbital invasion, exenteration is required.

Cryotherapy Because of the high recurrence rate of OSSN after surgical excision alone, Fraunfelder et  al.

advocated the use of cryosurgery in the treatment of eyelid and ocular surface tumors [55]. Later on, he and others reported the use of combined excision and cryotherapy treatment for OSSN with recurrence rate as low as 0–12%. Cryotherapy acts both by destroying the tumor cells and obliterating its microcirculation, resulting in ischemic infarction of both normal and tumor tissue. Side effects include iritis, altera-

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tions in intraocular pressure, inflammation, corneal edema, scarring, and superficial corneal vascularization, sector iris atrophy, ablation of the peripheral retina, and ectropion.

Brachytherapy Brachytherapy has been used for many years in the treatment of OSSN.  The most commonly used radioactive material has been strontium 90 with a recommended dose of 20–180 Gy to the tumor surface [56]. Other beta sources are ruthenium 106 with a recommended dose of 290– 320  Gy to the tumor bed (Fig.  15.23) [57] and phosphorus 32 [58]. Gamma radiation using Iodine 125 applicators was also reported [59]. Reported complications include post-irradiation conjunctivitis, dry eye, conjunctival telangiectasis and scarring, symblepharon, scleral ulceration, corneal perforation, and cataract. Recurrence rates after brachytherapy have ranged from 2% to 47%; therefore, brachytherapy alone is not recommended. However, in cases of intraocular invasion, brachytherapy can effectively treat the invasion and preserve the eye. Treatment of two cases of invasive SCC with proton beam therapy was also reported [60].

Topical Chemotherapy and Immunotherapy Because of the possible complications of surgical excision, cryotherapy, and brachytherapy, topical medical therapy has become an expanding field. Topical drops of mitomycin C (MMC), 5-­ fluorouracil (5FU), and interferon alpha-2b (INF-α2b) by injections and drops have shown promising results as primary therapy for OSSN. They have also been used as an adjuvant to surgical excision (Chap. 20, Pharmacotherapy for Eyelid and conjunctival malignancies).

 itomycin C Drops M Mitomycin C is an antineoplastic/antibiotic drug that acts as an alkylating agent. Our group introduced and promoted the use of topical MMC

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since the early 1990s (Fig. 15.11) [31]. Our protocol since then includes the use of 0.02% (0.2  mg/ml) MMC drops four times daily for 2 weeks of treatment and then 2 weeks without it [2, 31, 32], with repetitions as needed and with a response rate of 95%. Other groups have used 0.04% MMC in various lengths of cycles and periods between cycles with a good response (Fig.  15.24) [61–63]. The use of a low dose of 0.002% has also been reported [64]. The main adverse reactions to MMC are conjunctival hyperemia, superficial punctate epithelial erosions, allergic conjunctivitis, pain, photophobia, and blepharospasm. In using the higher concentration of 0.04% MMC, there was one case of punctal stenosis [61], and repeating this concentration in multiple courses, limbal cell deficiency was reported [61, 63, 65]. In treating OSSN, there is no reason to use 0.04% MMC. In using 0.02% MMC, the side effects disappear within 2 weeks of stopping the treatment with or without addition of lubricants and topical steroids. MMC is the most potent topical drug for treating OSSN, showing a fast response. It is cheap and stable. Because of its superficial effect, it should not be used for invasive SCC as a primary treatment. However, it has been used successfully in treating patients with partially excised invasive conjunctival SCC without evidence of recurrence [66]. It has also been used intraoperatively [67, 68]. 5-Fluorouracil Drops 5FU has been used for OSSN as a sole treatment or as an adjuvant treatment to surgical excision, with a good response and a low recurrence rate [68–70]. 5FU 1% has been administered in different protocols, such as four times daily for 1 week followed by 3 weeks off with repetitions up to four cycles [69]. Others used it four times daily for 4  weeks [70]. In these recent reports, complete tumor regression was achieved in 82–83%. With 5FU patients experience toxic keratoconjunctivitis including conjunctival hyperemia, superficial keratitis, filamentary keratitis, and sometimes pain, tearing and photophobia, but usually, no long-term side effects are found [68–70]. 5FU is a potent, relatively cheap and stable drug.

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Fig. 15.23  Invasive conjunctival SCC with extension into sclera (a) treated with iodine 125 brachytherapy (45 Gy to the depth of 3 mm) (b). The plaque was covered with donor pericardium (c) followed by temporary transmarginal tarsorrhaphy (d) to minimize postoperative dis-

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comfort for the duration of the implant placement (48 h). The patient is recurrence-free at 5 years with visual acuity of 20/25 due to minimal cataract (e) and without radiation retinopathy (f)

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Fig. 15.24  Diffuse CIN treated with MMC. Pretreatment appearance (a). Note partial resolution with 1 week of topical MMC (0.04% qid) (b)

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Fig. 15.25  Multiple recurrent CIN associated with limbal stem cell deficiency due to multiple previous excisions (a). Following treatment with topical interferon alpha-2b

Interferon Alpha-2b The use of recombinant interferon alpha-2b, initially by intralesional injections and later by topical applications, was pioneered and promoted by Karp and colleagues for the treatment of CIN [71]. In using interferon alpha-2b four times daily with a dose of one million IU/ml, the response rate was 81%, and in using three million IU/ml, the response rate was 92% (Figs.  15.20 and 15.25). There was no response of invasive

b

one million units/ml for 3  months, there was complete regression of the focal CIN (b)

SCC to topical interferon alpha-2b [72]. Shields and colleagues used interferon alpha-2b as an adjuvant treatment to surgical excision with complete control in 95% [73]. Krilis et  al. [74] showed a higher response to treatment by interferon alpha-2b when combining it with topical retinoic acid every other day, achieving a 97.75% response rate. Topical INF–α2b eye drops are well tolerated with minimal side effects such as conjunctival hyperemia and occasional follicular conjunctivi-

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Table 15.2  Local Chemotherapy for OSSN Response rate Time to resolution Side effects

b

Fig. 15.26  Diffuse conjunctival and corneal CIN right eye (a). He was treated with four subconjunctival injections of interferon alpha-2b (three million units/0.5  ml) given at 1–2 weeks interval combined with topical interferon alpha-2b (1million units/ml). There was total resolution after the 6 months of topical therapy (b). The patient has remained recurrence-free for 24 months

tis [72]. When injecting subconjuctivaly, the patients also experience systemic side effects such as a “flu-like” syndrome (Figs.  15.2 and 15.26) [75]. Using INF–α2b, tumor resolution takes longer than with MMC and 5FU, on average 4 months, with a high response rate of 92.5% and recurrence of 0–17% [73–76]. The downsides of topical INF–α2b are its high cost and that it must be refrigerated. Table 15.2 compares the main features of MMC, 5FU, and INF–α2b. For more details see Chap. 20.

The Combined Approach The fact that tumors recur after the most meticulous surgery even with the addition of cryotherapy hints to that not all the tumor cells have been destroyed. Thus, our group and others combined a surgical approach without wide surgical margins or cryotherapy, but adding local chemotherapy using mitomycin C or 5FU for intraepithelial

Systemic side effects Availability Cost Stability at room temperature

MMC 82–100%

5FU 80–93%

Fast

Medium

INF-­α2b 80– 100% Slow

+++ (0.04%) ++ ++ (0.02%) − −

−

+++ Low High

++ High Low

+++ Low High

+

diseases and adding, irrespective of histological clearance, brachytherapy for invasive disease. This combinatorial approach was successful both in preserving the ocular surface and effective in treating the OSSN.

Reconstruction Reconstruction of the ocular surface may be needed after a large excision of ocular surface tumors, and the use of autologous conjunctival transplantation and autologous limbal transplants to restore corneal and limbal areas after treating OSSN by surgery and cryotherapy have been described (Chap. 22). Amniotic membrane transplantation has been used for reconstruction after excision of large ocular surface neoplasia (Fig. 15.27) [77, 78].

Prognosis Local Recurrence OSSN is considered to be of low-grade malignancy [3, 8]. Conjunctival intraepithelial neoplasias (CIN), including dysplasia and carcinoma in situ, are regarded as precancerous lesions that rarely progress to invasive SCC. However, recurrences of these lesions are common after surgical excision, depending on the involvement of the surgical margins [3, 8]. Erie et  al. [8] reported 24% recurrence after excision of CIN and 41%

180

a

J. Pe’er et al.

b

Fig. 15.27  Conjunctival reconstruction. Incompletely excised CIN (a). Repeat surgical excision was 2 mm outside the visible margin. The surgical bed was also shaved off with partial thickness scleral dissection. The area of conjunctival defect was 15  mm vertically and 10  mm

horizontally. The conjunctiva was mobilized and anchored on the sclera. The remaining defect was covered with an amniotic membrane graft, tied in position using 8–0 Vicryl sutures. A 20-mm bandage contact lens was applied (b)

after excision of SCC.  Lee and Hirst [1] found recurrence rate of 17% for conjunctival dysplasia, 40% for carcinoma in situ, and 30% for SCC. In this series, 31% had a second recurrence, and 8% had more than two recurrences. Galor et al. [79] found that higher-grade lesions, tarsal involvement, and positive margins in the histopathologic evaluation are predictors of recurrence. Most recurrences develop within 2 years, but later recurrences have been reported. New methods of treatment reduce the recurrence rate significantly, as was discussed in the treatment section.

with involvement of the Schlemm’s canal, trabecular meshwork, anterior chamber, iris, ciliary body, suprachoroidal space, and choroid, sometimes extending even behind the equator. In very advanced cases the tumor may involve the entire orbit (Fig. 15.28b).

Intraocular Invasion Intraocular invasion, although rare, may occur in OSSN [52, 80]. It occurs in older patients who had SCC located near the corneoscleral limbus with one or more recurrences after surgical excision (Fig. 15.28a). Histopathologic examination may show growth of the SCC through the limbus

Metastasis Metastasis of conjunctival SCC is extremely rare [8, 51]. Sites of metastasis include preauricular, submandibular, and cervical lymph nodes; parotid gland; lungs; and bones (Fig. 15.29). The main cause of metastasis is a delay in diagnosis and treatment. Regional lymph node involvement preceded the development of distant metastases; therefore, regular examination of these lymph nodes should be performed in suspicious patients, to enable lymph node and radical neck dissection in cases of nodal involvement. Local invasion and distant metastases may lead to the patient’s death in very rare cases [51].

15  Conjunctival and Corneal Tumors: Ocular Surface Squamous Neoplasia

a

181

b

Fig. 15.28  Intraocular invasion of conjunctival SCC (a). Advanced conjunctival SCC protruding through the eyelid aperture. The tumor invaded the eyeball and the orbit (b)

a

b

c

d

Fig. 15.29  Conjunctival SCC with orbital extension (a). Note enlargement of parotid and cervical lymph nodes (b). CT shows enlarged lymph node (c, arrow) which is

hypermetabolic on PET scan (d, large arrow. The conjunctival/orbital tumor is also detectable (d, small arrow)

182

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J. Pe’er et al. 18. Goedert JJ, Cote TR. Conjunctival malignant disease with AIDS in USA. Lancet. 1995;346(8969):257–8. 19. Gichuhi S, Macharia E, Kabiru J, et al. Clinical presentation of ocular surface squamous neoplasia in Kenya. JAMA Ophthalmol. 2015;133:1305–13. 20. Perry JD, Polito SC, Chundury RV, et al. Periocular skin cancer in solid organ transplant recipients. Ophthalmology. 2016;123(1):203–8. 21. Dahlke E, Murray CA, Kitchen J, et al.  Systematic review of melanoma incidence and prognosis in solid organ transplant recipients. Transplant Res. 2014;6(3):10. 22. Clarke CA, Morton LM, Lynch C, et al. Risk of lymphoma subtypes after solid organ transplantation in the United States. Br J Cancer. 2013;9:109. 23. Kim C, Cheng J, Colegio OR.  Cutaneous squamous cell carcinomas in solid organ transplant recipients: emerging strategies for surveillance, staging, and treatment. Semin Oncol. 2016;43:390–4. 24. Shields CL, Ramasubramanian A, Mellen PL, et al.  Conjunctival squamous cell carcinoma arising in immunosuppressed patients (organ transplant, human immunodeficiency virus infection). Ophthalmology. 2011;118:2133–7. 25. Ashkenazy N, Karp CL, Wang G, et al.  Immuno­ suppression as a possible risk factor for interferon nonresponse in ocular surface squamous neoplasia. Cornea. 2017;36:506–10. 26. Lehmann J, Seebode C, Martens MC, et al. Xeroderma Pigmentosum  – facts and perspectives. Anticancer Res. 2018;38:1159–64. 27. Lim R, Sethi M, Morley AMS. Ophthalmic manifestations of Xeroderma Pigmentosum: a perspective from the United Kingdom. Ophthalmology. 2017;124:1652–61. 28. Chaurasia S, Mulay K, Ramappa M, et al.  Corneal changes in xeroderma pigmentosum: a clinicopathologic report. Am J Ophthalmol. 2014;157:495–500. 29. Brooks BP, Thompson AH, Bishop RJ, et al. Ocular manifestations of xeroderma pigmentosum: longterm follow-up highlights the role of DNA repair in protection from sun damage. Ophthalmology. 2013;120:1324–36. 30. Suarez MJ, Rivera-Michlig R, Dubovy S, et al.  Clinicopathological features of ophthalmic neoplasms arising in the setting of Xeroderma Pigmentosum. Ocul Oncol Pathol. 2015;2:112–21. 31. Frucht-Pery J, Rozenman Y. Mitomycin C therapy for corneal intraepithelial neoplasia. Am J Ophthalmol. 1994;117:164–8. 32. Frucht-Pery J, Sugar J, Baum J, et  al. Mitomycin C treatment for conjunctival-corneal intraepithelial neoplasia: a multicenter experience. Ophthalmology. 1997;104(12):2085–93. 33. Wilson FM 2nd. Rose bengal staining of epibul bar squamous neoplasms. Ophthalmic Surg. 1976; 7(2):21–3. 34. Machado LM, Castro RS, Fontes BM.  Staining patterns in dry eye syndrome: rose bengal versus lissamine green. Cornea. 2009;28:732–4.

15  Conjunctival and Corneal Tumors: Ocular Surface Squamous Neoplasia 35. Romero IL, Barros JD, Martins MC, et  al. The use of 1% toluidine blue eye drops in the diagnosis of ocular surface squamous neoplasia. Cornea. 2012;32(1):36–9. 36. Finger PT, Tran HV, Turbin RE, et al. High-frequency ultrasonographic evaluation of conjunctival intraepithelial neoplasia and squamous cell carcinoma. Arch Ophthalmol. 2003;121(2):168–72. 37. Xu Y, Zhou Z, Xu Y, et  al. The clinical value of in  vivo confocal microscopy for diagnosis of ocular surface squamous neoplasia. Eye (Lond). 2012;26(6):781–7. 38. Kieval JZ, Carp CL, Abou Shousha M, et  al. Ultra-­ high resolution optical coherence tomography for differentiation of ocular surface squamous neoplasia and pterygia. Ophthalmology. 2012;119(3):481–6. 39. Atallah M, Joag M, Galor A, et al. Role of high resolution optical coherence tomography in diagnosing ocular surface squamous neoplasia with coexisting ocular surface diseases. Ocul Surf. 2017;15:688–95. 40. Spinak M, Friedman AH. Squamous cell carcinoma of the conjunctiva. Value of exfoliative cytology in diagnosis. Surv Ophthalmol. 1977;21(4):351–5. 41. Semenova EA, Milman T, Finger PT, et al. The diagnostic value of exfoliative cytology vs. histopathology for ocular surface squamous neoplasia. Am J Ophthalmol. 2009;148(5):772–8. 42. Nolan GR, Hirst LW, Bancroft BJ. The cytomorphology of ocular surface squamous neoplasia by using impression cytology. Cancer. 2001;93(1):60–7. 43. Asnaghi L, Alkatan H, Mahale A, et al. Identification of multiple DNA copy number alterations including frequent 8p11.22 amplification in conjunctival squamous cell carcinoma. Invest Ophthalmol Vis Sci. 2014;9(55):8604–13. 44. Mishra DK, Veena U, Kaliki S, et  al. Differential expression of stem cell markers in ocular surface squamous neoplasia. PLoS One. 2016;11:e0161800. 45. AJCC Opthalmolic Oncology Task Force. Carcinoma of the conjunctiva. In: American Joint Committee on Cancer (AJCC) Cancer staging manual. 7th ed. New York: Springer; 2010.. Chapter 49, p. 531–7. 46. Conway RM, Graue GF, Pelaye DE, et al. Conjunctiva carcinoma. In: American Joint Committee on Cancer (AJCC) Cancer staging manual. 8th ed. New  York: Springer; 2017., Chapter 65. p. 787–93. 47. Bellerive C, Berry JL, Polski A, et al.  Conjunctival squamous neoplasia: staging and initial treatment. Cornea. 2018;37(10):1287–91. 48. Chauhan S, Sen S, Sharma A, et  al. American Joint Committee on cancer staging and clinicopathological high-risk predictors of ocular surface squamous neoplasia: a study from a tertiary eye center in India. Arch Pathol Lab Med. 2014;138:1488–94. 49. Waring GO III, Roth AM, Ekins MB.  Clinical and pathologic description of 17 cases of corneal intraepithelial neoplasia. Am J Ophthalmol. 1984;97(5):547–59. 50. Espana EM, Levine M, Schoenfield L, et al.  Ocular surface squamous neoplasia in an anophthalmic

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socket 60 years after enucleation. Surv Ophthalmol. 2011;56(6):539–43. 51. Iliff WJ, Marback R, Green WR. Invasive squamous cell carcinoma of the conjunctiva. Arch Ophthalmol. 1975;93(2):119–22. 52. Char DH, Crawford JB, Howers EL, et al. Resection of intraocular squamous cell carcinoma. Br J Ophthalmol. 1992;76(2):123–5. 53. Buus DR, Tse DT, Folberg R.  Microscopically controlled excision of conjunctival squamous cell carcinoma. Am J Ophthalmol. 1994;117(1):97–102. 54. Shields JA, Shields CL, Gunduz K, et  al. The 1998 Pan American Lecture. Intraocular invasion of conjunctival squamous cell carcinoma in five patients. Ophthal Plast Reconstr Surg. 1999;15(3):153–60. 55. Fraunfelder FT, Wallace TR, Farris HE, et al. The role of cryosurgery in external ocular and periocular disease. Trans Sect Ophthalmol Am Acad Ophthalmol Otolaryngol. 1977;83(4 Pt. 1):713–24. 56. Lommatzsch P. Beta-ray treatment of malignant epithelial tumors of the conjunctiva. Am J Ophthalmol. 1976;81(2):198–206. 57. Zehetmayer M, Menapace R, Kulnig W.  Combined local excision and brachytherapy with ruthenium106  in the treatment of epibulbar malignancies. ­ Ophthalmologica. 1993;207(3):133–9. 58. Marr BP, Abramson DH, Cohen GN, et al.  Intra­ operative high-dose rate of radioactive phosphorus 32 brachytherapy for diffuse recalcitrant conjunctival neoplasms: a retrospective case series and report of toxicity. JAMA Ophthalmol. 2015;133:283–9. 59. Arepalli S, Kaliki S, Shields CL, et al. Plaque radiotherapy in the management of scleral-invasive conjunctival squamous cell carcinoma: an analysis of 15 eyes. JAMA Ophthalmol. 2014;132:691–6. 60. El-Assal KS, Salvi SM, Rundle PA, et al. Treatment of invasive ocular surface squamous neoplasia with proton beam therapy. Eye (Lond). 2013;27:1223–4. 61. Khong JJ, Muecke J. Complications of mitomycin C therapy in 100 eyes with ocular surface neoplasia. Br J Ophthalmol. 2006;90(7):819–22. 62. Hirst LW. Randomized controlled trial of topical mitomycin C for ocular surface squamous neoplasia: early resolution. Ophthalmology. 2007;114(5):976–82. 63. Russell HC, Chadha V, Lockington D, et al. Topical mitomycin C chemotherapy in the management of ocular surface neoplasia: a 10-year review of treatment outcomes and complications. Br J Ophthalmol. 2012;94(10):1316–21. 64. Prabhasawat P, Tarinvorakup P, Tesavibul N, et  al. Topical 0.002% mitomycin C for the treatment of conjunctival-corneal intraepithelial neoplasia and squamous cell carcinoma. Cornea. 2005;24:443–8. 65. Lichtinger A, Pe’er J, Frucht-Pery J, et al.  Limbal stem cell deficiency after topical mitomycin C therapy for primary acquired melanosis with atypia. Ophthalmology. 2010;117:431–7. 66. Frucht-Pery J, Rozenman Y, Pe’er J. Topical mitomycin-­C for partially excised conjunctival squamous cell carcinoma. Ophthalmology. 2002;109(3):548–52.

184 67. Siganos CS, Kozobolis VP, Christodoulakis EV. The intraoperative use of mitomycin-C in excision of ocular surface neoplasia with or without limbal autograft transplantation. Cornea. 2002;21:12–6. 68. Sarici AM, Arvas S, Pazarli H.  Combined exci sion, cryotherapy, and intraoperative mitomycin C (EXCRIM) for localized intraepithelial and squamous cell carcinoma of the conjunctiva. Graefes Arch Clin Exp Ophthalmol. 2013;251:2201–4. 69. Joag MG, Sise A, Murillo JC, et  al. Topical 5-­ fluorouracil 1% as primary treatment for ocular surface squamous neoplasia. Ophthalmology. 2016;123:1442–8. 70. Parrozzani R, Frizziero L, Trainiti S, et al. Topical 1% 5-fluoruracil as a sole treatment of corneoconjunctival ocular surface squamous neoplasia: long-term study. Br J Ophthalmol. 2017;101:1094–9. 71. Karp CL, Moore JK, Rosa RH Jr. Treatment of conjunctival and corneal intraepithelial neoplasia with topical interferon alpha-2b. Ophthalmology. 2001;108(6):1093–8. 72. Galor A, Karp CL, Chhabra S, et al. Topical interferon alpha 2b eye-drops for treatment of ocular surface squamous neoplasia; a dose comparison study. Br J Ophthalmol. 2010;94(5):551–4. 73. Shields CL, Kaliki S, Kim HJ, et  al. Interferon for ocular surface squamous neoplasia in 81 cases: outcomes based on the American Joint Committee on cancer classification. Cornea. 2013;32(3):248–56. 74. Krilis M, Tsang H, Coroneo M.  Treatment of conjunctival and corneal epithelial neoplasia with retinoic acid and topical interferon alfa-2b: long-term follow­up. Ophthalmology. 2012;119:1969–73.

J. Pe’er et al. 75. Karp CL, Galor A, Chhabra S, et al. Subconjunctival/ perilesional recombinant interferon α2b for ocular surface squamous neoplasia: a 10-year review. Ophthalmology. 2010;117:2241–6. 76. Nanji AA, Moon CS, Galor A, et al. Surgical versus medical treatment of ocular surface squamous neoplasia: a comparison of recurrences and complications. Ophthalmology. 2014;121:994–1000. 77. Espana EM, Prabhasawat P, Grueterich M, et  al. Amniotic membrane transplantation for reconstruction after excision of large ocular surface neoplasias. Br J Ophthalmol. 2002;86(6):640–5. 78. Palamar M, Kaya E, Egrilmez S, et al.  Amniotic membrane transplantation in surgical management of ocular surface squamous neoplasias: long-term results. Eye. 2014;28:1131–5. 79. Galor A, Karp CL, Oellers P, et al. Predictors of ocular surface squamous neoplasia recurrence after excisional surgery. Ophthalmology. 2012;119(10):1974–81. 80. Murillo JC, Galor A, Wu MC, et al. Intracorneal and intraocular invasion of ocular surface squamous neoplasia after intraocular surgery: report of two cases and review of the literature. Ocul Oncol Pathol. 2017;3:66–72. 81. Holkar S, Mudhar HS, Jain A, et al.  Regression of invasive conjunctival squamous carcinoma in an HIV-­ positive patient on antiretroviral therapy. Int J STD AIDS. 2005;16(12):782–3. 82. Ganapathy PS, Plesec T, Singh AD.  Conjunctival squamous papilloma refractory to interferon α-2b in a patient on systemic immunosuppression (tacrolimus). Am J Ophthalmol Case Rep. 2017;6:1–3.

Conjunctival and Corneal Tumors: Primary Acquired Melanosis

16

Jacob Pe’er and Robert Folberg

Introduction The name applied to the condition described in this chapter has evolved over many years. Each name carried with it implications for diagnosis and therapy. Hutchinson, who was the first to describe these lesions clinically in 1892, called them “senile freckle” or “lentigo melanosis” [1], while Dubreuilh, who was the first to describe these lesions histologically in 1912, used the term “melanose circonscrite precancereuse” [1]. Miescher in 1936 used the term “melanotische precancerose” [1] and Reese in 1966 “precancerous melanosis” [2]. The name itself— “precancerous”—prompted surgeons at that time to perform radical surgery, including orbital exenteration, to treat a condition that is confined to the epithelium and that poses no risk of metastasis. In reaction to the overtreatment of these lesions, Zimmerman proposed the name “benign acquired melanosis” in 1966 [3, 4], but the inclusion of the word “benign” led ophthalmologists to treat these lesions conservatively, and patients managed by observation often developed malignant melanoma. Silvers, in 1978, used the terms “intraepithelial J. Pe’er (*) Ocular Oncology Service and Ophthalmic Pathology Laboratory, Department of Ophthalmology, Hadassah - Hebrew University Medical Center, Jerusalem, Israel e-mail: [email protected] R. Folberg Oakland University William Beaumont School of Medicine, Rochester, MI, USA

melanocytic hyperplasia” and “atypical melanocytic hyperplasia” [5] to describe the histology of lesions that were predisposed to evolve into melanoma if not treated appropriately. The histological name, however, could not be applied in a clinical setting by ophthalmologists. The term “primary acquired melanosis” (PAM) was adopted by the World Health Organization in 1980, representing flat, brown, intraepithelial conjunctival lesions, in its International Histological Classification of Tumors [6]. “Primary” denotes that the lesion is not the result of generalized (racial) dark pigmentation, systemic disease (e.g., Addison’s disease), or local factors (foreign body, injury, inflammation, medication, etc.). “Acquired” distinguishes these lesions from those that are congenital. “Melanosis” indicates that the pigment in the lesion is derived specifically from the production of melanin rather than another pigment or a drug deposit (Table 16.1) [7]. The terminology—primary acquired melanosis or PAM—may be used by the ophthalmologist in a clinical setting to describe any form of flat acquired conjunctival pigmentation that cannot be attributed to a secondary influence. This identification should trigger a biopsy that will allow the pathologist to determine if melanocytic atypia is present (PAM with atypia) or represents conjunctival pigmentation without any melanocytic atypia (PAM without atypia). The designation of atypia is reserved for the pathologist because it is not possible to predict melanocytic atypia from clinical criteria alone.

© Springer Nature Switzerland AG 2019 J. Pe’er et al. (eds.), Clinical Ophthalmic Oncology, https://doi.org/10.1007/978-3-030-06046-6_16

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186 Table 16.1  Types of conjunctival melanosis Category Congenital Acquired

Subtype Ocular melanosis Oculodermal melanosis Racial Primary Secondary

Etiology Developmental episcleral hyperpigmentation Normal pigmentation in darker races Idiopathic Localized Post-inflammatory Foreign body Systemic Addison’s disease Syndromic Carney complex

Most recently, Damato and Coupland suggested that the term “PAM” be reserved only to clinical diagnosis and offered the term “conjunctival melanocytic intraepithelial neoplasia (C-MIN) with or without atypia” for the histological terminology of these lesions, with more severe changes regarded as “melanoma in situ” [8]. Jakobiec in a recent paper recommended that “intraepithelial melanocytic proliferation” be adopted for histopathological diagnosis [9]. The authors of this chapter consider that the hybrid nomenclature—one term for the ophthalmologist and another for the pathologist—neither adds value to the classification of the disorder nor does it improve the management. For the remainder of the chapter, therefore, the terminology PAM will be used in a clinical context and PAM with and without atypia when discussing pathology. The prevalence and natural behavior of PAM are controversial. One study [10] reported the prevalence of PAM in Caucasians with no known non-European ancestry to be 36%. This number is exceptionally high compared with other studies. It is important to consider that the authors of this study included lesions that were detectable only by high-magnification slit-lamp examination, and some lesions were so small that they would not have been detected on routine clinical inspection. Furthermore, there was no histological confirmation of the diagnosis in this series.

Etiology PAM is more prevalent in fair-complexioned individuals than in patients with dark skin tones and is almost always unilateral. If bilateral con-

Posttraumatic Drug deposition Ochronosis Peutz-Jeghers syndrome

junctival pigmentation is encountered, the ophthalmologist should first consider either complexion-associated conjunctival pigmentation or a systemic condition associated with bilateral conjunctival pigmentation.

Sunlight Exposure The importance of sun exposure in the development of PAM is not apparent. However, in one study [10], those who lived south of Washington, DC, for 5 or more years had a significantly higher prevalence of PAM lesions of their exposed intrapalpebral conjunctiva than those who did not. Also, patients with pinguecula or pterygium had a higher prevalence of PAM.  Silvers et  al. [5] noted a high incidence of solar elastosis in biopsy specimens from patients with conjunctival pigmented lesions. These facts suggest a possible role of sunlight exposure, but while they might explain PAM arising in the bulbar conjunctiva in the interpalpebral fissure, they do not account for cases in which PAM originates in the fornices and the palpebral conjunctiva.

 elationship to Nevi and Dysplastic R Nevus Syndrome The prevalence of PAM has been shown to increase significantly as the number of facial nevi increases [10]. Seregard et al. [11], in a case-control study, observed that ocular melanocytic lesions, including PAM, are not more common in individuals with dysplastic nevus syndrome than in the general population.

16  Conjunctival and Corneal Tumors: Primary Acquired Melanosis

Cigarette Smoking Cigarette smoking and hypertension have been observed as significant independent factors in the development of PAM [10]. No other etiological factors have been implicated in the development of PAM.

Clinical Features Primary acquired melanosis appears clinically as a flat and variably brown conjunctival lesion, ranging from golden brown to dark chocolate in color (Figs. 16.1 and 16.2) [7]. There are no published size criteria for the clinical diagnosis of PAM [9], although in one large series [12], PAM extended circumferentially for a mean of 3 clock hours, ranging from 1 to 12 clock hours. PAM is usually monocular, although binocular cases may occur. The lesion may involve any area of the conjunctiva in a contiguous or multi-spotted pattern, necessitating eversion of the eyelids to examine both the upper and lower palpebral zones. PAM develops most commonly at the limbus and epibulbar intrapalpebral region and may extend into the corneal epithelium (Fig.  16.3). According to Shields et al.’s experience with 311 eyes [12], the conjunctival quadrants affected by PAM were temporal, 57%; inferior, 45%; nasal, a

187

42%; and superior, 37%. In the same study, the anatomic locations of PAM included bulbar conjunctiva in 91%, limbal conjunctiva in 55%, cornea in 23%, forniceal conjunctiva in 13%, palpebral conjunctiva in 12%, and caruncle in 11%. In some patients with widespread lesions, the eyelid epidermis may also be involved [7]. PAM occurs typically in middle-aged or elderly white patients, although it may also appear in young adults, but usually not in children. In one study [13], the mean age at the time of diagnosis

Fig. 16.1  PAM without atypia. Would the lesion be enough to make the diagnosis of PAM and justify a biopsy?

b

Fig. 16.2  Diffuse PAM with atypia entirely covering the temporal bulbar conjunctiva (a). After treatment with topical mitomycin C. Some pigmentation, probably PAM without atypia, has remained unchanged for 6 years (b)

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b

Fig. 16.3  Conjunctival PAM with atypia, with corneal involvement (a). Another case that has progressed to corneolimbal melanoma (b)

was 45  years, and in another study, this was 62 years [10]. There is no significant difference in the prevalence of PAM between males and females [10], although in one extensive study [12], 62% of patients with PAM were female. Primary acquired melanosis lesions may remain stable for long periods of time or may grow in size. A “waxing and waning” phenomenon in which areas in the lesions darken or lighten is well known [7]. Parts of, or rarely the entire, PAM lesion can be amelanotic (PAM sine pigmento); thus, the borders of the lesion often cannot be identified, and the clinically recognized borders are misleading [13].

Ancillary Studies The clinical suspicion of PAM is based on the features described in the previous section. Because PAM lesions are flat and intraepithelial, there are no established imaging tools that can aid in the diagnosis. However, Messmer et  al. [14], using in vivo confocal microscopy (OCT), could display small dendritic cells and hyperreflective granules confined to the basal epithelium in PAM without atypia and extensive networks of hyperreflective dendritic cells and hyperreflective granules and patches throughout the epithelium in all cases of PAM with atypia. Alzahrani et al.

showed a thick basal epithelial hyperreflective band in all instances of PAM using OCT [15] (Figs.  16.4 and 16.5), and Shousha et  al. also showed correlation between histopathological findings and ultra-high-resolution OCT [16]. A Wood’s lamp may help in the detection of subclinical pigmentation but is seldom used in clinical practice [17].

Histopathologic Features Histologically, PAM is divided into two major groups: PAM without atypia and PAM with atypia. Most conjunctival melanomas arise in the context of PAM with atypia. PAM with atypia is confined to the epithelium and is called by some pathologists “melanoma in situ” [1] and is thus not associated with any risk of metastasis. However, 11–46% transform to conjunctival melanoma [12, 13]. The mortality of conjunctival melanoma is approximately 25%. Therefore, a particularly effective treatment for conjunctival melanoma is through prevention by completely extirpating lesions showing histological evidence of PAM with atypia. The lesion designated as PAM without atypia does not evolve into melanoma. As mentioned above, it is important to remember that there are no clinical criteria by which ophthalmologists can anticipate the histo-

16  Conjunctival and Corneal Tumors: Primary Acquired Melanosis

a

Fig. 16.4  Diffuse conjunctival PAM (a) without atypia. Note (arrow) basal epithelial hyperreflective band of approximately 20 micron thickness (b, above) and corresponding melanotic hyperpigmentation that is restricted

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to the basal layer (b, below) (hematoxylin and eosin, original magnification, 200×). (Reprinted from Alzahrani et  al. [15]. Copyright © 2015, © 2015 S.  Karger AG, Basel)

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Fig. 16.5  Corneal PAM. (a) Clinical appearance. (b) Note corresponding epithelial hyperreflective band. (Reprinted from Alzahrani et al. [15]. Copyright © 2015, © 2015 S. Karger AG, Basel)

logical diagnosis. For that reason, an ophthalmologist who encounters a fair-complexioned patient with a unilateral, acquired, flat patch of brown pigmentation should biopsy the lesion to allow the pathologist to classify the lesion as PAM without atypia or PAM with atypia.

Light Microscopy Histologically, the detection of conjunctival epithelial pigmentation with or without melanocytic hyperplasia—but, without melanocytic atypia— qualifies a lesion to be designated as PAM with-

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a

Fig. 16.6  Histologic picture of conjunctival PAM without atypia, with pigmented melanocytes located only along the basal layer of the epithelium (a) (hematoxylin and eosin, ×20). In this case, melanin pigmentation is distributed throughout the conjunctival epithelium, yet there

a

b

is no evidence of melanocytic hyperplasia or atypia. This lesion would, therefore, be designated histologically as conjunctival PAM without atypia (b) (hematoxylin and eosin, ×20)

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Fig. 16.7  Histologic picture of conjunctival PAM with atypia, showing atypical melanocytes in the basal layers (a hematoxylin and eosin, ×20). Highly atypical melanocytes populate the conjunctival epithelium singly and in

nests. Note the lack of contact between these cells and the epithelium. This lesion should be designated as PAM with atypia (b, hematoxylin and eosin, ×40)

out atypia (Fig.  16.6). One might think conceptually of such a lesion as an “ephilis” (freckle) or lentigo (despite the fact that there are no rete structures in the normal conjunctiva and therefore “lentigo” is difficult to identify in this location). Histologically, the detection of atypical melanocytes within the epithelium qualifies the lesion to be designated as PAM with atypia. In rendering a diagnosis of PAM with atypia, the pathologist should take note of both cytologi-

cal and architectural features. Melanocytic atypia is identified through the detection of melanocytes of different size and shape that appear to have a “disregard” (i.e., they are spatially separated from) for adjacent epithelial cells (Fig.  16.7). These atypical cells may be small and round, spindleshaped, or even epithelioid. Architecturally, the atypical melanocytes may be distributed along the epithelial basement membrane (basilar hyperplasia pattern), may be segregated into nests that

16  Conjunctival and Corneal Tumors: Primary Acquired Melanosis

appear to be anchored along the basement membrane, or may be dispersed upward into the more superficial layers of the epithelium, either individually or as intraepithelial nests (pagetoid spread). In some areas, the atypical melanocytes may completely replace the epithelium. PAM with atypia that extends into pseudoglands of Henle should not be mistaken for invasion (the lining of the pseudoglands is considered to be contiguous with the epithelium). It is important for both pathologists and ophthalmologists to understand that junctional nevi of the conjunctiva are exceptionally rare—even in children. Therefore, the diagnosis of “junctional nevus” when rendered by a pathologist who is not experienced in ophthalmic pathology should prompt a review, especially if the lesion is not taken from a young child: the lesion is likely to represent PAM with atypia. The histological identification and differential diagnosis of PAM with atypia are among the most difficult tasks in the practice of surgical ophthalmic pathology. In two studies, the researchers graded the cellular changes in PAM with atypia and showed higher rates of recurrence [18] and transformation to melanoma [19] in the highly-graded lesions. A detailed description of the histological differential diagnosis is beyond the scope of this chapter, and the reader is referred to a more specialized discourse for details [20].

Immunohistochemistry Chowers et al. [21] showed that on immunostaining for Ki-67 and PCNA, PAM with atypia had significantly higher proliferation activity than PAM without atypia. Sharara et al. [22] observed significantly higher expression of HMB-45  in PAM with atypia compared to PAM without atypia and conjunctival nevi. Jiang et  al. found that Melan-A labels all melanocytes without discriminating between benign and malignant cells, while atypical melanocytes were most specifically labeled with HMB-45, which positively increases significantly with worsening atypia [23]. In investigating mutations in conjunctival melanocytic lesions, none of the PAM lesions

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with or without atypia showed BRAF [24] or GNAQ mutations [25].

Differential Diagnosis Primary acquired melanosis should be differentiated from all pigmented lesions of the conjunctiva, especially flat ones [26]. Like PAM, conjunctival nevi are always movable. The presence of cysts within the lesion supports a diagnosis of conjunctival nevus rather than PAM, although PAM may arise in the context of a nevus; therefore, the presence of cysts does not “guarantee” a diagnosis of nevus. In episcleral melanosis, as in congenital ocular melanosis or oculodermal melanosis, the pigmentation is bluegray, non-movable, and usually multifocal. Conjunctival melanoma is typically elevated or nodular, but in early stages, when it arises from PAM with atypia, it may appear flat. Other melanocytic lesions of the conjunctiva include pigmentation associated with a dark skin tone that is usually bilateral and typically most intense at the limbus, fading in intensity toward the fornices (Fig. 16.8). Other conditions that can be included in a differential diagnosis are postinflammatory melanosis and systemic conditions with flat bilateral conjunctival pigmented patches such as Addison’s disease. Various benign and malignant conjunctival tumors that are usually amelanotic may be pigmented so as to simulate a conjunctival pigmented lesion, which when flat may resemble PAM.

Treatment The management of PAM remains controversial.

Observation A small minority of ophthalmologists believe that subtle PAM lesions do not meet the criteria for biopsy and recommend periodic follow-up [10]. They advise a thorough examination of the bulbar and palpebral conjunctiva and documentation of

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Fig. 16.8 Race-associated melanosis in an AfricanAmerican patient. (a) Note perilimbal superficial flat pigmentation in the right eye. (b) The pigmentation in the left

eye is more prominent because of globe shrinkage (atrophic bulbi) and because of a possible secondary effect of chronic inflammation

each lesion’s location, size, and appearance. However, biopsy should be performed if a PAM lesion differs from the characteristic, subtle lesions, including widespread or large lesions, dark lesions, lesions of the palpebral conjunctiva, and progressive lesions.

Brownstein et  al. [27] and Jakobiec et  al. [28] recommended adding cryotherapy to the surgical excision. Shields et  al. [29] suggest a six-step surgical procedure: alcohol corneal epitheliectomy, no-touch local removal of distinct lesions, staging conjunctival biopsy specimens, limbal peritomy, double freeze-thaw cryotherapy to the involved bulbar conjunctiva, and wound closure. In the Jakobiec series [28], none of the patients treated by surgical excision and cryotherapy progressed to invasive melanoma. As mentioned above, in patients with PAM, clinical examination may not indicate the full extent of the intraepithelial melanocytic lesions.  Additionally, the waxing-and-waning phenomenon of PAM may prevent identification of all locations of proliferating intraepithelial melanocytes that require treatment. Therefore, local excision and localized cryotherapy, even in cases of PAM that seem to be localized, may not cover the entire lesion. Furthermore, cryotherapy can cause complications such as scarring of the substantia propria, loss of eyelashes, ptosis, lax eyelids, tarsal floppiness, symblepharon, pseudopterygium, iritis, anterior segment necrosis, macular edema, scleral melting, and cataract [27].

Surgery The overwhelming consensus among ophthalmic oncologists and pathologists endorses biopsy of all conjunctival lesions that meet the clinical criteria of PAM [13, 22]. Small lesions should be excised entirely, while in widespread lesions, incisional biopsies should be performed at various sites of the affected conjunctiva (“map biopsies”). The specimen(s) should be examined to determine the presence or absence of cytologic atypia, and, in the case of excisional biopsies, the surgical margins should also be assessed.

Cryotherapy Because of the tendency for PAM with atypia to recur, with the risk of melanoma development,

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Topical Mitomycin C Chemotherapy

Prognosis

To cover the entire conjunctival and corneal surface, treating hidden areas of PAM and preventing the complications of cryotherapy, we originally managed a patient with widespread PAM with atypia by using mitomycin C [30]. Summarizing our experience with the first 12 consecutive patients [31], we recommended a protocol of 0.04% (0.4  mg/ml) mitomycin C drops four times daily for 2 weeks. This regimen is repeated as necessary with a pause of 2 weeks between courses, until disappearance or stabilization of the remnants of the pigmentation. At least three courses were recommended. In all patients, there was a complete or partial disappearance of pigmentation. In four patients, the pigmentation disappeared, whereas in eight patients, some remnants of pigmentation remained (Fig.  16.2). In one patient, there was regrowth of the PAM, which was treated again by 0.04% mitomycin C, with success. Other groups have shown similar results in treating PAM with atypia by mitomycin C [32–34]. All patients had conjunctival hyperemia during the treatment, and some complained of irritation, tearing, and eyelid swelling; these side effects resolved after cessation of therapy. The most severe adverse effect of this treatment is limbal stem cell deficiency (LSCD) [35]. This outcome led us to change the mitomycin C concentration to 0.03%, resulting in a similar response of the PAM and preventing LSCD. It is important to note that treatment with mitomycin C should be applied only to intraepithelial lesions and should not be used for invasive conjunctival melanoma.

The study of the natural history of PAM in humans is not possible. A successful attempt in an animal model [39], generated by applying a 1% solution of DMBA to the conjunctiva in rabbits, showed a spectrum of disease, ranging from increased melanin production and melanocytic hyperplasia without atypia through atypical melanocyte hyperplasia of PAM. The incidence of PAM recurrence depends on the presence or absence of atypia [13]. Recurrence after excision is rare in PAM without atypia; when this happens, it appears without cytological atypia. On the other hand, about 60% of lesions designated as “PAM with atypia” recur after excision alone; half of these recur as malignant melanoma. In one study [13], the median interval between the biopsy of PAM and the biopsy of melanoma was 2.5  years. Progression after 6 years is very rare, and progression to melanoma more than 10 years after the biopsy of PAM with atypia has not been observed. Recurrence is more likely when the lesion is incompletely excised or when the cornea is involved. Thus, when treating PAM with atypia, it is essential to treat the entire conjunctival and corneal lesion. It is important to note that the mortality rate from conjunctival melanoma is about 25% with no difference between patients who had melanoma with PAM and those who had melanoma without PAM (Fig.  16.3) [22]. However, no mortality has been reported from PAM without transformation to melanoma. Although patients with PAM without atypia tend to be younger than patients with PAM with atypia [13], there is no evidence to indicate progression of PAM without atypia to PAM with atypia.

Topical Interferon α-2b

References

Interferon alpha-2b also has been shown to be effective in treating PAM with atypia in small case series [36–38]; further studies are needed to evaluate its use.

1. Ackerman AB, Sood R, Koenig M. Primary acquired melanosis of the conjunctiva is melanoma in situ. Mod Pathol. 1991;4:253–63. 2. Reese AB.  Precancerous and cancerous melanosis. Am J Ophthalmol. 1966;61:1272–7.

194 3. Zimmerman LE. Criteria for management of melanosis. Arch Ophthalmol. 1966;76:307–8. [Letter]. 4. Zimmerman LE.  The histogenesis of conjunctival melanoma; the first Algernon B.  Reese lecture. In: Jakobiec FA, editor. Ocular and adnexal tumors. Birmingham: Aesculapius; 1978. p. 600–30. 5. Silvers DN, Jakobiec FA, Freeman TR, et  al. Melanoma of the conjunctiva: a clinicopathologic study. In: Jakobiec FA, editor. Ocular and adnexal tumors. Birmingham: Aesculapius; 1978. p. 583–99. 6. Zimmerman LE, Sobin LH. International histological classification of tumours. No. 24: Histological typing of tumours of the eye and its adnexa. Geneva: World Health Organization; 1980. p. 30. 7. Jakobiec FA, Folberg R, Iwamoto T. Clinicopathologic characteristics of premalignant and malignant melanocytic lesions of the conjunctiva. Ophthalmology. 1989;96:147–66. 8. Damato B, Coupland SE. Conjunctival melanoma and melanosis: a reappraisal of terminology, classification and staging. Clin Exp Ophthalmol. 2008;36:786–95. 9. Jakobiec FA.  Conjunctival primary acquired melanosis: is it time for a new terminology? Am J Ophthalmol. 2016;162:3–19. 10. Gloor P, Alexandrakis G. Clinical characterization of primary acquired melanosis. Invest Ophthalmol Vis Sci. 1995;36:1721–9. 11. Seregard S, Trampe E, Mansson-Brahme E, et  al. Prevalence of primary acquired melanosis and nevi of the conjunctiva and uvea in the dysplastic nevus syndrome. A case-control study. Ophthalmology. 1995;102:1524–9. 12. Shields JA, Shields CL, Mashayekhi A, et al. Primary acquired melanosis of the conjunctiva: risks for progression to melanoma in 311 eyes. Ophthalmology. 2008;115:511–9. 13. Folberg R, McLean IW, Zimmerman LE.  Primary acquired melanosis of the conjunctiva. Hum Pathol. 1985;16:129–35. 14. Messmer EM, Mackert MJ, Zapp DM, et  al. In vivo confocal microscopy of pigmented conjunctival tumors. Graefes Arch Clin Exp Ophthalmol. 2006;244:1437–45. 15. Alzahrani YA, Kumar S, Abdul Aziz H, et al. Primary acquired melanosis: clinical, histopathologic and optical coherence tomographic correlation. Ocul Oncol Pathol. 2016;2:123–7. 16. Shousha MA, Karp CL, Canto AP, et  al. Diagnosis of ocular surface lesions using ultra-high-resolution optical coherence tomography. Ophthalmology. 2013;120:883–91. 17. Folberg R, McLean IW, Zimmerman LE. Conjunctival melanosis and melanoma. Ophthalmology. 1984;91:673–8. 18. Maly A, Epstein D, Meir K, et al. Histological criteria for grading of atypia in melanocytic conjunctival lesions. Pathology. 2008;40:676–81. 19. Sugiura M, Colby KA, Mihm MC Jr, et  al. Lowrisk and high-risk histologic features in conjunctival primary acquired melanosis with atypia:

J. Pe’er and R. Folberg clinicopathologic analysis of 29 cases. Am J Surg Pathol. 2007;31:185–92. 20. Folberg R.  Tumors of the eye and ocular adnexae. In: Fletcher C, editor. Diagnostic histopathology of tumors. 3rd ed. Philadelphia: Elsevier; 2007. p. 1792–6. 21. Chowers I, Livni N, Solomon A, et  al. MIB-1 and PC-10 immunostaining for the assessment of proliferative activity in primary acquired melanosis without and with atypia. Br J Ophthalmol. 1998;82:1316–9. 22. Sharara NA, Alexander RA, Luthert PJ, et  al. Differential immunoreactivity of melanocytic lesions of the conjunctiva. Histopathology. 2001;39:426–31. 23. Jiang K, Brownstein S, Lam K, et al.  Usefulness of a red chromagen in the diagnosis of melanocytic lesions of the conjunctiva. JAMA Ophthalmol. 2014;132:622–9. 24. Goldenberg-Cohen N, Cohen Y, Rosenbaum E, et al. T1799A BRAF mutations in conjunctival melanocytic lesions. Invest Ophthalmol Vis Sci. 2005;46:3027–30. 25. Dratviman-Storobinsky O, Cohen Y, Frenkel S, et al. Lack of oncogenic GNAQ mutations in melanocytic lesions of the conjunctiva as compared to uveal melanoma. Invest Ophthalmol Vis Sci. 2010;51:6180–2. 26. Folberg R, Jakobiec FA, Bernardino VB, et al. Benign conjunctival melanocytic lesions. Clinicopathologic features. Ophthalmology. 1989;96:436–61. 27. Brownstein S, Jakobiec FA, Wilkinson RD, et  al. Cryotherapy for precancerous melanosis (atypical melanocytic hyperplasia) of the conjunctiva. Arch Ophthalmol. 1981;99:1224–31. 28. Jakobiec FA, Rini FJ, Fraunfelder FT, et  al. Cryotherapy for conjunctival primary acquired melanosis and malignant melanoma. Experience with 62 cases. Ophthalmology. 1988;95:1058–70. 29. Shields JA, Shields CL, De Potter P.  Surgical management of conjunctival tumors. Arch Ophthalmol. 1997;115:808–15. 30. Frucht-Pery J, Pe’er J.  Use of mitomycin C in the treatment of conjunctival primary acquired melanosis with atypia. Arch Ophthalmol. 1996;114:1261–4. 31. Pe’er J, Frucht-Pery J.  The treatment of primary acquired melanosis (PAM) with atypia by topical mitomycin C. Am J Ophthalmol. 2005;139:229–34. 32. Yuen VH, Jordan DR, Brownstein S, et  al. Topical mitomycin treatment for primary acquired melanosis of the conjunctiva. Ophthal Plast Reconstr Surg. 2003;19:149–51. 33. Kurli M, Finger PT.  Topical mitomycin chemo therapy for conjunctival malignant melanoma and primary acquired melanosis with atypia: 12 years’ experience. Graefes Arch Clin Exp Ophthalmol. 2005;243:1108–14. 34. Chalasani R, Giblin M, Conway RM.  Role of topical chemotherapy for primary acquired melanosis and malignant melanoma of the conjunctiva and cornea: review of the evidence and recommendations for treatment. Clin Exp Ophthalmol. 2006;34:708–14. 35. Lichtinger A, Pe’er J, Frucht-Pery J, et  al. Limbal stem cell deficiency after topical mitomycin C ther-

16  Conjunctival and Corneal Tumors: Primary Acquired Melanosis apy for primary acquired melanosis with atypia. Ophthalmology. 2010;117:431–7. 36. Finger PT, Sedeek RW, Chin KJ.  Topical interferon alpha in the treatment of conjunctival melanoma and primary acquired melanosis complex. Am J Ophthalmol. 2008;145:124–9. 37. Herold TR, Hintschich C.  Interferon alpha for the treatment of melanocytic conjunctival lesions. Graefes Arch Clin Exp Ophthalmol. 2010;248:111–5.

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38. Garip A, Schaumberger MM, Wolf A, et al. Evaluation of a short-term topical interferon α-2b treatment for histologically proven melanoma and primary acquired melanosis with atypia. Orbit. 2016;35:29–34. 39. Folberg R, Baron J, Reeves RD, et  al. Animal model of conjunctival primary acquired melanosis. Ophthalmology. 1989;96:1006–13.

Conjunctival and Corneal Tumors: Melanoma

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Jacob Pe’er and Robert Folberg

Introduction Conjunctival melanoma may arise de novo, from preexisting conjunctival nevus or PAM with atypia or from a combination of nevus and PAM with atypia. All these arise from melanocytes that migrate from the neural crest to reside in the conjunctival epithelium. In the medical literature, conjunctival melanoma is sometimes labeled together with uveal melanoma as “ocular melanoma.” The clinical behavior, molecular biology, and the histopathologic features of conjunctival and uveal melanoma are clearly different; therefore, conjunctival melanoma should be approached as an entity separate from uveal melanoma.

Epidemiological Aspects According to several studies, conjunctival melanoma accounts for 2–5% of ocular melanomas [1] and fewer than 3% of excisional biopsies of conjunctival lesions [2]. Cutaneous melanoma is J. Pe’er (*) Ocular Oncology Service and Ophthalmic Pathology Laboratory, Department of Ophthalmology, Hadassah - Hebrew University Medical Center, Jerusalem, Israel e-mail: [email protected] R. Folberg Oakland University William Beaumont School of Medicine, Rochester, MI, USA

450–900 times more common than conjunctival melanoma, a ratio that is increasing. Due to the rarity of conjunctival melanoma, incidence studies based on population-based data are scarce. According to a Dutch survey, the annual incidence of conjunctival melanoma ranges between 0.28 and 0.34 per million inhabitants [3]. A Swedish study showed a significant increase in the incidence of conjunctival melanoma from 1960 to 2005, from 0.10 cases/million to 0.74 cases/million in males and from 0.06 cases/million to 0.45 cases/million in females [4]. Population-based registry data from the Surveillance, Epidemiology and End Results (SEER) program of the National Cancer Institute (NCI) of the USA show a significant increase in the incidence rate of conjunctival melanoma from 0.22 cases per million per year in 1973– 1979 to 0.46 in 1990–1999 [5]. The most significant increase is for white men. Because changes in incidence coincide with those seen in cutaneous melanoma, the authors suggest a link to sunlight exposure. A recent study from Denmark has also shown an increase in the incidence of conjunctival melanoma between 1960 and 2012 to 0.5 cases per million per year, mostly caused by an increase in older patients (>65 years) [6]. Population-based data indicate that an equal number of men and women develop conjunctival melanoma [3, 4], but recent studies report a higher incidence in males [5]. Conjunctival melanoma is more common in middle-aged and older

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persons, between the fourth and seventh decades of life [3, 4], and only few cases in children have been reported [7]. When conjunctival melanoma develops in xeroderma pigmentosum  – a rare event  – younger patients are affected [8]. Conjunctival melanoma is less common in the black population and in other non-white individuals [1, 5], and according to the SEER program, the overall white-to-black incidence ratio in conjunctival melanoma is 2.6:1 [9].

Etiology and Associated Diseases Until recently, there was no clear evidence that ultraviolet radiation is a causative factor in the development of conjunctival melanoma, even though most of these tumors develop in the sunlight-­ exposed bulbar conjunctiva [1, 10]. However, in recent molecular studies, mutations in the telomerase reverse transcriptase (TERT) promoter, typical of UV-induced DNA damage and identical to mutations in cutaneous melanoma, were found in conjunctival melanoma but not in uveal melanoma [11–13]. About 70–75% of conjunctival melanomas are associated with PAM with atypia, while 7–17% are associated with conjunctival nevus, and 8–19% develop de novo [14, 15]. No significant association with cutaneous melanoma, dysplastic nevus syndrome, or ocular or oculodermal melanocytosis has been observed.

Fig. 17.1  Melanoma of the peri-limbal bulbar conjunctiva with “feeder vessels” entering the tumor

Clinical Features

Fig. 17.2  Conjunctival PAM with atypia, which has progressed to corneo-limbal melanoma

Conjunctival melanoma usually affects one eye and is typically pigmented. Amelanotic conjunctival melanoma does occur and can be mistaken clinically for squamous cell carcinoma. Careful high-magnification slit-lamp examination typically reveals flecks of pigmentation even in amelanotic melanomas. Any region of the conjunctiva including the caruncle and plica semilunaris may be affected (Figs.  17.1, 17.2, 17.3, 17.4, 17.5, and 17.6). Most conjunctival melanomas, however, develop at the limbus.

Conjunctival nevi are very rare in the palpebral conjunctiva and fornix. Therefore, pigmented lesions in these areas should be viewed as suspicious for melanoma and should be excised. In vivo confocal microscopy [16], ultrasound biomicroscopy [17], and high-resolution optical coherence tomography (HR-OCT) [18] serve as additional diagnostic tools in differentiating conjunctival melanoma from other conjunctival melanocytic lesions.

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Fig. 17.3  Melanoma of the plica semilunaris

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Fig. 17.5  Multifocal melanoma arising from PAM with atypia, with a tumor in the bulbar conjunctiva and a tumor in the lower fornix

Fig. 17.4  Melanoma of the upper palpebral conjunctiva

Variants  onjunctival Melanoma Associated C with PAM Microinvasive melanoma arising in PAM with atypia can be difficult to identify clinically; therefore, one should search carefully for subtle placoid thickening within the area of PAM. The more dramatic clinical evidence for development of melanoma from PAM is the sudden emergence of

Fig. 17.6 Extensive conjunctival melanoma with involvement of the entire upper palpebral conjunctiva, which could be seen only upon inversion of the upper eyelid. No involvement of the bulbar conjunctiva was noted, leading to a delay in diagnosis

one or more nodules in flat lesions [19, 20]. Multifocal melanomas are usually associated with PAM with atypia and may appear simultaneously or sequentially in different parts of the conjunctiva [19, 20]. Melanoma with PAM may also involve the adjacent eyelid skin [14].

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 onjunctival Melanoma Associated C with Nevus Conjunctival melanoma arising from a nevus or de novo appears clinically as a solitary pigmented or non-pigmented smooth vascularized nodule, commonly in the limbal area. Rarely, these lesions are pedunculated [1].

Primary Melanoma of the Cornea Primary melanoma of the cornea is very rare, although several cases have been reported [1]. Many of these cases represent examples of corneal invasion from a limbal melanoma. It is important to remember that Bowman’s layer is a barrier to invasion of the corneal stroma. Therefore, pigmented neoplasms affecting the cornea are usually superficial to Bowman’s layer unless this tissue has been violated by previous surgery.

Differential Diagnosis Any conjunctival pigmented lesion may simulate conjunctival melanoma.

Epithelial Tumors (Non-melanocytic) Non-melanocytic epithelial tumors such as squamous papilloma, conjunctival intraepithelial neoplasia, and invasive squamous cell carcinoma may acquire melanin in darkly-complexioned individuals [21].

Intraocular Tumors Epibulbar extension of uveal melanoma or melanocytoma should also be considered in the differential diagnosis of conjunctival melanoma [22]. In these cases, the trans-scleral nature of the lesion can be identified by high-frequency ocular ultrasound.

Miscellaneous Lesions Staphyloma, subconjunctival hematoma, foreign body, and hematic cyst may also be confused clinically with conjunctival melanoma [1]. Rare occurrence of metastatic cutaneous melanoma to the conjunctiva has been reported [23].

Histopathologic Features

Conjunctival Nevus

Light Microscopy

Conjunctival nevi may be elevated and dark, and in the absence of cysts (typical of compound conjunctival nevi), it may be difficult to differentiate the nevus from melanoma by clinical examination alone [20]. Most conjunctival nevi are noticed in childhood and adolescence. Therefore, any newly-elevated pigmented conjunctival lesion that develops in adulthood should be viewed with suspicion. Conjunctival nevi almost always develop in the bulbar conjunctiva and caruncle. Therefore, any pigmented lesion presenting in the palpebral conjunctiva or fornix should be considered suspicious for melanoma [20].

The definitive diagnosis of conjunctival melanoma is made by histopathologic examination. Most cases can be diagnosed with confidence by light microscopy (Fig. 17.7). Four types of atypical melanocytes have been described in conjunctival melanoma: small polyhedral, spindle, balloon, and round epithelioid cells with eosinophilic cytoplasm [20]. Invasive melanoma is often accompanied by intraepithelial PAM with atypia, which may be the precursor to the melanoma (Fig. 17.8). Any breeching of the basement membrane by atypical melanocytes in PAM with atypia should be considered as invasive mela-

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gists without experience in ophthalmic pathology, who may mistakenly consider these findings as signs of malignancy.

Immunohistochemistry and Molecular Pathology

Fig. 17.7  Low-magnification histological picture showing thick conjunctival melanoma involving the specimen’s margin (hematoxylin and eosin; original magnification ×4)

Fig. 17.8  This photomicrograph illustrates conjunctival melanoma arising in the context of PAM with atypia. Note the lack of maturation or architectural organization from top to bottom and the presence of atypical intraepithelial melanocytes that do not appear to be cohesive or to have any architectural relationship with the epithelial cells (hematoxylin and eosin; original magnification ×20)

noma. The presence of atypical melanocytes within the epithelium of subepithelial cysts is considered to represent PAM with atypia and not invasive melanoma. The common presence of cystic and solid epithelial inclusions in compound conjunctival nevi may confuse patholo-

If in doubt, immunohistochemical stains such as HMB-45, MELAN-A, and SOX-10, either individually or in a cocktail, can demonstrate the presence of melanocytes [24–26], and Ki-67 proliferation index may help to differentiate melanoma from nevi [27]. BRAF mutations are found in about half of conjunctival melanoma cases, similar to cutaneous melanoma, while BRAF mutations are seldom encountered in uveal melanomas [28–31]. Conversely, GNAQ mutations, which occur in uveal melanomas, are not found in conjunctival melanomas [32]. TERT promoter mutations with a UV signature are found in 32–41% of conjunctival melanomas [11–13]. NRAS mutations and NF1 mutations are also found in these tumors [31, 33]. Expressions of programmed cell death protein-1 (PD-1) and programmed death-ligand 1 (PD-L1) [34, 35], as well as specific micro RNA [36], are reported in conjunctival melanoma. All these markers may have therapeutic implications.

Histopathologic Prognostic Factors There are several histopathologic features that indicate a poor prognosis in patients with conjunctival melanoma. The major prognostic factor predictive of metastasis is the depth of invasion, measured with an ocular micrometer from the top of the epithelium to the deepest point of invasion. The other important histologic prognostic factors are presence of pagetoid spread, mixed cell tumors versus spindle cell tumors, histologic evidence of lymphatic invasion, increased lymphangiogenic activity, high number of mitotic figures, and high cell proliferation index using immuno-

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histochemical stains such as PCNA or Ki-67 [1, 14, 37, 38]. Ulceration in conjunctival melanoma is also an important histopathologic predictor for adverse outcome [37, 39]. The presence of PAM with atypia does not appear to be a prognostic indicator [14].

Clinical Course

has been attributed to shedding of exfoliated melanoma cells in the tear film, by direct extension, and as regional hematogenous metastases [1]. Epistaxis or epiphora may indicate extension and recurrence of the conjunctival melanoma in the nasolacrimal system [44]. Rarely, conjunctival melanoma invades the eyeball or extends directly into the orbit [1, 45].

Local Recurrence

Regional and Distant Metastasis

Local recurrence of conjunctival melanoma has been reported in 56–65% of the patients, and nearly half of these patients develop more than one recurrence [1, 3, 4, 40]. The mean interval between the first treatment and the first recurrence is 2.5  years. Some authorities report that patients treated by surgical excision alone have more recurrences than those receiving adjuvant treatment such as cryotherapy or brachytherapy, but it is not known if this recommendation applies to surgical resection with clear margins. For example, patients with multifocal disease, usually originating in PAM with atypia, are prone to develop recurrences because it can be difficult to ensure a clear resection margin. Other risk factors for developing recurrence are melanoma in  locations other than the limbus and involvement of surgical margins [40]. Therefore, the pathologist’s report should specifically comment on the tumor involvement of surgical margins. Local recurrences are managed as the primary melanoma.

Conjunctival melanoma can metastasize to any organ in the body. In about half of the patients with metastases, regional lymph node metastases are detected before systemic disease [40, 46]. Other common locations are the brain, liver, and lung [40]. It is important, however, to emphasize that in conjunctival melanoma, the most common primary locations of the metastases are the regional parotid (preauricular) and submandibular lymph nodes. This reflects an important difference between conjunctival and uveal melanoma, which tends to disseminate almost exclusively to the liver, at least initially. Therefore, ophthalmologists should be specific when referring patients with conjunctival melanoma to oncologists and must avoid applying the general term “ocular melanoma” lest the oncologist assumes, incorrectly, that the first target for metastasis is likely to be the liver as is the case with uveal melanoma.

Local Spread

Surgery

Conjunctival melanoma can spread locally in the conjunctiva and can metastasize to regional lymph nodes systemically [41]. “In-transit” metastases of conjunctival melanoma, which are believed to represent local lymphatic spread within the conjunctiva, have been described [42, 43]. Dissemination of melanoma cells at the time of tumor excision has also been reported. Spread of conjunctival melanoma through the nasolacrimal duct to the nasal cavity and paranasal sinuses

The primary treatment of conjunctival melanoma is surgical excision of the entire tumor. Most authorities recommend an excision margin of 3–5 mm, but this is not always feasible. Complete tumor excision should always be combined with adjuvant therapy. When deep limbal and scleral involvements are suspected, lamellar scleral excision should be considered [47]. When the cornea is involved, some surgeons use absolute alcohol to devitalize corneal epithelial cells adjacent to a

Treatment

17  Conjunctival and Corneal Tumors: Melanoma

limbal melanoma before excision [47]. Areas of PAM with atypia, either around the excised melanoma or distant from it, must be treated because these lesions can give rise to recurrent melanomas. The PAM can be treated by surgery, cryotherapy, or brachytherapy and/or topical chemotherapy using mitomycin C (see Chap. 16).

Cryotherapy Cryotherapy to the surgical margins and/or to the surgical bed, using a double freeze-thaw cycle, is the usual form of adjunctive therapy [19]. However, it should not be used as a primary treatment modality.

Radiotherapy Conjunctival melanoma is not radio-sensitive; therefore, brachytherapy should not be used as the sole treatment modality [48]. However, brachytherapy has been advocated as a supplemental therapy, usually using beta radiation, and has been reported to be superior to cryotherapy as adjuvant therapy after surgical excision [48–52]. Proton beam radiotherapy has also been advocated in treating extensive conjunctival melanoma as an alternative to exenteration [53].

Topical Chemotherapy and Immunotherapy In recent years, topical mitomycin C [54–56] and topical interferon alpha-2b [57–59] have been used successfully as adjuvant treatment to surgical excision in treating conjunctival malignant melanoma.

Orbital Exenteration In the past, orbital exenteration was the preferred treatment for conjunctival melanoma and PAM.  However, a review of the literature has failed to demonstrate advantages of such mutilat-

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ing radical surgery over a conservative approach in treating conjunctival melanoma [60]. Therefore, exenteration of the orbit, including the eyelids in order to include the palpebral and forniceal conjunctiva, is currently performed only as a palliative treatment for advanced disease. Exenteration is not usually performed when there is systemic metastatic disease.

Reconstruction When wide excision is performed, reconstruction of the conjunctiva is often needed. Such reconstruction can be achieved by transplanting mucosal tissue either from the mouth or from the contralateral conjunctiva. The successful use of amniotic membrane after excision of large conjunctival melanoma, in order to prevent conjunctival scars and symblepharon, has been described [61].

Regional and Distant Metastasis Regional lymph node metastasis is associated with a poor prognosis [60]; however, it has been found that patients with regional metastases tend to live longer than those with systemic metastases. Regional metastases can be treated by lumpectomy and adjuvant radiotherapy [60]. Disseminated conjunctival melanoma has been treated with systemic chemotherapy, with a possible combination of interferon or interleukin-2. However, the results are poor, and the life expectancy is a few months. In recent years, there has been impressive progress in the treatment of systemic metastases of cutaneous melanoma by biological drugs. Because of the similarities between conjunctival and cutaneous melanoma, such treatment has been suggested for conjunctival melanoma, and clinical trials are currently ongoing to further evaluate and optimize these targeted therapies, as well as immunotherapy [62]. The drugs that have been tried are BRAF/MEK inhibitors, such as vemurafenib (zelboraf) and dabrafenib (tafinlar) [63–65], and immune checkpoint inhibitors

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(PD-1 inhibitors) such as nivolumab (opdivo) and pembrolizumab (keytruda) [66, 67].

Sentinel Lymph Node Biopsy In the recent two decades, some ophthalmic oncologists have advocated preoperative lymphoscintigraphy and sentinel lymph node biopsy to evaluate the metastatic status of patients with conjunctival melanoma [68–71], although other experts identify little if any advantage to this approach (see Chap. 21 for details).

Prognosis The conjunctival melanoma-related mortality rate is 12–19% in 5 years and 23–30% in 10 years [1, 3, 4, 40, 48, 72]. There are many risk factors for metastatic spread of conjunctival melanoma; the most important ones are tumor thickness or nodular tumor and tumor location. Some claim that tumor origin de novo is also a risk factor [15]. Unfavorable tumor locations with high risk of metastatic spread are non-limbal or non-bulbar conjunctival sites such as palpebral conjunctiva, fornices, plica semilunaris, caruncle, and eyelid margins [15, 32]. The risk of metastasis increases with tumor thickness, from 0.8 to 4.0 mm [1, 40, 46, 72]. It can be concluded that there is a continuous worsening in prognosis with increasing tumor thickness, without any critical threshold. However, thin lesions (less than 0.8 mm in thickness) seldom give rise to metastasis unless lymphatic involvement is identified. Patients who undergo incisional tumor biopsy, as well as those who have tumor excision without adjuvant treatment, are more likely to develop local recurrence and metastatic diseases [73, 74]. The American Joint Committee on Cancer Staging (AJCC, seventh edition), based on TNM classification, was found to be predictive of local control and systemic spread of conjunctival melanoma [75–77]. The new eighth edition of the AJCC has not been investigated yet with respect to conjunctival melanoma [78].

J. Pe’er and R. Folberg

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17  Conjunctival and Corneal Tumors: Melanoma 17. Ho VH, Prager TC, Diwan H, et  al. Ultrasound biomicroscopy for estimation of tumor thickness for conjunctival melanoma. J Clin Ultrasound. 2007;35(9):533–7. 18. Nanji AA, Sayyad FE, Galor A, et al. High-resolution optical coherence tomography as an adjunctive tool in the diagnosis of corneal and conjunctival pathology. Ocul Surf. 2015;1:226–35. 19. Jakobiec FA, Rini FJ, Fraunfelder FT, et  al. Cryotherapy for conjunctival primary acquired melanosis and malignant melanoma. Experience with 62 cases. Ophthalmology. 1988;95(8):1058–70. 20. Jakobiec FA, Folberg R, Iwamoto T. Clinicopathologic characteristics of premalignant and malignant melanocytic lesions of the conjunctiva. Ophthalmology. 1989;96(2):147–66. 21. Folberg R, Jakobiec FA, Bernardino VB, et al. Benign conjunctival melanocytic lesions. Clinicopathologic features. Ophthalmology. 1989;96(4):436–61. 22. Rummelt V, Naumann GO, Folberg R, et al. Surgical management of melanocytoma of the ciliary body with extrascleral extension. Am J Ophthalmol. 1994;117(2):169–76. 23. Kiratli H, Shields CL, Shields JA, et  al. Metastatic tumours to the conjunctiva: report of 10 cases. Br J Ophthalmol. 1996;80(1):5–8. 24. Heegaard S, Jensen OA, Prause JU. Immunohistochemical diagnosis of malignant melanoma of the conjunctiva and uvea: comparison of the novel antibody against melan-A with S-100 protein and HMB-45. Melanoma Res. 2000;19(4):350–4. 25. Sharara NA, Alexander RA, Luthert PJ, et  al. Differential immunoreactivity of melanocytic lesions of the conjunctiva. Histopathology. 2001;39(4):426–31. 26. Iwamoto S, Burrows RC, Grossniklaus HE, et  al. Immunophenotype of conjunctival melanomas: comparisons with uveal and cutaneous melanomas. Arch Ophthalmol. 2002;129(12):1625–9. 27. Jakobiec FA, Bhat P, Colby KA. Immunohistochemical studies of conjunctival nevi and melanomas. Arch Ophthalmol. 2010;128(2):174–83. 28. Goldenberg-Cohen N, Cohen Y, Rosenbaum E, et  al. T1799A BRAF mutations in conjunctival melanocytic lesions. Invest Ophthalmol Vis Sci. 2005;46(9):3027–30. 29. Lake SL, Jmor F, Dopierala J, et al. Multiplex ligation-­ dependent probe amplification of conjunctival melanoma reveals common BRAF V600E gene mutation and gene copy number changes. Invest Ophthalmol Vis Sci. 2011;52(8):5598–604. 30. Griewank KG, Westekemper H, Murali R, et  al. Conjunctival melanomas harbor BRAF and NRAS mutations and copy number changes similar to cutaneous and mucosal melanomas. Clin Cancer Res. 2013;19:3143–52. 31. Larsen AC, Dahl C, Dahmcke CM, et  al. BRAF mutations in conjunctival melanoma: investigation of incidence, clinicopathological features, prognosis and paired premalignant lesions. Acta Ophthalmol. 2016;94:463–70.

205 32. Dratviman-Storobinsky O, Cohen Y, Frenkel S, et  al. Lack of oncogenic GNAQ mutations in melanocytic lesions of the conjunctiva as compared to uveal melanoma. Invest Ophthalmol Vis Sci. 2010;51(12):6180–2. 33. Scholz SL, Cosgarea I, Süßkind D, et  al. NF1 mutations in conjunctival melanoma. Br J Cancer. 2018;118:1243–7. 34. Cao J, Brouwer NJ, Richards KE, et al. PD-L1/PD-1 expression and tumor-infiltrating lymphocytes in conjunctival melanoma. Oncotarget. 2017;8:54722–34. 35. Cao J, Brouwer NJ, Jordanova ES, et al. HLA class I antigen expression in conjunctival melanoma is not associated with PD-L1/PD-1 status. Invest Ophthalmol Vis Sci. 2018;59:1005–15. 36. Larsen AC, Mikkelsen LH, Borup R, et al. MicroRNA expression profile in conjunctival melanoma. Invest Ophthalmol Vis Sci. 2016;57:4205–12. 37. Esmaeli B, Roberts D, Ross M, et al. Histologic features of conjunctival melanoma predictive of metastasis and death (an American Ophthalmological thesis). Trans Am Ophthalmol Soc. 2012;110:64–73. 38. Briceño CA, Elner VM, Demirci H. Lymphangiogenic and chemotactic factors in conjunctival melanoma. Ophthalmic Plast Reconstr Surg. 2016;32:428–33. 39. Savar A, Esmaeli B, Ho H, et al. Conjunctival melanoma: local-regional control rates, and impact of high-risk histopathologic features. J Cutan Pathol. 2011;38(1):18–24. 40. Shields CL, Shields JA, Gunduz K, et al. Conjunctival melanoma: risk factors for recurrence, exenteration, metastasis and death in 150 consecutive patients. Arch Ophthalmol. 2000;118(11):1497–507. 41. Mudhar HS, Rennie IG.  Local conjunctival metastases from primary conjunctival melanoma: clinico-­ pathological correlation and implications. Br J Ophthalmol. 2013;97(1):33–9. 42. Heindl LM, Hofmann-Rummelt C, Adler W, et  al. Prognostic significance of tumor-associated lymphangiogenesis in malignant melanomas of the conjunctiva. Ophthalmology. 2011;118(12):2351–60. 43. Barnhill RL, Lemaitre S, Lévy-Gabrielle C, et  al. Satellite in transit metastases in rapidly fatal conjunctival melanoma: implications for angiotropism and extravascular migratory metastasis (description of a murine model for conjunctival melanoma). Pathology. 2016;48:166–76. 44. Missotten GS, Gambrelle J, de Wolff-Rouendaal D, et  al. Epistaxis or epiphora as a sign for extension of a conjunctival melanoma. A series of six patients with nasolacrimal recurrence. Br J Ophthalmol. 2010;94(10):1328–31. 45. Sandinha T, Russell H, Kemp E, et al. Malignant melanoma of the conjunctiva with intraocular extension: a clinicopathological study of three cases. Graefes Arch Clin Exp Ophthalmol. 2007;245(3):431–6. 46. Tuomaala S, Kivela T. Metastatic pattern and survival in disseminated conjunctival melanoma: implications for sentinel lymph node biopsy. Ophthalmology. 2004;111(4):816–21.

206 47. Shields JA, Shields CL, DePotter P.  Surgical management of conjunctival tumors. The 1994 Lynn B.  McMahan lecture. Arch Ophthalmol. 1997;115(6):808–15. 48. Lommatzsch PK, Lommatzsch RE, Kirsch I, et  al. Therapeutic outcome of patients suffering from malignant melanoma of the conjunctiva. Br J Ophthalmol. 1990;74(10):615–9. 49. Krause L, Ritter C, Wachtlin J, et al. Recurrence rate following adjuvant strontium-90 brachytherapy after excision of conjunctival melanoma. Klin Monatsbl Augenheilkd. 2008;225(7):649–52. 50. Damato B, Coupland SE.  An audit of conjuncti val melanoma treatment in Liverpool. Eye (Lond). 2009;23(4):801–9. 51. Karim R, Conway RM.  Conservative resection and adjuvant plaque brachytherapy for early-stage conjunctival melanoma. Clin Exp Ophthalmol. 2011;39(4):293–8. 52. Cohen VM, Papastefanou VP, Liu S, et al.  The use of strontium-90 Beta radiotherapy as adjuvant treatment for conjunctival melanoma. J Oncol. 2013;2013:349162. 53. Wuestemeyer H, Sauerwein W, Meller D, et  al. Proton radiotherapy as an alternative to exenteration in the management of extended conjunctival melanoma. Graefes Arch Clin Exp Ophthalmol. 2006;244(4):438–46. 54. Krause L, Mladenova A, Bechrakis NE, et  al. Treatment modalities for conjunctival melanoma. Klin Monatsbl Augenheilkd. 2009;226(12):1012–6. 55. Kurli M, Finger PT.  Topical mitomycin chemo therapy for conjunctival malignant melanoma and primary acquired melanosis with atypia: 12 years’ experience. Graefes Arch Clin Exp Ophthalmol. 2005;243(11):1108–14. 56. Ditta LC, Shildkrot Y, Wilson MW. Outcomes in 15 patients with conjunctival melanoma treated with adjuvant topical mitomycin C: complications and recurrences. Ophthalmology. 2011;118(9):1754–9. 57. Finger PT, Sedeek RW, Chin KJ.  Topical interferon alfa in the treatment of conjunctival melanoma and primary acquired melanosis complex. Am J Ophthalmol. 2008;145(1):124–9. 58. Garip A, Schaumberger MM, Wolf A, et al. Evaluation of a short-term topical interferon α-2b treatment for histologically proven melanoma and primary acquired melanosis with atypia. Orbit. 2016;35:29–34. 59. Kikuchi I, Kase S, Ishijima K, et al. Long-term follow-up of conjunctival melanoma treated with topical interferon alpha-2b eye drops as adjunctive therapy following surgical resection. Graefes Arch Clin Exp Ophthalmol. 2017;255:2271–6. 60. Tatla T, Hungerford J, Plowman N, et al. Conjunctival melanoma: the role of conservative surgery and radiotherapy in regional metastatic disease. Laryngoscope. 2005;115(5):817–22.

J. Pe’er and R. Folberg 61. Dalla Pozza G, Ghirlando A, Busato F, et  al. Reconstruction of conjunctiva with amniotic membrane after excision of large conjunctival melanoma: a long-term study. Eur J Ophthalmol. 2005;15(4):446–50. 62. Blum ES, Yang J, Komatsubara KM, Carvajal RD.  Clinical management of uveal and conjunctival melanoma. Oncology (Williston Park). 2016;30:29–32. 63. Cao J, Heijkants RC, Jochemsen AG, et al. Targeting of the MAPK and AKT pathways in conjunctival melanoma shows potential synergy. Oncotarget. 2016;8:58021–36. 64. Mor JM, Heindl LM. Systemic BRAF/MEK inhibitors as a potential treatment option in metastatic conjunctival melanoma. Ocul Oncol Pathol. 2017;3:133–41. 65. Dagi Glass LR, Lawrence DP, Jakobiec FA, et al.  Conjunctival melanoma responsive to combined systemic BRAF/MEK inhibitors. Ophthalmic Plast Reconstr Surg. 2017;33:e114–6. 66. Ford J, Thuro BA, Thakar S, et al. Immune checkpoint inhibitors for treatment of metastatic melanoma of the orbit and ocular adnexa. Ophthalmic Plast Reconstr Surg. 2017;3:e82–5. 67. Kini A, Fu R, Compton C, et al. Pembrolizumab for recurrent conjunctival melanoma. JAMA Ophthalmol. 2017;135:891–2. 68. Amato M, Esmaeli B, Ahmadi MA, et al. Feasibility of preoperative lymphoscintigraphy for identification of sentinel lymph node in patients with conjunctival and periocular skin malignancies. Ophthal Plast Reconstr Surg. 2003;19(2):102–6. 69. Savar A, Ross MI, Prieto VG, et al. Sentinel lymph node biopsy for ocular adnexal melanoma: experience in 30 patients. Ophthalmology. 2009;116(11):2217–23. 70. Cohen VM, Tsimpida M, Hungerford JL, et al.  Pro­ spective study of sentinel lymph node biopsy for conjunctival melanoma. Br J Ophthalmol. 2013;97:1525–9. 71. Aziz HA, Gastman BR, Singh AD.  Management of conjunctival melanoma: critical assessment of sentinel lymph node biopsy. Ocul Oncol Pathol. 2015;1:266–73. 72. Paridaens AD, Minassian DC, McCartney AC, et al. Prognostic factors in primary malignant melanoma of the conjunctiva: a clinicopathological study of 256 cases. Br J Ophthalmol. 1994;78(4):252–9. 73. Larsen AC, Dahmcke CM, Dahl C, et  al. A retrospective review of conjunctival melanoma presentation, treatment, and outcome and an investigation of features associated with BRAF mutations. JAMA Ophthalmol. 2015;133:1295–303. 74. Brouwer NJ, Marinkovic M, van Duinen SG, et al.  Treatment of conjunctival melanoma in a Dutch referral centre. Br J Ophthalmol. 2018;102(9):1277–82. 75. Coupland SE, Barnhill R, Conway RM, et al. Chapter 50: Malignant melanoma of the conjunctiva. In: Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, editors. AJCC cancer staging manual. 7th ed. New York: Springer; 2010. p. 539–536.

17  Conjunctival and Corneal Tumors: Melanoma 76. Yousef YA, Finger PT. Predictive value of the seventh edition American Joint Committee on Cancer staging system for conjunctival melanoma. Arch Ophthalmol. 2012;139(5):599–606. 77. Shields CL, Kaliki S, Al-Dahmash SA, et  al. American Joint Committee on Cancer (AJCC) clini-

207 cal classification predicts conjunctival melanoma outcomes. Ophthal Plast Reconstr Surg. 2012;28(5): 313–23. 78. Coupland SE, Barnhill R, Conway RM, et al. Chapter 66: Conjunctival melanoma. In: AJCC cancer staging manual. 8th ed. Chicago: Springer; 2018. p. 795–803.

Conjunctival Stromal Tumors

18

Jacob Pe’er and Shahar Frenkel

Introduction

Pyogenic Granuloma

The conjunctival stroma contains various tissue elements such as vascular, fibrous, and neural; naturally, benign and malignant tumors may originate from these types of tissue (Table  18.1). However, conjunctival stromal tumors are rare. This chapter describes the salient features of conjunctival stromal tumors according to their tissue of origin.

The term “pyogenic granuloma” is a misnomer, since it is neither pyogenic nor granulomatous. It is granulation tissue, although some consider it as a polypoid form of acquired capillary hemangioma [2]. Pyogenic granuloma is a fibrovascular response to tissue insult such as surgical or nonsurgical trauma or inflammation, although spontaneous pyogenic granulomas have also been reported. Pyogenic granuloma is commonly observed in the conjunctiva after chalazion surgery, strabismus surgery, and excision of conjunctival lesions and in the anophthalmic socket following enucleation, considered as an aberrant wound-healing response.

Vascular Tumors Vascular tumors of the conjunctiva are uncommon, and with the exception of Kaposi’s sarcoma, most are benign lesions that have no malignant potential. According to one large series [1], the most common conjunctival vascular lesions are lymphangioma/lymphangiectasia and pyogenic granuloma.

J. Pe’er (*) · S. Frenkel Ocular Oncology Service and Ophthalmic Pathology Laboratory, Department of Ophthalmology, Hadassah - Hebrew University Medical Center, Jerusalem, Israel e-mail: [email protected]

Clinical Features Pyogenic granuloma has been reported in every part of the conjunctiva and even in the limbus and the cornea, mostly following a corneal epithelial defect [3]. Pyogenic granuloma appears as a fleshy, elevated, red, often pedunculated, richly vascularized mass (Fig. 18.1a). Histopathologic Features Pyogenic granuloma is composed of granulation tissue with marked chronic inflammation with lymphocytes, plasma cells, and neutrophils and proliferation of small, mostly capillary-sized blood vessels (Fig. 18.1b).

© Springer Nature Switzerland AG 2019 J. Pe’er et al. (eds.), Clinical Ophthalmic Oncology, https://doi.org/10.1007/978-3-030-06046-6_18

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Table 18.1  Classification of stromal tumors of the conjunctiva Category Vascular tumors

Fibrous tumors Neural tumors Histiocytic tumors Myxoid tumors Myogenic tumors Lipomatous tumors Lymphoproliferative tumors Choristomas

Subtypes Pyogenic granuloma Capillary hemangioma Cavernous hemangioma Acquired sessile hemangioma Varix Malignant hemangioendothelioma Fibroma Benign fibrous histiocytoma Neurofibroma (localized) Schwannoma (neurilemoma) Xanthoma Reticulohistiocytoma Myxoma Rhabdomyosarcoma Lipoma Liposarcoma Benign reactive lymphoid hyperplasia Leukemic infiltrates Dermoid Osseous choristoma Complex choristoma

Racemose malformation Hemangiopericytoma Kaposi’s sarcoma Lymphangiectasia Lymphangioma Nodular fasciitis Malignant fibrous histiocytoma Neurofibroma (diffuse) Granular cell tumor Juvenile xanthogranuloma

Herniated orbital fat Lymphoma Dermolipoma Lacrimal gland choristoma

Metastatic tumors Secondary tumors

a

b

Fig. 18.1  Pyogenic granuloma. A 31-year-old man with a 3-week history of a rapidly growing recurrent conjunctival vascular growth in the inferonasal conjunctival fornix.

Note prominent vascularity (a). Polypoid lesion with lobular pattern of capillary proliferation. The vessels are variably dilated (b) (original magnification ×4)

Treatment Pyogenic granuloma often responds to topical corticosteroids when diagnosed early, but many cases require surgical excision. In a recent

report of a small case series, pyogenic granuloma of the ocular surface showed complete resolution after treatment with topical 0.5% timolol [4].

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Capillary Hemangioma Capillary hemangioma appears during early infancy and, like its counterpart in the skin, may grow over several months and then regress spontaneously within several years.

Clinical Features Capillary hemangioma is a distinct or diffuse red, elevated conjunctival lesion that can occur anywhere in the conjunctiva. It can be an isolated lesion or in association with an eyelid or orbital capillary hemangioma (Fig. 18.2a). Histopathologic Features Similar to capillary hemangiomas in other locations, it shows numerous capillary channels and proliferation of endothelial cells (Fig. 18.2b). Treatment Usually, no treatment is needed, and the child should only be observed. There are rare cases, especially when the lesion is large and potentially amblyogenic, in which surgical excision or local or systemic corticosteroids are employed [1, 5]. The experience in treating conjunctival capillary hemangioma by beta-blockers is still limited and showed response to oral propranolol in one of two babies [6].

Cavernous Hemangioma Cavernous hemangioma presents as a red or blue multiloculated lesion in the deep conjunctival a

Fig. 18.2  Capillary hemangioma. Color photograph of a circumscribed vascular conjunctival lesion overlying the upper tarsus (a). On histopathology examination, the tar-

stroma in children and adolescents (Fig.  18.3a) [5]. This lesion is usually isolated but may be associated with syndromes [1]. It may cause a recurrent subconjunctival hemorrhage [7]. Histologically, similar to such lesions in other locations, it is composed of large blood-filled spaces, lined by endothelial cells and separated by fibrous septa (Fig. 18.3b). It can be managed by a surgical excision.

Acquired Sessile Hemangioma Shields et  al. [8] described vascular lesions of adults that consist of a sessile network of convoluted blood vessels immediately beneath the conjunctival epithelium, usually on the bulbar conjunctiva. Histologically the lesion comprises of two to three layers of dilated congested blood vessels that are otherwise of normal appearance. There are no systemic associations. Since most of these lesions remain stable and have no known complications, they should be managed by observation.

Varix and Racemose Hemangioma Conjunctival Varix Varix and racemose hemangioma are rare vascular malformations of the conjunctiva. Varix is a mass of dilated venous channels that may range from a single channel to complex venous channels. Many of them are anterior extensions of orbital varix. The color ranges from blue-red to b

sal conjunctival stroma revealed numerous thin-walled capillary-type vessels, most of which contained red blood cells within their lumen (H&E 10×) (b)

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b

c

d

Fig. 18.3  Cavernous hemangioma. A clustered “grapelike” lesion involving the temporal conjunctiva was observed on slit-lamp examination (a). On OCT, there were clear spaces located into the subepithelial layer of the conjunctiva (b). Ultrasonography showed two well-­

defined lesions with many low reflective intrinsic cystic-­ like pockets (c). Large, well-circumscribed vascular proliferation of thin-walled veins that completely replaced the conjunctival stroma (H&E 4×). Most of the lumina were engorged with blood (d)

black [1]. It is usually movable and not fixed to the sclera. Thrombosis is frequent. Some consider it to be in the spectrum of lymphangioma. Management should be conservative, by observation and symptomatic treatment. When it is symptomatic, surgical excision should be considered, although the surgeon should bear in mind the risk of prolonged bleeding [1, 3].

tumor composed of spindle-shaped pericytes and small blood vessels [9]. Treatment is by complete surgical excision with tumor-free margins and close follow-up.

 onjunctival Racemose Hemangioma C Conjunctival racemose hemangioma is a lesion of dilated arteries and veins communicating directly without a capillary bed between them. It appears as a loop of dilated vessels in the conjunctival stroma (Fig. 18.4). It should be managed conservatively by observation. Wyburn–Mason syndrome should be ruled out in such cases [5].

Hemangiopericytoma Hemangiopericytoma is very rare in the conjunctiva. It appears as an elevated pedunculated red mass (Fig.  18.5). Histologically, it is a solid

Kaposi’s Sarcoma Prior to the AIDS era, Kaposi’s sarcoma in general, and the conjunctiva in particular, was a rare tumor that mainly affected elderly and immunosuppressed patients. Since the eruption of the AIDS epidemic, this malignant tumor is diagnosed much more frequently in AIDS patients. Sometimes conjunctival Kaposi’s sarcoma is the first sign of AIDS [10]. However, in recent years, it has been diagnosed less frequently because of the more effective treatment of AIDS in developed countries.

Clinical Features Kaposi’s sarcoma appears as a single isolated or multiple confluent red painless conjunctival masses.

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a

b

c

Fig. 18.4  Racemose hemangioma. A multilobulated vascular lesion was identified in the medial canthal region that was extending posteriorly along the anterior margin of the caruncle (a). The lesion consisted of highly reflective portions with well-defined, low reflective channels on

a

Fig. 18.5  Hemangiopericytoma. Patient at presentation showing a large ovoid conjunctival lesion that protruded over her right lower lid (a). Histopathology shows a relatively solid tumor composed of spindle-shaped cells and

d

ultrasonography (b). Vascular proliferation composed of a mixture of thick-walled arteries and thin-walled veins within a fibrotic conjunctival stroma (H&E, 4×) (c). The endothelial cells were negative for lymphatic marker D2–40 (10×) (d)

b

inconspicuous small blood vessels (b, H&E,450×). (Reprinted from Grossniklaus et al. [9]. With permission from Elsevier)

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Histopathologic Features The tumors are composed of malignant spindle-­ shaped cells with elongated oval nuclei, well-­ formed capillary channels, and vascular slits containing blood but no definite endothelial lining. Treatment Localized tumors can be excised surgically, with or without the addition of cryotherapy. However, Kaposi’s sarcoma is responsive to chemotherapy and low-dose radiation therapy [11]. A giant conjunctival Kaposi’s sarcoma in HIV-positive patients responded with complete remission to highly active antiretroviral therapy and systemic chemotherapy [12]. Treatment using intralesional interferon alpha-2b [13] or intralesional mitomycin C [14] has been reported.

Lymphangiectasia and Lymphangioma Lymphangiectasia When lymphatic channels in the conjunctiva are dilated and prominent, the condition is called “lymphangiectasia.”

Clinical Features Conjunctival lymphangiectasia can either be unilateral or bilateral with focal or diffuse bulbar chemosis [15]. As a result of the communication with conjunctival veins, these dilated channels may be filled with blood and if so are termed “hemorrhagic lymphangiectasia” (lymphangiectasia hemorrhagica conjunctivae of Leber) [16]. The surrounding conjunctiva appears edematous, and occasionally, an associated subconjunctival hemorrhage is present. This phenomenon can occur spontaneously or after trauma or inflammation (Fig. 18.6). Congenital cases have been reported.

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Histopathologic Features The lesion shows markedly dilated lymphatics, which may be filled with blood, partially surrounded by scattered inflammatory cells. The phenomenon is intermittent, with resolution of the channels’ congestion and the chemosis between episodes. Treatment Usually, no treatment is required, although surgical excision without or with amniotic membrane transplant or conjunctival autograft has been described [15]. Recently, treatment of symptomatic conjunctival lymphangiectasia by liquid nitrogen cryotherapy [17], high-frequency radio wave electrosurgery, and limited surgical drainage has been reported [18, 19]. A case of conjunctival lymphangiectasia fully resolved after subconjunctival injection of bevacizumab was reported [20].

Conjunctival Lymphangioma Conjunctival lymphangioma is a benign tumor of the lymphatic vessels that usually appears in the first decade of life. It can occur as an isolated conjunctival lesion but more often represents a superficial component of an orbital lymphangioma.

Clinical Features Conjunctival lymphangioma appears as a multiloculated lesion composed of dilated cystic spaces. These spaces may contain clear fluid, but often parts of them contain blood and are called “chocolate cysts.” Inflammation in the area, such as an upper respiratory tract infection, causes congestion and dilation of the spaces. Because of the common connection of the conjunctival part to an orbital part, dilatation of the lymphangioma cysts may cause proptosis of the eye.

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a

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Fig. 18.6  Lymphangiectasia. Slit-lamp photograph demonstrating the appearance of prominent circumferential vessels (a–d). FA image demonstrating complete absence of hyperfluorescence in the lesion (e). Histopathology confirmed dilated tortuous empty channels (top and bottom, arrows) next to normal vessels containing blood. Stroma is free of inflammation. Bar represents 50 mm (f, hematoxylin and eosin). Immunohistochemistry for D2–40/podoplanin highlights lymphatics. Dilated channels are lined by D2–40-positive endothelium. Note the negative blood ves-

sels in the background (g, *). Immunohistochemistry for CD34, a marker of fibroblasts and the vascular endothelium, shows that dilated channels are CD34 negative (consistent with lymphatics) (h). Blood vessels show mild CD34 positivity, and background stromal cells are positive. Slit-lamp photograph demonstrating appearance 4  months after surgical drainage (i). Anterior segment OCT demonstrating dilated conjunctival lymphatic channels (j). (Reprinted from Goshe et al. [18]. With permission from Wolters Kluwer Health, Inc.)

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g

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Fig. 18.6 (continued)

Histopathologic Features Conjunctival lymphangioma shows dilated lymphatic channels filled with lymph and/or blood, lined by endothelium, and separated by thin walls. Treatment Treatment of lymphangioma is difficult, and surgical excision or radiotherapy usually does not eradicate the tumor. Carbon dioxide laser [21] and brachytherapy [22] have been used for treating conjunctival lymphangioma, with partial success. When dilatation of the spaces raises the orbital pressure and threatens the optic nerve, a percutaneous drainage of blood may offer a temporary relief. Drainage and sclerotherapy has been offered as a safe and effective treatment [23–25].

Fibrous Tumors Fibroma Clinical Features Fibroma of the conjunctiva is rare [26]. It is generally a slowly-progressing acquired white stromal tumor in adults and may range from a well-circumscribed lesion to a multinodular lesion. One case of malignant fibrosarcoma has also been reported [27]. Histopathologic Features The tumor is composed of compact fibroblasts and collagen. Rare variants such as elastofibroma oculi, giant cell angiofibroma, and solitary fibrous tumor have been described [28].

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Treatment Conjunctival fibroma is treated by complete surgical excision.

FH generally occurs in adults, but a case of FH in a child with xeroderma pigmentosum has also been reported [30].

 enign and Malignant Fibrous B Histiocytoma

Clinical Features Conjunctival FH appears as an amelanotic mass that can range from a well-circumscribed mass to a diffuse one. It often presents in the limbus (Fig. 18.7) [31].

Fibrous histiocytoma (FH) of the conjunctiva can be benign, locally aggressive, or malignant [29]. a

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Fig. 18.7  A 10-year-old black boy presented with a limbal lesion that was excised about 2  months previously. The lesion recurred (a). Further excision with cryotherapy was performed. For yet another recurrence, excision was repeated. Histopathology revealed a moderately cellular spindle cell lesion composed of bland spindle cells arranged in a vaguely storiform configuration. Entrapped collagen bundles are witnessed at the periphery of the

lesion, and there are scattered inflammatory cells, mostly lymphocytes (b, Hematoxylin and eosin stain, 40×). A final diagnosis of benign fibrous histiocytoma (extension to margin) was made. Repeat cryotherapy was performed to the surgical site. Over a 6-year follow-up, there was no recurrence, and the patient maintained normal visual acuity (c). (Courtesy of David Meisler, MD and Thomas Plesec, MD, Cleveland Clinic, Ohio)

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Histopathologic Features FH shows a mixture of spindle-shaped fibroblasts, often arranged in a storiform pattern, and lipid-laden histiocytes. Conjunctival FH with benign histological appearance may show a malignant clinical course. Malignant FH of the conjunctiva is extremely rare and shows marked pleomorphism, many mitotic figures, and multinucleated giant cells. Malignant FH is accepted as originating from primitive mesenchymal cells with the capacity to differentiate along either or both histiocytes and fibroblasts [32]. Malignant FH can metastasize to regional lymph nodes and hematogenously to distant organs, causing death. Treatment While benign FH can be treated by complete surgical excision, malignant FH should be treated by radical surgery that may include exenteration and radical dissection of regional lymph nodes.

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Nodular Fasciitis Nodular fasciitis is a benign rare nodular tumor of unknown cause that can occur at any age.

Clinical Features Nodular fasciitis appears as a solitary white episcleral enlarging nodule at the limbus or over the sclera anterior to the insertion of one of the rectus muscles and can cause discomfort or pain [33] (Fig.  18.8). The nodule may grow quickly and show signs of inflammation. It is thought to originate from the Tenon’s capsule [34]. Histopathologic Features The lesion tends to be round or oval and is not encapsulated. It is composed of bundles of fibroblasts that vary in configuration from spindle to stellate. There is a variable amount of intercellular myxoid ground substance interspersed with

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Fig. 18.8  Preoperative (a) and postoperative (b) appearance on slit-lamp examination. Spindle cell proliferation composed of regular delicate cells with pale chromatin and small nucleoli arranged in short, irregular fascicles (c, hematoxylin and eosin, 200×). Smooth muscle actin stain

of spindle cells with variable positivity, consistent with myofibroblastic differentiation (d). (Reprinted from McClintic et  al. [33]. With permission from Wolters Kluwer Health, Inc.)

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slit-like vascular spaces or capillaries and scanty infiltration of chronic inflammatory cells. Numerous mitotic figures can lead to its being misdiagnosed as a sarcoma [35].

Clinical Features Neurilemmoma (Schwannoma) appears as a pink-yellow elevated mass in the conjunctival stroma.

Treatment The prognosis is excellent, and complete excision is usually sufficient therapy, although recurrence can occur.

Histopathologic Features The tumor is the result of proliferation of Schwann cells of a peripheral nerve sheath and is composed of spindle cells that may be arranged in Antoni A pattern or Antoni B pattern.

Neural Tumors

Treatment Conjunctival neurilemmoma is treated by complete excision within the tumor capsule. Incomplete excision may lead to recurrence. Malignant Schwannoma has not been recorded in the conjunctiva.

Neurofibroma Neurofibroma is a peripheral nerve sheath tumor that can occur in the conjunctival stroma as a solitary circumscribed, or as a diffuse or plexiform, tumor [36]. The solitary type usually is not associated with systemic disease, while the latter is generally associated with neurofibromatosis type 1 (von Recklinghausen’s disease).

Clinical Features The solitary neurofibroma is an amelanotic, translucent, gelatinous circumscribed growing mass [37], while the plexiform neurofibroma is diffuse. Histopathologic Features Neurofibroma demonstrates benign proliferation of Schwann cells, axons, and endoneural fibroblasts, which may be difficult to differentiate from other spindle cell tumors. Treatment Solitary tumors are usually treated by complete surgical excision. Plexiform neurofibroma may be difficult to excise completely. In such cases, debulking of the tumor is performed.

Granular Cell Tumor Conjunctival granular cell tumor, known also as myoblastoma, is a very rare benign tumor of disputed origin [39]. After being thought of striated muscle origin, the recent suggestion is that it is of neural derivation, probably from Schwann cells.

Clinical Features The tumor appears as a pink, elevated smooth mass of the conjunctival stroma, indistinguishable from other well-circumscribed tumors. Histopathologic Features The tumor is composed of groups and cords of cells with small round to oval nuclei and voluminous cytoplasm containing fine eosinophilic granules. Treatment The tumor should be completely excised.

Neurilemmoma (Schwannoma)

Histiocytic Tumors

Neurilemmoma (Schwannoma) of the conjunctiva is a benign rare ocular tumor that can arise from any part of the conjunctiva – bulbar, forniceal, or palpebral [38].

Xanthoma Conjunctival xanthoma appears as a yellow subepithelial mass on the epibulbar surface. In a case

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of xanthoma disseminatum, in which multiple lesions are found, lesions have been described in the limbus of both eyes [40]. Histopathologically, the lesion shows subepithelial infiltrate of lipid-­ laden histiocytes, eosinophils, and Touton giant cells. Cases of atypical fibroxanthoma of the conjunctiva have also been reported [41].

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pink stromal mass, usually near the limbus (Fig. 18.9) [42]. Sometimes associated systemic findings may not be present [42]. Bilateral conjunctival xanthogranuloma in adults has also been recorded [43].

Histopathologic Features The lesions show typical findings of histiocytes and Touton giant cells; in addition, lymphoXanthogranuloma cytes, plasma cells, and eosinophils can be found. Immunohistochemical stainings are posClinical Features itive for CD68 (histiocytic marker) and negaConjunctival involvement in juvenile xantho- tive for CD1a and S-100 (Langerhans cell granuloma usually occurs as a solitary orange-­ markers) [44].

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Fig. 18.9 Juvenile xanthogranuloma. A 3-year old female was referred by her pediatrician for evaluation of a “red spot” in her right eye (a). As there was no response to topical steroids, excisional biopsy was performed. On histopathology, there was submucosal infiltrate consisting of foamy histiocytes, lymphocytes, and typical Touton giant

cells (b, hematoxylin and eosin, 40× magnification). The giant cells have characteristic wreath of nuclei in central part of the cell surrounded by foamy cytoplasm (c, oil immersion. 100× magnification). Dermatologic evaluation was negative

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Fig. 18.10  Conjunctival myxoma appearing as a cyst-­ tive tissue in the conjunctival stroma containing abundant like mass in nasal bulbar conjunctiva of the right eye (a). hyaluronidase-sensitive mucopolysaccharides stained Histologically, myxoma is a mass of very loose connec- positively with Alcian blue (b) (original magnification ×4)

Treatment Most lesions are treated by excision. When xanthogranuloma is suspected clinically, it may be observed for spontaneous resolution or can be treated by topical or systemic corticosteroids. In resistant cases, brachytherapy has been successfully applied.

Reticulohistiocytoma Clinical Features Reticulohistiocytoma is a rare benign conjunctival lesion that usually occurs as an isolated skin nodule or as part of a systemic disorder known as “multicentric reticulohistiocytosis.” The cases reported in the ocular surface were of a single, painless mass localized to the cornea and limbus without systemic disease [45]. Histopathologic Features The lesions are composed predominantly of large mononuclear and a few multinucleated cells with finely granular “ground glass” cytoplasm and large nuclei with prominent nucleoli. Treatment The lesions are treated by complete excision.

Myxoid Tumors (Myxoma) Clinical Features Conjunctival myxoma is a rare benign stromal tumor that occurs in adults. It appears as a slowly-­growing asymptomatic, freely movable, usually unilateral solitary lesion in any part of the conjunctiva but primarily located in the temporal bulbar conjunctiva [46, 47] (Fig. 18.10a). The lesion may appear pink or fleshy in color. Eyelid and conjunctival myxoma may be associated with Carney complex (Chap. 24).

Histopathologic Features The tumors are well-circumscribed, located in the conjunctival substantia propria, and covered by conjunctival epithelium. They are hypocellular and composed of stellate- and spindle-shaped cells, some with small intracytoplasmic and intranuclear vacuoles that represent dilated cisternae of rough-surfaced endoplasmic reticulum. The stroma contains abundant mucoid material, which stains positively for hyaluronidase-­ sensitive mucopolysaccharides, and sparse reticulin and delicate collagen fibers (Fig.  18.10b). Scattered mast cells are found in many lesions

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[46, 47]. Immunohistochemistry (IHC) demonstrates positivity for vimentin and negativity for smooth muscle actin, SOX10, and GLUT1 [45].

Treatment Simple surgical excision is curative.

Myogenic Tumors

function. In most cases, the treatment also includes chemotherapy and radiotherapy.

Other Myogenic Tumors Some other myogenic tumors of the conjunctiva such as infantile myofibroma [51], leiomyosarcoma, and myofibrosarcoma have been very rarely recorded (Fig. 18.11) [52–54].

Rhabdomyosarcoma

Lipomatous Tumors

Rhabdomyosarcoma (RMS) is the most common childhood primary orbital malignancy, but the occurrence of this tumor in the conjunctiva alone, without orbital involvement, is rare.

True lipomatous tumors of the conjunctiva are very rare. On the other hand, herniated orbital fat under the conjunctiva is not rare and may be mistaken for a lipomatous tumor. Dermolipoma is discussed later in this chapter.

Clinical Features Rhabdomyosarcoma appears as pink, rapidly growing conjunctival vascular mass. The initial clinical manifestation of the tumor may be a noninflamed pedicle of soft tissue, but occasionally swelling and erythema precede visible tumor formation [48]. Histopathologic Features Most conjunctival rhabdomyosarcomas are of the embryonal type, and as a submucosal tumor, some call it “botryoid” rhabdomyosarcoma (sarcoma botryoides) [48, 49]. Prognosis used to rely on the histopathologic type of the tumor. Recently the weight has shifted to the gene fusion status of forkhead box protein O1 (FOXO1). The European Paediatric Soft Tissue Sarcoma Study Group (EpSSG) found that the FOXO1 fusion status in patients with lymph node-positive (N1) alveolar rhabdomyosarcoma is a powerful predictor of prognosis [50]. The fusion status will be used to stratify these patients in the next EpSSG RMS study, and treatment will be intensified in patients with fusion-positive tumors. Treatment Complete surgical excision is recommended when this is possible without affecting ocular

Lipoma Conjunctival lipoma occurs in adults and appears as a yellow-pink stromal mass. Histopathologically, they are usually of the pleomorphic type and show variable-sized adipocytes surrounded by stellate cells. The stroma shows loose myxoid connective tissue. Floret giant cells and nuclear pyknosis were described in this tumor. Mitotic activity is absent [55].

Liposarcoma Liposarcoma of the conjunctiva shows clinical features similar to lipoma. Histopathologically, the tumor reveals numerous neoplastic cells containing stellate and hyperchromatic nucleus [56]. The cytoplasm of these cells contains vacuoles resembling lipid droplets, and signet-ring-type cells can be observed. The stroma may be myxomatous. The tumor is treated by complete surgical excision. A case of conjunctival liposarcoma showing multiple recurrences and metastatic disease was reported [57].

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Lymphoproliferative Tumors The conjunctival lymphoid tumors may be subdivided into reactive lymphoid hyperplasia, atypical lymphoid hyperplasia, and the more common conjunctival lymphoma. The conjunctival lymphoid tumors belong to the group of lymphoid tumors that affect the orbit and the eyelids – the ocular adnexal lymphoma [58].

Clinical Features Conjunctival lymphoid tumors can occur as an isolated lesion of the conjunctiva, but in up to one-third of patients, it is a manifestation of

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systemic lymphoma, which can be present simultaneously with the conjunctival disease or during follow-up. Lymphoid tumors may involve additional ocular sites, mainly the orbit, but the simultaneous involvement of the eyelid and uvea has also been reported [59]. Most conjunctival lymphoid tumors occur in adults, commonly manifested in individuals aged 60–70  years [60], but occurrence in children has also been found [61]. An association between conjunctival lymphoma and Chlamydophila psittaci [62] or Helicobacter pylori [63] has also been reported. However, it appears that that bacterial involvement in the pathogenesis of conjunctival lymphoma is linked to the geographic location [64].

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Fig. 18.11  Myofibrosarcoma. Slit-lamp appearance at presentation (a). Outcome after excision, cryotherapy to the conjunctival margins, and first episcleral brachytherapy (b). Superior marginal recurrence (c). Histopathologic examination revealed cells with spindle nuclei in a fascicular patter with poorly defined eosinophilic cytoplasm (d. Hematoxylin and eosin, 100× magnification). Immunoreactivity to smooth muscle actin was positive (e. 100× magnification) and negative to H-caldesmon, desmin, myoglobin, S-100, melan A, HMB45, AE1/3, and

CAM5.2 (not shown). Five years after initial presentation. Slit-lamp photo of area treated with triple episcleral brachytherapy (f). Position of episcleral plaques (g). A planned dose of 85 Gy at a depth of 3 mm was used for the first and second plaques, and 60 Gy at a depth of 4 mm was used for the third plaque. Note absence of radiation retinopathy on wide-field fluorescein anagram (h) and by OCT (h, inset). (Reprinted from Platt et al. [54]. With permission from Wolters Kluwer Health, Inc.)

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Fig. 18.11 (continued)

Symptoms Most patients diagnosed as having lymphoproliferative conjunctival lesions are symptomatic at the time of diagnosis. Symptoms include the presentation of a conjunctival mass, or irritation, and, less commonly, ptosis, epiphora, blurred vision, proptosis, and diplopia. Some of the patients are asymptomatic [59]. Signs The lymphoproliferative tumors of the conjunctiva appear as a diffuse, slightly elevated pink mass, resembling smoked salmon in color; hence, it is termed “salmon patch” (Fig.  18.12). Most conjunctival lymphoid tumors are located at the bulbar conjunctiva and fornix, usually hidden by the eyelid in the superior and inferior quadrants and not in the horizontal exposed parts of the bulbar conjunctiva or the limbus. Some of these tumors appear in the caruncle or plica semiluna-

ris but almost never appear in the palpebral conjunctiva.

Histopathologic Features As it is not possible to differentiate between benign and malignant conjunctival lymphoid tumors by clinical examination, a biopsy is needed to establish the diagnosis. The vast majority of conjunctival lymphomas are non-­ Hodgkin’s B-cell lymphoma, mostly of low grade [60]; T-cell lymphoma is extremely rare in the conjunctiva [65]. The major lymphoma subtypes, according to the Revised European and American Lymphoma (REAL) classification, include extranodal marginal zone B-cell lymphoma (EMZL) which is by far the most common type, followed by follicular lymphoma (FL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL) and the

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Fig. 18.12  Conjunctival lymphoma with typical infiltrative appearance (a). Three months following treatment with radiation therapy (Total dose 25 Gy, 12 fractions) (b)

rare plasmacytoma, and lymphoplasmacytic lymphoma/immunocytoma [57, 59].

Treatment Systemic evaluation should be performed to exclude the presence of systemic lymphoma which is common in DLBCL and MCL [60]. Localized disease is commonly treated with low-­dose external beam radiation (2000–4000  cGy) [60], local interferon alpha injections [66, 67], and brachytherapy using an ophthalmic applicator or a radioactive plaque [68]. In cases of widespread lymphoma and when systemic lymphoma is diagnosed, chemotherapy is applied [60]. Intravenous anti-CD20 monoclonal antibody (rituximab) has been used successfully with or without chemotherapy as primary treatment [69] and in treating relapsed mucosa-associated lymphoid tissue lymphoma of the conjunctiva [70, 71]. Recently, intralesional rituximab has been used successfully for conjunctival lymphoma [72].

Prognosis Local treatment is usually effective, but semiannual systemic evaluation should be performed

because of possible recurrence in extranodal sites. In one study, systemic lymphoma was eventually discovered in 15% of patients at 5 years and in 28% at 10 years [58]. Since most conjunctival lymphomas are low grade, the mortality rate of conjunctival lymphoma is low. The main prognostic factor for the risk of developing systemic lymphoma is the histological subtype with MCL and DLBCL having a markedly poorer prognosis then EMZL and FL [60]. Older age also was found to be an important prognostic factor [60, 73].

Leukemic Infiltrates Leukemic infiltration in the eye most commonly occurs in the choroid and retina, but conjunctival infiltration is also a well-recognized complication of many types of leukemia. Conjunctival involvement in leukemia shows myriad clinical presentations that can involve one or both eyes, have focal or diffuse infiltration of the substantia propria, can occur on the bulbar or palpebral conjunctiva, and can cause microvascular changes due to hyperviscosity (leukostasis) from markedly elevated leukemic cell counts. Conjunctival lesions have also been reported as the presenting manifestation of acute leukemia in patients who were not

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r­ ecognized to have the disease, and in others, they signified disease relapse [74, 75]. Conjunctival leukemic involvement is consistent with good visual acuity, with no reports of vision reduction associated with the conjunctival infiltration; however, it portended a poor prognosis with median survival of 3 months. Although clinical reports of conjunctival leukemia in the literature are relatively uncommon, autopsy studies of leukemic patients indicate that many harbor unsuspected disease and that most cases of conjunctival leukemia are probably subclinical or go unrecognized.

Clinical Features Conjunctival leukemia occurs most commonly in patients with acute leukemia. Leukemic infiltrations are often firm and not tender, may appear as a pink smooth mass, and are usually associated with small areas of hemorrhage [74]. Granulocytic sarcoma (chloroma) may appear in the ocular adnexa in the course of acute myelogenous leukemia (AML) and appear as a gray-green mass in the eyelid or the forniceal or tarsal conjunctiva [76].

Histopathologic Features Clinicopathological studies indicate that conjunctival leukemic lesions are cellular invasions that occur at all levels of the substantia propria; they can be diffuse or patchy and are generally localized along the blood vessels.

Treatment The treatment includes various combinations of chemotherapy and, commonly, local radiotherapy, with good local response in most cases. However, patients who achieve a complete local response may eventually die of the systemic disease. These patients die from refractory leukemia or leukemia-related complications, most commonly from infections.

Choristoma Choristomas are congenital lesions representing normal tissue in an abnormal location. When the lesion is composed of one type of tissue, it is considered to be a simple choristoma; when combinations of displaced tissue are involved, it is termed “complex choristoma.” Epibulbar choristomas are the most common epibulbar tumors in children [77]. Among them, dermoids and dermolipomas are very common [78]. Epibulbar choristomas affect the cornea, limbus, or subconjunctival space and range in appearance from a small, flat lesion to large masses filling most of the epibulbar region. They often can cause astigmatism. Epibulbar choristomas can affect other parts of the eye and orbit and may be associated with coloboma, Goldenhar syndrome, or organoid nevus syndrome [77].

Dermoid Epibulbar dermoid is a well-circumscribed firm, solitary congenital mass that involves the bulbar conjunctiva and often the corneoscleral limbus (Fig. 18.13). Rarely, more than one is found.

Clinical Features Conjunctival dermoid is usually a solid yellow-­ white mass, and sometimes fine hairs protrude from the lesion. The size of epibulbar dermoids is variable, from the more common small limbal dermoid through large dermoid involving most or the entire corneal surface to extensive dermoids that involve also the anterior chamber and the iris. The typical dermoid occurs in the inferotemporal limbus. It may be associated with Goldenhar syndrome that, in addition to the epibulbar dermoid, may include preauricular skin appendages, vertebral anomalies, eyelid coloboma, hearing loss, and mandibular hypoplasia. Epibulbar dermoid, in addition to being a cosmetic blemish, can cause severe astigmatism and amblyopia, affecting the vision according to the level of corneal involvement [79].

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Fig. 18.13  Limbal dermoid in the lower temporal aspect of the cornea and conjunctiva (a). Note hair. Appearance after surface excision (b)

Histopathologic Features Epibulbar dermoid is a simple choristoma that consists of dense fibrous tissue covered by stratified squamous epithelium. It usually contains dermal elements such as hair follicles, sebaceous glands, sweat glands, and sometimes fat tissue. Treatment When the epibulbar dermoid is very small and does not cause visual symptoms, it can be managed by observation alone. Larger dermoids can be managed by excision (lamellar keratosclerectomy) without or with conjunctival flap. In most cases, a corneal scar will remain in the excision site. Lamellar or penetrating keratoplasty may be needed in advanced cases. When amblyopia is present, early treatment is advised.

Dermolipoma

Fig. 18.14  Dermolipoma in the temporal part of the bulbar conjunctiva

temporal conjunctival fornix. Epibulbar dermolipoma often extends between the lateral rectus and superior rectus muscles to lie close to the lacrimal gland. They also may extend posteriorly into the orbit or anteriorly toward the limbus. Dermolipoma should be differentiated from subconjunctival orbital fat prolapse [80].

Clinical Features Dermolipoma is a yellowish-tan, soft, fusiform tumor, usually localized to the temporal or supero-temporal aspect of the conjunctiva, near the lateral canthus (Fig.  18.14). Although it is H  istopathologic Features congenital, it may remain asymptomatic for years The epithelium on the surface of the dermoliuntil detected when it protrudes from the supero-­ poma is stratified squamous epithelium that may

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be partially keratinized. The stroma contains variable quantities of dense collagenous tissue and large amounts of adipose tissue, mainly in the deeper aspects of the lesion. Pilosebaceous structures are usually absent.

Treatment The majority of the dermolipomas require no treatment, but when symptomatic or cosmetically blemished, it can be managed by simple excision of the anterior portion of the lesion or by excising the entire lesion, including the orbital part, through the conjunctival fornix. When the conjunctiva over the dermolipoma is adherent to the lesion and has to be excised, rotational conjunctival flap and free conjunctival autograft have been applied to cover the conjunctival defect [81, 82].

Osseous Choristoma

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pealing, it may be treated by surgical excision. When lesions adhere to the sclera, superficial sclerectomy may be warranted. Imaging of the globe with the tumor may aid in avoidance of iatrogenic globe perforation during surgical excision [83, 84].

 acrimal Gland Choristoma (Ectopic L Lacrimal Gland) Clinical Features Epibulbar lacrimal gland choristoma is a simple choristomatous congenital lesion which presents as an asymptomatic pink stromal mass, typically in the supero-temporal or temporal parts of the conjunctiva, but it has been described also in the limbal area [85, 86].

Histopathologic Features Lacrimal gland tissue, similar to normal lacrimal gland, is seen in the conjunctival stroma. Clinical Features Epibulbar osseous choristoma is a rare solitary Epibulbar complex choristoma may contain congenital lesion that most frequently presents as ­lacrimal gland tissue together with other tissue an isolated epibulbar lesion in the supero-­ elements [87, 88]. temporal quadrant but may occur in other locations on the surface of the globe or in association Treatment with other choristomatous lesions [83, 84]. Excision of the lesion usually suffices. Bilateral lesions have been reported. The lesion may be freely movable or adherent to the bulbar conjunctiva and the sclera. Not uncommonly, the Complex Choristoma lesion may involve the extraocular muscle sheath. Complex choristoma is a congenital, unilateral Histopathologic Features lesion that contains tissue derived from two germ The lesion is composed of mature, compact bone layers – ectoderm and mesoderm. surrounded by connective tissue in which additional choristomatous elements occasionally may Clinical Features be found. Epibulbar complex choristoma has a variable clinical appearance and ranges from a localized Treatment lesion to a lesion that covers much of the epibulEpibulbar osseous choristoma typically remains bar surface. A large pedunculated mass protrudundetectable until palpated by the patient, who ing through the eyelid aperture has been reported feels the hard lesion. The diagnosis can be con- [89] (Fig.  18.15a). The choristoma may invade firmed by ultrasonography or computed tomogra- the cornea. The consistency and color depend on phy that illustrates the calcifications. The tumor the types of tissue present in the choristoma; for is generally managed by periodic observation, example, dermal elements containing fat appear but if causing ocular inflammation, foreign body yellowish, while lacrimal tissue appears pink. A sensation, and tearing, or is cosmetically unap- case series of epibulbar choristoma containing

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a

Treatment The management of epibulbar complex choristoma depends on the extent of the lesion and the symptoms it causes. Asymptomatic small lesions can be observed, while large symptomatic lesions should be excised. Reconstruction of the ocular surface is sometimes needed. In very advanced cases, enucleation may be needed.

Metastatic and Secondary Tumors Metastatic Tumors b

Fig. 18.15  Epibulbar complex choristoma in a 5-day-old child, associated with linear nevus sebaceous. A large pedunculated mass protrudes temporally through the left eyelid aperture (a). CT scan shows calcifications (bone) in the tumor base and a cyst-like structure in the polypoid mass (b)

cartilage, smooth muscle bundles, and fibrous connective tissue covered by pterygia was reported [90].

Histopathologic Features Complex choristoma may include a variable combination of ectopic tissue such as dermal tissue containing adipose tissue, collagen and pilosebaceous structures, lacrimal gland, smooth muscle, cartilage, bone, nerves, and blood vessels. It may appear cystic (Fig. 18.15b). Epibulbar complex choristoma may be associated with organoid nevus syndrome, of which the most frequent cutaneous feature is the sebaceous nevus of Jadassohn [89].

Metastatic tumors to the conjunctiva are rare and usually appear at an advanced stage of the systemic malignancy when there is evidence of other ocular and organ metastases [91]. Similar to sources of metastases in other ocular sites, the primary tumors are usually carcinomas, led by breast carcinoma or cutaneous melanoma. The metastatic carcinoma appears as fleshy, yellow or pink, vascularized stromal tumors, while metastatic cutaneous melanoma may be pigmented. The metastasis may be located in any part of the conjunctiva and is usually solitary but may be multiple. Conjunctival metastases are treated by excisional biopsy, radiotherapy, and chemotherapy. The survival time after diagnosis of the conjunctival metastasis is in the range of months.

Secondary Tumors The conjunctiva may be secondarily involved by extraocular extension of intraocular tumors and by extension of eyelid and orbital tumors [5]. The most important tumor in this category is sebaceous gland carcinoma of the eyelid, which often exhibits pagetoid invasion into the conjunctival epithelium. Ciliary body melanoma, when extending through the sclera into the subconjunctival tissue, may simulate conjunctival melanoma. Orbital tumors, such as rhabdomyosarcoma in children, can present first in the conjunctiva.

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c

d

Fig. 18.16  IgG4 sclerosing disease. Slit-lamp photos of left eye conjunctival lesion at presentation show a temporal conjunctival bulbar lesion that is raised, tan-colored, vascular, and immobile (a). Ultrasound biomicroscopy of the conjunctival lesion measuring 7.5 × 8 × 1.2 mm with low reflectivity and shallow focal invasion into the sclera (b). Photomicrograph of conjunctival lesion demonstrating haphazard fibrosis with intermixed plasma cell-rich inflammation as well as many eosinophils and a few lym-

IgG4-Related Disease

phoid follicles (c, hematoxylin and eosin, original magnification ×100). Photomicrograph of immunohistochemical stain for IgG4, in the same area as H&E photomicrograph (d). There are numerous IgG4-positive plasma cells, which, in conjunction with the H&E morphology and IgG4:IgG ratio of 64%, are diagnostic of IgG4-RD. (Reprinted from Li et  al. [94]. With permission from Wolters Kluwer Health, Inc.)

and orbit) is a rare entity. Varied presentations, vague symptoms, and rare incidence result in Isolated conjunctival inflammation from IgG4-­ delayed or missed diagnoses (Fig.  18.17) [95– related disease should be on the differential for 99]. Immunohistochemistry (IHC) [100], and, chronic and minimally symptomatic solitary con- more recently, mass spectrometry (MS) allows junctival lesions. Assessment of IgG4-RD is for amyloid protein subtype analysis [101]. MS based on the combination of clinical history, offers increased accuracy in protein subtype physical exam, histopathology, laboratory results, identification and may also allow for identificaand radiology studies [92–94] (Fig. 18.16). tion of new protein subtypes [102]. A recent study, with comprehensive review of the literature, concluded that amyloidosis-AL is the most Amyloidosis common form of amyloid deposit in ocular adnexal structures [103]. Hence work up to Amyloid deposit in ocular adnexal structures exclude systemic involvement or associated (conjunctiva, eyelid, lacrimal gland and sac, underlying lymphoproliferative disorder is extraocular muscles, levator palpebrae muscle, warranted.

231

18  Conjunctival Stromal Tumors

a

b

c

d

Fig. 18.17  A 63-year-old white woman with past history of sarcoidosis was noted to have an incidental left-sided conjunctival orbital mass (a). The mass was yellowish in color, multinodular, and firm in consistency. Ocular motility was full, and proptosis was absent. MRI confirmed enhancing mass that was localized to the anterior orbit (b,

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arrow). Congo red-stained section of conjunctival mucosa shows lobular accumulation of amorphous congophilic material in deep stroma (c, Congo red) which exhibits apple-green birefringence with polarized light (d). (Reprinted from: Blandford et  al. [103]. With permission from Elsevier) 7. Kiratli H, Uzun S, Tarlan B, et  al. Recurrent subconjunctival hemorrhage due to cavernous hemangioma of the conjunctiva. Can J Ophthalmol. 2012;47:318–20. 8. Shields JA, Kligman BE, Mashayekhi A, et  al. Acquired sessile hemangioma of the conjunctiva: a report of 10 cases. Am J Ophthalmol. 2011;152:55–9. 9. Grossniklaus HE, Green WR, Wolff SM, et al.  Hemangiopericytoma of the conjunctiva. Two cases. Ophthalmology. 1986;93:265–7. 10. Kurumety UR, Lustbader JM. Kaposi’s sarcoma of the bulbar conjunctiva as an initial clinical manifestation of acquired immunodeficiency syndrome. Arch Ophthalmol. 1995;113:978. 11. Ghabrial R, Quivey JM, Dunn JP Jr, et al. Radiation therapy of acquired immunodeficiency syndromerelated Kaposi’s sarcoma of the eyelids and conjunctiva. Arch Ophthalmol. 1992;110:1423–6.

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18  Conjunctival Stromal Tumors and immunohistochemical study. Arch Ophthalmol. 1986;104:1203–4. 49. Polito E, Pichierri P, Loffredo A, et al.  A case of primary botryoid conjunctival rhabdomyosarcoma. Graefes Arch Clin Exp Ophthalmol. 2006;244:517–9. 50. Gallego S, Zanetti I, Orbach D, et al. Fusion status in patients with lymph node-positive (N1) alveolar rhabdomyosarcoma is a powerful predictor of prognosis: experience of the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG). Cancer. 2018;124(15):3201–9. 51. Lascaratos G, Gupta M, Bridges L, et  al. J Pediatr Ophthalmol Strabismus. 2010;487:47.. Online:e1–3 52. White VA, Damji KF, Richards JS, et al. Leiomyo­ sarcoma of the conjunctiva. Ophthalmology. 1991;98:1560–4. 53. Kenawy N, Coupland SE, Austin M, et  al. Conjunctival leiomyosarcoma. Clin Exp Ophthalmol. 2012;40:328–30. 54. Platt SM, Schoenfield L, Basti S, et  al. Recurrent conjunctival myofibrosarcoma managed with triple application of episcleral brachytherapy. Cornea. 2017;36:628–30. 55. Bryant J. Pleomorphic lipoma of the bulbar conjunctiva. Ann Ophthalmol. 1987;19:148–9. 56. Miyashita K, Abe Y, Osamura Y. Case of conjunctival liposarcoma. Jpn J Ophthalmol. 1991;35:207–10. 57. Giuri S, Raica M, Munteanu M. Myxoid/round cell conjunctival liposarcoma. A case report. Romanian J Morphol Embryol. 2013;54:655–8. 58. Coupland SE, Hellmich M, Auw-Haedrich C, et al.  Prognostic value of cell-cycle markers in ocular adnexal lymphoma: an assessment of 230 cases. Graefes Arch Clin Exp Ophthalmol. 2004;242:130–45. 59. Shields CL, Shields JA, Carvalho C, et al. Conjunc­ tival lymphoid tumors: clinical analysis of 117 cases and relationship to systemic lymphoma. Ophthalmology. 2001;108:979–84. 60. Kirkegaard MM, Rasmussen PK, Coupland SE, et  al. Conjunctival lymphoma–an international multicenter retrospective study. JAMA Ophthalmol. 2016;134:406–14. 61. Beykin G, Pe’er J, Amir G, et al. Pediatric and adolescent elevated conjunctival lesions in the plical area: lymphoma or reactive lymphoid hyperplasia? Br J Ophthalmol. 2014;98(5):645–50. 62. Ferreri AJ, Dolcetti R, Dognini GP, et al. Chlamydophila psittaci is viable and infectious in the conjunctiva and peripheral blood of patients with ocular adnexal lymphoma; results of a single-­center prospective case– control study. Int J Cancer. 2008;125:1089–93. 63. Lee SB, Yang JW, Kim CS. The association between conjunctival MALT lymphoma and Helicobacter pylori. Br J Ophthalmol. 2008;92:534–6. 64. Carugi A, Onnis A, Antonicelli G, et al. Geographic variation and environmental conditions as cofactors in Chlamydia psittaci association with ocular

233 adnexal lymphomas: a comparison between Italian and African samples. Hematol Oncol. 2010;28:20–6. 65. Kirkegaard MM, Coupland SE, Prause JU, et al.  Malignant lymphoma of the conjunctiva. Surv Ophthalmol. 2015;60:444–58. 66. Blasi MA, Tiberti AC, Valente P, et al. Intralesional interferon-α for conjunctival mucosa-associated lymphoid tissue lymphoma: long-term results. Ophthalmology. 2012;119:494–500. 67. Platt S, Al Zahrani Y, Singh N, et al. Extranodal marginal zone lymphoma of ocular adnexa: outcomes following radiation therapy. Ocul Oncol Pathol. 2017;3(3):181–7. 68. Regueiro CA, Valcarcel FJ, Romero J, et al. Treatment of conjunctival lymphomas by beta-ray brachytherapy using a strongium-90-yttrium-90 applicator. Clin Oncol (R Coll Radiol). 2002;14:459–63. 69. Frenkel S, Gaitonde SS, Azar N, et al. Conjunctival marginal zone b-cell lymphoma in a 13-year-old child. J Pediatr Ophthalmol Strabismus. 2011;48 Online:e1–4. 70. Nuckel H, Meller D, Steuhl KP, et al.  Anti-CD20 monoclonal antibody therapy in relapsed MALT lymphoma of the conjunctiva. Eur J Haematol. 2004;73:258–62. 71. Kim SY, Yang SW, Lee WS, et al. Frontline treatment with chemoimmunotherapy for limited-stage ocular adnexal MALT lymphoma with adverse factors: a phase II study. Oncotarget. 2017;8:68583–90. 72. Ferreri AJ, Govi S, Colucci A, et  al. Intralesional rituximab: a new therapeutic approach for patients with conjunctival lymphomas. Ophthalmology. 2011;118:24–8. 73. Nam SW, Woo KI, Kim YD. Characteristics of primary extranodal marginal zone B-cell lymphoma in Korea: conjunctiva versus other ocular adnexa. Br J Ophthalmol. 2018;102:502–8. 74. Lee SS, Robinson MR, Morris JC, et al. Conjunctival involvement with T-cell polymorphocytic leukemia: report of a case and review of the literature. Surv Ophthalmol. 2004;49:525–36. 75. Mozaheb Z, Khooei A.  Bilateral conjunctival infiltration as an extramedullary relapse of AML. Case Rep Hematol. 2018;2018:9590469. 76. Aggarwal E, Mulay K, Honavar SG. Orbital extra-­ medullary granulocytic sarcoma: clinicopathologic correlation with immunohistochemical features. Surv Ophthalmol. 2014;59:232–5. 77. Mansour AM, Barber JC, Reinecke RD, et al. Ocular choristomas. Surv Ophthalmol. 1989;33:339–58. 78. Huang JJ, Li B, Liang QF, et al.  The clinical and histopathological analysis of 2 053 cases of conjunctival neoplasms. Zhonghua Yan Ke Za Zhi. 2016;52:738–44. 79. Zhong J, Deng Y, Zhang P, et al. New grading system for Limbal dermoid: a retrospective analysis of 261 cases over a 10-year period. Cornea. 2018;37:66–71. 80. Kim E, Kim HJ, Kim YD, et  al. Subconjunctival fat prolapse and dermolipoma of the orbit: dif-

234 ferentiation on CT and MR imaging. AJNR Am J Neuroradiol. 2011;32:465–7. 81. Sa HS, Kim HK, Shin JH, et al.  Dermolipoma surgery with rotational conjunctival flaps. Acta Ophthalmol. 2012;90:86–90. 82. Choi YJ, Kim IH, Choi JH, et  al. Early results of surgical management of conjunctival dermolipoma: partial excision and free conjunctival autograft. Br J Ophthalmol. 2015;99:1031–6. 83. Gayre GS, Proia AD, Dutton JJ. Epibulbar osseous choristoma: case report and review of the literature. Ophthalmic Surg Lasers. 2002;33:410–5. 84. Vachette M, Moulin A, Zografos L, et al. Epibulbar osseous choristoma: a clinicopathological case series and review of the literature. Klin Monatsbl Augenheilkd. 2012;229:420–3. 85. Pfaffenbach DD, Green WR. Ectopic lacrimal gland. Int Ophthalmol Clin. 1971;11:149–59. 86. Tuncer S, Araz B, Peksayar G, et al.  Solitary lacrimal gland choristoma of the limbal conjunctiva. Ophthalmic Surg Lasers Imaging. 2010;41 Online:e1–2. 87. Pokorny KS, Hyman BM, Jakobiec FA, et al. Epibul­ bar choristomas containing lacrimal tissue. Clinical distinction from dermoids and histologic evidence of an origin from the palpebral lobe. Ophthalmology. 1987;94:1249–57. 88. Grob SR, Jakobiec FA, Stagner AM, et al.  Diffuse epibulbar complex lacrimal-­ cartilaginous choristoma: diagnostic clues and management. Cornea. 2015;34:1321–3. 89. Pe’er J, Ilsar M.  Epibulbar complex choristoma associated with nevus sebaceous. Arch Ophthalmol. 1995;113:1301–4. 90. Zhang Z, Yang Z, Pan Q, et al. Epibulbar complex cartilaginous choristoma: a distinctive clinicopathological case series and literature review. Medicine (Baltimore). 2018;97:e9902. 91. Kiratli H, Shields CL, Shields JA, et al. Metastatic tumours to the conjunctiva: report of 10 cases. Br J Ophthalmol. 1996;80:5–8. 92. Goto H, Takahira M, Azumi A, et al. Diagnostic criteria for IgG4-­related ophthalmic disease. Jpn J Ophthalmol. 2015;59(1):1–7.

J. Pe’er and S. Frenkel 93. Aziz H, Villa-Forte A, Plesec T, et al. Isolated conjunctival inflammation suggestive of IgG4-­related disease. Ocul Oncol Pathol. 2015;2:51–3. 94. Li A, Plesec TP, Mileti L, et al. Isolated conjunctival inflammation as manifestation of IgG4 related disease. Cornea. 2018;37(9):1182–4. 95. Mora-Horna ER, Rojas-Padilla R, Lopez VG, et  al. Ocular adnexal and orbital amyloidosis: a case series and literature review. Int Ophthalmol. 2016;36:281–98. 96. Aryasit O, Preechawai P, Kayasut K.  Clinical presentation, treatment, and prognosis of periocular and orbital amyloidosis in a university-based referral center. Clin Ophthalmol. 2013;7:801–5. 97. Demirci H, Shields CL, Eagle RC Jr, et al. Conjunc­ tival amyloidosis: report of six cases and review of the literature. Surv Ophthalmol. 2006;51:419–33. 98. Leibovitch I, Selva D, Goldberg RA, et al. Periocular and orbital amyloidosis: clinical characteristics, management, and outcome. Ophthalmology. 2006;113:1657–64. 99. Suesskind D, Ziemssen F, Rohrbach JM.  Conjunctival amyloidosis  – clinical and histopathologic features. Graefes Arch Clin Exp Ophthalmol. 2015;253:1377–83. 100. Collins AB, Smith RN, Stone JR.  Classification of amyloid deposits in diagnostic cardiac specimens by immunofluorescence. Cardiovasc Pathol. 2009;18:205–16. 101. Vrana JA, Gamez JD, Madden BJ, et al. Classification of amyloidosis by laser microdissection and mass spectrometry-based proteomic analysis in clinical biopsy specimens. Blood. 2009;114:4957–9. 102. Gilbertson JA, Theis JD, Vrana JA, et  al. A comparison of immunohistochemistry and mass spectrometry for determining the amyloid fibril protein from formalin-fixed biopsy tissue. J Clin Pathol. 2015;68:314–7. 103. Blandford AD, Yordi S, Kapoor S, et  al. Ocular adnexal amyloidosis: a mass spectrometric analysis. Am J Ophthalmol. 2018;193:28–32.

Caruncle Tumors

19

Hans E. Grossniklaus, Daniel R. Capiz-Correa, and Jill R. Wells

Caruncle Tumors The caruncle (diminutive of the Latin word Caro = flesh) is a fleshy structure located at the inner canthus at the lacrimal lake. It has a tail that blends to the skin of the medial canthal angle and a round to ovoid head medial to the plica semilunaris. The distance from the common canaliculus is about 0.85  mm [1–3]. The caruncle develops from the nasal aspect of the lower lid fold and is sequestered from the lower lid by the growth of the lower canaliculus. It has an irregular surface, measuring about 5  mm vertically, 3  mm transversely, and 1.5 mm in thickness, containing conjunctival and skin elements. The caruncle has a nonkeratinized stratified squamous epithelium with goblet cells. The stroma contains fibroblasts and melanocytes interspersed with collagen, adipose tissue, sebaceous glands associated with hair follicles, striated muscle fibers (Horner’s muscle), inflammatory cells, and, in some individuals, sweat glands and accessory lacrimal tissue. Its blood supply is from the medial palpebral H. E. Grossniklaus (*) · J. R. Wells Department of Ophthalmology, Emory University School of Medicine/Emory Eye Center, Atlanta, GA, USA e-mail: [email protected] D. R. Capiz-Correa Department of Orbit and Oculoplastic, Fundacion Hospital Nuestra Senora de la Luz, I.A.P., Mexico City, Mexico

artery. The lymphatics drain to the submaxillary lymph nodes and are innervated by the infratrochlear nerve. The function of the caruncle is not well understood, but it may participate in lacrimal drainage through contractions of Horner’s muscle [1–4]. Because the caruncle is a transitional zone structure, it can give rise to tumors found in the skin, conjunctiva, and lacrimal gland. Few caruncle lesion series have been published since the first report by Von Graefe in 1858 [4–11]. Lesions of the caruncle are rare, and because of their multiple components, clinical diagnosis and management can be difficult. Caruncle lesions correspond to 0.3–1.1% of all specimens submitted to an ophthalmic pathology laboratory [4–9]. Inconsistency between clinical and histopathologic diagnosis as high as 50% has been reported [5–9]. In a report by Ostergaard of 574 caruncle lesions, 96% of lesions were classified as benign, with the benign nature of these tumors being recognized in only 29% prior to histopathologic study [9]. In the series reported by Ostergaard, tumors were classified as benign in 96% of lesions, premalignant in 1.7%, and malignant in 2.4%. The most affected age group was from 20 to 29 years (71%). Nevus and papilloma were the most common benign neoplasms, occurring in 43% and 22% of cases, respectively. Less common lesions included inclusion cysts (6.1%), sebaceous gland hyperplasia (5.4%), and chronic inflammatory

© Springer Nature Switzerland AG 2019 J. Pe’er et al. (eds.), Clinical Ophthalmic Oncology, https://doi.org/10.1007/978-3-030-06046-6_19

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236

lesions (4.4%). Rare lesions included oncocytoma in 16 cases, primary basal cell carcinoma in 3 cases of secondary basal cell carcinoma, lymphoma in 4 cases and sebaceous gland carcinoma [2], melanoma [2], and Kaposi’s sarcoma [2]. Vascular tumors were also found, corresponding to nine hemangiomas, seven pyogenic granulomas, and four lymphangiomas. Ectopic lacrimal gland was found in seven cases (Table 19.1) [9].

Table 19.1 Pathologic diagnoses of lesions of the caruncle Category Benign Degeneration  Elastoid degeneration  Amyloid deposits Inflammation  Chronic inflammation  Chalazion  Foreign body  Abscess  Folliculitis Neoplasia Cystic  Inclusion cyst  Ductal cyst Epithelial  Papilloma  Sebaceous gland hyperplasia  Oncocytoma  Ectopic lacrimal gland  Sebaceous gland adenoma  Hidrocystoma Lymphoid  Reactive lymphoid hyperplasia Mesenchymal  Leiomyoma Melanocytic  Nevus  Primary acquired melanosis Vascular  Hemangioma  Lymphangioma  Pyogenic granuloma Miscellaneous  Normal tissue  Dermoid tumor  Fribrolipoma  Xanthoma Premalignant

n 550

% 96

2 1

0.3 0.2

25 4 3 1 1

4.4 0.7 0.5 0.2 0.2

Table 19.1 (continued) Category Neoplasia  Papilloma with dysplasia  Dysplasia Melanocytic  Primary acquired melanosis with atypia Malignant Neoplasia Epithelial  Basal cell carcinoma (primary)  Basal cell carcinoma (secondary)  Sebaceous gland carcinoma Lymphoid  Lymphoma Melanocytic  Melanoma Vascular  Kaposi’s sarcoma Total

%

n 4 2

0.7 0.3

4

0.7

14

2.4

1 3 2

0.2 0.5 0.3

4

0.7

2

0.3

2 574

0.3 100.0

Modified from Ostergaard et al. [9]. With permission from John Wiley & Sons

Epithelial Lesions 35 9

6.1 1.6

127 31 16 7 3 1

22.1 5.4 2.8 1.2 0.5 0.2

2

0.3

1

0.2

248 5

43.2 0.9

9 4 7

1.6 0.7 1.2

5 1 1 1 10

0.9 0.2 0.2 0.2 1.7

Squamous Papilloma Papillomas are benign epithelial tumors of the conjunctiva with a cauliflower-like appearance, most of which are exophytic, and can be sessile or pedunculated, and they are more common in adults between 20 and 39 years of age and children. They can be solitary or multiple [4–5, 11, 13]. They are intimately related to human papilloma virus especially serotypes 6 and 11 [4, 5, 8, 9, 12, 13]. Histologically, they are composed of multiple fronds or fingerlike projections of conjunctival epithelium, which enclose cores of vascularized connective tissue [8, 13]. After removal, recurrence rates range from 6% to 27% [8]. Topical alpha-interferon can be used in case of recurrence or multiple lesions (Fig. 19.1).

Sebaceous Hyperplasia Sebaceous hyperplasia can present as a slow-­ growing, painless, yellow, “greasy,” granular,

237

19  Caruncle Tumors

a

Fig. 19.1  Squamous papilloma: (a) Pedunculated and sessile papilloma arising from the caruncle (clinical photograph). (b) Acanthotic epithelium arranged in a papil-

b

lomatous configuration overlaying central vascular cores (H&E stain, 10×)

nodular lesion, which is associated with overlying telangiectatic vessels of unknown etiology, although some reports present cases experiencing pain [4, 14]. Histologically, they are formed of hyperplastic glandular lobules situated around a single duct where the sebaceous cells maintain their normal maturation with a single, outer, dark, germinal layer changing abruptly to clear vacuolated cells in the inner layers. Excisional biopsy is recommended if malignancy is suspected, to improve cosmesis or lesion debulking (Fig. 19.2).

Oncocytoma Oncocytomas constitute 5.1% of caruncle lesions [15]. In the ocular region, they are most commonly found in the caruncle, but can arise from the conjunctiva, eyelid, lacrimal gland, and lacrimal sac. Clinically, they are slow-growing nodules, red, orange-tan, or red-blue in color, sometimes with a lobulated, fleshy, or cystic appearance, found in patients over 50  years of age (range, 51–89), with slightly higher prevalence in women. They develop from oncocytic metaplasia of the lacrimal or salivary acinar cells, or from conjunctiva adjacent to the caruncle. Histologically, they are composed of polygonal epithelial cells with round, central to paracentral, nuclei and abundant, finely granular, eosinophilic cytoplasm containing abundant mitochondria.

Fig. 19.2  Sebaceous hyperplasia: Lobules of enlarged subepithelial sebaceous glands, with normal maturation (H&E stain, 25×)

Lymphocytes can be present but are scanty, and lymphoid follicles are rare (Fig. 19.3).

Sebaceous Carcinoma More than 95% of sebaceous carcinomas originate in the eyelids, usually from the Meibomian glands of the tarsus and less often from the Zeiss glands, with only about 2% to 5% developing in the caruncle [16, 17]. Clinically, they can be misdiagnosed as sebaceous gland hyperplasia. Histologically, this tumor is composed of lobules of sebaceous gland with pleomorphic vacuolated

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a

H. E. Grossniklaus et al.

b

Fig. 19.3  Oncocytoma: (a) dark subepithelial nodule (clinical photograph). (b) Oncocytes forming glands. These cells have small, displaced nuclei with abundant eosinophilic cytoplasm (H&E stain, 100×)

cells and mitotic activity. The standard local treatment is complete surgical removal with negative margins and map biopsies to rule out pagetoid spread and regional and distant metastasis. Follow-up is recommended (Fig. 19.4).

Basal Cell Carcinoma Basal cell carcinoma is a rare tumor of the caruncle, although some studies report the incidence as being similar to that of melanoma [4, 7, 9]. Because of its close proximity to the medial canthus, it is not rare to find caruncular involvement from a basal cell carcinoma arising in the skin of the medial canthus. Clinically, most lesions are vascularized and nodular, more common in men, between the range of 24 and 82 years [18]. Basal cell carcinoma can arise from basal cells of the epithelium or infundibular cells of the hair follicles or from pluripotent stem cells. They should be treated by complete excision whenever possible.

Pigmented Lesions Nevus Nevus is the most commonly reported lesion of the caruncle [4–6, 8, 9, 15]. In a report by Shields, caruncular nevus accounted for 15% of all con-

junctival nevi [19]. They are usually noticed around the age of puberty and are regarded as hamartomas. They are mildly elevated, brown, pigmented lesions with a cystic component, but they can be amelanotic. Feeder and intrinsic vessels can be seen is up to one of three cases. Nevi are usually asymptomatic, but occasionally the patient can report a foreign body sensation. Surgical removal is mainly done for cosmetic reasons or if there is a clinical suspicion of malignancy. Histologically, nevi are composed of nest of nevus cells. Most are compound nevi, but some can have a subepithelial or junctional component (Fig. 19.5).

Melanoma Melanoma has been reported to be the most prevalent malignant lesion of the caruncle. Melanoma involving the caruncle has relatively poor prognosis (together with melanomas in the palpebral conjunctiva, plica semilunaris, and fornix) compared to epibulbar conjunctival lesions. One feature to distinguish melanoma from nevus is the absence of intralesional cysts on slit lamp examination. Treatment for conjunctival melanoma includes surgical removal with clear margins plus cryotherapy and/or radiotherapy, with topical chemotherapy for diffuse disease and exenteration if there is orbital invasion. Melanoma can arise from primary

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19  Caruncle Tumors

a

b

c

d

Fig. 19.4  Sebaceous carcinoma: (a) Fleshy nodule arising from the caruncle (clinical photograph). (b) Tumor composed of lobules of hyperplastic sebaceous glands (H&E stain, 10×). (c) Higher magnification showing cells with sebaceous differentiation, pleomorphic amphophilic

a

nuclei with prominent nucleoli, lobules of tumor surrounded by chronic inflammatory cells (H&E stain, 40×). (d) Sebaceous differentiation, with positive staining for adipophilin (adipophilin immunostain, 100×)

b

Fig. 19.5  Caruncle nevus: (a) Dark pigmented lesion with well-demarcated margin, note the absence of cysts (clinical photograph). (b) Subepithelial nest of nevus cells, some with melanin pigment in their cytoplasm (H&E stain, 25×)

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acquired melanosis in up to 40% of cases, from nevi in 30% or de novo in 30% of cases [5] (Figs. 19.6 and 19.7).

Inflammatory Lesions Most inflammatory lesions of the caruncle have been reported as unspecified nongranulomatous chronic inflmaation [8, 9]. Other reported inflammatory lesions include foreign body granuloma, abscess, folliculitis, actinomycosis, inflammatory pseudotumor, ocular cicatricial pemphigoid, cytomegalovirus infection, molluscum contagiosum, and spherocytosis (Fig. 19.8).

Fig. 19.6  Caruncle PAM with associated conjunctival melanoma: Extensive areas of PAM extending to the bulbar and tarsal conjunctiva, and the caruncle. Melanoma arising from PAM affecting the superior fornix (clinical photograph)

a

b

c

d

Fig. 19.7  Caruncle melanoma: (a) Exophytic, fleshy lesion originating from the caruncle (clinical photograph). (b) Tumor composed of sheets of spindle and epithelioid cells with a moderate amount of eosinophilic cytoplasm (H&E stain, 25×). (c) Higher magnification showing cells

with spindle-shaped and round nuclei with prominent nucleoli. There are also epithelioid cells and occasional mitotic Figs. (100×). (d) Caruncle melanoma: Positive staining for HMB-45 immunostain in tumor cells (HMB-­ 45 immunostain, 100×)

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19  Caruncle Tumors

Lymphoproliferative Tumors Reactive lymphoid hyperplasia is the most common lymphoproliferative disorder affecting the caruncle, accounting for up to 3% of all ­caruncular lesions [9, 10]. A few caruncular lymphomas

a

have been reported in the different series, of which low-grade B-cell lymphoma (MALT) was the most common. The clinical presentation of a salmon-colored mass on the caruncle should raise suspicion of a lymphoproliferative disorder. Incisional biopsy is recommended (Fig. 19.9).

b

Fig. 19.8  Chronic inflammation with secondary pigmentation: (a) Mild redness of caruncle and plica. (b) Cellular infiltrate with reactive vascular channels and secondary pigmentation (H&E stain, 100×)

a

Fig. 19.9 Marginal zone B-cell (MALT type) lymphoma: (a) Lymphocytic infiltrate in the substantia propria, composed of small, round lymphocytes and occasional plasma cells (H&E stain, 150×). (b) CD3 positive staining in lymphocytes (CD3 immunostain, 100×). (c) CD20 positive staining in many lymphocytes (CD20

immunostain, 100×). (d) Kappa light chain positive staining in scattered CD20 positive lymphocytes (Kappa light chain immunostain, 150×). (e) Lambda light chain positive staining in scattered CD20 lymphocytes in a greater > 2:1 ratio (Lambda light chain immunostain, 150×)

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b

c

d

e

Fig. 19.9 (continued)

Vascular Tumors Capillary Hemangioma A case report on capillary hemangioma of the caruncle by Ozdal reported three patients who developed a rapidly growing mass arising in the caruncle, without prior history of surgery or trauma, and all three lesions were nodular, lobulated and ulcerated, and excised because malignancy was suspected [20]. Histologically, capillary hemangiomas are composed by lobules of small, thin, and irregular vessels lined by a single layer of flattened, mature endothelial cells separated by thin fibrous septa (Fig. 19.10).

Fig. 19.10  Capillary hemangioma: Small and irregular vessels lined by a single row of endothelial cells with surrounding fibrous septa (25×)

19  Caruncle Tumors

References 1. Spencer W. Ophthalmic pathology: an atlas and textbook, vol. 1. 4th ed: Saunders: Philadelphia; 1996. 2. Kathuria SS, Howarth D, Hurwitz JJ, et al.  An anatomic and histologic study of the caruncle. Ophthal Plast Reconstr Surg. 1999;15(6):407–11. 3. Mori M.  The structure of the caruncula lacrimalis of Japanese. Okajimas Folia Anat Jpn. 1965;41(5):277–83. 4. Kaeser PF, Uffer S, Zografos L, et al.  Tumors of the caruncle: a clinicopathologic correlation. Am J Ophthalmol. 2006;142(3):448–55. 5. Luthra CL, Doxanas MT, Green WR.  Lesions of the caruncle: a clinicohistopathologic study. Surv Ophthalmol. 1978;23(3):183–95. 6. Santos A, Gómez-Leal A. Lesions of the lacrimal caruncle. Clinicopathologic features. Ophthalmology. 1994;101(5):943–9. 7. Shields CL, Shields JA, White D, et al. Types and frequency of lesions of the caruncle. Am J Ophthalmol. 1986;102(6):771–8. 8. Levy J, Ilsar M, Deckel Y, et al.  Lesions of the caruncle: a description of 42 cases and a review of the literature. Eye (Lond). 2009;23(5):1004–18. 9. Ostergaard J, Prause J, Heegard S. Caruncular lesions in Denmark 1978–2002: a histopathological study with correlation to clinical referral diagnosis. Acta Ophthalmol Scand. 2006;84:130–6. 10. Solari HP, Ventura MP, Orellana ME, et al. Histopath­ ological study of lesions of the caruncle: a 15-year single center review. Diagn Pathol. 2009;4:29.

243 11. Von Graefes A.  Geschwulste der Tranenkarunkel. Archiv fur Ophthalmologie. 1854;1:289–91. 12. Sjö NC, Heegaard S, Prause JU, et al. Human papillomavirus in conjunctival papilloma. Br J Ophthalmol. 2001;85(7):785–7. 13. Eagle R.  Eye pathology and atlas and text. 2nd ed. Lippincot Willims and Wilkins/Wolters Kluwer: Philladelphia; 2011. 14. Ogawa M, Shinzawa M, Dogru M, et al. Caruncular and pericaruncular sebaceous gland hyperplasia: a report of 2 cases and literature review. Eye Contact Lens. 2016;44(Suppl 1):S316–9. 15. Kapil JP, Proia AD, Puri PK. Lesions of the lacrimal caruncle with an emphasis on oncocytoma. Am J Dermatopathol. 2011;33(3):227–35. 16. Shields JA, Shields CL, Marr BP, et al. Sebaceous carcinoma of the caruncle. Cornea. 2006;25(7):858–9. 17. Pfeiffer ML, Yin VT, Myers J, et al. Regional nodal recurrence of sebaceous carcinoma of the c­aruncle 11 years after primary tumor resection. JAMA Ophthalmol. 2013;131(8):1091–2. 18. Ugurlu S, Ekin MA, Altinboga AA.  Primary basal cell carcinoma of the caruncle: case report and review of the literature. Ophthal Plast Reconstr Surg. 2014;30(3):e62–4. 19. Shields CL, Fasiuddin AF, Mashayekhi A, et al.  Conjunctival nevi: clinical features and natural course in 410 consecutive patients. Arch Ophthalmol. 2004;122(2):167–75. 20. Ozdal PC, Kargi S, Göka S, et al. Capillary hemangioma of the caruncle. Can J Ophthalmol. 2004; 39(5):560–2.

Pharmacotherapy for Conjunctival Malignancies

20

Ghada Al Bayyat, Dan Arreaza-Kaufman, Anat Galor, Jacob Pe’er, and Carol L. Karp

 cular Surface Squamous O Neoplasia Introduction Ocular surface squamous neoplasia (OSSN) involves a broad spectrum of neoplastic squamous epithelial abnormalities from squamous dysplasia to intraepithelail neoplasia in situ to squamous cell carcinoma (SCC). OSSN is usually slow growing and remains localized. However, SCC has the ability to invade the eye, orbit, or rarely even metastasize [1, 2]. Exposure to ultraviolet (UV) radiation in sunlight is the strongest risk factor [3]. Other environmental risk factors include human immunodeficiency virus (HIV), human papilloma virus (HPV), smoking, and immunosuppression [4]. Features of OSSN can include a fleshy gelatinous mass, leukoplakia, abnormal vascularity, and irregular corneal borders, and these features can be seen in isolation or combination [5, 6]. A wide variety of lesions can be con-

G. Al Bayyat · D. Arreaza-Kaufman A. Galor · C. L. Karp (*) Department of Ophthalmology, Bascom Palmer Eye Institute, Miami, FL, USA e-mail: [email protected] J. Pe’er Ocular Oncology Service and Ophthalmic Pathology Laboratory, Department of Ophthalmology, Hadassah - Hebrew University Medical Center, Jerusalem, Israel

fused with OSSN including pterygium, corneal pannus, pyogenic granuloma, sebaceous cell carcinoma, and amelanotic melanoma [5]. In many parts of the world, the pendulum has now shifted from surgical resection to a medical approach in OSSN [7]. Surveys done by Adler et al. [8] have shown increased use of medical therapies for OSSN (see Chap. 15).

Treatment In the past, the gold standard for the diagnosis and treatment of OSSN was surgical removal, but topical chemotherapeutic drugs are becoming a viable alternative [8, 9]. The advantages of surgery are that it is both diagnostic and therapeutic and it provides rapid resolution. It is covered by insurers in the USA and is a readily available modality for most patients. The disadvantage to a surgical approach includes residual tumor from positive margins, limbal stem cell deficiency from extensive excisions, symblepharon, and ocular surface issues. Medical therapy has the advantage of covering the entire ocular surface, including any subclinical disease. Especially in cases of extensive, annular, recurrent OSSN, topical therapies can cure the neoplasia with minimal sequelae to the ocular surface. Due to the mostly superficial effect of topical chemotherapy, their use for invasive SCC as primary treatment is not advised.

© Springer Nature Switzerland AG 2019 J. Pe’er et al. (eds.), Clinical Ophthalmic Oncology, https://doi.org/10.1007/978-3-030-06046-6_20

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Interferon Alpha-2b (IFNα-2b) Pharmacology Interferons are a group of pleiotropic proteins produced by human leukocytes that have antiviral and antineoplastic properties. There are three types of interferons, alpha (α), beta (β), and gamma (γ), based on their antigenic specificities. Interferon alpha-2b (IFNα-2b) is an immunomodulatory cytokine consisting of 165 amino acid residues, with arginine in position 23 [10, 11]. The effects of interferons are to inhibit the biosynthetic enzymes, induce apoptosis to cells, decrease blood vessels proliferation, inactivate viral RNA, and enhance phagocytic and cytotoxic mechanisms. Alpha-interferon is well absorbed via the intramuscular and subcutaneous routes. Peak concentrations occur at about 2 hours following the intramuscular injection and 4 hours following the subcutaneous route [11]. Role in OSSN Interferon activates the immune system by stimulating the expression of IL-2 and IFN-γ mRNA and decreasing the expression of IL-10. This process helps immune cells recognize and remove tumor cells. Interferon in the form of topical eye drops and intralesional IFNα-2b have been used in the treatment of OSSN, both as primary therapy and as an adjuvant after surgery [12–14]. IFNα-2b is one of our preferred treatments for

a Fig. 20.1  Slit-lamp photograph of a left eye with ocular surface squamous neoplasia (OSSN). Note large area of leukoplakia and adjacent gelatinous mass (a, arrow). Note

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OSSN, but the high cost and need for daily use can be prohibitive (Fig. 20.1).

Dosage For the topical treatment, 1 MIU/ml of IFNα-2b is typically dosed four times daily continuously until resolution of the tumor, followed by 1 or 2 more months of treatment even after clinical resolution. Higher doses of 3 MIU/ml have also been used but seem similar in effect without a therapeutic advantage over 1 MIU/ml dose [15]. The average time from the start of treatment to resolution is about 4 months [6, 13, 15]. The dose for subconjunctival injection ranges from 3 MIU in 0.5 cc given weekly or more [13, 16]. Side Effects Topical IFNα-2b eye drops are very well tolerated with minimal to no side effects. Unlike other topical agents like mitomycin and 5-fluorouracil, there is rarely hyperemia, but occasional follicular conjunctivitis and rare corneal microcysts have been reported [6, 13, 15, 17, 18]. When injected subconjunctivally, patients do experience systemic side effects. These include a “flu-like” syndrome that ensues after each injection. Pretreatment with oral antipyretic (e.g., acetaminophen, ibuprofen) is typically used to mitigate postinjection symptoms. Our protocol is to administer 1000 mg of acetaminophen prior to the injection and then every 4–6 hours as needed (Table 20.1).

b complete resolution of the conjunctival neoplasia after treatment with topical interferon 1 MIU/ml four times daily for 4 months (b)

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5-Fluorouracil (5-FU) Pharmacology 5-FU is a pyrimidine analog of the purine base uracil that works by inhibiting thymidine synthase, altering DNA and RNA synthesis, and reducing the rate of proliferation of neoplastic cells [19, 20].  ole in the Treatment of OSSN R 5-FU is another agent available as a primary treatment in OSSN. 5-FU is one of our preferred options when treating OSSN given its high effiTable 20.1  Common topical treatment drops for ocular surface squamous neoplasia OSSN-­ preferred treatment options IFNα-2b 5-FU

MMC

Most common dosage 1 MIU/ml 4 times daily continuously 1% 4 times a day for 1 week with 3 weeks off, cycled 0.02% to 0.04% 4 times a day for of 1–2 weeks, 2–3 weeks off, cycled

Main side effects Minimal side effects Mild pain, lid edema, epitheliopathy Hyperemia, keratopathy, pain photophobia

IFNα-2b interferon alpha-2b, 5-FU 5-fluorouracil, MMC mitomycin, LSCD limbal stem cell deficiency

a Fig. 20.2  Slit-lamp photograph of a right eye post-­ penetrating keratoplasty with large OSSN.  Note large papillary ocular surface squamous neoplasia at limbus and extending onto cornea and graft (a, arrow). Appearance

cacy, low cost, easy drop cycling schedule, and generally tolerable side effect profile [21–24].

Dosage Several dosing regimens have been reported for the primary treatment of OSSN [21, 22, 25]. Our protocol is to use compounded 1% 5-FU drops four times daily for 1 week, followed by 3 weeks off the medication [21] (Fig. 20.2). This pattern is generally repeated for 4 cycles. Other protocols have used 5-FU cycles four times a day for 4  days per month [25] or four times a day for 4 weeks [22]. We advocate refrigeration of the 5-FU, but it has been used at room ­temperature [21]. Side Effects 5-FU is associated with more side effects than IFNα-2b as it affects the synthesis of DNA and RNA of epithelial cells on the ocular surface [22]. Side effects include lid edema, conjunctival hyperemia, filamentary keratitis, superficial keratitis, and on rare occasion superficial stromal melting [22]. Lubricating drops and topical steroids can help reduce symptoms. While systemic 5-FU treatment can lead to punctal and canalicular stenosis, this side effect has not been reported with topical 5-FU, and punctal plugs are not normally placed before treatment [6] (Table 20.1).

b after four 1-week per month cycles of 5-FU 1% showing partial regression of the lesion (b). Residual tumor was still present on the corneal surface, and treatment was continued until fully resolved

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Mitomycin C Pharmacology Mitomycin (MMC) is an antineoplastic/antibiotic isolated in 1958 from the bacterium Streptomyces caespitosus and other Streptomyces bacterial species. It acts as an alkylating agent and binds to the cell DNA during the entire cell cycle [26]. This leads to irreversible cross-linking and inhibition of nucleotide synthesis. MMC also reacts with molecular oxygen-free radicals, causing cytotoxicity through lipid peroxidation. Therefore, MMC is toxic to both proliferating and nonproliferating cells. Applying MMC also inhibits fibroblast cell migration and leads to apoptosis [27].  ole in Treatment of OSSN R As topical drops, MMC is a potent medical therapy for OSSN but with more ocular surface toxicity than the other agents mainly when using the higher concentration [28–30]. It is also used intraoperatively as an adjunct to surgical tumor removal [31]. In terms of topical use as a primary treatment modality, we typically do not use MMC as a first-line therapy for OSSN. Instead, we use it as a secondary agent when individuals fail interferon and/or 5-FU. Dosage Several dosing regimens, using primarily 0.02– 0.04% concentrations, have been reported for the

a Fig. 20.3  Slit-lamp photograph of a left eye with extensive OSSN on the bulbar, limbal, and corneal surface (a). After three weekly cycles of MMC 0.04% with 2 weeks between cycles, the tumor is dramatically reduced, but

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primary treatment of OSSN concentration [6, 28–30]. Low dose (0.002%) has also been reported [32]. One protocol included treatment with 0.02% (0.2 mg/ml) MMC drops four times daily for 2 weeks with repetitions as needed [28]. In another protocol the compounded 0.04% drops are used four times daily for 1 week, followed by 2–3 weeks off until the eye is white and quiet. In general, three to four cycles are used. If intolerant of the 0.04%, lower concentrations of 0.03% or 0.02% may be used (Fig.  20.3). Other centers have reported 7-day on/7-day off regimens and 14-day on regimen with a variable amount of time between cycles [29, 33]. In one study, MMC 0.002% was applied four times daily continuously for a month [32]. The optimal regimen in terms of length of time, number of cycles, and dose for MMC use is yet to be determined, but the majority of clinicians use 0.02% or 0.04% four times daily and cycled [30]. MMC is best if refrigerated at (4 °C) [34]. MMC can also be used intraoperatively as an adjuvant to surgical removal. One protocol involves applying 0.02% MMC soaked on a surgical sponge to the scleral bed for 2–3 minutes, followed by closure of the conjunctiva [31]. Postoperatively, topical MMC has been used in patients with positive surgical margins [35, 36]. Topical 0.04% was used four times a day for a week after epithelial healing followed by a week off and then repeated [35].

b subtle leukoplakia is noted on the bulbar surface (b, arrows) and inferior fornix. The patient remains in treatment

20  Pharmacotherapy for Conjunctival Malignancies

Side Effects Topical eye drops of MMC have more side effects compared to IFNα-2b and 5-FU, especially when used in the higher concentration. The most common reported side effects are hyperemia, superficial punctate epithelial erosions, allergic conjunctivitis, photophobia, pain, and blepharospasm [28, 37]. Especially when using high concentration of 0.04% MMC, limbal cell deficiency may occur [38]. Alternate weeks of topical MMC increase patient comfort and compliance. Topical steroids are very helpful to mitigate the inflammation from the MMC.  Some have advocated also using cyclosporine 0.05% combined with the MMC therapy [39]. One case of punctal stenosis was reported; therefore, punctal plugs are typically placed before treatment in some centers [40] (Table 20.1).

Retinoic Acid Pharmacology Vitamin A (retinol), as well as its natural and synthetic derivatives (retinoid), is involved in several important physiological processes such as cell reproduction, proliferation, differentiation, and growth [41]. There is evidence that retinoids have potent growth-inhibiting effects on cancer in vitro and in vivo [42]. It regulates the activity of signaling pathways involved in either cellular growth or differentiation. Retinoids can also suppress the proliferation of cells by blocking cell cycle or by inducing apoptosis [41]. This effect has been used to treat epithelial cancers, precancerous lesions, and acute promyelocytic leukemia (APL) [43].  ole in Treatment of OSSN R Retinoic acid has been used as an adjuvant therapy for treatment of OSSN alone and in combination with IFNα-2b [44, 45]. In the study of combined use with interferon, it is not possible to distinguish the effect of retinoic acid from that of IFNα-2b. However, in theory, combination treatment may lead to more rapid tumor resolution based on synergistic mechanisms of action [45–47]. The data

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on the role of retinoic acid as sole agent in primary treatment of OSSN is limited.

Dosage Retinoic acid can be prepared into a 0.01% drop and is administered once every second day and can be also used with topical IFNα-2b drops of 1 MIU/ml four times daily for an average of 3–12 months [45]. Herbort et al. described retinoic acid 0.05% ointment, 1–3 times a day for 1–2  weeks, reporting complete resolution, but some cases needed to be treated for a month so the dose was then lowered to 0.01% in order to decrease skin irritation [44]. In another case report, 0.01% 1 eye drop was applied every second day for 9 months [47]. Side Effects Topical retinoic acid is generally well tolerated but can cause lid irritation [44]. One case of epithelial microcysts and one case of marginal keratitis have been described with its use [45].

Aloe Vera Drops Pharmacology Aloe plants exhibit antineoplastic properties through three important mechanisms: antiproliferative, immunostimulatory, and antioxidant. Aloe antiproliferative actions are mediated by anthraquinoic molecules such as aloin and aloe emodin [48, 49]. The aloe emodin has been shown to induce apoptosis in  vitro in multiple cell lines. Aloe’s immunostimulating effects are thought to be driven by acemannan and aloemannan [49].  ole in Treatment of OSSN R There has been one case published using commercially available skin aloe vera product for the primary treatment of clinically diagnosed OSSN [49]. Dosage In the only reported case, aloe vera oil drops (Aloe Fleur de Jouvence® [Forever Living

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Products®; Scottsdale, Arizona]) three times daily for 3 months were used [49].

Side Effects The drops were well tolerated without side effects [49].

Cidofovir Pharmacology Cidofovir is an active metabolite that inhibits viral replication with its activity against a broad spectrum of DNA viruses [50, 51]. As human papilloma virus has been implicated as a likely etiologic agent in the pathogenesis of squamous cell carcinoma of the conjunctiva, this is possibly its mechanism of action, and only one case has been published [50–52].  ole in Treatment of OSSN R There is only a single case report of topical cidofovir for the primary treatment of histologically proven OSSN [52].

the vascular endothelial growth factor (VEGF). Bevacizumab binds to VEGF and inhibits VEGF receptor binding, thereby preventing the growth and maintenance of tumor blood vessels [53, 54].

 ole in Treatment of OSSN R The role of anti-VEGF therapy in OSSN remains uncertain. It has been used topically and intralesionally. Studies had mixed results using ranibizumab [55] and bevacizumab [53, 56, 57]. Most of the tumors needed subsequent surgical intervention. Dosage Topical bevacizumab (5 mg/ml) has been used as an eye drop four times a day for a period up to 8 weeks [53]. Perilesional/subconjunctival bevacizumab injections (2.5  mg in 0.1  ml) were given 1 week apart, with a total of two injections [57]. In another study, bevacizumab (1.25 mg in 0.05 ml) was injected once [56]. Ranibizumab was injected perilesional (0.05  mg of 10  mg/ml) monthly or twice monthly with mean of 22 injections [55].

Dosage In this case report, topical cidofovir eye drops (2.5 mg/ml) were used at a frequency of 1 drop every 2 hours for 2 weeks, then four times daily for 2  weeks, and then thrice daily for 2  weeks. Most of the superior tarsal lesion resolved with this therapy. A focal area remained, which was excised with focal cryotherapy. There was no recurrence over a 2-year follow-up [52].

Side Effects No side effects have been reported with topical or perilesional/subconjunctival injections of bevacizumab [53, 55, 56]. Accidental intravitreal injections can cause endophthalmitis, rhegmatogenous retinal detachment, intraocular inflammation, intraocular pressure elevation, and ocular hemorrhage [58].

Side Effects In the above case, 6 months after treatment with cidofovir and cryotherapy, the patient developed cicatrization of the inferior punctum [52]. In our experience, topical cidofovir causes significant ocular surface irritation, which resolves with drop cessation.

Lymphoma of the Conjunctiva

 nti-Vascular Endothelial Growth A Factor (VEGF) Therapy Pharmacology Bevacizumab and ranibizumab are recombinant humanized monoclonal antibody directed against

Introduction Lymphomas are malignant neoplasms that arise from lymphocytes [59]. Extranodal marginal zone lymphoma (EMZL) is the predominant type of lymphoma seen in the conjunctiva and ocular adnexa. The systemic prognosis for conjunctival lymphomas varies with the cell type. It is best with EMZL and worse with mantle cell or diffuse B-cell subtypes [59–61]. Typically, a subconjunctival salmon patch lesion is seen in the bulbar conjunctiva (Fig.  20.4). Older age, exposure to radiation, and immunodeficiency are the principal

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a

b

Fig. 20.4  Slit-lamp photograph of a left eye with conjunctival lymphoma. Note elevated salmon-colored lesion on the superior temporal conjunctiva (a, arrow). After 20 sessions of external beam radiation over one month showing resolution of the conjunctival lymphoma(b) Table 20.2  Common pharmacotherapeutic treatment options for ocular adnexal lymphoma Lymphoma-­ preferred treatment options Most common dosage IFNα-2b Subconjunctival injection: 1 MU or 1.5 MU of IFNα-2b is administered 3 times a week for a total of 4 weeks Rituximab

Ibritumomab

Main side effects Subconjunctival injections: Flu-like syndrome, local inflammation IV: Varicella Zoster Virus. Subconjunctival injections: Pain at the site of injection

IV: 375 mg/ml rituximab every 3 weeks, maintenance dose every 2–3 months for 2 years. Subconjunctival injections: 1.5 cc of rituximab (10 mg/ml) with xylocaine 2% is received 4 times a week followed by a monthly injection for the next 6 months IV rituximab 250 mg/m2 followed by an infusion of 90 Y Thrombocytopenia, anemia, ibritumomab tiuxetan with a dose that depends on the platelet and neutropenia count. For patients with a platelet count of 100,000/mm3–149,000/ mm3, 0.3  Ci/kg was used and 0.4  Ci/kg for patients with counts of >150,000/mm3

IFN-α2b interferon alpha-2b, IV intravenous

risk factors associated with lymphoma. Bacterial and viral agents such as Helicobacter pylori, Borrelia burgdorferi, Chlamydophila psittaci, and hepatitis C virus have all been implicated in the pathogenesis. Lymphoma has a wide differential diagnosis ranging from benign lesions like reactive lymphoid hyperplasia, pyogenic granuloma, and lymphangiectasis to malignant tumors such as squamous cell carcinoma and amelanotic melanoma [60, 61] (see Chap. 18).

(Table 20.2). Rarely, aggressive bilateral disease or conjunctival lymphoma accompanied by systemic lesions will be treated with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), CVP (cyclophosphamide, vincristine, prednisolone), or chlorambucil. Interferon, rituximab, and ibritumomab are more commonly used for local treatment [62] (see also Chap. 18).

Treatment

Pharmacology Discussed above in OSSN section.

Radiation therapy has been the mainstay for unilateral isolated conjunctival lymphoma. Medical therapies have been utilized as alternative for unilateral disease and in systemic disease

Interferon Alpha-2b (IFNα-2b)

Role in Lymphoma The use of IFNα-2b has been described as a possible alternative in patients with unilateral ­

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localized conjunctival lymphoma who are not amenable to radiation treatment. There are case reports using intralesional injections of IFNα-2b as a part of the primary therapy [63, 64].

into the left lacrimal gland with B-scan ultrasound guidance. In a patient with adnexal lymphoma, this was followed by another injection 7 months later [70].

Dosage The dose of the intralesional IFNα-2b used was 1 MIU/0.5 cc or 1.5 MIU/0.5 cc, administered three times a week for a total of 4 weeks.

Side Effects Side effects of rituximab are rare but include Varicella zoster virus (VZV) reactivation following intravenous administration [67]. In addition, intravenous rituximab has been associated with hematologic side effects, such as neutropenia and thrombocytopenia [71, 72].

Side Effects For intralesional injections of IFNα-2b, side effects are rare as discussed above and include flu-like syndrome and malaise [63, 64].

Rituximab Pharmacology Rituximab is an anti-CD20 monoclonal antibody that kills CD20+ B cells via multiple mechanisms. These include direct effects on complement-­ mediated cytotoxicity and antibody-dependent cell-mediated and an indirect effect on cell structures, both of which lead to apoptosis. In addition, rituximab sensitizes cancer cells to other chemotherapy drugs [65, 66]. Role in Lymphoma Rituximab has been used systemically for bilateral ocular and adnexal lymphoma or for patients with systemic disease. In addition, there have been case reports of patients treated with intravenous and intralesional injections for localized disease [67–70]. Dosage Intravenous rituximab was administered in 6  cycles of 375  mg/m2 every 3  weeks with a maintenance dose every 2–3 months for 2 years [67]. The intralesional (subconjunctival) dose reported is 1.5 ml of rituximab (10 mg/ml) with xylocaine 2%, given four times a week followed by a monthly injection for the next 6 months [69]. Another protocol, used by Demirci et  al., consisted of 1 ml of rituximab (50 mg/1 ml) injected

Ibritumomab Tiuxetan (Zevalin) Pharmacology Ibritumomab tiuxetan (Zevalin, Spectrum pharmaceuticals, Henderson NV) links yttrium-90 to a monoclonal antibody that targets CD20 of the lymphocytes [73]. Role in Lymphoma As ocular and adnexal EMZL is highly sensitive to radiotherapy, it is certainly possible that radioimmunotherapy may also be very effective in controlling the disease as well as preventing relapse [73]. Preliminary studies suggest that Zevalin can be an effective alternative for the treatment of conjunctival lymphoma [73, 74]. Dosage Patients receive intravenous rituximab 250  mg/ m2 followed by an infusion of 90Y ibritumomab tiuxetan with the dose adjusted according to the platelet count. For patients with a platelet count of 100,000/mm3–149,000/mm3, 0.3  Ci/kg is used, with 0.4  Ci/kg being administered to patients with platelet counts exceeding 150,000/ mm3 [73, 74]. Side Effects Principal side effects are hematologic. Thrombocytopenia, anemia, and neutropenia have been noted in patients treated with this medication [75, 76].

20  Pharmacotherapy for Conjunctival Malignancies

Clarithromycin Pharmacology Clarithromycin is a member of the macrolide antibiotic family, structurally similar to erythromycin. The pharmacokinetic profile is more favorable than erythromycin, and it is dosed twice daily. Clarithromycin is well distributed in tissues, including the eye. Clarithromycin inhibits bacterial protein synthesis by preventing peptidyltransferase attachment to a growing peptide chain [61]. Role in Lymphoma Because of the association between lymphoma and chronic infections, and due to the antineoplastic effect of macrolide antibiotics, clarithromycin has been used in patients with relapsed or refractory ocular adnexal EMZL.  In addition, there is some data on the use of clarithromycin as a primary therapy. In two large prospective studies, the regimen consisted in using clarithromycin orally (500  mg bid) for 6  months [77] or 2 grams daily in 2-week cycles for 3 months [78]. Of the 36 patients treated, 8 (22%) had complete response, and 9 (25%) showed partial response. Half did not respond to the treatment. At 24 months, relapse rates were 30–50% [77, 78]. Dosage Clarithromycin (500  mg) is taken orally, twice daily, for 6 months [77]. Clarithromycin (2 grams) is taken daily for 14-day cycles with 1 week off and repeated for 3 months [78]. Side Effects Few side effects have been reported with clarithromycin. Most common side effects are nausea, diarrhea, and abnormal taste [79].

Doxycycline Pharmacology Doxycycline is a member of the tetracycline antibiotic family. It works by binding to the 30s ribosomal subunit and blocking the binding of

253

aminoacyl-tRNA to the ribosomal complex, thus interfering with protein synthesis and interrupting proper cell function [80].

Role in Lymphoma As mentioned above, due to the association between chronic antigen stimulation and lymphoma, doxycycline has been used with the aim of eradicating bacterial infection to induce regression of the lymphoma. Recent studies suggest that the use of doxycycline in patients with Cp DNA-positive infections can be beneficial, and interestingly, it has a positive impact on tumor regression in Cp DNA-negative patients as well. It has been used as a part of primary treatment or in patients with relapse of lymphoma. In two large prospective studies [81, 82], a total of 117 patients were treated with oral doxycycline 100 mg twice daily in 1–2 cycles. Out of the 117, 10 (8%) patients achieved complete response, and 27 (23%) had partial response. Approximately 40% had minimal to no response to treatment. When discontinued, relapse rates were approximately 25% [82] over 14–40 months. Dose Doxycycline, 100 mg, administered twice a day for 3 weeks in cycles [81, 82]. Side Effects The most common side effects of doxycycline are nausea, vomiting, and skin rash [83].

Pigmented Conjunctival Lesions Introduction Pigmented lesions of the ocular surface include conjunctival nevus, complexion associated melanosis, conjunctival primary acquired melanosis (PAM) with atypia, and conjunctival malignant melanoma (CMM) [84], all arising from the conjunctival melanocytes residing in the basal layer of the epithelium. PAM with atypia is the most common progenitor of CMM and appears clinically as a flat and variably brown conjunctival

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a Fig. 20.5  Slit-lamp photograph of a right eye with primary acquired melanosis with foci of conjunctival melanoma (a, arrow). Note minimal conjunctival scarring after

lesion [84] (Fig. 20.5). CMM can arise also from conjunctival nevus and de novo. CMM typically presents as a unilateral, pigmented, immobile, vascular lesion with heterogeneous pigmentation. It is commonly seen on the bulbar conjunctiva with associated feeder vessels. CMM can also present as an amelanotic lesion with variable vascularity. While the traditional treatment of PAM with atypia is surgical excision, in recent years, topical chemotherapy and immunotherapy have been used widely as adjuvant treatment (see Chaps. 16 and 17).

Treatment Complete surgical excision is the mainstay of treatment for conjunctival melanoma. Due to the high rate of local recurrence, surgical excision should always be combined with adjuvant therapy such as cryotherapy, chemotherapy, immunotherapy, and brachytherapy [85, 86]. Chemotherapy is used for diffuse disease (i.e., PAM with atypia and pagetoid spread from CMM). In terms of topical therapy, MMC has been the most studied therapy, followed by IFN-­α2b when MMC was not tolerated [5, 87]. These two drugs are used often also in treating PAM with atypia after diagnostic biopsy (Fig. 20.6).

Mitomycin C (MMC) Pharmacology Described above in section on OSSN.

G. Al Bayyat et al.

b surgical excision of the tumor cryotherapy followed by 2  cycles of postoperative topical weekly MMC 0.04% four times daily (b)

 ole in Pigmented Conjunctival Lesions R Topical MMC can be used as an adjuvant to excision preoperatively or postoperatively. MMC is not typically used as a primary therapy in conjunctival malignant melanoma (CMM) as results are poor [88]. Whereas in PAM preoperatively, a short regimen can be used to chemoreduce the tumor. It has also been used for extensive and unresectable PAM as primary treatment with some success. In three large retrospective studies [89–91], a total of 26 patients were treated primarily with MMC for PAM.  The regimen consisted of topical MMC 0.02–0.04%, four times a day for 28 days. Of the 26, 12 (46%) had complete response, and 12 (46%) showed partial response. One patient had no response to the MMC.  Follow-up ranges were 4–144  months, and relapse rates were approximately 27% [89–91]. Dosage When used pre- or postoperatively as an adjuvant therapy, MMC is typically administered at 0.04% four times a day for 7–28 days [90, 91]. MMC can be administered intraoperatively as well [92].

Interferon Alpha-2b Pharmacology Described above in OSSN section.

255

20  Pharmacotherapy for Conjunctival Malignancies

Pigmented conjunctival lesions

PAM

Without atypia

Observation

CMM

With atypia

Excision cryotherapy & AMT. Adjuvant chemotherapy

Excision cryotherapy & Adjuvant chemotherapy MMC MMC

IFNα-2b

Plaque radiotherapy

IFNα-2b

PAM: Primary acquired melanosis; CMM: Conjunctival malignant melanoma; MMC: Mitomycin; IFNα-2b: Interferon alpha 2b; AMT: Amniotic membrane transplant.

Fig. 20.6  Algorithm for management of pigmented conjunctival lesions

 ole in Pigmented Conjunctival Lesions R IFNα-2b is not commonly used in the treatment of pigmented conjunctival lesions as evidence is limited. However, due to its enhancement of the MHC class 1 surface antigen expression, there is biologic plausibility that it may have a positive immune response signaling for the removal of tumor cells. It can be administered topically and as subconjunctival/perilesional injections [84, 88]. The data for topical IFNα-2b for PAM is limited. In four retrospective studies [93–96], a total of 25 patients with PAM/MMC were treated with 1 MIU four to five times a day for 6–36 weeks. Of the 25 patients treated, 7 (28%) had eventual complete response to treatment, and 13 (52%) showed partial response. Approximately 20% did not respond to the IFNα-2b treatment. The follow-up of the previous studies was short (range, 4–17 months) [93–96]. Dose The dose of topical IFNα-2b is 1 MIU four or five times a day, for 3–6 months [88, 93–98].

 rogramed Cell Death 1 (PD-1) P Inhibitors Pharmacology Pembrolizumab is a humanized monoclonal immunoglobulin (Ig) G4 antibody directed against human cell surface receptor PD-1 (programed cell death 1). It mediates immune responses against tumor cells. In 2017, it was approved by the US Food and Drug Administration (FDA) for the treatment of metastatic cutaneous melanoma and of unresectable or metastatic solid tumor with certain genetic anomalies [99]. Pembrolizumab and other checkpoint inhibitors are known to cause proinflammatory side effects in the body including in the eye [100].  ole in Pigmented Conjunctival Lesions R Data using checkpoint inhibitors for conjunctival lesions is limited. Ford et al. described one patient with an invasive caruncular melanoma that was treated with total surgical excision and adjunctive topical MMC therapy. Five years later, the patient

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developed breast and chest metastases, which were treated with PD-1 inhibitors. Complete resolution of the metastatic disease was achieved. Kini et  al. described another patient who had a recurrence of conjunctival melanoma after surgical excision and cryotherapy. The patient was treated with systemic pembrolizumab, 150  mg, which was administered intravenously every 3 weeks for 6 months. The patient showed a clinical reduction of the conjunctival lesions with no adverse effects [99].

Dosage Systemic pembrolizumab, 150 mg, administered intravenously every 3 weeks for 6 months [99].

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259 melanosis with atypia. Ocul Immunol Inflamm. 2017;25(2):284–6. 94. Finger PT, Sedeek RW, Chin KJ. Topical interferon alfa in the treatment of conjunctival melanoma and primary acquired melanosis complex. Am J Ophthalmol. 2008;145(1):124–9. 95. Garip A, Schaumberger MM, Wolf A, Herold TR, Miller CV, Klingenstein A, et  al. Evaluation of a short-term topical interferon alpha-2b treatment for histologically proven melanoma and primary acquired melanosis with atypia. Orbit. 2016;35(1):29–34. 96. Herold TR, Hintschich C.  Interferon alpha for the treatment of melanocytic conjunctival lesions. Graefes Arch Clin Exp Ophthalmol. 2010;248(1):111–5. 97. Oellers P, Karp CL. Management of pigmented conjunctival lesions. Ocul Surf. 2012;10(4):251–63. 98. Bratton EM, Knutsen-Larson S, Durairaj VD, Gregory DG, Mellette JR.  Combination topical therapy for conjunctival primary acquired melanosis with atypia and periocular lentigo maligna. Cornea. 2015;34(1):90–3. 99. Kini A, Fu R, Compton C, Miller DM, Ramasubramanian A.  Pembrolizumab for recurrent conjunctival melanoma. JAMA Ophthalmol. 2017;135(8):891–2. 100. Dalvin LA, Shields CL, Orloff M, Sato T, Shields JA.  Checkpoint inhibitor immune therapy systemic indications and ophthalmic side effects. Retina. 2018;38:1063–78.

Sentinel Lymph Node Biopsy for Eyelid and Conjunctival Malignancies

21

Oded Sagiv and Bita Esmaeli

Introduction In the 1990s, the technique of sentinel lymph node (SLN) biopsy was developed as a less morbid alternative to complete lymphadenectomy [1–3]. SLN biopsy is based on the principle that the disease status of the first node in the lymphatic chain to which the tumor drains is representative of the disease status of the rest of the nodes in the chain. If pathologic analysis demonstrates that the SLN is cancer-free, then there is no need for complete lymphadenectomy. Various approaches have been used to identify SLNs. In 1992, Morton et al. described identifying SLNs through the use of intraoperative lymphatic mapping with vital dyes [3]. A year later, Alex and Krag introduced injection of radioactive tracer followed by use of a handheld gamma probe passed over the skin to allow dissection of SLNs through a small incision [4]. In 1996, Glass et  al. investigated the combination of dye and radiotracer; they concluded that using dye plus radiotracer had the potential to increase the rate

The authors of the chapter would like to thank Dr. Vivian T. Yin for her contribution towards previous edition of this chapter. O. Sagiv · B. Esmaeli (*) Department of Plastic Surgery, Orbital Oncology and Ophthalmic Plastic Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA e-mail: [email protected]

of successful SLN localization compared to the rate with blue dye alone [5]. SLN biopsy has been used for many years for patients with melanoma and breast cancer. The first reports of SLN biopsy in patients with eyelid and conjunctival neoplasms (e.g., melanoma, squamous cell carcinoma, sebaceous carcinoma, Merkel cell carcinoma) appeared around the year 2000 [6]. In this chapter, we will describe the clinical principles underlying SLN biopsy for periocular malignancies and then discuss various aspects of the application of this technique in clinical practice.

 ymphatic Drainage of the Eyelid L and Periocular Region The human eyelid has two distinct lymphatic systems: a superficial system between the skin and orbicularis muscle and a deeper system between the orbicularis muscle and tarsus [7]. The lymphatic drainage pattern for the periocular area was historically believed to be preauricular for the lateral aspect and submandibular for the medial aspect. However, in 2002, Cook et  al. published a report demonstrating that the drainage pattern was more complex [8]. Using lymphoscintigraphy in a monkey model, these investigators confirmed that the lateral canthus drained to the preauricular nodes, but they found that the central upper eyelid drained to both preauricular and submandibular-anterior

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cervical nodes [8]. Furthermore, these investigators demonstrated that the medial upper eyelid and medial canthus drained to the preauricular region, whereas the medial and central lower eyelid drained to the submandibular-anterior cervical region. Nijhawan et al. demonstrated the variable drainage patterns in the normal human eyelid. Their study included 28 patients who underwent injection of radioactive tracer followed by lymphatic mapping using a gamma camera. Sites of injection of radiotracer included the lateral and medial upper eyelid, medial canthus, and medial and lateral lower eyelid [9]. In the 25 patients with identifiable nodes, the preauricular area was the most common site of SLNs irrespective of the radiotracer injection site. Conversely, for each of the radiotracer injection sites, drainage could be to the preauricular area or the submandibular and deep cervical chains.

Fundamentals of Lymphoscintigraphy Lymphoscintigraphy is mapping of the lymphatic system through administration of a radioactive tracer followed by sequential or dynamic imaging (Fig. 21.1). One key factor in optimal lymphoscintigraphy is the imaging method. A cobalt 57 source behind the patient is useful for anatomical delineation of drainage along with lateral views [10]. The use of single photon emission computed tomography/ computed tomography (SPECT/CT) in addition to traditional lymphoscintigraphy has been advocated to help identify additional SLNs and drainage locations (Fig. 21.1b) [11, 12]. SPECT/CT is a system with a dual-head gamma camera and CT scanner. This system allows high-resolution anatomical images to be fused with functional images from the radioactive tracer. The other key factor in optimal lymphoscintigraphy is tracer characteristics. The smaller the tracer, the faster its drainage. Tracer smaller than 5 nm can penetrate the capillary membrane and enter the bloodstream, whereas tracer larger than 500 μm may be unable to migrate from the injection site [10]. The types of radioactive compounds used can be categorized as radiocolloids,

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radiolabeled molecules, and radiolabeled macromolecules. Colloids are phagocytosed by macrophages in lymph nodes and thus have a longer resident time in the lymph nodes than noncolloidal macromolecules such as human serum albumin. Antimony sulfide colloid is the most widely used colloid because of its ideal size, 3  nm to 25  nm, and its clearance rate of 40% over 4 h [13]. Colloids can be filtered to select for smaller particles, which will have shorter transit times. An example of a filtered colloid is filtered technetium 99mTc sulfur colloid. Many different technetium 99mTc-labeled compounds have been tried for lymphoscintigraphy in cutaneous melanoma, including sulfur colloid, tin colloid, phytate, and human serum albumin. 99mTclabeled human serum albumin has also been used commonly in melanoma involving the trunk. When 99m Tc-labeled human serum albumin is injected intradermally, it drains rapidly; some would argue that this radiotracer is associated with better definition of the lymphatic system and better reproducibility of results than sulfur colloid [14].

 echnical Considerations in SLN T Biopsy for Eyelid and Conjunctival Tumors Preoperative Lymphoscintigraphy Preoperative identification of the SLN through lymphoscintigraphy aids in surgical planning and preoperative patient counseling. For SLN biopsy of the eyelid or conjunctival tumors, most authors to date have performed preoperative lymphoscintigraphy using filtered 99mTclabeled sulfur colloid. The lymphoscintigraphy procedure is usually done 1–2  days before the SLN biopsy procedure as described in the following paragraphs. The filtered 99mTc-labeled sulfur colloid is injected intradermally 1–2 mm around the eyelid tumor or, in the case of conjunctival tumors, in the subconjunctival space at two to four spots around the tumor. The dose of 99mTc-labeled sulfur colloid used is from 0.3 to 0.4 mCi in a volume of 0.2 mL [15, 16]. It is important to ensure

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Fig. 21.1  Preoperative lymphoscintigraphy in a patient with a lower eyelid melanoma (a). The area of injection and the draining nodes are seen. SPECT/CT scan in the same patient (b). The area of injection of technetium (in

blue) in the lower eyelid is seen (c). The draining sentinel lymph node (in blue) in the right parotid area is seen with much higher anatomic resolution compared with the standard lymphoscintigraphy image

that the injection is in the area immediately surrounding the tumor of interest so that the lymphatic drainage mapped reflects the pattern of lymphatic drainage from the tumor site. At 15 min after radiotracer injection and every 5 min thereafter, a gamma camera is used to take dynamic photos at 30 seconds per frame (Fig. 21.1a). Transmission images are also taken with a lowactivity cobalt 57 sheet source every 3  min. It is important to obtain lateral images with and without transmission images. Anatomical markers with cobalt 57 disks are also taped at the thyroid cartilage and suprasternal notch for reference [15, 16]. To allow more precise anatomical delineation, SPECT/CT has been utilized in conjunction with preoperative lymphoscintigraphy [17]. In this approach, SPECT images are acquired with a matrix size of 128 × 128 pixels, at 22 seconds per view over 180°. Axial CT images are used for classification of lymph node level, but the param-

eters for CT acquisition depend on the CT scanner used and site-specific protocols. Figure 21.1b, c shows the specific identification of an SLN in a patient with conjunctival melanoma using SPECT/CT and traditional lymphoscintigraphy. A study of 403 patients with cutaneous melanoma in which 149 (37%) patients had preoperative SPECT/CT found that lymphoscintigraphy plus SPECT/CT identified more SLNs per patient than lymphoscintigraphy alone: a median of 0.34 SLNs versus 0.32 SLNs [12]. The increase in the number of SLNs per patient with SPECT/CT compared to lymphoscintigraphy alone was particularly pronounced in patients who were obese (body mass index of 30 kg/m2 or higher): 25% of such patients had SLNs detected with SPECT/CT, and only 9.1% had SLNs detected with lymphoscintigraphy alone. Furthermore, univariate and multivariate analysis showed the use of SPECT/CT to be significantly correlated with better disease-free survival.

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Intraoperative SLN Detection In the preoperative holding area, approximately 1–1.5  h prior to planned surgery, 99mTc-labeled unfiltered sulfur colloid (0.3 mCi in 0.2 mL) can be injected in the same fashion as described above for preoperative lymphoscintigraphy.

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Alternatively if the preoperative lymphoscintigraphy or SPECT/CT scan is scheduled 1 day prior to surgery, there is usually no need for reinjection of sulfur colloid. Intraoperatively, the surgeon passes a handheld gamma probe (Fig. 21.2a) over the skin in the area where SLNs were identified on preoperative lymphoscintigraphy, using

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Fig. 21.2  Steps involved in sentinel lymph node biopsy for a conjunctival melanoma are outlined. (a) Intraoperative photograph of the gamma probe which detects the area of increased radioactive uptake (of technetium) corresponding to the draining sentinel lymph nodes based on the preoperative lymphoscintigraphy or preoperative SPECT/CT scan. (b) This photograph shows small skin incisions that are made directly overlying the areas of increased uptake in the draining lymphatic basins to facilitate biopsy of the sentinel lymph nodes. (c) The photograph shows a sentinel lymph node that has been removed from its lymphatic basin. The amount of radioactivity in the sentinel node is checked compared with the background to ensure it represents the draining lymph

node from the primary eyelid or conjunctival lesion. (d) Subconjunctival injection of blue dye can be done using a 30-gauge needle, but given the very small volume that would be required to avoid nonspecific spread of the blue dye in the subconjunctival space, the yield of “blue nodes” was so low in our early experience that the use of the blue dye was abandoned after the first 16 patients who had SLN biopsy for conjunctival tumors as part of the prospective clinical trial at MD Anderson. We now use technetium only as the tracer for sentinel lymph node biopsy for conjunctival and eyelid tumors and find excellent identification rate of the sentinel lymph nodes using technetium alone. (Reprinted from Esmaeli [83]. With permission from Wolters Kluwer Health, Inc.)

21  Sentinel Lymph Node Biopsy for Eyelid and Conjunctival Malignancies

the lymphoscintigram as a guide. Once the area of high radioactivity is identified, an incision is made directly over this area (Fig.  21.2b). The SLN is then carefully dissected and sent for histopathologic evaluation (Fig. 21.2c). Some authors have injected isosulfan blue dye (Fig. 21.2d) in addition to technetium 99mTc sulfur colloid to facilitate visual identification of SLNs in patients with eyelid and conjunctival tumors, but this technique has proven to be of no additional value. One possible reason for the lack of benefit is the fast transition in the head and neck region. Another possible reason is that in the case of conjunctival melanoma, the volume of blue dye injected is smaller (0.2 cc) than for tumors at other anatomic sites in order to avoid diffuse infiltration of the blue dye in all conjunctival quadrants and thus inaccurate and nonspecific drainage [15]. This small volume of blue dye used for conjunctival tumors is probably not large enough to make the SLN blue.

Histopathologic Processing The histologic evaluation of SLNs is one of the most important aspects of SLN biopsy and can significantly impact the rate of detection of micrometastases. In the past, lymph nodes dissected during elective lymph node dissection were bisected through the hilum, which contains a number of lymphatic vessels, and then cut into 5- to 7-μm-thick sections. However, this method can be inconsistent when the nodes are small and can leave areas of the capsule unexamined. Pathologic evaluation of the SLN entails making very thin slices perpendicular to the long axis from one end of the node to the other to yield 1to 2-mm-thick slices, a technique sometimes referred to as “bread loafing the SLN.” Each slice is then cut into 5- to 7-μm-thick sections, which are stained with hematoxylin–eosin in the usual fashion. The bread-loafing technique allows for better evaluation of the capsule but may miss the hilum. If the initial section is negative, deeper sections of the block are cut [18]. Using careful serial sectioning of the sentinel lymph nodes can

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lead to the detection of very small foci of microscopic metastasis that are well below the resolution of even the most sophisticated imaging studies (Fig. 21.3). Immunohistochemical staining is done if hematoxylin–eosin staining of the bread-loafed sections is negative for metastasis or when there are areas of suspicious morphology. Immunohistochemical stains used to evaluate SLNs include anti-S100, HMB-45, anti-MART1, and anti-tyrosinase for melanoma [18]; cytokeratin 20, chromogranin, and antibodies to Cam5.2 for Merkel cell carcinoma and sebaceous carcinoma [19]; and anti-adipophilin and anti-­perilipin antibodies for sebaceous carcinoma [20].

I ndications for SLN Biopsy for Eyelid and Conjunctival Tumors Accurate determination of regional lymph node status in patients with eyelid and conjunctival neoplasms not only is important for staging disease and estimating prognosis but also may increase survival through early detection of microscopic metastasis. This begins with the clinical examination on palpation of the lymph nodes in the preauricular, submandibular, or cervical areas. If no enlarged lymph node is palpated, we routinely request an ultrasonographic examination of the head and neck by an experienced radiologist to detect suspicious lymph nodes which can then undergo a fine needle aspiration biopsy. Large areas of lymph node metastasis could sometimes be detected on standard computed tomography or positron–emission tomography/computed tomography (PET/CT) prior to surgery, but smaller metastases may be detected on ultrasonography and otherwise missed on CT or PET/CT.  If any of the above examinations show a suspicious lymph node, a fine needle aspiration (FNA) is done to assess for malignant cells in the lymph node. Sentinel lymph node biopsy is only appropriate after the above tests are done and are negative. Here, we discuss the rationale for and indications for SLN biopsy for the major types of eyelid and conjunctival neoplasm.

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Fig. 21.3 (a) External photograph of a lower eyelid amelanotic melanoma (Breslow thickness 3.8 mm Clark level IV). The patient had a negative systemic work-up including a negative MRI of head and neck and a negative ultrasound of the parotid area prior to undergoing sentinel lymph node biopsy. (b) Wide surgical excision of the lesion was carried out along with sentinel lymph node biopsy. One positive lymph node was detected in the parotid tail. (c) Histologic section through the parotid sen-

tinel lymph node shows a very small focus of metastatic melanoma that measures 0.8 × 0.5 mm with no extracapsular extension. (d) High-power magnification of the microscopic melanoma metastasis in the sentinel lymph node. This patient subsequently underwent completion neck dissection and parotidectomy which did not reveal any additional positive lymph nodes. (Reprinted from Sanchez et al. [84]. With permission from Wolters Kluwer Health, Inc.)

Melanoma

vival, and overall survival compared with patients with s­ imilar characteristics who did not have SLN biopsy. Five-year melanoma-specific survival rate with Kaplan–Meier analysis was 84.8% in patients with SLN biopsies versus 80.3% without [21]. The international Multicenter Selective Lymphadenectomy Trial (MSLT-I) randomly assigned 1661 patients with primary cutaneous melanoma to undergo wide excision and nodal observation with lymphade-

Experience with SLN biopsy for cutaneous malignancy started with melanoma, and most of the research to date on SLN biopsy for cutaneous malignancy has been done in patients with this disease. A study of 670 consecutive patients with melanoma found that patients who had SLN biopsy had a significantly better recurrence-free survival, distant metastasis-free sur-

21  Sentinel Lymph Node Biopsy for Eyelid and Conjunctival Malignancies

nectomy for nodal relapse (observation group), or wide excision and SLN biopsy with immediate lymphadenectomy for nodal metastases detected on biopsy (biopsy group). The 10-year results of this important study found that the 10-year disease-free survival rates were significantly improved in the biopsy group as compared with the observation group, among patients with intermediate-thickness melanomas (defined as 1.20–3.50  mm; 71.3% vs. 64.7%, p  =  0.01) and those with thick melanomas (defined as >3.50  mm; 50.7% vs. 40.5%, p  =  0.03). They found that biopsy-based management improved the 10-year rate of distant disease-­ free survival and the 10-year rate of melanoma-specific survival for patients with intermediate-thickness melanoma with a positive SLN compared with those who had nodal metastasis discovered during the observation period. The authors concluded that biopsybased staging of melanomas thicker than 1.2 mm provides important prognostic information and early identification of patients with nodal metastases leads to better survival outcomes for the subset of patients with melanoma who harbor nodal metastasis [22]. The subsequent MSLT-II study found that immediate completion LN dissection was not associated with increased melanoma-specific survival among 1934 patients with sentinel node metastases, underscoring the potential therapeutic effect of SLN biopsy [23]. Based on a study of 44 patients with eyelid skin melanoma, the Collaborative Eyelid Skin Melanoma Group concluded that melanoma of the eyelid has a regional nodal metastasis rate of 11% and a distant metastasis rate of 7%, with a mean follow-up of 34  months [24]. A larger single-­ center study of 64 well-documented cases of eyelid melanomas reported 10% of patients diagnosed with lymph node metastasis at presentation (8% via SLN biopsy and 2% via ultrasound-­guided FNA) [25]. In this series, 5 of 14 patients (36%) who had SLN biopsy had a positive SLN detected, and all 5 patients had a T category greater than T2b (AJCC 7th edition) Breslow thickness greater than 1.5  mm and more than one mitotic figure per mm2. Six of 17 patients (35%) who presented with greater

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than T2b tumor (AJCC 7th edition) had nodal metastatic at presentation, compared with none of 46 patients who presented with the T category of T2b or less (p = 0.0026). Another study, of 29 patients with eyelid skin melanoma from Australia, found that 17% of patients experienced local recurrence and 7% (2 of 29 patients) of patients died of metastatic melanoma [26]. Several studies have demonstrated that the risk of nodal metastasis increases with increasing tumor thickness [24, 27]. The first report of an SLN biopsy for conjunctival melanoma came from our institution in 2001 and served as a proof of concept that preoperative lymphoscintigraphy and SLN biopsy can be performed safely in patients with conjunctival melanoma [15]. Since then we have published our experience with SLN biopsy of melanoma of the eyelid or conjunctiva in several reports [28–30]. In the largest series to date of SLN biopsy for ocular adnexal melanomas, 51 patients with conjunctival and/or eyelid melanoma had SLN biopsy [27]. The report was a mix of eyelid melanoma and conjunctival melanoma, since eight patients (16%) had melanoma involving both structures. When comparing patients with and without nodal metastases, histologic features associated with a positive SLN included greater tumor thickness (median thickness 3.5  mm vs. 2.2 mm, p = 0.04), greater number of mitotic figures (median count/10hpf of 6 vs. 2, p  =  0.03), and presence of ulceration (80% vs. 26%, p  =  0.003) (Fig.  21.4) [27]. Cohen et al. conducted a prospective study in which they performed SLN biopsy on patients with conjunctival melanoma who met the following selection criteria: tumor thickness ≥2 mm, were in an unfavorable (e.g. non-bulbar) location, or recurrent conjunctival melanoma associated with the “florid phase” of primary acquired melanosis [31]. These features were determined based on previous reports that found thickness greater than 1–2 mm to carry a higher risk for metastases [32, 33]. Only 26 patients met the selection criteria, of 70 patients who presented with conjunctival melanoma to that center over the 4 years of the study, and 22 patients eventually consented to undergo SLN biopsy. Their SLN identification rate using

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Fig. 21.4 (a) Left lower eyelid melanoma (Breslow thickness 7.2 mm with histologic ulceration Clark level II) with no palpable lymph nodes with a negative ultrasound and MRI of the regional lymph nodes. The patient underwent surgical removal of the melanoma simultaneous with sentinel lymph node biopsy which demonstrated one positive sentinel lymph node in the parotid gland. (b) The patient subsequently had completion neck dissection and parotidectomy which showed two additional positive nodes (in addition to the previous positive sentinel lymph

node). The photograph shows the incision for the parotidectomy/neck dissection which is much larger than the incisions needed for the sentinel lymph node biopsy; parotidectomy and completion lymph node dissection only become necessary in patients who have a positive sentinel lymph node. (c) This patient was doing well without evidence of disease at last follow-up 3  years after removal of her eyelid melanoma and additional treatments for her positive sentinel lymph node. (Reprinted from Savar et al. [30]. With permission from Elsevier Inc.)

Tc injection was 82%, which the authors term “injection failure” and attribute to previous local surgeries that led to scarring and disruption of the normal lymphatic drainage. Two of 18 patients (11%) had an SLN which was positive for metastases, and no false-negative cases were identified over a median follow-up of 20  months (range

6–36). A recently published review of the literature by Aziz et al. confirmed that high-risk features for nodal involvement associated with conjunctival melanoma included clinical features of nonlimbal location and thickness >2 mm and histologic features of ulceration and mitotic rate >1 per mm2 [34].

99m

21  Sentinel Lymph Node Biopsy for Eyelid and Conjunctival Malignancies

Squamous Cell Carcinoma Although it accounts for only 9% of eyelid tumors, squamous cell carcinoma is the second most common eyelid malignancy after basal cell carcinoma [35]. Squamous cell carcinoma has a higher rate of local recurrence than basal cell carcinoma, and squamous cell carcinoma, unlike basal cell carcinoma, has the potential for regional nodal metastasis. In a series of 111 patients with advanced eyelid squamous cell carcinoma treated at our center, local recurrence occurred in 41 patients (36.9%), and regional nodal metastasis occurred in 27 patients (24.3%) [36]. Distant metastasis occurred in only seven patients, but five of them died of the metastatic disease. In a more recent review of less advanced cases from MD Anderson, we found that local recurrence occurred in 7 of 65 patients (11%) with a median time of 30 months from presentation to local recurrence, and no patient was found to have distant metastases at last follow-up (median, 27 months; range, 1–150 months) [37]. These had routine screening for LN metastases prior to surgery (see paragraph 21.5) but did not undergo SLN biopsy. Four patients (6%) had regional LN metastasis at the time of diagnosis (with T-stage tumors of T2b, T3b, and T4), and two patients with a T3a and T4 disease (AJCC 7th edition) were found with LN metastases on follow-up 2  weeks and 8  months after surgery, respectively. These findings may suggest a potential role for sentinel lymph node biopsy or at least strict nodal surveillance for patients with tumors more advanced than T2b. A recent review of the literature found 14 retrospective studies and case series that reported an SLN biopsy positivity rate of 0–44% in patients with SCC (in various locations in the body) and high-risk features [38]. The definition of high-­ risk features was variable between studies but mostly included size >2  cm, depth of invasion >4–5  mm, perineural invasion, and anatomic location. Some of these retrospective studies suggest that positive SLN biopsy was associated with worse prognosis [39–42], but this was not consistent in all studies [43].

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Experience with SLN for periocular SCC has been reported in small case-series. Maalouf et al. reported their experience with SLN biopsy in nine patients with squamous cell carcinoma of the eyelid and conjunctiva with a median follow­up of 22 months. SLNs were successfully identified in all nine patients, and one of the nine patients had a positive SLN [44]. There were no local recurrences or deaths in their series. In another small case series, Chak et  al. described five patients with a large (2.0–4.3  cm) primary poorly differentiated periocular squamous cell carcinoma who underwent SLN biopsy using preoperative 99mTc injection and intraoperative isosulfan blue injection after imaging failed to show metastatic disease. All patients were found to have a positive SLN and therefore had adjuvant radiation or systemic treatment [45]. With advances in medical treatments for metastatic cutaneous carcinomas, for example, the efficacy of immune checkpoint inhibitors and EGFR inhibitors for metastatic squamous carcinomas, and given the potential prognostic implication of a positive SLN biopsy, there may be a role for an SLNB in cases with periocular SCC with high-risk features, such as lesions wider than 2 cm, locally recurrent disease, or those with depth of invasion greater than 4–5 mm.

Sebaceous Carcinoma Sebaceous carcinoma is often associated with a delay in diagnosis because it can mimic benign lesions such as chalazion and blepharoconjunctivitis. In a series of 60 patients with sebaceous carcinoma of the eyelid, 11 patients (18%) had local recurrence, and 5 patients (8%) had clinical nodal metastasis. Of the patients with clinically palpable nodal metastasis, 4 patients (80%) died of metastatic disease [46]. Another study of 50 patients demonstrated that lymph node metastasis was correlated with American Joint Committee on Cancer (AJCC) T category for eyelid ­carcinoma (7th edition) in patients with eyelid sebaceous carcinoma [29, 47]. This study further demonstrated that the T category of T2b is sig-

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nificantly associated with worse prognosis and that patients with the T category of T3b or worse (AJCC 7th edition) at presentation had poorer disease-specific survival. In our most recent series of 100 patients with eyelid sebaceous carcinoma, 10 patients (10%) had LN metastases and none had distant metastases at presentation (unpublished data, manuscript under review at the time of writing this chapter). During a median follow-up of 32 months (range, 1–192), 12 additional patients (12%) developed LN metastasis for a total of 22% lymph node metastasis during the study period. At the University of Texas MD Anderson Cancer Center, we have performed SLN biopsy for sebaceous carcinoma of the eyelid as part of a prospective clinical trial for the past 17 years. In an early report of ten patients with sebaceous carcinoma of the eyelid, one patient had a positive SLN [29]. In a later report, we described a patient with a T3 tumor (AJCC 7th edition) in the upper eyelid who had a positive SLN identified at the time of tumor excision. The patient underwent complete neck dissection and parotidectomy and adjuvant radiation therapy and was without recurrence at 20 months of follow-up [48]. These early reports suggested that SLN biopsy can be successfully carried out for sebaceous carcinoma of the eyelid, can identify microscopic metastasis, and may be most appropriate for tumors with the T category greater than T2b (AJCC 7th edition) [47]. In our most recent data of 100 patients with eyelid sebaceous carcinoma, 30 patients (30%) underwent SLN biopsy, and 5 of them (20%) with T3c tumor (3 patients, AJCC 8th edition), T4a (1 patient), and T4b (1 patient) were found to have positive lymph nodes (unpublished data, personal communication, B Esmaeli).

Merkel Cell Carcinoma Merkel cell carcinoma is a rare and aggressive malignancy. Twenty percent of all cases of Merkel cell carcinoma occur in the periocular and eyelid area [49]. The 5-year survival rate is only 40–45% overall and 25% in patients diagnosed with distant metastasis [32]. The incidence

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of positive SLNs in patients with Merkel cell carcinoma who present with localized disease has been reported to be as high as 20–30% [50]. An analysis of the National Cancer Data Base that included more than 5800 patients with Merkel cell carcinoma found that the 5-year survival rate was 76% in patients with pathologically proven negative nodal status but only 42% in patients with positive nodes [51]. A recent report of 150 patients with MCC (in various body locations) who underwent SLN biopsy found that 26% had a positive SLN, and patients with a positive SLN had a higher risk for in-transit recurrence [52]. This study, however, failed to find a difference in overall survival or disease-specific survival between patients with a positive or negative SLN [52]. The importance of nodal status in Merkel cell carcinoma is reflected in the 2018 American Joint Committee on Cancer staging system 8th edition, in which disease associated with positive lymph nodes, or micrometastasis, is classified as stage III irrespective of tumor size. The National Comprehensive Cancer Network (NCCN) guidelines for MCC also include SLN biopsy for patients with clinical N0 disease as part of the management algorithm (NCCN guidelines for Merkel cell carcinoma, version 1.2018). MCC is rare in the periocular region, and data is available from relatively small cohorts. In a study of 14 patients, lymph node metastasis occurred in 3 patients (21.4%), all of whom had negative margins at surgery [53]. Two of these patients had metastasis to the parotid nodes and one to the submandibular nodes. The time from diagnosis to nodal metastasis ranged from 11 months to 30 months. Only one patient died of metastatic disease, and this patient was one of the patients with nodal involvement. As a proof of concept, in 2002 we described a 61-year-old man with Merkel cell carcinoma of the eyelid who had a positive SLN in the parotid area and subsequent underwent parotidectomy and neck dissection, which revealed Merkel cell carcinoma in an additional lymph node and the deep parotid gland [54]. This report provided proof of the principle that SLN biopsy can be successfully carried out for Merkel cell carcinoma of the eyelid. Since then SLN biopsy has become part of the

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management algorithm recommended by NCCN. In a more recent study of 18 patients with periocular MCC from MD Anderson Cancer Center, 22% of patient had LN involvement at presentation with the T category of T3a in three patients and Tx in one patient (AJCC 7th edition) [55]. Of these four patients, two had clinically positive LN verified by biopsy, and two of three other patients who underwent SLN biopsy were found with a positive LN. In a series of 21 patients with MCC of the eyelid from five different centers from Australia and the United Kingdom, the authors reported regional nodal metastatic rate of 10% and distant metastatic rate of 19% and with the lowest T-category tumor of T2a (AJCC 7th edition for eyelid carcinoma) measuring 8 mm to develop either [56]. However, the methodology of systemic work-up in this study was inconsistent between centers, and only one patient underwent SLN biopsy, and only eight patient had head/neck imaging. Recent advances in medical therapy for MCC, such as the use of immune checkpoint inhibitors, make a more compelling argument to support the use of SLNB, and future studies will examine its effect on survival [57, 58].

 dverse Effects of SLN Biopsy A in the Head and Neck and Periocular Region SLN biopsy is a relatively noninvasive procedure associated with much less morbidity than elective neck dissection. A meta-analysis of the morbidity of SLN biopsy in patients with melanoma found that SLN biopsy is associated with lymphedema in 0.66–6% of patients, hematoma or seroma in 1.12–2.31%, and wound infection in 1.08–4% [59]. In the same study, pain was reported by only 0.75% of patients. Analyses of SLN biopsy specifically in the head and neck region also indicate that complications are rare. In a study by Wasserberg et al. of 35 patients who had SLN biopsy in the head and neck region, one patient had seroma, and one patient had sensory disturbance [60]. Furthermore, a large series of SLN biopsy in the

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periocular region showed that complications were rare and insignificant [27, 29]. An infrequent (6%) reported side effect is the temporary weakness of the marginal mandibular branch of the facial nerve that resolved spontaneously after a few weeks [27]. The SLN biopsy procedure typically adds 30–90 min of additional surgery time and probably is best done at the same time as the definitive surgery for the eyelid tumor. In our prospective trials at MD Anderson of SLN biopsy for more than 90 patients with sebaceous carcinoma and melanoma of the ocular adnexa, we used the blue dye in only the first 16 patients and then stopped using it and now use technetium as a tracer only. This is due to the fact that the addition of blue dye did not improve the rate of detection of SLNs. Furthermore for conjunctival tumors, in particular, the volume of blue dye needed to expect a draining blue lymph node which is typically 1 cc would be too large to inject in the subconjunctival space and would lead to nonspecific drainage from the wide area of the ocular surface. In the 16 patients who had blue dye injection in our early experience with SLN biopsy for conjunctival melanomas we used only 0.2 cc volume of blue dye. In these 16 patients, there were no blue SLNs although among these patients some had microscopically positive SLNs found using technetium as the tracer. Furthermore, there were no cases of permanent blue discoloration of the ocular surface, and there were no cases of anaphylactic shock secondary to the blue dye [29].

Salient Diagnostic Findings Lymph Node Identification Rate The SLN identification rate for ocular tumors (eyelid and conjunctival tumors) is high and reported to be more than 95% in most series. Of the three largest series published to date on SLN biopsy for ocular tumors, two are from MD Anderson and describe patients enrolled in ­prospective trials of SLN biopsy for melanoma and sebaceous carcinoma; the third report is from France.

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In the earlier report from MD Anderson, published in 2007, Ho et al. reported successful identification of SLNs in 24 of 25 patients with sebaceous carcinoma of eyelid (10 patients) and melanoma (15 patients) [29]. One patient had an SLN identified on preoperative lymphoscintigraphy, but no SLN was identified intraoperatively with use of a gamma probe. In a follow-up report from MD Anderson on SLN biopsy in conjunctival and eyelid melanomas, Savar et al. reported successful SLN identification in 29 of 30 patients (96.7%) on preoperative lymphoscintigraphy and in all 30 patients on intraoperative mapping using a gamma probe [30]. Yet an updated report with a larger cohort of patients with longer follow-up from MD Anderson reported an overall intraoperative identification rate of 98% [27]. We have observed that in the rare patient who has poor drainage on preoperative lymphoscintigraphy, often a slight modification of the injection technique leads to successful drainage on the day of surgery. We have also observed that in patients with sebaceous carcinoma, who often have had multiple eyelid procedures prior to correct diagnosis and appropriate referral for definitive oncologic surgery, lymphatic drainage may be altered, and as a consequence, there may be no drainage during lymphoscintigraphy or surgery. Maalouf et  al. reported on results of SLN biopsy in 17 patients with a variety of types of eyelid tumors, including melanoma (4 patients), Merkel cell carcinoma (4 patients), squamous cell carcinoma (8 patients), and sebaceous carcinoma (1 patient) [44]. SLNs were identified in all patients; however, the authors did not specify whether SLNs were identified on lymphoscintigraphy, SLN biopsy, or both. Although both preoperative lymphoscintigraphy and intraoperative use of a gamma probe are associated with high rates of SLN identification, it is important to use the two techniques in combination. Savar et  al. in one of the published reports from MD Anderson found a poor correlation between findings on preoperative lymphoscintigraphy and findings on intraoperative use of a gamma probe [30]. Only 7 of 30 patients (23%) had correlation between preoperative and intraoperative findings in all basins, and 16 patients

(53%) had correlation in at least one basin. More recently, the use of intraoperative indocyanine green angiography has been reported for sentinel lymph node biopsy for breast carcinomas [61–63].

False-Negative Rate Findings on SLN biopsy are deemed false-­ negative if a patient in whom SLN biopsy is negative (meaning no microscopic metastasis found) is later diagnosed with clinical nodal metastasis. In an early report from MD Anderson, Ho et al. found that with a median follow-up time of 25  months, one of ten patients with sebaceous carcinoma who had a negative SLN biopsy result developed nodal metastasis after SLN biopsy [29]. In this patient, rereview of the pathology slides of the SLN demonstrated the presence of a microscopic focus that had been missed during the initial pathologic review. In a more recent updated report from MD Anderson in a larger cohort of patients and with longer follow-up time, Pfeiffer et al. reported on 51 patients with ocular adnexal melanoma, of whom 41 patients had a negative SLN. Three of these 41 patients later developed a nodal recurrence, making the false-negative rate to be 7% (95%CI, 1.5–9.9) [27]. The authors pointed out that all three patients with false-negative findings on SLN biopsy were among the first patients who had SLN biopsy at MD Anderson; there were no false-negative events in any of the subsequent patients after the year 2004 suggesting the presence of a learning curve and importance of experience with sentinel lymph node biopsy in the head and neck region and for ocular adnexal cancers in particular. Maalouf et  al. reported no false-negative events—none of their patients with negative findings on SLN biopsy had had a nodal recurrence at median follow-up times of 18.7 months for the 4 patients with Merkel cell carcinoma, 22 months for the 8 patients with squamous cell carcinoma, 27.2  months for the 4 patients with melanoma, and 30 months for the 1 patient with carcinoma [44].

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Care of Patients with a Positive SLN Once micrometastasis is discovered on SLN biopsy, historically completion lymph node dissection is recommended according to the 2018 National Comprehensive Cancer Network Melanoma Practice Guideline (version 2.2018). In a series of 90 patients with cutaneous melanoma and positive SLNs, 15–29% of patients with positive SLNs had metastasis in non-SLNs based on findings on completion lymphadenectomy [64–66]. In a recent publication of the Multicenter Selective Lymphadenectomy Trial II, immediate-completion lymph node dissection increased the rate of regional disease control and provided prognostic information. However, it did not increase the melanoma-specific survival of patients with melanoma and SLN metastases at a median follow-up of 43 months [23]. The authors conclude that the lack of survival benefit with completion lymph node dissection suggests that any increase in survival with early surgery occurred in patients with disease that was limited to the SLN and that in patients with non-SLN metastases, the timing of that intervention did not seem to be critical. Adjuvant high-dose radiation therapy, with or without concurrent chemotherapy, has been shown to be effective in obtaining local–regional control for patients with melanoma [67], squamous cell carcinoma [68], sebaceous carcinoma [69], and Merkel cell carcinoma with positive lymph nodes [70]; however, a long-term survival benefit from radiation with or without concurrent chemotherapy has not been established. Systemic chemotherapy alone has also been used as postoperative adjuvant therapy for patients with lymph node metastasis. Historically, adjuvant systemic chemotherapy with single agents, with multiple agents, or in combination with interferon had not demonstrated benefit over observation [71]; similar negative results were found in patients with melanoma treated with immune stimulants or vaccination [72]. Some benefit had been observed from adjuvant use of interferon as demonstrated in the Eastern Cooperative Oncology Group trial E1694, of 774 patients with melanoma, high-dose interferon-alpha-2b

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resulted in longer relapse-free and overall survival than GMK vaccine at a median follow-up time of 16 months [73]. Despite these not so great historical data for patients with metastatic melanoma, we have seen a remarkable improvement in disease-free and overall survival in patients with metastatic melanoma in large part due to the advent of immune checkpoint inhibitors for the treatment of metastatic or recurrent melanoma [74, 75]. These promising results provide an even stronger argument for identifying patients with microscopically positive early metastasis in the sentinel lymph nodes so that we can offer early adjuvant treatments with immune checkpoint inhibitors. In addition to melanoma patients, immune checkpoint inhibitors have demonstrated efficacy for several other historically resistant solid tumors, such as head and neck SCC and MCC [57, 76, 77]. We have reported a positive response to anti­PD1 immune checkpoint inhibitor therapy in several patients with metastatic conjunctival melanoma or with melanoma metastatic to the orbit [78].

Future Research The studies to date on SLN biopsy for eyelid and conjunctival tumors have proven the feasibility of SLN biopsy for this anatomic location; demonstrated excellent rates of success in identification of SLNs; and demonstrated positive SLNs in patients with eyelid melanoma, conjunctival melanoma, sebaceous carcinoma of the eyelid, squamous cell carcinoma of the eyelid, and Merkel cell carcinoma of the eyelid. These findings support continued use and further study of SLN biopsy for ocular tumors. A positive SLN indicates a more advanced cancer stage and should prompt additional treatments. A negative SLN, on the other hand, augurs a better prognosis. Given the steep learning curve for SLN biopsy studies in the head and neck region and for ocular tumors in particular and given the risk, albeit low, of false-negative events, we recommend continued surveillance of the regional lymph nodes in all patients with high-risk tumors with negative

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SLNs. There is no question that early detection of microscopic metastasis in the regional lymph nodes leads to earlier interventions for nodal metastasis and potential eligibility of patients for additional systemic treatments. This is particularly true given the recent drug discoveries for metastatic melanoma and the very real possibility that early microscopic detection of metastasis would allow for earlier treatments with immune checkpoint inhibitors, or multi-drug targeted therapy, all recent strategies that have proven effective and associated with prolonged survival for patients with metastatic melanoma. Whether there is a survival benefit from the addition of SLN biopsy to the treatment regimen for patients with eyelid or conjunctival tumors specifically is more difficult to address. Determining whether such a benefit exists would require much larger studies and longer follow-up times than are reflected in the currently available literature on SLN biopsy for ocular tumors. However, the MSLT I, in which 1347 patients with intermediate-thickness (1.2–3.5  mm) cutaneous melanoma were randomly assigned to SLN biopsy or observation, showed a significantly better 5-year disease-free survival rate for patients with nodal metastasis found early via SLN biopsy than for patients with nodal metastasis detected when the nodes became palpable on clinical examination: 72.3% versus 52.4% [79]. Future research should focus on identifying primary tumor characteristics that correlate with a positive SLN for each diagnosis category. Some recent strides have been made in this direction. For example, several studies on patients with conjunctival melanoma have suggested that tumor thickness of at least 2 mm, presence of histologic ulceration, presence of mitotic figures, and for conjunctival melanoma, palpebral location are correlated with a higher risk of nodal metastasis [27, 80, 81]. In a series of 150 patients with conjunctival melanoma, Shields et al. found on multivariate analysis that lateral tumor margin involvement and melanoma not involving the limbus were also associated with a higher risk of nodal metastasis [82]. For SCC we have previously shown that all patients who had a nodal metastasis at presentation or during follow-up

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had a stage T2b or higher tumor (AJCC 7th edition) and 18 mm or higher in greatest diameter at presentation [37]. For sebaceous carcinoma, we have previously found that primary tumors with the T category greater than T2b (AJCC 7th edition) are associated with a higher risk of nodal metastasis [47]. For Merkel cell carcinoma we found that in our series of 18 patients, all patients with a positive nodal metastasis had a T3a disease (AJCC 7th edition eyelid carcinoma criteria) except for 1 patient who had a Tx disease [55]. Similar studies are currently underway to determine what tumor size and what other histologic features are associated with a higher risk of nodal metastasis for squamous carcinoma of the eyelid and for Merkel cell carcinoma of the eyelid. The long-term goal of these studies is to help determine which patients are the optimal candidates for SLN biopsy. Multi-institutional controlled studies of SLN biopsy for ocular tumors would be optimal for yielding higher-level evidence regarding the indications for and yield of SLN biopsy for ocular adnexal tumors.

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276 39. Reschly MJ, Messina JL, Zaulyanov LL, et al. Utility of sentinel lymphadenectomy in the management of patients with high-risk cutaneous squamous cell carcinoma. Dermatol Surg. 2003;29(2):135–40. 40. Ross AS, Schmults CD. Sentinel lymph node biopsy in cutaneous squamous cell carcinoma: a systematic review of the English literature. Dermatol Surg. 2006;32(11):1309–21. 41. Renzi C, Caggiati A, Mannooranparampil TJ, et  al. Sentinel lymph node biopsy for high risk cutaneous squamous cell carcinoma: case series and review of the literature. Eur J Surg Oncol. 2007;33(3):364–9. 42. Takahashi A, Imafuku S, Nakayama J, et al. Sentinel node biopsy for high-risk cutaneous squamous cell carcinoma. Eur J Surg Oncol. 2014;40(10):1256–62. 43. Durham AB, Lowe L, Malloy KM, et  al. Sentinel lymph node biopsy for cutaneous squamous cell carcinoma on the head and neck. JAMA Otolaryngol. 2016;142(12):1171–6. 44. Maalouf TJ, Dolivet G, Angioi KS.  Sentinel lymph node biopsy in patients with conjunctival and eyelid cancers: experience in 17 patients. Ophthal Plast Reconstr Surg. 2012;28:30–4. 45. Chak G, Morgan PV, Joseph JM, et al. A positive sentinel lymph node in periocular invasive squamous cell carcinoma: a case series. Ophthal Plast Reconstr Surg. 2013;29(1):6–10. 46. Shields JA, Demirci H, Marr BP.  Sebaceous carcinoma of the eyelids: personal experience with 60 cases. Ophthalmology. 2004;111:2151–7. 47. Esmaeli B, Nasser QJ, Cruz H, et al. American Joint Committee on Cancer T category for eyelid sebaceous carcinoma correlates with nodal metastasis and survival. Ophthalmology. 2012;119(5):1078–82. 48. Connor M, Droll L, Ivan D. Management of perineural invasion in sebaceous carcinoma of the eyelid. Ophthal Plast Reconstr Surg. 2011;27:356–9. 49. Agelli M, Clegg LX.  Epidemiology of primary Merkel cell carcinoma in the United States. J Am Acad Dermatol. 2003;49:832–41. 50. Donepudi S, DeConti RC, Samlowski WE.  Recent advances in the understanding of the genetics, etiology, and treatment of Merkel cell carcinoma. Semin Oncol. 2012;39:163–72. 51. Lemos BD, Storer BE, Iyer JG.  Pathologic nodal evaluation improves prognostic accuracy in Merkel cell carcinoma: analysis of 5823 cases as basis of the first consensus staging system. J Am Acad Dermatol. 2010;63:751–61. 52. Sims JR, Grotz TE, Pockaj BA, et al. Sentinel lymph node biopsy in Merkel cell carcinoma: The Mayo Clinic experience of 150 patients. Surg Oncol. 2018;27(1):11–7. 53. Peters GB, Meyer DR, Shields JA. Management and prognosis of Merkel cell carcinoma of the eyelid. Ophthalmology. 2001;108:1575–9. 54. Esmaeli B, Naderi A, Hidaji L.  Merkel cell carcinoma of the eyelid with a positive sentinel node. Arch Ophthalmol. 2002;120:646–8.

O. Sagiv and B. Esmaeli 55. Sniegowski MC, Warneke CL, Morrison WH, et al. Correlation of American Joint Committee on Cancer T category for eyelid carcinoma with outcomes in patients with periocular Merkel cell carcinoma. Ophthal Plast Reconstr Surg. 2014;30(6):480–5. 56. Herbert HM, Sun MT, Selva D, et  al. Merkel cell carcinoma of the eyelid: management and prognosis. JAMA Ophthalmol. 2014;132(2):197–204. 57. Nghiem PT, Bhatia S, Lipson EJ, et al. PD-1 blockade with pembrolizumab in advanced Merkel-cell carcinoma. N Engl J Med. 2016;374(26):2542–52. 58. Kaufman HL, Russell J, Hamid O, et  al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-­ group, open-label, phase 2 trial. Lancet Oncol. 2016;17(10):1374–85. 59. Cigna E, Gradilone A, Ribuffo D. Morbidity of selective lymph node biopsy for melanoma: meta-analysis of complications. Tumori. 2012;98:94–8. 60. Wasserberg N, Tulchinsky H, Schachter J. Sentinel-­ lymph-­node biopsy for melanoma is not complication-­ free. Eur Oncol. 2004;30:851–6. 61. Troyan SL, Kianzad V, Gibbs-Strauss SL.  The F. intraoperative near-infrared fluorescence imaging system: a first-in-human clinical trial in breast cancer sentinel lymph node mapping. Ann Surg Oncol. 2009;16:2943–52. 62. Sugie T, Sawada T, Tagaya N.  Comparison of the indocyanine green fluorescence and blue dye methods in detection of sentinel lymph nodes in early-stage breast cancer. Ann Surg Oncol. 2013;20:2213–8. 63. Rubinstein TJ, Perry JD, Korn JM, et al. Indocyanine green-guided sentinel lymph node biopsy for periocular tumors. Ophthalmic Plast Reconstr Surg. 2014;30(4):301–4. 64. McMasters K, Swetter SM.  Current management of melanoma: benefits of surgical staging and adjuvant therapy. J Surg Oncol. 2003;82:209–16. 65. Elias N, Tanabe KK, Sober AJ. Is completion lymphadenectomy after a positive sentinel lymph node biopsy for cutaneous melanoma always necessary? Arch Surg. 2004;139:400–5. 66. Yasuhiro F, Otsuka F.  Japanese Melanoma Study Group. The benefit of a sentinel lymph node biopsy and adjuvant therapy in thick 4 mm melanoma multicenter retrospective study of 291 Japanese patients. Melanoma Res. 2012;22:362–7. 67. Mendenhall WM, Amdur RJ, Grobmyer SR. Adjuvant radiotherapy for cutaneous melanoma. Cancer. 2008;112:1189–96. 68. D’Souza J, Clark J.  Management of neck in metastatic cutaneous squamous cell carcinoma of the head and neck. Curr Opin Otolaryngol Head Neck Surg. 2011;19:99–105. 69. Yen MT, Tse DT, Wu X. Radiation therapy for local control of eyelid sebaceous cell carcinoma: report of two cases and review of literature. Ophthal Plast Reconstr Surg. 2000;16:211–5.

21  Sentinel Lymph Node Biopsy for Eyelid and Conjunctival Malignancies 70. Hedina-Franco H, Urist MM. Multimodality treatment of Merkel cell carcinoma: case series and literature review of 1024 cases. Ann Surg Oncol. 2001;8:204–8. 71. Sondak VK, Wolfe JA.  Adjuvant therapy for melanoma. Curr Opin Oncol. 1997;9:189–204. 72. Eggermont AMM, Gore M.  Randomized adjuvant therapy trials in melanoma: surgical and systemic. Semin Oncol. 2007;34:509–15. 73. Kirkwood JM, Ibrahim JG, Sosman JA.  High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/ QS-21 vaccine in patients with resected stage IIb-III melanoma: results of intergroup trial E1694/S9512/ C509801. J Clin Oncol. 2001;19:2370–80. 74. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–23. 75. Larkin J, Chiarion-Sileni V, Gonzalez R, et  al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(1):23–34. 76. Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti–PD-1) in melanoma. N Engl J Med. 2013;369(2):134–44. 77. Taube JM, Galon J, Sholl LM, et al. Implications of the tumor immune microenvironment for staging and therapeutics. Mod Pathol. 2018;31(2):214–34.

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78. Ford J, Thuro BA, Thakar S, et al. Immune checkpoint inhibitors for treatment of metastatic melanoma of the orbit and ocular adnexa. Ophthal Plast Reconstr Surg. 2017;33(4):e82–5. 79. Morton DL, Thompson JF, Cochran AJ, et al. Sentinel-­ node biopsy or nodal observation in melanoma. N Engl J Med. 2006;355(13):1307–17. 80. Esmaeli B, Roberts D, Ross M. Histologic features of conjunctival melanoma predictive of metastasis and death. Trans Am Ophthalmol Soc. 2012;110:64–73. 81. Tuomaala S, Kivela T. Metastatic pattern and survival in disseminated conjunctival melanoma: implications for sentinel lymph node biopsy. Ophthalmology. 2004;111:816–21. 82. Shields CL, Shields JA, Gunduz K.  Conjunctival melanoma: risk factors for recurrence, exenteration, metastasis, and death in 150 consecutive patients. Arch Ophthalmol. 2000;118:1497–507. 83. Esmaeli B.  Advances in the management of malignant tumors of the eyelid and conjunctiva: the role of sentinel lymph node biopsy. Int Ophthalmol Clin. 2002;42(2):151–62. 84. Sanchez R, Ivan D, Esmaeli B. Eyelid and periorbital cutaneous malignant melanoma. Int Ophthalmol Clin. 2009;49(4):25–43.

Surgical Techniques

22

Anat Galor, Bennie H. Jeng, Arun D. Singh, and Carol L. Karp

Introduction A variety of tumors affect the conjunctiva and cornea, ranging from benign growths to malignant neoplasms. Several types of conjunctival neoplasms originate from or involve the limbus region and extend into the cornea. Therefore, surgical techniques involve excision of both corneal and conjunctival tissues.

Presurgical Evaluation A detailed slit lamp examination is not only vital to correctly diagnose conjunctival and corneal tumors but also critical for planning the appropriate surgery. It is also important to evaluate the upper and lower palpebral conjunctivae to look

for extension of lesions and to palpate the preauricular and submandibular areas for enlarged lymph nodes. Corneal involvement must be accurately documented since it is difficult to appreciate under the diffuse lighting of an operating microscope. Rose Bengal stain can be used to help delineate abnormal epithelium. A drawing or photograph clearly depicting the extent of involvement, which can be readily seen during surgery, is helpful for obtaining adequate surgical margins. Free movement of the abnormal conjunctiva, as tested by gentle pushing with a cotton-­tipped applicator, indicates sparing of the sclera. Anterior segment optical coherence tomography (OCT) [1, 2] and ultrasound biomicroscopy can greatly aid in the preoperative evaluation of surface extension (OCT) and depth (UBM) of conjunctival lesions (Chap. 12).

Anesthesia A. Galor (*) · C. L. Karp Department of Ophthalmology, Bascom Palmer Eye Institute, Miami, FL, USA e-mail: [email protected] B. H. Jeng Department of Ophthalmology and Visual Sciences, University of Maryland School of Medicine, Baltimore, MD, USA A. D. Singh Department of Ophthalmic Oncology, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA

Local anesthesia can be used for most procedures, depending on patient cooperation. Most authors recommend retrobulbar anesthesia with sedation to avoid disruption of conjunctival architecture and to control the pain associated with conjunctival manipulation and cryotherapy [3]. Others prefer subconjunctival injection of 1% lidocaine with epinephrine to elevate the lesion from underlying sclera [4].

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General Surgical Principles The goal of surgery is the total removal of tissues (conjunctiva, cornea, sclera) that are affected by the neoplasm. All but the most extensive conjunctival lesions can be approached by excisional biopsy to achieve this goal. However, incisional biopsy may be performed in some circumstances.

General Surgical Technique In general, the surgical technique depends on location and the type of tumor. The surgical procedure can be divided into four sequential steps: conjunctival excision, corneal excision (if corneal involvement is present), supplemental cryotherapy (if needed), and ocular surface reconstruction.

Conjunctival Excision The removal technique for the conjunctival portion of a neoplasm depends on the type of lesion and its depth of invasion.

 imple Incisional Biopsy S A simple incisional biopsy should be considered in cases where medical therapy is the planned pria

Fig. 22.1  Simple conjunctival excision for PAM.  The depth of incision was limited to the full thickness of the conjuctiva sparing the underlying Tenon’s fascia (a).

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mary therapy for an ocular surface squamous neoplasia (OSSN). This procedure can be performed at the slit lamp under topical anesthesia. Forceps are used to grasp nearby uninvolved tissue and scissors are then used to remove a sufficient tumor sample. Given the certainty of positive margins, specimen orientation is not needed. The sample is positioned on a small piece of paper and placed in formalin to allow for pathologic review. A Beaver blade then can be used to separate and remove abnormal corneal epithelium, which should also be sent to the pathologist. While this technique is a good option in cases of suspected OSSN, it should be avoided in cases of suspected melanoma as complete excisional biopsy is preferred in the latter malignancy.

 imple Conjunctival Excision S Benign lesions that do not penetrate the Tenon or sclera can be removed by a simple excisional biopsy. The surrounding conjunctiva is grasped with non-toothed forceps and excised along with a 1- to 2-mm margin of clinically non-affected tissue using scissors. The depth of incision can be limited only to the full thickness sparing the underlying Tenon’s fascia or may extend up to the sclera (including Tenon’s fascia) (Fig. 22.1). It is important not to touch the affected conjunctiva and use different instruments for affected and non-affected b

The wound (8  ×  6  mm) was left to heal by secondary intention (with approximation – avoiding sutures or glue). Note full surface epithelialization at 4 weeks (b)

22  Surgical Techniques

conjunctiva so as not to iatrogenically plant tumor cells on the unaffected tissue [5].

 omplex Conjunctival Excision C For potentially malignant tumors, a more extensive excision is suggested with a wider margin of excision of clinically non-affected tissue (3–4  mm) and lamellar sclerectomy if scleral involvement is present. The area to be resected is first outlined with a surgical marker, with care to include 3–4  mm of unaffected conjunctival tissue. Using a no-touch technique, the conjunctiva and Tenon’s fascia are then incised with scissors to expose the underlying sclera (Fig.  22.2a). Once the conjunctival margins have been released, tumor removal should be completed by cutting flush with the corneal margin. Bipolar cautery is applied to the episcleral vessels to achieve hemostasis. In cases where scleral involvement is suspected, a partial sclerectomy should be performed with a fresh no. 57 Beaver blade by fashioning a semicircular groove, approximately 20% of scleral depth and 2  mm posterior to the tumor margin (Fig. 22.2b). A thin scleral flap can then be dissected with a crescent blade anteriorly up to the limbus (Fig. 22.2c). For tumors extending more than 5  mm posterior to the limbus, it is helpful to hook and isolate the appropriate rectus muscle with a suture to provide traction, to allow for better exposure and to avoid inadvertent injury to the muscle.

Corneal Excision As corneal involvement by a conjunctival tumor tends to be superficial, the corneal excision is usually limited to removal of corneal epithelium (corneal epitheliectomy). Care must be taken not to disrupt Bowman’s layer as it is thought to serve as a natural ocular barrier to invasion. Deeper invasion of the cornea, if present, necessitates lamellar keratectomy. Prior to scraping off the affected epithelium with no. 57 Beaver blade, absolute alcohol is applied for 1  min with a Weck-cell applicator to the involved corneal epithelium and a 2-mm margin of clinically non-­ affected tissue. The purpose of alcohol application

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is to denature the cells, thereby minimizing the risk of seeding of cancer cells. Alcohol is applied to dry cornea so as to limit spillage. The uninvolved cornea may also be protected with a viscoelastic applied to unaffected areas. The corneal epithelium is removed in one piece, placed on a filter paper, and submitted to pathology. An alternative approach is to first loosen and remove epithelium and then proceed with conjunctival resection of tumor.

Supplemental Cryotherapy Cryotherapy with a flat-tipped nitrous oxide probe is used as a supplemental treatment of malignant lesions to decrease recurrence rates. Galor et  al. demonstrated that application of cryotherapy to the surgical margins decreased the OSSN recurrence rate by approximately 50% (31% versus 16% at 5  years) [6]. The probe is placed on the underside of the conjunctival edge, lifting the conjunctiva to avoid damage to the sclera, and applied to the tissue for 3–10  s (Fig.  22.2d) [5]. The tissue is allowed to thaw spontaneously and is refrozen in a similar manner for a “double freeze-thaw” cycle. The probe is applied to the margin to overlap with the previously treated area, and the process is repeated until all margins have been treated. The affected limbus is then similarly treated with a double freeze-thaw cycle.

Ocular Surface Reconstruction To prevent the possibility of planting tumor cells on unaffected tissue, it is important to use a different set of instruments for reconstructing the ocular surface than those that were used for lesion removal. The preferred technique involves ­cutting an amniotic membrane to the appropriate size, placing it (substrate side down) over the defect area, and tucking the margins under the healthy conjunctivae. Fibrin glue is then utilized to secure the membrane to the underlying sclera. The thicker component (fibrinogen) is first introduced under the graft with a 27-gauge cannula and

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a

b

c

d

e

Fig. 22.2  Complex conjunctival excision. Large conjunctival lesion being excised with a 4-mm margin of unaffected conjunctiva. (a) Conjunctival flap being fashioned. (b) Partial-thickness scleral incision with a no. 57

Beaver blade. (c) Lamellar scleral dissection with a crescent blade. (d) Cryotherapy to the edges of the conjunctival wound. (e) Closure of the wound

22  Surgical Techniques

g­ently spread so that a thin layer of uniform thickness is achieved. The thinner component (thrombin) is then introduced under the graft with a separate cannula, and again, a thin layer is applied. A muscle hook is then used to smooth the graft and remove excess glue. Once graft position is acceptable, a 2-min wait is usually sufficient for good adherence to develop between the graft and underlying sclera (Fig. 22.2e). Use of amniotic membrane helps to decrease inflammation and to facilitate epithelialization [7–9]. Superficial excision that spare the Tenon’s fascia can be left to heal by secondary intention (with approximation – avoiding sutures or glue).

Specific Surgical Techniques Melanocytic Tumors Conjunctival Nevus Excision of conjunctival nevus is considered for cosmetic reasons, ocular irritation, or parental concern. A simple excisional biopsy is the procedure of choice [5].  rimary Acquired Melanosis P Because of the diffuse nature of primary acquired melanosis (PAM), the surgical approach is different from that of an isolated conjunctival lesion. Corneal epitheliectomy is performed if corneal involvement is documented. Suspicious nodules are excised to evaluate for the possibility of melanoma. Staging consists of removing 3-mm pieces of bulbar conjunctiva with the use of fresh forceps and scissors halfway between the rectus muscles and fornix in all four quadrants. These small areas can be left to heal without sutures [3]. Complete removal is possible with small areas of PAM, whereas diffuse areas may be treated with double freeze-thaw cycle cryotherapy alone (one quadrant per session) if atypia is documented histopathologically [10]. Topical mitomycin-C (MMC) has also been reported as a possible primary or adjuvant treatment for diffuse PAM [11, 12].

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 onjunctival Malignant Melanoma C Conjunctival melanomas are managed by excision and cryotherapy [13, 14]. Recurrent conjunctival melanoma is managed by repeat excision, cryotherapy, MMC eye drops, or irradiation. More extensive recurrences may require exenteration [5].

Squamous Tumors  quamous Cell Papilloma S If removal is contemplated, combined modality treatment should be used since simple excision often leads to a more extensive recurrence than the original lesion [5]. Cryotherapy, as described above, is the supplemental treatment of choice. Alternatively, a medical approach using interferon alpha 2b drops or injections may be utilized.  onjunctival Epithelial Neoplasia C Combined modality treatment (excision supplemented with cryotherapy) as described above is advocated given the high rate of recurrence of simple excision [5]. Other variations to the above technique have been described and include application of cryotherapy to the scleral bed as well as the surrounding conjunctivae [15] and performing cryosurgery prior to and after excision [4]. A variant of Mohs’ micrographic surgery has been described as an approach to treating CIN [16]. Topical interferon alpha [17, 18], topical MMC [19, 20], or topical 5-fluorouracil [21] can be used as an adjuvant treatment for patients with incompletely excised lesions (i.e., those with positive surgical margins). In patients with positive surgical margins, the use of postoperative interferon therapy reduced recurrences to a level similar to the one seen in patients with negative surgical margins [6]. Medical modalities can also be considered as a primary treatment, especially in patients with diffuse disease or in those with multiple recurrences after surgery [22].

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Substantia Propria Tumors Lymphoid Tumor An incisional approach is typically reserved for suspected lymphoid tumors. Tissue must be kept fresh to allow for flow cytometric assessment to differentiate between hyperplasia and malignancy. Medical approaches including external beam radiation or chemotherapy are typically used to treat such malignancies. Limbal Dermoid Limbal dermoids can cause irregular astigmatism, irritation, or unacceptable cosmesis. Given the deep extent of these tumors, one surgical approach is a lamellar sclerectomy and keratectomy [5]. The lesion can be excised manually by lifting the conjunctival edge with forceps and locating a plane of normal sclera under the tumor with a blade. Alternatively, a handheld trephine on bare sclera can be used to delineate the boundaries of the lesion. A slightly oversized trephine is then used to remove donor corneoscleral tissue after a lamellar dissection is performed of equal depth. The donor is sewn into the recipient bed with interrupted 10-0 nylon sutures [23]. Another surgical approach involves cutting the lesion flush with the surrounding tissue [24].

Specimen Preparation Prior discussion with a pathologist is important to identify the proper fixative agent; most commonly, 10% formalin is used. For suspected lymphoid tumors, tissue should be transported fresh in a small amount of saline for flow cytometric analysis. Specimens are prepared by laying the tissue flat, epithelial side up, on sterile paper wetted with balanced salt solution. Orientation is drawn with a graphite pencil. The tissue can then be sent to pathology for final diagnosis and margin assessment (Fig. 22.3).

Fig. 22.3  Intraoperative photograph demonstrating the orientation of an ocular surface squamous neoplasia after excisional removal and prior to placement in formalin. (Courtesy of Dr. Carol L.  Karp, Bascom Palmer Eye Institute, Miami, Florida)

Postsurgical Management Following surgery, topical antibiotics are used until reepithelialization is complete. A corticosteroid eye drops is typically used for approximately 1  month, on a tapering schedule. However, the frequency and duration is titrated based on the degree of inflammation in the surgical bed. Patients in whom a graft is used may require a bandage contact lens and topical treatment for a longer time [5].

Complications Although uncommon, complications can occur after surgical resection including infection, bleeding, delayed epithelial healing, pyogenic granuloma formation, Tenon’s cyst formation, conjunctival and corneal scarring, restrictive strabismus, and limbal stem cell deficiency. Complications related to MMC use include scleral ischemia and cataract formation. Vigorous

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11. Finger PT, Czechonska G, Liarikos S.  Topical mitomycin C chemotherapy for conjunctival melanoma and PAM with atypia. Br J Ophthalmol. 1998;82(5):476–9. 12. Pe’er J, Frucht-Pery J.  The treatment of primary acquired melanosis (PAM) with atypia by topical mitomycin C. Am J Ophthalmol. 2005;139(2):229–34. 13. Jakobiec FA, Rini FJ, Fraunfelder FT, et al.  Cryo­ References therapy for conjunctival primary acquired melanosis and malignant melanoma. Experience with 62 cases. Ophthalmology. 1988;95(8):1058–70. 1. Kieval JZ, Karp CL, Abou Shousha M, et  al. Ultra-­ high resolution optical coherence tomography for dif- 14. Jakobiec FA, Brownstein S, Albert W, et al. The role of cryotherapy in the management of conjunctival ferentiation of ocular surface squamous neoplasia and melanoma. Ophthalmology. 1982;89(5):502–15. pterygia. Ophthalmology. 2012;119(3):481–6. 2. Thomas BJ, Galor A, Nanji AA, et  al. Ultra high-­ 15. Fraunfelder FT, Wingfield D. Management of intraepithelial conjunctival tumors and squamous cell carciresolution anterior segment optical coherence nomas. Am J Ophthalmol. 1983;95(3):359–63. tomography in the diagnosis and management of ocular surface squamous neoplasia. Ocul Surf. 16. Buus DR, Tse DT, Folberg R, et al.  Microscopically controlled excision of conjunctival squamous cell car2014;12:46–58. cinoma. Am J Ophthalmol. 1994;117(1):97–102. 3. Shields JA, Shields CL, De Potter P.  Surgical management of conjunctival tumors. The 1994 17. Chen HC, Chang SW, Huang SF.  Adjunctive treatment with interferon alpha-2b may decrease the risk Lynn B.  McMahan Lecture. Arch Ophthalmol. of papilloma-associated conjunctival intraepithelial 1997;115(6):808–15. neoplasm recurrence. Cornea. 2004;23(7):726–9. 4. Peksayar G, Altan-Yaycioglu R, Onal S. Excision and 18. Karp CL, Moore JK, Rosa RH Jr. Treatment of cryosurgery in the treatment of conjunctival malignant conjunctival and corneal intraepithelial neoplasia epithelial tumours. Eye (Lond). 2003;17(2):228–32. with topical interferon alpha-2b. Ophthalmology. 5. Schwartz GS, Holland EJ. Management of conjuncti2001;108(6):1093–8. val and corneal neoplasia, vol. III. St. Louis: Mosby; 19. Frucht-Pery J, Sugar J, Baum J, et  al. Mitomycin C 1997. p. 1991–24. treatment for conjunctival-corneal intraepithelial 6. Galor A, Karp CL, Oellers P, et al. Predictors of ocuneoplasia: a multicenter experience. Ophthalmology. lar surface squamous neoplasia recurrence after exci1997;104(12):2085–93. sional surgery. Ophthalmology. 2012;119:1974–81. 7. Paridaens D, Beekhuis H, van Den Bosch W, et  al. 20. Frucht-Pery J, Rozenman Y, Pe’er J. Topical mitomycin-­C for partially excised conjunctival squamous cell Amniotic membrane transplantation in the mancarcinoma. Ophthalmology. 2002;109(3):548–52. agement of conjunctival malignant melanoma and primary acquired melanosis with atypia. Br J 21. Yamamoto N, Ohmura T, Suzuki H, et al. Successful treatment with 5- fluorouracil of conjunctival Ophthalmol. 2001;85(6):658–61. intraepithelial neoplasia refractive to mitomycin-C.  8. Chen Z, Yan J, Yang H, et  al. Amniotic membrane Ophthalmology. 2002;109(2):249–52. transplantation for conjunctival tumor. Yan Ke Xue 22. Galor A, Karp CL, Chhabra S, et al. Topical interferon Bao. 2003;19(3):165–7, 145. alpha 2b eye-drops for treatment of ocular surface 9. Kobayashi A, Takahira M, Yamada A, et al. Fornix and squamous neoplasia: a dose comparison study. Br J conjunctiva reconstruction by amniotic membrane Ophthalmol. 2010;94(5):551–4. in a patient with conjunctival mucosa-­ associated lymphoid tissue lymphoma. Jpn J Ophthalmol. 23. Mader TH, Stulting D. Technique for the removal of limbal dermoids. Cornea. 1998;17(1):66–7. 2002;46(3):346–8. 10. Hungerford JL.  Surgical treatment of ocular mela- 24. Burillon C, Durand L. Solid dermoids of the limbus and the cornea. Ophthalmologica. 1997;211(6):367–72. noma. Melanoma Res. 1993;3(5):305–12.

cryotherapy to the scleral bed can result in damage to the sclera, iris, and ciliary body [5]. These complications can be minimized by adhering to good surgical techniques.

Radiation Therapy: Conjunctival and Eyelid Tumors

23

Christopher Fleming, Shlomo Koyfman, and Arun D. Singh

Introduction Several forms of radiation therapy are used to treat eyelid and conjunctival malignancies. As with other ocular tumors, the goal of radiation therapy is to sterilize the tumor while conserving visual function and avoiding collateral damage. In this chapter, we overview the role of radiation therapy in the treatment of selected eyelid and conjunctival tumors. More detailed information (e.g., dosimetry) is provided in the relevant chapters.

Techniques of Radiation Therapy Radiation therapy for eyelid tumors is most commonly delivered via external beam radiation therapy (EBRT), including traditional megavoltage photons, proton therapy, orthovoltage X-rays, and electron beam therapy. The rapid adoption of intensity-modulated radiation therapy (IMRT) and image-guided radiation therapy (IGRT) over the past decade has significantly improved the conformality of treatment plans, leading to sizeC. Fleming · S. Koyfman Department of Radiation Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, USA A. D. Singh (*) Department of Ophthalmic Oncology, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA e-mail: [email protected]

able reductions in dose to nearby organs at risk (Volume 1: Chapter 11). Dose sparing can be further achieved with the use of spacers, lead eye shields, and eye deviation. Brachytherapy is another commonly used modality, especially for conjunctival tumors. Such brachytherapy is delivered via handheld applicators, plaques, or interstitial seeds; compared to external beam, brachytherapy has more rapid dose falloff, but with higher surface doses and more difficulty with reproducible application for eyelid tumors.

Eyelid Tumors Squamous Cell Carcinoma The primary treatment for squamous cell carcinoma (SCC) of the eyelid is surgical excision, performed either using Mohs micrographic technique or with wide safety margins. Radiation therapy may alternatively be recommended for patients with advanced disease, where surgical excision would result in poor cosmesis and loss of eyelid function, and for patients unable to undergo extensive surgery because of poor health (Chap. 5). For both squamous and basal cell carcinomas, many different radiation therapy doses have proved efficacious, ranging from single fraction to multi-week treatment courses delivering 20–60 Gray via external beam radiation therapy (Fig.  23.1). Interstitial brachytherapy is

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Fig. 23.1  Squamous cell carcinoma (eyelid). This man presented with a large squamous cell carcinoma of the right upper eyelid. He was treated primarily with volumet-

ric modulated arc radiation therapy (VMAT) delivering 64 Gy in 32 daily fractions (a). Note response 3 months after completion of radiation therapy (b)

another available technique, whereby radioactive sources are inserted into the tumor using a plastic tubing system. Surface brachytherapy, where a radiation therapy source is placed on the tumor, is yet another treatment option for smaller tumors. SCC of the skin is generally quite radio-­ responsive. Retrospective studies have generally reported excellent long-term local control rates of 70–95% for both EBRT [1–3] and brachytherapy [4–8]. Experiences with proton therapy have been published showing feasibility of the technique [9].

apy (fractionated, total dose 40–70 Gy) [13]. All tumors showed histopathological remission within 3 months and sustained clinical remission was documented in each patient at 24  months. Overall, cosmesis and functional results were better with IMQ than with radiation therapy [13]. Lesions that are recurrent after prior surgery have worse control rates than those treated primarily with radiation therapy [14].

Basal Cell Carcinoma Multiple large retrospective series have reported long-term local control with radiation therapy to be 90% or higher (Fig.  23.2). These results are consistent between EBRT and brachytherapy (Chap. 4) [4–8, 10–12]. Assuming equal extent of disease, radiation therapy dosing is not significantly different between squamous cell carcinoma and basal cell carcinoma. Comparison of topical therapy with imiquimod cream (IMQ) and radiation therapy was assessed in 27 patients with clinical and histopathological diagnosis of nodular BCC randomized to receive IMQ 5% cream once daily, 5 days/week for 6 weeks or radiation ther-

Sebaceous Gland Carcinoma Sebaceous gland carcinoma is a rare cancer with limited data on efficacy for radiation therapy (Chap. 6). Initial reports suggested radio-­ resistance of this tumor [1], though recent studies have challenged this notion, showing long-term local control rates of 90% or higher [15, 16]. Doses greater than 55  Gy are associated with increased local control [17], and brachytherapy has also been used to successfully treat sebaceous gland carcinoma [8].

Melanoma Melanoma is generally considered less radio-­ responsive than squamous and basal cell

289

23  Radiation Therapy: Conjunctival and Eyelid Tumors

a

c

b

d

Fig. 23.2  Basal cell carcinoma (eyelid). A patient with a large basal cell carcinoma of the lower eyelid, treated with radiation therapy alone at a dose of 35 Gy in five fractions. A blue spacer is placed over the eye to increase the distance between the target volume and the globe. Proparacaine drops are first placed on the eye for topical anesthesia. Once the spacer is placed, the eye is then taped shut. Wiring outlines the anticipated treatment volume (a). A custom mask is made to immobilize the head during

treatment (b). The radiation therapy is delivered using VMAT plan consisting of non-coplanar arcs oriented perpendicular to each other, where the dose is continuously delivered and modulated, while the gantry is in motion around the patient (c). The isodose lines are shaped to avoid the right globe while still providing acceptable coverage of the target (d). The spacer is seen anterior to the globe to increase the distance between the target volume (purple region) and the globe

c­arcinoma. Primary radiation therapy alone is therefore not recommended, though it may be used as an adjuvant for more invasive lesions, particularly those with regional nodal metastases (Chap. 7). The use of I-125 brachytherapy has been reported, though is not standard [18].

Merkel Cell Carcinoma Merkel cell carcinoma is very radiosensitive. Radiation therapy is commonly delivered post-­ operatively to the tumor bed and regional lymph nodes, as the risk for residual/recurrent local

290

d­ isease and regional lymph node metastases is high (Chap. 9) [17, 19]. EBRT is the most ­commonly employed modality, though there are published case reports on the efficacy of brachytherapy with I-125 seed implantation [20].

Conjunctival Tumors Conjunctival Melanoma For neoplasms of the conjunctiva, brachytherapy is generally favored over external beam radiation therapy due to its rapid dose fall off and the relative ease of application at this site. Strontium-90 brachytherapy has been used as an adjuvant therapy for incompletely excised conjunctival melanoma showing long-term local control rates of 80–95% for cumulative doses of 50–60 Gy; significantly worse tumor control is observed in patients who receive doses less than 40 Gy [21]. Primary therapy with Sr-90 brachytherapy has also been reported [22, 23]. Ru-106 brachytherapy prescribed to 100 Gy, used as adjuvant therapy, shows significantly improved local control compared to patients treated with adjuvant cryotherapy (Fig.  23.3) [24]. Other radioactive sources, including I-125, have also been utilized [25, 26]. Adjunctive radiotherapy avoids the need

a

Fig. 23.3  Conjunctival melanoma. Nodular conjunctival melanoma of the left eye of a 62-year-old man (a). Following resection and brachytherapy with ruthenium-

C. Fleming et al.

for wide surgical safety margins and, in some cases, the use of an amniotic membrane graft. As with other disease of the head and neck, patients with regional but not distant metastatic disease should undergo external beam radiation therapy post-operatively, if surgery is not feasible (Chap. 17). The presence of regional nodal disease indicates a poor prognosis, and these patients will likely require additional systemic therapy [27]. Advanced conjunctival melanomas may be treated by local excision with adjunctive external beam radiation therapy as an alternative to exenteration for carefully selected patients (Fig. 23.4); experience with proton therapy delivering 45 Gy in eight fractions has been published [28].

 onjunctival Invasive Squamous C Carcinoma Management of conjunctival carcinoma is similar to conjunctival melanoma, with resection being the primary treatment modality. Strontium-90 brachytherapy has been used post-operatively in the treatment of ocular surface squamous neoplasia with doses of 30 Gy in a single fraction and 60 Gy in four fractions. Higher doses of 60 Gy single fraction and 140 Gy in seven fractions are used in the primary treatment setting (i.e., patients

b

1­06 episcleral implant (b) 34  months after treatment, there was an absence of residual pigmentation or recurrent tumor. (Case provided by Dr. Bertil Damato)

291

23  Radiation Therapy: Conjunctival and Eyelid Tumors

a

b

Fig. 23.4  Conjunctival melanoma. Fungating conjunctival melanoma of the left eye of an 87-year-old woman. The tumor obscured almost the entire cornea and had invaded the orbit; however, the patient had declined exen-

teration (a). Following extensive resection and external beam radiation therapy (b), note absence of residual pigmentation or recurrent tumor over a period of 28 months. (Case provided by Dr. Bertil Damato)

who do not undergo surgical resection) [29]. Small applicators have increased risk of marginal failure [30, 31]. I-125 and Ru-106 are other radioactive isotopes that may be used for brachytherapy [14]. The main indication is scleral invasion or deep margin being positive on histopathology (Chap. 15). As above, external beam radiation therapy may be used for very advanced tumors as an alternative to exenteration [32–34].

lymphoma confined to the conjunctiva or eyelid [38, 39]. Higher-grade lymphomas (e.g., diffuse large B-cell lymphoma and mantle cell lymphoma) are treated with higher doses (30– 45 Gy) with similar efficacy or may be managed with systemic therapy alone [40, 41]. Brachytherapy carries increased risk of local recurrence at the treatment margins [42] and is therefore not recommended.

Conjunctival Lymphoma

Radiation-Induced Ocular Morbidity

Lymphomas are exquisitely radiosensitive neoplasms with a high tendency for local, regional, and distant spread. Therefore, radiation therapy alone or in combination with systemic therapy is the preferred modality for treatment. Pathology generally reveals indolent histologic subtypes, the most common being extranodal marginal zone and follicular lymphoma [35]. Doses of 24–30  Gy have shown 10-year local control rates up to 100% [36], although patients remain at high risk for distant relapse [37]. For retrobulbar or lacrimal gland involvement, the entire orbit is the target of radiation therapy, although partial orbit radiation is acceptable for

The likelihood and severity of toxicity are determined by total and daily dose of radiation therapy, as well as irradiated volume of the affected organ at risk (Volume 1: Chapter 12) [43]. Generally, a more protracted treatment will deliver improved cosmesis and is therefore selected for more locally invasive tumors. Potential side effects of radiation therapy include keratoconjunctivitis sicca, corneal stem cell deficiency, cataract, radiation retinopathy, and radiation optic neuropathy (Fig.  23.5) [10, 14, 15, 44–46]. When used in conjunction with surgery, radiation may lead to worse toxicity than when used alone as definitive treatment [9].

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Fig. 23.5  Radiation toxicity. A patient with recurrent high-grade apocrine adenocarcinoma of the right lower eyelid, for which he underwent complete resection followed by adjuvant radiation. During treatment he developed radiation-induced conjunctivitis and keratitis

Brachytherapy has rapid dose falloff, which may reduce toxicity compared to EBRT, though may not be feasible for all locations [8].

Conclusions The indications for radiation therapy depend on tumor type, location and extent, as well as the expected outcomes of other therapeutic modalities. A multidisciplinary approach is required for optimal results.

References 1. Fitzpatrick PJ, Thompson GA, Easterbrook WM, et al. Basal and squamous cell carcinoma of the eyelids and their treatment by radiotherapy. Int J Radiat Oncol Biol Phys. 1984;10(4):449–54. 2. Petsuksiri J, Frank SJ, Garden AS, et  al. Outcomes after radiotherapy for squamous cell carcinoma of the eyelid. Cancer. 2008;112(1):111–8. 3. Inaba K, Ito Y, Suzuki S, et  al. Results of radical radiotherapy for squamous cell carcinoma of the eyelid. J Radiat Res. 2013;54(6):1131–7. 4. Krengli M, Masini L, Comoli AM, et  al. Interstitial brachytherapy for eyelid carcinoma. Outcome analysis in 60 patients. Strahlenther Onkol. 2014;190(3):245–9.

C. Fleming et al. 5. Mareco V, Bujor L, Abrunhosa-Branquinho AN, et al. Interstitial high-dose-rate brachytherapy in eyelid cancer. Brachytherapy. 2015;14(4):554–64. 6. Caccialanza M, Piccinno R, Gaiani F, et al. Relevance of dermatologic radiotherapy in the therapeutic strategy of skin epithelial neoplasms: excellent results in the treatment of lesions localized on eyelids and skin overlying the cartilage of the nose. G Ital Dermatol Venereol. 2013;148(1):83–8. 7. Conill C, Sanchez-Reyes A, Molla M, et al. Brachy­ therapy with 192Ir as treatment of carcinoma of the tarsal structure of the eyelid. Int J Radiat Oncol Biol Phys. 2004;59(5):1326–9. 8. Frakulli R, Galuppi A, Cammelli S, et  al. Brachytherapy in non melanoma skin cancer of eyelid: a systematic review. J Contemp Brachytherapy. 2015;7(6):497–502. 9. Holliday EB, Esmaeli B, Pinckard J, et  al. A multidisciplinary orbit-sparing treatment approach that includes proton therapy for epithelial tumors of the orbit and ocular adnexa. Int J Radiat Oncol Biol Phys. 2016;95(1):344–52. 10. Krema H, Herrmann E, Albert-Green A, et  al. Orthovoltage radiotherapy in the management of medial canthal basal cell carcinoma. Br J Ophthalmol. 2013;97(6):730–4. 11. Schlienger P, Brunin F, Desjardins L, et al. External radiotherapy for carcinoma of the eyelid: report of 850 cases treated. Int J Radiat Oncol Biol Phys. 1996;34(2):277–87. 12. Murchison AP, Walrath JD, Washington CV.  Non-­ surgical treatments of primary, non-melanoma eyelid malignancies: a review. Clin Exp Ophthalmol. 2011;39(1):65–83. 13. Garcia-Martin E, Gil-Arribas LM, Idoipe M, et  al. Comparison of imiquimod 5% cream versus radiotherapy as treatment for eyelid basal cell carcinoma. Br J Ophthalmol. 2011;95(10):1393–6. 14. Swanson EL, Amdur RJ, Mendenhall WM, et  al. Radiotherapy for basal cell carcinoma of the medial canthus region. Laryngoscope. 2009;119(12):2366–8. 15. Hata M, Koike I, Maegawa J, et  al. Radiation therapy for primary carcinoma of the eyelid: tumor control and visual function. Strahlenther Onkol. 2012;188(12):1102–7. 16. Pardo FS, Borodic G. Long-term follow-up of patients undergoing definitive radiation therapy for sebaceous carcinoma of the ocular adnexae. Int J Radiat Oncol Biol Phys. 1996;34(5):1189–90. 17. Yen MT, Tse DT, Wu X, et al. Radiation therapy for local control of eyelid sebaceous cell carcinoma: report of two cases and review of the literature. Ophthalmic Plast Reconstr Surg. 2000;16(3):211–5. 18. Stanowsky A, Krey HF, Kopp J, et al. Irradiation of malignant eyelid melanoma with iodine 125 plaque. Am J Ophthalmol. 1990;110(1):44–8. 19. Silverman N, Shinder R. What’s new in eyelid tumors. Asia Pac J Ophthalmol (Phila). 2017;6(2):143–52.

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20. Hao S, Zhao S, Bu X. Radioactive seed implantation in treatment of an eyelid primary Merkel cell carcinoma. Can J Ophthalmol. 2016;51(1):e31–3. 21. Cohen VM, Papastefanou VP, Liu S, et  al. The use of strontium-90 Beta radiotherapy as adjuvant treatment for conjunctival melanoma. J Oncol. 2013;2013:349162. 22. Wetzel W.  Radiotherapy treatment of malignant melanoma of the corneoscleral zone. Klin Monatsbl Augenheilkd. 1985;186(5):371–3. 23. Lommatzsch PK, Lommatzsch RE, Kirsch I, et al.  Therapeutic outcome of patients suffering from malignant melanomas of the conjunctiva. Br J Ophthalmol. 1990;74(10):615–9. 24. Damato B, Coupland SE.  An audit of conjuncti val melanoma treatment in Liverpool. Eye (Lond). 2009;23(4):801–9. 25. Stannard CE, Sealy GR, Hering ER, et al. Malignant melanoma of the eyelid and palpebral conjunctiva treated with iodine-125 brachytherapy. Ophthalmology. 2000;107(5):951–8. 26. Walsh-Conway N, Conway RM.  Plaque brachy therapy for the management of ocular surface malignancies with corneoscleral invasion. Clin Exp Ophthalmol. 2009;37(6):577–83. 27. Tatla T, Hungerford J, Plowman N, et al. Conjunctival melanoma: the role of conservative surgery and radiotherapy in regional metastatic disease. Laryngoscope. 2005;115(5):817–22. 28. Wuestemeyer H, Sauerwein W, Meller D, et  al. Proton radiotherapy as an alternative to exenteration in the management of extended conjunctival melanoma. Graefes Arch Clin Exp Ophthalmol. 2006;244(4):438–46. 29. Cerezo L, Otero J, Aragon G, et  al. Conjunctival intraepithelial and invasive squamous cell carcinomas treated with strontium-90. Radiother Oncol. 1990;17(3):191–7. 30. Lecuona K, Stannard C, Hart G, et al. The treatment of carcinoma in situ and squamous cell carcinoma of the conjunctiva with fractionated strontium-90 radiation in a population with a high prevalence of HIV. Br J Ophthalmol. 2015;99(9):1158–61. 31. Kearsley JH, Fitchew RS, Taylor RG.  Adjunctive radiotherapy with strontium-90  in the treatment of conjunctival squamous cell carcinoma. Int J Radiat Oncol Biol Phys. 1988;14(3):435–43. 32. Murthy R, Gupta H, Krishnatry R, et al.  Electron beam radiotherapy for the management of recurrent extensive ocular surface squamous neoplasia with orbital extension. Indian J Ophthalmol. 2015;63(8):672–4.

33. Graue GF, Tena LB, Finger PT.  Electron beam radiation for conjunctival squamous carcinoma. Ophthalmic Plast Reconstr Surg. 2011;27(4):277–81. 34. Caujolle JP, Maschi C, Chauvel P, et  al. Surgery and additional proton therapy for treatment of invasive and recurrent squamous cell carcinomas: technique and preliminary results. J Fr Ophtalmol. 2009;32(10):707–14. 35. Zhou P, Ng AK, Silver B, et  al. Radiation therapy for orbital lymphoma. Int J Radiat Oncol Biol Phys. 2005;63(3):866–71. 36. Platt S, Al Zahrani Y, Singh N, et al. Extranodal marginal zone lymphoma of ocular adnexa: outcomes following radiation therapy. Ocul Oncol Pathol. 2017;3(3):181–7. 37. Goda JS, Le LW, Lapperriere NJ, et  al. Localized orbital mucosa-associated lymphoma tissue lymphoma managed with primary radiation therapy: efficacy and toxicity. Int J Radiat Oncol Biol Phys. 2011;81(4):e659–66. 38. Binkley MS, Hiniker SM, Donaldson SS, et al. Partial orbit irradiation achieves excellent outcomes for primary orbital lymphoma. Pract Radiat Oncol. 2016;6(4):255–61. 39. Yahalom J, Illidge T, Specht L, et al. Modern radiation therapy for extranodal lymphomas: field and dose guidelines from the International Lymphoma Radiation Oncology Group. Int J Radiat Oncol Biol Phys. 2015;92(1):11–31. 40. Bhatia S, Paulino AC, Buatti JM, et al. Curative radiotherapy for primary orbital lymphoma. Int J Radiat Oncol Biol Phys. 2002;54(3):818–23. 41. Kirkegaard MM, Coupland SE, Prause JU, et al. Malig­ nant lymphoma of the conjunctiva. Surv Ophthalmol. 2015;60(5):444–58. 42. Regueiro CA, Valcarcel FJ, Romero J, et al. Treatment of conjunctival lymphomas by beta-ray brachytherapy using a strontium-90-yttrium-90 applicator. Clin Oncol (R Coll Radiol). 2002;14(6):459–63. 43. Jeganathan VS, Wirth A, MacManus MP.  Ocular risks from orbital and periorbital radiation therapy: a critical review. Int J Radiat Oncol Biol Phys. 2011;79(3):650–9. 44. Hayashi K, Hatsuno K, Yoshimura R, et al. Electron therapy for orbital and periorbital lesions using customized lead eye shields. Ophthalmologica. 2009;223(2):96–101. 45. Bessell EM, Henk JM, Whitelocke RA, et al. Ocular morbidity after radiotherapy of orbital and conjunctival lymphoma. Eye (Lond). 1987;1. (Pt 1:90–6. 46. Westekemper H, Anastassiou G, Sauerwein W, et al. Analysis of ocular surface alterations following proton beam radiation in eyes with conjunctival malignant melanoma. Ophthalmologe. 2006;103(7):588–95.

Conjunctival and Corneal Tumors: Systemic Associations

24

Matteo Scaramuzzi, Lucy T. Xu, Arun D. Singh, and Elias I. Traboulsi

Abbreviations AL Light chain CHRPE Congenital hypertrophy of the retinal pigment epithelium GS Goldenhar syndrome MEN Multiple endocrine neoplasia OAV Oculoauriculovertebral dysplasia OAVS Oculoauriculovertebral spectrum PJS Peutz–Jeghers syndrome PS Proteus syndrome TTR Transthyretin XP Xeroderma pigmentosum

Carney Complex Carney complex is characterized by cutaneous pigmentary abnormalities, myxomas, endocrine tumors, and schwannomas [1]. Benign conjunctival and caruncular pigmentation may be present M. Scaramuzzi · E. I. Traboulsi (*) Department of Pediatric Ophthalmology and Strabismus, Center for Genetic Eye Diseases, Cole Eye Institute (i-32), Cleveland Clinic, Cleveland, OH, USA e-mail: [email protected] L. T. Xu · A. D. Singh Department of Ophthalmic Oncology, Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA

in about one-fourth of cases [2]. Similar pigmentation of the skin is also present on the lips and genital mucosa (Table 24.1) [3].

Peutz–Jeghers Syndrome Peutz–Jeghers syndrome (PJS) refers to the association of gastrointestinal hamartomatous polyposis and mucocutaneous pigmentation [4]. Peutz– Jeghers syndrome is inherited in an autosomal dominant fashion and results from mutations of STK11 (also known as LKB1), a tumor suppressor gene on chromosome 19p13.3 in about 70–90% of patients [5, 6]. Many missense mutations and deletions occur throughout the whole LKB1 gene without any particular genotype/phenotype correlation [6]. Congenital hypertrophy of the retinal pigment epithelium (CHRPE)-like lesions of the fundus that are characteristic of patients with familial adenomatous polyposis (Gardner syndrome) do not occur in Peutz–Jeghers syndrome [7]. However, pigmented spots of the eyelids and conjunctiva have been observed (Fig. 24.1) [8]. The three clinical features of PJS are mucocutaneous melanin hyperpigmentation, multiple distinctive intestinal hamartomatous polyps, and a dominant inheritance of the condition with a positive family history [6]. Hamartomatous polyps are non-cancerous tumors that occur mainly in the small bowel. Dysplastic transformation of a PJS polyp is very rare [6].

© Springer Nature Switzerland AG 2019 J. Pe’er et al. (eds.), Clinical Ophthalmic Oncology, https://doi.org/10.1007/978-3-030-06046-6_24

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M. Scaramuzzi et al.

296 Table 24.1  Conjunctival tumors that are markers of syndromic association Pattern Pigmentation

Entity Carney complex

Peutz–Jeghers syndrome Benign tumors

Dermoid Organoid nevus syndrome Goldenhar syndrome Proteus

Neuroma MEN 2B

Malignant tumors

Xeroderma pigmentosum

Amyloidosis

Conjunctival features Conjunctival pigmentation

Conjunctival pigmentation Epibulbar dermoid Coloboma Epibulbar dermoid

Epibulbar dermoid Strabismus Orbital exostoses Conjunctival neuroma Conjunctival xerosis Keratitis Ocular surface neoplasms Conjunctival nodule Conjunctival hemorrhage

Associated features Spotty mucocutaneous pigmentation Schwannoma Endocrine overactivity Testicular tumor Mucocutaneous pigmentation Gastrointestinal polyposis Cutaneous sebaceous nevus Preauricular appendages Pretragal fistula Vertebral anomalies Connective tissue nevi Lipoma Vascular malformations Epidermal nevi Thickened corneal nerves Mucocutaneous neuroma Endocrine tumor Skin atrophy with pigmentary changes Neurological abnormalities

Locus/gene 17q

Variable

Sporadic

PRKAR1A gene chromosome 2 19p13.3 STK11 Sporadic Sporadic

Sporadic

10q11.2 RET proto-oncogene Variable

Familial

MEN multiple endocrine neoplasia

a

b

Fig. 24.1  Pigmentation of lips (a) and eyelid (b) in a patient with Peutz–Jeghers syndrome

The pigmentation appears usually around the lips, eyes, hands, or feet, forming smooth melanin deposits in a round or oval shape, and fades with advancing age [6]. Perioral pigmentation is

pathognomonic, particularly if it occurs across the vermilion border of the lips. Oral mucosa and fingertips are also commonly affected. About 50% of patients develop a wide variety of cancers

24  Conjunctival and Corneal Tumors: Systemic Associations Table 24.2  Peutz–Jeghers syndrome diagnostic criteria Positive family history of PJS Negative family history of PJS

Any number of histologically confirmed PJS polyps, or characteristic, prominent, mucocutaneous pigmentation ≥3 histologically confirmed PJS polyps, or any number of histologically confirmed PJS polyps and characteristic pigmentation

PJS Peutz–Jeghers Syndrome

such as breast, colorectal, and pancreatic cancers in adulthood [9]. An overexpression of COX-2 has been reported in polyps and cancers related to PJS [10]. Diagnostic criteria were suggested by Van Lier et al. (Table 24.2) [11]. An annual physical examination with a complete blood count to detect iron-deficiency anemia because of occult bleeding from GI tract polyps or cancer is important, and a baseline endoscopic screening of the gastrointestinal tract is usually initiated around the age of 8 years [10].

Sebaceous Nevus Syndrome Sebaceous nevus syndrome (of Jadassohn), also known as Schimmelpenning–Feuerstein–Mims syndrome, is a distinct clinical disorder within the spectrum of epidermal nevus syndrome (of Solomon) characterized by cutaneous sebaceous nevus and extracutaneous manifestations [12]. Up to 95% of patients have heterozygous mutations in HRAS, with the mutation c.37G  >  C (p.Gly13Arg) accounting for the majority of cases; most other cases result from mutations in KRAS (c.35G  >  A or c.35G  >  T) [13]. The HRAS and KRAS mutations are found in lesional keratinocytes only, confirming a mosaic RASopathy [13]. The classic triad is one of facial lesions, seizures, and mental retardation [14]. Ocular involvement is observed in about 40% of cases with epibulbar choristomas and coloboma of the eyelid being most common. Posterior segment tumors have included chondroid choristomas (intrascleral cartilage) with ossification [14–16]. The limbal choristomas can be simple or com-

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plex and usually are dermoid or lipodermoid in nature. The HRAS and KRAS mutations lead to activation of MAPK and PI3K-Akt signaling and cellular proliferation, which are associated with many cancers, providing an explanation for the high incidence of secondary tumors in approximately 25% of cases [13]. Trichoblastomas and syringocystadenoma papilliferum are the most common benign tumors, while malignant tumors occur in