Handbook of Gynecology 9783319170022

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Diagnosis and Management of Epithelial Ovarian Cancer Katherine Nixon and Christina Fotopoulou

Contents 1

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2

2

Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3

3 3.1

Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . History and Assessment . . . . . . . . . . . . . . . . . . . . . . .

3 3

4

Bloods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4

5

Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4

6

Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5

7

Staging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5

8

Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6

9

Definition of Surgery in EOC . . . . . . . . . . . . . . .

6

10

Tumor Dissemination Patterns at Relapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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11

Value of Secondary Cytoreduction . . . . . . . . . .

8

12

Value of Tertiary Cytoreduction . . . . . . . . . . . . 10

13

Beyond Tertiary Cytoreduction: Quaternary Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . 11

14

Salvage Surgery in Acute Situations: Bowel Obstruction and Intestinal Perforation in the Era of Targeted Antiangiogenetic Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

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Systemic Treatment of Epithelial Ovarian Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Early-Stage Disease (FIGO I-IIb) . . . . . . . . . . . . . Advanced Stage Disease (FIGO IIc – IV) . . . . . Intermediate Platinum Response (PFS 6–12 Months) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Platinum Resistant/Refractory EOC Relapse (PFI 25

Percent

58.5

BMI > 30 39.5

38.1

31.8

9.8

7.7

20-39

40-59

BMI > 40

6.8

>60

Age Group Fig. 1 Obesity category by age group in American women (Data adapted from Ogden et al. (2014))

2.4

Special Populations: Hereditary Syndromes

While endometrial cancer has not been classically thought of as a heredity-based cancer, there is a subpopulation of endometrial cancer patients that do develop endometrial cancer as a result of a genetic syndrome. These include patients with Lynch syndrome, which may account for approximately 5 % of endometrial cancer cases. Lynch syndrome, also referred to as hereditary nonpolyposis colorectal cancer, is an autosomal dominant condition characterized by having a germline mutation in one of four mismatch repair genes (MLH1, MSH2, MSH6, and PMS2) with an inherited propensity to develop colon, endometrial, ovarian, genitourinary, and gastric cancers. Women with Lynch syndrome have a lifetime risk of 15–66 %, depending on the type of MMR mutation, for developing endometrial cancer and the risk increases sharply after age 40, with the median age of diagnosis of 46 (Bonadona et al. 2011; Burke et al. 2014b). The identification of patients with Lynch syndrome has previously depended on clinical suspicion and inquiry into a detailed family history of a patient newly diagnosed with colon cancer based on the Bethesda and Amsterdam criteria (Matthews et al. 2008) (Table 1).

Table 1 Amsterdam criteria Amsterdam criteria: familial risk for Lynch syndrome or hereditary nonpolyposis colorectal cancera Minimum 3 relatives with an HNPCC-associated cancer 1. One first-degree relative of the other 2 relatives 2. At least 2 successive generations are affected 3. At least 1 relative diagnosed before age 50 4. Must exclude familial adenomatous polyposis 5. Tumors verified by pathological examination a

Approximately half of all patients meeting listed criteria will have Lynch syndrome. Importantly, many families with Lynch syndrome will not meet these criteria

According to Lindor et al., approximately half of women meeting Amsterdam criteria will have Lynch syndrome (Lindor et al. 2006). While colorectal cancers are commonly expected sentinel events, more than 50 % of women with Lynch syndrome will present with gynecologic malignancy first (Lu et al. 2005). For women with newly diagnosed endometrial cancer, immunohistochemistry (IHC)-based screening off of paraffin-embedded tissue has been found to have a higher detection rate of identifying Lynch syndrome affected patients than (especially in those age 25. Protective factors included treatment with MPA, maintenance therapy after complete response, and pregnancy (Park et al. 2013a). Park et al. also examined the recurrence rates for women receiving infertility treatment compared to those who conceived without assistance and found no significant difference (P = 0.335). Again, pregnancy appeared to be protective as 76 % of women who conceived were disease free at 5-year follow-up versus 62 % of women who did not conceive (Park et al. 2013d). Ichinose et al. report similar findings in a smaller cohort of women who had achieved complete response: 19 % recurrence in the group achieving live birth versus 70 % recurrence in the nulliparous group (Ichinose et al. 2013). In women with grade 2–3 disease or myometrial invasion, recurrence rises to 23–71 % in Park’s study, and the highest relapse rate was seen in the patients with evidence of myometrial invasion. On multivariate analysis, however, the group found that myometrial invasion itself was not an independent predictor of treatment failure (Park et al. 2013b). Retreatment with oral progestins for recurrence after initial complete response continues to be studied. Park et al. have shown high complete (re)response rates with both MA and MPA

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(85 %) as well as 85 % durable complete response (Park et al. 2013c).

7

Fertility Outcomes

Pregnancy data after conservative management of endometrial cancer is relatively reassuring. In general, women who have achieved a complete response from endometrial cancer should be counseled to promptly pursue fertility if desired, as the reported recurrence rates are relatively high and frequently base-line risk factors for development of endometrial cancer have not changed. Referral to a reproductive endocrinologist is reasonable as many of these patients likely have underlying clinical risk factors for decreased fertility (PCOS, anovulation). Conversely, some patients have been diagnosed with EC while undergoing evaluation for infertility. The data on the safety of assisted reproductive therapies in the setting of prior endometrial cancer are limited. Most of the concern relates to the use of highdose estrogen-based ovarian stimulation protocols, though a few studies have reported their relative safety. If patients do not seek immediate fertility, one should consider use of some type of hormonal maintenance therapy (progesteronebased, LNG-IUD, or combination oral contraceptive). Reported pregnancy rates range from 25 % to nearly 73 % (Minig et al. 2011; Park et al. 2013d; Shan et al. 2013). In a large meta-analysis including 559 women, the live birth rate was approximately 28 % (Gallos et al. 2012). Multiple studies have reported on nearly every form of assisted reproductive technology utilized by women achieving a complete response after conservative management. No studies have specifically compared the reported methods including ovulation induction with timed intercourse, hyperstimulation with intrauterine insemination, and in vitro fertilization. The largest study to date by Park et al. followed 141 women who achieved remission with oral progestins. The overall live birth rate for the entire cohort was 26 %, though if considering only those who attempted pregnancy, 73 % conceived and

66 % resulted in live births. Of those attempting pregnancy, one third had no assistance with reproduction, while two thirds underwent infertility treatments. Patients receiving infertility therapies were more successful at conceiving (86 % vs. 50 %) though both groups reported on patients who achieved multiple pregnancies. There were almost twice as many multiples in the treatment group compared to no treatment (11 % vs. 6 %). Out of a total 52 live births, only 2 anomalies were noted: one child with polydactyly and another with club foot. Ectopic and spontaneous abortion rates were similar in each group and approached population incidence. The preterm delivery rate was higher in the infertility treatment group (8 % vs. 18 %); however, this is likely related to higher incidence of multiple gestation pregnancies (Park et al. 2013d).

8

Surveillance

Upon achievement of remission, or complete response to therapy, surveillance measures must be performed thereafter, in order to monitor for potential recurrence and/or metastases. The National Comprehensive Cancer Network (NCCN) recommends surveillance with history, physical exam, and endometrial sampling every 3–6 months via D&C or in-office endometrial biopsy. Some investigators also have recommended checking serial CA-125, and use of imaging such as transvaginal ultrasound, MRI, or CT scans. These are not universally recommended but may be considered particularly if symptoms of potential metastases arise (pain, gastrointestinal, or genitourinary irregularities). Park et al. recommend against hysteroscopic biopsy during the follow-up period for women planning to conceive. The prevailing notion underlying this recommendation is that repetitive surgical disruption of the endometrium could negatively impact the basal layer and increase risk of intrauterine adhesions (Park and Nam 2015).

Conservative Management of Endometrial Cancer

9

Definitive Management

In his review on conservative management of endometrial cancer, Park writes: “Surveillance after successful progestin therapy should include periodic interviews to explore any symptoms, physical examinations, and transvaginal ultrasonography at 3-month intervals. However, periodic pathologic evaluations of the endometrium, using office endometrial biopsy, D&C, or hysteroscopy, need not be recommenced in patients who do not have symptoms or signs of recurrence”(Park and Nam 2015). The caveat to this recommendation is that once childbearing is complete, even in the absence of verified recurrence, hysterectomy should be performed. While some studies recommend hysterectomy if no response by 6–9 months, management and retreatment for up to 12 months without adverse effect has been reported (Park and Nam 2015). While the discussion around ovarian preservation at the time of hysterectomy has been somewhat fraught, it appears this is a safe option especially in younger populations who stand to benefit from endogenous estrogens in their premenopausal years. Some studies have reported relatively high rates (19–25 %) of concurrent ovarian malignancy in young patients undergoing hysterectomy and BSO for endometrial cancer (Soliman et al. 2005; Walsh et al. 2005). However, in a study of over 3000 women with endometrial cancer, 400 had ovarian preservation. In this large study, ovarian preservation had no effect on either cancer-specific or overall survival suggesting that ovarian preservation is safe (Wright et al. 2009).

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cancers and provide good support for this option. A 2004 GOG study using MPA and Tamoxifen to treat advanced or recurrent endometrial cancer showed 33 % response rate lending support to combinations of oral regimens (Whitney et al. 2004). The LNG-IUD has been more recently studied in populations whose multiple comorbidities prevent surgical management of endometrial cancer. Dhar et al. employed the IUD alone, while Montz et al. performed D&C with insertion of IUD. In each of these studies, complete response was observed in less than half of the study population (Dhar et al. 2005; Montz et al. 2002). Given favorable side effect profiles, progestins or the LNG-IUD may be preferable for early stage patients. Primary radiation and chemotherapy for medically inoperable patients are alternative methods which, though effective, carry high rates of side effects and toxicities. In a consensus statement from the American Brachytherapy Society, Schwarz et al. recommend dosing uterus, cervix, and upper 1–2 cm of vagina with brachytherapy and combining this treatment with external beam radiation (Schwarz et al. 2015). The Society of Gynecologic Oncology makes a Level A recommendation for chemotherapy in advanced endometrial cancer of any cell type. Moreover, chemotherapy in combination with radiotherapy provides improved response over either modality alone (Burke et al. 2014a). Finally, in a recent study conducted by Slomovitz et al., patients who had failed 2 chemotherapy regimens were treated with an mTOR inhibitor and aromatase inhibitor combination. The study population achieved 40 % complete response with low toxicity (Slomovitz et al. 2015).

Medically Inoperable Patients 11

Medically inoperable patients fall into two groups: low-grade/early stage whose medical comorbidities preclude surgical management, and advanced stage cases with diffuse metastatic disease that is considered unresectable. Data gathered in younger populations desiring fertility can be extrapolated to women with severe comorbidities who have low-grade endometrial

Conclusion

Conservative management of endometrial cancer, particularly in women with low-grade, early stage disease is a timely issue that is becoming more prominent with the rising obesity epidemic. There is increasing evidence in support of therapies that are largely hormone based; however, patients must be counseled in detail regarding the potential risk for cancer recurrence and that definitive

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treatment with hysterectomy is still recommended when feasible. With careful patient selection and adequate surveillance, fertility can be preserved for many young endometrial cancer patients, and those who achieve response are likely to be able to conceive and bear children. Conservative therapy may also be a very reasonable option for patients with severe comorbidities who are deemed nonsurgical candidates. Future studies may identify additional therapies in addition to progesterone-based agents for the conservative treatment of endometrial cancer

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Cross-References

▶ Benign and Malignant Pathology of the Endometrium ▶ Diagnosis and Management of the Cancer of the Uterus ▶ Endometrial Hyperplasia ▶ Impact of Obesity on Gynecological Diseases ▶ Workup and Management of Polycystic Ovary Syndrome

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15 endometrial carcinoma: a Gynecologic Oncology Group Study. J Clin Oncol. 1996;14(2):357–61. Lindor NM, Petersen GM, Hadley DW, Kinney AY, Miesfeldt S, Lu KH, et al. Recommendations for the care of individuals with an inherited predisposition to Lynch syndrome: a systematic review. JAMA. 2006;296(12):1507–17. Lu KH, Dinh M, Kohlmann W, Watson P, Green J, Syngal S, et al. Gynecologic cancer as a “sentinel cancer” for women with hereditary nonpolyposis colorectal cancer syndrome. Obstet Gynecol. 2005;105 (3):569–74. Mariani A, Webb MJ, Keeney GL, Haddock MG, Calori G, Podratz KC. Low-risk corpus cancer: is lymphadenectomy or radiotherapy necessary? Am J Obstet Gynecol. 2000;182(6):1506–19. Matthews KS, Estes JM, Conner MG, Manne U, Whitworth JM, Huh WK, et al. Lynch syndrome in women less than 50 years of age with endometrial cancer. Obstet Gynecol. 2008;111(5):1161–6. Mazzon I, Corrado G, Masciullo V, Morricone D, Ferrandina G, Scambia G. Conservative surgical management of stage IA endometrial carcinoma for fertility preservation. Fertil Steril. 2010;93(4):1286–9. Mills AM, Liou S, Ford JM, Berek JS, Pai RK, Longacre TA. Lynch syndrome screening should be considered for all patients with newly diagnosed endometrial cancer. Am J Surg Pathol. 2014;38(11):1501–9. Minig L, Franchi D, Boveri S, Casadio C, Bocciolone L, Sideri M. Progestin intrauterine device and GnRH analogue for uterus-sparing treatment of endometrial precancers and well-differentiated early endometrial carcinoma in young women. Ann Oncol. 2011;22 (3):643–9. Montz FJ, Bristow RE, Bovicelli A, Tomacruz R, Kurman RJ. Intrauterine progesterone treatment of early endometrial cancer. Am J Obstet Gynecol. 2002;186 (4):651–7. NCCN. National Comprehensive Cancer Network: uterine neoplasms (Version 2.2016). 2015 11/20/2015. Report No.: Contract No.: 11/24/2015. Nevadunsky NS, Van Arsdale A, Strickler HD, Moadel A, Kaur G, Levitt J, et al. Obesity and age at diagnosis of endometrial cancer. Obstet Gynecol. 2014;124(2 Pt 1):300–6. Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of childhood and adult obesity in the United States, 2011–2012. JAMA. 2014;311(8):806–14.doi:10.1001/ jama.2014.732. Park JY, Nam JH. Progestins in the fertility-sparing treatment and retreatment of patients with primary and recurrent endometrial cancer. Oncologist. 2015;20 (3):270–8. Park JY, Kim DY, Kim JH, Kim YM, Kim KR, Kim YT, et al. Long-term oncologic outcomes after fertilitysparing management using oral progestin for young women with endometrial cancer (KGOG 2002). Eur J Cancer. 2013a;49(4):868–74.

16 Park JY, Kim DY, Kim TJ, Kim JW, Kim JH, Kim YM, et al. Hormonal therapy for women with stage IA endometrial cancer of all grades. Obstet Gynecol. 2013b;122(1):7–14. Park JY, Lee SH, Seong SJ, Kim DY, Kim TJ, Kim JW, et al. Progestin re-treatment in patients with recurrent endometrial adenocarcinoma after successful fertilitysparing management using progestin. Gynecol Oncol. 2013c;129(1):7–11. Park JY, Seong SJ, Kim TJ, Kim JW, Kim SM, Bae DS, et al. Pregnancy outcomes after fertility-sparing management in young women with early endometrial cancer. Obstet Gynecol. 2013d;121(1):136–42. Pronin SM, Novikova OV, Andreeva JY, Novikova EG. Fertility-sparing treatment of early endometrial cancer and complex atypical hyperplasia in young women of childbearing potential. Int J Gynecol Cancer. 2015;25(6):1010–4. Reeves GK, Pirie K, Beral V, Green J, Spencer E, Bull D, et al. Cancer incidence and mortality in relation to body mass index in the Million Women Study: cohort study. BMJ. 2007;335(7630):1134. Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet. 2008;371(9612):569–78. Saltzman BS, Doherty JA, Hill DA, Beresford SA, Voigt LF, Chen C, et al. Diabetes and endometrial cancer: an evaluation of the modifying effects of other known risk factors. Am J Epidemiol. 2008;167(5):607–14. Schwarz JK, Beriwal S, Esthappan J, Erickson B, Feltmate C, Fyles A, et al. Consensus statement for brachytherapy for the treatment of medically inoperable endometrial cancer. Brachytherapy. 2015;14 (5):587–99. Setiawan VW, Yang HP, Pike MC, McCann SE, Yu H, Xiang YB, et al. Type I and II endometrial cancers: have they different risk factors? J Clin Oncol. 2013;31 (20):2607–18.

L. Buckingham and E. Ko Shan BE, Ren YL, Sun JM, Tu XY, Jiang ZX, Ju XZ, et al. A prospective study of fertility-sparing treatment with megestrol acetate following hysteroscopic curettage for well-differentiated endometrioid carcinoma and atypical hyperplasia in young women. Arch Gynecol Obstet. 2013;288(5):1115–23. Slomovitz BM, Jiang Y, Yates MS, Soliman PT, Johnston T, Nowakowski M, et al. Phase II study of everolimus and letrozole in patients with recurrent endometrial carcinoma. J Clin Oncol. 2015;33 (8):930–6. Soliman PT, Oh JC, Schmeler KM, Sun CC, Slomovitz BM, Gershenson DM, et al. Risk factors for young premenopausal women with endometrial cancer. Obstet Gynecol. 2005;105(3):575–80. Truong PT, Kader HA, Lacy B, Lesperance M, MacNeil MV, Berthelet E, et al. The effects of age and comorbidity on treatment and outcomes in women with endometrial cancer. Am J Clin Oncol. 2005;28(2):157–64. Ushijima K, Yahata H, Yoshikawa H, Konishi I, Yasugi T, Saito T, et al. Multicenter phase II study of fertilitysparing treatment with medroxyprogesterone acetate for endometrial carcinoma and atypical hyperplasia in young women. J Clin Oncol. 2007;25(19):2798–803. Walsh C, Holschneider C, Hoang Y, Tieu K, Karlan B, Cass I. Coexisting ovarian malignancy in young women with endometrial cancer. Obstet Gynecol. 2005;106(4):693–9. Whitney CW, Brunetto VL, Zaino RJ, Lentz SS, Sorosky J, Armstrong DK, et al. Phase II study of medroxyprogesterone acetate plus tamoxifen in advanced endometrial carcinoma: a Gynecologic Oncology Group Study. Gynecol Oncol. 2004;92 (1):4–9. Wright JD, Buck AM, Shah M, Burke WM, Schiff PB, Herzog TJ. Safety of ovarian preservation in premenopausal women with endometrial cancer. J Clin Oncol. 2009;27(8):1214–9.

Management of Metastatic and Recurrent Cervical Cancer Seiji Mabuchi, Mahiru Kawano, Ryoko Takahashi, and Hiromasa Kuroda

Contents

11

1

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

2

Stage IVB Cervical Cancer . . . . . . . . . . . . . . . . . . . 2

3 3.1 3.2

Recurrent Cervical Cancer . . . . . . . . . . . . . . . . . . . 2 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

4

Invasive Cancer that is Detected After Simple Hysterectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

5

Cancer of the Cervical Stump . . . . . . . . . . . . . . . . 6

6

Cervical Bleeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

7

Invasive Cervical Cancer with Bulky Lymph Nodes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

8

Ureteral Obstruction . . . . . . . . . . . . . . . . . . . . . . . . . . 6

9 9.1 9.2 9.3 9.4 9.5 9.6 9.7

Cervical Cancer in Pregnancy . . . . . . . . . . . . . . . . Incidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Distribution by Stage . . . . . . . . . . . . . . . . . . . . . . . . . . . . Staging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6 6 6 7 7 7 7 8

10 10.1 10.2 10.3 10.4

Unusual Histological Types . . . . . . . . . . . . . . . . . . . Glassy Cell Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . Small Cell Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . Sarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

8 8 8 9 9

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

S. Mabuchi (*) • M. Kawano • R. Takahashi • H. Kuroda Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan e-mail: [email protected] # Springer International Publishing Switzerland 2016 D. Shoupe (ed.), Handbook of Gynecology, DOI 10.1007/978-3-319-17002-2_5-1

1

2

S. Mabuchi et al.

Abstract

Treatment guidelines for uterine cervical cancer have been established based on the findings of randomized clinical trials conducted in the past few decades. Although most cases of cervical cancer can be adequately managed with standard treatments, problems can arise in cases involving unusual presentations. Metastatic and recurrent cervical cancers are considered to be incurable. Although attempts have been made to treat patients with metastatic or recurrent cervical cancer with a variety of approaches including chemotherapy, radiotherapy, and surgery (as monotherapies or in combination), such patients have a dismal prognosis, with a reported 5-year survival rate of 10 mm (Kyrgiou et al. 2006).

2.2

Stage IA1 Disease with LVSI, Stage IA2 Disease, and Stage IB1 Disease

A previous report has shown that 8.2 % of stage IA1 patients with LVSI have lymph node

metastasis, compared with 0.8 % of those without LVSI (Mota 2003). Thus, pelvic lymphadenectomy should be included in the fertility-sparing surgical options for stage IA1 patients with LVSI. Radical trachelectomy plus pelvic lymphadenectomy or conization plus pelvic lymphadenectomy is recommended for childbearing women with stage IA1 disease and LVSI, stage IA2 disease, or stage IB1 disease.

2.2.1

Radical Trachelectomy Plus Pelvic Lymphadenectomy Regarding cases in which the patient wants to preserve their fertility, women with stage IA1 disease and LVSI, stage IA2 disease, or stage IB1 disease are indicated for radical trachelectomy plus pelvic lymphadenectomy. Radical trachelectomy can be performed either through a vaginal or abdominal approach and can also be carried out using laparoscopic or robotic methods. The criteria for radical trachelectomy vary slightly among institutions, but remain essentially unchanged from the original set proposed by Roy et al. in 1998 (Table 1) (Roy and Plante 1998). Although previous studies have shown that a tumor size of >2 cm is associated with increased risk of recurrence after radical trachelectomy (Marchiole et al. 2007; Mathevet et al. 2003; Plante et al. 2011), tumors that measure >2 cm, are very exophytic, and exhibit minimal stromal invasion might also be considered for radical trachelectomy. A previous study of radical trachelectomy for cervical cancer found that 28 % of cervical tumors Table 1 Criteria of radical trachelectomy 1. A desire for fertility 2. Histologically proven invasive cervical cancer 3. Squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma, without high-risk histology (e.g., neuroendocrine carcinoma) 4. Stage IA1 with lymphovascular space invasion, stage IA2, or stage IB1 5. Tumor size 2 cm 6. Tumor limited to the cervix 7. No evidence of lymph node metastasis and distant metastasis

Fertility-Sparing Treatment for Early-Stage Cervical Cancer

3

Table 2 Oncological outcomes according to surgical procedures Surgery VRT

ART

VRH

ARH

Author Year Burnett et al. 2003 Mathevet et al. 2003 Shepherd et al. 2006 Hertel et al. 2006 Marchiole et al. 2007 Beiner et al. 2008 Sonoda et al. 2008 Plante et al. 2011 Cao et al. 2013 Total Ungár et al. 2005 Abu-Rustum et al. 2008 Pareja et al. 2008 Nishio et al. 2009 Cibula et al. 2009 Yao et al. 2010 Saso et al. 2012 Muraji et al. 2012 Wethington et al. 2012 Cao et al. 2013 Total Steed et al. 2004 Jackson et al. 2004 Marchiole et al. 2007 Beiner et al. 2008 Total Roy et al. 1996 Steed et al. 2004 Jackson et al. 2004 Malzoni et al. 2009 Zhang et al. 2014 Total

No. of surgeries 21 109 123 108 118 90 43 125 71 765 30 22 15 61 17 10 30 23 93 55 356 71 50 139 90 350 27 205 50 62 90 434

Follow-up Months 31 76 45 29 95 51 21 93 34.4 47 12 32 27 21.2 NA 24 NA 32 20.6 17 52 113 58 27 21 49 71.5 12.5

Recurrences n (%) 2 (9.5) 4 (3.7) 5 (4.1) 4 (3.7) 7 (5.9) 5 (5.5) 1 (2.3) 6 (4.8) 7 (9.9) 41 (5.4) 0 (0) 0 (0) 0 (0) 6 (9.8) 1 (5.9) 0 (0) 3 (10) 0 (0) 4 (4.3) 0 (0) 14 (3.9) 4 (5.6) 2 (4.0) 9 (6.4) 1 (1.1) 16 (4.6) 1 (3.7) 13 (6.3) 2 (4.0) 4 (6.5) 0 (0) 20 (4.6)

Deaths n (%) 0 (0) 3 (2.8) 4 (3.3) 2 (1.9) 5 (4.2) 3 (3.3) 0 (0) 2 (1.6) 2 (2.8) 21 (2.6) 0 (0) 0 (0) 0 (0) NAa 0 (0) 0 (0) 2 (6.7) 0 (0) 0 (0) 0 (0) 2 (0.7)b NA 2 (4.0) 7 (5.0) 1 (1.1) 10 (3.6)c NA NA 2 (4.0) NA 0 (0) 2 (1.4)d

NA not available, VRT vaginal radical trachelectomy, ART abdominal radical trachelectomy, VRH vaginal radical hysterectomy, ARH abdominal radical hysterectomy a Three of six patients were lost to follow-up as of the time of the review b Estimated without the data of Nishio et al. 2009 c Estimated without the data of Steed et al. 2004 d Estimated with the data of Jackson et al. 2004 and Zhang et al. 2014

that are resected by radical trachelectomy exhibit LVSI and that LVSI is associated with an increased risk of recurrence (Beiner and Covens 2007). However, when LVSI is the only risk factor

present, it is not an exclusion criterion for radical trachelectomy, as it does not justify adjuvant therapy (Beiner and Covens 2007; Plante et al. 2011).

4

H. Kuroda et al.

2.2.2

Conization Plus Pelvic Lymphadenectomy Radical trachelectomy plus pelvic lymphadenectomy is a safer approach for stage IA1–IA2 disease when LVSI is present; however, conization plus pelvic lymphadenectomy might also be a useful treatment option (Maneo et al. 2011).

3

Outcomes

3.1

Surgical Outcomes

Approximately 10 % of planned radical trachelectomy procedures have to be abandoned because of the presence of lymph node metastasis on frozen sections or positive endocervical margins (Tables 3 and 4). In a previous study, the mortality rate of patients who underwent vaginal radical trachelectomy (VRT) was 3.1 %, which was comparable with the 0–1.4 % observed in patients that were treated with abdominal radical hysterectomy (ARH) or abdominal radical trachelectomy (ART) (Averette et al. 1993).

3.2

Oncological Outcomes

A previous study suggested that the oncological outcomes of patients who undergo ART or VRT are similar to those of patients treated with ARH. As shown in Table 2, these procedures result in recurrence and death rates of approximately 5 % and 2 %, respectively. According to a recent review of VRT, recurrent lesions can develop predominantly in the parametrium or pelvis (Beiner and Covens 2007).

3.3

Prognostic Factors

The risk factors for recurrence have been intensively investigated, and tumors that measure >2 cm in diameter are consistently associated with an increased risk of recurrence. In addition, some studies have suggested that the presence of LVSI (Marchiole et al. 2007; Mathevet et al. 2003;

Plante et al. 2011) and deep stromal invasion (DSI) of >10 mm (Diaz et al. 2008) are risk factors for recurrence; however, others have found that they are not associated with a higher risk of recurrence (Hertel et al. 2006; Plante et al. 2011). Although the prognostic significance of LVSI and DSI needs to be investigated further in larger studies, they are not considered to be contraindications for radical trachelectomy at this point. As neuroendocrine tumors are an aggressive subtype of cervical cancer and often recur rapidly, even if they have been completely removed and there is no lymph node or distant metastasis, radical trachelectomy cannot be recommended for women with this histological subtype of cervical cancer (Beiner and Covens 2007; Marchiole et al. 2007).

4

Surgical Procedures

The first successful trachelectomy procedure was performed via a vaginal approach by Dargent et al. in 1986, and the oncological and reproductive outcomes of patients who underwent VRT were presented at the Society of Gynecologic Oncologists meeting in 1994 (Ribeiro Cubal et al. 2012). A laparoscopic pelvic lymph node evaluation should be performed prior to VRT to rule out lymph node metastasis. The abdominal approach was first reported by Smith et al. in 1997 (Ribeiro Cubal et al. 2012). The main advantages of ART are its greater radicality and feasibility compared with VRT. Basically, the procedure for radical trachelectomy begins with the creation of paravesical and pararectal spaces and the dissection of the caudal bladder. Then, after the vesicouterine ligaments and cardinal ligaments have been divided, the cervix is removed. Finally, the uterine corpus and vaginal stump are reconstructed. The endocervical margin of the specimen needs to be evaluated after the cervix has been removed to ensure that no residual disease remains. It is well known that the outcomes of post-conization pregnancies are influenced by the depth and size of the excised cervical tissue

19

95

106

16

41

13

158

NA

125

14

212

120

929

21

108

108

16

43

15

158

135

140

14

NA

NA

770

NA not available

10

12

Schlaerth et al. 2003 Burnett et al. 2003 Mathevet et al. 2003 Hertel et al. 2006 Chen et al. 2008 Sonoda et al. 2008 Pahisa et al. 2008 Shepherd and Milliken 2008 Diaz et al. 2008 Plante et al. 2011 DańskaBidzińska et al. 2011 Speiser et al. 2011 Hauerberg et al. 2015 Total number

Trachelectomy done

No. of planned trachelectomies

Author (year)

1006

108

212

14

122

118

138

13

36

16

106

95

18

10

Fertility preserved

159

72

76

NA

NA

NA

NA

NA

11

NA

NA

NA

NA

NA

Attempting to conceive

275

55

50

2

58

33

NA

3

11

5

18

33

3

4

Pregnant women

Table 3 Reproductive outcomes for patients who underwent vaginal radical trachelectomy

489

77

60

2

106

56

88

3

11

5

18

56

3

4

Pregnancies

96

16

5

1

21

14

19

0

3

0

3

14

0

41

2

3

0

3

8

12

0

0

2

0

8

1

Miscarriages 1st 2nd trimester trimester 0 2

195

20

27

1

58

29

19

1

4

1

4

29

1

116

33

18

0

19

5

25

0

0

1

8

5

1

Deliveries At term Preterm 1 1

24

3

4

0

0

NA

7

2

4

1

3

0

0

0

Patients pregnant at the time of report

Fertility-Sparing Treatment for Early-Stage Cervical Cancer 5

30

15

10

61

20

10 62 60 24

30

21

81

8

432

15

10

71

24

10 64 68 25

30

23

101

8

482

Trachelectomy done

33

No. of planned trachelectomies

NA not available a The timing of miscarriage was not described b The timing of delivery was not described

Ungár et al. 2005 Pareja et al. 2008 Olawaiye et al. 2009 Nishio et al. 2009 Cibula et al. 2009 Yao et al. 2010 Li et al. 2011 Du et al. 2011 Nick et al. 2012 Saso et al. 2012 Muraji et al. 2012 Wethington et al. 2012 Karateke and Kabaca 2012 Total

Author (year)

NA 120

346

38

NA

10

NA 10 15 NA

9

29

3

6

NA

Attempting to conceive

8

70

20

NA

10 59 60 21

17

57

10

14

NA

Fertility preserved

63

3

28

1

3

2 2 5 NA

6

4

3

3

3

Pregnant women

Table 4 Reproductive outcomes for patients who underwent abdominal radical trachelectomy

72

3

31

1

3

2 2 8 3

6

4

3

3

3

Pregnancies

7

0

3

0

0

0 0 1a 1

1

0

1

0

9

1

6

0

1

1

0 0

0

0

0

0

Miscarriages 1st 2nd term term 1 0

17

1

16b

0

2

1 1 3 0

2

2

1

2

13

1

1

0

1 0 2 1

3

2

1

1

Deliveries At term Preterm 2 0

9

0

6

0

0

0 1 2 0

0

0

0

0

0

Patients pregnant at the time of report

6 H. Kuroda et al.

Fertility-Sparing Treatment for Early-Stage Cervical Cancer

specimen (Kyrgiou et al. 2006), which also holds true for post-radical trachelectomy pregnancies. As a shorter cervix can provide an easy route for ascending infections, which increase the risk of premature delivery, most clinicians aim to preserve at least 5 mm–1 cm of the endocervix during both procedures. There is no clear consensus regarding whether cervicoisthmic cerclage should be performed during radical trachelectomy or only after a patient has become pregnant. Radical trachelectomy can also be performed via either a laparoscopic (Marchiole et al. 2007) or robotic approach (Persson et al. 2008). A previous retrospective study involving a relatively small number of patients suggested that these approaches are feasible, less invasive, and similarly effective, i.e., achieve comparable oncological outcomes, to conventional vaginal or abdominal approaches (Marchiole et al. 2007).

5

7

dyspareunia, dysmenorrhea, prolonged amenorrhea, and chronic discharge. Similar rates of these complications are seen after VRT and ART (Beiner and Covens 2007; Cao et al. 2013; Pareja et al. 2013).

6

Adjuvant Treatments

The recommendations for post-trachelectomy adjuvant therapy are based on the presence/ absence of pathological risk factors, such as nodal metastasis, parametrial involvement, LVSI, or DSI. Clinicians have to recognize that adjuvant radiotherapy affects patients’ fertility (Beiner and Covens 2007; Hertel et al. 2006; Marchiole et al. 2007). Chemotherapy is an alternative adjuvant therapy. However, the clinical efficacy of adjuvant chemotherapy remains unclear.

Surgical Complications 7

The intraoperative complications rate of VRT seems to be higher than that of ART (5.6 % vs. 0.7 %) (Pareja et al. 2013; Plante et al. 2011). The most common intraoperative complication of VRT is urinary tract damage. However, in comparisons of laparoscopic-assisted VRT versus laparoscopic-assisted vaginal radical hysterectomy (Marchiole et al. 2007) or ART versus ARH (Cao et al. 2013), all of the procedures exhibited similar perioperative complication rates, indicating that radical trachelectomy can be performed safely in carefully selected cases of early-stage cervical cancer. The immediate postoperative complications associated with radical trachelectomy include bladder dysfunction, lymphedema, and lymphocele, which are comparable to the complications associated with RH (Pareja et al. 2013). In addition, the specific long-term postoperative complications associated with radical trachelectomy include cervical stenosis,

Radical Trachelectomy for Tumors Larger Than 2 cm in Diameter

As the ART is more radical than VRT (Ungár et al. 2005; Wethington et al. 2012), it might have broader indications than other types of trachelectomy. However, in patients with larger tumors, radiotherapy is often indicated postoperatively because of the patient’s pathological risk factors, which usually results in a loss of fertility. Neoadjuvant chemotherapy (NACT) is the only way to reduce the size of cervical tumors, which might allow some patients with bulky tumors to undergo radical trachelectomy. Recent retrospective studies have suggested that NACT followed by radical trachelectomy is feasible and effective (Plante 2015). However, the oncological and reproductive issues have not been fully investigated. To draw a definitive conclusion regarding the benefits of NACT, further large-scale prospective studies are needed.

8

8

H. Kuroda et al.

Hysterectomy in the PostChildbearing Period

So far, there is no evidence that hysterectomy has beneficial effects in patients that do not want any more children.

9

Reproductive Issues

9.1

Fertility Issues

There is no clear consensus about the optimal interval between radical trachelectomy and attempts to get pregnant. However, as the tissue healing process can last at least 3 months, most authors suggest that patients should wait for 6–12 months before attempting to get pregnant. Fertility might be impaired after radical trachelectomy because of anatomical and physiological changes, such as adhesion, cervical stenosis, and a loss of cervical function. In addition, the impact of pre-radical trachelectomy NACT on fertility remains unknown; however, a retrospective study found that 50 % of patients who received NACT followed by trachelectomy and retained their fertility subsequently became pregnant (Robova et al. 2014). The pregnancy outcomes seen in previous studies are summarized in Tables 3 and 4. Among the women who attempted to get pregnant after VRT, 73.0 % (116 out of 159 women) were able to conceive, which is higher than the 45 % (54 out of 120 women) observed in the women who underwent ART. The reasons for the worse fertility outcomes of the ART group remain to be elucidated.

9.2

Obstetric Outcomes

Clinicians should inform patients who undergo radical trachelectomy that post-radical trachelectomy pregnancies are associated with an increased risk of obstetric complications. As shown in Tables 3 and 4, the first-trimester miscarriage rate was 19.6 % (96 of

489 pregnancies) in the VRT group and 11.0 % (7 of 64 pregnancies) in the ART group, which are comparable to those of the general population. However, the second-trimester miscarriage rates of the patients in the VRT (8.4 %; 41 out of 489 pregnancies) and ART groups (14.1 %; 9 out of 64 pregnancies) were higher than that observed in the general population. Of the women who reached the third trimester, roughly two-thirds delivered their babies at term, and the remaining women (37.8 %) delivered prematurely (Tables 3 and 4). At present, there are no effective interventions for preventing preterm labor or preterm premature rupture of membranes.

9.3

Cesarean Section for Women Who Undergo Radical Trachelectomy

Cesarean section should be selected as the mode of delivery after radical trachelectomy. However, the optimal timing of cesarean section remains unclear. Moreover, it is disputed whether a low transverse incision or a low vertical incision should be performed in such cases.

10

Oocyte Cryopreservation for Women with Advanced Disease

Oocyte cryopreservation has been proposed to be an option for patients who are at risk of infertility due to RH or gonadotoxic adjuvant treatment. However, it is recommended that patients should be counseled about the current lack of data about the efficacy, risks, and costs of oocyte cryopreservation (Oocyte cryopreservation. Committee Opinion No. 584. American College of Obstetricians and Gynecologists).

11

Conclusion

Previous studies have shown that trachelectomy is a safe and feasible procedure and produces good oncological and reproductive outcomes in

Fertility-Sparing Treatment for Early-Stage Cervical Cancer

patients with early-stage cervical cancer. To optimize the fertility and oncological outcomes of such patients, the strict indications for radical trachelectomy should be emphasized.

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9 Du XL, Sheng XG, Jiang T, Li QS, Yu H, Pan CX, Lu CH, Wang C, Song QQ. Sentinel lymph node biopsy as guidance for radical trachelectomy in young patients with early stage cervical cancer. BMC Cancer. 2011;11:157. Hauerberg L, Høgdall C, Loft A, Ottosen C, Bjoern SF, Mosgaard BJ, Nedergaard L, Lajer H. Vaginal radical trachelectomy for early stage cervical cancer. Results of the Danish National Single Center Strategy. Gynecol Oncol. 2015;S0090-8258(15)30001-9. Hertel H, Köhler C, Grund D, Hillemanns P, Possover M, Michels W, Schneider A, German Association of Gynecologic Oncologists (AGO). Radical vaginal trachelectomy (RVT) combined with laparoscopic pelvic lymphadenectomy: prospective multicenter study of 100 patients with early cervical cancer. Gynecol Oncol. 2006;103(2):506–11. Jackson KS, Das N, Naik R, Lopes AD, Godfrey KA, Hatem MH, Monaghan JM. Laparoscopically assisted radical vaginal hysterectomy vs. radical abdominal hysterectomy for cervical cancer: a match controlled study. Gynecol Oncol. 2004;95(3):655–61. Karateke A, Kabaca C. Radical abdominal trachelectomy is a safe and fertility preserving option for women with early stage cervical cancer. Eur J Gynaecol Oncol. 2012;33(2):200–3. Kyrgiou M, Koliopoulos G, Martin-Hirsch P, Arbyn M, Prendiville W, Paraskevaidis E. Obstetric outcomes after conservative treatment for intraepithelial or early invasive cervical lesions: systematic review and metaanalysis. Lancet. 2006;367:489–98. Li J, Li Z, Wang H, Zang R, Zhou Y, Ju X, Ke G, Wu X. Radical abdominal trachelectomy for cervical malignancies: surgical, oncological and fertility outcomes in 62 patients. Gynecol Oncol. 2011;121 (3):565–70. Malzoni M, Tinelli R, Cosentino F, Fusco A, Malzoni C. Total laparoscopic radical hysterectomy versus abdominal radical hysterectomy with lymphadenectomy in patients with early cervical cancer: our experience. Ann Surg Oncol. 2009;16(5):1316–23. Maneo A, Sideri M, Scambia G, Boveri S, Dell’anna T, Villa M, Parma G, Fagotti A, Fanfani F, Landoni F. Simple conization and lymphadenectomy for the conservative treatment of stage IB1 cervical cancer. An Italian experience. Gynecol Oncol. 2011;123:557–60. Marchiole P, Benchaib M, Buenerd A, Lazlo E, Dargent D, Mathevet P. Oncological safety of laparoscopicassisted vaginal radical trachelectomy (LARVT or Dargent’s operation): a comparative study with laparoscopic-assisted vaginal radical hysterectomy (LARVH). Gynecol Oncol. 2007;106(1):132–41. Mathevet P, Laszlo de Kaszon E, Dargent D. Fertility preservation in early cervical cancer. Gynecol Obstet Fertil. 2003;31(9):706–12. Mota F. Microinvasive squamous carcinoma of the cervix: treatment modalities. Acta Obstet Gynecol Scand. 2003;82(6):505–9.

10 Muraji M, Sudo T, Nakagawa E, Ueno S, Wakahashi S, Kanayama S, Yamada T, Yamaguchi S, Fujiwara K, Nishimura R. Type II versus type III fertility-sparing abdominal radical trachelectomy for early-stage cervical cancer: a comparison of feasibility of surgical outcomes. Int J Gynecol Cancer. 2012;22(3):479–83. National Cancer Institute: Browse the SEER Cancer Statistics Review (CSR) 1975–2010. Available from http:// seer.cancer.gov/archive/csr/1975_2010/browse_csr. php?sectionSEL=5&pageSEL=sect_05_table.07.html Nick AM, Frumovitz MM, Soliman PT, Schmeler KM, Ramirez PT. Fertility sparing surgery for treatment of early-stage cervical cancer: open vs. robotic radical trachelectomy. Gynecol Oncol. 2012;124(2):276–80. Nishio H, Fujii T, Kameyama K, Susumu N, Nakamura M, Iwata T, Aoki D. Abdominal radical trachelectomy as a fertility-sparing procedure in women with early-stage cervical cancer in a series of 61 women. Gynecol Oncol. 2009;115(1):51–5. Olawaiye A, Del Carmen M, Tambouret R, Goodman A, Fuller A, Duska LR. Abdominal radical trachelectomy: Success and pitfalls in a general gynecologic oncology practice. Gynecol Oncol. 2009;112(3):506–10. Oocyte cryopreservation. Committee opinion no. 584. American College of obstetricians and gynecologists. Obstet Gynecol. 2014;123:221–2. Pahisa J, Alonso I, Torné A. Vaginal approaches to fertilitysparing surgery in invasive cervical cancer. Gynecol Oncol. 2008;110:S29–32. Pareja FR, Ramirez PT, Borrero FM, Angel CG. Abdominal radical trachelectomy for invasive cervical cancer: a case series and literature review. Gynecol Oncol. 2008;111(3):555–60. Pareja R, Rendón GJ, Sanz-Lomana CM, Monzón O, Ramirez PT. Surgical, oncological, and obstetrical outcomes after abdominal radical trachelectomy – a systematic literature review. Gynecol Oncol. 2013;131 (1):77–82. Persson J, Kannisto P, Bossmar T. Robot-assisted abdominal laparoscopic radical trachelectomy. Gynecol Oncol. 2008;111(3):564–7. Plante M. Bulky early-stage cervical cancer (2–4 cm lesions): upfront radical trachelectomy or neoadjuvant chemotherapy followed by fertility-preserving surgery: which is the best option? Int J Gynecol Cancer. 2015;25(4):722–8. Plante M, Gregoire J, Renaud MC, Roy M. The vaginal radical trachelectomy: an update of a series of 125 cases and 106 pregnancies. Gynecol Oncol. 2011;121 (2):290–7. Ribeiro Cubal AF, Ferreira Carvalho JI, Costa MF, Branco AP. Fertility-sparing surgery for early-stage cervical cancer. Int J Surg Oncol. 2012;2012:936534. Robova H, Halaska MJ, Pluta M, Skapa P, Matecha J, Lisy J, Rob L. Oncological and pregnancy outcomes after high-dose density neoadjuvant chemotherapy and fertility-sparing surgery in cervical cancer. Gynecol Oncol. 2014;135(2):213–6.

H. Kuroda et al. Roy M, Plante M. Pregnancies after radical vaginal trachelectomy for early-stage cervical cancer. Am J Obstet Gynecol. 1998;179:1491–6. Roy M, Plante M, Renaud MC, Têtu B. Vaginal radical hysterectomy versus abdominal radical hysterectomy in the treatment of early-stage cervical cancer. Gynecol Oncol. 1996;62(3):336–9. Saso S, Ghaem-Maghami S, Chatterjee J, Naji O, Farthing A, Mason P, McIndoe A, Hird V, Ungar L, Del Priore G, Smith JR. Abdominal radical trachelectomy in West London. BJOG. 2012;119(2):187–93. Schlaerth JB, Spirtos NM, Schlaerth AC. Radical trachelectomy and pelvic lymphadenectomy with uterine preservation in the treatment of cervical cancer. Am J Obstet Gynecol. 2003;188(1):29–34. Shepherd JH, Milliken DA. Conservative surgery for carcinoma of the cervix. Clin Oncol (R Coll Radiol). 2008;20(6):395. Shepherd JH, Spencer C, Herod J, Ind TE. Radical vaginal trachelectomy as a fertility-sparing procedure in women with early-stage cervical cancer-cumulative pregnancy rate in a series of 123 women. BJOG. 2006;113(6):719–24. Sonoda Y, Chi DS, Carter J, Barakat RR, Abu-Rustum NR. Initial experience with Dargent’s operation: the radical vaginal trachelectomy. Gynecol Oncol. 2008;108(1):214–9. Speiser D, Mangler M, Köhler C, Hasenbein K, Hertel H, Chiantera V, Gottschalk E, Lanowska M. Fertility outcome after radical vaginal trachelectomy: a prospective study of 212 patients. Int J Gynecol Cancer. 2011;21 (9):1635–9. Steed H, Rosen B, Murphy J, Laframboise S, De Petrillo D, Covens A. A comparison of laparoscopic-assisted radical vaginal hysterectomy and radical abdominal hysterectomy in the treatment of cervical cancer. Gynecol Oncol. 2004;93(3):588–93. Ungár L, Pálfalvi L, Hogg R, Siklós P, Boyle DC, Del Priore G, Smith JR. Abdominal radical trachelectomy: a fertility-preserving option for women with early cervical cancer. BJOG. 2005;112(3):366–9. Wethington S, Cibula D, Duska LR, Garrett L, Kim CH, Chi DS, Sonoda Y, Abu-Rustum NR. An international series on abdominal radical trachelectomy: 101 patients and 28 pregnancies. Int J Gynecol Cancer. 2012;22 (7):1251–7. Wright JD, NathavithArana R, Lewin SN, Sun X, Deutsch I, Burke WM, Herzog TJ. Fertility-conserving surgery for young women with stage IA1 cervical cancer: safety and access. Obstet Gynecol. 2010;115(3):585–90. Yao T, Mo S, Lin Z. The functional reconstruction of fertility-sparing radical abdominal trachelectomy for early stage cervical carcinoma. Eur J Obstet Gynecol Reprod Biol. 2010;151(1):77–81. Zhang D, Li J, Ge H, Ju X, Chen X, Tang J, Wu X. Surgical and pathological outcomes of abdominal radical trachelectomy versus hysterectomy for early-stage cervical cancer. Int J Gynecol Cancer. 2014;24(7):1312–8.

Management of Cervical Dysplasia Katherine E. Tierney, Lynda D. Roman, and Koji Matsuo

Abstract

Contents 1

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2

2

Cervical Cytology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2

3 Human Papillomavirus . . . . . . . . . . . . . . . . . . . . . . . . 3.1 Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3 3

4

Management of Abnormal Screening Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1 Colposcopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4 4

5 5.1 5.2 5.3 5.4 5.5

Types of Cervical Dysplasia . . . . . . . . . . . . . . . . . . . Cervical Intraepithelial Neoplasia . . . . . . . . . . . . . . Adenocarcinoma In Situ . . . . . . . . . . . . . . . . . . . . . . . . Management of Dysplasia . . . . . . . . . . . . . . . . . . . . . . Special Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . Human Papillomavirus Prevention . . . . . . . . . . . . .

5 5 5 6 9 9

6

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

7

Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

K.E. Tierney (*) Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Kaiser Permanente Orange County, California, Irvine, CA, USA e-mail: [email protected]; [email protected] L.D. Roman (*) • K. Matsuo (*) Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA e-mail: [email protected]; [email protected] # Springer International Publishing AG 2016 D. Shoupe (ed.), Handbook of Gynecology, DOI 10.1007/978-3-319-17002-2_7-1

Abnormal cervical screening tests are diagnosed in millions of women each year in the United States. In some, the abnormality is indicative of cervical dysplasia or even invasive cervical cancer. The work-up of an abnormal cervical screening test includes colposcopy and cervical biopsies. Based on those results, treatment for cervical dysplasia can consist of observation or intervention with an excisional biopsy. In deciding to intervene aggressively, one must consider special circumstances including patient age, desire for future fertility, and concurrent pregnancy. Understanding the role human papillomavirus (HPV) plays in cancer development has led to advancements in detection and treatment of cervical dysplasia. Both preventative and therapeutic vaccinations against HPV provide promise in decreasing the number of women affected by this disease. This chapter highlights key changes in the recent ASCCP guidelines including the importance of conservative management among younger women as well as recommendations on the proper utilization of HPV cotesting. The rationale for HPV vaccination is also discussed. Keywords

Human papillomavirus • Cervical intraepithelial neoplasia • Adenocarcinoma in situ • Loop electrosurgical excision procedure • Cold-knife cone 1

2

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K.E. Tierney et al.

Introduction

Since the 1940s, the Pap smear has provided practitioners an opportunity to diagnose cervical dysplasia and prevent cancer development. From 1973 to 2007, invasive cervical cancer incidence declined by 54 % in the United States (Adegoke et al. 2012). Furthermore, coordinated testing for human papillomavirus (HPV) has enabled healthcare providers the ability to appropriately triage patients based on risk. HPV infection is common and does not always cause cervical dysplasia; however, recognition and early intervention of high-risk HPV-related changes may prevent progression to cancer. In addition, early administration of vaccines against certain types of high-risk HPV could diminish the number of people diagnosed with cervical cancer precursors (BaldurFelskov et al. 2014). In the United States, there are an estimated two million abnormal cytology tests each year (Insinga et al. 2004). Among these women, 175,000 cervical intraepithelial neoplasia (CIN) 1 and 225,000 CIN 2/CIN 3 diagnoses are made. Progression from CIN to invasive cervical cancer is a slow process taking between 8.1 and 12.6 years for CIN 3 to progress to invasive cancer (ACOG Bulletin #140, December 2013). Despite advancements in the diagnosis and treatment of cervical dysplasia, cervical cancer continues to claim more than 4,000 lives each year in the United States http://seer.cancer.gov/statfacts/ html/cervix.html. The body of knowledge on HPV, cervical dysplasia, and cervical cancer continues to grow bringing potential to decrease the number of deaths from cervical cancer each year. The focus of this chapter is to provide readers with the most pertinent information on cervical dysplasia and, in turn, enable them to impart accurate and helpful information on their patients.

2

Cervical Cytology

Cervical cytology refers to cells that are obtained from the surface of the cervix and ideally include cells from the transformation zone of the cervix.

Using a spatula and/or brush, cellular material from the cervix can be either spread and fixed directly onto a slide or transferred into a fixative liquid. In detecting precancerous lesions, the conventional Pap test using a slide- and liquid-based cytology proves to be equally sensitive and specific (Arbyn et al. 2008). Overall, sensitivity and specificity for cytologic testing for cervical dysplasia are about 60 % and 70 %, respectively (Nanda et al. 2000). In an effort to standardize diagnosis and treatment, Bethesda 2001 developed terminology in the evaluation of cervical cytology. Management guidelines are based on these interpretations. The following information is adapted from the 2001 Bethesda system (Solomon et al. 2002). For any given cytologic sample, pathologists provide information on specimen adequacy and give an interpretation/result. Adequacy refers to whether the specimen is satisfactory for evaluation or unsatisfactory for evaluation. Interpretation can either reflect that the specimen is “negative for intraepithelial lesion or malignancy” or specify a type of epithelial cell abnormality. The most common cytologic abnormality is “atypical squamous cells” (ASC). Women with ASC have a 10–20 % risk of underlying CIN 2–3 and 1 in 1000 risk of invasive cancer. The category is further subdivided between “atypical squamous cells of undetermined significance” (ASC-US) and “cannot exclude HSIL” (ASC-H) (Solomon et al. 2002). Squamous intraepithelial lesions are categorized in a two-tier system. Low-grade squamous intraepithelial lesions (LSIL) refer to mild dysplastic or HPV-related changes and frequently correspond to a histologic diagnosis of CIN 1. High-grade squamous intraepithelial lesions (HSIL) refer to moderate and severe dysplasia and typically correspond to a histologic diagnosis of CIN 2 or CIN 3. Squamous cell carcinoma can be detected by cytology; however, confirmation should be pursued with a biopsy for histologic diagnosis (Solomon et al. 2002). Atypical glandular cells (AGC) refer to a glandular abnormality that could be arising from the cervix, endocervix, or endometrium. This diagnosis reflects a high-grade abnormality in 10–39 %

Management of Cervical Dysplasia

of cases. “Atypical glandular cells, favor neoplastic,” endocervical adenocarcinoma in situ (ACIS), and adenocarcinoma are other examples of diagnoses included in this standard terminology (Solomon et al. 2002). According to the American College of Obstetricians and Gynecologists (ACOG), cervical cancer screening with cervical cytology should being at age 21 regardless of age at coitarche. Between the ages of 21 and 29, cytology testing alone can be done every 3 years. After age 30, cytology alone every 3 years or combined cytology and HPV cotesting every 5 years can be recommended. In the absence of a history of abnormal cytology, screening can stop at age 65. If a patient undergoes hysterectomy for a benign gynecologic indication without history of cervical dysplasia, cervical cancer screening can be stopped after hysterectomy.

3

Human Papillomavirus

Papillomaviruses are a double-stranded, circular DNA genome virus with more than 100 different described subtypes. The viral DNA is divided into three regions: upstream regulatory region, early region, and late region. The early region of the genome includes six open reading frames, and, of these, E6 and E7 are required for the development of invasive cervical cancer. The E7 protein binds to the tumor suppressor retinoblastoma (Rb) gene blocking suppression and allowing cell proliferation. The E6 protein binds and degrades tumor suppressor P53 resulting in blockage of apoptosis and increased cell proliferation (Wright 2009). HPV types 16 and 18 are present in 70 % of diagnosed squamous cell carcinomas and over 80 % of adenocarcinomas (de Sanjose et al. 2010). Persistent HPV is essential for the development of cervical cancer precursors and invasive cancer. When compared to cytology, high-risk HPV testing has proven to have higher sensitivity and reproducibility but less specificity (ACOG Bulletin #140, December 2013). At this time, HPV panels only detect a finite number of high-risk HPV types. Not all tests specify the exact HPV

3

type that is positive in the panel, i.e., genotype. According to the College of American Pathologists, the most common indication for HPV testing remains reflex testing after ASC-US cytology; however, laboratories are reporting a general increase in the rate of cotesting (Zhao et al. 2015). Transmission of HPV occurs via sexual exposure. Breaks in the skin and mucosal surfaces are susceptible to infection with the cervix being the most common site of transmission. Although condom use is still recommended for protection against HPV, external genitalia are susceptible to microtrauma and infection; thus, condom use is less protective than it is against other sexually transmitted infections. Vertical transmission from mother to infant is possible; however, the neonate can clear the vast majority of these infections within the first year of life (Erickson et al. 2013). Overall prevalence of high-risk HPV is reported to be between 12 % and 15 % (Wright et al. 2012). The prevalence of HPV is highest in women 21–24 years old with a second spike occurring after menopause (Wright et al. 2012; Erickson et al. 2013). Most HPV infections will clear spontaneously; however, some infections will persist and cause cellular changes. Young women are more likely to clear HPV than older women. The clearance rate within 1 year of infection ranges from 40 % to 70 % and can reach a 2–5-year clearance rate of 100 % in young women (Erickson et al. 2013). Certain types of HPV are more virulent and are more likely to be persistent than other types. HPV 16 and HPV 18 are the most common HPV subtypes found in carcinoma of the cervix and found to be the most persistent (Wheeler 2013). HPV types considered to be oncogenic include 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59 (Erickson et al. 2013).

3.1

Risk Factors

Risk factors for the development of dysplasia and invasive cervical cancer are interlinked with HPV infection and clinical conditions that make patients more susceptible to infection with HPV. Risk factors associated with HPV infection in

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K.E. Tierney et al.

women include number of lifetime male sexual partners, early-onset sexual activity, coinfection with other sexually transmitted diseases, and current smoking (Erickson et al. 2013). Since HPV activity is dependent on the host immune system, immunosuppressed patients infected with HPV are at increased risk of developing cervical dysplasia and invasive cervical cancer. Immunosuppressed patients include patients with HIV, autoimmune disease, those who are status post organ transplant, and others who require chronic immunosuppressive therapies. These patients are recommended to have more frequent screening evaluation. Current recommendations are to screen these patients every 6 months for the first year after diagnosis of immunocompromised status followed by annual screening (Nguyen and Flowers 2013).

4

Management of Abnormal Screening Tests

The following management guidelines are based on the findings in the 2006 consensus guidelines for the management of women with abnormal cervical cancer screening tests and the ACOG Practice Bulletin on the management of abnormal cervical cancer screening test results and cervical cancer precursors (Wright 2007; ACOG Bulletin #140, December 2013; ASCCP guidelines). Most abnormal cytology results will require further evaluation of the cervix with colposcopy. The following are examples of abnormal results that do not require immediate colposcopy: • For a woman older than 30 years of age with negative cervical cytology and her first positive HPV test, the ASCCP recommendation is to repeat cotesting in 1 year and proceed with colposcopy if cytology is abnormal or HPV remains positive at 1-year follow-up. • For women with ASC-US cytology and a negative HPV test, ACOG recommends repeat cytology with HPV testing in 3 years. • For women between the ages of 21 and 24 with ASC-US or LSIL, HPV testing can be done. The patient should have repeat

cytology 1 year after the test if positive and repeat cytology in 3 years if the test is negative. • Unsatisfactory cytology with negative or unknown HPV results can be repeated in 2–4 months. Two consecutive unsatisfactory cytology results warrant evaluation with colposcopy. Algorithms for the management of specific screening test results are available at the ASCCP website (http://www.asccp.org/Guidelines) and can also be downloaded as an application for mobile devices.

4.1

Colposcopy

Colposcopy is microscopic examination of the cervix under low power magnification after application of acetic acid. The goal of this procedure is to visually detect any cervical changes suspicious for precancerous transformation. The procedure consists of a speculum exam during which gauze is soaked with 3–5 % acetic acid and placed directly on the cervix for approximately 30 s to 1 min. After exposure to acetic acid, a reversible reaction occurs causing the abnormal cells to swell and turn white due to hyperchromatin within the nucleus of the dysplastic cells. Identification of acetowhite epithelium (AWE) allows for directed biopsies of suspicious lesions. The transformation zone is identified, and a small cotton-tipped swab can be used to manipulate the cervical canal and identify whether the AWE extends into the canal. An endocervical speculum can be used for this part of the procedure. Other abnormal features to note include punctation, mosaic patterns that suggest underlying highgrade dysplasia, and abnormal neovascularization that could be an indication of possible invasive cancer. In addition to the cervix, the upper vagina should be examined. Directed biopsies are performed with a sharp cervical biopsy device. A sharper device will lead to less manipulation and stretch of the cervical fibers and diminish pain. Bleeding is a risk of this procedure. Silver

Management of Cervical Dysplasia

nitrate and Monsel solution can be used to hamper bleeding; however, spotting and brown discharge are common after biopsies. Excellent photographs and additional descriptions of colposcopic findings can be found in text by Baggish (2003). Even if colposcopic examination is negative for any abnormal findings, a single random biopsy can increase detection of high-grade disease in high-risk HPV-positive patients (Huh et al. 2014). It remains unclear why some lesions are not visible colposcopically and whether this reflects a difference in the biological or clinical nature of non-visible lesions as compared with visible lesions. Ultimately, studies show that colposcopy has similar sensitivity and specificity when compared to cervical cytology in detecting high-grade lesions. Women with limited access to screening cytology in under-resourced countries that cannot afford to implement routine HPV testing may benefit from immediate colposcopic examination. The limitation of “see-and-treat” methodology remains the possibility of overtreating (Nooh et al. 2015).

5

Types of Cervical Dysplasia

5.1

Cervical Intraepithelial Neoplasia

Cervical intraepithelial neoplasia (CIN) is a term used to describe a continuum of dysplastic changes in cervical intraepithelial tissue. These changes are precursors to cervical cancer development. The continuum consists of mild, moderate, and severe cellular changes referred to as CIN 1, 2, and 3, respectively. A histopathologic diagnosis of CIN depends on the level of nuclear abnormality, mitotic activity, and level of differentiation (Robboy et al. 2002). In CIN 1, extensive differentiation can be seen in the upper two-thirds of the cervical epithelium. There is minimal amount of nuclear atypia and few, if any, mitotic figures that are located in the basal third of the epithelium (Robboy et al. 2002). CIN 1 has a high rate of regression and can be managed conservatively with repeat cytology and HPV testing 12 months after initial

5

diagnosis. Patients should be counseled that this lesion usually represents a transient HPV infection and has very low premalignant potential. Over a period of 2 years, the risk of progression of CIN 1 to CIN 2 was 13 %, and the risk of progression of CIN 1 to CIN 3 was 8.9 % (ALTS 2003). If a patient has persistent CIN 1 for over 2 years, observation or excision is acceptable. Excision is recommended if the transformation zone cannot adequately be evaluated on colposcopy. In addition, if CIN 1 was found on endocervical curettage (ECC) at the time of colposcopy, ECC should be performed with the subsequent cytologic sampling (ACOG Bulletin #140, December 2013). In CIN 2, mitotic figures are located in the basal two-thirds of the epithelium, differentiation can be seen in the upper half of the epithelium, and the nuclei are more atypical and larger than in CIN 1 (Robboy et al. 2002). Although CIN 2 can regress, patients should be counseled that 35 % persist and 22 % progress to CIN 3 (ACOG Bulletin #140, December 2013). Except in special populations, patients with CIN 2 are offered excision in an effort to prevent progression to CIN 3 and, ultimately, invasive cancer. In young age women, either close observation or ablation of the lesion can be considered. In CIN 3, nuclear abnormalities and mitotic figures populate the entire thickness of the epithelium. The nuclei can occupy almost the entire cell and are bizarre in shape. Data on the natural history of CIN 3 revealed that 56 % persist and 14 % progress to invasive cancer (ACOG Bulletin #140, December 2013). The term carcinoma in situ (CIS) was included in prior terminology; however, this diagnosis is no longer used. Rather, that which was labeled as CIS is now considered CIN 3. Excisional biopsy is the preferred management for CIN 3.

5.2

Adenocarcinoma In Situ

Adenocarcinoma in situ (ACIS) describes a precursor lesion to invasive adenocarcinoma of the cervix. Pathologists describe ACIS as replacement of endocervical glandular cells with tall columnar cells with nuclear atypia and elevated

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K.E. Tierney et al.

Table 1 Recommendations for follow-up after cone biopsy for cervical dysplasia Cone (LEEP or CKC) CIN 3 CIN 3

Internal margin neg neg

CIN 3

ECC neg CIN 3

Desiring future fertility n/a Yes

Risk of residual dysplasia 18 % 40 %

Risk of microinvasion 0% 0%

Risk of frank invasion 0% 0%

neg

CIN 3

No

40 %

0%

0%

CIN 3

CIN 3

neg

Yes

30 %

0%

0%

CIN 3

CIN 3

neg

No

30 %

0%

0%

CIN 3

CIN 3

CIN 3

Yes

44 %

19 %

11 %

CIN 3

CIN 3

CIN 3

50/ postmenopausal

46 %

9%

18 %

ACIS

neg

neg

Yes

14 %

0%

0%

ACIS ACIS ACIS ACIS ACIS

neg + neg + Either +/

neg neg + + Either +/

No No No No Yes

14 40 80 77 59

0% 7% 20 % 15 % 13 %

0 0 0 0 0

% % % % %

mitotic activity. Less prevalent than CIN, the management of ACIS has proven to be a challenge. Estimates for the risk of underlying malignancy can be up to 17 %. After biopsy diagnosis, all patients should have a cone biopsy to exclude the diagnosis of underlying cancer. Standard treatment for ACIS is hysterectomy; however, fertility-sparing measures can be taken in special circumstances (Tierney et al. 2014). See Special Considerations for information of fertility preservation.

5.3

% % % % %

Follow-Up Cotesting in 1 year 4–6-month cotesting with ECC 4–6-month cotesting with ECC 4–6-month cotesting with ECC 4–6-month cotesting with ECC 4–6-month cotesting with ECC preferred; repeat CKC acceptable 4–6-month cotesting with ECC preferred; repeat CKC acceptable CKC - > clear margins = follow as above; CKC - > positive margins/ ECC - > hyst v. MRH 6-month cotesting; recommend completion hyst after childbearing Hyst CKC – > Hyst CKC – > Hyst CKC – > Hyst CKC until margins negative; recommend completion hyst after childbearing

Management of Dysplasia

In managing a diagnosis of cervical dysplasia, the simple objectives are to prevent progression to invasive cervical cancer and to exclude the presence of concurrent carcinoma. Management decisions can only be made after thorough review of cytologic and colposcopic findings.

5.3.1 Observation As previously mentioned, CIN 1 can safely be monitored without excision. Given the high

Management of Cervical Dysplasia

likelihood of regression, ACOG recommends repeat cotesting 1 year from the diagnosis. For CIN 2, the risk of progression must be weighed against the risk to future pregnancies. Observation is preferred in women ages 21–24 and “young women.” A “young woman” is considered someone in whom the risks to future pregnancies outweigh the risk of disease progression. Conservative management using serial cytologic sampling, HPV testing, and colposcopy at regular intervals appears to be appropriate in this population. Recommendations are for repeat exams every 6 months for at least the first year (ACOG Bulletin #140, December 2013).

5.3.2 Ablation Ablative procedures for the treatment of cervical dysplasia include cryosurgery, CO2 laser vaporization, and electrocoagulation. The primary benefits of these procedures are that they are costeffective and simple. These methods are not commonly utilized secondary to their obvious disadvantages. Ablative procedures do not predictably destroy tissue and they do not provide a specimen. Therefore, diagnosis of an underlying cancer could be inadvertently overlooked (Morrow and Sideri 2013; Baggish 2003). 5.3.3 Excision The objective of an excisional procedure is to treat the existing precancerous lesion and, if present, diagnose any underlying microinvasive disease. If a cone is not feasible secondary to distorted anatomy, one may proceed with a hysterectomy. The patient must be informed of the risk of invasive cancer that may result in postoperative adjuvant therapy or additional surgery. The specimen should be evaluable for the presence or absence of dysplasia at the margins (endocervical and ectocervical). Post-excisional endocervical curettage (ECC) should be performed routinely. Information on the margin status and ECC has been shown to predict the presence of residual disease for both squamous and glandular lesions (Kobak et al. 1996; Tierney et al. 2014). Positive endocervical margins and positive ECC are more concerning than a positive ectocervical margin. Ectocervical lesions are

7

more easily detected on Pap smear and colposcopy. Follow-up recommendations are summarized in Table 1 (ACOG Bulletin #140, December 2013; Kobak et al. 1996; Tierney et al. 2014). Following cone biopsy for CIN 3, ACOG recommends repeat cotesting in 1 year for those with negative margins and ECC. For those with positive margins and/or ECC, ACOG recommends closer follow-up with repeat cotesting in 4–6 months and repeat ECC at the time of cotesting. Providers and patients must understand that, although most who have positive margins and/or ECC will not have recurrent or persist cervical dysplasia, those with both positive margins and positive ECC are at the highest risk of recurrence/ persistence. Some patients will find that the risk is unacceptable and will be more comfortable with a follow-up procedure such as a repeat cone. Age should be considered when counseling patients on risk of persistent cervical dysplasia and invasive cervical cancer. Data suggests that women over 50 years of age (or postmenopausal women) who have a positive endocervical cone margin and a positive ECC have a 9–18 % risk of having invasive cervical cancer. These women should have a repeat excisional procedure. If the margins and ECC are negative on the second conization, follow-up with cotesting and an ECC in 4–6 months is reasonable. If margins and/or ECC are positive on the second conization, recommendations are for repeat conization. If repeat conization is not feasible secondary to anatomy, the patient must be counseled on risk of concurrent cancer and consider a modified radical hysterectomy versus a simple hysterectomy (Kobak et al. 1996). The following text will describe both coldknife cone (CKC) and loop electrosurgical excision procedure (LEEP) as methods of excision. These methods have been found to be equivalent in treating dysplasia (Huang and Hwang 1999). An important risk of excisional procedures is the risk to future pregnancies. Women who undergo these procedures are at an increased risk of having cervical stenosis, cervical shortening, and preterm birth. Studies show about a 30 % increased incidence of preterm birth in patients who have

8

undergone an excisional procedure (Frey and Conner 2015). Cold-knife cone (CKC), otherwise known as scalpel cone or sharp conization, is removal of a cone-shaped piece of tissue from the cervix. The specimen includes the transformation zone and a segment of the endocervical canal. The cone is typically 1.5–2.5 cm in height. The procedure is performed under anesthesia in the operating room. After colposcopy and/or Lugol application, the surgeon can determine the size and shape of the cone based on the extent of dysplasia. A sound should be used to determine the cervical length and direction of the canal. After traction sutures are placed and vasopressin is injected intracervically in select cases, a #15 or #11 blade is pushed into the cervical stroma at an angle that points toward the cervical canal. A single-tooth tenaculum can be applied to 12 and 6 o’clock to stabilize the cervix. An Allis clamp can be used to gently manipulate the specimen without losing orientation. After removal of the specimen from the cervix, suture is used to mark the 12 o’clock location to orient the specimen. An endocervical curettage follows the removal of the cone biopsy using a Kevorkian curette and endocervical cytobrush. Bleeding from the cone bed can usually be controlled with cautery. Monsel solution, Surgicel packing, and various suturing techniques can also be utilized (Morrow and Sideri 2013). The advantage of CKC is lack of thermal artifact allowing the pathologist to confidently comment on margin status. The disadvantage is that it requires anesthesia and an operating room to complete with possible increased risk of bleeding. When compared with CKC, the LEEP procedure also provides a specimen for pathologic examination; however, it is an in-office procedure that is simple and inexpensive. In the office, the procedure is performed using local anesthetic with 1–2 % lidocaine injected directly into the cervical stroma. Colposcopy with acetic acid application is performed followed by Lugol application if indicated. The appropriate loop electrode is selected based on the size of the lesion. Power is set at between 40 and 50 W using a blend of cutting and coagulation current. The loop is passed through the cervical stroma at a steady rate, careful to

K.E. Tierney et al.

avoid both bleeding and thermal effect to the specimen. Endocervical curettage is performed after the specimen is obtained. Hemostasis can be achieved with the rollerball and Monsel solution (Morrow and Sideri 2013).

5.3.4 Pharmacological Agents The utility of topical agents in the treatment of cervical dysplasia is under investigation. Both 5-flourouracil (5-FU) and imiquimod have been used as agents to treat vulvar dysplasia and are being considered in the treatment of cervical precancerous lesions. 5-FU is an antimetabolite that inhibits thymidylate synthase causing cell death. In young women, 5-FU used to treat CIN 2 was shown to cause regression in 93 % of patients as compared to 56 % regression among those who were observed. This data came from a randomized controlled trial of two groups (treatment with 5-FU versus observation) over a 6-month treatment period during which there were no reported moderate to severe side effects (Rahangdale et al. 2014). More common side effects include pain, burning, and dermatitis. Suggested treatment dosing is 2 g via transvaginal applicator every 2 weeks for a total of 8 doses. The use of 5-FU in this setting is considered off-label and should only be considered in young patients attempting to conserve fertility with informed consent. The topical immune-response modulator imiquimod is another agent that could to be efficacious in treating cervical dysplasia. Imiquimod activates the innate immune system via a toll-like receptor (TLR-7) and recruits macrophages, natural killer cells, and B-lymphocytes to the treated site. In the treatment of CIN 2–3, remission rates in patients treated with imiquimod were higher when compared with those observed over time; 73 % of those treated with imiquimod regressed while only 39 % of those treated with placebo regressed (Grimm et al. 2012). Common side effects of imiquimod include mild pruritus, pain, and a systemic “flu-like” reaction. Long-term and larger studies are needed to determine the ideal therapeutic application of these agents. With more investigation, topical agents could prove to be a reasonable alternative to excisional biopsy in

Management of Cervical Dysplasia

those who plan to reduce risk of preterm birth in future pregnancies.

5.3.5 Hysterectomy Hysterectomy is not a standard treatment as primary therapy for CIN 2 or CIN 3 (ACOG Bulletin #140, December 2013). After diagnosis of recurrent disease, repeat excisional biopsy is preferred to exclude the presence of invasive cancer. Indications for hysterectomy include: • Recurrent disease after evaluation with repeat excisional procedure • Situations in which a repeat excisional procedure is not feasible due to distorted anatomy, i.e., minimal residual cervix or a flush cervix For a diagnosis of ACIS, hysterectomy is standard of care in women who have completed childbearing. However, excisional biopsy needs to be preformed prior to hysterectomy to rule out concurrent invasive cancer.

5.4

Special Considerations

5.4.1 Dysplasia in Pregnancy For women with dysplasia diagnosed during pregnancy, most dysplasia will regress, and evolution to cancer is extremely rare (Fader et al. 2010). Evidence-based guidelines for management of cervical dysplasia in pregnancy suggest cervical biopsies should only be performed if frank cancer is suspected on colposcopy. Repeat colposcopy at 6 weeks postpartum is recommended. If a biopsy is performed with a result of CIN 2 or CIN 3, colposcopy no sooner than every 12 weeks can be performed. A biopsy should only be done if the lesion appears to worsen (ACOG Bulletin #140, December 2013). 5.4.2 Fertility-Sparing and ACIS For those who desire to maintain future fertility, patients with a diagnosis of ACIS should have a cone biopsy to exclude the diagnosis of underlying cancer. If cone margins or ECC is positive for ACIS, repeat cone can be performed in these

9

patients. If both margins and ECC are negative, data show that no patients had underlying cancer and about 14 % had residual ACIS. Patients should be closely monitored with cotesting every 6 months (Tierney et al. 2014).

5.5

Human Papillomavirus Prevention

Vaccination against HPV has demonstrated efficacy in preventing development of cervical dysplasia. Additionally, therapeutic vaccines have emerged and may change the future treatment landscape for cervical dysplasia. HPV has two capsid proteins (L1 and L2), and the HPV vaccine is made with recombinant L1 protein (a virus-like particle) to target the L1 capsid protein (Erickson et al. 2013). Currently, there are three FDA-approved HPV vaccines available in the United States. Available vaccines include a bivalent vaccine targeting HPV 16 and HPV 18 (Cervarix by GlaxoSmithKline, Brentford, United Kingdom), quadrivalent (Gardasil by Merck & Co Inc., Kenilworth, NJ, USA), and 9-valent (9vHPV by Merck & Co Inc., Kenilworth, NI, USA) types. The quadrivalent vaccine Gardasil protects against two high-risk types of HPV (16 and 18) and two low-risk types of HPV commonly seen in patients with genital warts (6 and 11). Administration is indicated to prevent HPV-related genital warts and precancerous and cancerous lesions in women and men for ages 9 through 26 years www.merckvaccines.com/products/gardisil. HPV vaccines have the secondary benefit of protection against all HPV-related cancers including some head and neck cancers and anal and penile cancer. In those who have been vaccinated, there is a 60 % risk reduction for atypia, and the risk of CIN 2/CIN3 and CIN 3 is reduced up to 80 % (Baldur-Felskov et al. 2014). Women vaccinated at an older age have been shown to have less of a risk reduction presumably because they have previously been exposed to HPV 16/HPV 18. Recommendations are to advocate for vaccination before sexual activity (Baldur-Felskov et al. 2014; Mahmud et al. 2014). However, current

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recommendations are to vaccinate all people between the ages of 9 and 26 regardless of sexual history or history of diagnosed cervical dysplasia. Indications for HPV vaccination in women older than 26 need to be developed in the future. The 9-valent HPV (9vHPV) vaccine builds immunity against HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58. The efficacy against types 6, 11, 16, and 18 has been shown to be equivalent to the quadrivalent vaccine. 9vHPV has been shown to prevent disease associated with the HPV types covered by the vaccine (Joura et al. 2015). For those who have been vaccinated, screening recommendations do not change (ACOG Bulletin #140, December 2013). Long-term follow-up is needed to see the effect these vaccines have on cervical and vulvar cancer prevalence as well as other HPV-related cancers such as head and neck and anal and penile cancer prevalence. The use of therapeutic vaccinations in the treatment of infection-mediated precancerous and cancerous lesions is under investigation. For those patients with high-grade dysplasia, the efficacy of the available vaccines proves to be low (Mahmud et al. 2014). A therapeutic vaccine elicits an adaptive immune response against the lesion. A recent phase 2 trial shows promising results for a therapeutic vaccine, VGX-3100 (Inovio Pharmaceuticals, Inc, Plymouth Meeting, PA, USA), against cervical dysplasia (CIN 2/3). These findings lend hope for a nonsurgical treatment of cervical dysplasia (Trimble et al. 2015).

6

Conclusion

In conclusion, cervical cancer screening with cytology and HPV testing has decreased the overall incidence of cervical cancer over the last century. The standardization of dysplasia management has been facilitated by easily accessible ASCCP guidelines. Treatment of cervical dysplasia has remained relatively consistent; however, given the high rate of regression in certain populations, more conservative management has been recommended in younger patients and pregnant patients. Ultimately, ACOG and ASCCP

give guidelines for the management of dysplasia; however, care should still be individualized. Recommendations are based on “acceptable risk” meaning that negative screening does not guarantee the absence of an abnormality. Worrisome findings may warrant close follow-up and more frequent exams. Informed consent is key. Patients need to know the pathophysiology of HPV-related disease, risk of disease progression, and risks of invasive intervention. There are few preventative interventions for patients once they are diagnosed with HPV. Gynecologic and pediatric care providers should take every opportunity to discuss risk reduction and the benefits of HPV vaccination.

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Cross-References

▶ Pathology

References ACOG. Practice Bulletin Number 140: management of abnormal cervical cancer screening test results and cervical cancer precursors. Obstet Gynecol. 2013;122 (6):1338–67. ASCUS-LSIL Triage Study (ALTS) Group. Results of a randomized trial on the management of cytology interpretations of atypical squamous cells of undetermined significance. Am J Obstet Gynecol. 2003;90:366–371. Adegoke O, Kulasingam S, Virnig B. Cervical cancer trends in the United States: a 35-year population based analysis. J Women’s Health. 2012;21 (10):1031–7. Arbyn M, Bergeron C, et al. Liquid compared with conventional cervical cytology: a systemic review and meta-analysis. Obstet Gynecol. 2008;111(1):167–77. ASCCP: http://www.asccp.org/Guidelines Baggish MS. Colposcopy of the cervix, vagina and vulva: a comprehensive textbook. Philadelphia: Mosby; 2003. p. 79–97. Baldur-Felskov B, Dehlendorff C, Munk C, Kjaer SK. Early impact of human papillomavirus vaccination on cervical neoplasia: nationwide follow-up of Young Danish women. JNCI J Natl Cancer Inst. 2014;106(3): djt460. de Sanjose S, Quint WG, Alemany L, et al. Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study. Lancet Oncol. 2010;11:1048–56.

Management of Cervical Dysplasia Erickson BK, Alvarez RD, Huh WK. Human papillomavirus: what every provider should know. Am J Obstet Gynecol. 2013;208(3):169–75. Fader AN, Alward EK, Niederhauser A, et al. Cervical dysplasia in pregnancy: a multi-institutional evaluation. Am J Obstet Gynecol. 2010;203:113.e1–6. Frey HA, Conner SN. Treatment of cervical dysplasia and the risk of preterm birth: understanding the association. Am J Obstet Gynecol. 2015;213(4):445–6. Grimm C, Polterauer S, Natter C, et al. Treatment of cervical intraepithelial neoplasia with topical imiquimod: a randomized controlled trial. Obstet Gynecol. 2012;120:152–9. Huang LW, Hwang JL. A comparison between loop electrosurgical excision procedure and cold knife conization for treatment of cervical dysplasia: residual disease in a subsequent hysterectomy specimen. Gynecol Oncol. 1999;73(1):12–5. Huh W, Sideri M, et al. Relevance of random biopsy at the transformation zone when colposcopy is negative. Obstet Gynecol. 2014;124(4):670–8. Insinga RP, Glass AG, Rush BB. Diagnoses and outcomes in cervical cancer screening: a population-based study. Am J Obstet Gynecol. 2004;191:105–13. Joura EA, Giuliano AR, Iversen OE, et al. A 9-valent HPV vaccine against infection and intraepithelial neoplasia in women. N Engl J Med. 2015;372:711–23. Kobak WH, Roman LD, et al. The role of endocervical curettage at cervical conization for high-grade dysplasia. Obstet Gynecol. 1996;85:197–201. Mahmud SM, Kliewer EV, Lambert P, Bozat-Emre S, Demers AA. Effectiveness of the quadrivalent human papillomavirus vaccine against cervical dysplasia in Manitoba, Canada. J Clin Oncol. 2014;32:438–43. Merck: www.merckvaccines.com/products/gardasil Morrow CP, Sideri M. Surgery for cervical neoplasia. In: Gynecologic cancer surgery. Encinitas: South Coast Medical Publishing; 2013. p. 513–33. Nanda K, McCrory DC, et al. Accuracy of the papanicolaou test in screening for and follow-up of cervical cytologic abnormalities: a systemic review. Ann Intern Med. 2000;132:810–9. Nguyen ML, Flowers L. Cervical cancer screening in immunocompromised women. Obstet Gynecol Clin N Am. 2013;40(2):339–57.

11 Nooh AM, Mohamed ME, El-Alfy Y. Visual inspection of cervix with acetic acid as a screening modality for cervical cancer. J Low Genit Tract Dis. 2015;19:340–4. Rahangdale L, Lippmann OK, Garcia K, et al. Topical 5-fluorouracil for treatment of cervical intraepithelial neoplasia 2: a randomized controlled trial. Am J Obstet Gynecol. 2014;210:314.e1–8. Robboy SJ, Anderson MC, Russel P. Pathology of the female reproductive tract. Philadelphia: Churchill Livingstone; 2002. p. 165–93. Seer database: http://seer.cancer.gov/statfacts/html/cervix. html Solomon D, Darvy D, Kurman R, et al. The 2001 Bethesda system: terminology for reporting results of cervical cytology. JAMA. 2002;287:2114–9. Tierney KE, Lin PS, Amezcua C, et al. Cervical conization of adenocarcinoma in situ: a predicting model of residual disease. Am J Obstet Gynecol. 2014;210:366.e1–5. Trimble CL, Morrow MP, Kraynyak KA, et al. Safety, efficacy, and immunogenicity of VGX-3100, a therapeutic synthetic DNA vaccine targeting human papillomavirus 16 and 18 E6 and E7 proteins for cervical intraepithelial neoplasia 2/3: a randomized, doubleblind, placebo-controlled phase 2b trial. Lancet. 2015;386:2078. Published online. Wheeler CM. The natural history of cervical human papillomavirus infection and cervical cancer: gaps in knowledge and future horizons. Obstet Gynecol Clin N Am. 2013;40:165–76. Wright TC Jr, Massad LS, et al. 2006 consensus guidelines for the management of women with abnormal cervical screening tests. J Low Genit Tract Dis. 2007;11 (4):201–22. Wright TC. Pathogenesis and diagnosis of preinvasive lesions of the lower genital tract. In: Principles and practice of gynecologic oncology. Philadelphia: Lippincott/Williams and Wilkins; 2009. Wright TC, Stoler MH, et al. The ATHENA human papillomavirus study: design, methods, and baseline results. Am J Obstet Gynecol. 2012;206:46.e8–11. Zhao C, et al. Human papillomavirus testing and reporting rates in 2012: results of a College of American Pathologists National Survey. Arch Pathol Lab Med. 2015;139:756–61.

Diagnosis and Management of Vaginal Cancer E. Clair McClung, Ardeshir Hakam, and Mian M. K. Shahzad

Abstract

Contents 1

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2

2

Vaginal Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2

3

Natural History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3

4

Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3

5

Signs and Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . .

4

6

Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4

7

Evaluation and Staging . . . . . . . . . . . . . . . . . . . . . . . .

5

8

Screening and Prevention . . . . . . . . . . . . . . . . . . . . .

6

9 9.1 9.2 9.3 9.4 9.5 9.6

Histologic Subtypes and Management . . . . . . . Vaginal Intraepithelial Neoplasia (VAIN) . . . . . . Invasive Squamous Cell Carcinoma . . . . . . . . . . . . Adenocarcinomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mesenchymal Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . Other Histologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6 6 9 13 14 14 15

10

Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

E.C. McClung • M.M.K. Shahzad (*) Department of Gynecologic Oncology, University of South Florida/H. Lee Moffitt Cancer Center, Tampa, FL, USA e-mail: Emily.mcclung@moffitt.org; Mian.Shahzad@moffitt.org A. Hakam Department of Pathology, University of South Florida/H. Lee Moffitt Cancer Center, Tampa, FL, USA e-mail: Ardeshir.Hakam@moffitt.org # Springer International Publishing Switzerland 2016 D. Shoupe (ed.), Handbook of Gynecology, DOI 10.1007/978-3-319-17002-2_8-1

Primary malignancies of the vagina are rare, comprising only about 1–4 % of all gynecologic malignancies. The majority of vaginal cancers are metastases from other sites. Among primary vaginal tumors, squamous cell carcinoma (SCC) is the most common, followed by adenocarcinoma, melanoma, and other rare histologies. Squamous cell carcinomas are frequently associated with chronic human papillomavirus (HPV) infection, whereas adenocarcinomas are associated with in utero diethylstilbestrol (DES) exposure. Vaginal intraepithelial neoplasia (VAIN) is a premalignant condition thought to progress to invasive squamous cell carcinoma if untreated. Vaginal intraepithelial neoplasia is generally asymptomatic and diagnosed by abnormal vaginal cytology followed by vaginal colposcopy and biopsies. Most vaginal cancers present with abnormal vaginal bleeding or a vaginal mass. Diagnosis is made by physical exam and confirmatory biopsy. Treatment of vaginal cancer depends on the primary histology, stage at diagnosis, and patient characteristics. Treatment options include surgical excision, radiation therapy, and chemotherapy. The majority of vaginal cancers are treated with radiation, frequently in combination with chemotherapy. Prognosis varies depending on underlying histology and stage at presentation; however, with advances in radiation

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techniques, survival rates are similar to those seen in cervical cancer. Keywords

Vaginal intraepithelial neoplasia (VAIN) • Vaginal squamous cell carcinoma • Vaginal adenocarcinoma • Vaginal melanoma • Vaginal rhabdomyosarcoma

1

Introduction

Primary malignancies of the vagina are quite rare, comprising only about 1–4 % of all gynecologic malignancies (Siegel et al. 2015). In the USA, approximately 4000 women are diagnosed with vaginal cancer each year, and approximately 900 women die of the disease (Siegel et al. 2015). The majority of cancers involving the vagina are actually secondary metastases or direct extensions from other primary sites. In a series of 355 invasive carcinomas involving the vagina, only 58 (16 %) represented primary vaginal lesions. Among secondary sites metastatic to the vagina, the cervix was most common (32 %), followed by the endometrium (18 %), colon and rectum (9 %), ovary (6 %), vulva (6 %), bladder and urethra (4 %) (Fu and Reagan 1989). In this chapter, we will focus on the diagnosis and management of primary vaginal malignant neoplasms and premalignant conditions. Due to the rarity of the disease, most treatment strategies are derived from small retrospective case series and extrapolated from prospective studies for the treatment of cervical and anal cancers. Squamous cell carcinoma is the most common and wellstudied histology, representing 65–79 % of vaginal cancers in two large cancer registry studies (Creasman et al. 1998; Shah et al. 2009). Adenocarcinoma is the second most common histology representing 9–14 % of tumors, followed by melanoma (3–6 %) and other rare histologies including mesenchymal, germ cell, neuroendocrine, and hematologic cell types collectively accounting for the remaining 4–15 % (Creasman et al. 1998; Shah et al. 2009). The majority of vaginal cancers are treated with radiation, frequently in

combination with chemotherapy. Prognosis varies depending on underlying histology and stage at presentation; however, with advances in radiation techniques, survival rates are similar to those seen in cervical cancer.

2

Vaginal Anatomy

The vagina is a fibro-muscular, distensible tube extending from the uterine cervix superiorly to the vestibule of the vagina, vulva, and perineum inferiorly. Embryologically, the vagina is formed by fusion of the urogenital sinus epithelium inferiorly with the mullerian ducts superiorly. Structural support for the vagina includes the cardinal and uterosacral ligaments superiorly and the muscular supports of the pelvic floor including the levator ani, the bulbospongiosus muscle, and urogenital diaphragm. The vagina shares fascial support anteriorly with the bladder and posteriorly with the rectum. Between these attachments, the lateral vaginal wall opens into the paravaginal space. The vaginal fornix describes the recesses around the uterine cervix and can be divided into anterior, posterior, and lateral regions. The posterior fornix is the largest and is separated from the rectum by a fold of peritoneum, forming the pouch of Douglas. The vaginal wall consists of three layers: the mucosa, the muscularis, and the adventitia. The mucosa is lined by the nonkeratinized stratified squamous epithelium, rich in glycogen and estrogen. There are no glands or crypts in the vagina, and the mucosa is primarily lubricated by cervical glands. Vaginal atrophy, characterized by mucosal thinning and blunting of the vaginal rugae, is common in low estrogen states such as prior to onset of puberty and after menopause. Underlying the epithelial basement membrane is the submucosal layer, highly vascular and rich in lymphatics. The muscularis layer consists of smooth muscle fibers, and adventitia is a thin layer of connective tissue continuous with the adventitia layer of other surrounding organs. The arterial supply of the upper vagina comes from the internal iliac artery frequently off a trunk shared with the uterine artery, called vaginal

Diagnosis and Management of Vaginal Cancer

artery, while the middle and lower portions of the vagina are supplied by branches of the middle rectal and internal pudendal arteries. Venous drainage is facilitated by vaginal venous plexuses in the lateral vagina which drain into the internal iliac vein. The vagina is innervated by nerves derived from the inferior hypogastric plexus. Classically, lymphatic vessels from the upper 2/3 of the vagina drain into the internal iliac and external iliac lymph nodes, while vessels from the lower 1/3 drain into the superficial inguinal lymph nodes via lymphatic channels in the lateral vagina (Plentl and Friedman 1971). Posterior vaginal lesions may also drain into para-rectal nodes (Plentl and Friedman 1971).

3

Natural History

Most data about the natural history of vaginal carcinoma emanates from early case reports where few treatment modalities were available, and many patients presented with advanced disease. In a compilation of early case series, Plentl and Friedman report that of 1204 vaginal cancer cases, 57.2 % were located on the posterior wall, 26.9 % on the anterior wall, and 15.9 % on the lateral wall (Plentl and Friedman 1971). Among 743 cases with data available, 50.7 % of tumors were located in the upper 1/3 of the vagina, 18.8 % in the middle 1/3, and 30.4 % in the lower 1/3. VAIN also has a predilection for the upper vagina, which is thought to be due to an HPV-related field effect in patients with cervical HPV infections. Vaginal cancers may spread by contiguous growth and local invasion, lymphatic drainage, and hematogenously. Because of closely approximated structures including the urethra, bladder, rectum, and pelvic bones, locally advanced disease is generally symptomatic and carries a high rate of morbidity. Due to the rich lymphatic drainage of the vagina, lymph node metastases occur relatively early in the disease. By contrast, hematogenous dissemination to distant sites, such as the liver, lung, or bone, occurs late in the disease process.

3

4

Epidemiology

Vaginal squamous cell carcinoma is primarily a disease of older women, with peak incidence between ages 60 and 80 (Creasman et al. 1998; Shah et al. 2009). Vaginal squamous cell carcinoma is considered to be an HPV-related disease and shares many risk factors with other HPV-related squamous cell carcinomas, including prior documented HPV infection (particularly HPV 16), history of cervical or vulvar dysplasia (CIN or VIN), immunosuppression, five or more sexual partners or sexual debut prior to age 17, smoking, and low socioeconomic status (Daling et al. 2002). VAIN and squamous cell carcinomas are strongly associated with a prior history of cervical cancer. Prior radiation therapy (Hellman et al. 2004) and chronic vaginal irritation related to pelvic organ prolapse and pessary use have also been proposed as possible risk factors (Wang et al. 2014). Vaginal adenocarcinoma is associated with precursor lesions including vaginal adenosis, endometriosis, and mesonephric rests. Vaginal clear cell carcinoma, associated with in utero diethylstilbestrol (DES) exposure is the most commonly described form in the literature. DES is a nonsteroidal estrogen that has been implicated in congenital reproductive tract abnormalities including persistence of vaginal glandular tissue in a condition called vaginal adenosis. In review of registry cases, Herbst reported that among women exposed to DES in utero, the risk of clear cell carcinoma of the vagina or cervix was approximately 1/1000, with age at diagnosis ranged from 7 to 34 years, with peak incidence at age 14–22 (Herbst and Andersond 1990). Vaginal adenosis occurred in 45 %, and structural genital tract anomalies in 25 %. The incidence of vaginal clear cell carcinoma has declined significantly since the 1990s. Non-DES-related vaginal adenocarcinomas occur in older women, with a median age at diagnosis of 54 (Frank et al. 2007). A small subset of vaginal cancer has a predilection for the pediatric population. Vaginal rhabdomyosarcoma, also known as sarcoma botryoides, accounts for approximately 4 % of

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rhabdomyosarcomas, which are the most common tumors in childhood. The median age at presentation is 16.3 months (Magné et al. 2008). Vaginal and cervical yolk sac tumors, also known as endodermal sinus tumors, are another rare vaginal tumor of childhood. Only about 100 cases have been reported in the literature, all diagnosed prior to age 3.

5

Signs and Symptoms

Approximately 15–17 % of vaginal cancers are asymptomatic and identified by abnormal cytology or incidental mass on routine pelvic examination (Eddy et al. 1991; Hellman et al. 2004). Abnormal vaginal bleeding is the most commonly reported symptom of invasive carcinoma; however, abnormal vaginal discharge and dysuria are also frequently reported. In the case of more advanced disease, patients may present with pain, the sensation of a mass, or symptoms related to the involvement of adjacent pelvic organs. Tumors involving the bladder may present with urinary incontinence or retention, hematuria, urgency, or frequency. Tumors involving the rectum may present with constipation, tenesmus, or rectal bleeding. Sarcoma botryoides presents with a characteristic edematous, grape-like mass protruding from the vagina. Vaginal intraepithelial neoplasia (VAIN) is generally asymptomatic, but may present with abnormal vaginal discharge which is often the result of a coincidental vaginitis. Most cases of VAIN are diagnosed after abnormal vaginal cytology in women who have a history of cervical dysplasia

6

Diagnosis

Vaginal cancer should be diagnosed after a thorough focused history and physical exam, careful inspection of the vagina, confirmatory biopsies, and exclusion of more common gynecologic malignancies which may have metastasized to the vaginal mucosa. According to the International Federation of Gynecology and Obstetrics

(FIGO) definitions, any vaginal lesion also involving the cervix or the vulva should be classified as a cervical or vulvar primary cancer, respectively (Hacker et al. 2015). Similarly, in women with a prior history of cervical carcinoma, a vaginal carcinoma lesion should not be considered a second primary unless the patient has been without evidence of disease for at least 5 years (Hacker et al. 2015). Inquiry of clinical history should include symptoms and risk factors associated with vaginal carcinoma and a complete past medical and gynecological history. Physical examination should focus on evaluation of potential metastatic sites, with particular care to palpate the inguinal and supraclavicular lymph nodes, which may be enlarged in advanced disease. During pelvic examination, the vulva and anus should be carefully inspected for HPV-related lesions, with care to visualize folds of the labia and the vaginal vestibule prior to speculum insertion. The entire vaginal surface should be visualized, which may require an exam under anesthesia in women with locally advanced disease or vaginal stenosis secondary to severe vaginal atrophy or prior radiation. Most vaginal cancers are located in the upper vagina, frequently on the posterior wall. A speculum examination should be performed with care to inspect the anterior and posterior fornix as well as the distal vagina. Lesions in the distal anterior and posterior vagina may be obscured by the blades of the speculum unless the speculum is gently rotated to expose the circumferential surface of the vagina. Small lesions may be difficult to identify in parous or obese women with redundant vaginal folds. In women who have had a prior hysterectomy, lesions also may be concealed by folds of mucosa buried within the vaginal cuff closure. Partial upper vaginectomy may be required to adequately evaluate these patients. Vaginal cancers are frequently exophytic, papillary appearing tumors, but infiltrating, ulcerative and flat spreading forms are also seen (Morrow and Curtin 1998). Carcinomas arising in the setting of extensive VAIN may be multifocal. Any visible lesions should be evaluated with fullthickness mucosal biopsies. Vaginal cytology

Diagnosis and Management of Vaginal Cancer

may also be useful to identify cellular atypia, but should not be used alone to evaluate for VAIN or vaginal malignancies. Any woman with a suspicious vaginal lesion who has not had a total hysterectomy should also have consideration of cervical biopsies and endocervical sampling to evaluate for an occult cervical malignancy. Similarly, women with abnormal bleeding and an intact uterus should have an endometrial biopsy or dilation and curettage to evaluate for endometrial cancer. A bimanual exam should be performed to palpate the size and extent of an intravaginal mass and assess for any pelvic masses. This exam should be followed by a rectovaginal exam to identify gross invasion through the rectal mucosa, tumor infiltration of the rectovaginal septum, and parametrial or pelvic sidewall involvement. When locally advanced disease is suspected based on the size and location of the primary tumor, cystourethroscopy and/or proctoscopy are indicated. Biopsies should be obtained if there is any question of mucosal bowel or bladder involvement. Sigmoidoscopy may also be considered for women with large tumors in the posterior vaginal fornix that are suspected to extend into the pelvis. All patients with abnormal cytology but no grossly visible lesion should be further evaluated with vaginal colposcopy. Some providers advocate colposcopy for all cases of vaginal carcinoma in order to visualize any areas of occult mucosal involvement or associated dysplasia. Colposcopy can be performed in the office during initial examination and may be repeated in the operating room as needed to guide biopsies or excision of lesions identified. Acetic acid solution should be liberally applied to the vagina, and the mucosa should be inspected under magnification using a colposcope. Lugol’s iodine solution may be a useful adjunct to identify nonstaining mucosa. Colposcopically abnormal mucosa should be biopsied for diagnosis. When there is a question of high-grade dysplasia versus invasive carcinoma, lesions should be excised, as a large superficial lesion may contain a small focus of deeper invasion that could be missed on biopsy alone. A complete upper vaginectomy may be necessary in order to adequately rule out invasive carcinoma in

5 Table 1 FIGO stage and 5-year overall survival rates for vaginal cancer

FIGO stagea I II

III

IVA

IVB

Definition Limited to the vaginal wall Involving subvaginal tissue Pelvic sidewall involvement Bladder or rectum invasion or extension beyond the pelvis Distant metastases

Creasman et al. 1998b (NCDB data, n = 4885) 73 %

Shah et al. 2009c (SEER data, n = 2149) 84 %

58 %

75 %

36 % (stages III and IV)

57 % (stages III and IV)

Compiled from: Hacker et al. (2015) b Creasman et al. (1998) c Shah et al. (2009) a

the setting of multifocal or extensive high-grade VAIN. In a series of sequential upper vaginectomies for VAIN2 or VAIN3 from 1985 to 2004, Indermaur et al. reported that 12/105 (12 %) had a previously unsuspected invasive carcinoma (Indermaur et al. 2005).

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Evaluation and Staging

Similar to cervical cancer, vaginal cancer staging is clinical. Two commonly used staging systems are defined by the International Federation of Gynecology and Obstetrics (FIGO) and American Joint Committee on Cancer (AJCC) TNM staging system (Edge et al. 2010; Hacker et al. 2015). In both systems stage I/T1 describes tumors confined to the vaginal wall; stage II/T2 tumors invade the paravaginal tissues; stage III/T3 involves the pelvic sidewall; stage IV/T4 invades the bladder or rectal mucosa; and distant metastases (M) are labeled stage IVB (Table 1).

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Lymph node involvement is not directly addressed in the FIGO system, whereas in the AJCC system it is designated by N, and all patients with positive pelvic or inguinal lymph nodes are assigned to N1 (clinical stage III). Metastatic sites (AJCC designation M1) include, but are not limited to, aortic lymph nodes, lungs, liver, bone, and others outside the pelvis. Currently FIGO staging is used more commonly in the treatment of vaginal cancer. In the FIGO system, studies officially recommended for clinical staging of a tumor are limited in order to preserve consistent labeling across historical data and low resource settings. These studies include pelvic examination, cystoscopy, proctoscopy, chest radiograph, and intravenous pyelogram. Where advanced imaging techniques such as computed tomographic (CT) scans and magnetic resonance imaging (MRI) are available, many providers extrapolate results from these studies into the clinical staging model. Because of its high resolution and ability to discriminate soft tissue plains, MRI of the pelvis can be a particularly useful adjunct to physical exam for determining the extent of tumor invasion into the bladder, rectum, or parametrial tissues. Taylor et al. correlated MRI findings with clinical outcomes in 25 vaginal cancer patients and concluded that MRI could identify 95 % of primary lesions and accurately predicted clinical stage (Taylor et al. 2007). Primary vaginal lesions appear with low-intermediate intensity on T1and hyperintensity on T2-weighted images (Taylor et al. 2007) and may be better visualized if the vagina is instilled with gel during the study to separate and distend the vaginal walls. Positron emission tomography (PET) scans have become a standard tool for evaluating local, nodal, and metastatic disease for initial evaluation and surveillance of cervical cancer. Not surprisingly, PET has also been widely adopted for evaluation of vaginal cancers and has been shown to have superior sensitivity compared with standard CT for detecting both primary vaginal tumors (100 % with PET vs. 43 % for CT) and nodal metastasis (Lamoreaux et al. 2005).

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Screening and Prevention

Similar to other rare cancers, screening for vaginal cancer among low-risk populations is not recommended. The American Cancer Society and American Society for Colposcopy and Cervical Pathology (ASCCP) recommend routine vaginal cytology in women who have had a hysterectomy only if there is a history of highgrade cervical dysplasia (CIN2/CIN3) (Saslow et al. 2012). Because VAIN and squamous cell carcinomas are closely associated with HPV infection, HPV vaccination campaigns are likely to be the most important strategy to prevent these diseases.

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Histologic Subtypes and Management

9.1

Vaginal Intraepithelial Neoplasia (VAIN)

Vaginal intraepithelial neoplasia (VAIN), also known as vaginal carcinoma in situ, is a form of squamous cell atypia that is confined to the squamous epithelium of the vagina, without any evidence of invasion. The characteristics of VAIN include nuclear atypia, loss of squamous cell maturation, and the presence of suprabasilar mitoses. Similar to cervical intraepithelial neoplasia (CIN), VAIN1 involves the deepest 1/3 of the epithelium, VAIN2 the deepest 2/3, and VAIN3 the full thickness of the epithelial layer (Fig. 1). VAIN is almost always associated with HPV infection in more than 90 % of cases, with HPV 16 being the most common subtype, found in up to 65 % of cases of VAIN2/VAIN3 (Smith et al. 2009). The true natural history of VAIN is not known; however, it is considered premalignant because of its association with high-risk HPV types. Invasive squamous cell carcinoma has been identified in up to 12 % of vaginectomies performed for VAIN2/VAIN3 (Indermaur et al. 2005). Treatment strategies for VAIN include observation, local excision, partial or total vaginectomy, ablation with laser vaporization or

Diagnosis and Management of Vaginal Cancer

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Fig. 1 Vaginal mucosa, high-grade dysplasia, and invasive carcinoma (Ardeshir Hakam 2015)

electrocoagulation, topical 5 % fluorouracil, or intracavitary radiation therapy. Observation is limited to the treatment of VAIN1, which is more likely to regress spontaneously. For VAIN2/VAIN3, published disease control rates are similar for all approaches. Most studies consist of small, single institutional case series, and modalities have not been directly compared for efficacy. The choice of therapy should be individualized based on the size, location, and severity of VAIN lesions, as well as the patient’s age, general health and life expectancy, desire for sexual function, and prior history of treatment failures. In a significant subset of women, VAIN is chronically persistent and recurrent and may require repeated treatment with multiple modalities. Risk factors for recurrence include multifocal disease, VAIN3, and older age (Dodge et al. 2001). In all cases,

invasive carcinoma should be ruled out with adequate sampling biopsies prior to initiating treatment. Treatment strategies are summarized in Table 2. Surgical excision is the most appropriate management when invasive carcinoma cannot be ruled out, as this is the only approach that will provide tissue for diagnosis. For patients with a focal, well-circumscribed lesion, local excisional colpectomy is the best choice. In more extensive disease, an upper or total vaginectomy may be necessary to obtain adequate margins. These procedures are usually performed vaginally; however upper vaginectomy may require an abdominal approach in some cases, ideally using minimally invasive technique. Vaginectomy can lead to shortening or stenosis of the vagina and loss of sexual function. Reconstructive procedures and

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Table 2 Treatment modalities for vaginal intraepithelial neoplasia Method of treatment Surgical excision

Applications/advantages Pathologic diagnosis Evaluate for invasive cancer Total vaginectomy provides definitive treatment

Ablation (CO2 laser or electrocautery)

Preservation of vaginal length Treatment of multifocal or extensive disease Lower rates of sexual dysfunction Coverage of diffuse or multifocal disease Does not require anesthesia

5-Fluorouracil

Imiquimod

Vaginal estrogen Radiation therapy

Coverage of diffuse or multifocal disease Does not require anesthesia May augment other treatment modalities Usually definitive Effective when other modalities have failed

skin grafts may be necessary after total vaginectomy. Women with a prior history of radiation therapy are also at increased risk of surgical complications and fistula formation following colpectomy and vaginectomy procedures. CO2 laser vaporization is proposed as relatively noninvasive approach that may be useful for large VAIN lesions and multifocal disease in women who want to retain sexual function. The procedure is generally well tolerated, and patients report minimal sexual dysfunction. Ablation procedures should only be performed if an underlying invasive carcinoma can be adequately ruled out and if the entire lesion can be visualized. Lesions that are partially obscured should be excised. Topical therapies may be useful for women with low-grade persistent VAIN or diffuse, multifocal disease in women who are poor surgical candidates, after invasive carcinoma has been ruled out. The advantage of these modalities is that the entire vaginal surface can be treated, including difficult to access crevices at the

Risks and side effects Vaginal shortening or stenosis (large excision) Loss of sexual function (vaginectomy) Possible laparotomy or other surgical complications Generally requires anesthesia Vaginal stenosis may occur Diagnosis of invasive cancer can be delayed Generally requires anesthesia Vaginal burning Vaginal ulceration Diagnosis of invasive cancer can be delayed May cause vaginal adenosis in rare cases after CO2 ablation Vaginal burning Vaginal ulceration Diagnosis of invasive cancer can be delayed Unproven as monotherapy Vaginal shortening or stenosis Vaginal fibrosis Sexual dysfunction or loss of function Impaired wound healing Radiation cystitis/proctitis Premature menopause/ovarian ablation

vaginal apex. Proposed topical agents include 5-fluorouracil (5FU), imiquimod, and vaginal estrogen. Of these, 5FU is the best studied. Several 5FU dose regimens have been proposed, but none have been directly compared, and the most commonly used dose is 2 g once weekly for 10–12 weeks (Gurumurthy and Cruickshank 2012). Side effects of vaginal 5FU include burning and vaginal ulceration. Zinc and other barrier creams may be used to protect unaffected areas, and vaginal estrogen may reduce vaginal discomfort. Vaginal columnar metaplasia (adenosis) has been reported when 5FU is administered after prior CO2 laser ablation, but the significance of this finding is unknown (Paczos et al. 2010; Gurumurthy and Cruickshank 2012). Imiquimod, a topical immune modulator, has also been shown to have activity against VAIN in a few small studies. As with 5FU, dosing regimens vary from series to series. Buck et al. reported that 86 % of a 42-patient series experience regression of VAIN after a 3-week course of once weekly application of 0.25 g 5 %

Diagnosis and Management of Vaginal Cancer

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Table 3 Histologic subtypes of vaginal cancer and their characteristics

Epidemiology

Signs/ symptoms

Squamous cell carcinoma Age >60 HPV (HPV 16) History of cervical dysplasia Chronic irritation Abnormal pap (ASCUSHSIL) Vaginal bleeding Vaginal mass

Adenocarcinoma Age 14–22 or >60 DES exposure (clear cell) Vaginal adenosis, endometriosis, or mesonephric rests Abnormal pap (AGUS) Vaginal bleeding Vaginal mass

Melanoma Age ~60 White, non-Hispanic

Pigmented lesion Vaginal bleeding Discharge Surgery Targeted therapies Immunotherapy

Rhabdomyosarcoma (sarcoma botryoides) Early childhood

Grape-like vaginal mass

Chemoradiation Conservative surgery Chemotherapy (EBRT + brachytherapy) Fertility sparing (young Conservative surgery Vaginectomy (localized patients) Radiation stage I in upper vagina) Chemoradiation Pelvic exenteration (central disease) Other histologies: leiomyosarcoma, carcinosarcoma, endometrial stromal sarcoma, yolk sac tumors, neuroendocrine tumor, glassy cell carcinoma, verrucous carcinoma, Wilms tumor, Ewing sarcoma, lymphoma

Treatment modalities

HPV human papillomavirus, ASCUS atypical squamous cells of undetermined significance, HSIL high-grade squamous intraepithelial lesion, AGUS atypical glandular cells of undetermined significance, EBRT external beam radiation therapy

imiquimod cream (Buck and Guth 2003). Side effects of Imiquimod include vaginal burning and irritation. In the Buck et al. series, these side effects were well tolerated, and there were no reports of vaginal ulceration. Topical estrogen cream has been advocated as a useful adjunct to all VAIN treatment modalities. Particularly in postmenopausal women with significant vaginal atrophy, topical estrogen therapy may improve detection of VAIN by normalizing adjacent epithelium. Estrogen may also play a role in promoting regression of VAIN (Rhodes et al. 2014). Radiation therapy is one of the most effective therapies for VAIN, but is less commonly used because of toxicities associated with radiation including vaginal shortening, stenosis, and fibrosis which may interfere with both sexual function and future examinations. Other toxicities include impaired wound healing, risk of inducing premature menopause through ovarian ablation, and radiation cystitis or proctitis. Vaginal intracavitary brachytherapy is most frequently used for definitive treatment of persistent and recurrent VAIN that has failed other modalities, with disease control rates of 86–100 % (Gurumurthy and Cruickshank 2012).

Posttreatment surveillance should be similar to follow up schedules in women with cervical dysplasia: every 6 months for 1–2 years and then annually, with vaginal cytology at each visit. HPV testing has not yet been established in the followup of VAIN, but may improve the sensitivity of surveillance exams and allow for improved risk stratification and less frequent follow-up.

9.2

Invasive Squamous Cell Carcinoma

(Summarized in Table 3) Invasive squamous cell carcinoma (SCC) shares cytologic features with VAIN, along with evidence of invasion beyond the epithelial basement membrane. Approximately 65 % of vaginal SCC is HPV positive (Smith et al. 2009). Similar to VAIN, HPV 16 is the most common HPV type found in vaginal cancer, and p16 staining is highly sensitive and specific for HPV infection in vaginal tumors. SCC may be divided into keratinizing and nonkeratinizing subtypes, and other variants including basaloid, warty, and papillary squamotransitional have also been described.

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Vaginal SCC is graded by the degree of differentiation. Grade 1 tumors are keratinizing and generally very similar in appearance to squamous epithelium, with abundant cytoplasm. Grade 2 tumors have less cytoplasm, but are easily recognized as squamous cells, whereas grade 3 tumors are both nonkeratinizing and poorly differentiated. Verrucous carcinoma is a distinct type of SCC also found on the cervix and vulva which presents with a large exophytic mass and is generally very well differentiated and cytologically bland appearing. Verrucous carcinoma spreads locally and is generally treated surgical resection. Treatment strategies for vaginal SCC may include surgery, radiation, or chemotherapy – alone or in combination. Chemoradiation including a combination of external beam and brachytherapy is currently the most recommended treatment modality for vaginal cancer of all stages. Because of the rare incidence of the disease, there are no phase III clinical trials to guide management. Overall, management strategies are based on the results of small case series; extrapolation of treatment strategies for cervical, vulvar, and anal cancers; and expert opinion. Therapy should be individualized for each patient based on the stage of disease, size and location of the tumor, and personal goals for vaginal function. Whenever possible, patients should be referred to tertiary centers to receive care from providers experienced in treating vaginal cancers. Surgery has limited utility in the treatment of vaginal cancer because of the close proximity of other organs including the bladder and rectum making it nearly impossible to obtain adequate margins with organ-sparing approach, especially when the tumor has invaded beyond the vaginal mucosa. In the 2015 FIGO Cancer Report, Hacker et al. recommend only four situations in which surgery may be useful (Hacker et al. 2015): 1. Patients with stage I disease located in the upper posterior vagina: When a negative tumor margin of at least 1 cm can be obtained, and an adequate pelvic lymph node dissection performed, patients with small stage I tumors

E.C. McClung et al.

may benefit from radical upper vaginectomy (and hysterectomy if the uterus is in situ). 2. Ovarian transposition prior to radiation therapy for young patients. The authors note that debulking of large primary tumors and/or pelvic nodes larger than 2 cm in diameter may be performed at the time of this procedure. 3. Patients with locally advanced, stage IVA tumors may benefit from primary pelvic exenteration, but should also have a pelvic lymphadenectomy and consideration of bilateral groin dissection. This approach may also be combined with preoperative radiation therapy. 4. Patients with a central recurrence following primary radiation therapy should be offered pelvic exenteration if there is no evidence of distant metastases. Surgical case series report 5-year overall survival rates of 56–90 % for patients with stage I disease treated with partial or total vaginectomy (Davis et al. 1991; Creasman et al. 1998; Ling et al. 2008; Di Donato et al. 2012). Laparoscopic radical vaginectomy with neovagina construction has also been described with excellent overall survival and patient satisfaction. Cancer registrybased studies suggest a survival advantage for patients who are treated surgically when compared with radiation therapy (Ling et al. 2008). Creasman et al. report a 5-year survival rate of 90 % for women with stage I disease in the National Cancer Data Base treated with surgery, compared with 63 % for women who received radiation therapy alone and 79 % for women who received combined surgery and radiation therapy (Creasman et al. 1998). Similarly, Shah et al. also reported a trend toward improved survival in the SEER database for women with stage I disease treated by primary surgery; however, differences in the hazard ratios were only statistically significant when surgery was compared with no treatment for stage I disease (Shah et al. 2009). Trends toward improved survival with surgical management have also been reported for women with stage II disease, but these are not statistically significant, and survival rates are lower overall when compared to women with stage I disease.

Diagnosis and Management of Vaginal Cancer

In general, improved survival among women treated with primary surgery likely reflects careful selection criteria biased toward women with small, superficial tumors and little comorbidity. The true advantage of primary surgery for patients with early-stage vaginal cancer is preservation of ovarian and sexual function and avoidance of other radiation-related toxicities. For women with locally advanced disease, anterior, posterior, or total pelvic exenteration is necessary in order to achieve adequate margins around the tumor. Eddy et al. reported 50 % 5-year survival among six patients with stage IVA disease who underwent pelvic exenteration following preoperative radiation (Eddy et al. 1991). In general, exenteration should only be offered to patients who have a reasonable chance of long-term survival after the procedure. Preoperative evaluation should include efforts to rule out pelvic sidewall involvement or nodal and distant metastases. Most surgeons advocate beginning the procedure with exploratory laparotomy and pelvic lymphadenectomy to evaluate for peritoneal or nodal disease prior to beginning the exenteration. Radiation therapy techniques may include intracavitary or interstitial brachytherapy, external beam radiation therapy (EBRT), or intensitymodulated radiation therapy (IMRT). Practical considerations in the selection of radiation modality, dosing, and technique are summarized in the American Brachytherapy Society consensus guidelines and American College of Radiology Appropriateness Criteria for the management of vaginal cancer (Beriwal et al. 2012; Lee et al. 2013). Because of the high rate of local recurrence and lymph node involvement, most vaginal cancers should be treated with a combination of EBRT and brachytherapy. Most vaginal cancers are treated with pelvic EBRT to a dose of 45–50.4Gy in 25–28 fractions, followed by a boost to a cumulative dose of approximately 70Gy to the primary tumor site. The clinical target volume includes the gross tumor volume with a 1–2 cm margin, the entire vagina and paravaginal/parametrial tissues out to the pelvic sidewalls, and the bilateral pelvic lymph nodes, which generally correspond to the

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L5/S1 interspace. For tumors involving the middle or distal 1/3 of the vagina, inguinal nodes should also be included (Yeh et al. 2001). When pelvic lymph nodes are known to be involved, or bulky para-aortic nodes are present on pretreatment imaging studies, extended field coverage of the para-aortic region may be necessary. The boost to the primary tumor site may be accomplished through brachytherapy or IMRT or a combination. Selection of brachytherapy technique depends on the residual tumor thickness following EBRT. Vaginal cylinder brachytherapy is appropriate for residual disease mainly confined to the mucosa. Tandem and ovoids are typically used for women who have an intact uterus. When the depth of tumor involvement is greater than 5 mm, interstitial implants are required to adequately provide a definitive dose to the entire tumor. Interstitial applicator placement is usually done with epidural anesthesia in order to provide adequate pain control during the procedure and therapy. Laparoscopy or laparotomy may be necessary for appropriate interstitial catheter placement in large tumors in order to prevent inadvertent injury to the bowel. Marker seeds of fiducial gold, platinum, or carbon fiber can be used to define the extent of gross disease. Both low and high dose rate (LDR and HDR) protocols have been reported for the treatment of vaginal cancer, and neither has been definitively shown to be superior. There are fewer studies describing HDR; however, the advantage of this dose schedule is fewer fractions, and rather than continuous radiation dosing requiring radiation precautions, HDR protocols allow for visits and nursing care in between treatments (Beriwal et al. 2012). Among radiation therapy series of more than ten patients, 5-year disease-specific survival ranges from 36 to 100 % for stage I disease, 31 to 80 % for stage II disease, 8 to 80 % for stage III disease, and 0 to 40 % for stage IV disease (Di Donato et al. 2012). The range of survival rates likely reflects differences in radiation protocol as well as differences in the characteristics of each tumor. Concurrent chemoradiation therapy has become the standard of care for locally advanced cervical cancer and has been increasingly adopted

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as the primary treatment strategy for most vaginal cancers (Lee et al. 2013). In small series, chemotherapeutics including 5FU, mitomycin C, and cisplatin with concurrent radiation therapy resulted in 5-year survival rates of approximately 65 % (Di Donato et al. 2012). Some authors report locoregional recurrence rates as high as 61 % following chemoradiation (Roberts et al. 1991), but these reports are difficult to interpret due to variations in stage and tumor size among studies. In the largest single institution report, Miyamoto et al. present a significantly lower recurrence rate (15 % vs. 45 %, p = 0.027) for 20 patients with stage I–IV disease who received chemoradiation (mainly weekly cisplatin) compared with 51 patients who received radiation therapy alone (Miyamoto and Viswanathan 2013). Recently, a large National Cancer Data Base study by Rajagopalan et al. found that 48.6 % of 8086 patients who received radiation also received concurrent chemotherapy. Concurrent chemoradiation therapy was significantly associated with improved 5-year overall survival in all stages and for the entire cohort (48.8 % for chemoradiation vs. 41.9 % for radiation alone). Median overall survival was also significantly increased for all stages of disease when compared with patients who received radiation alone (109 vs. 85 months for stage I, 85.8 vs. 41.7 months for stage II, 43 vs. 19.9 months for stage III, and 18.5 vs. 9 months for stage IV) (Rajagopalan et al. 2014). Neoadjuvant chemotherapy prior to radical surgery has also been advocated in patients with stage II disease. Panici et al. describe 11 patients who received 3 cycles of cisplatin and paclitaxel followed by radical surgery. In this series, 27 % had a complete response and 64 % had a partial response prior to surgery, and 73 % were diseasefree at a median follow-up of 75 months (Panici et al. 2008). Posttreatment surveillance for vaginal cancer should follow Society of Gynecologic Oncology guidelines (Salani et al. 2011). For high-risk patients (those who were treated with chemotherapy, radiation, or surgery followed by adjuvant therapy or who had advanced disease), a focused history and careful exam should be performed

E.C. McClung et al.

every 3 months for the first 2 years after completing therapy and then every 6 months until 5 years without evidence of disease, after which visits can be repeated annually. Low-risk patients who have stage I disease and were treated by surgery alone may follow up every 6 months for the first 2 years and then annually. Vaginal cytology should be obtained annually to screen for microscopic recurrence, and any cytologic abnormalities should be evaluated with colposcopy. Symptoms such as vaginal bleeding or discharge, pelvic or abdominal pain, new palpable mass, or change in bowel or bladder habits should prompt a CT abdomen pelvis or PET CT to assess for recurrence. There is no evidence to support routine imaging in the absence of symptoms. Treatment complications affecting vaginal function and the lower urinary and GI tracts are the most common due to the close proximity of vaginal cancers to these pelvic structures. Radiation-related toxicity to the pelvic organs may include radiation cystitis or proctitis and vesicovaginal or rectovaginal fistula. Vesicovaginal and rectovaginal fistulas have also been reported as a complication of radical surgery. Vaginal radiation toxicity includes acute vaginitis, vaginal stricture, vaginal stenosis, or, rarely, vaginal necrosis. In series reporting rates of toxicity, the incidence of grade 2 complications has been reported to be 15–25 % (Gadducci et al. 2015). Factors that increase risk of complications include older age, smoking, medical comorbidities affecting vascular profusion and healing such as diabetes and hypertension, and prior pelvic surgery. Vaginal stricture and stenosis can be reduced with a combination of topical estrogen cream and dilator use. Women who are sexually active should continue to have intercourse on a regular basis if tolerated. Sexual dysfunction following treatment for vaginal cancer is likely multifactorial, and alterations in body image are common. Loss of fertility and premature menopause are important considerations in the treatment of young women. We recommend that women of reproductive age be offered consultation with reproductive endocrinology regarding fertility preservation options such as oocyte or embryo cryopreservation prior to initiating therapy for

Diagnosis and Management of Vaginal Cancer

vaginal cancer. Ovarian transposition to the anterior abdominal wall may reduce the likelihood of radiation-induced menopause and should be considered for some young patients. Patterns and rates of recurrence vary with initial stage at diagnosis. For stage I disease, the recurrence risk is approximately 10–20 %, compared with 30–40 % for stage II, and 50–70 % for stage III and IV (Davis et al. 1991; Chyle et al. 1996; Perez et al. 1999; Tabata et al. 2002). Among patients with stage I disease, locoregional recurrence is far more common, whereas patients with advanced locoregional disease at the time of diagnosis also have higher rates of both persistent disease and new distant metastases, which may occur in up to 47 % of patient (Perez et al. 1999; Tabata et al. 2002). Recurrent disease portends a very poor prognosis, with a 5-year survival rate of only 12 % (Chyle et al. 1996). As in the primary setting, salvage treatment strategies include surgical resection, radiation, and chemotherapy. Patients with stage I disease who did not receive radiation initially may be may receive radiation therapy with curative intent. Radiation protocols in this setting are similar to those used at the time of diagnosis and should include EBRT for empiric coverage of pelvic lymph nodes. Recurrences in the distal 1/3 of the vagina should also be treated with empiric sterilization of the bilateral groins. Similarly, in patients with a prior history of radiation, radiation may still be a reasonable option for disease outside the previously radiated field. Patients who have previously received chemoradiation present a therapeutic challenge because bone marrow reserves have been depleted. Women with local recurrence limited to the central pelvis should be offered pelvic exenteration, which offers the only path to long-term disease-free survival, particularly among patients who have failed definitive radiation. Distant metastases are best treated with systemic chemotherapy, palliative radiation if focal in nature, or best supportive care. Few studies evaluating chemotherapy for recurrent vaginal cancer exist, and most report a poor response to therapy. In a phase II trial presented by Thigpen et al. of the Gynecologic Oncology Group (GOG

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26C), only 1/22 women experienced a complete response to cisplatin 50 mg/m2 given every 3 weeks. Combination therapy appears to be similarly ineffective. In a study of combination of bleomycin, vincristine (Oncovin), mitomycin C, and cisplatin (BOMP), only 1/15 women treated for recurrent disease experienced a response, compared with 5/6 treated in the primary setting (Belinson et al. 1985). For this reason, many patients who are not candidates for exenteration pursue palliative care. Prognosis has improved with advances in radiation and chemotherapy and particularly with adoption of chemoradiation (Rajagopalan et al. 2014). In a SEER database study by Shah et al. in 2009, stage is the most important predictor of prognosis. A summary of survival rates by stage at diagnosis is provided in Table 1. Other factors linked to shorter overall survival in large cancer registry studies include larger tumor size (>4 cm), lymph node involvement, and older age (Creasman et al. 1998; Shah et al. 2009; Rajagopalan et al. 2014; Gadducci et al. 2015).

9.3

Adenocarcinomas

(Summarized in Table 3) As discussed earlier in this chapter, most vaginal adenocarcinomas reported in the literature are DES-related clear cell carcinomas occurring in adolescents and young women. The prognosis of vaginal clear cell carcinoma is better than for squamous cell carcinoma, with 5-year survival rates of 92 % for stage I and 83 % for stage II disease (Senekjian et al. 1987, 1988). In contrast, non-DES-related vaginal adenocarcinomas carry a relatively poor prognosis. In a series from MD Anderson, the median age at diagnosis was 54 and 5-year survival of only 34 %, compared with 58 % among squamous cell carcinoma patients at the same institution (Frank et al. 2007). Both DES-related and non-DES-related adenocarcinomas are treated similarly to vaginal squamous cell carcinoma. The management of adolescent and young women should include efforts to preserve fertility and sexual function when possible. When a tumor is too large for local excision and

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radiation is planned, laparoscopic ovarian transposition should be considered to reduce risk of premature menopause.

9.4

Melanoma

(Summarized in Table 3) Primary vaginal melanoma is the third most common primary malignancy of the vagina, representing 3–6 % of all vaginal cancers (Creasman et al. 1998; Shah et al. 2009) and only approximately 1 % of all melanomas. Vaginal melanomas most often present as a pigmented or ulcerated lesion in the distal 1/3 of the vagina. Amelanotic lesions have also been described and can be mistaken for squamous cell carcinoma. Immunohistochemistry staining for S-100, HMB45, or Melan-A may be helpful in confirming the diagnosis. The average age at diagnosis is approximately 60, and the majority of patients are white non-Hispanic (Leitao et al. 2014). The prognosis of vaginal melanoma is very poor, with 5-year overall survival of 5–20 % (Creasman et al. 1998; Leitao et al. 2014). Survival for vaginal melanoma is also poor compared to melanomas arising in other sites, likely due to diagnosis at later stages of disease. Melanomas are classically thought to be resistant to radiation, and few traditional systemic chemotherapies have been shown to be active. As a result, surgical resection is the mainstay of therapy for vaginal melanoma, with clear surgical margins being the most important determinant of disease control. Acceptable clinical margins for melanoma are 0.5 cm for melanoma in situ, 1 cm for Breslow thickness less than or equal to 2 mm (AJCC T1 or T2 tumors), and 2 cm for Breslow thickness greater than 2 mm (Garbe et al. 2010). Breslow thickness has not been evaluated for vaginal melanoma, and FIGO staging of vaginal cancer is frequently used. Pelvic exenteration has not demonstrated superior survival compared with wide local excision. Even though sentinel lymph node dissection (SLND) is associated with improved survival in cutaneous melanoma, it has not been widely adopted or evaluated in vaginal melanoma

cases. Adjuvant radiation using a similar approach to that used for vaginal squamous cell carcinoma has also been reported, with the possibility of cure. Preoperative radiation can also be considered as a way to improve the chance of complete resection for larger tumors. Treatment should be approached with consultation with a melanoma specialist at a tertiary center whenever possible. Traditional chemotherapeutics have not been demonstrated to improve overall survival, but there is promising data supporting combination of chemotherapy with targeted agents and immunotherapies. While targeted therapies have not been formally evaluated for primary vaginal melanoma, the BRAF inhibitor vemurafenib and immune modulator ipilimumab have yielded promising results in the melanoma field. In light of recent developments and rapidly improving outcomes using novel agents, women with vaginal melanoma should be encouraged to consider clinical trial participation when such opportunities are available.

9.5

Mesenchymal Tumors

Vaginal leiomyosarcoma, a bulky, rapidly growing smooth muscle tumor with a high mitotic index, is the most common mesenchymal tumor of the vagina in adults, but is extremely rare in general. Radical surgical resection offers the best chance of cure, but 5-year overall survival is only 36 % (Peters et al. 1985). Vaginal carcinosarcoma and primary vaginal endometrial stromal sarcoma have also been reported. Treatment of these tumors is generally extrapolated from strategies employed for the corresponding uterine primaries. Embryonal rhabdomyosarcoma (sarcoma botryoides, summarized in Table 3) is characterized by the presence of cross-striated rhabdomyoblasts. This rare tumor has been treated with radical surgery including pelvic exenteration in the past, but is now more commonly treated with chemotherapy in combination with more conservative surgery and radiation. The Intergroup Rhabdomyosarcoma Study Group (IRSG) has conducted four clinical trials from

Diagnosis and Management of Vaginal Cancer

1972 to 1997, including all tumor sites that are used to guide therapy and is now in the process of a fifth study (Raney et al. 2001). The IRSG classifies tumors into four groups: (I) localized disease that is completely excised with no microscopic residual tumor; (II) complete gross resection of disease with microscopic residual disease, including regional disease with positive lymph nodes; (III) incomplete resection with gross residual disease; and (IV) distant metastases. In the IRS-I through IRS-IV studies, patients in groups I–III received a combination of vincristine, actinomycin D, and cyclophosphamide (VAC) for 12 months sometimes in combinations with ifosfamide, or etoposide, and patients in group IV were randomized to receive vincristine and melphalan (VM) or ifosfamide and doxorubicin (ID) followed by VAC and radiation therapy.

9.6

Other Histologies

Rare variants of vaginal cancer have been reported including primary vaginal lymphoma, Wilms tumor, and Ewing sarcoma, as well as germ cell tumors including childhood vaginal endodermal sinus tumors and variants of epithelial carcinomas such as glassy cell and small cell neuroendocrine carcinomas. Treatment of such variants should be individualized and may include elements of management for vaginal cancer combined with therapies adapted for similar histologies at more common disease sites.

10

Summary

Primary vaginal cancer is a rare entity. Squamous cell carcinoma is the most commonly seen histology affecting women in their sixth and seventh decade of life. Most, but not all, squamous cell carcinomas of the vagina are related to HPV infection. Majority of women are asymptomatic or present with vaginal bleeding or a vaginal mass. The diagnosis and staging are accomplished primarily through physical exam, with confirmatory biopsies, although PET and MRI studies are likely

15

to have an increasing role in predicting prognosis and determining optimal treatment. Radiation is the mainstay of therapy except in select cases of focal, early-stage disease or central recurrences. With the introduction of chemoradiation, overall survival approaches rates seen in cervical cancer. Because of the rarity of this disease, there is no recommended screening; however HPV vaccination efforts hold promise for reducing the incidence of this disease in the future.

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16 associated with diethylstilbestrol (DES) exposure. Gynecol Oncol. 2007;105(2):470–4. Fu YS, Reagan JW. Pathology of the uterine cervix, vagina, and vulva. Philadelphia: WB Saunders; 1989. Gadducci A, Fabrini MG, Lanfredini N, Sergiampietri C. Squamous cell carcinoma of the vagina: natural history, treatment modalities and prognostic factors. Crit Rev Oncol Hematol. 2015;93(3):211–24. Garbe C, Peris K, Hauschild A, Saiag P, Middleton M, Spatz A, Grob J-J, Malvehy J, Newton-Bishop J, Stratigos A. Diagnosis and treatment of melanoma: European consensus-based interdisciplinary guideline. Eur J Cancer. 2010;46(2):270–83. Gurumurthy M, Cruickshank ME. Management of vaginal intraepithelial neoplasia. J Low Genit Tract Dis. 2012;16(3):306–12. Hacker NF, Eifel PJ, van der Velden J. Cancer of the vagina. Int J Gynaecol Obstet. 2015;131 Suppl 2: S84–7. PubMed PMID: 26433679. Epub 2015/10/05. eng. Hellman K, Silfversw€ard C, Nilsson B, Hellström A, Frankendal B, Pettersson F. Primary carcinoma of the vagina: factors influencing the age at diagnosis. The Radiumhemmet series 1956–96. Int J Gynecol Cancer. 2004;14(3):491–501. Herbst AL, Andersond D. Clear cell adenocarcinoma of the vagina and cervix secondary to intrauterine exposure to diethylstilbestrol. Semin Surg Oncol. 1990;6 (6):343–346. Wiley Online Library. Indermaur MD, Martino MA, Fiorica JV, Roberts WS, Hoffman MS. Upper vaginectomy for the treatment of vaginal intraepithelial neoplasia. Am J Obstet Gynecol. 2005;193(2):577–81. Lamoreaux WT, Grigsby PW, Dehdashti F, Zoberi I, Powell MA, Gibb RK, Rader JS, Mutch DG, Siegel BA. FDG-PET evaluation of vaginal carcinoma. Int J Radiat Oncol Biol Phys. 2005;62(3):733–7. Lee LJ, Jhingran A, Kidd E, Cardenes HR, Elshaikh MA, Erickson B, Mayr NA, Moore D, Puthawala AA, Rao GG. Acr appropriateness criteria management of vaginal cancer. Oncology (Williston Park). 2013;27 (11):1166–73. Leitao Jr MM, Cheng X, Hamilton AL, Siddiqui NA, Jurgenliemk-Schulz I, Mahner S, Avall-Lundqvist E, Kim K, Freyer G. Gynecologic Cancer InterGroup (GCIG) consensus review for vulvovaginal melanomas. Int J Gynecol Cancer. 2014;24(9 Suppl 3): S117–22. Ling B, Gao Z, Sun M, Sun F, Zhang A, Zhao W, Hu W. Laparoscopic radical hysterectomy with vaginectomy and reconstruction of vagina in patients with stage I of primary vaginal carcinoma. Gynecol Oncol. 2008;109(1):92–6. Magné N, Oberlin O, Martelli H, Gerbaulet A, Chassagne D, Haie-Meder C. Vulval and vaginal rhabdomyosarcoma in children: update and reappraisal of Institut Gustave Roussy brachytherapy experience. Int J Radiat Oncol Biol Phys. 2008;72 (3):878–83.

E.C. McClung et al. Miyamoto DT, Viswanathan AN. Concurrent chemoradiation for vaginal cancer. PLoS One. 2013;8 (6):e65048. Morrow CP, Curtin JP. Synopsis of gynecologic oncology. Newyork: Churchill Livingstone; 1998. Paczos TA, Ackers S, Odunsi K, Lele S, MhawechFauceglia P. Primary vaginal adenocarcinoma arising in vaginal adenosis after CO2 laser vaporization and 5-fluorouracil therapy. Int J Gynecol Pathol. 2010;29 (2):193–6. Panici PB, Bellati F, Plotti F, Di Donato V, Antonilli M, Perniola G, Manci N, Muzii L, Angioli R. Neoadjuvant chemotherapy followed by radical surgery in patients affected by vaginal carcinoma. Gynecol Oncol. 2008;111(2):307–11. Perez CA, Grigsby PW, Garipagaoglu M, Mutch DG, Lockett MA. Factors affecting long-term outcome of irradiation in carcinoma of the vagina. Int J Radiat Oncol Biol Phys. 1999;44(1):37–45. Peters III WA, Kumar NB, Andersen WA, Morley GW. Primary sarcoma of the adult vagina: a clinicopathologic study. Obstet Gynecol. 1985;65 (5):699–704. Plentl AA, Friedman EA. Lymphatic system of the female genitalia. Philadelphia: WB Saunders; 1971. Rajagopalan MS, Xu KM, Lin JF, Sukumvanich P, Krivak TC, Beriwal S. Adoption and impact of concurrent chemoradiation therapy for vaginal cancer: a National Cancer Data Base (NCDB) study. Gynecol Oncol. 2014;135(3):495–502. Raney RB, Maurer HM, Anderson JR, Andrassy RJ, Donaldson SS, Qualman SJ, Wharam MD, Wiener ES, Crist WM. The Intergroup Rhabdomyosarcoma Study Group (IRSG): major lessons from the IRS-I through IRS-IV studies as background for the current IRS-V treatment protocols. Sarcoma. 2001;5(1):9–15. Rhodes HE, Chenevert L, Munsell M. Vaginal intraepithelial neoplasia (VaIN 2/3): comparing clinical outcomes of treatment with intravaginal estrogen. J Low Genit Tract Dis. 2014;18(2):115–21. Roberts WS, Hoffman MS, Kavanagh JJ, Fiorica JV, Greenberg H, Finan MA, Cavanagh D. Further experience with radiation therapy and concomitant intravenous chemotherapy in advanced carcinoma of the lower female genital tract. Gynecol Oncol. 1991;43 (3):233–6. Salani R, Backes FJ, Fung MFK, Holschneider CH, Parker LP, Bristow RE, Goff BA. Posttreatment surveillance and diagnosis of recurrence in women with gynecologic malignancies: Society of Gynecologic Oncologists recommendations. Am J Obstet Gynecol. 2011;204(6):466–78. Saslow D, Solomon D, Lawson HW, Killackey M, Kulasingam SL, Cain JM, Garcia FAR, Moriarty AT, Waxman AG, Wilbur DC, Wentzensen N, Downs LSJ, Spitzer M, Moscicki A-B, Franco EL, Stoler MH, Schiffman M, Castle PE, Myers ER. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical

Diagnosis and Management of Vaginal Cancer Pathology screening guidelines for the prevention and early detection of cervical cancer. J Low Genit Tract Dis. 2012;16(3):175–204. Senekjian EK, Frey KW, Anderson D, Herbst AL. Local therapy in stage I clear cell adenocarcinoma of the vagina. Cancer. 1987;60(6):1319–24. Senekjian EK, Frey KW, Stone C, Herbst AL. An evaluation of stage II vaginal clear cell adenocarcinoma according to substages. Gynecol Oncol. 1988;31 (1):56–64. Shah CA, Goff BA, Lowe K, Peters III WA, Li CI. Factors affecting risk of mortality in women with vaginal cancer. Obstet Gynecol. 2009;113(5):1038. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5–29. Smith JS, Backes DM, Hoots BE, Kurman RJ, Pimenta JM. Human papillomavirus type-distribution in vulvar

17 and vaginal cancers and their associated precursors. Obstet Gynecol. 2009;113(4):917–24. Tabata T, Takeshima N, Nishida H, Hirai Y, Hasumi K. Treatment failure in vaginal cancer. Gynecol Oncol. 2002;84(2):309–14. Taylor MB, Dugar N, Davidson SE, Carrington BM. Magnetic resonance imaging of primary vaginal carcinoma. Clin Radiol. 2007;62(6):549–55. Wang Y, Li Q, Du H, Lv S, Liu H. Uterine prolapse complicated by vaginal cancer: a case report and literature review. Gynecol Obstet Invest. 2014;77 (2):141–4. Yeh AM, Marcus Jr RB, Amdur RJ, Morgan LS, Million RR. Patterns of failure in squamous cell carcinoma of the vagina treated with definitive radiotherapy alone: what is the appropriate treatment volume? Int J Cancer. 2001;96(S1):109–16.

Diagnosis and Management of Vulvar Cancer Mariko Shindo, Yutaka Ueda, Tadashi Kimura, and Koji Matsuo

Abstract

Contents 1

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2

2

Diagnosis and Staging . . . . . . . . . . . . . . . . . . . . . . . . .

2

3

Tumor Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4

4

Prognostic Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5

5 Treatment of Early Stage Disease . . . . . . . . . . . . 5.1 Surgical Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2 Surgical Management of the Primary Tumor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3 Management of Lymph Nodes . . . . . . . . . . . . . . . . . . 5.4 Adjuvant Radiotherapy . . . . . . . . . . . . . . . . . . . . . . . . .

5 5

6 Management of Advanced Stage Tumors . . . . 6.1 Surgery Advanced Disease . . . . . . . . . . . . . . . . . . . . . 6.2 Management of Groin Lymph Nodal Metastasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3 Role of Chemoradiation Therapy . . . . . . . . . . . . . . . 6.4 Role of Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . 6.5 Recurrence and Prognosis . . . . . . . . . . . . . . . . . . . . . . 6.6 Follow-up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.7 Melanoma of the Vulva . . . . . . . . . . . . . . . . . . . . . . . . . 6.8 Vulvar Cancer in Pregnancy . . . . . . . . . . . . . . . . . . . . 7

5 7 8 10 10 10 12 13 14 15 15 16

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

M. Shindo • Y. Ueda • T. Kimura Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan e-mail: [email protected]; [email protected]; [email protected] K. Matsuo (*) Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA e-mail: [email protected] # Springer International Publishing AG 2017 D. Shoupe (ed.), Handbook of Gynecology, DOI 10.1007/978-3-319-17002-2_9-2

Vulvar cancer is rare, comprising only 5 % of all gynecologic malignancies. However, the incidence of invasive vulvar carcinoma has been increasing moderately over the past two decades, and the incidence of in situ vulvar carcinoma has increased more than fourfold in the same period. Vulvar squamous cell carcinoma, the most common form of this cancer, is commonly divided into two basic types: HPV-associated and HPV-independent. To improve vulvar cancer survival, early detection by careful screening is important. FIGO surgical staging system for vulvar cancer was updated in 2009, incorporating prognostic factors such as inguinal lymph node metastasis. The number and morphology including the size, extracapsular spread of the involved nodes have been taken into account. The presence of fixed or ulcerated inguino-femoral nodes is also included to a staging system. The standard treatment for vulvar cancer has been primarily surgery; however, to decrease morbidity and improve survival outcome, more conservative and individualized treatment practices have recently been explored. The benefit of postoperative adjuvant therapy has been shown in the past decades; although an indication for adjuvant therapy needs further discussion. In advanced vulvar cancer, multimodality therapy including neoadjuvant chemoradiotherapy followed by surgical resection and definitive chemoradiotherapy has 1

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M. Shindo et al.

been investigated to avoid exenterative surgery or stoma formation. For patients with clinical positive inguino-femoral lymph nodes, node dissection or neoadjuvant chemoradiation therapy are now recommended. Keywords

Vulvar cancer • Squamous cell carcinoma • HPV • Conservative therapy • Management

1

Introduction

Vulvar cancer is a relatively rare disease of the female genital tract, accounting for roughly only 5 % of all gynecologic cancers. In 2015, the estimated number of expected new cases of vulvar cancer in the United States alone will be 5,150, with 1,080 accompanying deaths (Siegel et al. 2015). One large retrospective study found that, from the years 1973 to 2000, the incidence of invasive vulvar cancer in women had increased by approximately 20 %, from 1.8 cases per 100,000 to 2.2 cases per 100,000 (Judson et al. 2006), whereas the incidence of in situ carcinoma rose by an alarming 411 %, from 0.56 cases per 100,000 women to 2.86 per 100,000, during the same period. The same study observed that the incidence of invasive vulvar cancer begins to increase quickly after age 50 and that it peaks between the ages of 65–70. Conversely, the incidence of the noninvasive in situ form increases only until roughly the age of 40–49, whereupon it declines Histologically, vulvar squamous cell carcinoma (SCC) is the most common histologic subtype of vulvar cancer, accounting for 80–90 % of such malignancies (Beller et al. 2006), with vulvar melanoma being the second most common type. Other significant histological types include vulvar basal cell carcinoma, Paget’s disease of the vulva, vulvar adenocarcinoma, and Bartholin’s gland carcinoma. Vulvar Paget’s disease is discussed in the separate chapter. There are at least three main histological types of vulvar SCC: warty, basaloid, and keratinizing. Rarer histological variants of SCC are verrucous carcinoma, keratoacanthoma-like SCC, sarcomatoid carcinoma, and SCC with giant tumor cells. The warty

and basaloid patterns affect younger women, having risk factors similar to cervical cancer, and both are highly associated with high-grade vulvar dysplasia. The keratinizing pattern, which is a dominant pattern consisting 65–80 % of invasive vulvar SCC, affects older women and often accompanies lichen sclerosis or squamous hyperplasia. In the large study which reports over 1,700 cases of vulvar SCC, 25.1 % were human papilloma virus (HPV) positive. Of all invasive vulvar SCC, 72.2 % was the keratinizing pattern and 19.1 % was the warty and basaloid patterns. The warty and basaloid patterns were more likely to be HPV positive (69.5 %) compared to the keratinizing pattern (11.5 %). HPV type16 was the most common type in invasive vulvar SCC (de Sanjosé et al. 2013). Two distinct pathways, HPV-associated and non-HPV-associated, were proposed for development of vulvar SCC. In the HPV-associated vulvar SCC, the virus-encoded E6 and E7 oncoproteins cause inactivation of at least two important tumor suppressor proteins, p53 and Rb. In the non-HPVassociated type, it is the direct inactivation of p53 by missense and deletion mutations that is most frequently identified, although a number of other somatic mutational events are usually present as well. Because of the rarity of vulvar cancer, most studies have been retrospective clinicopathological reviews. Such studies have shown that the management of vulvar cancer has been making steady progress towards more conservative and individualized treatment plans. The standard treatment for early stage vulvar cancer remains surgery; however, more advanced disease cases are now treated with additional radiation and/or chemotherapy. Unfortunately, the choices of which treatments to use, and when, are still based mostly on case by case.

2

Diagnosis and Staging

The vulva consists of several distinct anatomical structures, the labia majora and minora, clitoris, mons pubis, vaginal vestibule, urinary meatus, and perineum. Over 70 % of vulvar cancers arise

Diagnosis and Management of Vulvar Cancer

Fig. 1 Squamous cell carcinoma of vulva

in the labia majora and minora. The overt symptoms of vulvar cancer can include pruritus, a palpable mass, a localized pain, vaginal discharge, dysuria, bleeding, or ulceration. However, a significant diagnostic delay for patients with vulvar cancer frequently occurs because the lesion is so often asymptomatic or lacks many of the more alarming symptoms, like unexpected bleeding, associated with other gynecological cancers. This lack of early warning symptoms means that, unfortunately, almost 40 % of patients with vulvar cancer are at advanced stage when first diagnosed (Homesley et al. 1991). Lack of suspicion for vulvar cancer is another reason for delay in diagnosis. At exam presentation, neoplastic vulvar lesions are usually visible and palpable (Fig. 1). Careful visual evaluation by a physician is important so as not to miss frequently occurring multiple skip lesions. To detect and treat these neoplasms at the earliest possible stages, all suspicious vulvar lesions need to be carefully biopsied. The biopsy will include the surface epithelial lesion and stroma to evaluate depth of lesion invasion, and each lesion needs to be fully histologically assessed. Clinically viable tumor sites but not necrotic areas are recommended for the biopsy site. Along with assessment of the vulva, the groin lymph nodes need to be evaluated carefully. Colposcopy of the cervix and vagina can be performed to detect other squamous intraepithelial neoplasms.

3

Invasive vulvar cancer usually spreads in two distinct ways: (i) by lymphatic spread to the regional lymph nodes or (ii) by direct expansion into any adjacent structures, such as the vagina, urethra, bladder, rectum, or anal sphincter. Distal hematogenous spread of vulvar cancer is relatively rare. During lymphatic spread, the first nodal metastasis usually involves the superficial inguinofemoral nodes, and moves subsequently into the deep inguino-femoral and pelvic nodes. Deep inguinal lymph node involvement occurs only in patients with superficial inguinal node metastasis (Andrews et al. 1994). The presence of pelvic lymph node metastasis with an absence of groin nodal metastasis is very rare. Lateral lesions generally drain to the ipsilateral groin nodes. Midline lesions and lesions within 1 cm of the midline can drain to bilateral nodes. In 1988, the International Federation of Gynecology and Obstetrics (FIGO) committee adopted a surgical staging system for vulvar cancer in which the pathological evaluation of the primary tumor and regional nodes was emphasized, based on the fact that, at the time, metastasis to regional nodes was the most important known prognostic factor and that clinical palpation evaluation of the lymph nodes was known to be unreliable. For example, in one study of 477 patients assessed with vulvar lesions, but having palpably normal groin lymph nodes, 24 % were later found at surgery to have positive nodes (Hoffman et al. 1985; Homesley et al. 1991). In 1991, problems with the 1988 FIGO surgical staging system for vulvar cancer became more apparent when the Gynecologic Oncology Group (GOG) reported on an analysis of survival outcome of 588 patients. When the patient had both a primary tumor 40 kg/m2 (or >35 kg/m2 with comorbidities) (Xanthakos and Inge 2006). The roux-en-Y gastric bypass (65%) or adjustable gastric banding (24%) (Xanthakos and Inge 2006) aims to cause weight loss by restricting food intake, food malabsorption, or both. All bariatric surgery candidates should undergo contraceptive options and preconception

The recommended weight gain for pregnancy is based on prepregnancy BMI. Pregnant women require 15% more calories than nonpregnant women, usually 300–500 kCal more per day, depending on the patient’s weight and activity. The total weight gain recommended is 25–35 lb for women with a normal BMI. Underweight women may gain 40 lb or more, and overweight women should limit weight gain to 90 cm and >80 cm, respectively, is considered abnormal. In patients with a BMI >35 kg/m2, measuring waist circumference is unnecessary since these individuals are already at high risk. Obese individuals are at increased risk of all-cause mortality, in addition to many serious illnesses including hypertension, dyslipidemia, type 2 diabetes, coronary artery disease, stroke, some types of cancer, sleep apnea, osteoarthritis, and mental disorders such as depression and anxiety. Obese women have a separate set of complications from men resulting from their elevated BMI. The effect of obesity on women’s gynecologic health is reviewed in this chapter.

Impact of Obesity on Gynecological Diseases

2

Obesity and the Menstrual Cycle

2.1

Puberty

Increases in weight and body fat are associated with a higher likelihood of early menarche. The decreasing age of puberty in the United States is thought to be due to, at least in part, the increasing prevalence of childhood obesity. According to the CDC, data collected over the past 30 years suggest that obesity rates have doubled in children and quadrupled in adolescents. Meanwhile, the overall age of puberty has decreased from approximately 12.75 years in the 1960s to approximately 12.5 years in the 1990s. Frisch and Revelle (1971) proposed a “critical fat hypothesis”, suggesting that puberty is initiated after a threshold level of fat is established (Frisch and McArthur 1974). The link between puberty and fat appears to be a protein hormone named leptin (Ahima et al. 1996). Leptin is produced in adipose tissue, circulates to the brain, and plays a crucial role in controlling hunger. Levels of leptin increase with increasing adiposity. Although a threshold level is necessary for the onset of puberty in females, evidence supports that leptin plays a permissive role. Leptin stimulates Kiss 1 neurons causing the Kiss 1 neurons to transmit metabolic information to GnRH neurons. Some studies have indicated that leptin also has direct gonadal effects that may contribute to the accelerated puberty in obese adolescents (Sanchez-Garrido and Tena-Sempere 2013). • Leptin-deficient mice fail to develop puberty, and injection of leptin in prepubertal mice triggers puberty. • Data derived from observation of children with untreated leptin deficiency or leptin receptor deficiency has demonstrated hypogonadotropic hypogonadism and failure to initiate puberty. Hence, leptin may be the link that determines a critical level of fat and allows/ triggers the onset of puberty by communicating with higher centers that control the hypothalamic pulses that trigger puberty.

3

• It has been reported that girls with an early onset of puberty have an increased risk of PCOS and cardiovascular events later in life.

2.2

PCOS and Insulin Resistance

Notoriously associated with insulin resistance, polycystic ovary syndrome (PCOS) is a complex functional endocrine disorder with clinical features of chronic anovulation, hyperandrogenism, and a derangement in follicular development resulting in polycystic-appearing ovaries. Women with PCOS have a unique disorder of insulin action resulting in a significant insulin resistance that is independent of obesity (Dunaif et al. 1989). The combination of PCOS and obesity has synergistic adverse effects glucose tolerance (Dunaif et al. 1989). Obesity is characterized by insulin resistance. With increasing weight, the levels of circulating insulin increase, causing a downregulation and decrease in the number of insulin receptors coupled with a concomitant increase in insulin resistance. In insulin resistance, fat, muscle, and liver cells are unable to respond normally to circulating insulin, and thus, higher levels of insulin are needed to help glucose enter the cells. The metabolism of proteins, carbohydrates, and fat and the catabolism of triglycerides are affected by high levels of glucose, leading to an increase in the levels of circulating free fatty acids and LDL cholesterol. The hyperinsulinemia associated with obesity is reversible with weight loss. Obesity contributes to chronic anovulation in several ways. First, the previously described hyperinsulinemia stimulates androgen production in the ovarian stroma, impairing follicular development. Also, with increasing adipose tissue, peripheral aromatization of androgens results in increased levels of estrogen that exert a negative feedback on the hypothalamo-pituitary-ovarian axis. Furthermore, levels of sex hormone-binding globulin (SHBG), a protein carrier produced in the liver that transports the principal sex steroids, are inversely related to body weight. In obese women, low levels of hepatic SHBG lead to further

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increases in unbound levels of testosterone and estradiol in the circulation. The chronic anovulation associated with obesity results in a state of unopposed estrogen that drives the proliferation of endometrial tissue and the resultant frequent, irregular bleeding. Studies have suggested that more than a third of overweight and obese women have irregular menses and that menstrual irregularity correlates with increasing BMI (Hedley et al. 2004). The effect of unopposed estrogen on the endometrium can also result in endometrial hyperplasia and cancer (discussed below, Sect. 7). Weight loss alone can restore ovulation in patients with PCOS. A moderate decrease in body weight of 5–10% has been shown to be associated with a return of ovulatory function in the majority of obese anovulatory women with PCOS (Crosignani et al. 2003). The state of hyperestrogenism associated with obesity has also been implicated in the pathogenesis of endometrial polyps. A study by Onalan et al. (2009) demonstrated that obesity was an independent factor in the development of endometrial polyps and positively correlated with their size and number, which could be another factor manifesting with abnormal uterine bleeding in obese women.

3

Infertility and ART

While many obese patients are not infertile, obesity was found to be associated with decreased fertility, diminished response to infertility treatments, and increased risk of miscarriage.

3.1

Fertility

A cohort study of 53,910 couples enrolled in the Danish National Birth Cohort found a doseresponse relationship between increasing BMI and decreased fecundity (Ramlau-Hansen et al. 2007). As described above (Sect. 2.2), obesity is associated with an endocrinopathy that manifests by hyperinsulinemia and insulin resistance, coupled with hyperandrogenemia, leptin

deficiency, increased LH, abnormal FSH-LH ratio, decreased sex hormone-binding globulin, increased estrogen, and decreased progesterone levels. This hormonal profile affects neuroregulation of the hypothalamic-pituitarygonadal axis resulting in anovulation and decreased fertility. Weight loss is capable of correcting the anovulation associated with obesity and PCOS. Insulin-sensitizing drugs, predominantly metformin, have also been shown to restore ovulation in some women with PCOS. Beyond anovulation, obesity itself appears to be associated with a lower fecundity (Gesink Law et al. 2007). In a cohort study by Zaadstra et al. (1993), an increased waist to-hip ratio was found to be associated with delay in time to conception, even after adjustment for patient weight and cycle length or regularity. A Dutch study found that the probability of natural conception declined by 4% per kg/m2 in women with a BMI >29 kg/m2 (van der Steeg et al. 2008). The mechanisms related to this decrease in fertility in obese ovulatory women are not completely understood.

3.2

Miscarriage

There is evidence that obesity increases the rate of spontaneous abortions by almost threefold compared to women of normal weight. In a retrospective study of 712 egg donation cycles (Bellver et al. 2007), showed the rate of miscarriages to be 13.3% in normal-weight women, 15.5% in overweight women, and 38.1% in obese women. Various theories have been proposed to explain this increased rate. Obesity and the associated endocrine alterations may affect corpus luteum function (Sherman and Korenman 1974; Fedorcsák et al. 2000), early embryo development (Kawamura et al. 2002; Fedorcsák and Storeng 2003), or endometrial receptivity (Alfer et al. 2000; Gonzalez et al. 2000) hence affecting embryo implantation and early development.

Impact of Obesity on Gynecological Diseases

3.3

Assisted Reproductive Technology (ART)

In addition to affecting the chances of spontaneous pregnancy, obesity also diminishes success rates with ART. With increasing BMI, there is evidence for an increase in in-vitro fertilization (IVF) cycle cancelation states, increasing gonadotropin requirements, a decrease in the number of oocytes collected, and an overall decrease in the rate of live births. An increase in body habitus also makes the procedure of oocyte retrieval technically challenging with increased rate of complications. At this point in time, many fertility practices will counsel their morbidly obese patients about weight loss prior to initiating ART aiming at a threshold BMI of less than 40 to qualify for IVF.

4

Contraception

4.1

Combination Oral, Transdermal, and Vaginal Contraceptives

Obesity may impair the efficacy of combined contraceptives. There is evidence of a higher risk of oral contraceptive (OC) failure in obese women when compared to normal-weight women. In a study by Holt et al. (2005), it was shown that women with a BMI >27.3 had a 60% higher risk of OC failure and those with a BMI >32.2 had a 70% higher risk. Similar results were seen in clinical trials of the combination transdermal patch, showing increased failure in women weighing above 90 kg (Zieman et al. 2002). Also, combination OC (COC) and obesity are both independent risk factors for venous thromboembolism (VTE). A case-control study found that in women using oral contraceptives with a BMI greater than 25, the rate of VTE is tenfold higher than in lean women not using oral contraceptives (Abdollahi et al. 2003). While the American Congress of Obstetricians and Gynecologists (ACOG) (American College of Obstetrics and Gynecology 2006) does not label obesity an absolute contraindication for combined contraceptives, it states OCs should be

5

used with caution in obese women above the age of 35. The CDC Medical Eligibility Criteria [USMEC] rate obesity with BMI 30 kg/m2 at category 2 [benefits generally outweigh the risks]; they also say the obese women who use COCs are more likely than obese women who do not use the pill to develop a VTE. • USMEC puts malabsorptive bariatric surgery into category 3 (risks generally outweigh benefits) although restrictive bariatric procedures [sleeves or bands] are category 2. • Obese women with hypertension or previous DVT/PE would fall into category 3/4 based on these factors. Accordingly, consideration should be given to a progestin-only contraceptive or to intrauterine devices. The levonorgestrel intrauterine device is a particularly attractive option for obese women given its non-contraceptive benefits of endometrial cancer risk reduction and decreased menstrual bleeding.

4.2

Progestin-Only Contraceptives

Progestin-only pills (POPs) are not as widely used as COC. They are particularly a good option for postpartum women, where the risk of thrombosis is elevated, since they do not increase the risk of VTE and do not negatively affect breast milk. Despite their increased safety profile, POPs used in the United States are associated with undesirable side effects such as irregular bleeding, and they have a very stringent daily timing (within 3 hours). POPs do not reliably suppress ovulation; however, their effectiveness relies on the changes they exert on the cervical mucus and the endometrium. For obese women, and women with other contraindications to COCs, the POPs offer the advantage that they do not increase the risk of venous thromboembolism while they maintain a success rate similar to that of OC. Injectable progestins have mechanisms of action similar to POPs that include increased cervical mucus viscosity, creation of an endometrium

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unfavorable for implantation, and unpredictable ovulation suppression. Their use is very popular in the United States. Depot medroxyprogesterone acetate (DMPA) has a contraceptive efficacy equivalent or better than that of COC but has a much better safety profile. In obese women, DMPA is safe. There are studies showing possible weight gain with the use of DMPA; however, not all studies have shown this effect.

4.3

Intrauterine Devices (IUD)

IUDs are one of the most effective methods of contraception. There are currently five different IUDs available in the United States, and they include one copper containing IUD and four different levonorgestrel-releasing IUDs. The effectiveness of IUDs is not affected by BMI as the mechanism of action does not rely on systemic hormone levels. In the Contraceptive CHOICE project, the overall failure rates of IUDs were less than one per hundred woman-years with no differences between various BMIs (Xu et al. 2012). The levonorgestrel-releasing IUD is a particularly attractive option for obese women. It exerts its contraceptive function by rendering the endometrium atrophic and stimulating thick cervical mucus, but its non-contraceptive uses are equally attractive. Since obese women have high rates of dysfunctional uterine bleeding and endometrial hyperplasia (Sect. 2.2), the levonorgestrelreleasing IUD is often used in obese women to minimize vaginal bleeding and decrease the risk of premalignant endometrial lesions.

5

Surgical Risk

Obese women are at higher risk of experiencing surgical and anesthetic complications. In a paradox referred to as the “obesity paradox” (Mullen et al. 2009), otherwise healthy obese patients undergoing non-bariatric surgery were found to have lower mortality and morbidity than normalweight patients. However, obese patients commonly have comorbid conditions such as

hypertension, obstructive sleep apnea, coronary artery disease, or a difficult airway, and these patients have an increased rate of surgical mortality and morbidity compared to the normal-weight patients.

5.1

Surgery in the Obese Patient

Physical exam and particularly the bimanual exam may be difficult in the clinic setting to decide on the preferred route of surgery. In this case, further imaging such as MRI is recommended for guidance. As in all patients, the least invasive route should be considered for better outcomes. Abdominal surgery in obese women takes longer and has a higher blood loss and higher rate of wound complications and surgical site infections, increased risk of VTE, and increased hospital stay. As the BMI rises, so do the risk of surgical site infection (Olsen et al. 2009) and wound complications (Nugent et al. 2011). Some intraoperative considerations have been suggested for surgery in obese patients. First, placement of the skin incision needs to be tailored to each patient, as anatomy of the abdominal wall may be distorted. In cases where an abdominal fat pad covers the lower abdomen, one must be aware that an incision under the fat pad is subjected to an intense maceration. Also, surgical instruments must be adapted to the situation, using wide retractors to maintain the thick abdominal wall. Mass closure, subcutaneous drains, and prophylactic antibiotics can be considered in order to minimize wound disruption. The implications for laparoscopic surgery are also present. The position of the umbilicus relative to the aortic bifurcation and the rest of the abdomen vary and may make abdomen penetration with a Veress needle challenging. Open laparoscopic entry has been found to be safer in obese subjects (Byron et al. 1989). Also of concern is that operating in the pelvis requires the patient to be in the Trendelenburg position. This positioning is known to increase intrathoracic pressure and particularly for obese patient may be associated with impaired oxygenation and difficulty in

Impact of Obesity on Gynecological Diseases

ventilation. The use of longer trocars and instruments needs to be anticipated. Laparoscopic surgery in obese patients may be more complicated and the risk of conversion to laparotomy is elevated, but these obstacles can be partly overcome with surgical experience (Wattiez et al. 2002). As with all patients, efforts to choose the least invasive surgery should be exerted. If appropriate, the vaginal route for hysterectomy is preferred to reduce postoperative pain and morbidity. This technique can also be challenging because of the size of the obese patient’s legs and buttocks, as well as the presence of redundant vaginal sidewalls, all of which can make visualization and surgery more difficult. According to the American College of Chest Physicians, obese woman who undergo gynecologic surgery for longer than 45 min fall in the category of moderate risk of VTE and should receive some form of prophylaxis unless at high risk of major bleeding. VTE prophylaxis can either be low molecular weight heparin, low-dose unfractionated heparin, or mechanical prophylaxis with intermittent pneumatic compression. Appropriately positioning the obese patient is of paramount importance and can prove to be challenging. The operating table can usually accommodate a patient weighing up to 205 kg, and some tables can accommodate up to 455 kg. Positioning of the patient should take into account surgeon ergonomics and provide protection to the patient from nerve injury and pressure sores. If the patient is to be placed in the lithotomy position, the boot-type stirrups are preferred for better lower extremity alignment and decreased pressure on the knees and hips as compared to the candy cane stirrups.

5.2

Anesthesia in the Obese Patient

Risks of anesthesia are higher in obese women with most issues related to technical problems such as constructing an airway, gaining venous access, or providing effective ventilation. Before undertaking gynecologic surgery, a preoperative consultation with an anesthesiologist should be

7

considered. The obese patient has an increase in cardiac output and a relatively lesser increase in blood volume, resulting in a relative hypovolemia with poor tolerance to fluid overloading and hemorrhage. Respiratory function is altered as well. There is a decrease in functional residual capacity and reserve expiratory volume, associated with an increase in the closure capacity and alveolar dead space. This results in a mismatch of ventilation and perfusion that can lead to hypoxia. The oral airway in the obese patient is suboptimal due to decreased neck mobility and narrowing of the pharyngeal space soft tissue effect. In addition, there is an increased risk of aspiration of gastric contents due to the higher intra-abdominal pressure. All of these concerns must be addressed at the preoperative consultation.

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Urinary Incontinence

Urinary incontinence, a loss of bladder control, affects more than 13 million women in the United States. The four main types of urinary incontinency include stress urinary incontinence (SUI), urge incontinence, overflow incontinence and functional incontinence. Patients often present with mixed symptoms. Obesity is an independent risk factor for the development of both stress and urge incontinence, with obese women having up to a 4.2-fold greater risk of than women of normal weight (Alling Moller et al. 2000). The severity of incontinence appears to be influenced by the duration and extent of obesity; which could be explained by the raised intra-abdominal pressure caused by central obesity conveying additional pressure on the pelvis and bladder. This association is further corroborated by studies showing that weight loss among obese women leads to a reduction in episodes of urinary incontinence (Subak et al. 2009). The mid-urethral sling procedure for the management of SUI has been found to be safe and effective in both obese and nonobese women, regardless of BMI (Weltz et al. 2015).

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Endometrial Cancer and Other Malignancies

Obesity is directly associated with a number of malignancies including colon cancer, kidney cancer, esophageal cancer, as well as endometrial cancer and postmenopausal breast cancer (Bianchini et al. 2002). The normal balance between cell proliferation and apoptosis in vulnerable tissues may be distorted by the endocrinopathies of obesity that includes fat cell alterations in the metabolism of sex steroids, insulin, and growth factors. Obese women are at a two-fourfold higher chance of developing endometrial cancer than women of normal weight. In obese women presenting for bariatric surgery, the rate of endometrial hyperplasia was found to be 10% (Modesitt et al. 2015). There are two types of endometrial cancer. Type I endometrioid adenocarcinomas are the most common, comprising 75% of all cases. They are estrogen-dependent and low-grade and are preceded by endometrial hyperplasia. On the other hand, type II endometrial cancers have a serous or clear cell histology and no precursor lesion and are generally more aggressive. Type I is the endometrial cancer that is more common in obese women; since obesity is often associated with hyperestrogenism due to peripheral aromatization of androgens to estrogen in the adipose tissue. More importantly, the chronic anovulatory status, which is frequently seen in obese women, results in the endometrium being exposed to unopposed estrogen. In the absence of progesterone-induced endometrial shedding, endometrial hyperplasia can frequently develop. While at this time performing an endometrial biopsy for all women with a BMI >30 is not recommended, ACOG recommends sampling the endometrium of all obese women with symptoms of heavy or irregular uterine bleeding regardless of age (ACOG 2012). Almost half of women with endometrial cancer or hyperplasia don’t know that obesity affects their cancer risk (Beavis et al. 2015), so it is the role of providers to identify these patients at high

risk and provide them with the appropriate counseling and education.

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Pelvic Imaging in the Obese Patient

8.1

Ultrasound

Ultrasound is often the imaging modality of choice in gynecology. However, transabdominal ultrasound is the radiologic modality that is the most affected by obesity because of the attenuation of the ultrasound beam by the layers of adipose tissue. Nonetheless, the availability of transvaginal imaging provides easier accessibility to the reproductive organs by bypassing the abdominal pannus. An often-used solution to the decreased penetration of the transvaginal ultrasound is by placing a hand on the pelvic organs to push them closer to the probe, which in some cases may afford better visualization. Abdominal scanning in the obese patient is often more challenging. The abdominal pannus limits visualization by both increasing the depth of insonation required and by attenuating the strength of the ultrasound beam. The abdominal pannus also increases the ergonomic challenge for the sonographer. Since the pannus is usually at its thickest between the pubis symphysis and the umbilicus, the patient or an assistant can be enlisted for help by lifting the fat pad upwards toward the patient’s head, thus providing a flatter and thinner abdominal wall and closer distance to the pelvic organs. The use of technology such as harmonic imaging, a nonlinear propagation of ultrasound through body tissues, can improve the quality of the image because fat will act to increase the harmonic waves created. Also, when available, the use of the preset “penetration” mode may result in higher quality image. When ultrasound imaging fails to provide adequate visualization of the pelvic organs, the imaging modality of choice is MRI when a gynecologic condition is suspected. CT scan is preferred in urologic and gastrointestinal conditions.

Impact of Obesity on Gynecological Diseases

8.2

Computed Tomography (CT)

CT imaging of the pelvis is generally adequate in obese patients. The main limiting factors for CT imaging in obesity are size of the patient relative to the machine, positioning, artifacts, and radiation exposure. In fact, CT scan manufacturers set a weight limit for the table beyond which the table can be damaged and the warranty is void. Also, the aperture through which the patient should go is set at a diameter of 70 cm, with newer enhanced models fitting up to an 80–90 cm diameter. The best practice in the case of patients with severe obesity is to obtain an exact weight and abdominal girth immediately prior to the procedure. In cases where the abdominal girth may be over the limit, there are abdominal binders that can be used for this purpose, also serving the additional benefit of preventing the pannus from hanging asymmetrically to the side causing artifacts. Another consideration in the use of CT scan is the quantity of contrast material used. The dose is typically obtained by considering the patient’s weight, and this may expose obese patients to a higher-thannecessary dose of contrast. A solution to this problem may be to use the lean body weight as opposed to the actual weight.

8.3

Magnetic Resonance Imaging (MRI)

Compared with ionizing radiation or sound waves, the radiofrequency used by MRI penetrates large amount of fat. Hence, MRI is the modality least affected by obesity. Challenges for MRI, like for CT scan, are mostly related to the size of the patient and the problems with positioning and length of the procedure. The tight fit of the patient in the aperture can cause claustrophobia and even motion artifacts. Also, there is a risk of skin burn if the patient is tightly fitting in the gantry. This can be minimized by placing cloth protections at the areas of friction (Glanc et al. 2012).

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9

Weight Loss

More than two-thirds of adults in the United States are either attempting to lose weight or preserve their weight. For patients who are overweight or obese and at risk for obesity-associated disorders, a number of weight loss interventions are available, including lifestyle, diet, exercise, pharmacotherapy, and surgery. Even moderate weight loss of 5–10% is associated with a reduction in obesity-associated morbidity. The role of the physician is to identify patients who would benefit from losing weight, determining an ideal body weight, and educating the patient about available options. The initial management is a combination of diet, exercise, and lifestyle modifications with a goal to create an energy deficit by either decreasing intake or increasing expenditure or ideally both. Pharmacological agents can be a useful adjunct to diet and exercise, with bariatric surgery increasingly used as a final option.

9.1

Diet

In a normal adult, approximately 22 calories are required to maintain a kilogram of body weight. Once a patient’s daily energy expenditure is calculated, one can calculate their daily caloric intake that generates a daily deficit. This is also used to estimate the resulting weekly weight loss. Diets providing less than 800 calories per day are not generally recommended. Balanced low calorie/portion-controlled diets are the most commonly recommended diets. They encourage the intake of foods with adequate nutrients, in addition to proteins, minimal carbohydrates, and essential fatty acids, while eliminating alcohol, sugar-containing beverages, and other sources of food that are high in carbs/ calories but poor in nutrients. • Low and very low carbohydrate diets have been popular for many years. Low carbohydrate diets contain 60–130 g of carbohydrates and very low carbohydrate diets contain up to

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L. Bou Nemer

59 g of diets. They are based on the fact that restriction of carbohydrates leads to glycogen mobilization and rapid weight loss primarily due to glycogen breakdown. Hence, they are more effective for short-term weight loss than low-fat diets. • Low-fat diets are another commonly used strategy for weight loss, recommending a reduction in the daily intake of fat to less than 30% of total dietary intake. Considering a diet of approximately 1500 calories, this would mean about 45 g or less of fat, which can be counted using the nutrition information labels on food packages. • The Mediterranean diet is inspired from the traditional diets of Greece, Spain, and the south of Italy. It includes primarily plantbased foods, such as vegetables, fruits, whole grains, legumes, and nuts. It replaces butter with monounsaturated fats such as olive oil and contains a moderate amount of dairy products and low amount of meat. A meta-analysis of eight cohort studies demonstrated that patients that adhered to a Mediterranean diet had a significantly improved health status, with a reduction in overall mortality, mortality from cardiovascular diseases, incidence and decreased mortality from cancer, and incidence of Parkinson’s disease and Alzheimer disease (Sofi et al. 2008).

9.2

Exercise

Exercise alone, without dietary changes, results in only modest reductions or no loss in weight. Adding exercise to diet has only slight additional benefits than diet alone. In a systematic review of 17 randomized trials, it was found that there was only a slight increase in weight loss in the diet and exercise group compared to the diet alone group and that this difference was statistically significant in only two of the studies (Catenacci and Wyatt 2007). However, adding exercise to diet has other important benefits independent of weight loss, such as attenuating the diet-induced loss of muscle mass.

9.3

Pharmacotherapy

In addition to diet, exercise, and lifestyle modification, drug therapy can be a helpful adjunct to weight loss in overweight patients with comorbidities and obese patients. The role of medications for weight loss has been questioned because of concerns about efficacy and safety; hence, the decision to initiate medications should only be made after a thorough evaluation of risks and benefits. There are five drugs currently approved for long-term use: orlistat, lorcaserin, phenterminetopiramate, bupropion-naltrexone, and liraglutide. Phentermine, benzphetamine, phendimetrazine, and diethylpropion have only been approved for short-term use. • Orlistat alters fat digestion by inhibiting pancreatic lipases, resulting in incomplete hydrolysis of fat and increased fat excretion in feces. The efficacy of orlistat has been demonstrated in many clinical trials demonstrating that initial weight loss is greater and that weight regain is slowed as compared with lifestyle/placebo. In addition, orlistat showed other beneficial effects such a reduction in HbA1c, improvement in blood pressure, and an improvement in lipid values more than what can be explained by weight loss alone. The predominant side effects are gastrointestinal, mainly cramps, flatus, fecal incontinence, and oily spotting. These side effects are high initially and then subside as patients learn to avoid them by avoiding high-fat diets. Absorption of fat-soluble vitamins (A, D, E, K) is lowered by orlistat therapy. • Lorcaserin is a selective agonist of the serotonin 2C receptor; it reduces appetite and therefore body weight. It appears to have similar efficacy as and fewer side effects than orlistat. In addition to weight loss, lorcaserin has other beneficial effects including decreases in blood pressure, lipid levels, fasting glucose, and insulin levels. Side effects are generally mild, and they include headache, upper respiratory infections, dizziness, and nausea.

Impact of Obesity on Gynecological Diseases

• Liraglutide is a long-acting glucagon-like peptide-1 analog that is available for use in the United States for treatment of type 2 diabetes. It is also approved for use at higher doses in the treatment of obese patients or patients with a BMI 27 kg/m2 with at least one weightrelated comorbidity. Liraglutide has been associated with a significant reduction in weight when compared to placebo in diabetes and non-diabetes trials. At the higher doses used for obesity treatment, liraglutide has higher rates of nausea and vomiting, side effects that may be partly responsible for the weight loss effect of the drug. Other side effects include diarrhea, hypoglycemia, and anorexia. • A preparation of combined phentermine and extended-release topiramate has been approved for obese adults or adults with BMI 27 kg/m2 with at least one weight-related comorbidity. This combination has been shown to increase weight loss in the first year of use. The most common side effect is dry mouth, constipation, and paresthesia. • The combination preparation of bupropionnaltrexone is not recommended as first-line therapy, but can be used for the obese smoker who desires therapy for smoking cessation and weight loss. Naltrexone is an opioid receptor antagonist used to treat alcohol and opioid dependence, and bupropion is used for depression and the prevention of weight gain during smoking cessation. The combination reduces weight by 4–5% compared to placebo. Side effects include nausea, headache, and constipation. • The sympathomimetic drugs phentermine, diethylpropion, benzphetamine, and phendimetrazine are only approved for shortterm treatment, up to 12 weeks. They reduce food intake by causing early satiety. Phentermine is the most widely prescribed weight loss drug; however, because of the potential side effects, potential for abuse, and limited duration of use, they are usually not recommended. They are contraindicated in patients with coronary artery disease, hypertension, and hyperthyroidism or in patients who have a history of drug abuse.

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9.4

Bariatric Surgery

Candidates for bariatric surgery include obese patients with a BMI 40 kg/m2 or patients with a BMI 35 kg/m2 with at least one serious comorbidity, such as type 2 diabetes or hypertension. Adults with BMI between 30 and 34.9 Kg/m2 can also be candidates if they suffer from uncontrolled type 2 diabetes or metabolic syndrome. Bariatric surgical procedures cause weight loss through two main mechanisms: malabsorption and restriction. Some procedures have both components. Malabsorptive procedures shorten the length of the functional small intestine and decrease the absorption of nutrients. Restrictive procedures work by limiting the caloric intake by reducing the stomach’s capacity. • The Roux-en-Y gastric bypass (RYGB) is the most commonly performed bariatric procedure. It involves the creation of a small gastric pouch that is divided and separated from the distal stomach and anastomosed to a limb of small bowel. While it is mainly a restrictive procedure, it also has a malabsorptive component that participates in weight loss. • The laparoscopic adjustable gastric banding is a restrictive procedure where an adjustable silicone ring is placed around the entrance of the stomach. Saline can be injected through an infusion port into the band to reduce its diameter, to increase the amount of restriction. • Another restrictive procedure, the sleeve gastrectomy is a partial resection of the greater curvature of the stomach, which creates a tubular stomach. This procedure is easier to perform than the RYGB. The created tubular stomach is small and resistant to stretching due the absence of the fundus.

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Conclusion

The impact of obesity on women’s reproductive health is significant with harmful effects noted on the menstrual cycle, fertility, contraception, urinary incontinence, surgical risk, imaging studies, and certain malignancies. Weight loss is a difficult

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but an achievable solution to many of these consequences. Weight loss can be achieved best in a multidisciplinary approach.

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Cross-References

▶ Conservative Management of Endometrial Cancer ▶ Work Up and Management of Polycystic Ovary Syndrome

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Crosignani PG, Colombo M, Begetti W, Somigliana E, Gessati A, Ragni G. Overweight and obese anovulatory patients with polycystic ovaries: parallel improvements in anthropometric indices, ovarian physiology and fertility rate induced by diet. Hum Reprod. 2003;18:1928–32. Dunaif A, Segal KR, Futterweit W, Dobrjansky A. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes. 1989;38(9):1165–74. Fedorcsak P, Dale PO, Storeng R, Tanbo T, Abyholm T. The impact of obesity and insulin resistance on the outcome of IVF or ICSI in women with polycystic ovarian syndrome. Hum Reprod. 2001;16:1086–91. Fedorcsák P, Storeng R. Effects of leptin and leukemia inhibitory factor on preimplantation development and STAT3 signaling of mouse embryos in vitro. Biol Reprod. 2003;69:1531–8. Frisch RE, McArthur JW. Menstrual cycles: fatness as a determinant of minimum weight for height necessary for their maintenance or onset. Science. 1974;185:949–51. Frisch RE, Revelle R. Height and weight at menarche and a hypothesis of menarche. Arch Dis Child. 1971;48:695–701. Gesink Law DC, Maclehose RF, Longnecker MP. Obesity and time to pregnancy. Hum Reprod. 2007;22:414–20. Glanc P, O'Hayon BE, Singh DK, Bokhari SA, Maxwell CV. Challenges of pelvic imaging in obese women. Radiographics. 2012;32(6):1839–62. Gonzalez RR, Caballero-Campo P, Jasper M, Mercader A, Devoto L, Pellicer A, Simon C. Leptin and leptin receptor are expressed in the human endometrium and endometrial leptin secretion is regulated by the human blastocyst. J Clin Endocrinol Metab. 2000;85:4883–8. Hedley AA, Ogden CL, Johneson CL, Carroll MD, Curtin LR, Flegal KM. Prevalence of overweight and obesity among U.S children, adolescents, and adults, 19992002. JAMA. 2004;291:2847–50. Holt VL, Scholes D, Wicklund KG, Cushing-Haugen KL, Daling JR. Body mass index, weight, and oral contraceptive failure risk. Obstet Gynecol. 2005;105:46–52. Kawamura K, Sato N, Fukuda J, et al. Leptin promotes the development of mouse preimplantation embryos in vitro. Endocrinology. 2002;143:1922–31. Modesitt S et al. Women at extreme risk for obesity-related carcinogenesis: baseline endometrial pathology and impact of bariatric surgery on weight, metabolic profiles and quality of life. Gynecol Oncol. 2015;138 (2):238–45. Mullen JT, Moorman DW, Davenport DL. The obesity paradox: body mass index and outcomes in patients undergoing nonbariatric general surgery. Ann Surg. 2009;250:166–72. Nugent EK, Hoff JT, Gao F, Massad LS, Case A, Zighelboim I, et al. Wound complications after gynecologic cancer surgery. Gynecol Oncol. 2011;121:347–52.

Impact of Obesity on Gynecological Diseases Olsen MA, Higham-Kessler J, Yokoe DS, Butler AM, Vostok J, Stevenson KB, Prevention Epicenter Program, Centers for Disease Control and Prevention, et al. Developing a risk stratification model for surgical site infection after abdominal hysterectomy. Infect Control Hosp Epidemiol. 2009;30:1077–83. Onalan R, Onalan G, Tonguc E, Ozdener T, Dogan M, Mollamahmutoglu L. Body mass index in an independent risk factor for the development of endometrial polyps in patients undergoing in vitro fertilization. Fertil Steril. 2009;91(5):1056–60. Ramlau-Hansen CH, Thulstrup AM, Nohr EA, Bonde JP, Sorensen TIA, Olsen J. Subfecundity in overweight and obese couples. Hum Reprod. 2007;22:1634–7. Sanchez-Garrido MA, Tena-Sempere M. Metabolic control of puberty: roles of leptin and kisspeptins. Horm Behav. 2013;64:187–94. doi:10.1016/j. yhbeh.2013.01.014. Sherman BM, Korenman SG. Hormonal characteristics of the human menstrual cycle throughout reproductive life. J Clin Invest. 1975;55:699–706. Sofi F, Cesari F, Abbate R, et al. Adherence to Mediterranean diet and health status: meta-analysis. BMJ. 2008;337:a1344. Subak LL, Wing R, West DS et al. Weight loss to treat urinary incontinence in overweight and obese women. N Engl J Med 2009; 360, 481-490

13 Van der Steeg JW, Steures P, Eijkemans MJ, Habbema JD, Hompes PG, Burggraaff JM, et al. Obesity affects spontaneous pregnancy chances in subfertile, ovulatory women. Hum Reprod. 2008;23:324–8. Wattiez A, Soriano D, Cohen SB, Nervo P, Canis M, Botchorishvili R, et al. The learning curve of total laparoscopic hysterectomy: comparative analysis of 1647 cases. J Am Assoc Gynecol Laparosc. 2002;9:339–45. Weltz V, Guldberg R, Lose G. Efficacy and perioperative safety of synthetic mid-urethral slings in obese women with stress urinary incontinence. Int Urogynecol J. 2015;26(5):641–8. Xu H, Wade JA, Peipert JF, et al. Contraceptive failure rates of etonogestrel subdermal implants in overweight and obese women. Obstet Gynecol. 2012;120(1):21–6. Zaadstra BM, Seidell JC, Van Noord PA, te Velde ER, Habbema JD, Vrieswijk B, et al. Fat and female fecundity: prospective study of effect of body fat distribution on conception rates. BMJ. 1993;306:484–7. Zieman M, Guillebaud J, Weisberg E, Shangold GA, Fisher AC, Creasy GW. Contraceptive efficacy and cycle control with Ortho Evra/Evra transdermal system: the analysis of pooled data. Fertil Steril. 2002;77:S13–8.

Abnormal Vaginal Bleeding During the Early Reproductive Years Anita L. Nelson

Abstract

Contents 1

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2

2

Secondary Amenorrhea . . . . . . . . . . . . . . . . . . . . . . .

3

3

Infrequent Menses . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6

4

Postcoital Bleeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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5

Intermenstrual Bleeding . . . . . . . . . . . . . . . . . . . . . .

8

Heavy Menstrual Bleeding . . . . . . . . . . . . . . . . . . . . Acute Heavy Bleeding . . . . . . . . . . . . . . . . . . . . . . . . . . Chronic Heavy Menstrual Bleeding . . . . . . . . . . . . Medical Therapies for Chronic Heavy Menstrual Bleeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.4 Surgical Therapies for Heavy Menstrual Bleeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 6.1 6.2 6.3

9 10 12 13 15

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Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

8

Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

New terminology was introduced by the Menstrual Disorder Working Group of the International Federation of Gynecology and Obstetrics (FIGO) and approved by ACOG several years ago to facilitate accurate descriptions of all dimension of each woman’s bleeding. These descriptors better characterize abnormal uterine bleeding patterns than the older imprecise terms, such as “dysfunctional uterine bleeding” and “menorrhagia.” The new PALM-COEIN classification system was implemented shortly thereafter to standardize reporting of etiologies of abnormal bleeding. Utilizing these new tools and current practice guidelines, this chapter will provide an overview of the differential diagnoses, evaluations, and treatment of women presenting with abnormal uterine bleeding from adolescence through the end of a woman’s reproductive years. Keywords

Abnormal uterine bleeding • Amenorrhea • Infrequent bleeding • Postcoital bleeding • Intermenstrual bleeding • Heavy menstrual bleeding • PCOS

A.L. Nelson (*) David Geffen School of Medicine at UCLA, Los Angeles, CA, USA e-mail: [email protected] # Springer International Publishing AG 2016 D. Shoupe (ed.), Handbook of Gynecology, DOI 10.1007/978-3-319-17002-2_23-1

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A.L. Nelson

Introduction

Information about uterine bleeding is an essential vital sign for reproductive age women. At every clinical encounter, a woman should be asked about the normalcy and timing of her last menses. At initial and periodic well-woman visits, a full description of a patient’s menstrual bleeding should be documented, including the frequency of her bleeding, duration of flow, volume of flow, and cycle-to-cycle variability. Table 1 shows the latest FIGO definition as well as normal values and acceptable words to use to describe abnormal patterns of bleeding. Self-characterization of bleeding, e.g., “irregular” versus “normal,” is not sufficient; numerical estimates are needed (Fraser et al. 2011). Abnormal uterine bleeding patterns range from complete absence of any uterine spotting to excessive and/or prolonged bleeding. Many different reproductive and general health conditions can result in abnormal bleeding, so evaluation should always be comprehensive. When a woman first complains of “abnormal bleeding,” careful questioning can provide the information needed to describe her bleeding patterns utilizing the terms in Table 1 (Fraser et al. 2011). A through physical exam is needed because it may reveal the Table 1 Menstrual parameters in the reproductive years Clinical dimensions of menstruation and menstrual cycle Frequency of menses, days Regularity of menses: cycle-to-cycle variation over 12 months, days

Descriptive term Frequent Normal Infrequent Absent Regular Irregular

Duration of flow, days

Volume of monthly blood loss, mL

Prolonged Normal Shortened Heavy Normal Light

Normal limits (5th–95th percentiles) 20 >8.0 4.5–8.0 80 5–80 80 mL) characterized their monthly flow as light or moderate and did not recognize that their loss was excessive. Prolonged bleeding is more easily diagnosed probably because it is more easily quantified than heavy blood loss. Surprisingly, many women who routinely have menstrual flow for more than 8 days frequently report it as “normal,” often because many or all of the women in their families had similar bleeding patterns. Some women may think heavy or prolonged blood loss indicates higher fertility or femininity or more through “cleaning out” (Coutinho and Segal 1999). On the other hand, some women overestimate their losses. In Hallberg’s classic study, over 30% of women who lost 20–40 mL of objectively measured blood characterized their bleeding as “heavy” (Hallberg et al. 1966). Fortunately, today the definition of HMB has been expanded to include women who lose less than an average 80 mL each cycle, but report their flow is heavy enough to interfere with their functioning. Sometimes this represents occasional heavy cycles, and sometimes it results from a short term (hours) of heavy bleeding during every cycle. Women in this group may not need extensive work-ups, but they certainly can be offered treatments that can reduce their bleeding. However, there are instances when a woman’s blood loss may not meet the definitional threshold, but it is distinctly greater than losses she has experienced in the past. This may be an indication of new pathology and needs attention. On physical examination, signs of anemia should be sought, such as pale conjunctiva or tachycardia. Examination should rule out obvious non-uterine sources of blood lose (large hemorrhoids). Iron deficiency anemia in a woman with a normal diet substantiates a woman’s claim of

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excessive blood loss, but it may be necessary to perform the hemoglobin testing at the end of menses that can detect their anemia. Heavy menstrual bleeding is generally divided into two categories: acute excessive bleeding and chronic heavy menstrual bleeding.

6.1

Acute Heavy Bleeding

Hemodynamic stability must be quickly evaluated by symptoms and vital signs in women who present with acute heavy uterine bleeding. Acute rapid blood loss, even at higher levels of hemoglobin, is not as well tolerated as slow, chronic losses. Pregnancy tests and rapid point-of-care hemoglobin tests are needed to direct further actions. Women who are not stable or who have signs of hypovolemia should receive fluids through large-bore IVs and blood transfusion with appropriate clotting factor replacement. A rapid abbreviated history should be conducted that includes information about the current bleeding episode (duration, flow, pain, and associated symptoms such as headache, palpitations, shortness of breath, dizziness, fatigue, pica, and past episodes (when, what diagnoses, what therapies) as well as any relevant medical problems that may cause losses (bleeding disorders, acute leukemia, immune thrombophilia purpura, aplastic anemia) and those be adversely impacted by anemia (diabetes, hypertension, cardiac disease). Recent surgical procedures (e.g., endometrial, cervical, or other uterine) should also be documented. Examination should first confirm that the source of the bleeding is uterine. Quick laboratory testing should include complete blood count, blood type and partial thromboplastin time, prothrombin time, activated partial thromboplastin, and fibrinogen. After the woman has been stabilized, evaluation should proceed as outlined below to arrest her bleeding, establish its etiology, and prevent future episodes.

Table 5 Medications that increase menstrual blood loss Anticoagulants: warfarin, heparin Antiepileptic agents: Dilantin, phenobarbital Digitalis Nonsteroidal anti-inflammatory drugs, including ASA Contraceptives: copper IUD, steroidal hormones Herbal agents: ginkgo, ginseng, motherwort

For women without life-threatening acute blood loss and those who have been stabilized, a more expanded history is needed. Details of the current episode of bleeding and any related symptoms should be expanded to include the past menstrual history and obstetrical and gynecology history. Information about medication use can be helpful especially if it contributes to bleeding (anticoagulants) or induces anovulation and unopposed estrogen (see Table 5). The woman should also be asked about any previous treatments she has been given to treat heavy bleeding. Family history of coagulation or thromboembolic disorders and any contraindication to medication usually used to treat HMB should be identified. Physical examination should focus on physical findings suggestive of anemia, systemic disease (hepatic or renal failure, sepsis or hematopoietic cancers), endocrine disorders (thyroid), coagulopathy (bruising), and pelvic abnormalities (masses, evidence of trauma, or cervical or vaginal abnormalities that could account for the bleeding) (see Table 5). Laboratory testing should be guided by the findings from the woman’s history and physical examination. Thyroid-stimulating hormone, liver function tests, renal function tests, cervical infection tests, and iron reserve tests (serum iron, total iron binding capacity, and ferritin) may each provide important information for different clinical presentations. Imaging tests (especially ultrasound and saline infusion sonography) may be helpful at some point to assess the PALM structural causes (see above). Endometrial sampling to rule out endometrial disease should be performed after the woman is

Abnormal Vaginal Bleeding During the Early Reproductive Years

stabilized in reproductive-aged women over 45 years and in younger women with a history of unopposed estrogen or a history of failed medical management of abnormal bleeding (ACOG Practice Bulletin 128 2012). Most women with acute excessive bleeding will respond rather rapidly to appropriate medical therapy. However, in some cases, emergent surgical treatments may be required, especially if trauma is suspected. The procedures vary. Dilation and curettage may be needed to halt bleeding from retained products of conception or bleeding polyps; myomectomy is needed for an aborting fibroid; surgical repair may be needed for trauma. Emergency hysterectomy can be lifesaving in certain cases. Medical therapy recommendations for acute bleeding have undergone evolution: • Classically high-dose estrogen therapy has been recommended to be used to halt acute excessive bleeding. Intravenous conjugated equine estrogen is specifically approved by the US Food and Drug Administration for treatment of acute abnormal uterine bleeding (ACOG Committee Opinion 557 2013). Dosing regimens include 25 mg CEE IV every 4 h for unstable patients or 2.5 mg CEE orally every 4–6 h for 14–21 days for hemodynamically stable women. Progestin is generally added (MPA 5 mg once or twice a day) to support the endometrium 12–24 h after initiation of estrogen (when bleeding slows) and is continued until estrogen therapy is terminated. This approach mimicked the processes seen in the normal menstrual cycle. However, the only randomized, prospective, placebo-controlled study for a high-dose estrogen was a 5-h trial in which 17 women were given high-dose conjugated estrogen therapy and 17 received saline in an ER setting (DeVore et al. 1982). Intravenous estrogen is still the most common treatment prescribed for women who require hospitalization for transfusion and stabilization. However, women with iron deficiency

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anemia can often have reactive thrombocytosis This reactive thrombocytosis places the woman at higher risk for deep venous thrombosis and pulmonary embolism (Nelson and Ritchie 2015). Addition of high-dose estrogen increases that risk factor. However, progestinonly therapies outlined below have not been tested in the setting of acute bleeding. • For outpatient therapy, high-dose estrogencontaining oral contraceptives have been the mainstay of therapy for decades, despite the fact that there is little in the literature to support any of the classically recommended regimens. Over time, the dose used in those regimens has been reduced to minimize the risk of thrombosis. The initial regimens popularized in textbooks called for 50 mcg ethinyl estradiol/ 30 mcg norgestrel oral contraceptives to be taken four times a day for 5 days (essentially a pill pack). Later regimens called for twice daily dosing for 5 days. Most recently, the recommendation is that two tablets of a 1/35 formulation be given the first day followed by one pill a day until the pill pack is finished (Fritz and Speroff 2011). • In the largest randomized, comparative clinical trial for outpatient treatment of acute excessive uterine bleeding, Munro et al. demonstrated that medroxyprogesterone acetate (MPA) 20 mg taken orally three times a day for 7 days followed by MPA 20 mg taken once daily for an additional 21 days was at least as effective as high-dose oral contraceptives (one tablet 1/35 oral contraceptive taken three times a week for 7 days followed by any 1/20 formulation taken one tablet a day for 21 more days) in stopping bleeding, in avoiding surgery, and in achieving patient satisfaction (Munro et al. 2006). Although Munro’s patients were all hemodynamically stable and treated as outpatients, the ACOG Committee Opinion on the topic does not restrict the use of this progestinonly therapy to outpatients (ACOG Committee Opinion 557 2013). The fact that progestin-

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only approaches avoid VTE risk makes this their used first-line treatment option. Medroxyprogesterone acetate (MPA) 20 mg taken orally three times a day for 7 days followed by MPA 20 mg once daily for an additional 21 days is a safe and effective treatment to stop acute bleeding with a wide range of endometrial pathology.

Some authorities have recommended using progestin when the endometrial lining is thickened and estrogen treatments when it appears to be atrophic. This recommendation assumes the clinician has access to imaging equipment, which may not be true in many settings. Furthermore, the imaging can add extra cost. Fortunately, in the largest prospective trial of management of acute bleeding in patients eligible for outpatient therapy, progestin-only therapy was very effective in all women. Bleeding was stopped in women with biopsy-proven atrophy as well as those whose endometrial sample revealed endometrial hyperplasia (Ammerman and Nelson 2013). Once the acute bleeding has been arrested, it is important to ensure that future episodes are prevented. This can usually be achieved using therapies outlined for treatment of chronic heavy menstrual bleeding below.

6.2

Chronic Heavy Menstrual Bleeding

The goals of the work-up of heavy menstrual bleeding are to establish whether the heavy bleeding is due to a treatable organic disorder and whether the bleeding is ovulatory or anovulatory and to assess the burden the woman’s symptoms place on her. The history includes all the items described in the acute HMB section above. Iatrogenic causes, especially medications, need to be thoroughly evaluated (see Table 5). Serious medical

conditions can also present with new onset or chronic heavy menstrual bleeding. Women who have renal insufficiency approaching anuria experience very heavy bleeding. Once renal failure is complete, these women become amenorrheic. However, after dialysis is started, they again may experience very heavy menses. These losses are very significant, because the woman has no ability to stimulate production of red blood cells with erythropoietin. With loss of vitamin K in hepatic failure (liver cirrhosis or active hepatitis), women can develop heavy menses. Hypersplenism and adrenal hyperplasia can also cause HMB. As noted earlier, endocrine abnormalities (thyroid myxedema) can induce heavy bleeding. For women with hematopoietic carcinoma, heavy bleeding can be their first symptom. Physical examination would include vital signs (including BMI); thyroid exam; tests for abdominal tenderness, hepatomegaly or abdominal distention, striae, skin bruising, petechiae, and pallor; and pelvic exam. Imaging studies can be selected based on the woman’s history, and exam findings to define any structural/anatomic causes (PALM) as described above. The function causes (COIEN) summarized above must also be evaluated. In recent years, there has been a growing awareness that coagulopathies are very common in women of any age. Whenever other etiologies are not identified, it is necessary to evaluate the ability of the woman to form clots and to maintain them. Some bleeding disorders are classically genetic (von Willebrand disease, some forms of thrombocytopenia), but many are acquired. Inherited bleeding disorders are found in 10–20% of adult women with objectively verified heavy menstrual bleeding. In one study of 115 women with idiopathic heavy menstrual bleeding, 47% were found to have a hemostatic abnormality, the most common of which was acquired platelet aggregation defects (44%). Platelet disorders can include abnormal numbers of platelets (ITP or leukemia) or disorders of platelet function (Philipp et al. 2005). In a subsequent study, bleeding disorders were found in 31% of women with HMB (average PBAC of 271) and platelet disorders accounted for 69% of

Abnormal Vaginal Bleeding During the Early Reproductive Years

those cases; von Willebrand was a distinct second at 22% (Knol et al. 2013). Philipp et al. have developed a detailed screening tool to detect bleeding disorders in women with heavy menstrual bleeding (Philipp et al. 2011). This diagnosis is often overlooked; in a survey of over 500 OB-GYNs, only 38.8% said that they would consider bleeding disorders for adult women with HMB: • ACOG recommends screening for an underlying disorder of hemostasis in an adult woman if she has had heavy menstrual bleeding since menarche, and she has experienced excessive blood loss postpartum, with surgery or with dental work, and she has had at least two of the following conditions: nose bleeds one to two times per month, frequent gum bleeding, and family history of bleeding symptoms (ACOG Adolescent Committee Opinion 580 2013). The initial work-up recommended is a CBC with platelet count, PT, PTT, and possible fibrinogen. Specific tests for von Willebrand are also listed; either ristocetin cofactor assay or antigen testing is generally recommended as screening test. Specific von Willebrand defects require more detailed testing, usually best done by hematologist [x ref. Committee Opinion 580]. Ovulatory dysfunction is one of the most easily diagnosed conditions. Usually a menstrual history is sufficient, but hormonal testing can be helpful in identifying medical conditions underlying the menstrual disorder (see above). Anovulatory bleeding can be heavy for several reasons involving the endometrial environment. Unopposed estrogen stimulation induces thicker endometrial layer; endometrial sloughing is dyssynchronous and, therefore, prolonged. Without ovulation, the levels of PGF2α responsible for vasoconstriction do not rise in the “luteal phase” to exceed the levels of PGE2 responsible for vasodilation. Abnormalities can also occur in the balance in production of thromboxane (promotes platelet aggregation promotion) and prostacyclin (inhibits platelet aggregation). In ovulatory women with HMB, similar imbalances can be seen because of abnormal prostaglandin synthesis and/or

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increased numbers of receptors. Diagnosis of these problems has to be clinical; response to NSAIDs helps support the diagnosis. Targeted therapies are needed to treat heavy menstrual bleeding due to systemic diseases. For example, excessive bleeding due to thyroid dysfunction requires only temporary menstrual suppression until euthyroidism can be restored. Endometrial polyps can be excised. Women with underlying disordered hemostasis will need targeted therapy with agents such as DDAVP (desmopressin acetate) as outlined in Management Guidelines from the National Health, Lung and Blood Institute. Treatment of endometrial hyperplasia is covered in other chapters. However, for a woman with chronic conditions, such as bleeding diatheses, hypersplenism, bone marrow suppression, as well as those with uterine abnormalities, such as leiomyoma or adenomyosis or idiopathic heavy menstrual bleeding, two questions need to be answered to determine her best treatment options: • Is she seeking pregnancy? • How excessive is her blood loss? (or how much of a reduction does she need?)

6.3

Medical Therapies for Chronic Heavy Menstrual Bleeding

For women seeking pregnancy and for women who need only slight reductions in their blood loss, nonhormonal methods may be offered. In this case, nonsteroidal anti-inflammatory agents (NSAIDs) taken at high enough doses at appropriate intervals reduce blood loss by 20–30% (Lethaby et al. 2013). One typical regimen is ibuprofen 800 mg orally every 8 h from onset of menses until end of heavy flow (up to 5 days). Antifibrinolytic agents can reduce blood loss about 40% (Freeman et al. 2011). A typical treatment would include Lysteda 650 mg, two tabs orally, three times a day starting at the onset of bleeding and continuing through the last day of heavy flow (but not more than 5 days). These agents have the advantages that they do not affect

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fertility and they are used only at the time of menses. For women who are not seeking pregnancy, endometrial suppression can provide significant reductions in menstrual blood loss even though for many of them, such use would be off-label. Usually first-line therapy is medical [combined hormonal contraceptives, progestin-only pills, injectable progestin contraceptives, LNG-IUS20 mg/day, cyclic oral progestin). Surgery should generally be reserved for those who have other pelvic pathology and those whose bleeding is not medically controlled (infra vide). Unfortunately, in a recent study of over 2,200 women who underwent hysterectomy for benign conditions in 2013, over one-third of the cases had no documentation that any medical treatments had been used prior to surgery (Corona et al. 2015). Hormonal contraceptives are the therapy most frequently prescribed to control heavy bleeding. Traditionally oral contraceptives, contraceptive patches, and contraceptive vaginal rings have been used cyclically to reduce the amount of scheduled bleeding by 50–70%. Extended cycle (AKA continuous) use of oral contraceptives or vaginal contraceptive rings has been shown to reduce endometrial thickness and to substantially reduce the total numbers of days of scheduled bleeding even further (Edelman et al. 2014). Extended use of the current transdermal patch is not recommended given the increasing estrogen levels associated with its prolonged use. One oral contraceptive pill has been approved by the FDA for treatment of heavy menstrual bleeding; the multiphasic desogestrel/estradiol valerate pill reduced heavy menstrual bleeding almost as well as the high dose LNG-IUS did in its pivotal clinical trial (Kaunitz et al. 2010; Wasiak et al. 2013). Despite decades of clinical experience utilizing DMPA to achieve amenorrhea, there is very little in the literature about its use to treat heavy menstrual bleeding. There is evidence that DMPA is useful in preventing recurrent hemorrhagic ovarian cysts in women on chronic anticoagulation therapy, and DMPA was shown to reduce blood loss among 20 women with uterine fibroidassociated HMB. DMPA in conjunction with GNRH agonists has been helpful in treating

A.L. Nelson

women at risk for severe thrombocytopenia from myelosuppressive therapy for cancer. One recent review concluded that DMPA use was not contraindicated for use by women with inherited bleeding disorders. Although menstrual blood loss diminishes with longer-term contraceptive implant use, its unpredictable impact on bleeding discourages the use of the implant to treat HMB. GnRH agonists can be used short term to suppress estrogen protection and endometrial growth. Usually add-back therapy is used for longer-term use to reduce the associated estrogen deficiency symptoms and adverse reactions on bone health (Bradley and Gueye 2016). The LNG-IUS-20mcg/24 h is the most effective medical therapy for idiopathic heavy menstrual bleeding (Bitzer et al. 2015; Lethaby et al. 2015). In the comparative open-label randomized trial against luteal phase MPA 10 mg per day, this LNG-IUS reduced blood loss by at least 50% and normalized blood loss to 5 cm. The outer surface of the cyst may appear smooth, but it is important to do a close gross examination to note any surface projections/involvement as it changes the tumor FIGO staging as discussed below. The cyst is usually filled with serous fluid and the cyst lining usually exhibits very soft, friable white projections (Fig. 3). Microscopically, the cyst lining shows papillary projections lined by stratified cuboidal cells. In places, these cells are marked by hobnail features reflected by eosinophilic cytoplasm, mild to moderate atypia, and high nuclear/cytoplasmic ratio. The critical finding of a borderline tumor is the lack of invasion of the ovarian stroma (Fig. 4). Serous borderline tumor may be associated with omental implants. Peritoneal implants are classified as noninvasive epithelial implants, invasive epithelial implants, or desmoplastic implants. Since implants are a heterogeneous group and various types may coexist, it is important that multiple biopsies of numerous foci of suspicious

Fig. 4 The cut surface of these projections show papillary structure lined by stratified cuboidal cells. These cells exhibit mild to moderate atypia and few mitotic figures are also present. There is no stromal invasion

3.1.2

lesions are done at the time of surgery and that extensive tumor sampling by the pathologist is done to accurately exclude an invasive implant. The diagnosis of peritoneal implants is very challenging and very difficult. It is therefore recommended of the opinion that the final diagnosis is cleared by an expert gynecologic pathologist, especially in cases where the diagnosis may change a patient’s treatment options and management.

3.1.3

Serous Borderline Tumor (SBT) Micropapillary Variant (MSBT) Serous borderline tumors account for 5–10% of all SBTs. Microscopically, MSBT shows highly complex micropapillary growth in a filigree pattern, growing in a nonhierarchical fashion from stalk. It has been described as “Medusa head”-like appearance. Micropapillae are at least five times as long as they are wide (Fig. 5). The significance of this subtype has generated a lot of debate in pathology. Some authors have found a close association between MSBT and invasive implants and have urged that this lesion be labeled as a “micropapillary serous carcinoma.” Others prefer the terminology of MSBT, avoiding the use of the term of “carcinoma,” to minimize the possibility of overtreating patients (Chang et al. 2008). The general agreement on the significance of micropapillary architecture in

Surface Epithelial Neoplasms of the Ovary

Fig. 5 Serous borderline, micropapillary variant where there is highly complex micropapillary growth in a filigree pattern looking like “medusa head.” These micropapillae are long and wide

SBTs is that they are related to significant increases in the incidence of invasive peritoneal implants. Molecular studies show that MSBTs have a similar gene expression profile to low-grade serous carcinomas (LG-serous carcinoma) that are distinct from typical SBT (May et al. 2002). The underlying genes involved in the pathogenesis of LG-serous carcinoma and in MBST include mutations in a number of different genes including KRAS and BRAF. MSBT is the only surface epithelial-stromal tumor with a well-defined adenoma-carcinoma sequence, whereas LG-serous tumors are thought to arise in a stepwise fashion from a benign cystadenoma (through BST to an invasive LG-serous carcinoma) (Shih and Kurman 2005). Since micropapillary foci of less than 5 mm have no bearing on clinical outcome, these tumors with low levels of micropapillary foci and atypia can be classified as SBT with focal micropapillary features (Slomovitz et al. 2002).

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Low-grade serous carcinomas (LG-SC) are type I tumors that are relatively rare. They are genetically very stable, and they frequently harbor alterations in the mitogen-activated protein kinase (MAPK) signaling pathway. Recent pathologic evidence showed that there are three possible origins for LG-SC: ovarian surface epithelium, fallopian tube origin, and endometrial cells ectopically located in the ovary by retrograde menstruation. They are cytologically very low grade with mild atypia and low mitotic rate. LG-SC are usually cisplatin resistant leading to new clinical trials with tyrosine kinase inhibitors in several cancer centers (Kurman et al. 2014). High-grade serous carcinomas (HG-SC) are the most common histotype (70%) of the epithelial ovarian cancer. They are considered type II ovarian cancers. They occur in women a bit older than women with SBT, with an average age of 56 years. Patients with serous adenocarcinoma often present with advanced stage disease (stages III and IV) at first presentation. They are characterized by multiple gene abnormalities such as TP 53 mutation in almost 97%, and BRCA1/BRCA2 loss is frequent (30–45%, including germline and somatic alterations). Many of these tumors are thought to originate from the fallopian tube (serous tubal intraepithelial carcinoma/STIC). Grossly, the tumor varies considerably in size from a few cm to 30 cm (Fig. 6). They can be multicystic or solid. When these tumors are diagnosed at advanced stage frequently, the omentum is replaced by tumor creating what is called “omental caking.” Cytologically the tumor exhibits moderate to severe atypia with a high mitotic rate (Mhawech-Fauceglia and Pejovic 2015).

3.2 Low-Grade and High-Grade Serous Carcinoma The majority of epithelial ovarian carcinomas are of serous histology. The new WHO classification of ovarian serous carcinomas places them into two distinct categories: high grade and low grade. The two types are distinct in terms of site of origin, molecular pathways, and treatment response.

Mucinous Tumors

3.1.4

3.2.1 Mucinous Cystadenoma Mucinous cystadenomas are the most common type (75%) of mucinous tumors. They can be very large (up to 20 cm) and can be unilocular or multilocular. They are filled with mucoid fluid and in 95% of cases they are unilateral. The cyst is lined by one layer of cells that have small bland

6

Fig. 6 Ovarian mass with serous carcinoma. The cut surface is partially cystic and partially solid, soft, and friable

looking nuclei with ample mucin-filled cytoplasm creating what is called “picket fence” appearance.

3.2.2

Mucinous Borderline Tumor/ Mucinous Tumor of Low Malignant Potential Mucinous borderline tumors (MBT) (mucinous tumors of low malignant potential), as defined by the WHO, are tumors exhibiting an epithelial proliferation of mucinous-type cells greater than those seen in their benign counterparts but without evidence of stromal invasion. MBT can be of intestinal type or endocervical-like type. Mucinous borderline tumors account for 10% of mucinous tumors. They can be multilocular and are bilateral in 40% of the cases. MBT are cystic tumors with a visible solid vegetating mass protruding from the cystic wall. Careful gross examination of the cyst wall to identify these lesions is crucial. Histologically, the lining of the cyst is composed of stratified epithelial cells having high N/C ratio and prominent nucleoli. Goblet cells and Paneth cells are present in the intestinal type. No stromal invasion is seen. Borderline tumors remain a controversial issue concerning their pathogenesis, progression, and treatment (Fischerova et al. 2012).

P. Mhawech-Fauceglia

Fig. 7 Cut surface of mucinous adenocarcinoma where it is spongy with numerous tiny cystic spaces. These cysts were filled with mucin

3.2.3 Mucinous Adenocarcinoma Mucinous adenocarcinoma (MAC) accounts for 15% of mucinous tumors and 2–4% of all ovarian surface epithelial tumors. They are rare and unilateral in 95% of cases. Therefore, when they are bilateral, metastatic tumors especially from the gastrointestinal tract, namely, the colon, should be in question. They can be very large masses reaching more than 10 cm in the vast majority of the cases. They can be multicyctic/partially cystic and partially solid or solid tumors (Fig. 7). They have two patterns of invasion, the first and most common, pushing or expansile pattern where there are complex glands with back to back architecture and no intervening stroma. The glands are evidently malignant exhibiting mild to moderate cytologic atypia, high nuclear/cytoplasmic ratio, and lack of mucin. The second pattern is infiltrative pattern where single or groups of malignant cells are seen to invade the ovarian stroma with desmoplastic reaction. The origin of MAC is very elusive but some cases have been associated with endometriosis. They harbor Ras pathway alterations, and like LG-SC they may contain a spectrum of mucinous cystadenoma to borderline tumor to MAC in the same tumor (Brown and Frumovitz 2014). 3.2.4 Pseudomyxoma Peritonei Pseudomyxoma peritonei (PP) is a clinical term used to describe the finding of mucoid, gelatinous material in the abdominal cavity, often

Surface Epithelial Neoplasms of the Ovary

accompanied by an ovarian or gastrointestinal tumor. In 1995, Ronnett et al. classified PP as either a low-grade variety “diffuse peritoneal adenomucinosis” (DPAM) or a high-grade variety “peritoneal mucinous carcinomatosis” (PMCA). The classification of the tumor is prognostically significant with 5-year survival rates of 84% for DPAM and 6.7% for PMCA (Ronnett et al. 2001). PP may originate from an ovarian primary or from an appendiceal primary. Cytoreductive surgery involves removal of the peritoneum and it is common to remove the ovaries, fallopian tubes, uterus, and parts of the large intestine, including the appendix. Whether the primary origin of this tumor is from an ovarian mucinous tumor or from an appendiceal primary or has synchronous origins is still a subject of great debate.

3.2.5

Mucinous Tumors with Mural Nodule Mucinous tumors of the ovary, whether benign, borderline, or malignant, may contain one or more mural nodules. These nodules are more frequent in borderline and malignant tumors. Grossly, mural nodules are different than the overlying mucinous neoplasm. Grossly, nodules are yellow and pink with areas of hemorrhage and necrosis. Morphologically, they are classified as benign (sarcoma-like) or malignant anaplastic carcinoma and sarcoma. It is important to distinguish between benign and malignant mural nodules, because benign mural nodules are of no prognostic significance (Mhawech-Fauceglia et al. 2015). Whether malignant mural nodules represent a form of dedifferentiation or a collision of two divergent tumor types is still unsolved mystery.

3.3

Clear Cell Tumor

3.3.1 Borderline Clear Cell Tumor Borderline clear cell tumors are extremely rare. The gross appearance is nonspecific as it can range from solid to spongy. Microscopic findings include a proliferation of small glands with or without cystic dilatation that are lined by flat and

7

Fig. 8 Cut surface of a clear cell carcinoma. It is unusually cystic. The surface is hemorrhagic and friable

hobnail atypical cells. No stromal invasion is present.

3.3.2 Clear Cell Carcinoma Clear cell carcinomas (CCC) represent 6–10% of surface epithelial tumors. They occur in postmenopausal women, with a mean age of 57 years. CCC of the ovary have a few notable characteristics. (1) They are almost always unilateral (Fig. 8), and when they are bilateral, a metastatic renal cell carcinoma should be excluded. (2) They are admixed with endometrioid-type adenocarcinoma in 20–25% of cases. (3) They are often accompanied by endometriosis of the same ovary. (4) They may be associated with paraneoplastic hypercalcemia. And (5) they have frequent mutations of ARID1A and PIK3CA genes and express HNF1B. CCC are generally chemoresistant. They have numerous histological patterns including tubulocystic, papillary, solid, or a mixture of any of those patterns. Typically, the cysts are lined by atypical hobnail cells with clear cytoplasm and numerous intracytoplasmic hyaline globules (Fig. 9) (Okamoto et al. 2014).

3.4

Endometrioid Tumors

3.4.1 Endometriotic Cyst Endometriotic cyst or endometriomas are simply endometriosis cells that have undergone a cystic dilation. They are among the most common

8

Fig. 9 Microscopic section shows diffuse sheets of tumor cells. These cells have clear cytoplasm. The nuclei are round with prominent nucleoli

ovarian cystic lesions in the fourth and fifth decade. Grossly, they consist of a large simple cyst. The content is characteristic of chocolate brown fluid. Microscopically, they are a simple cyst lined by cuboidal endometrial cells with hemorrhage, hemosiderin deposits, and macrophages present in the cyst wall.

3.4.2 Borderline Endometriotic Tumor Borderline endometriotic tumors are such rare tumors that some gynecologic pathologists doubt their existence. Morphologically, they are very similar to endometrial hyperplasia occurring in the endometrium. There are composed of crowded glands that are embedded in very fibrotic stroma. The glands exhibit mild atypia and focal squamous morules. 3.4.3 Endometrioid Adenocarcinoma Endometrioid adenocarcinoma (EAC) accounts for 10–20% of ovarian carcinomas. They occur in postmenopausal women in the fifth and sixth decade, with an average age of 56 years. They are associated with endometriosis in the same ovary or pelvis, and they can coexist with endometrioid adenocarcinoma of the endometrium in 15–20% of cases. PTEN, CTNNB1, PIK3CA, and ARID1A are commonly mutated in EAC and tumors frequently express estrogen/progesterone

P. Mhawech-Fauceglia

Fig. 10 Endometrioid adenocarcinoma characterized by glands back to back with no intervening stroma

receptors and TFF3 by immunohistochemistry (Kobel et al. 2013). They are bilateral in 20% of cases. About half of EAC cases present as low-grade/well-differentiated tumors and with early stage disease (stages I and II). Grossly, the ovary may be cystic or solid with friable cut surface. EAC is microscopically very similar to those occurring in the endometrium, where there is back to back glandular architecture, with no intervening stroma and squamous differentiation in the form of squamous morules and keratin pearls (Fig. 10). However, EAC is the most chameleon ovarian cancer in existence as it can have numerous histologic variants such as tubular/ tubulovillous, spindle shape, mucin-rich, eosinophilic, secretory, ciliated, and resembling sex-cord stromal tumors. In these cases, immunohistochemistry is necessary for accurate diagnosis.

3.5

Brenner Tumors

3.5.1 Benign Brenner Tumor Benign Brenner tumors account for 5% of benign ovarian epithelial tumors. They occur at a wide range group age, between 30- and 60-year-old women. They are usually asymptomatic and can be totally accidental finding. In 20–30% of cases, Brenner tumors develop synchronously with other neoplasms including mucinous neoplasm, dermoid cyst, or mature cystic teratoma. They

Surface Epithelial Neoplasms of the Ovary

9

are small generally less than 2 cm in size. They are unilateral in 95% of cases. Grossly, they are a sharply delineated mass seen in a normal ovary with a whitish firm cut surface. Microscopically, benign Brenner tumors appear as islands of transitional cells with nuclear grooving embedded in a fibrotic stroma. Sometimes, cystic dilation lined by transitional or mucinous epithelium can be seen. No atypia, mitotic figures, and necrosis are seen.

3.5.2 Malignant Brenner Tumor Malignant Brenner tumors are the least common of the surface epithelial tumors of the ovary. They occur in women over 50 years of age. They are usually large and they might be cystic or solid. Histologically, they resemble urothelial/transitional carcinoma of the urinary tract. They are composed of sheets of transitional-like epithelium exhibiting moderate atypia and fair numbers of mitotic figures. Cystic areas can be present. With extensive sampling, islands of benign Brenner tumor are seen in the background. However, if no benign Brenner tumor cells are seen after extensive sampling, a high-grade serous or endometrioid adenocarcinoma should be suspected.

3.6

Seromucinous Tumors

Seromucinous tumors is a new entity that was introduced in the 2014 WHO classification. It has three categories: benign, borderline, and malignant (carcinoma). They are rare neoplasms. They are composed of a variable admixture of serous and mucinous (endocervical) epithelial lining. They are likely derived from endometriosis cells but this is still subject to speculation.

3.7

Undifferentiated Carcinoma

By the WHO definition “undifferentiated tumor is a malignant tumor showing no differentiation of any specific Mullerian cell type.” Undifferentiated carcinomas usually present at the late stage. They are characterized by proliferation of high-grade

Fig. 11 Residual serous adenocarcinoma post neoadjuvant chemotherapy. Tumor cells are in single files or clusters with abundant fibrous stroma

tumor cells with high mitotic rate in a diffuse pattern with areas of necrosis.

3.8

Ovarian Carcinoma After Neoadjuvant Therapy

Traditionally, advanced stage ovarian carcinoma is treated by debulking surgery followed by chemotherapy. In some circumstances, neoadjuvant chemotherapy followed by debulking surgery may be done. Neoadjuvant chemotherapy is increasingly being used in the management of patients with advanced ovarian cancer, and pathologists should be aware of the morphologic changes in ovarian cancer after neoadjuvant chemotherapy. Treated tumors may be mistaken for metastatic carcinoma from breast primary or other sites. The morphologic changes seen in response to neoadjuvant chemotherapy include small groups or single tumor cells in a densely fibrotic stroma (Fig. 11). The tumor cells are characterized by nuclear and cytoplasmic alteration making the grading and sometimes the tumor typing impossible and inaccurate. Nuclear changes include nuclear enlargement, hyperchromasia, irregular nuclear outlines, and chromatin smudging. Cytoplasmic alterations include eosinophilic cytoplasm, vacuolation, and foamy cell changes (Fig. 8). The stroma

10

P. Mhawech-Fauceglia

may have pronounced fibrosis, inflammation, foamy histiocytic infiltrates, hemosiderin deposits, necrosis, calcification, and numerous free psammoma bodies (McCluggage et al. 2002; Miller et al. 2008). Fortunately, tumor cells seem to keep their antigens and therefore express antibodies similar to those seen in pretreatment including CK7+, WT1+, and p53+ (Chew et al. 2009).

3.9

Ovarian Grading Systems

Ovarian cancer is a very challenging task and it is still performed haphazardly with several systems and nonsystems used in different institutes and in different research studies. The lack of uniformity in grading has resulted in little consensus as to whether ovarian tumor grade has any significance in predicting disease outcome. The grading systems used most commonly worldwide are the International Federation of Gynecology and Obstetrics (FIGO) system and the World Health Organization (WHO) system. The FIGO grading system for the ovary is similar to the grading system used in the uterus. It is based on architectural features. The grade depends on the ratio of glandular or papillary structures versus solid tumor growth. Grade 1 is equivalent to 50% solid growth. In the WHO system, the grade is assessed by both the architectural and cytologic features, without any quantitative evaluation. The Gynecologic Oncology (GOG) system is the most commonly used system in the United States (Bendaj and Zaino 1994). It employs a method based on the histologic type. For example, ovarian carcinoma of endometrioid type is graded similarly to the endometrial adenocarcinoma of endometrioid type. Ovarian carcinoma of transitional type is graded similar to transitional cell carcinoma (TCC) of the bladder. Clear cell carcinomas are not graded at all. Silverberg et al. proposed a new grading system similar to that used in breast carcinoma, and it depends on architectural features (glandular 1, papillary 2, and solid 3), cytologic atypia (mild 1, moderate 2, severe 3), and

Fig. 12 Low-grade serous carcinoma defined by mild atypia and few mitotic figures

mitotic rate (1 0–9 mitosis/10HPF, 2 10–24, 3 >25). A score is given by adding the parameters, a score of 3–5 is grade 1, a score of 6–7 is grade 2, and a score of 8–9 is grade 3 (Silverberg 2000). Figure 12 and 13 is an example of grade 1 and grade 3 serous carcinomas. This grading system was confirmed to be reproducible in subsequent studies (Ishioka et al. 2003). Another study from MD Anderson Cancer Center group suggested adopting a two-tier system that is based primarily on the assessment of nuclear atypia (uniformity vs. pleomorphism) in the worst area of the tumor (Malpica et al. 2004). The tumor is graded into low grade (Fig. 12) and high grade (Fig. 13). A few years after its introduction, the authors confirmed its reproducibility and urged its use to facilitate the clinical trials and protocols (Malpica et al. 2007). This grading system has gained huge popularity and even it was adopted by the 2014 WHO classification. However, this grading could be applied to only serous carcinomas.

3.10

Ovarian Staging FIGO 2014

The International Federation of Gynecology and Obstetrics (FIGO) staging has revised the staging for ovarian cancer, and the approved and new ovarian cancer staging went into effect on 1 January 2014. There were some major differences between the old FIGO and new FIGO staging system.

Surface Epithelial Neoplasms of the Ovary

11

2010). Due to these advancements in reclassification, it will not be a surprise if 10 years from now, ovarian tumors will be reclassified using not just morphology alone but will heavily incorporate the molecular findings. All the gynecologic oncologic communities are excited about these developments. Targeted therapy and personalized medicine are very promising venues for patients’ care.

References Fig. 13 High-grade serous carcinoma defined by moderate to severe atypia and high mitotic figures

Stage I: IC (ovaries with any of the following: capsule rupture, tumor on surface, positive washings/ascites) was subdivided in IC1 (surgical spill), IC2 (capsule rupture before surgery or tumor on surface ovarian surface), and IC3 (malignant cells in the ascites or peritoneal washings). Stage II: IIC in the old system (IIA or IIB with positive washings/ascites) was canceled. So in the new system is only stage IIA and IIB. Stage III: IIIA was modified and subclassified into IIIA1 (positive retroperitoneal lymph nodes only) and IIIA2 (microscopic, extrapelvic peritoneal involvement  positive retroperitoneal lymph nodes).

4

Conclusion

Epithelial ovarian tumors are very interesting and fascinating tumors. They still are a subject of debate regarding their pathogenesis, molecular pathways, diagnosis, and treatment. However, the discovery of new genetic mutations and pathways had revolutionized our understanding of ovarian cancer and has provided us with a fresh outlook based on their molecular fingerprints. In the past, histologic classification of surface epithelial tumor had poor interobserver agreement (60%), but because of the advancement of the molecular testing, the immunohistochemistry agreement has risen to 80–90% (Kobel et al.

Bendaj A, Zaino R. GOG pathology manual. Buffalo: Gynecologic Oncologic Group; 1994. Brown J, Frumovitz M. Mucinous tumors of the ovary: current thoughts on diagnosis and management. Curr Oncol Rep. 2014;16(6):389. Chang SJ, Ryu HS, Chang KH, Yoo SC, Yoon JH. Prognostic significance of the micropapillary pattern in patients with serous borderline ovarian tumors. Acta Obstet Gynecol Scand. 2008;87:476–81. Chew I, Soslow RA, Park KJ. Morphologic changes in ovarian carcinoma after neoadjuvant chemotherapy: report of a case showing extensive clear cell changes mimicking clear cell carcinoma. Int J Gynecol Pathol. 2009;28(5):442–6. Fischerova D, Zikan M, Cibula D. Diagnosis, treatment and follow-up of borderline ovarian tumors. Oncologists. 2012;17(12):1515–33. Ishioka S-I, Sagae S, Terasawa K, Sugimura M, Nishioka Y, Tsukada K, Kudo R. Comparison of the usefulness between a new universal grading system for epithelial ovarian cancer and the FIGO grading system. Gynecol Oncol. 2003;89:447–52. Köbel M, Kalloger SE, Baker PM, Ewanowich CA, Arseneau J, Zherebitskiy V, Abdulkarim S, Leung S, Duggan MA, Fontaine D, Parker R, Huntsman DG, Gilks CB. Diagnosis of ovarian carcinoma cell type is highly reproducible: a transcanadian study. Am J Surg Pathol. 2010;34(7):984–93. Köbel M, Kalloger SE, Lee S, Duggan MA, Kelemen LE, Prentice L, Kalli KR, Fridley BL, Visscher DW, Keeney GL, Vierkant RA, Cunningham JM, Chow C, Ness RB, Moysich K, Edwards R, Modugno F, Bunker C, Wozniak EL, Benjamin E, Gayther SA, Gentry-Maharaj A, Menon U, Gilks CB, Huntsman DG, Ramus SJ, Goode EL; Ovarian tumor tissue analysis consortium. Biomarker-based ovarian carcinoma typing: a histologic investigation in the ovarian tumor tissue analysis consortium. Cancer Epidemiol Biomark Prev. 2013;22(10):1677–86. doi: 10.1158/1055-9965. EPI-13-0391. Epub 2013 Jul 23. Kurman RJ, Carcangiu ML, Herrington CS, Young RH. WHO classification of tumors of female

12 reproductive organs. 124th ed. Lyon: International Agency of Research on Cancer (IARC); 2014. Longacre TA, McKenney JK, Tazelaar HD, Kempson RL, Hendrickson MR. Ovarian serous tumors of low malignant potential (borderline tumors), outcome-based study of 276 patients with long term (> or = 5 year) follow-up. Am J Surg Pathol. 2005;29:707–23. Malpica A, Deavers MT, Lu K, Bodurka DC, Atkinson EN, Gershenson DM, Silva EG. Grading ovarian serous carcinoma using two-tier system. Am J Surg Pathol. 2004;28:496–504. Malpica A, Deavers MT, Tornos C, Kurman RJ, Soslow R, Seidman JD, Munsell MF, Gaertner E, Frishberg D, Silva EG. Interobserver and intraobserver variability of a two-tier system for grading serous carcinoma. Am J Surg Pathol. 2007;31:1168–74. May T, Virtanen C, Sharma M, Milea A, Begley H, Rosen B, Murphy KJ, Brown TJ, Shaw PA. Low malignant potential tumors with micropapillary features are molecularly similar to low-grade serous carcinoma of the ovary. Gynecol Oncol. 2002;117:9–17. McCluggage WG, Lyness RW, Atkinson RJ, Dobbs SP, Harley I, McClelland HR, Price JH. Morphological effects of chemotherapy on ovarian carcinoma. J Clin Pathol. 2002;55:27–31. Mhawech-Fauceglia, Pejovic T. Hypothesis on the origin and risk genes of high grade serous ovarian carcinoma. IJGORMR. 2015;1(2):1–5. Mhawech-Fauceglia P, Ramzan A Walia S, Pham HQ, Yessaian A. Microfocus of anaplastic carcinoma arising in mural nodule of ovarian mucinous borderline tumor with very rapid and fatal outcome. Int Gynecol Pathol. 2015 [epud ahead of print} PMID 26598983. Miller K, Price JH, Dobbs SP, McClelland RH, Kennedy K, McCluggage WG. An immunohistochemical and morphological analysis of past-chemotherapy ovarian carcinoma. J Clin Pathol. 2008;61:652–7.

P. Mhawech-Fauceglia National Cancer institute, Surveillance, Epidemiology, and End Results Program (SEER) Ovarian Cancer Statistics, [internet] 2015; available from http://www.seer. cancer.gov/statfacts/ovary. Okamoto A, Glasspool RM, Mabuchi S, Matsumura N, Nomura H, Itamochi H, Takano M, Takano T, Susumu N, Aoki D, Konishi I, Covens A, Ledermann J, Mezzanzanica D, Steer C, Millan D, McNeish IA, Pfisterer J, Kang S, Gladieff L, Bryce J, Oza A. Gynecologic Cancer InterGroup (GCIG) consensus review for clear cell carcinoma of the ovary. Int J Gynecol Cancer. 2014;24(9 Suppl 3):S20–5. doi:10.1097/IGC.0000000000000289. Prat J, FIGO Committee on Gynecologic Oncology. Staging classification of cancer of the ovary, fallopian tube and peritoneum. Int J Gynaecol Obstet. 2014;124:1–5. Ronnett BM, Yan H, Kurman RJ, Shmookler BM, Wu L, Sugarbaker PH. Patients with pseudomyxoma peritonei associated with disseminated peritoneal adenomucinosis have a significantly more favorable prognosis than patients with peritoneal mucinous carcinomatosis. Cancer. 2001;92:85–91. Shih I-M, Kurman RJ. Molecular pathogenesis of ovarian borderline tumors: new insights and old challenges. Clin Cancer Res. 2005;11(20):7273–9. Silverberg SG. Histopathologic grading of ovarian carcinomas: a review and proposal. Int J Gynecol Pathol. 2000;19:7–15. Slomovitz BM, Caputo TA, Gretz HF 3rd, Economos K, Tortoriello DV, Schlosshauer PW, Baergen RN, Isacson C, Soslow RA. A comparative analysis of 57 serous borderline tumors with and without a noninvasive micropapillary component. Am J Surg Pathol. 2002;26(5):592–600.

Sex Cord–Stromal Tumors of the Ovaries Mohamed Mokhtar Desouki and Oluwole Fadare

Abstract

Contents 1

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9

Epidemiology and Clinical Presentation . . . . . 2 Fibromas and Cellular Fibromas . . . . . . . . . . . . . . . . 2 Fibrosarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Thecoma and Luteinized Thecoma . . . . . . . . . . . . . 4 Steroid Cell Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Granulosa Cell Tumors . . . . . . . . . . . . . . . . . . . . . . . . . 7 Sertoli–Leydig Cell Tumor . . . . . . . . . . . . . . . . . . . . . 9 Sertoli Cell Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Sex Cord–Stromal Tumors, Unclassified . . . . . . . 12 Immunohistochemistry . . . . . . . . . . . . . . . . . . . . . . . . . . 12

3

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Ovarian sex cord–stromal tumors (SCSTs) are uncommon neoplasms that are known to have a wide morphologic spectrum and which accordingly may be diagnostically challenging. The keys to accurately diagnosing the tumors in this group is to recognize the full pathologic spectrum of every constituent entity and to consider the possibility for each ovarian neoplasm encountered that is plausibly in the differential diagnosis.

1

Keywords

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Ovary • Sex cord–stromal tumors • Fibroma • Fibrothecoma • Fibrosarcoma • Sertoli–Leydig cell tumor • Sertoli cell tumor • Granulosa cell tumor • Leydig cell tumor • Steroid cell tumor

1

M.M. Desouki (*) Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA e-mail: [email protected]; [email protected] O. Fadare Department of Pathology, University of California San Diego, San Diego, CA, USA e-mail: [email protected] # Springer International Publishing Switzerland 2016 D. Shoupe (ed.), Handbook of Gynecology, DOI 10.1007/978-3-319-17002-2_67-1

Introduction

Patient age, clinical manifestations (e.g., hormone production), morphologic features, and occasionally ancillary diagnostic studies (e.g., immunohistochemistry (IHC)) are important tools in assigning an ovarian neoplasm to one of the tumors among the diverse sex cord–stromal tumors (SCSTs) (Kurman et al. 2014). SCSTs are derived from or display differentiation towards ovarian cortical stroma, hilar, and other steroidal cells and granulosa-theca cells of the ovarian follicles. Apart from fibroma, all other SCSTs are uncommon. The differential diagnosis 1

2

M.M. Desouki and O. Fadare

for a given case typically includes many other SCST. Similarly, SCST is frequently in the differential diagnosis for a wide variety of non-SCST. Accordingly, familiarity with the morphologic spectrum of SCST is crucial to their accurate pathologic categorization (Kurman et al. 2014).

2

Table 1 World Health Organization classification of ovarian sex cordstromal tumorsa Pure stromal tumors Fibroma Fibrosarcoma Thecoma Steroid cell tumor Pure sex cord tumors Granulosa cell tumor Sertoli cell tumor Mixed sex cord–stromal tumors Sertoli–Leydig cell tumors Sex cord–stromal tumors, unclassified

Epidemiology and Clinical Presentation

SCSTs constitute two per 10 HPFs), necrosis, and severe nuclear atypia (Hayes and Scully 1987). The gross morphology is yellow to dark brown (Fig. 9). The cells form diffuse aggregates in linear or circular pattern separated by thin fibrous septae. The nuclei are centrally placed with prominent nucleoli and minimal atypia. The cytoplasm is frequently vacuolated and lipid rich (Hayes and Scully 1987) (Fig. 10).

Sex Cord–Stromal Tumors of the Ovaries

7

Fig. 9 Ovarian steroid cell tumor. Gross photograph showing well circumscribed yellow mass

Stromal Luteoma This tumor presents with estrogenic symptoms mainly vaginal bleeding and a few cases present with androgenic symptoms. The lesion is characterized by centrally located neoplasm within the ovarian parenchyma. A uniform cell population with centrally placed nuclei and prominent nucleoli are evident. The cytoplasm is pale, finely granular, pink to vacuolated with demarcated cellular outlines (Fig. 11). Hyperthecosis with vacuolated cells in the surrounding ovarian stroma is common (Vilain et al. 1992).

2.5

Granulosa Cell Tumors

Granulosa cell tumors (GCTs) are rare tumors constituting 1–2 % of all ovarian tumors. The tumors contain at least 10 % of follicular granulosa cells. Despite the fact that GCTs are rare, they are the second most common SCSTs after fibromas (Schumer and Cannistra 2003).

2.5.1 Clinical Features Traditionally GCTs are classified into adult and juvenile types. As the name implies with exceptions both ways, adult type predominates in postmenopausal women and juvenile type in younger age (average age of 13 years) (Schumer and Cannistra 2003; Young et al. 1984a). The tumor may produce estrogenic or androgenic effects,

Fig. 10 Ovarian steroid cell tumor, not otherwise specified. The cells form diffuse aggregates separated by thin fibrous stroma. The cytoplasm is vacuolated and lipid rich. The nuclei are centrally placed with prominent nucleoli

including abnormal uterine bleeding with cystic hyperplasia due to anovulation. Associated endometrial carcinoma have been reported in ~5 % of cases with GCTs. Juvenile GCTs are rarer (less than 5 % of GCTs) and commonly associated with hyperestrinism resulting in isosexual pseudoprecocity in prepubertal girls (Young et al. 1984a).

2.5.2 Gross Pathology GCTs are unilateral in ~91 % of cases, and stage I is the most common stage at diagnosis. Grossly, GCTs are typically solid with variable cystic spaces and hemorrhagic. Tumors with prominent

8

Fig. 11 Ovarian stromal luteoma. The tumor composed of a uniform cell population with centrally placed nuclei and prominent nucleoli. The cytoplasm is finely granular with demarcated cellular outlines

M.M. Desouki and O. Fadare

Fig. 12 Adult granulosa cell tumor of the ovary. The tumor composed of monotonous cells with scant cytoplasm, uniform nuclei with evenly dispersed chromatin and nuclear grooves

theca component are often yellow and firm. Rupture at the time of surgery is not uncommon and do occur in up to 15 % of cases (Schumer and Cannistra 2003; Young et al. 1984a).

2.5.3 Histopathology Adult GCTs exhibit a range of epithelioid to spindle cell pattern with organoid or diffuse architecture. Combination of patterns is usually seen in a single tumor. Morphologic patterns include trabecular, insular, gland-like, microfollicular and macrofollicular, diffuse, “watered silk,” pseudopapillary, and cystic. The nuclei are uniform, with evenly dispersed chromatin and nuclear grooves (Figs. 12 and 13). Call–Exner bodies are characteristic of GCTs and defined as granulosa cells which arrange haphazardly around a space filled with eosinophilic material. Focal marked atypia is more common in juvenile GCT and is not independently correlated with malignant behavior. Luteinization of cells with plump pale cytoplasm is a common finding (Schumer and Cannistra 2003). The morphology of juvenile GCT is characterized by a nodular or diffuse proliferation of neoplastic cells in a myxoid and edematous background. Follicle-like spaces of different sizes and shapes containing proteinaceous material are characteristic with rare Call–Exner bodies (Fig. 14). In contrast to adult GCTs, the nuclei are

Fig. 13 Adult granulosa cell tumor of the ovary. The characteristic tumor cells grow in a pseudopapillary pattern

larger and hyperchromatic with no to scarce grooves (Young et al. 1984a). JGCTs are known to display a notably higher mitotic index than AGCTs, whose mitotic index is generally 2 fingerbreadths in width at the apex or if the uterus is at least stage 1 when the Valsalva maneuver is performed. If there was adequate vaginal access, then uterine size was taken into consideration. If the uterus was estimated to be less than 12 weeks or 280 gm, then a vaginal approach was appropriate. Although other formulas exist, the simplest and easiest to remember formula to estimateuterineweightis0.52 length widthdepth based on ultrasound measurements (Goldstein et al. 1988). If the clinical history or pelvic examination indicated possible extrauterine disease (endometriosis, pelvic inflammatory disease, ovarian disease, or chronic pelvic pain), laparoscopic

3

assistance was performed to confirm the presence and the extent of extrauterine pathologic condition accurately and whether operative laparoscopy would permit vaginal hysterectomy to be performed. Consideration was also given to the appropriateness and ability to perform uterine size reduction techniques, such as morcellation, myomectomy, or coring. Using these criteria, 92% of planned vaginal hysterectomies could be accomplished vaginally in a resident clinic population (Kovac et al. 2002). There were no conversions from vaginal hysterectomy to abdominal hysterectomy due to findings on laparoscopy; the remainder of the cases was performed abdominally or with laparoscopic assistance. Vaginal hysterectomy may be appropriate in women with uterus >12 weeks without an increased rate of complications (Cho et al. 2014; Fantania et al. 2014; Sahin 2007). However, mean operating time was significantly longer in the uteri 280 gm than in the 4 g/100 mL. (8.43% versus 1.2%) in women with uteri 280 gm (Sahin 2007). Although there is some data suggesting that women with two or more prior cesarean deliveries may be at higher risk of bladder injury with a vaginal hysterectomy (Duong and Patterson 2014), prior cesarean delivery does not contraindicate a vaginal hysterectomy (Purohit et al. 2013; Unger and Meeks 1998), and a history cesarean delivery is known to be a risk factor for bladder injury regardless of the route of hysterectomy (Rooney et al. 2005). Obesity is not a contraindication, and vaginal hysterectomy remains the procedure of choice in obese women who are having a hysterectomy (Harmanli et al. 2011; Muffly and Kow 2014; Sheth 2010).

3

Contraindications

There are contraindications to a vaginal hysterectomy which include cervical cancer, endometrial hyperplasia, or malignancy when morcellation

4

B. Özel

407 Yes

Hysterectomy Indicated for Benign Disease

388 Yes

Uterus Accessible Transvaginally

No 343 Yes

This flow chart not appropriate for decision support

Uterus < 280g (12–16 weeks. The Cochrane review included nine trials with 762 women comparing vaginal versus abdominal hysterectomy. Women returned to normal activities sooner after vaginal hysterectomy compared to abdominal hysterectomy (Median difference 9.5 days, 95% CI 6.4 to 12.6 days; 176 women, three trials). More women would choose a vaginal hysterectomy again when compared to an abdominal hysterectomy. There were three times as many urinary tract injuries after vaginal versus abdominal hysterectomy, although there was no statistical difference (OR 3.09, 95% CI 0.48 to 19.97, four RCTs, 439 women) (Aarts et al. 2015). There was no difference in other intraoperative complications or operative time. Hospital stay was shorter in vaginal hysterectomy compared to standard abdominal hysterectomy. Wound/abdominal wall infection (OR 0.21, 95% CI 0.04 to 1.00, three RCTs, 355 women), urinary tract infection (OR 0.59, 95% CI 0.08 to 4.61, three RCTs, 176 women), and febrile episodes or unspecified infections (OR 0.62, 95% CI 0.36 to 1.08, five RCTs, 495 women) all occurred less after VH than after AH, but there was no statistical difference.

Vaginal Hysterectomy: Indications, Avoiding Complications

The Cochrane group also reviewed 16 studies including 1440 women comparing vaginal hysterectomy to laparoscopic hysterectomy (including both laparoscopic-assisted vaginal hysterectomy and total laparoscopic hysterectomy). No advantage of laparoscopic-assisted vaginal hysterectomy or total laparoscopic hysterectomy over vaginal hysterectomy was demonstrated (Aarts et al. 2015). Hospital stay was 1 day shorter after vaginal hysterectomy. Women undergoing laparoscopic hysterectomy returned to work 1 day earlier than women undergoing VH, but the time to return to normal activities showed no evidence of a difference. There was no statistical difference in intraoperative or postoperative complications. Operating time is longer with a laparoscopic approach compared to vaginal hysterectomy. Although one study demonstrated lower post-op pain with laparoscopic hysterectomy (Ghezzi et al. 2010), other studies have not found similar results. Cost analysis has shown that mean total hospital charge when surgery was performed on an outpatient basis was significantly higher for laparoscopic hysterectomy compared to vaginal hysterectomy (Summit et al. 1992). The eVALuate study was a major multicenter study that consisted of two parallel randomized trials – one that compared abdominal hysterectomy to total laparoscopic hysterectomy and the other compared vaginal hysterectomy and total laparoscopic hysterectomy (Garry et al. 2004). Included in the study were women who needed a hysterectomy for nonmalignant conditions, and excluded were those who had a second or third degree uterine prolapse, a uterine size greater than the size of a 12-week pregnancy, a medical illness precluding laparoscopic surgery, or a requirement for bladder or other pelvic support surgery. It is the largest study to date comparing vaginal and total laparoscopic hysterectomy; 504 women were enrolled in the vaginal trial. There was no difference between vaginal and total laparoscopic hysterectomy in terms of complications, pain, and length of stay. Vaginal hysterectomy had a significantly shorter operating time (46.6 versus 76.5 min for vaginal versus laparoscopic, respectively).

11

While most randomized trials included women with only a slightly enlarged uterus, less than 12 weeks, Sesti and colleagues conducted a randomized study of women having a hysterectomy for benign reasons with a uterus between 12 and 16 weeks in size (Sesti et al. 2014). Women were randomized to vaginal hysterectomy, laparoscopicassisted vaginal hysterectomy, or total laparoscopic hysterectomy; there were 36 women in each group. All surgeons were experienced in all three techniques, having performed at least 100 of each type of hysterectomy. Operating time (mean 70 min) and estimated blood loss (mean 182.8 mL) was significantly less in the vaginal hysterectomy group compared to both laparoscopic-assisted vaginal hysterectomy and total laparoscopic hysterectomy. The mean hospital discharge time was also significantly shorter after VH (50.7 h). There were no differences in complication rates. In another study of hysterectomies for enlarged uterine size >280 g with at least one additional risk factor, previous pelvic surgery, history of pelvic inflammatory disease, moderate or severe endometriosis, concomitant adnexal masses, or indication for adnexectomy, Darai and colleagues randomized 80 women to laparoscopic-assisted vaginal hysterectomy versus vaginal hysterectomy (Darai et al. 2001). They found lower rate of complications with vaginal hysterectomy (15% with vaginal hysterectomy versus 37% with laparoscopic-assisted vaginal hysterectomy, p < 0.05) and shorter operating time with vaginal hysterectomy [mean operating time (range) was 108 (60–270 min) min for vaginal hysterectomy and 160 min (60–180 min) for laparoscopicassisted vaginal hysterectomy ( p < 0.001)]. Conversion to laparotomy was required in 3 of 40 (7.5%) women who had laparoscopic-assisted vaginal hysterectomy, compared with none in the vaginal hysterectomy group ( p < 0.05). No difference was found in the mean uterine weight (range) between vaginal hysterectomy and LAVH groups [424 g (280–930) and 513 g (290–1560), respectively]. The study included 13 cases (32.5%) of uterine size at least 500 gm in the vaginal hysterectomy group that were successfully completed vaginally.

12

B. Özel

Wright and colleagues looked at actual patient charges for the various modes of hysterectomy and found that at their institution, Brigham and Women’s Hospital, women who had a vaginal hysterectomy had the shortest operating time [mean 153 min (95% confidence interval 143.8–163.5, p < 0.001)] and women who had a vaginal, laparoscopic, and robotic hysterectomy had a significantly shorter hospital stay compared to those who had an abdominal hysterectomy. The mean length of stay for vaginal hysterectomy was 1.24 days. Based on this they calculated mean total patient costs and found that it was significantly lower for vaginal hysterectomy compared to other modes of hysterectomy (Wright et al. 2012); the mean cost for vaginal hysterectomy was $31,934, whereas robotic hysterectomy, the most expensive of the four modes of hysterectomy, costs $49,526.

Geller 2013). The estimated blood loss for a vaginal hysterectomy is 215–287 mL (ClarkePearson and Geller 2013). Urinary tract infection is reported in 3.1% of cases (Lake et al. 2013). Vaginal cuff dehiscence is lowest after vaginal hysterectomy compared to other routes of hysterectomy and is reported in 0.11% of cases (Hur et al. 2011). Pulmonary complications, defined as postoperative pneumonia, respiratory failure, symptomatic atelectasis (requirement of intervention, such as bronchoscopy, respiratory therapy consultation, or SICU admission), or pneumothorax within 365 days of the procedure, occur in 1.2 per 1000 of women after vaginal hysterectomy (Solomon et al. 2013). Venous thromboembolism after a vaginal hysterectomy occurs in 0.2% and is less common than with abdominal hysterectomy (Swenson et al. 2015).

6 5.8

Conclusion

Complications

Vaginal hysterectomy is associated with complications in 5.2% of women (Makinen et al. 2013). The most common complications are cuff cellulitis and abscess and incidental cystotomy. Surgical site infections are reported in 12 per 1000 women (Roy et al. 2014).The rate of cuff cellulitis is 0.6%, and the rate of deep/organ space surgical site infection is 1.0% after a vaginal hysterectomy (Lake et al. 2013). Bladder and ureteric injury are reported to occur at a rate of 5.1 per 1000 women and 0.4 per 1000 women, respectively (Teeluckdharry et al. 2015). In one large retrospective study where universal cystoscopy was used, the authors found that the rate of ureteral injury is higher when there is concomitant prolapse repair (0.9% versus 1.7%) (Ibeanu et al. 2009). The use of routine cystoscopy has been suggested to be cost effective if the rate of ureteral injury is greater than 2% for vaginal hysterectomy (Visco et al. 2001). The risk of vesicovaginal fistula formation is the lowest after vaginal hysterectomy for prolapse with a rate of 1 in 3861 or 0.26 per 1000 (Hilton and Cromwell 2012). The rate of bowel injury during vaginal hysterectomy ranges from 0.1% to 1.0% (Clarke-Pearson and

Vaginal hysterectomy should be considered first line for all women having a hysterectomy and has been shown to be cost effective with low risk of complications.

7

Cross-References

▶ Abdominal Hysterectomy: Indications, Avoiding Complications ▶ Laparoscopic Hysterectomy ▶ Management of Abnormal Bleeding in Late Reproductive Years ▶ Management of Uterine Fibroids

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Vaginal Hysterectomy: Indications, Avoiding Complications ACOG Committee Opinion No. 444. Obstet Gynecol. 2009;114:1156–8. Antosh DD, Gutman RE, Iglesia CB, Sokol AI, Park AJ. Resident opinions on vaginal hysterectomy training. Female Pelvic Med Reconstr Surg. 2011;17 (6):314–7. Ascher-Walsh CJ, Capes T, Smith J, Michels A. Cervical vasopressin compared with no premedication and blood loss during vaginal hysterectomy: a randomized controlled trial. Obstet Gynecol. 2009;113(2 Pt 1):313–8. Burkett D, Horwitz J, Kennedy V, Murphy D, Graziano S, Kenton K. Assessing current trends in resident hysterectomy training. Female Pelvic Med Reconstr Surg. 2011;17(5):210–4. Cavkaytar S, Kokanali MK, Topcu HO, Aksakal OS, Doganay M. Effects of horizontal vs. vertical vaginal cuff closure techniques on vagina length after vaginal hysterectomy: a prospective randomized study. J Minim Invasive Gynecol. 2014;21(5):884–7. Cho HY, Park ST, Kim HB, Kang SW, Park SH. Surgical outcome and cost comparison between total vaginal hysterectomy and laparoscopic hysterectomy for uteri weighing >500 g. J Minim Invasive Gynecol. 2014;21 (1):115–9. Clarke-Pearson DL, Geller EJ. Complications of hysterectomy. Obstet Gynecol. 2013;121(3):654–73. Cruikshank SH, Kovac SR. Randomized comparison of three surgical methods used at the time of vaginal hysterectomy to prevent posterior enterocele. Am J Obstet Gynecol. 1999;180(4):859–65. Cruikshank SH, Pixley RL. Methods of vaginal cuff closure and preservation of vaginal depth during transvaginal hysterectomy. Obstet Gynecol. 1987;70 (1):61–3. Culligan PJ, Kubik K, Murphy M, Blackwell L, Snyder J. A randomized trial that compared povidone iodine and chlorhexidine as antiseptics for vaginal hysterectomy. Am J Obstet Gynecol. 2005;192(2):422–5. Dain L, Abramov Y. Factors affecting the feasibility of bilateral salpingo-oophorectomy during vaginal hysterectomy for uterine prolapse. Aust N Z J Obstet Gynaecol. 2011;51(4):307–9. Daraï E, Soriano D, Kimata P, Laplace C, Lecuru F. Vaginal hysterectomy for enlarged uteri, with or without laparoscopic assistance: randomized study. Obstet Gynecol. 2001;97(5 Pt 1):712–6. Dayaratna S, Goldberg J, Harrington C, Leiby BE, McNeil JM. Hospital costs of total vaginal hysterectomy compared with other minimally invasive hysterectomy. Am J Obstet Gynecol. 2014;210:120.e1–6. Desai VB. An update on inpatient hysterectomy routes in the United States. AJOG. 2015;213(5):742–743. Dua A, Galimberti A, Subramaniam M, Popli G, Radley S. The effects of vault drainage on postoperative morbidity after vaginal hysterectomy for benign gynaecological disease: a randomised controlled trial. BJOG. 2012;119(3):348–53. Duong TH, Patterson TM. Lower urinary tract injuries during hysterectomy in women with a history of two

13

or more cesarean deliveries: a secondary analysis. Int Urogynecol J. 2014;25(8):1037–40. Engh ME, Hauso W. Vaginal hysterectomy, an outpatient procedure. Acta Obstet Gynecol Scand. 2012;91:1293–9. Fatania K, Vithayathil M, Newbold P, Yoong W. Vaginal versus abdominal hysterectomy for the enlarged non-prolapsed uterus: a retrospective cohort study. Eur J Obstet Gynecol Reprod Biol. 2014;174:111–4. Fitz-Gerald AL, Tan J, Chan KW, Polyakov A, Edwards GN, Najjar H, Tsaltas J, Vollenhoven B. Comparison of ultrasonic shears and traditional suture ligature for vaginal hysterectomy: randomized controlled trial. J Minim Invasive Gynecol. 2013;20(6):853–7. Garry R, Fountain J, Mason S, Hawe J, Napp V, Abbott J, Clayton R, Phillips G, Whittaker M, Lilford R, Bridgman S, Brown J. The eVALuate study: two parallel randomised trials, one comparing laparoscopic with abdominal hysterectomy, the other comparing laparoscopic with vaginal hysterectomy. BMJ. 2004;328 (7432):129. Ghezzi F, Uccella S, Cromi A, Siesto G, Serati M, Bogani G, Bolis P. Postoperative pain after laparoscopic and vaginal hysterectomy for benign gynecologic disease: a randomized trial. Am J Obstet Gynecol. 2010;203(2):118.e1–8. Goldstein SR, Horii SC, Snyder JR, Raghavendra BN, Subramanyam B. Estimation of nongravid uterine volume based on a nomogram of gravid uterine volume: its value in gynecologic uterine abnormalities. Obstet Gynecol. 1988;72(1):86–90. Guntupalli SR, Doo DW, Guy M, Sheeder J, Omurtag K, Kondapalli L, Valea F, Harper L, Muffly TM. Preparedness of obstetrics and gynecology residents for fellowship training. Obstet Gynecol. 2015;126(3):559–68. Harmanli OH, Dandolu V, Isik EF, Panganamamula UR, Lidicker J. Does obesity affect the vaginal hysterectomy outcomes? Arch Gynecol Obstet. 2011;283 (4):795–8. Hilton P, Cromwell DA. The risk of vesicovaginal and urethrovaginal fistula after hysterectomy performed in the English National Health Service – a retrospective cohort study examining patterns of care between 2000 and 2008. BJOG. 2012;119(12):1447–54. Hristovska AM, Kristensen BB, Rasmussen MA, Rasmussen YH, Elving LB, Nielsen CV, Kehlet H. Effect of systematic local infiltration analgesia on postoperative pain in vaginal hysterectomy: a randomized, placebocontrolled trial. Acta Obstet Gynecol Scand. 2014;93 (3):233–8. Hur HC, Donnellan N, Mansuria S, Barber RE, Guido R, Lee T. Vaginal cuff dehiscence after different modes of hysterectomy. Obstet Gynecol. 2011;118(4):794–801. Ibeanu OA, Chesson RR, Echols KT, Nieves M, Busangu F, Nolan TE. Urinary tract injury during hysterectomy based on universal cystoscopy. Obstet Gynecol. 2009;113:6–10.

14 Jeppson PC, Rahimi S, Gattoc L, Westermann LB, Cichowski S, Raker C, Lebrun EW, Sung VW, Fellows’ Pelvic Research Network of Society of Gynecologic Surgeons. Impact of robotic technology on hysterectomy route and associated implications for resident education. Am J Obstet Gynecol. 2015;212 (2):196.e1–6. Kammerer-Doak DN, Rogers RG, Johnson Maybach J, Traynor Mickelson M. Vasopressin as an etiologic factor for infection in gynecologic surgery: a randomized double-blind placebo-controlled trial. Am J Obstet Gynecol. 2001;185(6):1344–7. discussion 1347–1348 Karp DR, Mukati M, Smith AL, Suciu G, Aguilar VC, Davila GW. Predictors of successful salpingooophorectomy at the time of vaginal hysterectomy. J Minim Invasive Gynecol. 2012;19(1):58–62. Kjølhede P, Halili S, Löfgren M. Vaginal cleansing and postoperative infectious morbidity in vaginal hysterectomy. A register study from the Swedish National Register for Gynecological Surgery. Acta Obstet Gynecol Scand. 2011;90(1):63–71. Kovac SR, Barhan S, Lister M, Tucker L, Bishop M, Das A. Guidelines for the selection of the route of hysterectomy: application in a resident clinic population. Am J Obstet Gynecol. 2002;187(6):1521–7. Kroft J, Selk A. Energy-based vessel sealing in vaginal hysterectomy: a systematic review and meta-analysis. Obstet Gynecol. 2011;118(5):1127–36. Lake AG, McPencow AM, Dick-Biascoechea MA, Martin DK, Erekson EA. Surgical site infection after hysterectomy. Am J Obstet Gynecol. 2013;209(5):490.e1–9. Lakeman M, The S, Schellart R, Dietz V, ter Haar J, Thurkow A, Scholten P, Dijkgraaf M, Roovers J. Electrosurgical bipolar vessel sealing versus conventional clamping and suturing for vaginal hysterectomy: a randomised controlled trial. BJOG. 2012;119:1473–82. Lipscomb GH, Ling FW, Stovall TG, Summitt Jr RL. Peritoneal closure at vaginal hysterectomy: a reassessment. Obstet Gynecol. 1996;87(1):40–3. Long JB, Eiland RJ, Hentz JG, Mergens PA, Magtibay PM, Kho RM, Magrina JF, Cornella JL. Randomized trial of preemptive local analgesia in vaginal surgery. Int Urogynecol J Pelvic Floor Dysfunct. 2009;20(1):5–10. Mäkinen J, Brummer T, Jalkanen J, Heikkinen AM, Fraser J, Tomás E, Härkki P, Sjöberg J. Ten years of progress – improved hysterectomy outcomes in Finland 1996–2006: a longitudinal observation study. BMJ Open. 2013;3(10):e003169. Muffly TM, Kow NS. Effect of obesity on patients undergoing vaginal hysterectomy. J Minim Invasive Gynecol. 2014;21(2):168–75. O’Neal MG, Beste T, Shackelford DP. Utillity of preemptive local anesthesia in vaginal hysterectomy. Am J Obstet Gynecol. 2003;189(6):1539–41. discussion 1541–1542 Purohit RK, Sharma JG, Singh S, Giri DK. Vaginal hysterectomy by electrosurgery for benign indications

B. Özel associated with previous cesarean section. J Gynecol Surg. 2013;29(1):7–12. Robert M, Cenaiko D, Sepandj J, Iwanicki S. Success and complications of salpingectomy at the time of vaginal hysterectomy. J Minim Invasive Gynecol. 2015;22 (5):864–9. Rooney CM, Crawford AT, Vassallo BJ. Is previous cesarean section a risk for incidental cystotomy at the time of hysterectomy? A case-controlled study. Am J Obstet Gynecol. 2005;193:2041. Rorarius M, Mennander S, Suominen P, Rintala S, Puura A, Pirhonen R, Salmelin R, Haanpaa M, Kujansuu E, Yli-Hankala A. Gabapentin for the prevention of postoperative pain after vaginal hysterectomy. Pain. 2004;110:175–81. Roy S, Patkar A, Daskiran M, Levine R, Hinoul P, Nigam S. Clinical and economic burden of surgical site infection in hysterectomy. Surg Infect. 2014;15 (3):266–73. Sahin Y. Vaginal hysterectomy and oophorectomy in women with 12–20 weeks’ size uterus. Acta Obstet Gynecol Scand. 2007;86(11):1359–69. Sesti F, Cosi V, Calonzi F, Ruggeri V, Pietropolli A, Di Francesco L, Piccione E. Randomized comparison of total laparoscopic, laparoscopically assisted vaginal and vaginal hysterectomies for myomatous uteri. Arch Gynecol Obstet. 2014;290(3):485–91. Sheth SS. Vaginal hysterectomy as a primary route for morbidly obese women. Acta Obstet Gynecol Scand. 2010;89(7):971–4. Silva-Filho AL, Rodrigues AM, Vale de Castro Monteiro M, da Rosa DG, Pereira e Silva YM, Werneck RA, Bavoso N, Triginelli SA. Randomized study of bipolar vessel sealing system versus conventional suture ligature for vaginal hysterectomy. Eur J Obstet Gynecol Reprod Biol. 2009;146(2):200–3. Solomon ER, Muffly TM, Barber MD. Common postoperative pulmonary complications after hysterectomy for benign indications. Am J Obstet Gynecol. 2013;208(1):54.e1–5. Summitt Jr RL, Stovall TG, Lipscomb GH, Ling FW. Randomized comparison of laparoscopy-assisted vaginal hysterectomy with standard vaginal hysterectomy in an outpatient setting. Obstet Gynecol. 1992;80 (6):895–901. Summitt Jr RL, Stovall TG, Bran DF. Prospective comparison of indwelling bladder catheter drainage versus no catheter after vaginal hysterectomy. Am J Obstet Gynecol. 1994;170(6):1815–8. discussion 1818–1821 Sutton C. Hysterectomy: a historical perspective. Baillieres Clin Obstet Gynaecol. 1997;11:1–22. Sutton C. Past, present and future of hysterectomy. J Minim Invasive Gynecol. 2010;17(4):421–35. Swenson CW, Berger MB, Kamdar NS, Campbell Jr DA, Morgan DM. Risk factors for venous thromboembolism after hysterectomy. Obstet Gynecol. 2015;125 (5):1139–44. Teeluckdharry B, Gilmore D, Flowerdew G. Urinary tract injury at benign gynecologic surgery and the role of

Vaginal Hysterectomy: Indications, Avoiding Complications cystoscopy: a systematic review and meta-analysis. Obstet Gynecol. 2015;126:1161. E pub ahead of print Unger JB, Meeks GR. Vaginal hysterectomy in women with history of pervious cesarean delivery. AJOG. 1998;179:1473–8. Vassallo BJ, Culpepper C, Segal JL, Moen MD, Noone MB. A randomized trial comparing methods of vaginal cuff closure at vaginal hysterectomy and the effect on vaginal length. Am J Obstet Gynecol. 2006;195 (6):1805–8. Visco AG, Taber KH, Weidner AC, Barber MD, Myers ER. Cost-effectiveness of universal cystoscopy to identify ureteral injury at hysterectomy. Obstet Gynecol. 2001;97(5 Pt 1):685–92. Washburn EE, Cohen SL, Manoucheri E, Zurawin RK, Einarsson JI. Trends in reported resident surgical experience in hysterectomy. J Minim Invasive Gynecol. 2014;21(6):1067–70.

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Woelk JL, Borah BJ, Trabuco EC, Heien HC, Gebhart JB. Cost differences among robotic, vaginal, and abdominal hysterectomy. Obstet Gynecol. 2014;123 (2 Pt 1):255–62. Wright KN, Jonsdottir GM, Jorgensen S, Shah N, Einarsson JI. Costs and outcomes of abdominal, vaginal, laparoscopic and robotic hysterectomies. JSLS. 2012;16:519–24. Wright JD, Herzog TJ, Tsui J, Ananth CV, Lewin SN, Lu YS, Neugut AI, Hershman DL. Nationwide trends in the performance of inpatient hysterectomy in the United States. Obstet Gynecol. 2013a;122 (201):233–41. Wright JD, Ananth CV, Lewin SN, Burke WM, Lu YS, Neugut AI, Herzog TJ, Hershman DL. Robotically assisted vs. laparoscopic hysterectomy among women with benign gynecologic disease. JAMA. 2013b;309 (7):689–98.

Pelvic Organ Prolapse: Diagnosis, Treatment, and Avoiding Complications Christina Dancz and Morgan Fullerton

Contents 1

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2

2 2.1

2

2.2 2.3

Anatomy/Pathophysiology . . . . . . . . . . . . . . . . . . . Level 1: The Cardinal and Uterosacral Ligament Complex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Level 2: The Endopelvic Fascia . . . . . . . . . . . . . . . Level 3: The Perineal Body . . . . . . . . . . . . . . . . . . .

2 3 3

3

Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3

4 4.1 4.2 4.3 4.4

Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Patient History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Physical Exam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sensory Exam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pelvic Exam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4 4 4 4 4

5

Complications of Prolapse . . . . . . . . . . . . . . . . . . .

5

6 6.1

Nonsurgical Management of Prolapse . . . . . . Pessary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6 6

7

Pelvic Floor Muscle Training . . . . . . . . . . . . . . . .

9

8

Surgical Management . . . . . . . . . . . . . . . . . . . . . . . .

9

9

Anterior Prolapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

10 10.1 10.2 10.3 10.4

Anterior Colporrhaphy . . . . . . . . . . . . . . . . . . . . . . Vaginal Paravaginal Repair . . . . . . . . . . . . . . . . . . . . Site-Specific Repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . Graft and Mesh Augmentation . . . . . . . . . . . . . . . . Types of Grafts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

11

Transvaginal Mesh for Anterior/Apical Prolapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 Concomitant Hysterectomy . . . . . . . . . . . . . . . . . . . 15

11.1

10 12 12 12 14

12

Apical Prolapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

13 13.1

Vaginal Approach for Apical Prolapse . . . . . 16 Mayo/McCall Culdoplasty . . . . . . . . . . . . . . . . . . . . 16

14 14.1 14.2

Uterosacral Ligament Suspension . . . . . . . . . . 18 Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 Outcomes and Complications . . . . . . . . . . . . . . . . . 18

15 15.1 15.2

Sacrospinous Ligament Fixation . . . . . . . . . . . . 18 Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 Outcomes and Complications . . . . . . . . . . . . . . . . . 19

16

Alternative Vaginal Approaches . . . . . . . . . . . . 19

17 17.1 17.2 17.3 17.4 17.5

Abdominal Approach to Apical Prolapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sacral Colpopexy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Obliterative Procedures . . . . . . . . . . . . . . . . . . . . . . . . Technique/Considerations . . . . . . . . . . . . . . . . . . . . . Total Colpectomy/Colpocleisis . . . . . . . . . . . . . . . . Partial/LeFort Colpocleisis . . . . . . . . . . . . . . . . . . . .

18 18.1 18.2

Posterior Prolapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 Outcomes and Complications . . . . . . . . . . . . . . . . . 25

19

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

20 20 22 22 22 22

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

C. Dancz (*) • M. Fullerton University of Southern California, Los Angeles, CA, USA e-mail: [email protected]; morgan. [email protected] # Springer International Publishing AG 2016 D. Shoupe (ed.), Handbook of Gynecology, DOI 10.1007/978-3-319-17002-2_70-1

1

2

C. Dancz and M. Fullerton

Abstract

Pelvic organ prolapse (POP) is defined as the descent of one or more of the anterior vaginal wall, posterior vaginal wall, the uterus (cervix), or the apex of the vagina (vaginal vault or cuff scar after hysterectomy). Prolapse is extremely common and is one of the leading reasons for surgery in the United States. The main symptom of prolapse is the sensation of bulge or pressure in the vagina. Severe prolapse may interfere with successful urination, defecation, or sexual function. Prolapse diagnosis is usually based on physical exam, though several formal staging systems exist. Asymptomatic or minimally symptomatic prolapse may not require any intervention. Patients with significant bother may elect to use a plastic device (pessary) to hold their prolapsed organs in place, or they may elect for surgery. There are a variety of surgical procedures for prolapse, depending on the patient’s health, preferences, degree, and location of prolapse.

with sexual complaints and urinary symptoms such as voiding difficulty, bladder outlet obstruction, and detrusor overactivity (Romanzi et al. 1999). It is rare that prolapse will cause significant morbidity or mortality, but it is commonly associated with sexual, urinary, and defecatory symptoms that may interfere with activities of daily living and affect quality of life. It is not uncommon for women to digitally reduce their prolapse (splint) in order to urinate or defecate. In extreme cases, obstructed urination may result in obstructive uropathy causing hydronephrosis and even progressing to renal failure (Sudhakar et al. 2001). Many patients with prolapse will elect for conservative management or go without treatment altogether (Culligan 2012). Conservative management strategies include pelvic floor muscle training and pessaries. A variety of surgical options are available, depending on the type and degree of prolapse, as well as patient preference and comorbidities. The necessity of hysterectomy at the time of prolapse repair is controversial, as is the need for mesh or graft to augment native tissue repairs.

Keywords

Pelvic organ • Prolapse • Pessary • Surgery

1

Introduction

Pelvic organ prolapse (POP) is defined as the descent of one or more of the anterior vaginal wall, posterior vaginal wall, uterus (cervix), or apex of the vagina (vaginal vault or cuff after hysterectomy) (Haylen et al. 2010). POP is estimated to affect 3.3 million women in the United States alone, and the number of women affected is projected to increase by nearly 50% by 2050 (Wu et al. 2009). Prolapse is one of the most common reasons for surgery in the United States and is projected to increase from 166,000 surgeries annually in 2010 to 245,970 in 2050 (Wu et al. 2011). The most common symptom of prolapse is the sensation or discomfort of vaginal or uterine tissue prolapsing from the vagina and between the legs (Fig. 1). Severe prolapse may be associated

2

Anatomy/Pathophysiology

Pelvic organ prolapse is the result of disruption of one or more of the supports that normally hold the pelvic organs in place. There are three primary supports of the uterus and upper vagina: 1) the cardinal/uterosacral ligament complex, 2) the lateral/paravaginal attachments of the endopelvic fascia, and 3) the perineal membrane (DeLancey 1992).

2.1

Level 1: The Cardinal and Uterosacral Ligament Complex

First, a note on terminology: Although the cardinal and uterosacral ligaments are commonly described as ligaments, true ligaments attach bone to bone, while the cardinal and uterosacral “ligaments” are more of a condensation of fibrous tissue, collagen, muscle, and nerves.

Pelvic Organ Prolapse: Diagnosis, Treatment, and Avoiding Complications

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bottom of the pubic symphysis to the ischial spine on either side. Injury to this fascial layer or disruption of these lateral attachments is commonly seen after childbirth, even in the absence of a perineal laceration and is thought to be one of the primary causative factors for pelvic organ prolapse.

2.3

Fig. 1 Pelvic organ prolapse (Photograph courtesy of Dr. Begüm Özel)

The cardinal ligament stretches between the base of the uterus and the lateral wall of the pelvis, thereby preventing inferior movement of the uterus. The uterosacral ligament connects the lateral edge of the uterus to the anterior surface of the sacrum, which prevents the uterus from being displaced inferiorly and anteriorly (Drake et al. 2008). These ligaments may be disrupted through surgical or obstetric trauma. However, it is more common that these ligaments are intact, but stretched out by consistent downward traction of the uterus and vagina. Similarly, collagen vascular disorders may be associated with lengthening and stretching of these ligaments and result in pelvic organ prolapse.

2.2

Level 2: The Endopelvic Fascia

Another note on terminology: The “endopelvic fascia“ is not a true fascial layer, rather a condensation of areolar and connective tissue; however, it will hereafter be referred to as “fascia.” The endopelvic fascia is essentially the tendinous insertion of the levator ani complex where it attaches on the arch of the pelvis. This tendinous arch (arcus tendineus fascia pelvis) runs from the

Level 3: The Perineal Body

The perineal body is the third and most distal level of support. This layer is made up of the superficial perineal muscles that form the anterior urogenital triangle (bulbocavernosus, ischiocavernosus, and transverse perineal). Within the triangle is a confluence of connective tissue that provides additional support to the vulva and lower vagina. Disruption of this layer may occur during childbirth, or due to chronic traction of the uterus and vagina due to defects in the upper two levels of support.

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Risk Factors

The causes of prolapse are multifactorial. There are some genetic risk factors; a family history of prolapse is associated with increased risk, as is Caucasian race and Hispanic ethnicity, when compared to Asian and African Americans. The most common risk factors include vaginal childbirth, increasing age, and increasing body mass index. Vaginal childbirth is strongly associated with anatomic disruption of the pelvic organ supports, and pregnancy is associated with laxity/stretching of the pelvic floor ligaments. Increasing age is thought to be associated with changes in the collagen composition of the ligamentous supports, leading to increased risk of prolapse. Body mass index is likely a risk factor for prolapse due to chronic increases in abdominal pressure and straining. In fact, other causes of chronic increase in abdominal pressure have also been associated with prolapse (constipation, chronic cough) (Koelbl et al. 2013). Although there have not been any proven effective strategies to reduce risk, it is reasonable

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to think that weight loss, reduction of heavy lifting, treatment of constipation, modification of obstetric risk factors, and pelvic floor physical therapy may be effective in preventing the development or progression of pelvic organ prolapse.

of prolapse with Valsalva. Additional testing for incontinence may be indicated in patients with urinary or fecal incontinence and some advocate testing for occult incontinence in women with prolapse considering surgical intervention.

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Diagnosis

4.3

4.1

Patient History

Sensation to the vulva and perineum is primarily provided by the pudendal nerve, a branch of the S2–S4 nerve root. Intact sensation to the inner thigh and perineum to light touch and pinprick confirms function of the pudendal nerve to the cerebral cortex. The anal wink reflex or clitoral reflex requires an intact levator ani and pudendal nerves, as well as connection to the cerebral cortex. The anal wink may be checked by gently stroking perianally with the soft edge of a cotton swab; a positive test will result in contraction of the external anal sphincter. The clitoral reflex may be checked by gently squeezing the clitoris and looking for contraction of the pelvic floor. Both of these tests are specific but not sensitive, meaning that a positive test confirms intact nerves, but the absence of the reflex is not diagnostic of neurologic disruption.

As pelvic organ prolapse is rarely associated with significant morbidity or mortality, the most important principle in prolapse evaluation is assessing the degree of bother for the patient. The most effective strategy in managing prolapse is to allow the patient to express what aspect of the prolapse bothers her most. This allows the practitioner to tailor treatment plans to the patients’ needs and wishes, rather than focusing on the anatomic outcomes that may or may not reflect successful treatment for the patient. The most specific complaint of women with pelvic organ prolapse is the sensation of bulge or pressure in the vagina. This sensation may be difficult to distinguish from the sensation of pressure in the lower abdomen. Low abdominal pressure is often nonspecific, and, in the absence of vaginal pressure, is unlikely to be due to prolapse. Urinary, defecatory, and sexual symptoms are also common and should be evaluated in women with prolapse.

4.2

Physical Exam

Pelvic organ prolapse can almost always be evaluated completely with physical exam. Ancillary radiologic testing is rarely indicated. A comprehensive physical exam is indicated when considering any surgical intervention for pelvic organ prolapse. A complete evaluation should include: basic sensory testing, visual inspection of the external genitalia and cervix, bimanual and rectovaginal examination and visual assessment

4.4

Sensory Exam

Pelvic Exam

A careful speculum, bimanual, and rectovaginal exam is important to look for other etiologies of bulge in the vagina and to screen for cervical, vaginal, and vulvar cancers. The presence of prolapse does not increase the risk for any type of cancer, but prolapse may exist concomitantly with other gynecologic conditions, and these need to be ruled out. Careful evaluation of the degree of prolapse must be documented for all patients with complaints of prolapse. The maximum amount of prolapse that can be elicited should be documented. This usually requires the patient to perform Valsalva or cough and may require the patient to

Pelvic Organ Prolapse: Diagnosis, Treatment, and Avoiding Complications

stand in order to demonstrate the maximum descent of her prolapse. Often, it is appropriate to separate a speculum and use the lower half to reduce the compartment not being evaluated. The posterior wall may be reduced in order to completely see and evaluate the anterior wall, and vice versa. There are a variety of staging systems that have been proposed for prolapse. The most common are the Baden-Walker grading system and the Pelvic Organ Prolapse Quantification (POP-Q) staging system (Bump et al. 1996), which have been developed and endorsed by the International Continence Society and the International Urogynecological Association (Haylen et al. 2010). The Baden-Walker grading system divides the vagina into three compartments: anterior, apical, and posterior. The anterior compartment consists of the upper vagina between the cervix and urethra and generally corresponds to the area just under the bladder and urethra. The apical compartment is the upper vagina and cervix, while the posterior compartment is the pelvic floor between the cervix and perineal body. Each compartment is considered separately and the maximum descent of each compartment evaluated. Prolapse in the upper half of the vagina is considered grade 1, in the lower half of the vagina is grade 2, coming out halfway is grade 3, and completely everted is considered grade 4 (Table 1). Such a grading system is easy to understand and remember and is often used by gynecologists to document the degree of prolapse (Baden and Walker 1992).

Table 1 Baden-Walker grading system for pelvic organ prolapse Grade of Prolapse Grade 0 Grade 1 Grade 2 Grade 3 Grade 4

Extent of prolapse in relationship to the hymen Normal position for each respective site Descent halfway to the hymen Descent to the hymen Descent halfway past the hymen Maximum possible descent for each site

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In an effort to further quantify prolapse and to describe and compare treatment outcomes, the POP-Q examination was developed. This technique is more complicated to learn, but is more quantitative and uses clear anatomic landmarks. It uses 9 points. All points of the POP-Q are measured in cm, relative to the hymen. Inside of the body are negative values, and outside of the body are measured as positive values. GH, PB, and TVL are measured at rest. The remainder of the points should be measured with the maximum prolapse elicited. Prolapse may be elicited with patient on Valsalva maneuver, with standing, or both (Table 2).

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Complications of Prolapse

Significant complications from untreated pelvic organ prolapse are rare. The most common complications include vaginal abrasions, bleeding, and urinary retention. In rare cases, the prolapse may become so edematous that it is difficult or impossible to reduce – an incarcerated prolapse. Vaginal abrasions or ulcerations with bleeding may be avoided with reduction of prolapse, either surgically or with pessary (Fig. 2). Vaginal abrasions related to atrophy may be treated with topical estrogen cream. Occasionally, the vaginal epithelium is so dry and irritated that additional treatment with Vaseline or vitamin A and D ointment is necessary. Symptoms of urinary retention may be treated with reduction of prolapse. A recent study showed that in women with stage 3–4 prolapse, the prevalence of hydronephrosis was up to 55% (Dancz et al. 2015; Hui et al. 2011). Therefore, in women who decline intervention, it may be indicated to screen for retention with post-void residual, creatinine level, and renal ultrasound. Prolapse that is traumatized, usually from a fall or other inadvertent harsh manipulation of the prolapse, may become edematous and irreducible. These may usually be reduced with adequate pain control and gentle, consistent pressure. The fundus must be gently aimed into the body in order to return the uterus to the pelvis.

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Table 2 POP-Q staging system for pelvic organ prolapse Aa – anterior wall 3 cm proximal to the urethral meatus (range, 3 to +3) gh – genital hiatus Mid-urethral meatus to the posterior fourchette Ap – posterior wall 3 cm proximal to the hymenal remnant (range, 3 to +3)

Ba – anterior wall Most distal part of the anterior wall pb – perineal body Posterior fourchette to the mid-anus Bp – posterior wall Most distal part of the posterior wall

C – cervix or cuff Most distal descent of cervix/vaginal cuff tvl – total vaginal length Greatest depth of the vagina when prolapse is reduced D – posterior fornix (omitted if there is no cervix)

women with multiple comorbidities or in women who prefer to avoid surgical risks (Culligan 2012). Pessary use has been shown to be as effective as surgery in improving patients’ symptoms of prolapse including bowel complaints, bladder complaints, sexual function, and overall quality of life (Abdool et al. 2011).

Fig. 2 Pelvic organ prolapse with ulcerations (Photograph courtesy of Dr. Begüm Özel)

6

Nonsurgical Management of Prolapse

6.1

Pessary

Pessaries are devices of various shapes and sizes that are placed in the vagina to reduce pelvic organ prolapse and restore normal anatomy. Pessary use can be temporary or long term. It provides immediate relief from pelvic organ prolapse symptoms, but requires some maintenance. Long-term pessary use may be an alternative to surgery in

6.1.1 Fitting of Pessary The success of pessaries lies in a proper fitting. Pessaries can be successfully fitted 60–90% of the time (Clemons et al. 2004; Lone et al. 2011). When a pessary is successful at the 4-week point, most women continue to use a pessary at 5 years (Lone et al. 2011). When choosing a pessary, the provider needs to consider the stage of pelvic organ prolapse, the size of vaginal vault, and the ability of the patient to manage their own pessary. The goal is to find the smallest pessary that effectively treats their prolapse symptoms. Initial fitting may require a trial of several different pessary types and/or sizes to adequately and comfortably reduce their prolapse (Culligan 2012). Ring with support pessaries (Fig. 3) is widely available and the most commonly used (Cundiff et al. 2000). The initial choice of pessary size should be based on the examiner’s bimanual exam and appreciation of the width of the vaginal canal (Culligan 2012). Once the exam is performed, the provider should identify an appropriate size and shape pessary. The pessary should be placed by the provider and tested by the patient. Initial tests for correct sizing can be performed by having the patient cough or stand with the pessary in place. If it stays in place, then the patient should attempt a Valsalva maneuver while sitting. If the

Pelvic Organ Prolapse: Diagnosis, Treatment, and Avoiding Complications

Fig. 3 Ring with support pessary

pessary continues to remain in place with these measures and is comfortable, it is likely the correct size. The patient should also be able to ambulate and urinate with the pessary in place. Well-fit pessaries should not be felt by the patient. Once a pessary is successfully fit, the patient should return for close follow-up. Typically the patient is given a return appointment in 1–2 weeks to make sure the pessary continues to comfortably reduce the patient’s prolapse and allows for normal daily functions (Trowbridge and Fenner 2007). At this time, if the patient is uncomfortable or has lost the pessary with activity, this is an opportunity to change pessary size or type. This visit also provides a good opportunity to educate a motivated patient on how to remove and clean her pessary so that she can manage her pessary at home. Once a patient is comfortable and has learned to manage her pessary, she can then be followed every 3–6 months. She is instructed to remove and clean the pessary with soap and water approximately once a week. If the patient is comfortable, but cannot change her own pessary, she should be seen every 2–3 months for outpatient exchange by her provider (Culligan 2012; Trowbridge and Fenner 2007).

6.1.2 Types of Pessaries There are two general categories of pessaries – support and space filling. Support pessaries typically sit between the pubic symphysis and

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posterior fornix. They reduce prolapse by elevating the superior vagina and often have perforations that allow the escape of vaginal secretions. Examples of support pessaries are the ring, ring with support, Gehrung, and Hodge. Space-filling pessaries work by elevating the prolapse and maintaining the normal anatomic position by creating a barrier within the vagina that is larger than the genital hiatus. The cube pessary (Fig. 4) may be used for refractory cases, as it stays in place by creating suction to the vaginal walls. A commonly used option is the Gellhorn pessary, (Fig. 5) which acts both as suction and barrier (Cundiff et al. 2000). A randomized crossover trial showed no difference in patient satisfaction or symptom relief from the ring versus Gellhorn pessary (Cundiff et al. 2007). The ring with support pessary is relatively easy to place/remove and is well tolerated by patients (Cundiff et al. 2000). If the ring with support does not work, the next choice is typically the Gellhorn. If neither of these work, chances of successful prolapse management with pessary are unlikely (Culligan 2012). A variety of other pessaries may be used, each with slightly different features. Overall, these pessaries are typically more difficult for patients to manage (Culligan 2012; Trowbridge and Fenner 2007). The inflatoball (Fig. 6) is an option for women with stage 3 or 4 pelvic organ prolapse who desire the ability to manage their pessary at home. It is more easily placed and removed by the patient compared to a Gellhorn or donut pessary because it can be inflated after insertion and deflated prior to removal, though the stem does protrude from the vagina and may cause discomfort for the patient (Trowbridge and Fenner 2007). Pessaries are generally made of surgical-grade silicone; therefore, patients with latex allergies may use them without concern. Over time, the silicone may develop some discoloration. The structural integrity of the pessary is not affected, and discolored pessaries may be used indefinitely. The inflatoball pessary (Fig. 6) is the only pessary that is made of rubber. The rubber material in the inflatoball pessary may absorb a slight odor, and the rubber may dry out over time. Inflatoball pessaries should be checked and replaced periodically.

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Fig. 4 Cube pessary

Fig. 5 Gellhorn pessary

6.1.3 Complications Reported complication rates from pessaries vary, but in a large study of over a thousand women, 88.5% had no complications (Hanson et al. 2006). The most commonly reported complications are vaginal discharge, vaginal ulcerations, and abrasions. It is normal for women to have increased vaginal discharge with a pessary in place, but

C. Dancz and M. Fullerton

there is concern for infection if they report itching, foul odor, or burning sensation. With a pessary in place, the vaginal flora is altered, and women are more predisposed to bacterial vaginosis (Alnaif and Drutz 2000). A vaginal wet prep will distinguish between bacterial vaginosis and physiologic discharge and should be used prior to administration of antibiotics. If the patient is bothered by the physiologic vaginal discharge, it may be alleviated by more frequent removal and cleaning of the pessary. Vaginal ulcerations or abrasions due to local pressure effects are also common and typically occur if the pessary is left in place over time. Symptoms of vaginal ulcerations or abrasions include discharge, odor, and bleeding. If the patient can change it herself, the pessary may be removed for a few hours or overnight and replaced. At each follow-up visit, a speculum exam should be performed to evaluate for the presence of any ulcerations or abrasions. The patient should also be instructed to make an appointment if she notices any vaginal bleeding. Vaginal abrasions and ulcerations may be treated with removal of the pessary for a few weeks, and use vaginal estrogen cream on a daily basis for a short-term course (Clemons et al. 2004; Trowbridge and Fenner 2007). The patient should be followed regularly until the ulceration has resolved, and then the pessary may be replaced with continued use of vaginal estrogen cream two to three times a week (Trowbridge and Fenner 2007). Another potential side effect of pessary is urinary incontinence. Typically, it is the reduction of prolapse and return of normal anatomic positioning of the urethra that may unmask occult incontinence or worsen existing incontinence. In cases with incontinence, a specific incontinence pessary (incontinence ring, incontinence dish, or incontinence dish with support) may be used. The incontinence pessaries have an additional knob to provide support at the urethrovesical junction (Trowbridge and Fenner 2007). Severe complications with pessary are rare. Pessary impaction can occur if a pessary is in place for a prolonged period of time without removal. There have been case reports of severe complications from

Pelvic Organ Prolapse: Diagnosis, Treatment, and Avoiding Complications

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Fig. 6 Inflatoball pessary

pessaries, including impaction of or erosion into the urethra, rectum, or cervix (Figs. 7 and 8). Potential for compression of the urethra should be evaluated at pessary placement; anyone who cannot urinate should have the pessary removed and a smaller one placed. Obstructed voiding may lead to urinary retention, infection, and urosepsis (Wheeler et al. 2004). Rectal compression can lead to obstructed defecation or bowel obstruction (Roberge et al. 2001). Some pessaries are designed with a central space, through which the cervix may prolapse and become incarcerated (Thubert and Deffieux 2014). There are case reports of pessaries left in situ for years that then erode into the bladder or rectum (Arias et al. 2008; Rogo-Gupta et al. 2012). These severe complications may be avoided with regular pessary removal and replacement. It is also reasonable to advise patients to confide in a family member or close friend of the presence of the pessary. In case of accident or incapacitation, someone should be aware the pessary should be removed at least once every 3 months.

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The goal of pelvic floor muscle training is to increase muscle volume and thereby diminish the size of the levator hiatus and provide improved structural support for the pelvic organs (Bø 2006). A prospective randomized trial demonstrated that with regimented pelvic floor muscle training over the course of 6 months, women with up to stage 3 pelvic organ prolapse were able to symptomatically and objectively improve their pelvic organ prolapse (Braekken et al. 2010). That study also demonstrated increased muscle thickness, elevated location of the bladder and rectum, and decreased hiatal size with the regimented exercises. Similar improvement in symptoms and reduction of prolapse have been reported in women with training as brief as 14 weeks with improved symptoms and up to stage 2 improvement of pelvic organ prolapse as measured by the POP-Q, though the majority showed no change or reduction of stage 1 of pelvic organ prolapse (Hagen et al. 2009; Stüpp et al. 2011). Limitations of this course of therapy are patient motivation and access to trained therapists.

Pelvic Floor Muscle Training 8

Pelvic floor muscle training has been suggested as management for mild to moderate prolapse. It consists of both sessions with a trained therapist to assess muscle strength and teach exercises for muscle strengthening and regimented exercise programs for the patient to complete at home.

Surgical Management

A variety of surgical treatments are available for pelvic organ prolapse. The choice of surgery depends on many factors including compartment of prolapse, severity of prolapse, patient health and overall treatment goals, prior surgeries, and

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Fig. 7 Computed tomography (CT) of intravesical pessary demonstrating a Gellhorn pessary (A) located in the bladder (B) (Originally published in Rogo-Gupta L, Le NB, Raz S. Foreign body in the bladder 11 years after intravaginal pessary. Int Urogynecol J 2012; 23:1311–1313; with kind permission of # Springer Science+Business Media. All Rights Reserved)

surgeon preference. Graft or mesh augmentation may be considered in select cases. The surgical techniques used for pelvic organ prolapse can broadly be categorized by compartment: anterior, apical, and posterior.

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Anterior Prolapse

The anterior compartment is the most common site of pelvic organ prolapse and the most difficult to repair. Anatomic and symptomatic outcomes after surgical repair are generally good, but when prolapse recurs, it is most commonly in the anterior compartment.

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Anterior Colporrhaphy

The mainstay of surgical management of anterior prolapse is the anterior colporrhaphy (Fig. 9). During this procedure, a transverse incision is made at the apex of the anterior vagina (if concurrent hysterectomy is performed, then the anterior colpotomy site may be used). The anterior vagina is then put on traction using Allis clamps, to essentially evert the anterior wall (or ceiling of the vagina). Using

Fig. 8 Intraoperative image of pessary (A) within the bladder (B) (Originally published in Rogo-Gupta L, Le NB, Raz S. Foreign body in the bladder 11 years after intravaginal pessary. Int Urogynecol J 2012; 23:1311–1313; with kind permission of # Springer Science+Business Media. All Rights Reserved)

Metzenbaum scissors, the anterior vaginal epithelium is undermined to separate it from the underlying muscularis. This epithelium is then incised in a linear fashion from the apex of the vagina to approximately 3–4 cm below the urethral meatus. Allis clamps or Pratt-Smith clamps may be placed on the cut edge of the epithelium, and the epithelium dissected off the underlying muscularis. This dissection is extended laterally to the pelvic sidewall. The underlying muscularis is then plicated with a series of U stitches of 0 polyglactin suture. These stitches should be placed along the junction of where the epithelium has been dissected off the muscularis, taking care that the tissue plicated is the muscularis and not the vaginal epithelium. While these sutures are tied down, the underlying prolapsed tissue is reduced. The result is a midline reduction of the anterior prolapse. The excess vaginal epithelium is then trimmed, and the epithelium is plicated in the midline using 2–0 polyglactin suture. Studies on the success of prolapse repair are difficult to compare, as different outcomes are often reported. Symptomatic success does not necessarily require anatomic success, and often

Pelvic Organ Prolapse: Diagnosis, Treatment, and Avoiding Complications

Fig. 9 Traditional anterior colporrhaphy. (a) Initial midline anterior vaginal wall incision. (b) Midline incision is extended. (c) Sharp dissection of the bladder off the vaginal wall. (d) The bladder has been mobilized off the vagina. (e) Initial plication layer is placed. (f) Second plication layer is placed. (g) Trimming of excess vaginal

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epithelium. (h) Closure of vaginal epithelium (Reprinted from Surgical Management of Pelvic Organ Prolapse, 1st Edition, Maher CF, Karram M. Surgical Management of Anterior Vaginal Wall Prolapse, p117–137, with kind permission from Elsevier)

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both are reported as separate measures. In general, the reported success rates of anterior colporrhaphy range from 80% to 100% in retrospective series, though in prospective studies, the rates are much lower (30–55%) (Menefee et al. 2011; Nguyen and Burchette 2008; Weber et al. 2001). Multiple procedures have been developed to try to improve anatomic and symptomatic outcomes of anterior colporrhaphy. Variations on the anterior colporrhaphy include the paravaginal (or ultralateral) repair, site-specific repair, anterior colporrhaphy with mesh augmentation, and anterior colporrhaphy with graft augmentation. Several studies have compared reoperation rates, as well as anatomic and symptomatic outcomes between these procedures. In general, anatomic outcomes are slightly better using mesh or graft augmentation, but the symptomatic outcomes and reoperation rates are the same between procedures (Maher et al. 2013).

10.1

Vaginal Paravaginal Repair

Some surgeons advocate an ultralateral approach to anterior colporrhaphy, referred to as a vaginal paravaginal repair (Fig. 10). The paravaginal repair is based on the theory that prolapse may be caused by a detachment of the underlying muscularis from its lateral attachments to the arcus tendineus fascia pelvis (ATFP). This technique involves opening the anterior vaginal wall, similar to the dissection used in a traditional anterior colporrhaphy as described above. The vaginal epithelium is dissected off the underlying muscularis farther laterally than for a traditional anterior colporrhaphy, and the paravaginal space is developed between the obturator internus muscle and the vaginal muscularis layer. This space is extended along the ischiopubic rami using palpation in order to identify the ischial spines and the ATFP. The ATFP runs between the pubic symphysis and the ischial spine on either side. The ATFP is palpated and then visualized using BreiskyNavratil retractors. Upon clear identification of the ATFP, three to six sutures of 0 polyglactin suture are placed through the ATFP. These sutures may be held if a concomitant anterior colporrhaphy or apical suspension is being performed. The sutures through

the ATFP are then brought through the muscularis tissue close to the midline, so that the muscularis is brought up and laterally toward the ATFP. The stitch is then carried to the underside of the vaginal epithelium. This technique obliterates the paravaginal space and essentially brings the epithelium, the muscularis, and the ATFP into close approximation. The excess vaginal epithelium is trimmed, and the vaginal epithelium is reapproximated in the midline. This technique has a high success rate (67–100%), which is tempered by complications including bilateral ureteric obstruction, retropubic hematomas, abscesses, and transfusion (Maher et al. 2013). This procedure may be performed abdominally or laparoscopically, but requires a high degree of surgical skill, and efficacy data is limited.

10.2

Site-Specific Repair

An additional variation of the anterior colporrhaphy is a site-specific repair. The concept behind this repair is that although some cases of anterior prolapse are due to complete separation of the muscularis from its lateral attachments, other cases of anterior prolapse are due to specific defects in the muscularis. When these defects are sought out and identified during anterior colporrhaphy, they should be repaired individually. A midline plication may be performed at the same time as a site-specific repair.

10.3

Graft and Mesh Augmentation

Due to the relatively high failure rates of prolapse repairs, there has been significant interest in augmenting repairs with synthetic or biologic materials. Although mesh and graft augmentation has been used with wide success in the hernia repair literature, vaginal augmentation has been more controversial. Generally, mesh or graft augmentation may be considered for patients who fail a native tissue repair. The technique for the placement of synthetic mesh or biologic graft is essentially the same. Several companies have developed prefabricated meshes to fit the various vaginal compartments.

Pelvic Organ Prolapse: Diagnosis, Treatment, and Avoiding Complications

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Fig. 10 Vaginal paravaginal repair. (a) Numerous sutures are passed through the arcus tendineus fascia pelvis (white line). (b) Each suture is passed through the edge of the detached fascia. (c) Each suture is passed through the vaginal wall excluding the epithelium (Reprinted from

Surgical Management of Pelvic Organ Prolapse, 1st Edition, Maher CF, Karram M. Surgical Management of Anterior Vaginal Wall Prolapse, p117–137, with kind permission from Elsevier)

These mesh kits vary in size and shape of the mesh, as well as the introducer to fix the mesh to the vaginal tissues. Many of the kits use a trocar introducer to fix the apical portion of the mesh to the sacrospinous ligament, and the lateral or distal portion of the mesh may be sutured to the ATFP (as described above for a paravaginal

repair) or may be trocar guided through the obturator space. When a kit is not used, the mesh or graft may be cut to fit the patient’s anterior vaginal wall. The vaginal wall is incised in the midline, taking care to dissect full thickness through the vaginal muscularis down to the bladder. This is in contrast

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to the anterior colporrhaphy, where the vaginal epithelium is split from the underlying muscularis. After dissection of the epithelium and muscularis off the bladder, the graft/mesh is placed loosely under the tissue and sutured to the ATFP laterally. The overlying vagina is not trimmed and is then reapproximated in the midline.

10.4

Types of Grafts

10.4.1 Biologic Grafts Biologic grafts may be used as an alternative to synthetic mesh grafts. Biologic graft options include: Autograft – graft material is harvested from the patient herself. Generally it is taken from the rectus sheath or fascia lata. The use of autologous fascia has the advantage of lower risk of infection and host rejection. The size of the graft is generally 6–8 cm long and 4 cm wide. The harvest of an autologous fascial graft of this size may be associated with significant morbidity and is rarely used. It may be considered in patients with contraindications to mesh (Cormio et al. 2015). Allograft – fascial material is harvested from donor or cadaveric tissue. Several small studies have demonstrated success rates ranging from 81% to 100%, with acceptable complication rates, though the only randomized controlled trial failed to show an improvement over traditional anterior colporrhaphy. Concerns regarding prior transmission and residual antigenicity resulting in host-graft reactions have limited the acceptance of allograft materials for prolapse repair. Xenograft – Porcine dermis, porcine small intestine submucosa, bovine pericardium, or bovine dermis. Xenografts have been used in the anterior compartment with mixed results. One study retrospectively compared anterior colporrhaphy, porcine dermis, and polypropylene graft, with the porcine dermis significantly less effective than the other two treatments,

with a 21% rate of vaginal extrusion of the porcine dermis. Other groups have found much better success rates, with graft extrusion rates of 1–17% (Maher et al. 2013). A Cochrane meta-analysis found that when graft was used to augment the anterior compartment, the objective failure rate was higher than when no graft was used (Maher et al. 2013). Overall, some advocate biologic grafts as an alternative to synthetic mesh, although no subjective benefit has been reported by patients, and the complication rates are similar to synthetic meshes. Biologic grafts should be considered in patients who refuse synthetic meshes or those with contraindications to synthetic mesh. Synthetic mesh is contraindicated in patients who have had a prior mesh complication and those who desire future fertility (as the synthetic meshes do not stretch). Biologic grafts may be preferred to synthetic meshes in patients with impaired wound healing such as those with prior pelvic irradiation. Both meshes and grafts should be used with caution in patients with chronic pelvic pain, endometriosis, painful bladder syndrome, vulvodynia, and other vulvar pain disorders.

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Transvaginal Mesh for Anterior/ Apical Prolapse

Starting in 2004, a variety of prepackaged kits were introduced to augment prolapse repair in the vagina (Figs. 11 and 12). These kits use a variety of techniques to augment the anterior, apical, and posterior compartments. There is reasonable evidence to support that anatomic outcomes in the anterior and apical compartments are improved relative to native tissue repairs (Maher et al. 2013). However, there is no difference in patient subjective improvement, quality of life measures, or reoperation rates for prolapse. The improvement in anatomic outcomes comes at the cost of increased complications related to the mesh, with mesh erosion rates reported up to 25% (Maher et al. 2013). The consequences of mesh

Pelvic Organ Prolapse: Diagnosis, Treatment, and Avoiding Complications

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Fig. 11 Mesh augmentation of anterior wall prolapse repair. (a) Anterior prolapse is visualized. (b) Midline plication is completed. (c–d) Self-styled mesh is sutured in place (Reprinted from Surgical Management of Pelvic

Organ Prolapse, 1st Edition, Maher CF, Karram M. Surgical Management of Anterior Vaginal Wall Prolapse, p117–137, with kind permission from Elsevier)

complications can be significant and often result in reoperation. These findings prompted the FDA to release an alert about transvaginal mesh placement in 2011. The alert essentially states that mesh may improve outcomes, but the complications in most cases outweigh the benefits. However, it is important to note that no transvaginal mesh has been recalled and that in selected patients who are appropriately counseled, transvaginal mesh augmentation may be preferred to more invasive, abdominal procedures.

11.1

Concomitant Hysterectomy

The role of concomitant hysterectomy for anterior prolapse is controversial. The uterus, if normal and not significantly prolapsed, may be left in situ during anterior colporrhaphy. However, anterior prolapse rarely occurs in isolation and is most commonly associated with apical (uterine) prolapse. Support of the apex is important to creating a durable and effective repair of the anterior wall (Hsu et al. 2008; Rooney et al. 2006). Many of the

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Fig. 12 Transvaginal mesh kit for anterior/apical prolapse. The elevate incisionless mesh (American Medical Systems) is bilaterally anchored to the sacrospinous ligament and obturator internus muscle near the distal end of the arcus tendineus fascia pelvis (Reprinted from Surgical

apical suspension techniques described below can be adapted to leave the uterus in situ. The decision to remove the uterus must be approached by the physician in consultation with the patient and take into account the patient’s comorbidities, degree of prolapse, and preferences, as well as the surgeon’s experience with the surgical procedures.

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Apical Prolapse

Apical prolapse includes descent of the uterus and the vault after prior hysterectomy. Apical prolapse repairs generally have good results, and there are a variety of approaches to apical prolapse. Apical repairs can broadly be categorized into vaginal, abdominal, and obliterative approaches. Abdominal repairs may be performed via laparotomy, laparoscopy, or robotically.

Management of Pelvic Organ Prolapse, 1st Edition, Maher CF, Karram M. Surgical Management of Anterior Vaginal Wall Prolapse, p117–137 (2013); with kind permission from Elsevier)

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Vaginal Approach for Apical Prolapse

13.1

Mayo/McCall Culdoplasty

One of the most common procedures for apical suspension, the Mayo/McCall culdoplasty, is often performed at the time of vaginal hysterectomy for non-prolapse indications. There are a number of variations, but there are several key steps to the Mayo/McCall culdoplasty (Fig. 13). After removal of the uterus, the vaginal cuff is examined for hemostasis. The vaginal cuff is transfixed to the cut edges of the uterosacral ligaments in order to suspend the cuff within the vagina. One to three sutures are placed through the uterosacral ligament as high as possible. Sequential bites are taken superficially across the peritoneum overlying the rectum until the opposite uterosacral

Pelvic Organ Prolapse: Diagnosis, Treatment, and Avoiding Complications

Fig. 13 Modified McCall culdoplasty. (a) The cul-de-sac is palpated and excessive peritoneum and posterior vaginal wall are noted. (b) A wedge of tissue (dotted line) is excised to decrease the caliber of the upper portion of the posterior vaginal wall. (c) External McCall stitches are placed in the traditional fashion. (d) Tying these sutures

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obliterates the cul-de-sac, supports the vaginal cuff, and increases posterior vaginal wall length (Reprinted from Urogynecology and reconstructive pelvic surgery, 4th Edition, Karram MM, Ridgeway BM, Walters MD. Surgical treatment of vaginal apex prolapse, p360–382. (2015); with kind permission from Elsevier)

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ligament is sutured. When tied down, the uterosacral ligaments are plicated in the midline, and the posterior cul-de-sac is obliterated. Variations on this procedure are commonly performed, but outcome data is limited. The few retrospective studies available show success rates of up to 85%, with reoperation rates ranging from 0% to 14% (Barber and Maher 2013).

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Uterosacral Ligament Suspension

14.1

Technique

Much of the support of the uterus comes from the cardinal/uterosacral ligament complex (Level 1 support). Uterosacral ligament suspension uses the patient’s own ligaments to suspend the vaginal cuff above the level where the uterus has been amputated (Fig. 14). After the uterus is removed, the cuff is examined for hemostasis (if hysterectomy is not performed, the vaginal apex is grasped and incised). The ischial spines are identified and palpated intraperitoneally. The cut edge of the uterosacral ligament is grasped with Allis clamps on either side (at approximately 5:00 and 7:00 on the clockface). Traction allows for palpation of the uterosacral ligaments. Several sutures of permanent or delayed absorbable suture are placed through the uterosacral ligament at the level of the ischial spine. This procedure is repeated on the opposite side. The distal edge of the uterosacral ligaments is then plicated in the midline to obliterate the cul-de-sac. The highest delayed absorbable suture is placed full thickness through the posterior vaginal wall. If necessary, an anterior colporrhaphy may be performed. The vagina is trimmed and closed with 0 or 2-0 absorbable suture. After closure of the vagina, the uterosacral sutures are tied down on either side with suspension of the vault. Abdominal and laparoscopic approaches to this procedure have also been described.

14.2

Outcomes and Complications

Outcomes after uterosacral ligament suspension are generally good, with anatomic success ranging from 81% to 98%, and symptomatic improvement in 82–100% of patients (Margulies et al. 2010). In a recent large, prospective, randomized, controlled trial, the composite outcome of anatomic success and subjective success and lack of reoperation were reported to be 59.2% (Barber et al. 2014). The most commonly identified complication is ureteral injury or kinking, which should be looked for and identified intraoperatively. Ureteral kinking can be managed by removal of the offending suture and usually requires no further intervention. The incidence of ureteral injury or kinking ranges from 1% to 11% (Margulies et al. 2010) with most studies reporting a low incidence. However, intraoperative cystoscopy is highly recommended to ensure ureteral patency.

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Sacrospinous Ligament Fixation

15.1

Technique

The sacrospinous ligaments extend from the ischial spines to the lower portion of the sacrum and coccyx and should be palpated prior to initiation of the procedure. The vagina is typically fixed unilaterally to the sacrospinous ligament, though bilateral fixations have been described. The posterior vaginal wall is incised in the midline and the vaginal epithelium dissected off the rectovaginal fascia. If an enterocele is encountered, it should be dissected off the posterior vaginal wall and closed with a high purse-string suture. The dissection of the epithelium off the rectovaginal fascia is extended laterally to identify the arcus tendineus fascia pelvis. The perirectal space is identified in this area by using blunt or sharp dissection and by mobilizing the rectum medially. The ischial spine is identified, and the

Pelvic Organ Prolapse: Diagnosis, Treatment, and Avoiding Complications

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Fig. 14 Uterosacral ligament suspension. The vaginal cuff is fixed to the cut uterosacral ligaments on either side at the level of the ischial spines (Originally published in Cvach K, Dwyer P. Surgical management of pelvic organ prolapse: abdominal and vaginal approaches. World J Urol 2011;30 (4):471–7; with kind permission of Springer Science+Business Media. All Rights Reserved)

sacrospinous ligament is palpated dorsal and medial to the ischial spine. Once the ligament is identified, a rectal exam should be performed to confirm that no inadvertent injury has occurred. A suture is then passed through the sacrospinous ligament. The position of the ligament makes this suture passage difficult, and a variety of instruments have been designed to facilitate passage of the suture through the sacrospinous ligament. Commonly used techniques include the long-handled Deschamps ligature carrier, the Miya Hook, or proprietary instruments such as the Capio Suture device (Boston Scientific) (Figs. 15 and 16) or the Nichols-Veronikis ligature carrier (Cooper).

most commonly reported complication of sacrospinous ligament fixation is buttock pain, which is seen in 12.4% of cases (Barber et al. 2014). Such pain is usually self-limiting and should resolve completely by 6 weeks postoperatively. Additional rare but serious intraoperative complications have been reported, including hemorrhage (0.2%) and rectal injury (0.4%) (Sze and Karram 1997). Hemorrhage may result from laceration of the inferior gluteal vessels, the hypogastric venous plexus, or the internal pudendal vessels. If a rectal injury occurs, it can usually be repaired transvaginally.

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Alternative Vaginal Approaches

Outcomes and Complications

Overall, outcomes for sacrospinous ligament fixation are similar to uterosacral ligament suspension. A large randomized trial compared the two and found no significant difference in composite outcome of 60.5% at 2 years (composite outcome combines: anatomic success and subjective success and no reoperation) (Barber et al. 2014). The

Several procedures have been described for the suspension of the vaginal vault, with or without hysterectomy. The most notable of which are the levator myorrhaphy and the iliococcygeus fascial suspension. The technique for the levator myorrhaphy involves a wide plication of the levator muscles and fixation of the vaginal cuff to the plicated

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Fig. 15 Suture device for sacrospinous ligament fixation. The sacrospinous ligament is palpated at the level of the ischial spine. The suture device is placed medial to the operator finger, and the suture is passed through the ligament (Image reproduced with kind permission from Boston Scientific)

muscles (Francis and Jeffcoate 1961). Packing is placed in the rectum to avoid narrowing of the rectum. Comparative studies to uterosacral ligament suspension have shown no difference in anatomic success or subjective outcomes; however, the total vaginal length was shorter after levator myorrhaphy (7.9 vs. 8.9 cm, p = 0.04) (Natale et al. 2010). Iliococcygeus fascial suspension is also known as the Inmon technique (Inmon 1963). It is used to suspend the vaginal apex to the iliococcygeus fascia just below the ischial spine. The initial studies describing the procedure reported a case series of 152 patients. In that initial series, four intraoperative complications occurred (one rectal and one bladder laceration and two cases of hemorrhage requiring transfusion) (Shull et al. 1993; Meeks et al. 1994). Retrospective reviews have shown that iliococcygeus fascial suspension is similar in outcomes to abdominal procedures and sacrospinous ligament fixation (Barber and Maher 2013). However, there are no randomized trials that evaluate this technique.

C. Dancz and M. Fullerton

Fig. 16 Sacrospinous ligament fixation. The apex of the vagina is fixed unilaterally to the sacrospinous ligament (Image reproduced with kind permission from Boston Scientific)

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Abdominal Approach to Apical Prolapse

17.1

Sacral Colpopexy

Sacral colpopexy has been shown to be effective and durable for the correction of apical prolapse. Traditionally, sacral colpopexy is performed via laparotomy; however, laparoscopic and robotic approaches are also commonly used. Regardless of approach, the basic steps of the procedure stay the same (Fig. 17). The peritoneal cavity is entered, and if indicated, hysterectomy is performed and the cuff is closed. The vagina is elevated using a sponge stick, probe, or end-toend anastomosis sizer. The bladder is dissected off of the anterior vagina. Attention is then turned to the posterior vagina, and the peritoneum over the posterior wall is incised and dissected off of the vaginal tissue for several centimeters on either side. The mesh is trimmed to fit the anterior and posterior vaginal walls and transfixed using three to six stitches of nonabsorbable suture. Sutures are placed full thickness through the fibromuscular layer of the vagina, but not through the vaginal epithelium. The mesh is placed such that it reaches approximately two-thirds of the way down the

Pelvic Organ Prolapse: Diagnosis, Treatment, and Avoiding Complications

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Fig. 17 Abdominal sacral colpopexy. The vaginal cuff is fixed to the anterior longitudinal ligament over the sacral promontory, using a piece of mesh or graft (Originally published in Cvach K, Dwyer P. Surgical management of

pelvic organ prolapse: abdominal and vaginal approaches. World J Urol 2011;30(4):471–7; with kind permission of Springer Science+Business Media. All Rights Reserved)

anterior vagina, and a separate piece is placed at least halfway down the posterior vaginal wall. The two meshes are then sutured together above the cuff. The cul-de-sac is then obliterated using a Halban or Moschcowitz procedure. Attention is then turned to the sacral promontory. The sigmoid colon, right ureter, aortic bifurcation, and common iliac vessels should be identified. The peritoneum over the sacral promontory is incised longitudinally and the underlying fatty tissue dissected off of the promontory. The middle sacral artery and vein should be identified at this step. The mesh is then transfixed to the anterior longitudinal ligament using two to three stitches of nonabsorbable suture. The mesh should be tensioned to avoid undue traction on the vagina. The peritoneum is then closed over the mesh. Additional procedures at the time of sacral colpopexy may be indicated. A large randomized controlled trial showed that the addition of Burch urethropexy at the time of open sacral colpopexy reduced the rate of postoperative stress incontinence at 2 years from 57% to 37% in women who did not have stress incontinence preoperatively (Brubaker et al. 2008). As apical prolapse rarely

occurs in isolation, repair of posterior prolapse may also be indicated at the time of colpopexy. Outcomes and Complications The success rate of abdominal sacral colpopexy for apical suspension ranges from 78% to 100% (Barber and Maher 2013). Over time, anatomic and subjective success rates tend to decrease, as prolapse tends to recur between 2 and 7 years (Nygaard et al. 2013). Severe intraoperative complications specific to colpopexy are rare and include hemorrhage from the sacral vascular plexus; complications from laparotomy may include enterotomy, ureteral damage, cystotomy, and wound infections. The most common long-term complications after sacral colpopexy include recurrent prolapse, de novo stress incontinence, and mesh exposure. The median reoperation rates are 4.4% for recurrent prolapse, 4.9% for postoperative stress incontinence, and 3.4–5.1% for mesh exposure (Nygaard et al. 2004, 2013). Abdominal Uterosacral Ligament Suspension The abdominal approach to the uterosacral ligament suspension involves the same principles as the vaginal approach as described previously. The remnants of the uterosacral ligament are identified

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and tagged at the level of the ischial spines. The ureters are identified, and the uterosacral ligaments are fixed to the vaginal cuff using permanent or delayed absorbable sutures.

17.2

Obliterative Procedures

All of the above procedures focus on reconstructing the vagina. An alternative approach is to obliterate the vagina. This approach may be considered in women who are no longer sexually active and do not have plans to have vaginal intercourse in the future. Obliterative procedures may be performed for post-hysterectomy vault prolapse or for uterovaginal prolapse (colpectomy/colpocleisis). The uterus may be left in situ (LeFort colpocleisis) or removed. Even with removal of the uterus, these procedures offer a relatively quick operative time, low risk of morbidity, and high rate of success.

17.3

Technique/Considerations

As these procedures are generally performed on older women with multiple comorbidities, the focus of the preoperative evaluation should be on optimization of their functional status and control of their comorbidities. These patients should be carefully counseled on the procedure and the permanent loss of access to the vagina for sexual function. When the uterus is to be left in situ, these patients should be carefully screened for risk factors for endometrial and cervical pathology. They should be screened for postmenopausal vaginal bleeding and consider a pelvic ultrasound to evaluate the endometrium. Cervical cytologic screening should be up to date and negative.

17.4

Total Colpectomy/Colpocleisis

Total colpocleisis refers to the removal of the vaginal epithelium (Fig. 18) within the hymenal ring posteriorly to within 0.5–2 cm of the external

urethral meatus anteriorly (FitzGerald et al. 2006). Generally, the vaginal tissue is grasped and everted. The vaginal epithelium is excised in strips from the underlying vaginal muscularis. The muscularis is then inverted using a series of purse-string stitches. Once the prolapse is reduced, an aggressive perineorrhaphy and/or levator plication is performed. The anterior and posterior epithelia are sutured together with closure of the vagina.

17.5

Partial/LeFort Colpocleisis

A partial colpocleisis refers to when portions of the vaginal epithelium are left in place (Fig. 19). The LeFort modification is when the uterus is left in situ, and the epithelium is reconstructed in a manner to leave channels, through which vaginal discharge or blood can escape. The procedure is started by grasping the cervix and applying gentle traction. Rectangle sections are marked on the anterior and posterior vaginal walls; these are the areas to be denuded. The uterus is then reduced, and the cut edges of the remaining epithelium above and below the cervix are sewn together using interrupted sutures, such that the epithelium is inverted and it creates a tunnel in front of the cervix. A urinary catheter may be placed in this tunnel to ensure it is adequate and patent. The plication sutures are then continued laterally on either side to create lateral channels. As these sutures are placed, the prolapse is gradually reduced until it is entirely within the body. The final sutures may be placed at the level of the hymenal ring. The anterior and posterior epithelia are then reapproximated, using care to leave the lateral channels open. As above, an aggressive perineorrhaphy and levator plication are often performed to augment this repair (Evans et al. 2015). Multiple studies have shown low rates of prolapse recurrence, high rates of patient satisfaction, and low rates of regret in appropriately counseled patients. Major complications of these procedures tend to be related to the performance of procedures on the elderly (cardiac, pulmonary, and cerebrovascular complications) and occur at a rate of

Pelvic Organ Prolapse: Diagnosis, Treatment, and Avoiding Complications

Fig. 18 Total colpectomy/colpocleisis. (a, b) The vagina is circumscribed and marked into quadrants. Each quadrant is removed by sharp dissection. (c) Purse-string sutures are placed; the leading edge is inverted by the tip of the forceps. Purse-string sutures are tied 1 before 2 and 2 before 3, with progressive inversion of the tissue. (d) The final

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relationship is shown in cross section (Reprinted from Urogynecology and reconstructive pelvic surgery, 4th Edition, Evans J, Silva WA, Karram MM. Obliterative procedures for pelvic organ prolapse, p400–410 (2015); with kind permission from Elsevier)

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Fig. 19 LeFort colpocleisis. (a) A rectangular piece of the vagina has been removed. (b) A similar rectangular piece of the posterior vagina has been removed. (c) The cut edge of the interior incision is sewn to the distal cut edge of the posterior incision. Once the cervix is inverted, the sutures are continued up the lateral edges of the incisions on either side. (d) The entire vagina is inverted and the proximal

C. Dancz and M. Fullerton

incisions are sewn together horizontally. Note: draining channels are left in the lateral portions of the vagina to allow drainage of cervical discharge or uterine bleeding (Reprinted from Urogynecology and reconstructive pelvic surgery, 4th Edition, Evans J, Silva WA, Karram MM. Obliterative procedures for pelvic organ prolapse, p400–410 (2015); with kind permission from Elsevier)

Pelvic Organ Prolapse: Diagnosis, Treatment, and Avoiding Complications

approximately 2% (FitzGerald et al. 2006). Specific complications of the procedure include hemorrhage and pyelonephritis and appear at a rate of about 4%.

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Posterior Prolapse

Women with symptomatic pelvic organ prolapse often have defects of the posterior vaginal wall. One study found that in women undergoing surgery for prolapse, 40% had posterior vaginal wall defects (Olsen et al. 1997). The posterior vaginal wall must usually be addressed separately from an anterior or apical suspension.

18.1

Technique

The traditional repair for posterior vaginal wall defects is the posterior colporrhaphy (Fig. 20). Two Allis clamps are placed on the perineum, which is then incised in a transverse fashion. If a perineorrhaphy is to be included, an inverted triangle of the skin is removed from the perineal body. The posterior vaginal wall is placed on gentle tension, and the vaginal epithelium is undermined using the Metzenbaum scissors up to the apex of the rectocele. The edges of the incision are grasped, and the epithelium is dissected off the underlying rectovaginal fascia bilaterally to expose the lateral attachments to the levator ani muscles. At this point, a traditional midline plication or a site-specific repair may be performed.

18.1.1 Midline Plication The rectovaginal fascia is plicated in the midline with interrupted sutures, starting proximally and progressing toward the hymenal ring. Placement of these sutures should incorporate good purchase of the fibromuscularis and should be placed close to the junction with the epithelium to avoid injury to the rectum. The redundant vaginal epithelium is trimmed and the incision closed in a running, locked fashion. The caliber of the vagina at the end of the procedure should allow three fingerbreadths to fit comfortably.

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18.1.2 Site-Specific Repair The operator finger is placed in the rectum, and specific, palpable, or visual defects are repaired using interrupted, delayed, absorbable sutures (Fig. 21). If diffuse attenuation of the fascia is identified, a site-specific repair may not be technically feasible, and a midline plication is preferred. The redundant vaginal epithelium is trimmed and the incision closed in a running, locked fashion. 18.1.3 Graft or Mesh Augmentation A posterior colporrhaphy may be augmented using graft or mesh. The material is cut to fit the space and sewn with permanent suture to the rectovaginal fascia at the level of the attachment to the levator ani muscles on either side. If the patient is undergoing a concomitant apical suspension, the graft may be fixed to the apical support sutures. The distal end is sutured to the perineum using absorbable sutures. The epithelium is then closed over the graft or mesh.

18.2

Outcomes and Complications

Traditional midline plication has success rates ranging from 76% to 97%. The most common complication of posterior colporrhaphy is dyspareunia. Postoperative dyspareunia is found in 11–27% after traditional posterior colporrhaphy, with de novo dyspareunia reported in 4–16% (Arnold et al. 1990; Lopez et al. 2001; Mellgren et al. 1995; Maher 2004). A three-way randomized controlled trial comparing traditional colporrhaphy to site-specific repair to porcine-derived graft showed that traditional colporrhaphy and sitespecific repair had similar anatomic and functional outcomes. Porcine-derived graft augmentation resulted in improvement in symptoms similar to the other methods, but graft augmentation had significantly greater anatomic failures than the other two techniques (Paraiso et al. 2006). Graft augmentation may be considered in selected patients who have failed primary native tissue repair, with adequate preoperative counseling.

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Fig. 20 (continued)

C. Dancz and M. Fullerton

Pelvic Organ Prolapse: Diagnosis, Treatment, and Avoiding Complications

Fig. 20 Traditional posterior colporrhaphy. (a) The perineal skin is incised in the midline. (b) The posterior vaginal epithelium is mobilized off the rectum. (c, d) The enterocele sac is mobilized and entered. (e) The enterocele sac is excised or reduced, and the fibromuscular layer of the vagina is plicated in the midline. (f) A second layer may be

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plicated across the midline. (g) Perineorrhaphy is performed (Reprinted from Surgical Management of Pelvic Organ Prolapse, 1st Edition, Karram M. Surgical Correction of posterior pelvic floor defects, p139–164; with kind permission from Elsevier)

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References

Fig. 21 Site-specific posterior defect repair. With finger in the rectum, discrete defects in the fibromuscular layer are identified. These defects are subsequently repaired using interrupted sutures (Reprinted from Surgical Management of Pelvic Organ Prolapse, 1st Edition, Karram M. Surgical Correction of posterior pelvic floor defects, p139–164; with kind permission from Elsevier)

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Conclusion

Pelvic organ prolapse is a common problem that affects the daily activities for millions of women. The sensation of bulge in the vagina can be easily assessed and characterized by pelvic examination. Many patients may elect for expectant management or conservative management with a pessary. Radiologic testing is rarely indicated, and ancillary urodynamic testing may be indicated if the patient desires surgical intervention. Surgical treatment of prolapse is highly varied and depends greatly on the location of the prolapse, the degree of prolapse, and the patients’ comorbidities and preferences. Surgical procedures are generally safe and well tolerated. Procedural success rates are hard to interpret, as success is generally considered anatomic success, symptomatic success, and absence of reoperation.

Abdool Z, Thakar A, Sultan AH, Oliver RS. Prospective evaluation of outcome of vaginal pessaries versus surgery in women with symptomatic pelvic organ prolapse. Int Urogynecol J. 2011;22(3):273–8. Alnaif B, Drutz HP. Bacterial vaginosis increases in pessary users. Int Urogynecol J. 2000;11(4):219–23. Arias BE, Ridgeway B, Barber MD. Complications of neglected vaginal pessaries: case presentation and literature review. Int Urogynecol J. 2008;19(8):1173–8. Arnold MW, Stewart WR, Aguilar PS. Rectocele repair. Four years’ experience. Dis Colon Rectum. 1990;33 (8):684–7. Baden WF, Walker T. Fundamentals, symptoms and classification. In: Baden WF, Walker T, editors. Surgical repair of vaginal defects. Philadelphia: J.B. Lippincott; 1992. p. p14. Barber MD, Maher C. Apical prolapse. Int Urogynecol J. 2013;24:1815–33. Barber MD, Brubaker L, Burgio KL, Richter HE, Nygaard I, Weidner AC, Menefee SA, Lukacz ES, Norton P, Schaffer J, Nguyen JN, Borello-France D, Goode PS, Jakus-Waldman S, Spino C, Warren LK, Gantz MG, Meikle SF. Comparison of 2 transvaginal surgical approaches and perioperative behavioral therapy for apical vaginal prolapse: the OPTIMAL randomized trial. JAMA. 2014;311(10):1023–34. Bø K. Can pelvic floor muscle training prevent and treat pelvic organ prolapse? Acta Obstet Gynecol Scand. 2006;85(3):263–8. Braekken IH, Majida M, Engh ME, Bø K. Can pelvic floor muscle training reverse pelvic organ prolapse and reduce prolapse symptoms? An assessor-blinded, randomized, controlled trial. Am J Obstet Gynecol. 2010;203(2):170e1–7. Brubaker L, Nygaard I, Richter HE, Visco A, Weber AM, Cundiff GW, Fine P, Chetti C, Brown MB. Two-year outcomes after sacrocolpopexy with and without Burch to prevent stress urinary incontinence. Obstet Gynecol. 2008;112(1):49–55. Bump RC, Mattiasson A, Bø K, Brubaker LP, DeLancey JOL, Klarskov P, Shull BL, Smith ARB. The standardization of terminology of female pelvic organ prolapse and pelvic floor dysfunction. Am J Obstet Gynecol. 1996;175:10–7. Clemons JL, Aguilar VC, Tillinghast TA, Jackson ND, Myers DL. Patient satisfaction and changes in prolapse and urinary symptoms in women who were fitted successfully with a pessary for pelvic organ prolapse. Am J Obstet Gynecol. 2004;190(4):1025–9. Cormio L, Mancini V, Liuzzi G, Lucarelli G, Carrieri G. Cystocele repair by autologous rectus fascia graft: the pubovaginal cystocele sling. J Urol. 2015;194 (3):721–7. Culligan PJ. Nonsurgical management of pelvic organ prolapse. Obstet Gynecol. 2012;119(4):852–60. Cundiff GW, Weidner AC, Visco AG, Bump RC, Addison WA. A survey of pessary use by members of the

Pelvic Organ Prolapse: Diagnosis, Treatment, and Avoiding Complications American Urogynecologic Society. Obstet Gynecol. 2000;95(6):931–5. Cundiff GW, Amundsent CL, Bent AE, Coates KW, Schaffer JI, Strohbehn K, et al. The PESSRI study: symptom relief outcomes of a randomized crossover trial of the ring and Gellhorn pessaries. Am J Obstet Gynecol. 2007;196(4):405–8. Dancz C, Walker D, Thomas D, Özel B. Prevalence of hydronephrosis in women with advanced pelvic organ prolapse. Urology. 2015;86(2):250–4. DeLancey JO. Anatomic aspects of vaginal eversion after hysterectomy. Am J Obstet Gynecol. 1992;166(6 Pt 1):1717–24. discussion 1724-28 Drake R, Vogl AW, Mitchell AWM, Ribbits R, Richardson P. Gray’s Atlas of anatomy. Philadelphia: Elsevier Health Sciences; 2008. p. 229. Evans J, Silva WA, Karram MM. Obliterative procedures for pelvic organ prolapse. In: Walters MD, Karram MM, editors. Urogynecology and reconstructive pelvic surgery. 4th ed. Philadelphia: Saunders; 2015. FitzGerald MP, Richter HE, Siddique S, Thompson P, Zyczynski H. Colpocleisis: a review. Int Urogynecol J Pelvic Floor Dysfunct. 2006;17(3):261–71. Francis W, Jeffcoate T. Dyspareunia following vaginal operations. J Obstet Gynaecol Br Commonw. 1961;68:1–10. Hagen S, Stark D, Glazener C, Sinclair L, Ramsay I. A randomized controlled trial of pelvic floor muscle training for stages I and II pelvic organ prolapse. Int Urogynecol J. 2009;20(1):45–51. Hanson LA, Schulz JA, Flood CG, Cooley B, Tam F. Vaginal pessaries in managing women with pelvic organ prolapse. Obstet Gynecol. 2006;108(1):93–9. Haylen BT, de Ridder D, Freeman RM, Swift SE, Berghmans B, Lee J, Monga A, Petri E, Rizk DE, Sand PK, Schaer GN. An International Urogynecological Association (IUGA)/International Continence Society (ICS) Joint Report on the Terminology for Female Pelvic Floor Dysfunction. NeurourolUrodyn. 2010;29:4–20. Hsu Y, Chen L, Summers A, Ashton-Miller JA, DeLancey JO. Anterior vaginal wall length and degree of anterior compartment prolapse seen on dynamic MRI. Int Urogynecol J Pelvic Floor Dysfunct. 2008;19 (1):137–42. Hui SY, Chan SC, Lam SY, Lau TK, Chung KH. A prospective study on the prevalence of hydronephrosis in women with pelvic organ prolapse and their outcomes after treatment. Int Urogynecol J. 2011 Dec;22 (12):1529–34. Inmon WB. Pelvic relaxation and repair including prolapse of vagina following hysterectomy. South Med J 1963;56:577–82. Karram MM, Ridgeway BM, Walters MD. Surgical treatment of vaginal apex prolapse. In: Walters MD, Karram MM, editors. Urogynecology and reconstructive pelvic surgery. 4th ed. Philadelphia: Elsevier; 2015. Koelbl H, Igawa T, Salvatore S, Laterza RM, Lowry A, Sievert KD, Sultan A. Pathophysiology of urinary

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incontinence, faecal incontinence and pelvic organ prolapse. In: Abrams P, Cardozo L, Khoury S, Wein A, editors. Incontinence. 5th ed. Paris: European Association of Urology; 2013. Lone F, Thakar R, Sultan AH, Karamalis G. A 5-year prospective study of vaginal pessary use for pelvic organ prolapse. Int J Gynecol Obstet. 2011;114 (1):56–9. Lopez A, Anzen B, Bremmer S, Mellgren A, Nilsson BY, Zetterstrom J, et al. Durability of success after rectocele repair. Int Urogynecol J Pelvic Floor Dysfunct. 2001;12:97–103. Maher C. Midline rectovaginal fascial plication for repair of rectocele and obstructed defecation. Obstet Gynecol. 2004;104(4):685–9. Maher C, Karram M. Surgical management of anterior vaginal wall prolapse. In: Maher C, Karram M, editors. Surgical management of pelvic organ prolapse. 1st ed. Philadelphia: Saunders, an imprint of Elsevier; 2013. Maher C, Feiner B, Baessler K, Schmid C. Surgical management of pelvic organ prolapse in women. Cochrane Database Syst Rev. 2013;(4). Margulies RU, Rogers MA, Morgan DM. Outcomes of transvaginal uterosacral ligament suspension: systematic review and meta-analysis. Am J Obstet Gynecol. 2010;202(2):124–34. Meeks GR, Washburne JF, McGehee RP, Wiser WL. Repair of vaginal vault prolapse by suspension of the vagina to iliococcygeus (prespinous) fascia. Am J Obstet Gynecol. 1994;171(6):1444–52;discussion 52–4. Mellgren A, Anzen B, Nilsson BY, Johansson D, Dolk A, Gillgren P, et al. Results of rectocele repair. A prospective study. Dis Colon Rectum. 1995;38(1):7–13. Menefee A, Dyer Y, Lukacz S, Simsiman J, Luber M, Nguyen N. Colporrhaphy compared with mesh or graft-reinforced vaginal paravaginal repair for anterior vaginal wall prolapse: a randomized controlled trial. Obstet Gynecol. 2011;118(6):1337–44. Natale F, La Penna C, Padoa A, Agostini M, Panei M, Cervigni M. High levator myorrhaphy versus uterosacral ligament suspension for vaginal vault fixation: a prospective, randomized study. Int Urogynecol J Pelvic Floor Dysfunct. 2010;21(5):515–22. Nguyen N, Burchette J. Outcome after anterior vaginal prolapse repair: a randomized controlled trial. Obstet Gynecol. 2008;111(4):891–8. Nygaard IE, McCreery R, Brubaker L, Connolly A, Cundiff G, Weber A, Zycynski H. Abdominal sacrocolpopexy: a comprehensive review. Obstet Gynecol. 2004;104(4):805–23. Nygaard I, Brubaker L, Zyczynski H, Cundiff G, Richter H, Gantz M, Fine P, Menefee S, Ridgeway B, Visco A, Warren LK, Zhang M, Meikle S. Long-term outcomes following abdominal sacrocolpopexy for pelvic organ prolapse. JAMA. 2013;309(19):2016–24. Olsen AL, Smith VJ, Bergstrom JO, Colling JC, Clark AL. Epidemiology of surgically managed pelvic

30 organ prolapse and urinary incontinence. Obstet Gynecol. 1997;89(4):501–6. Paraiso MFR, Barber MD, Muir TW, Walters MD. Rectocele repair: a randomized trial of three techniques including graft augmentation. Am J Obstet Gynecol. 2006;195:1762–71. Roberge RJ, Keller C, Garfinkel M. Vaginal pessaryinduced mechanical bowel obstruction. J Emerg Med. 2001;20(4):367–70. Rogo-Gupta L, Le NB, Raz S. Foreign body in the bladder 11 years after intravaginal pessary. Int Urogynecol J. 2012;23:1311–3. Romanzi L, Chaikin D, Blaivas J. The effect of genital prolapse on voiding. J Urol. 1999;161(2):581–6. Rooney K, Kenton K, Mueller ER, FitzGerald MP, Brubaker L. Advanced anterior vaginal wall prolapse is highly correlated with apical prolapse. Am J Obstet Gynecol. 2006;195(6):1837–40. Shull BL, Capen CV, Riggs MW, Kuehl TJ. Bilateral attachment of the vaginal cuff to iliococcygeus fascia: an effective method of cuff suspension. Am J Obstet Gynecol. 1993;168(6 Pt 1):1669–74. Stüpp L, Resende APM, Oliveira E, Castro RA, Girão MJBC, Sartori MGF. Pelvic floor muscle training for treatment of pelvic organ prolapse: an assessor-blinded randomized controlled trial. Int Urogynecol J. 2011;22 (10):1233–9.

C. Dancz and M. Fullerton Sudhakar A, Reddi V, Schein M, Gerst P. Bilateral hydroureter and hydronephrosis causing renal failure due to a procidentia uteri: a case report. Int Surg. 2001;86:173–5. Sze EH, Karram MM. Transvaginal repair of vault prolapse: a review. Obstet Gynecol. 1997;89(3):466–75. Thubert T, Deffieux X. Inside out: on rare occasions, ring pessaries can cause genital incarceration. Am J Obstet Gynecol. 2014;210(3):278.e1. Trowbridge ER, Fenner DE. Practicalities and pitfalls of pessaries in older women. Clin Obstet Gynecol. 2007;50(3):709–19. Weber A, Walters M, Piedmonte M, Ballard L. Anterior colporrhaphy: A randomized trial of three surgical techniques. Am J Obstet Gynecol. 2001;185:1299–306. Wheeler LD, Lazarus R, Torkington J, O’Mahony MS, Woodhouse KW. Lesson of the week: perils of pessaries. Age Ageing. 2004;33(5):510–1. Wu JM, Hundley AF, Fulton RG, Myers ER. Forecasting the prevalence of pelvic floor disorders in U.S. Women: 2010 to 2050. Obstet Gynecol. 2009;114(6):1278–83. Wu JM, Kawasaki A, Hundley AF, Dieter AA, Myers ER, Sung VW. Predicting the number of women who will undergo incontinence and prolapse surgery, 2010 to 2050. Am J Obstet Gynecol. 2011;205(3):230.e1–5.

Urinary Incontinence: Diagnosis, Treatment, and Avoiding Complications Renee Rolston, and Begüm Özel,

Abstract

Urinary incontinence is defined as the complaint of involuntary leakage of urine. Urinary incontinence impacts physical, psychological, and social well-being. In order to achieve an accurate diagnosis, a detailed history and physical exam are important. An initial evaluation should include a detailed history, urinalysis, cough stress test, evaluation of post-void residual, focused neurologic assessment, and examination for urethral hypermobility and pelvic organ prolapse. Urodynamic testing and cystoscopy may be indicated in some patients. Treatment varies based on the type of urinary incontinence and symptom severity. First-line therapy should always consist of less invasive and more conservative treatment options as they have been shown to be highly effective with minimal risk. These therapies include pelvic floor exercises, biofeedback, bladder training, weight loss, modification in fluid and caffeine intake, urethral inserts, and incontinence pessaries. Depending on the type of incontinence characterized, more invasive treatment options can be implemented if no improvement with conservative management.

R. Rolston, (*) • B. Özel, Division of Female Pelvic Medicine and Reconstructive Surgery, Department of Obstetrics and Gynecology, Keck School of Medicine, Los Angeles, CA, USA e-mail: [email protected]; Begum.Ozel@med. usc.edu # Springer International Publishing AG 2017 D. Shoupe (ed.), Handbook of Gynecology, DOI 10.1007/978-3-319-17002-2_71-2

Typically, women with stress incontinence who have failed conservative therapies are offered surgical intervention, whereas women with urgency incontinence may be treated with pharmacologic management, intradetrusor onabotulinum toxin A, or neuromodulation. Most incontinence can be made better with available therapies. Keywords

Stress urinary incontinence • Urgency urinary incontinence • Mixed urinary incontinence • Sling

Contents 1

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

2 2.1 2.2 2.3 2.4

Diagnosis and Evaluation . . . . . . . . . . . . . . . . . . . . . History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Physical . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Additional Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Urodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2 2 2 3 3

3 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 3.9 3.10 3.11

Stress Incontinence . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathophysiology/Anatomy . . . . . . . . . . . . . . . . . . . . . . Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pelvic Floor Muscle Training (PFMT) . . . . . . . . . Incontinence Pessary . . . . . . . . . . . . . . . . . . . . . . . . . . . . Urethral Inserts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mid-urethral Sling (MUS) . . . . . . . . . . . . . . . . . . . . . . Transobturator . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pubovaginal (Autologous Sling) . . . . . . . . . . . . . . . . Retropubic Urethropexy . . . . . . . . . . . . . . . . . . . . . . . . Urethral Bulking Agents . . . . . . . . . . . . . . . . . . . . . . . .

3 4 4 4 5 5 5 5 6 6 7 7

4 4.1

Urgency Incontinence . . . . . . . . . . . . . . . . . . . . . . . . . 8 Conservative . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 1

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R. Rolston and B. Özel

4.2 4.3 4.4 4.5 4.6

Pharmacologic Management . . . . . . . . . . . . . . . . . . 9 Percutaneous Tibial Nerve Stimulation . . . . . . . 9 Intradetrusor Onabotulinum Toxin A . . . . . . . . . 9 Sacral Neuromodulation . . . . . . . . . . . . . . . . . . . . . . . 10 Mixed Urinary Incontinence . . . . . . . . . . . . . . . . . . 10

5

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

6

Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

1

Introduction

Urinary incontinence is defined as the complaint of involuntary leakage of urine (Haylen et al. 2010). The prevalence of urinary incontinence is estimated to range from 12% to 55% depending on the population studied (Castro et al. 2015). Urinary incontinence has been reported to affect up to 75% of older women (ACOG 2015). Urinary incontinence is associated with both depression and anxiety in women who are affected (Felde et al. 2016) and can lead to decrease in quality of life and negative impact on sexual function (Lim et al. 2016).

2

Diagnosis and Evaluation

2.1

History

History is a key part of the evaluation of urinary incontinence, and careful attention should be made to understanding the patient’s complaints (Komesu et al 2016). History should include duration of incontinence, precipitating events, severity, frequency of occurrence, the presence or absence of nocturia, daytime urinary frequency, hesitancy or dysuria, fluid intake, daily pad use, and interference with activities of daily living (Haylen et al. 2010). The history obtained can be used to characterize and classify the type of incontinence or to identify underlying conditions that may cause incontinence. Tools that can be utilized to aide in obtaining a detailed history include a bladder diary and validated questionnaires such as the urogenital distress inventory, incontinence impact questionnaire, questionnaire for urinary

incontinence diagnosis, incontinence quality for life questionnaire, and incontinence severity index (Staskin et al. 2005). When completing a bladder diary, patients are asked to record the timing and amount of fluid intake, voids and voided volumes, leakage episodes, and activity during leakage for 24–72-h period. As part of the history, medications should be reviewed to determine whether any of them might be contributing to urinary symptoms, such as diuretics, caffeine, alcohol, narcotic analgesics, anticholinergic drugs, antihistamines, psychotropic drugs, alphaadrenergic blockers, alpha-adrenergic agonists, and calcium channel blockers (ACOG 2015).

2.2

Physical

Physical exam should include a pelvic exam, including evaluating for prolapse and an assessment of urethral mobility. When performing the pelvic exam, it is important to evaluate for pelvic organ prolapse and to exclude the presence of a urethral and/or pelvic mass. A urethral mass such as a diverticulum or pelvic masses such as fibroids may cause symptoms of urinary incontinence. As part of the pelvic exam, a speculum exam should be performed to evaluate for extraurethral urinary leakage which can occur if a fistula is present. A cough stress test during the pelvic exam, when positive, may confirm stress incontinence. The Q-tip or cotton-tipped swab test is a simple test to evaluate urethral hypermobility. Urethral hypermobility does not have an official definition from the International Continence Society/International Urogynecologic Association, but it can be defined as a resting angle or displacement angle of the urethra–bladder neck with maximum Valsalva of at least 30 degrees from the horizontal (Zyczynski et al. 2007). In the absence of prior anti-incontinence surgery, when point Aa is 1 or greater on the Pelvic Organ Prolapse Quantification Scale, nearly all patients demonstrate urethral hypermobility, and a Q-tip test may be deferred in these patients (Cogan et al. 2002). During the initial evaluation of all women with incontinence, a focused neurologic examination is indicated, including assessment of gait, sensation

Urinary Incontinence: Diagnosis, Treatment, and Avoiding Complications

over the perineum and perianal skin, and evaluation for sacral reflexes. A detailed neurologic examination is not necessary unless there is presence of sudden onset incontinence or new onset of neurologic symptoms. A simple test for the sacral reflexes is the anal wink in which the skin near the anus is stroked lightly with a soft cotton-tipped swab. A reflex contraction of the anus should be seen. However, the reflex can be absent in some neurologically intact women.

2.3

Additional Testing

Before initiating further therapy, it is recommended to check a urinalysis to evaluate for urinary tract infection and hematuria; a urine culture may be performed if indicated. It may be necessary to check a post-void residual (PVR) via straight catheterization or bladder ultrasound to rule out retention and overflow incontinence in women with symptoms of incomplete bladder emptying or difficulty voiding, or in women with risk factors such as neurologic disease or diabetes mellitus. A PVR volume less than 50 mL is considered indicative of adequate bladder emptying (Haylen et al. 2010), and a PVR volume greater than 200 mL is considered indicative of inadequate emptying (Gehrich et al. 2007). An isolated finding of a raised PVR requires confirmation before being considered significant.

2.4

Urodynamics

Cystometry is a graphic depiction of bladder and abdominal pressure relative to fluid volume during filling, storage, and voiding. The information obtained during cystometry can be used to assess bladder sensation, capacity, and compliance and to determine the presence and magnitude of voluntary and involuntary detrusor contractions. Uroflowmetry and pressure-flow studies measure the rate of urine flow and the mechanism of bladder emptying (Walters and Karram 2015). Urethral pressure profiles and Valsalva leak point pressures can also be measured to make the diagnosis of urodynamic intrinsic sphincter

3

deficiency. Studies have suggested that low urethral pressure measurements may be associated with poorer continence outcomes; a reliable cutoff measure to accurately predict surgical failure has not been found (Lim et al. 2016). Although Valsalva leak point pressures have been found to be weakly associated with subjective measures of incontinence severity, they have not been able to reliably predict surgical outcomes. Neuromuscular activity of the pelvic muscles and urethral sphincter during voiding can also be assessed during cystometry by using electromyography. The main role of electromyography is detecting coordination between detrusor muscle contraction and simultaneous urethral sphincter relaxation (Haylen et al. 2010). Urodynamic testing should be used to evaluate patients with complicated urinary symptoms and inability to elicit evidence of stress urinary incontinence of cough stress test or to evaluate for occult stress incontinence in patients with pelvic organ prolapse. A multicenter randomized controlled study has demonstrated that for women with uncomplicated, demonstrable stress urinary incontinence, preoperative office evaluation alone was not inferior to evaluation with urodynamic testing for outcomes at 1 year; uncomplicated stress incontinence was defined as women with predominantly stress incontinence symptoms, negative urinalysis, PVR < 150 ml, the presence of urethral hypermobility, no history of pelvic irradiation, recent pelvic surgery, or significant prolapse (Nager et al. 2012). When evaluating for urinary incontinence, cystourethroscopy is not routinely indicated. It should be considered in the setting of hematuria, acute-onset or refractory urgency incontinence, recurrent urinary tract infections, and suspicion for fistula or foreign body after gynecologic surgery.

3

Stress Incontinence

Stress urinary incontinence (SUI) is the complaint of involuntary leakage of urine on effort or exertion or on sneezing or coughing (Haylen et al.

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2010). Stress incontinence is the most common type of incontinence in younger women. Risk factors are not well known but are believed to be attributable to age, obesity, menopause and the loss of circulating estrogen, straining when evacuating the bowels, childbirth including the number of pregnancies, vaginal delivery, and operative vaginal delivery (McIntosh et al. 2015). A basic office evaluation as described above has been shown to be a sufficient preoperative workup for a patient with uncomplicated SUI (Nager et al. 2012).

3.1

Pathophysiology/Anatomy

The proposed mechanisms of stress urinary incontinence are urethral hypermobility and intrinsic sphincter deficiency. It is theorized that urethral hypermobility is caused by insufficient support of the pelvic floor musculature and vaginal connective tissue to the urethra and bladder neck. This causes the urethra and bladder neck to lose the ability to completely close against the anterior vaginal wall with increases in intra-abdominal pressure leading to incontinence. Treatments for hypermobility stress incontinence are aimed at providing a backboard of support for the urethra. Intrinsic sphincter deficiency (ISD) is attributed to a loss of urethral tone that normally keeps the urethra closed. This can occur in the presence or absence of urethral hypermobility and typically results in severe urinary leakage even with minimal increases in abdominal pressure. Urodynamic ISD is defined as a maximum urethral closure pressure of 20 cm H2O and/or abdominal/Valsalva leak point pressure 60 cm H2O (Lim et al. 2016). In general, ISD results from neuromuscular damage and can be seen in women who have had multiple pelvic or incontinence surgeries. Patients with ISD can be challenging to treat and tend to have worse surgical outcomes (Lukacz 2016).

3.2

Treatment

3.2.1

Conservative

Behavioral Modifications First-line treatment for stress incontinence includes behavioral and lifestyle modifications. Depending on symptom severity, treatment with these conservative therapies should be tried for at least 6 weeks before considering subsequent therapies (Lukacz 2016). Implementation of dietary changes in which the consumption of beverages that exacerbate incontinence such as alcohol, as well as caffeinated and carbonated beverages, is reduced may be helpful. It is also advisable for women to normalize fluid intake if they are drinking >64 oz. of fluid/day. Another behavioral modification is the management of constipation; constipation can exacerbate urinary incontinence and increase risk of urinary retention. Obesity is a known risk factor for urinary incontinence, and weight loss in obese women has been shown to reduce urinary incontinence in multiple welldesigned studies (Vissers et al. 2014; Wing et al. 2010).

3.3

Pelvic Floor Muscle Training (PFMT)

In addition to behavioral and lifestyle modifications, pelvic floor muscle training is also grouped with conservative first-line treatment for SUI and has been shown to be very effective in treating stress incontinence. The Cochrane Review found that in 18 studies, there was high-quality evidence that PFMT is associated with cure of stress incontinence (RR, 8.38; 95% CI, 3.68–19.07) and moderate-quality evidence of cure or improvement of stress incontinence (RR, 17.33; 95% CI, 4.31–69.64) (Dumoulin et al. 2015). Pelvic muscle exercises, also called Kegel exercises, aim to strengthen the pelvic floor musculature to provide a backboard for the urethra and reflexively inhibit detrusor contractions. When performing pelvic muscle exercises, different regimens have been prescribed. One simple

Urinary Incontinence: Diagnosis, Treatment, and Avoiding Complications

instruction is to tell the patient to contract her pelvic floor using the same muscles they would use to stop urine flow or gas. The basic regimen consists of three sets of 8–12 contractions sustained for 8–10 s each, performed three times a day.

3.4

Incontinence Pessary

Incontinence pessary restores continence by stabilizing the proximal urethra and urethrovesical junction. Incontinence pessaries are thought to improve urinary incontinence in some women by increasing urethral functional length, urethral closure pressures, and cough profiles (McIntosh et al. 2015). The knob of the incontinence pessary should be placed at or below the bladder neck in order to stabilize the posterior urethra (McIntosh et al. 2015). A randomized controlled trial comparing the use of behavioral therapy alone (including pelvic floor muscle training), pessary alone, and combined behavioral therapy and pessary found that at 3 months pessaries were not as effective as behavioral therapy based in patient satisfaction. Therefore, although incontinence pessaries are a treatment option, they are not first line given the effectiveness of pelvic muscle exercise (Richter et al. 2010).

3.5

Urethral Inserts

A urethral insert is an occlusive device that acts as a mechanical barrier to prevent urinary leakage by sealing the urethral lumen (Sirls et al. 2002). They are self-inserted and designed for single use. The only urethral insert currently available for use is the FemSoft (Rochester Medical, Stewartville, MN). The most common side effects are urethral discomfort, hematuria, urinary tract infections, and bladder irritation. Contraindications for the use of urethral inserts include pregnancy, significant urge incontinence and unstable bladder contractions, neuropathic bladder, a history of recurrent bladder infections, the use of anticoagulants, and inflammatory or malignant lesions of the lower urinary tract.

3.6

5

Surgery

Stress urinary incontinence should be demonstrated objectively before any surgery is performed. This can be done with a cough stress test or with simple or multichannel urodynamic testing. A positive cough stress test is the visualization of fluid loss from the urethra simultaneously with a cough. This test should be performed with a full bladder in the supine and/or standing position. If the cough stress test is negative and patient reports symptoms of SUI, it is appropriate to perform urodynamic testing as next step. Once stress incontinence is objectively identified, surgical options include mid-urethral sling, pubovaginal sling, and Burch colposuspension. The most common surgical intervention for SUI is the mid-urethral sling procedure (Lim and Swyer 2009).

3.7

Mid-urethral Sling (MUS)

The first commercially available mid-urethral sling (MUS) was the tension-free vaginal tape (TVT) (Gynecare, Ethicon Women’s Health and Urology, Somerville, New Jersey, USA), first described by Ulmsten in 1996 (Ulmsten et al. 1996) and introduced into the US market in 1998. According to the American Urogynecologic Society (AUGS) and the Society of Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction (SUFU), the polypropylene mesh is considered the standard of care in the surgical treatment of SUI. There are two types of mid-urethral slings the retropubic sling and the transobturator (TOT) sling. Mid-urethral slings function by providing a backboard for the urethra, facilitating compression of the mid-urethra when intra-abdominal pressure increases. When performing a retropubic MUS, a segment of synthetic material is inserted via the vagina and passed on each side of the urethra through the retropubic space through two exit incisions on the anterior abdominal wall. Once the sling is placed, position is assessed and confirmed to be tension-free. Absolute contraindications to the retropubic MUS include pregnancy,

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active oral anticoagulation, and the presence of important structures in the path of the trocars or sling, which may include a pelvic kidney, vascular graft, and low ventral hernias. A retrospective study comparing retropubic MUS, transobturator tape (TOT), and pubovaginal sling in women with ISD showed that retropubic MUS and pubovaginal slings had similar cure rates – retropubic MUS (86.9%) versus pubovaginal sling (87.3%) (Jeon et al. 2008). Potential complications of retropubic slings include bladder perforation, pelvic visceral injuries, vascular injuries and hemorrhage, mesh exposure, de novo development of urgency and urge incontinence, bladder outlet obstruction, pelvic pain, and urinary tract infection.

3.8

Transobturator

In 2001, Delorme described the transobturator technique for mid-urethral sling placement which avoided going in the retropubic space and is associated with less bladder perforation and visceral and vascular injury (Delorme 2001). The TOT can be performed via inside out or outside in technique in which the entry/exit point is the medial border of the obturator foramen at the level of the clitoris. The needle passage avoids any significant passage through the space of Retzius and nearly eliminates the possibility of intraperitoneal passage. As a result, the risk of bladder injury is lower after the TOT compared to the retropubic sling (0.6 vs. 4.5%; RR 0.13, 95% CI 0.08–0.20). Major vascular or visceral injury and operative blood loss is also lower with the TOT sling (Ford et al. 2015). Another important complication is voiding dysfunction, which is less common after the TOT sling compared to the retropubic sling (RR 0.53, 95% CI 0.43–0.65) (Ford 2015). Groin pain appears more frequently after the TOT sling (6.4 vs. 1.3%; RR 4.12, 95% CI 2.71–6.27), whereas suprapubic pain is less common after the TOT (0.8 vs. 2.9%; RR 0.29, 95% CI 0.11–0.78). There is no difference in rates of mesh exposure or extrusion (Ford et al. 2015).

One important study that compared the TOT sling with the retropubic sling was the trial of mid-urethral slings (TOMUS); this was a multicenter, randomized equivalence trial comparing outcomes with retropubic and TOT mid-urethral slings in women with stress incontinence (Richter et al. 2010). Objective and subjective outcomes at 12 months were similar between the two approaches, with objective outcome of about 80% for both groups. Clinically important complications included voiding dysfunction requiring surgery, the use of catheter, or both, which was seen in 2.7% in women who had the retropubic sling versus none of the women who had a TOT sling ( p = 0.004) and neurologic symptoms, seen in 9.4% of women in the TOT sling versus 4% in the retropubic sling ( p = 0.01). Overall, the lower risk of most complications seen with the TOT sling makes it an excellent option in appropriately selected patients; however, there is a higher rate groin pain and neurologic complications, which must be considered. Indications for TOT sling placement are the same as for retropubic MUS with the exception of intrinsic sphincter deficiency. In women with either a maximum urethral closure pressure of 20 cm H2O or less or a pressure rise from baseline required to cause incontinence (Δ Valsalva or cough leak point pressure) of 60 cm H2O or less, the retropubic sling appears to be more effective. Of the 138 women randomized in one study, objective failure as defined as urodynamic stress incontinence at 6 months follow-up, 45% of women who had the TOT sling and 21% of women who had the retropubic sling had USI, and 13% of women in the TOT sling group went on to have another anti-incontinence procedure (Schierlitz et al. 2008).

3.9

Pubovaginal (Autologous Sling)

Autologous slings work by supporting the proximal urethra and bladder neck achieving continence by providing a direct compressive force on the urethra/bladder outlet. Long-term success is based on the healing and fibrosis of the sling

Urinary Incontinence: Diagnosis, Treatment, and Avoiding Complications

7

which passes through the endopelvic fascia. Autologous slings are placed at the bladder neck and are mainly reserved for women with severe stress urinary incontinence (SUI) and a nonmobile, fixed urethra, declining to have synthetic mesh implanted, recurrent SUI after a synthetic sling or history of a complication after a synthetic sling such as vaginal exposure or extrusion (Blaivas et al. 2013). It is also preferred to use an autologous sling in patients who have been irradiated, have had urethral injuries, and those who are undergoing either simultaneous or prior urethrovaginal fistula or diverticulum repair (Swierzewski and McGuire 1993). Compared to the mid-urethral sling, the pubovaginal sling is more invasive because it requires an abdominal incision to harvest fascia for the sling. Complications of the pubovaginal sling include injury to the bladder and urethra, pelvic visceral injury, voiding dysfunction, superficial wound infection, seromas, and fascial hernias (Walters and Karram 2015). In a meta-analysis, when compared to mid-urethral slings, the autologous sling is equally efficacious (RR 0.97 for incontinence at 12 months; 95% CI 0.78–1.20) but had longer operating time (mean difference 60 min; 5% CI 57–63 min), greater perioperative complications (RR, 1.59; 95% CI, 1.03–2.44), and greater de novo detrusor overactivity (RR, 3.21; 95% CI, 1.29–8.03) (Rehman et al. 2011). When compared to the Burch urethropexy, in a well-designed multicenter randomized trial, at 24 months of followup, success rates were found to be higher for women who had an autologous sling compared to the Burch urethropexy, but there were more urinary tract infections, difficulty voiding, and postoperative urgency incontinence after the autologous sling (Albo et al. 2007).

the use of permanent suture to secure the paravaginal tissue to periosteum of pubic symphysis; a known complication is osteitis pubis, a painful, noninfectious inflammation of the pubic symphysis. The Burch colposuspension involves the use of suture to secure paravaginal tissue to Cooper’s ligament. The Burch colposuspension requires a low transverse incision to assess the space of Retzius. Two delayed absorbable or nonabsorbable sutures are placed through the pubocervical fascia; one is placed 2 cm lateral to the mid-urethra, and the other is 2 cm lateral to bladder wall at the level of the urethrovesical junction bilaterally. The suture is then passed through Cooper’s ligament. With a hand in the vagina to elevate the pubocervical fascia, the sutures are tied down; a suture bridge is created. Healing occurs by fibrosis in the space of Retzius, and support for the urethra is created. The Burch colposuspension can be utilized in patients with SUI undergoing a concomitant abdominal procedure or in women who decline the use of mesh. Studies comparing the Burch colposuspension to slings (both mid-urethral and autologous) show similar effectiveness at 12 months (RR, 1.24; 95% CI, 0.93–1.67) (Lapitan and Cody 2016). There is a lower risk of voiding dysfunction with the Burch colposuspension compared to slings (RR, 0.41; 95% CI, 0.26–0.67). There is no difference in overall risk of perioperative complications between the Burch urethropexy and the mid-urethral slings (RR, 1.11; 95% CI, 0.66–1.87). However, women undergoing open retropubic colposuspension were nearly twice at risk of developing new or recurrent prolapse compared to those undergoing sling procedures (33.9 vs. 20.1%; RR, 1.85; 95% CI, 1.25–2.75) (Lapitan and Cody 2016).

3.10

3.11

Retropubic Urethropexy

Retropubic procedures include the Burch colposuspension and the Marshall-MarchettiKrantz (MMK) procedure. The MMK procedure is generally no longer performed but involved in

Urethral Bulking Agents

Urethral bulking agents consist of nonbiodegradable and nonimmunologic material which is injected transurethral or periurethral into the periurethral tissue around the bladder

8

R. Rolston and B. Özel

neck and proximal urethra to increase urethral resistance. Durasphere EXP (Carbon Medical Technologies, St. Paul, Minnesota, USA), Coaptite (Boston Scientific, Franksville, Wisconsin, USA), and Macroplastique (Cogentix Medical, Minnetonka, Minnesota, USA) are the bulking agents that are currently available. The most common indications for urethral bulking agents include intrinsic sphincter deficiency with or without urethral hypermobility, persistent SUI after sling or urethropexy, and in women who cannot tolerate the risk of general anesthesia; other indications include women who cannot discontinue anticoagulation, are young and desire future fertility, and have SUI and poor bladder emptying (Cespedes and Serkin 2009). Urethral bulking agents have been shown to be less effective than surgery and usually require the need for repeat injections. Metaanalysis for the efficacy of Macroplastique found improvement rate of 75% (95% CI 69–81%) and cure/dry rates of 43% (95% CI 33–54%) at shortterm follow-up (Ghoniem and Miller 2013). This is similar to success rates with other products (Reynolds and Dmochowski 2012). Managing patient expectations of outcome is important. Relative contraindications to the use of urethral bulking injections include active urinary tract infection, high post-void residual urine (>100 mL), urinary stricture/obstruction, severe detrusor overactivity, and fragile urethral mucosa. If no relief after two or three injections, further injections should not be attempted (Walters and Karram 2015).

4

Urgency Incontinence

Urgency urinary incontinence (UUI) is the complaint of involuntary urine leakage associated with urgency defined as the complaint of sudden compelling desire to pass urine that is difficult to defer, and overactive bladder (OAB) is defined as urinary urgency, usually accompanied by frequency and nocturia, with or without urgency urinary incontinence, in the absence of urinary tract infection (UTI) or other obvious pathologies

(Haylen et al. 2010). UUI is more common in older women and may be associated with comorbid conditions that occur with age. It is believed to result from detrusor overactivity, leading to involuntary detrusor muscle contractions during bladder filling (Lukacz 2016). The American Urological Association has identified behavioral therapy as the first-line treatment option and pharmacologic treatment as the second-line treatment option for nonneurogenic OAB in adults. In patients with UUI refractory to behavioral and pharmacologic management, sacral nerve stimulation and intradetrusor injection of onabotulinum toxin A may be recommended (Singh et al. 2015).

4.1

Conservative

Pelvic floor exercises have been demonstrated to be effective in the treatment of UUI. They are more effective when combined with biofeedback or verbal feedback. Weight loss with diet and exercise, caffeine reduction, and 25–50% reduction in fluid intake gave all been demonstrated to be efficacious and should comprise the initial management (Olivera et al. 2016). Bladder training has been shown to be effective for women with urgency incontinence. Bladder training starts with timed voiding. Patients should keep a voiding diary to identify their shortest voiding interval. Patients are instructed to void by the clock at regular intervals based on the shortest time interval identified between voids in voiding diary. Urgency between voiding is controlled with either distraction or relaxation techniques. When the patient can go two days without leakage, the time between scheduled voids is increased. The intervals are gradually increased until the patient is voiding every 3–4 h without urinary incontinence or frequent urgency. Successful bladder training can take up to 6 weeks (Lukacz 2016).

Urinary Incontinence: Diagnosis, Treatment, and Avoiding Complications

4.2

Pharmacologic Management

If behavioral treatments fail, the next step is a trial of antimuscarinics. Antimuscarinics block the basal release of acetylcholine during bladder filling resulting in increasing bladder capacity and decreased urgency (Lukacz 2016). The currently available antimuscarinic drugs for the treatment of UUI and OAB are listed in Table 1. Treatment should be started at the lowest dose and titrated up if there is insufficient response in treatment and minimal side effects. Improvement in symptoms may take up to 4 weeks. A systematic review, including 23 studies, concluded that improvement with anticholinergics, either alone or combined with bladder training, is significantly greater than improvement with bladder training alone (Castro et al. 2015). Despite the effectiveness of antimuscarinics therapy, it has a low adherence rate secondary to their side effect profile including dry mouth, constipation, blurred vision for near objects, tachycardia, drowsiness, and decreased cognitive function. Antimuscarinics are contraindicated in patients with gastric retention and untreated angle-closure glaucoma. In patients that have contraindications to antimuscarinic or cannot tolerate antimuscarinics, β3adrenergic agonist may be an option. The current β3 agonist on the market is mirabegron, and it has been shown to be effective in the management urgency. Mirabegron acts by promoting relaxation of the detrusor muscle and increasing the bladder capacity without increasing the residual volume (Castro et al. 2015). Patients with severe or uncontrolled hypertension should not be prescribed mirabegron. Vaginal estrogen therapy is another medication used for treatment of either stress or urgency incontinence. Vaginal atrophy can lead to symptoms of urinary frequency and dysuria and can contribute to incontinence, and correction of vaginal atrophy with topical estrogen may improve urinary symptoms. Vaginal estrogen therapy can be in the form of a cream, ring, or tablet (Cody et al. 2012). Evidence suggests that vaginal estrogen therapy may improve continence (RR, 0.74;

9

95% CI, 0.64–0.86). There are 1–2 fewer voids in 24 h among women treated with vaginal estrogen, and there is less urgency and frequency (Cody et al. 2012).

4.3

Percutaneous Tibial Nerve Stimulation

Percutaneous tibial nerve stimulation (PTNS) delivers neuromodulation to the pelvic floor through the S2–4 junction of the sacral nerve plexus via the posterior tibial nerve. A 34-gauge needle electrode is inserted above the ankle, and the tibial nerve is accessed. This area has projections to the sacral nerve plexus, creating a feedback loop that modulates bladder innervation. Initial therapy consists of 12-weekly 30-min treatments (Gaziev et al. 2013). In a randomized trial of 220 adults, the 13-week subject global response assessment for overall bladder symptoms demonstrated statistically significant improvement in bladder symptoms from baseline with PTNS over sham therapy; 54.5% reported being moderately or markedly improved with PTNS compared to 20.9% of participants who received the sham therapy ( p < 0.001) (Peters et al. 2010).

4.4

Intradetrusor Onabotulinum Toxin A

Onabotulinum toxin A blocks neuromuscular transmission by binding to receptor sites on nerve terminals and inhibiting the release of acetylcholine. This inhibition occurs as the neurotoxin cleaves SNAP-25, a protein integral to the successful docking and release of acetylcholine from vesicles situated within nerve endings (Balchandra and Rogerso 2014). The most commonly recommended dose for nonneurogenic UUI/DO is BoNT-A 100 units. It is administered under cystoscopic visualization by evenly distributed intradetrusor injections across 20 sites approximately 1 cm apart, sparing the trigone of the bladder (Liao and Kuo 2015). Onabotulinum toxin A is indicated in urgency refractory to

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R. Rolston and B. Özel

Table 1 Antimuscarinic medications for treatment of women with urgency urinary incontinence or overactive bladder Medication Darifenacin Fesoterodine Oxybutynin

Solifenacin Tolterodine Trospium

Available formulations Extended release Extended release Immediate release Extended release Transdermal patch Transdermal gel Extended release Immediate release Extended release Immediate release Extended release

medical treatment. Contraindications include active infection, acute urinary retention, unwillingness or inability to self-catheterize, and known hypersensitivity to the toxin (Liao and Kuo 2015). In a large, randomized controlled trial of onabotulinum toxin A compared to placebo, at 12 weeks, onabotulinum toxin A significantly decreased urinary incontinence episodes per day ( 2.95 vs. 1.03, p < 0.001), and reduction in all OAB symptoms as assessed by validated quality of life questionnaires was significantly greater with onabotulinum toxin A compared to placebo (Chapple et al. 2013). The need to self-catheterize occurred in 6.9% of participants, and urinary tract infections were seen in 20.4%, which was the most common complication seen (Chapple et al. 2013).

4.5

Sacral Neuromodulation

Sacral neuromodulation consists of the surgical implantation of electrodes in the S3 sacral nerve root and of an electric impulse generator, which is implanted in the subcutaneous tissue. It is reserved for severe cases of urgency refractory to conventional treatments. The mechanism of action is not fully understood, but electrical impulses are believed to act in both afferent and efferent fibers. The electrode implantation is performed in two stages in order to reduce

complications and false-negative rates (Balchandra and Rogerso 2014). The first stage is the testing phase in which the electrode is implanted and positioned using radioscopy. The definitive implant is offered to patients who exhibit a positive response at least a 50% symptom improvement in the first stage after 1–4 weeks. Cure and improvement rates are 30–50% and 60–90%, respectively (Castro et al. 2015; Yamanishi et al. 2015). Complication rates are low and include adverse change in bowel habits, electrically induced discomfort, pain at the implantable pulse generator site, and infection (Olivera et al. 2016).

4.6

Mixed Urinary Incontinence

Mixed urinary incontinence is defined as the complaint of involuntary loss of urine associated with urgency and also with effort or physical exertion or on sneezing or coughing. The pathophysiology is poorly understood. Initial treatment is conservative and should aim at treating both the SUI and UUI components. Subsequent therapy needs to be individualized to the patient’s primary complaint and degree of bother from the SUI and UUI. Typically, outcomes with anti-incontinence surgery for women with MUI are poorer than women with SUI alone. Persistent DO after antiincontinence surgeries is seen in up to 74% of women, typically leading to lower satisfaction with outcome of surgery (Bandukwala and Gousse 2015). Preoperative counseling on persistent UUI and DO after surgery is important when offering these women surgical treatment (Komesu et al. 2016).

5

Conclusion

Urinary incontinence is a treatable medical condition that significantly affects quality of life. A variety of conservative, pharmacologic, and interventional therapies exist to treat this condition.

Urinary Incontinence: Diagnosis, Treatment, and Avoiding Complications

6

Cross-References

▶ Avoiding Complications ▶ Minimally Invasive Procedures for Incontinence and Lower Urinary Tract Disorders: Indications ▶ Pelvic Organ Prolapse: Diagnosis ▶ Treatment and Avoiding Complications

References Albo M, Richter H, Brubaker L, Norton P, et al. Burch colposuspension versus fascial sling to reduce urinary stress incontinence. N Engl J Med. 2007;356 (21):2143–55. American College of Obstetricians and Gynecologists (ACOG). Urinary incontinence in women. Practice Bulletin No. 155. American College of Obstetricians and Gynecologists. 2015. Balchandra P, Rogerso L. Women’s perspective: intradetrusor botox versus sacral neuromodulation for overactive bladder symptoms after unsuccessful anticholinergic treatment. Int Urogynecol J. 2014;25(8):1059–64. Bandukwala NQ, Gousse AE. Mixed urinary incontinence: what is first? Curr Urol Rep. 2015;16(3):9. Blaivas J, Purohit R, Weinberger J, Tsui J, et al. Surgery after failed treatment of synthetic mesh sling complications. J Urol. 2013;190(4):1281–6. Castro R, Arruda R, Bortolini M. Female urinary incontinence: effective treatment strategies. Climacteric. 2015;18(2):135–41. Cespedes RD, Serkin FB. Is injection therapy for stress urinary incontinence dead? No Urology. 2009;73 (1):11–3. Chapple C, Sievert K, MacDiarmid S, Khullar V, et al. Onabotulinum toxin A 100 U significantly improves all idiopathic overactive bladder symptoms and quality of life in patients with overactive bladder and urinary incontinence: a randomised, double-blind, placebocontrolled trial. Eur Urol. 2013;64(2):249–56. Cody J, Jacobs M, Richardson K, Moehrer B, Hextall A. Oestrogen therapy for urinary incontinence in postmenopausal women. Cochrane Database Syst Rev. 2012;10:CD001405. doi:10.1002/14651858. cd001405.pub3. Cogan SL, Weber AM, Hammel JP. Is urethral mobility really being assessed by the pelvic organ prolapse quantification (POP-Q) system? Obstet Gynecol. 2002;99(3):473–6. Delorme E. Transobturator urethral suspension: miniinvasive procedure in the treatment of stress urinary incontinence in women. Prog Urol. 2001;11 (6):1306–13. Dumoulin C, Hay-Smith J, Habée-Séguin GM, Mercier J. Pelvic floor muscle training versus no treatment, or

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inactive control treatments, for urinary incontinence in women: a short version Cochrane systematic review with meta-analysis. Neurourol Urodyn. 2015;34 (4):300–8. Felde G, Ebbesen MH, Hunskaar S. Anxiety and depression associated with urinary incontinence. A 10-year follow-up study from the Norwegian HUNT study (EPINCONT). Neurourol Urodynam. 2016; doi:10.1002/nau.22921. Ford A, Rogerson L, Cody JD, Ogah J. Mid-urethral sling operations for stress urinary incontinence in women. Cochrane Database Syst Rev. 2015;7:CD006375. doi:10.1002/14651858.cd006375.pub3. Gaziev G, Topazio L, Lacovelli V, Asimakopoulos A, et al. Percutaneous Tibial Nerve Stimulation (PTNS) efficacy in the treatment of lower urinary tract dysfunctions: a systematic review. BMC Urol. 2013; doi:10.1186/1471-2490-13-61. Gehrich A, Stany M, Fischer J, Buller J, Zahn C. Establishing a mean postvoid residual volume in asymptomatic perimenopausal and postmenopausal women. Obstet Gynecol. 2007;110(4):827–32. Ghoniem G, Miller C. A systematic review and metaanalysis of Macroplastique for treating female stress urinary incontinence. Int Urogynecol J. 2013;24 (1):27–36. Haylen B, De Ridder D, Freeman R, Swift S, et al. An International Urogynecological Association (IUGA)/ International Continence Society (ICS) joint report on the terminology for female pelvic floor dysfunction. Neurourol Urodyn. 2010;29:4–20. Jeon M, Jung H, Chung S, Sei-Kwang K, et al. Comparison of the treatment outcome of pubovaginal sling, tensionfree vaginal tape, and transobturator tape for stress urinary incontinence intrinsic sphincter deficiency. Am J Obstet Gynceol. 2008;199(1):76.e1–4. Komesu Y, Schrader R, Ketai L, Rogers R, Dunivan C. Epidemiology of mixed, stress, and urgency urinary incontinence in middle-aged/older women: the importance of incontinence history. Int Urogynecol J. 2016;27(5):763–72. Lapitan M, Cody J. Open retropubic colposuspension for urinary incontinence in women. Cochrane Database Syst Rev. 2016;6:CD002912. doi:10.1002/14651858. CD002912.pub5. Liao C, Kuo H. Practical aspects of Botulinum Toxin-A treatment in patients with overactive bladder syndrome. Int Neurourol J. 2015;19(4):213–9. Lim Y, Swyer P. Effectiveness of midurethral slings in intrinsic sphincteric-related stress urinary incontinence. Curr Opin Obstet Gynecol. 2009;21(5):428–33. Lim R, Liong M, Leong W, Khan N, Yuen K. Effect of stress urinary incontinence on the sexual function of couples and the quality of life of patients. J Urol. 2016; doi:10.1016/j.juro.2016.01.090. Lukacz E. Treatment of urinary incontinence in women[Internet]; 2016. Available from: http://www.uptodate.com/con tents/treatment-of-urinary-incontinence-in-women

12 McIntosh L, Andersen E, Reekie M. Conservative treatment of stress urinary incontinence in women: a 10-year (2004-2013) scoping review of the literature. Urologic Nursing. 2015;35(4):179–86. Nager C, Brubaker L, Litman H, Zyczynski H, et al. A randomized trial of urodynamic testing before stressincontinence surgery. Urinary Incontinence Treatment Network. N Engl J Med. 2012;366(21):1987–97. Olivera C, Meriwether K, El-Nashar S, et al. Systematic review group for the society of gynecological surgeons. Nonantimuscarinic treatment for overactive bladder: a systematic review. Am J Obstet Gynecol. 2016; doi:10.1016/j.ajog.2016.01.156. Peters K, Carrico D, Perez-Marrero R, et al. Randomized trial of percutaneous tibial nerve stimulation versus sham efficacy in the treatment of overactive bladder syndrome: results from the SUMIT trial. J Urol. 2010;183(4):1438–43. Rehman H, Berzerra C, Bruschini H, Cody J. Traditional suburethral sling operations for urinary incontinence in women. Cochrane Database Syst Rev. 2011;1: CD001754. doi:10.1002/14651858.CD001754.pub3. Reynolds W, Dmochowski R. Urethral bulking: a urology perspective. Urol Clin North Am. 2012;39(3):279–87. Richter H, Albo M, Zyczynski H, Kenton K, et al. Urinary incontinence treatment network. Retropubic versus transobturator midurethral slings for stress incontinence. N Engl J Med. 2010;362(22):2066–76. Schierlitz L, Dwyer P, Rosamilia A, Murray C, et al. Effectiveness of tension-free vaginal tape compared with transobturator tape in women with stress urinary incontinence and intrinsic sphincter deficiency: a randomized controlled trial. Obstet Gynecol. 2008;112 (6):1253–61. Singh E, El Nashar A, Trabuco E, et al. Comparison of short term outcomes of sacral nerve stimulation and intradetrusor injection of Onabotulinum toxin A (Botox) in women with refractory overactive bladder. Female Pelvic Med Reconstr Surg. 2015;21(6):369–73.

R. Rolston and B. Özel Sirls L, Foote J, Kaufman J, Lightner D, et al. Long-term results of the FemSoft urethral insert for the management of female stress urinary incontinence. Int Urogynecol J Pelvic Floor Dysfunct. 2002;13 (2):88–95. Staskin D, Hilton P, Emmanuel A, et al. Initial assessment of incontinence. In: Abrams P, Cardozo L, Khoury S, Wein A, editors. Incontinence: 3rd international consultation on incontinence. Paris: Health Publications Ltd; 2005. p. 485. Swierzewski S, McGuire E. Pubovaginal sling for treatment of female stress urinary incontinence complicated by urethral diverticulum. J Urol. 1993;149(5):1012–4. Ulmsten U, Henriksson L, Johnson P, Varhos G. An ambulatory surgical procedure under local anesthesia for treatment of female urinary incontinence. Int Urogynecol J Pelvic Floor Dysfunct. 1996;7(2):81–5. Vissers D, Neels H, Vermandel A, De Wachter S, et al. The effect of non-surgical weight loss interventions on urinary incontinence in overweight women: a systematic review and meta-analysis. Obes Rev. 2014;15 (7):610–7. Walters M, Karram M. Urogynecology and reconstructive pelvic surgery. 4th ed. Philadelphia: Saunders Elsevier; 2015. Wing R, West D, Grady D, Creasman J, et al. Effect of weight loss on urinary incontinence in overweight and obese women: results at 12 and 18 months. Program to reduce incontinence by diet and exercise group. J Urol. 2010;184(3):1005–10. Yamanishi T, Kaga K, Fuse M, Shibata C, Uchiyama T. Neuromodulation for the treatment of lower urinary tract symptoms. Low Urin Tract Symptoms. 2015;7 (3):121–32. Zyczynski H, Lloyd L, Kenton K, Menefee S, et al. Correlation of Q-tip values and point Aa in stress-incontinent women. Urinary Incontinence Treatment Network (UITN). Obstet Gynecol. 2007;110(1):39–43.

Diagnosis and Management of Delayed Postoperative Complications in Gynecology: Neuropathy, Wound Complications, Fistulae, Thromboembolism, Pelvic Organ Prolapse, and Cuff Complications Christina Dancz and Anastasiya Shabalova Contents

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1

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2

2

2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8

Delayed Complications Presenting in the Immediate Postoperative Period (Within 2 Weeks) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Neurologic Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Femoral Nerve . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lateral Femoral Cutaneous Nerve . . . . . . . . . . . . . . Ilioinguinal and Iliohypogastric . . . . . . . . . . . . . . . . Genitofemoral . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Common Peroneal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sciatic Nerve . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Obturator Nerve . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2 2 2 3 3 4 4 4 4

3

Wound Complications . . . . . . . . . . . . . . . . . . . . . . . . .

5

4

Cuff Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6

5

Cuff Evisceration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7

Delayed Complications Presenting in the Early Postoperative Period (Within 3 Months) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1 Urinary Tract Fistulae . . . . . . . . . . . . . . . . . . . . . . . . . . .

7 7

7

Rectovaginal and Enterovaginal Fistulae . . . .

9

8

Thromboembolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

Delayed Complications Presenting in the Late Postoperative Period (Months to Years) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 9.1 Pelvic Organ Prolapse . . . . . . . . . . . . . . . . . . . . . . . . . . 12 10

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

6

C. Dancz (*) • A. Shabalova University of Southern California, Los Angeles, CA, USA e-mail: [email protected]; anastasiya. [email protected] # Springer International Publishing AG 2016 D. Shoupe (ed.), Handbook of Gynecology, DOI 10.1007/978-3-319-17002-2_73-1

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C. Dancz and A. Shabalova

Abstract

Surgical complications are an inevitable occurrence for any surgeon. Such complications may be a source of significant morbidity and even mortality. Delayed surgical complications typically present after the patient is discharged from the hospital. This chapter describes the presentation, evaluation, and management of the most common delayed postoperative complications. Delayed complications may be broadly categorized into those found in the early postoperative period and those in the later postoperative period. The first 2 weeks after surgery is a key time to evaluate and diagnose nerve injuries and wound complications, including infectious complications. Genital tract fistulae and thromboembolism may also present in this time period, but are also commonly seen in the first 3 months after surgery. Pelvic organ prolapse and cuff complications may present months to years after surgical intervention. The surgeon must be vigilant in the postoperative period for any sign of a delayed surgical complication, as prompt diagnosis and management is critical to minimize the effect upon the patient. Keywords

Coagulation • Cuff complications • Fistula • Nerve injury • Postoperative • Prolapse • Thromboembolism • Wound

1

Introduction

Some of the most commonly performed surgical procedures are performed by obstetrician/gynecologists. Cesarean section and hysterectomies are among the most commonly performed major surgeries in the United States, accounting for 1.8 million procedures in 2010 alone (National Center for Health Statistics (NCHS) 2010). These procedures are generally safe; however, occasionally complications may occur. Surgical complications range in both severity and acuity. When injuries occur during surgery, they may be immediately

repaired, often with minimal impact on the patient. Intraoperative injuries that are not recognized until the postoperative period generally have worse outcomes than those repaired at the time of surgery. In order to minimize the impact on patients, it is critical for any surgeon to promptly identify and appropriately manage any complications of these common surgical procedures.

2

Delayed Complications Presenting in the Immediate Postoperative Period (Within 2 Weeks)

2.1

Neurologic Injury

Neurologic injury complicates approximately 1–2 % of gynecological surgery. Many injuries are due to improper positioning or self-retaining retractors; however, direct surgical trauma, suture entrapment, or hematoma formation can also be involved (Bohrer et al. 2009; Warner et al. 2000). Symptoms almost always present soon after surgery, and, although most resolve completely with appropriate treatment, some patients continue to have long-term neurologic consequences. Therefore, prevention, early recognition, and treatment initiation are paramount. Nerves that may be injured after pelvic surgery include: femoral, lateral femoral cutaneous, ilioinguinal, iliohypogastric, genitofemoral, common perineal, sciatic, and obturator.

2.2

Femoral Nerve

Femoral nerve (L2-L4) is the largest branch of the lumbar plexus that courses between the psoas and the iliacus muscles in the abdomen, then passes under the inguinal ligament, and enters the thigh. Gynecologic surgery and particularly the abdominal hysterectomy are the most frequent causes of iatrogenic injury to the femoral nerve.

Diagnosis and Management of Delayed Postoperative Complications in. . .

Injury to the femoral nerve can occur throughout its course due to variable mechanisms. The most frequent cause is related to the use of selfretaining retractors. Retractor blades placed on the psoas muscle cause injury by compressing the nerve, particularly with the use of longer retractor blades. The retractor can also compress the nerve where it traverses the abdominal wall by lateral displacement of the psoas muscle. To avoid such injury, the shortest retractor blades should be used, particularly in thin patients. Folded laparotomy sponges or towels can be placed between the retractor and the abdominal wall. Disposable retractors that don’t use blades and therefore distribute the pressure evenly can be considered. The risk of injury is directly related to length of surgery. Another mechanism of injury of the femoral nerve is patient positioning. In dorsal lithotomy position excessive hip flexion, external rotation or abduction can compress the nerve against the inguinal ligament. Close attention to proper positioning is imperative to decrease the risk of compression injury. Thighs should not be excessively abducted or externally rotated and hip flexion should not exceed 80–90 . Although less common, injury can also occur due to direct transection, incorporation into a suture, or a hematoma causing nerve compression. The classic presentation of postoperative femoral nerve injury is a patient who cannot climb stairs or falls when trying to get out of bed. The motor deficits include inability to flex the hip or extend the knee as well as an absent patellar reflex. Sensory deficits usually involve paresthesia over the anterior-medial thigh and leg. If a neurological injury is suspected after surgery, a thorough neurological examination may provide the diagnosis. Electromyography and nerve conduction studies may narrow down the location of injury. Imaging studies such as MRI, CT scan, or ultrasound can be used to detect formation of a hematoma or other fluid collections causing nerve compression.

3

After diagnosis, treatment should be initiated immediately. In cases of suspected transection or suturing, surgical reexploration and repair may be needed. Nerve compression from a hematoma can be relieved with drainage. Physical therapy should be initiated as soon as possible to prevent muscle atrophy. Knee stabilizers may be used to counteract thigh muscle weakness during standing. Most patients will achieve full recovery, although time till recovery varies and may take up to several months (Bradshaw and Advincula 2010; Chan and Manetta 2002; Craig 2013; Irvin et al. 2004).

2.3

Lateral Femoral Cutaneous Nerve

Lateral femoral cutaneous nerve (L2-L3) courses over the iliacus muscle and passes under the inguinal ligament near the anterior superior iliac spine. Similarly to the femoral nerve, it is at risk of compression from excessive hip flexion in dorsal lithotomy position as well as with inappropriate placement of lateral retractor blades. Neurologic deficits associated with this nerve are loss of sensation, paresthesia, and pain over the anterior lateral thigh from the inguinal ligament to the knee, a condition sometimes referred to as meralgia paresthetica (Bradshaw and Advincula 2010; Craig 2013; Irvin et al. 2004).

2.4

Ilioinguinal and Iliohypogastric

Ilioinguinal (T12-L1) and iliohypogastric (T12-L1) nerves are frequently grouped together due to difficulty in distinguishing individual effects. The nerves run laterally through the head of the psoas muscle, pass diagonally along the anterior surface of quadratus lumborum, penetrate transversus abdominis, and enter the anterior abdominal wall. The nerves are susceptible to injury if a transverse abdominal incision is extended laterally, particularly beyond the edge of the rectus muscle at which point the edge of the

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fascia is close to the nerve branches. Injury from trocar placement in laparoscopic surgery has also been reported. The nerve damage typically occurs from direct surgical injury or nerve incorporation during fascial closure as well as scar formation after surgery. To decrease the risk of injury, the width of a transverse incision should be kept within the width of the rectus muscle. Neuropathy typically manifests with burning or pain at the incision site that radiates to the groin as well as paresthesia over mons pubis, labia, and inner thigh. The symptoms typically improve after infiltration with local anesthetic. Treatment typically includes pharmacologic agents such as tricyclic antidepressants or gabapentin; however, nerves blocks, trigger point injection, or surgical nerve resection may also be necessary. Resecting the nerve requires extending the prior transverse incision to the anterior superior iliac spine and exposing the interface between the external oblique and the internal oblique muscle. The two nerves course between these two muscles and can be identified and sectioned close to the lateral sidewall. Complete relief of pain can occur after nerve resection in more than 70 % of patients. Ilioinguinal and iliohypogastric nerve entrapment is typically under recognized and should be considered in cases of chronic pelvic pain associated with history of abdominal surgery (Bradshaw and Advincula 2010; Irvin et al. 2004).

2.5

Genitofemoral

The genitofemoral nerve (L1-L2) runs along the ventral surface of the psoas muscle, lies lateral to the external iliac artery, and branches near the inguinal ligament. Similarly to the femoral nerve, it is at risk of compression during laparotomy with the use of self-retaining retractors. In addition it can be directly damaged during retroperitoneal dissection, removal of pelvic masses adherent to the side wall, or with removal of external iliac lymph nodes. During such dissections the nerve should be isolated and preserved if possible. Neural deficits include groin pain and

paresthesia over the ipsilateral mons, labia, and anterior thigh below the inguinal ligament (Bradshaw and Advincula 2010; Irvin et al. 2004).

2.6

Common Peroneal

Common peroneal nerve (L4-S2) courses laterally across the knee in close proximity to bone with little superficial protection. It can be injured due to poor positioning of the knee and lower leg by pressing against the hard surface of stirrups. The nerve may be pressed against the fibular head; therefore, careful positioning, avoiding pressure on the lateral knee, and use of padding may decrease the chance of injury. Neurological deficits include paresthesia over the lateral lower leg and dorsum of the foot, weakness of ankle extension, or foot dorsiflexion. The patients typically present with foot drop (Bradshaw and Advincula 2010; Craig 2013; Irvin et al. 2004).

2.7

Sciatic Nerve

Sciatic nerve (L4-S3) courses beneath the piriformis muscle and through the greater sciatic foramen as it exits the pelvis to travel down the posterior thigh to the popliteal fossa. Injury during open surgery is rare but may result in an event of a sudden hemorrhage requiring placement of sutures deep within lateral pelvis to control bleeding. The injury has also been reported with pelvic exenteration surgery. Symptoms of injury typically involve pain as well as weakness affecting most of the lower leg musculature and hamstrings while sparing hip flexion, extension, abduction, adduction, and knee extension. Sensory loss involves the lower leg. The ankle reflex is absent, while the knee reflex is normal (Craig 2013; Irvin et al. 2004).

2.8

Obturator Nerve

Obturator nerve (L2-L4) courses through psoas muscle, passes behind the common iliac arteries and laterally to the internal iliac artery and ureter,

Diagnosis and Management of Delayed Postoperative Complications in. . .

then runs along the lateral wall of pelvis anterior to the obturator vessels to the obturator foramen, and enters the thigh through the obturator canal. In gynecologic surgery it is most frequently injured during retroperitoneal dissection for malignancies or endometriosis resection (Cardosi et al. 2002). The nerve can be exposed with gentle medial or lateral traction on the external iliac artery and vein. If perioperative injury is diagnosed, the damage should be immediately repaired with microsurgical technique. Nerve injury can also occur during mid-urethral sling operations, particularly the transobturator tape (TOT) procedure (Aydogmus et al. 2014). Nerve injury presents postoperatively with loss of sensation over the inner thighs and motor loss in the hip adductors. Postoperative physical therapy should be initiated promptly including neuromuscular electrical stimulation, electromyographic biofeedback, exercise, and home-treatment regimen. Complete motor recovery is common after physiotherapy (Craig 2013; Irvin et al. 2004).

3

Wound Complications

Wound complications are one of the most common causes of postoperative morbidity. Wound complications (separation, hematoma, seroma, and infection) are estimated to affect 2–5 % of abdominal incisions (Sherertz et al. 1992). Poor wound healing or collections of fluid/blood under the skin may cause the incision to separate and predispose the wound to infection. Wound complications usually present as swelling, pain, and/or drainage of fluid from the incision, most often within 3–10 days after surgery. When infected, the wound is often erythematous, indurated, and tender. Wound infections may be accompanied by fever and/or leukocytosis. Patients presenting in the postoperative period with any of these symptoms should be carefully evaluated with a thorough history and physical exam. Most of these complications may be managed without imaging or surgical intervention. Wound separation: Wound separation is defined as separation of the superficial layers of

5

the wound (subcutaneous fat and skin). The underlying fascia is intact. Wound separation in the absence of a fluid collection or infection is uncommon, and if identified within 7–10 days of the initial surgery, delayed surgical re-approximation of the wound may be considered. Seroma/hematoma: A seroma is a collection of serum under the skin, while a hematoma is a similar collection of blood. A seroma or hematoma separates the superficial layers under the skin and prevents adequate wound healing. These wound complications are commonly related to obesity, immunocompromised and inadequate hemostasis. The fluid collects under the skin and gradually leaks out the incision line. Small hematomas and seromas (= 7 is high risk.

Fig. 4 Rectovaginal fistula

Clinical parameter to predict DVT (Wells et al. 1997) Paralysis or recent plaster immobilization of lower extremities Recently bedridden for more than 3 days or major surgery within 12 weeks Local tenderness in the distribution of the deep venous system Entire leg swollen Calf swelling 3 cm larger than asymptomatic side (measured 10 cm below tibial tuberosity) Pitting edema confined to the symptomatic leg Collateral superficial veins (non-varicose) Alternative diagnosis at least as likely as DVT

Score

+1 +1 +1 +1 +1 +1 2

Pretest assessment of clinical factors uses validated criteria, such as the Wells criteria. The Wells criteria to predict DVT include nine different clinical factors, which are scored as a clinical probability. A score of < = 0 is low, 1–2 is intermediate, and > = 3 is high. In patients with a low pretest probability based on clinical criteria, a high-sensitivity D-dimer assay may be used to rule out DVT. If the D-dimer assay is positive, or if the patient is

Clinical parameter to predict PE (van Belle et al. 2006) Previous PE or DVT Heart rate >100 beats per minute Recent surgery or immobilization Clinical signs of deep venous thrombosis Alternative diagnosis less likely than pulmonary embolism Hemoptysis Cancer

Score +1.5 +1.5 +1.5 +3 +3 +1 +1

If the clinical suspicion for DVT or PE is high, it is reasonable to begin treatment while the workup is confirming the diagnosis. The risks of untreated DVT or PE are high and may outweigh the risks of a brief treatment of anticoagulation, even if such treatment is ultimately unnecessary. Once diagnosed, the mainstay of treatment for DVT or PE is anticoagulation. Low-molecularweight heparin (LMWH) should be used for initial inpatient treatment of DVT. LMWH is superior to unfractionated heparin for the treatment of DVT for ease of dosing and maintenance, as well as an overall reduction in mortality and major bleeding. Treatment is generally administered for 3–6 months for DVT due to transient risk factors such as surgery. Outpatient treatment is reasonable and may consist of daily injections with LMWH or transition to an oral treatment, such as a vitamin K antagonist. Compression stockings should be used to prevent post-thrombotic syndrome, a chronic syndrome of leg pain, swelling,

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C. Dancz and A. Shabalova

hysterectomy for other indications (0.3–1.8 %) (Mant et al. 1997; Marchionni et al. 1999). The main symptom of pelvic organ prolapse is the sensation of pressure or bulge in the vagina (Fig. 5). Severe complications of prolapse are rare. Prolapse diagnosis is usually based on physical exam, though several formal staging systems exist. Asymptomatic or minimally symptomatic prolapse may not require any intervention. Patients with significant bother may elect to use a plastic device (pessary) to hold their prolapsed organs in place, or they may elect for surgery. There are a variety of surgical procedures for prolapse, depending on the patient’s health, preferences, degree, and location of prolapse.

9.1.1

Fig. 5 Pelvic organ prolapse after hysterectomy

and ulceration that occurs in up to half of patients with DVT. The stockings should be worn staring within 1 month of DVT diagnosis and continued for at least a year (Vazquez and Kahn 2010).

9

Delayed Complications Presenting in the Late Postoperative Period (Months to Years)

9.1

Pelvic Organ Prolapse

Pelvic organ prolapse is the descent of any of the pelvic organs. Hysterectomy is a known risk factor for the development of pelvic organ prolapse. A large study of community dwelling women found that women with prolapse were 1.68 more likely to have undergone a prior hysterectomy (Lawrence et al. 2008). The incidence of prolapse after hysterectomy is higher for women who had a hysterectomy for prolapse (1.6–11.6 %) compared to women who had a

Cuff Complications

Granulation Tissue The most common abnormal postoperative finding at the vaginal cuff is granulation tissue. Granulation tissue is an over-proliferation of healing tissue that may be found on any wound. Granulation tissue is usually described as beefy red and friable (see Fig. 6). Most cases of vaginal granulation tissue are asymptomatic, but may also cause vaginal bleeding, particularly after intercourse. Granulation tissue at the cuff is benign and may be treated with topical cautery using (Saropola and Ingsirorat 1998) sticks or may be excised. Excision may be preferred when the tissue is large and symptomatic or if the diagnosis is in question. Other conditions may occasionally be mistaken for granulation tissue, including malignancy or fallopian tube prolapse (Song et al. 2005). Fallopian Tube Prolapse Fallopian tube prolapse is a rare complication of hysterectomy, whereby the fallopian tube is either incorporated into the vaginal cuff or prolapses through an open cuff. This complication usually presents with severe low abdominal pain or a pulling sensation and tenderness to palpation of the cuff. The tube may be visible at the apex of the vagina, and biopsy or excisional biopsy can confirm the diagnosis (Figs. 7 and 8).

Diagnosis and Management of Delayed Postoperative Complications in. . .

Fig. 6 Granulation tissue at cuff (Originally published in: Stember et al. 2003; with kind permission of Springer Science + Business Media. All rights reserved)

13

Fig. 7 Fallopian tube prolapse (Originally published in: Bower et al. 1940; with kind permission of Elsevier. All rights reserved)

If the diagnosis is confirmed, revision of the cuff is usually necessary to relieve symptoms. This revision may be performed vaginally, and the cuff is opened up, the damaged tube is often excised, and the remaining cuff is closed. Laparoscopic/open approach may also allow confirmation of diagnosis and evaluation for additional etiologies of the pain.

10

Conclusion

All surgical procedures have the risks of postoperative complications. These complications may be immediate or delayed. Delayed postoperative complications can have serious effects for patients, and prompt diagnosis and management is critical. This chapter discusses a variety of complications that can be managed clinically or operatively. A thorough understanding of the mechanism of neurologic injury allows for insight into prevention and recognition, which can reduce the effect on the patient. Wound complications can generally be managed conservatively, and

Fig. 8 Vaginal evisceration of small bowel through vaginal cuff (Originally published in: Partsinevelos et al. 2008; with kind permission of Springer Science + Business Media. All rights reserved)

only the most severe infections or fascial dehiscences need surgical management. Fistulae are among the most dreaded complications by surgeons, as they generally represent unrecognized surgical injury; however, with prompt recognition and surgical treatment, most fistulae can be

14

completely cured. Thromboembolism is probably the most dangerous of the postoperative complications, though studies have shown improvement of morbidity and mortality with aggressive prevention and early diagnosis. Finally, pelvic organ prolapse and cuff complications are varied and require clinical insight into diagnosis and management. There is no such thing as a surgeon with no complications, but with enough understanding, preparation, and care, a surgeon can minimize their complications and mitigate the impact upon their patients.

References ACOG practice bulletin #104: antibiotic prophylaxis for gynecologic procedures. Obstet Gynecol. 2009; 113 (5):1180–9. Adelman MR, Bardsley TR, Sharp HT. Urinary tract injuries in laparoscopic hysterectomy: a systematic review. J Minim Invasive Gynecol. 2014;21(4):558–66. Aydogmus S, Kelekci S, Aydogmus H, Ekmekci E, Secil Y, Ture S. Obturator nerve injury: an infrequent complications of TOT procedure. Case Rep Obstet Gynecol. 2014; 1–3. Bohrer JC, Walters MD, Park A, Polston D, Barber MD. Pelvic nerve injury following gynecologic surgery: a prospective cohort study. Am J Obstet Gynecol. 2009;209:1–7. Bower JO, Pearce AE, Conway EW. Prolapse and torsion of the right fallopian tube with vaginal bleeding, following vaginal hysterectomy. Am J Obstet Gynecol. 1940;40(6):1047–50. Bradshaw A, Advincula A. Postoperative neuropathy in gynecologic surgery. Obstet Gynecol Clin North Am. 2010;37:451–9. Cardosi RJ, Cox CS, Hoffman MS. Postoperative neuropathies after major pelvic surgery. Obstet Gynecol. 2002;100(2):240–4. Ceccaroni M, Berretta R, Malzoni M, Scioscia M, Roviglione G, Spagnolo E, Rolla M, Farina A, Malzoni C, De Iaco P, Minelli L, Bovicelli L. Vaginal cuff dehiscence after hysterectomy: a multicenter retrospective study. Eur J obstet Gynecol Repro Bio. 2011;158:308–13. Chan JK, Manetta A. Prevention of femoral nerve injuries in gynecologic surgery. Am J Obstet Gynecol. 2002;186:1–7. Craig A. Entrapment neuropathies of the lower extremity. Phys Med Rehabil. 2013;5:31–40. Croak AJ, Gebhart JB, Klingele CJ, Schroeder G, Lee RA, Podratz KC. Characteristics of patients with vaginal

C. Dancz and A. Shabalova rupture and evisceration. Obstet Gynecol. 2004;103:572–6. Cronin B, Sung VW, Matteson KA. Vaginal cuff dehiscence: risk factors and management. Am J Obstet Gynecol. 2012;206:284–8. Duff P, Park RC. Antibiotic prophylaxis in vaginal hysterectomy: a review. Obstet Gynecol. 1980;55(5):193s. Gandhi P, Jha S. Review: vaginal vault evisceration. Obstetrician Gynecologist. 2011;13:231–7. Greenstein Y, Shah AJ, Vragovic O, Cabral H, SotoWright V, Borgatta L, Kuching W. Tuboovarian abscess. Factors associated with operative intervention after failed antibiotic therapy. J Reprod Med. 2013;58 (3–4):101–6. Irvin W, Anderson W, Taylor P, Rice L. Minimizing the risk of neurologic injury in gynecologic surgery. Obstet Gynecol. 2004;103:374–82. Jaiyeoba O. Postoperative infections in obstetrics and gynecology. Clin Obstet Gyencol. 2012;55(4):904–13. Kho RM, Akl MN, Cornella JL, Magtibay PM, Wechter ME, Magrina JF. Incidence and characteristics of patients with vaginal cuff dehiscence after robotic procedures. Obstet Gynecol. 2009;114:231–5. Lawrence JM, Lukacz ES, Nager CW, Hsu JY, Luber KM. Prevalence and co-occurrence of pelvic floor disorders in community-dwelling women. Obstet Gynecol. 2008;111:670–85. Mahdi H, Goodrich S, Lockhart D, DeBernardo R, Moslemi-Kebria M. Predictors for surgical site infection in women undergoing hysterectomy for benign gynecologic disease: a multicenter analysis using the national surgical quality improvement program data. J Minim Invasive Gynecol. 2014;21(5):901–9. Mant J, Painter R, Vessey M. Epidemiology of genital prolapse observations from the Oxford Family Planning Association study. Br J Obstet Gynaecol. 1997;104:579–85. Marchionni M, Bracco GL, Checcucci V, Carabaneanu A, Coccia EM, Mecacci F, Scarselli G. True incidence of vaginal vault prolapse: thirteen years experience. J Reprod Med. 1999;44:679–84. Meeks GR, Roth TM. Vesicovaginal fistula and urethrovaginal fistula. In: Rock JA, Jones III HW, editors. Te Linde’s operative gynecology. 10th ed. Philadelphia: J.B. Lippincott; 2011. p. 973–93. National Center for Health Statistics. National Hospital Discharge Survey, 2010. [Internet] Number of all-listed procedures for discharges for short-stay hospitals, by procedure category and age: United States, 2010. [Cited 2016 Mar 15]. Available from: http:// www.cdc.gov/nchs.data/ndsp/4procedures/2010pro4_ numberprocedureage.pdf Nick AM, Lange J, Frumovitz M, Soliman PT, Schmeler KM, Schlumbrecht MP, dos Reis R, Ramirez PT. Rate of vaginal cuff separation following laparoscopic or robotic hysterectomy. Gynecol Oncol. 2011;120:47–51. Partsinevelos GA, Rodolakis A, Athanasiou S, Antsaklis A. Vaginal evisceration after hysterectomy: a rare

Diagnosis and Management of Delayed Postoperative Complications in. . . condition a gynecologist should be familiar with. Arch Gynecol Obstet. 2008;279(2):267. Qaseem A, Snow V, Barry P, Hornbake ER, Rodnick JE, Tobolic T, Ireland B, Segal JB, Bass EB, Weiss KB, Green L, Owens DK. Current diagnosis of venous thromboembolism in primary care: a clinical practice guideline from the American Academy of Family Physicians and the American College of Physicians. Ann Fam Med. 2007;5:57–62. Saropola N, Ingsirorat C. Conservative treatment of vaginal vault granulation tissue following total abdominal hysterectomy. Int J Gynecol Obstet. 1998; 62:55–8. Sherertz RJ, Garibaldi RA, Marosok RD, Mayhall CG, Scheckler WE, Berg R, Gaynes RP, Jarvis WR, Martone WJ, Lee JT. Consensus paper on the surveillance of surgical wound infections. Infect Control Hosp Epidemiol. 1992;13(10):599. Snow V, Qaseem A, Barry P, Hornbake ER, Rodnick JE, Tobolic T, Ireland B, Segal J, Bass E, Weiss KB, Green L, Owens DK. Management of venous thromboembolism: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med. 2007;146(3):204–10. Song YS, Kang JS, Park MH. Fallopian tube prolapse misdiagnosed as vault granulation tissue: a report of three cases. Pathol Res Pract. 2005;201(12):819–22. Stember DS, Scarpero HM, Nitti VW. Vaginal granulation tissue secondary to bone anchors: experience in two patients. J Urol. 2003;169(6):2300–1.

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Tapson VF. Acute pulmonary embolism. N Engl J Med. 2008;358(10):1037–52. Teeluckdharry B, Gilmour D, Flowerdew G. Urinary tract injury at benign gynecologic surgery and the role of cystoscopy: a systematic review and meta-analysis. Obstet Gynecol. 2015;126(6):1161. van Belle A, Buller HR, Huisman MV, Huisman P, Kaasjager K, Kamphuisen PW, Kramer MHH, Kruip MJHA, Kwakkel-vanErp JM, Leebeek FWG, Nijkeuter M, Prins MH, Sohn M, Tick LW. Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, d-dimer testing and computed tomography. JAMA. 2006;295:172. van Ramshorst GH, Nieuwenhuizen J, Hob WCJ, Arends P, Boom J, Jeekel J, Lange JF. Abdominal wound dehiscence in adults: development and validation of a risk model. World J Surg. 2010;34(1):20–7. Vazquez SR, Kahn SR. Postthrombotic syndrome. Circulation. 2010;121:e217–9. Warner MA, Warner DO, Harper CM, Schroeder DR, Maxson PM. Lower extremity neuropathies associated with lithotomy positions. Anesthesiology. 2000;93:938–42. Wells PS, Anderson DR, Bormanis J, Guy F, Mitchell M, Gray L, et al. Value of assessment of pretest probability of deep-vein thrombosis in clinical management. Lancet. 1997;350:1795–8. Wild TT, Bradley CS, Erickson BA. Successful conservative management of a large iatrogenic vesicovaginal fistula after loop electrosurgical excision procedure. Am J Obstet Gynecol. 2012;207(3):e4–6.

Breast Cancer Screening Heather R Macdonald

Abstract

Contents 1

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

2

Who Is at Increased Risk for Breast Cancer? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

3

Breast Screening Techniques and Technologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Breast Exam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Breast Exam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mammography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Tomosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Breast Ultrasound . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Breast MRI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3.1 3.2 3.3 3.4 3.5 3.6

4 4 4 4 5 6 6

4

Characterization of Image-Detected Breast Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

5

When to Conclude Breast Cancer Screening . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

6

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

It is expected in 2016 246,660 women in the United States will be newly diagnosed with breast cancer and 40,450 women will die of the disease. The purpose of breast cancer screening is to identify preclinical disease in asymptomatic women as breast cancer survival is improved with early detection. Digital mammography remains the mainstay of breast cancer screening. Tomosynthesis (3-D mammogram) has improved sensitivity with fewer false-positive studies, especially in women with dense breasts. Concerns have been raised about harms of false positives (repeat imaging and/or biopsies for benign findings), overdiagnosis of clinically insignificant breast cancers, and overtreatment. Thus, breast cancer screening recommendations range from initiation of screening at 40 years and performed annually to initiation at 50 years and performed biannually. All guidelines recommend cancer risk assessment with a physician and development of an individualized screening program.

H.R. Macdonald (*) Keck School of Medicine, University of Southern California, Los Angeles, CA, USA e-mail: [email protected]; hmacdona@med. usc.edu # Springer International Publishing AG 2016 D. Shoupe (ed.), Handbook of Gynecology, DOI 10.1007/978-3-319-17002-2_74-1

Women with the strongest risk factor for breast cancer, including personal history of cancer or atypical breast biopsy or family history of breast cancer, should undergo annual screening mammography. Women known to carry a 1

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H.R. Macdonald

familial breast cancer gene or at a lifetime risk of breast cancer greater than 20% should undergo annual breast MRI in addition to annual mammogram. Screening should conclude when a woman’s life expectancy is less than 5 years. Keywords

Breast cancer risk factors • Familial breast cancer syndromes • Breast cancer risk assessment • Mammography • Breast MRI • Tomosynthesis • BIRADS score

1

Introduction

It is expected in 2016 246,660 women in the United States will be newly diagnosed with breast cancer and 40,450 women will die of the disease (American Cancer Society 2016). One in 12 women will develop breast cancer in their lifetime, a statistic that has not decreased in recent years. The purpose of breast cancer screening is to identify preclinical disease in asymptomatic women as breast cancer survival is improved with early detection (Nelson et al. 2009). Implementation of screening mammography (regular mammograms performed in asymptomatic women with normal breast exams) has been associated with improved survival from breast cancer of 23–40% (Lauby-Secretan et al. 2015). Breast cancer mortality has been dropping by 1.9% per year, likely due to a combination of improved early detection (screening) and improved treatment (Ryerson et al. 2016). However, concerns have been raised about harms of false positives (repeat imaging and or biopsies for benign findings), overdiagnosis of clinically insignificant breast cancers, and overtreatment. Thus, breast cancer screening recommendations are in flux, and the optimal age of initiation and screening interval is controversial for low-risk women. Major medical associations have released conflicting screening recommendations leading to confusion and frustration among physicians and patients. As research has demonstrated a better understanding of how breast cancer risk changes over a woman’s lifetime, screening

recommendations are moving to an individualized risk-based approach. This chapter will summarize the range of recommendations for breast cancer screening in low-risk women and briefly summarize the data behind them. Risk factors for breast cancer will be reviewed as well as screening recommendations for women at risk for breast cancer.

2

Who Is at Increased Risk for Breast Cancer?

Risk factors for breast cancer are listed in Table 1 with their relative risks. As demonstrated below factors associated with the highest risk of breast cancer are female gender, older age, history of previous breast cancer, family history of breast cancer in a first-degree relative, and history of atypical breast biopsy. Patients with both a family history of breast cancer in a first-degree relative and a personal history of an atypical breast biopsy are at highest risk, with relative risk approaching those of BRCA mutation carriers (Dupont and Page 1985). A strong family history of breast or related cancers is a red flag for an inherited familial breast cancer syndrome. Each patient should be assessed for familial cancer syndromes by eliciting a threegeneration family history that includes ethnicity, any cancers in the family, who was diagnosed with cancer and their relationship to the patient, how the cancer was diagnosed and treated, if the afflicted family member survived or died, and if any genetic testing was performed. If there is a pattern of cancers running through the family or a clustering of rare cancers occurring in related relatives, consideration should be given to a genetic counseling referral. Table 2 lists the American College of Obstetricians and Gynecologists recommendations for genetic testing and counseling. Table 3 includes characteristics of the most common familial breast cancer syndromes. Personalized cancer risk assessment is an important tool to guide physicians and patients in quantifying breast cancer risk and designing an appropriate screening regimen. Counseling should focus on lifestyle changes targeting high-

Breast Cancer Screening

3

Table 1 Risk factors for breast cancer Risk factor Highest risk Female gender Increasing age Inherited gene mutation (i.e., BRCA) >2 young first-degree relatives with breast cancer Personal history of breast cancer History of atypical breast biopsy Moderate risk One first-degree relative with breast cancer History of chest wall radiation 30 years Menarche 55 Nulliparity No history of breast feeding Use of combination hormone replacement therapy Postmenopausal weight gain Alcohol consumption Smoking Physical inactivity

Table 2 ACOG recommendations for genetic counseling referral Cancer diagnosed at young age (i.e., breast cancer younger than 50) Several different cancer diagnoses in the same individual (i.e., breast and ovarian or colon and endometrial) Close blood relatives with the same type of cancer (i.e., mother-daughter pairs) Unusual cancer presentation (i.e., male relative with breast cancer) Ashkenazi Jewish ancestry Occurrence of adult cancer known to be associated with familial cancer syndromes: Triple negative breast cancer (ER/PR/her 2 neu negative suggestive of BRCA 1 mutation) Epithelial or serous ovarian cancer (suggestive of a BRCA mutation) Colorectal or endometrial cancer with DNA mismatch repair deficiency (suggestive of Lynch syndrome)

Type

Relative risk

Reproductive Reproductive Familial Familial Personal medical history Personal medical history

>4

Familial Personal medical history

2.1–4

Reproductive Reproductive Reproductive Reproductive Reproductive Personal medical history Lifestyle Lifestyle Lifestyle Lifestyle

1.1–2

Table 3 Familial breast cancer syndromes

Syndrome Hereditary breast and ovarian cancer syndrome

Gene mutation BRCA 1 and 2

Lifetime breast cancer risk 80% (BRCA 1) 60% (BRCA 2)

LiFraumeni

p53

90% (all cancer types)

Cowden

pTEN

30–50%

Hereditary diffuse gastric cancer

CDH1

40–50%

Associated cancers Ovarian

Prostate Pancreatic Melanoma Bone and soft tissue sarcoma Brain Adrenocorticoid Colon Leukemia Endometrial Nonmedullary thyroid Lobular breast cancer Diffuse gastric cancer

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H.R. Macdonald

risk behaviors (see lifestyle factors above) and estimating risk from intrinsic risk factors like family history, past medical history, and atypical cells on biopsy. Clinicians should be aware of the various familial breast cancer syndromes and refer patients with suspicious family history for genetic counseling and possible genetic testing. Table 3 describes the more common hereditary cancer syndromes and relative risks of breast cancer. For further discussion of ovarian cancer, please see the chapter entitled “Diagnosis and Management of Epithelial Ovarian Cancer.” The US Preventive Services Task Force recommended in 2009 each patient consult their physician regarding their personal risk of breast cancer and designs an individualized screening program (Nelson et al. 2009). Several online calculators have been designed and made publicly available to assist in breast cancer risk assessment, including the Gail model, IBIS, and BRCAPro. They incorporate varying details of family history, population-based risk factors like menstrual history and age at first birth, as well as personal history of breast atypia. For the highest risk patients, if lifetime breast cancer risk exceeds 20%, annual screening breast MRI is recommended (National Comprehensive Cancer Network 2016). Please see “Breast MRI” section for further explanation.

3

Breast Screening Techniques and Technologies

Breast screening modalities include breast exam, self-administered (self breast exam or SBE) or by a clinician (clinical breast exam or CBE), Table 4 Sensitivity of common breast cancer screening modalities Modality Self breast exam Clinical breast exam Mammography Tomosynthesis Breast MRI

Sensitivity 2–4% 40–69%

Specificity Finds more benign than malignant disease 88–99%

77–95% 90% 71–100%

94–97% 79% 81–97%

mammography which can include full field, digital, or tomosynthesis (three dimensional), breast ultrasound, or breast MRI. Table 4 lists the sensitivities and specificities of each. The remainder of the chapter will discuss the relative advantages and drawbacks to each.

3.1

Breast Exam

Breast exam is the most commonly utilized breast screening tool but is falling out of favor due to low sensitivity and specificity. Self breast exam has been demonstrated to increase patient anxiety without improving cancer detection and is no longer routinely recommended. Breast selfawareness can be taught at a routine health maintenance visit. It entails being aware of the normal texture of one’s breast tissue, as well as knowledge of any benign masses or cysts that may be present, so a patient can seek medical attention if changes occur. Breast self-awareness should also involve education of menstrual patients regarding the expected fluctuations in breast tissue associated with phases of the menstrual cycle.

3.2

Clinical Breast Exam

Clinical breast exam is perhaps the most commonly utilized breast cancer screening tool as it is commonly included in well woman annual health screening. However, because of its low sensitivity, annual CBE is no longer recommended outside high-risk patient populations.

3.3

Mammography

Screening mammography is the mainstay of breast cancer screening. The identification of breast cancer before it becomes clinically apparent leads to improved survival, as demonstrated in several randomized control trials in the United States and Europe starting in the 1970s. Screendetected cancers were diagnosed at earlier stage and led to lower cancer-related mortality (Tabar

Breast Cancer Screening Table 5 Summary recommendations

Society American Cancer Society

5

of

breast

Age 40–44

45–55 >55

US Preventive Services Task Force

40–49 50–74

>75

American College of Obstetricians and Gynecologists American College of Radiology National Cancer Institute National Comprehensive Cancer Network

>40 >40 >40 >40

cancer

screening

Recommended screening for average-risk women Optional annual screening mammogram Annual screening mammogram Screening mammogram every 2 years; screen until life expectancy is >10 years Screening optional at patient’s discretion Screening mammogram every 2 years No recommendations due to lack of evidence Annual screening mammogram Annual screening mammogram Annual screening mammogram Annual screening mammogram

et al. 1985, 2000; Andersson et al. 1988). This was confirmed in subsequent meta-analyses (Oeffinger et al. 2015). Recently, controversy has arisen over screening guidelines for averagerisk women, specifically at what age to initiate regular screening and at what frequency (Nelson et al. 2009). Concerns were raised by the US Preventive Services Task Force in 2009 regarding potential harms of overscreening including falsepositive studies requiring additional imaging and/or biopsy and overdiagnosis leading to overtreatment and additional costs. The American Cancer Society stratified their screening recommendations by age-adjusted risk. The American College of Radiology and American College of Obstetricians and Gynecologists have continued to recommend annual screening due to benefits of early detection. Table 5 summarizes

recommendations from several major medical societies regarding screening mammogram for average-risk women. Women with a high risk factor like breast atypia should undergo screening mammogram annually. Women with a family history of breast cancer should undergo screening mammography annually starting 5–10 years younger than the youngest affected family member or at age 30. For the women with extensive family history, MRI should be considered in addition to annual mammography. (Please see “MRI” section.) The variation among recommendations has caused confusion among patients and providers and concern regarding insurance coverage of breast cancer screening in women under 50. A careful reading of all published guidelines demonstrates an emphasis by each of personalized screening based on the patient’s risk factors and concern regarding cancer detection. Guidelines agree that average-risk women should have the option to start mammographic screening at 40 should they desire screening for early cancer detection and understand the risks of falsepositive studies.

3.4

Tomosynthesis

A major advance in mammographic screening has been three-dimensional digital breast tomosynthesis (DBT). Tomosynthesis takes a series of images that allows the mammographer to review images in thin reconstructed slices, allowing the viewer to scroll up and down or side to side through breast tissues. Radiation exposure is comparable to standard mammography (Gur et al. 2009). The technology is better able to discern overlapping normal tissues and underlying lesions (Lei et al. 2014). Tomosynthesis was found in a recent meta-analysis of breast imaging techniques to have a higher sensitivity and specificity (90% and 79%, respectively) than digital and plain field mammography. DBT was found to have reduced recall rate and improved detection of breast lesions, resulting in fewer false positives and false negatives. It has been found to be most effective with increased invasive cancer detection

6

H.R. Macdonald

rate when used in conjunction with full-field digital mammography but requires two radiation exposures of the patient (Hodgson et al. 2016). Patients with dense breasts may particularly benefit from tomosynthesis as a screening technique. Dense breasts impede cancer detection on screening mammography as suspicious lesions can be obscured by overlapping dense tissues. By allowing mammographers to scroll through breast tissue in 1 mm slices, tomosynthesis has been shown to increase cancer detection and reduce false-positive studies in women with dense breasts (Houssami and Turner 2016).

For women with a family history of breast cancer, screening with annual mammography is recommended to begin 10 years younger than the youngest affected family member, although not before 30. Patients who carry a BRCA mutation screening with annual breast MRI are recommended to start at 25 years with the addition of annual breast mammogram at 30. Women who have a history of an atypical breast biopsy are recommended to undergo annual screening mammography starting at 40 or at the time of identification of the lesion.

4 3.5

Breast Ultrasound

Characterization of ImageDetected Breast Lesions

Breast ultrasound has been investigated as a breast screening tool due to its ease of use, minimal patient discomfort, and lack of radiation exposure. It has been demonstrated to minimally improve cancer detection but at the cost of increased falsepositive studies prompting further investigations to identify benign disease (Berg et al. 2008). Thus, it remains a diagnostic tool, useful for clarifying physical exam, mammography, or MRI findings and assessing axillary lymph nodes.

Lesions identified on mammography that raise the concern of breast cancer include calcifications, masses, architectural distortion, and asymmetry. To reduce confusion regarding mammographic findings, the American College of Radiology has devised a scoring system that reflects levels of concern for occult malignancy. Table 6 summarizes the BIRADS scoring system and the associated risk of cancer.

3.6

Table 6 Summary of BIRADS scoring system of radiographically detected breast lesions

Breast MRI

Breast MRI affords the greatest sensitivity for breast cancer detection. Utilizing intravenous contrast, breast MRI demonstrates blood flow through the breast in addition to detailed soft tissue imaging, highlighting cancers by both their appearance and their preferential perfusion. Limitations include risks of false positives, limited resources (breast MRI requires a dedicated breast coil and software), placement of intravenous access, and contrast administration. Contrast allergies are rare but can occur, and IV contrast is contraindicated in patients with underlying renal disease. Additionally claustrophobic patients may find MRI challenging. Generally, when lifetime risk of breast cancer exceeds 20%, consideration should be given to add annual breast MRI to annual mammogram.

BIRADS score 0 1 2 3 4 4A 4B 4C 5 6

Description Incomplete Negative Benign Probably benign Suspicious Low suspicion Moderate suspicion High suspicion Highly suspicious Tissue-confirmed cancer

Associated risk of breast cancer Needs additional testing No or minimal risk No or minimal risk 0–2% 2–95% 2–10% 10–50% 50–90% 95% or greater Biopsy-proven cancer

Modified from Sickles et al. (2013. http://www.acr.org/ Quality-Safety/Resources/BIRADS/About-BIRADS/ How-to-Cite-BIRADS)

Breast Cancer Screening

7

Table 7 Summary of breast screening protocol Population All women Average-risk women Increased-risk women Women with a family history of breast cancer Familial breast cancer syndrome or known gene mutation carriers

Modality Clinical breast exam and breast cancer education Mammography Mammography Mammography Mammography and breast MRI

Low-risk lesions (BIRADS 3) should be reevaluated with short-term repeat imaging, usually in 6 months. Lesions that confer a suspicion of cancer (BIRADS 4 or 5) warrant a biopsy. Image-guided needle biopsy is preferable over open surgical biopsy to allow for most complete evaluation while minimizing risk to the patient (Silverstein et al. 2005). Needle biopsy has not been shown to cause cancer metastasis and avoids the risks of surgery for patients with benign lesions. Discordant biopsies (benign results in a highly suspicious lesion) should be further evaluated by repeat needle biopsy or surgical excision to avoid missing an underlying breast cancer.

5

When to Conclude Breast Cancer Screening

Breast cancer risk continues to rise through the eighth decade of life and remain elevated until the end of life (American Cancer Society 2016). More than one-third of cases are diagnosed after age 65 years (cite 2007 lancet oncology). There are no randomized control studies demonstrating a survival benefit from breast cancer screening over age 70 (Nelson et al. 2009). When to stop screening is confusing. The US Preventive Services Task Force declined to issue a recommendation regarding breast cancer screening due to lack of evidence. Because breast cancer risk remains elevated in later decades of life and women are living longer and with better health, most experts including the American Cancer Society recommend an individualized decision between the patient and physician regarding ongoing breast cancer screening.

Age at initiation 20 years

Frequency Annual

40–50 years 40 years 10 years younger than the youngest affected family member or 25 years 25 years (MRI) 30 years (mammography)

1–2 years Annual Annual Annual

If the patient is in good health and has life expectancy of more than 5–10 years, then continuing screening mammography is reasonable.

6

Conclusion

Despite recent confusion regarding breast cancer screening, early detection of breast cancer remains an important method to reduce breast cancer mortality and improve survival. Individualized breast cancer risk assessment allows physicians to educate patients about modifiable risk factors and design a personalized screening regimen. Screening guidelines are conflicting for average-risk women only; all guidelines agree that at-risk women should undergo annual screening mammography. By encouraging a dialogue between patients and providers regarding breast cancer risk, benefits of early detection and intervention, and harms of false-positive studies, providers can increase breast cancer awareness. Table 7 summarizes a reasonable approach to breast cancer screening.

References American Cancer Society. Breast Cancer Facts and Figures 2015–2016. Available from: http://www.cancer. org/research/cancerfactsstatistics/cancerfactsfigures2016 Andersson I, Aspergren K, Janzon L, Landberg T, Lindholm K, Linell F, Ljungberg O, Ranstam J, Sigfusson B. Mammographic screening and mortality from breast cancer: the Malmo mammographic screening trial. Br Med J. 1988;297(6654):943–8.

8 Berg WA, Blume JD, Cormack JB, Mendelson EB, Lehrer D, Bohm-Velez M, Pisano ED, Jong RA, Evans WP, Morton MJ, Mahoney MC, Larsen LH, Barr RG, Farria DM, Marques HS, Boparai K, ACRIN 6666 Investigators. Combined screening with ultrasound and mammography vs mammography alone in women at elevated risk of breast cancer. JAMA. 2008;299(18):2151–63. Dupont WD, Page DL. Risk factors for breast cancer in women with proliferative breast disease. N Engl J Med. 1985;312:146–51. Gur D, Abrams GS, Chough DM, Ganott MA, Hakim CM, Perrin RL, Rathfon GY, Sumkin JH, Zuley ML, Bandos AI. Digital breast tomosynthesis: observer performance study. Am J Roentgenol. 2009;193(2):586–91. Hodgson R, Heywang-Kobrunner SH, Harvey SC, Edwards M, Shaikh J, Arber M, Glanville J. Systematic review of 3D mammography for breast cancer screening. Breast. 2016;27:52–61. Houssami N, Turner RM. Rapid review: estimates of incremental breast cancer detection from tomosynthesis (3D-mammography) screening in women with dense breasts. Breast. 2016;30:141–5. Lauby-Secretan B, Scoccianti C, Loomis D, BenbrahimTallaa L, Bouvard V, Bianchini F, Straif K. NEJM’ N Eng J Med. 2015;372(24):2353–8. Lei J, Yang P, Zhang L, Wang Y, Yang K. Diagnostic accuracy of digital breast tomosynthesis versus digital mammography for benign and malignant lesions in breasts: a meta-analysis. Eur Radiol. 2014;24:595–602. National Comprehensive Cancer Network. Breast cancer screening and diagnosis version 1. 2016. Available from http://www.nccn.org Nelson HD, Tyne K, Nalk A, Bougatsos C, Chan B, Humphrey L. Screening for breast cancer: an update for the

H.R. Macdonald US Preventive Services Task Force. Ann Intern Med. 2009;151:727–37. Oeffinger KC, Fontham ET, Etzioni R, Herzig A, Michaelson JS, Shih YC, Walter LC, Church TR, Flowers CR, LaMonte SJ, Wolf AM, DeSantis C, Lortet-Tieulent J, Andrews K, Manassaram-Baptiste D, Saslow D, Smith RA, Brawley OW, Wender R, American Cancer Society. Breast Cancer Screening for Women at Average Risk: 2015 guideline update from the American Cancer Society. JAMA. 2015;314 (15):1599–614. Ryerson AB, Eheman CR, Altekruse SF, Ward JW, Sherman RL, Henley SJ, Holtzman D, Lake A, Noone AM, Anderson RN, Ma J, Ly KN, Cronin KA, Penberthy L, Kohler BA. Annual report to the Nation on the Status of Cancer, 1975–2012, featuring increasing incidence of liver cancer. Cancer. 2016;122(9):1312–37. Sickles EA, D/Orsi CJ, Basett LW et al. ACR BIRADS mammography. In: ACR BI-RADS Atlas, breast imaging reporting and data system. Reston: American College of Radiology; 2013. http://www.acr.org/Qual ity-Safety/Resources/BIRADS/About-BIRADS/Howto-Cite-BIRADS Silverstein M, LAgios M, Recht A, et al. Image-detected breast cancer: state of the art diagnosis and treatment. J Am Coll Surg. 2005;201:586–97. Tabar L, Gad A, Holmberg LH, Ljungquist U, Fagerberg CJG, BAldetorp L, Grontoft O, Lundstrom B, Manson JC, Eklund G, Day NE, Pettersson F. Reduction in mortality from breast cancer after mass screening with mammography. Lancet. 1985;325(8433):829–32. Tabar L, Vitak B, Chen H, Duffy SW, Yen M, Chiang C, Krusemo UB, Tot T, Smith RA. The Swedish two-county trial twenty years later. Radiol Clin. 2000;38(4):625–51.

Benign Diseases of the Vulva Sigita Cahoon

Abstract

Contents 1

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2

2 2.1 2.2 2.3 2.4 2.5

Vulvar Dermatoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contact Dermatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lichen Simplex Chronicus . . . . . . . . . . . . . . . . . . . . . . Lichen Planus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lichen Sclerosus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Psoriasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2 2 3 3 5 7

3 Neoplasms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1 Vulvar Intraepithelial Neoplasia . . . . . . . . . . . . . . . .

8 8

4

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

9

5

Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

S. Cahoon (*) Department of Obstetrics and Gynecology, University of Southern California, Los Angeles, CA, USA e-mail: [email protected] # Springer International Publishing Switzerland 2016 D. Shoupe (ed.), Handbook of Gynecology, DOI 10.1007/978-3-319-17002-2_75-1

Many benign diseases can affect the vulva. These varied conditions can present similarly, often with pain, burning, pruritus, vaginal discharge, and dyspareunia. Physical exam findings can be nonspecific, with erythema, excoriations, and lichenification. Contact dermatitis is a frequent cause of vulvar pruritus and pain, and nearly all topical vaginal products can cause irritation. Removal of common irritants usually results in disease resolution. Lichen simplex chronicus is a condition characterized by severe pruritus leading to a persistent itch-scratch cycle. Lichen planus is a chronic, immune-mediated dermatosis presenting with pruritic papules on the vulvar skin and white lacy striae on mucosal surfaces. Lichen sclerosus is an immune-mediated disorder that results in waxy white “cigarette paper” changes to vulvar skin and can also affect the perianal region resulting in a classic “figure of eight” appearance. Patients with lichen sclerosus should be followed closely due to an increased risk of vulvar squamous cell carcinoma. Psoriasis is a dermatologic condition which can manifest as painful and pruritic vulvar erythema. Topical corticosteroids are the first-line therapy for lichen simplex chronicus, lichen planus, lichen sclerosus, and vulvar psoriasis. Vulvar intraepithelial neoplasia (VIN) is a premalignant condition which can present variably with raised or flat lesions, ranging in color from white to red or 1

2

S. Cahoon

black. It can be associated with carcinogenic human papillomavirus (HPV) infections as well as with vulvar dermatoses. All cases should be treated, and options range from excision, to laser ablation, to topical medical therapy with Imiquimod. Patients remain at risk for recurrence and require continued surveillance.

dermatoses will be reviewed here. Given that many of these conditions can become recurrent or chronic, it is important that physicians remain mindful of the potential impact on patients’ quality of life that these diseases can have and continue to work with patients to achieve good symptom control.

Keywords

Vulva • Dermatoses • Contact dermatitis • Lichen simplex chronicus • Lichen planus • Lichen sclerosus • Psoriasis • Vulvar intraepithelial neoplasia • VIN

1

Introduction

This chapter focuses on the diagnosis and management of common benign vulvar diseases. Benign vulvar disease encompasses numerous disorders, including infections, autoimmune diseases, topical irritation, dermatoses, neoplasms, cysts, and masses. Many of these varied diseases can present quite similarly. Patients often complain of vulvar irritation, burning, pain, pruritus, dysuria, dyspareunia, and vaginal discharge. On exam many vulvar conditions appear similar, with erythema, edema, signs of excoriations leading to ulcerations, and lichenification in cases of chronic scratching. This review will focus primarily on dermatoses commonly affecting the vulvovaginal region, including contact dermatitis, lichen simplex chronicus, lichen planus, and lichen sclerosus, as well as psoriasis and vulvar intraepithelial neoplasia. Diagnoses are often made clinically after assessing for a history of medication and product use and ruling out common infections including vulvovaginal candidiasis. Treatment is usually initiated empirically, and the majority of vulvar dermatoses are treated with topical corticosteroids. However clinicians should have a low threshold to obtain a biopsy in cases of unusual appearing lesions or in instances of treatment failure. Disease prevalence, common symptoms, physical exam findings, recommended diagnostics, treatments, and prognoses of common vulvar

2

Vulvar Dermatoses

2.1

Contact Dermatitis

Contact dermatitis affects approximately 15–30 % of the population (Crone et al. 2000; Moyal-Barracco and Wendling 2014). Common causes of vulvar contact dermatitis are irritants and allergens. Fragrances, topical medications, and preservatives are the most frequent culprits (Hoang et al. 2014; O’Gorman and Torgerson 2013). Acute cases of contact dermatitis can present with erythema, edema, and even vesicles or erosions. Chronic contact dermatitis often presents as erythema with lichenified or excoriated areas. Patients complain of pruritus, pain, vulvovaginal dryness, burning, and dyspareunia (Fischer et al. 1995; Hoang et al. 2014). Irritant contact dermatitis is the most common subtype. Factors including moisture from sweat or urine, heat, friction from clothing or scratching, estrogen deficiency, or enzymes can damage the skin’s barrier properties and exacerbate irritation due to topical products (Margesson 2004; MoyalBarracco and Wendling 2014). The list of potential irritants is extensive and essentially includes anything that comes in contact with the vulvovaginal region. Common irritants include soaps and detergents, dyes, perfumes, deodorants, lotions, condoms, spermicides, lubricants, sanitary products including tampons and pads, topical medications including anesthetics, antibacterials, antifungal preparations, corticosteroids, and bodily fluids including semen, saliva, and urine (ACOG 2008; Margesson 2004; Marren et al. 1992). Allergic contact dermatitis is an immunemediated type IV hypersensitivity reaction to an allergen which occurs in sensitized patients

Benign Diseases of the Vulva

(Margesson 2004; Moyal-Barracco and Wendling 2014). Numerous allergens have been identified; however, topical medications, including lidocaine, corticosteroids, and neomycin, as well as perfumes and metal such as nickel, are known to be causative agents (Marren et al. 1992; MoyalBarracco and Wendling 2014). Patch testing in conjunction with a dermatologist can be considered if the etiologic agent cannot be identified (Crone and Stewart, 2000). Patients with vulvar contact dermatitis often complain of burning or pruritus, and the course can be either acute or chronic. Poorly defined erythema is often noted on exam, and associated findings including edema, erosions or ulcers, and papules or vesicles can be found, especially in the area covered by diapers or sanitary napkins. If pustules or crusting are noted, a superimposed bacterial infection may be present. In chronic cases excoriation, changes in pigmentation and lichenification may be noted (Margesson 2004; Moyal-Barracco and Wendling 2014). On biopsy, contact dermatitis is characterized by histopathological findings of intraepidermal edema, spongiosis, acanthosis, parakeratosis, and infiltrating lymphocytes and eosinophils (Hoang and Reuter 2014; Moyal-Barracco and Wendling 2014). In cases of contact dermatitis, use of all topical products should cease, and patients should use only water to clean the vulva. Resolution of symptoms is expected once the causative factor is removed. Patients may feel greater symptomatic relief with the addition of petrolatum for moisturization, and systemic antihistamines can be added for relief of pruritus (Margesson 2004; Moyal-Barracco and Wendling 2014).

2.2

Lichen Simplex Chronicus

Lichen simplex chronicus is a common dermatosis which causes severe vulvar pruritus. Initial symptoms may have been triggered by a topical irritant, candidiasis, moisture, heat, or friction, or concurrent lichen sclerosus (ACOG 2008; Virgili et al. 1997). Subsequent scratching alleviates the itch but damages the skin, over time resulting in a

3

thickened epidermis which can appear leathery with areas of hyper- and hypopigmentation. Patients complain of a chronic recurrent pruritus, which often becomes worse at night. Frequent scratching results in erosions with accompanying pain and burning (ACOG 2008; Moyal-Barracco and Wendling 2014; Virgili et al. 2001). Lichen simplex chronicus predominantly affects the hair-bearing skin on the labia majora. Skin often appears thickened and may be erythematous, pigmented, or pale, and excoriations are frequently noted. This condition often exhibits a chronic, relapsing pattern; however, it has not been associated with an increased risk of squamous cell carcinoma (Moyal-Barracco and Wendling 2014; Stewart 2010). Potent topical corticosteroids are the mainstay of treatment for lichen simplex chronicus. Daily application for 3–4 weeks is recommended initially, followed by a taper or switch to a less potent topical steroid for the following 3–6 months to prevent recurrence (Lynch 2004; Moyal-Barracco and Wendling 2014). Topical calcineurin inhibitors such as tacrolimus or pimecrolimus ointment applied once or twice daily for 6 weeks, then tapered, are second line therapies for patients who do not tolerate or do not respond to topical corticosteroids (Goldstein et al. 2007; MoyalBarracco and Wendling 2014).

2.3

Lichen Planus

Lichen planus is an inflammatory condition which can affect the vulvovaginal region as well as oral mucosa. The epidemiology of lichen planus is not well studied, but prevalence estimates range from 0.22–5 %, affecting both males and females (Gorouhi et al. 2014; Shiohara and Kano 2008). Vulvovaginal lichen planus most often affects peri- or postmenopausal women, though there have been reports of affected children (Gorouhi et al. 2014; McPherson and Cooper 2010). Lichen planus is thought to be a T-cell-mediated inflammatory autoimmune disease. Studies have suggested possible genetic susceptibility as well as environmental triggers associated with lichen planus. Associations have also been noted

4

between lichen planus and coexisting stress, anxiety, and depression as well as hepatitis C infection, other autoimmune illnesses, dyslipidemia, and other viral infections (Gorouhi et al. 2014; Shengyuan et al. 2009; Vallejo et al. 2001). Several subtypes of lichen planus have been described, based on morphology as well as the primary site of involvement (Gorouhi et al. 2014). Oral involvement is the most common subtype of mucosal lichen planus, with vulvovaginal involvement being the next most common and esophageal, laryngeal, and conjunctival involvement being rare (Eisen 1999; Gorouhi et al. 2014). In addition to affecting the mucous membranes of the mouth, vulvovaginal and anogenital region, gastro intestinal tract, conjunctiva, and mouth, lichen planus can affect the skin, nails, and hair. Among patients with vulvar lichen planus, 43–100 % also have oral lesions, and 25–57 % of patients who initially present for oral lesions are found to also have vulvar lesions (Belfiore et al. 2006; Eisen 1999; Gorouhi et al. 2014). Approximately 17–22 % of patients with vulvovaginal disease will also have skin lesions (Gorouhi et al. 2014, Simpson et al. 2012). Lichen planus can have a variable appearance. Classic dermatologic presentations include the “6 Ps”: “Pruritic, Purple, Polygonal, Planar, Papules, and Plaques” (Gorouhi et al. 2014; Lazar and Murphy 2009). When present on mucosal surfaces, the classic description is of white, lacy, or fernlike striae known as Wickham striae. Pruritic papules ranging in color from pink to violaceous can also be observed (ACOG 2008; Rogers and Eisen 2003). Vulvovaginal lichen planus has three major subtypes: erosive, papulosquamous, and hypertrophic, with erosive being the most common (Gorouhi et al. 2014). Erosive vulvar lichen planus affects only the mucous membranes and can lead to vulvovaginal scarring, agglutination and resorption of the labia minora and clitoral hood, formation of synechiae, introital stenosis, and vaginal obliteration in extreme cases (Fig. 1). Affected women often complain of dyspareunia, burning, vaginal discharge, and postcoital bleeding and can have significant psychological

S. Cahoon

Fig. 1 A case of erosive lichen planus with early vaginal agglutination. (Reprinted from American Journal of Obstetrics and Gynecology, Vol 214, Issue 2, Fairchild PS, Haefner HK, Surgical management of vulvovaginal agglutination due to lichen planus, 289.e1-2, 2016, with permission from Elsevier)

distress due to the condition (Gorouhi et al. 2014; Lewis 1998). Vaginal pH is frequently increased to 5 or 6 in lichen planus, and a wet mount often reveals numerous inflammatory cells as well as immature parabasal and basal epithelial cells (ACOG 2008; Rogers and Eisen 2003). Biopsy of the lesion confirms the diagnosis, and immunofluorescence staining can be used to distinguish between lichen planus and other similarly presenting immunobullous diseases. A dense continuous band of infiltrating lymphohystiocytes at the dermal-epidermal junction in the upper dermis is the classic histologic finding (Fung 2016; Gorouhi et al. 2014; Ramer et al. 2003). Other findings include hyperkeratosis, areas of wedgeshaped hypergranulosis, spongiosis in the spinous layer, squamatization, as well as elongated and rounded rete ridges. However, erosive vulvovaginal lichen planus can often have nonspecific histopathological findings, lacking the classic markers (Fung 2016; Gorouhi et al. 2014). Topical application of super potent corticosteroids is the first-line treatment of vulvovaginal lichen planus with up to 55 % of patients experiencing symptomatic improvement with topical corticosteroids alone, while some patients will require oral therapy with prednisolone or a combination of topical and oral corticosteroids

Benign Diseases of the Vulva

(Schlosser and Microwski 2015). Topical corticosteroid therapy has been shown to be effective in treating symptoms including burning, pruritus, discharge, and dyspareunia; however the symptoms caused by vaginal stenosis were not significantly improved by topical corticosteroid therapy (Anderson et al. 2002; Schlosser and Microwski 2015). A variety of systemic immunomodulators have been studied with limited benefits observed and often with significant adverse effects noted. As such, systemic treatments are often limited to use for severe disease or refractory cases (Lotery and Galask 2003; Schlosser and Microwski 2015). Vaginal dilators can be helpful in both treatment and prevention of adhesion and synechiae formation, which can occur in cases of inflamed, ulcerated vaginal mucosa. Dilators are often used in conjunction with topical corticosteroids, estrogen creams, or topical calcineurin inhibitors and can be used twice daily initially, then taped down to three times per week. Dilator therapy has been shown to be beneficial in helping patients resume sexual intercourse (Lotery and Galask 2003; Schlosser and Microwski 2015). In addition to dilators, use of vaginal hydrocortisone suppositories at a dose of 25 mg, initially used twice daily, then tapered down to twice weekly maintenance therapy, has been demonstrated to be effective for controlling symptoms of lichen planus (Anderson et al. 2002). If synechiae do form, surgical therapy should not be attempted until the inflammation due to lichen planus is well controlled. Lysis of adhesions and careful tissue dissection should be performed under general anesthesia, and vaginal dilators along with topical corticosteroids, with the addition of topical estrogen therapy in certain cases, must be used during the healing process to prevent scarring and additional adhesion formation (Kortekangas-Savolainen and Kiilholma 2007; Schlosser and Microwski 2015). Regarding prognosis, cutaneous lichen planus can resolve in about 6 months to 1 year; however some types of oral lichen planus can become chronic and progressive. Erosive lichen planus, which is the most common subtype affecting the vulvovaginal region, can display a chronic, waxing and waning, cyclic pattern. Risk of

5

malignant transformation of lichen planus has been suggested, but studies have been inconclusive, and further study is required (Cooper et al. 2004; Gorouhi et al. 2014).

2.4

Lichen Sclerosus

Lichen sclerosus is one of the most common inflammatory dermatoses of the vulva. It is a chronic autoimmune inflammatory condition affecting the vulvovaginal region, thought to be mediated by lymphocytes. It is more common in women than men (Schlosser and Microwski 2015). Lichen sclerosus exhibits a bimodal age distribution. It occurs commonly in prepubertal girls with a prevalence of 1 in 900 and a mean onset at 5 years of age. Perimenopausal to postmenopausal women are usually affected between ages 45 and 55; however, it can also present in women of reproductive age. There is often a delay in diagnosis of approximately 2 years in young patients and 5–15 years in older women. Cutaneous lesions outside of the genital region can be present in 6–15 % of patients affected by lichen sclerosus (Cooper et al. 2004; Schlosser and Microwski 2015). Reports suggest a familial predisposition, though the mode of inheritance has not been identified. Several genes have been studied with possible protective as well as predisposing genes under investigation. There is also a significant link between lichen sclerosus and autoimmune disorders, including autoimmune thyroid disease, as well as vitiligo, alopecia areata, pernicious anemia, and diabetes mellitus, among others (Meyrick et al. 1988; Schlosser and Microwski 2015). Additionally the role of estrogen and androgens in lichen sclerosus has been investigated but remains a subject for further study (Schlosser and Microwski 2015; Taylor et al. 2008). Patients commonly present with vulvar pruritus which can be more severe at night. They can develop painful vulvar and perianal erosions and fissures which lead to dysuria, dyspareunia, and dyschezia. Patients can develop urinary retention and constipation secondary to pain. As such, stool

6

retention is commonly the presenting symptom of lichen sclerosus in young girls. Disease progression and labial agglutination are concerns for young girls diagnosed with lichen sclerosus, and abnormal voiding with weak urinary stream can result from labial agglutination (Powell and Wojnarowska 2001; Schlosser and Microwski 2015). Lichen sclerosus typically affects the labia majora and minora, clitoris and clitoral hood, and the posterior fourchette. The perianal area is affected in 30–60% of women, often with a classic hourglass or “figure of eight” pattern when both the vulva and perianal region are affected. The vaginal mucosa is usually spared. A white, hypopigmented vulvar skin with a waxy or wrinkled texture, classically described as appearing like “cigarette paper,” is the typical clinical exam finding. Patients may also have fissures, erosions, and ulceration as well as hyperkeratosis or purpura, and clitoral hood edema (Schlosser and Microwski 2015; Virgili et al. 2014). Scarring can occur to varying degrees, most commonly affecting the clitoral hood and labia minora as well as the posterior fourchette and introitus (Fig. 2). Resorption of the labia minora has been observed, and scarring can result in stenosis of the vaginal introitus or urethral meatus to the point that intercourse and voiding are impaired. Lichen sclerosus can also result in areas of hyperpigmentation which can be difficult to differentiate from potential melanoma, and as such, biopsy is recommended. Extragenital lesions in cutaneous lichen sclerosus can also be observed and predominantly affect the trunk, though rare cases affecting the face, scalp, mouth, and nails have been reported (Schlosser and Microwski 2015). Treatment with topical corticosteroids is recommended if clinical signs are suggestive of lichen sclerosus. Biopsy is indicated if lesions do not respond to topical therapy; if there is concern for malignancy, including melanoma; or if ulcerated lesions are present (Schlosser and Microwski 2015). Hyperkeratosis, an atrophic epidermis, loss of rete ridges, and band-like lymphocytic infiltrate are classic histopathological signs of lichen sclerosus (Schlosser and Microwski 2015).

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Fig. 2 Scarring of the vulva from lichen sclerosus. (Reprinted from the American Journal of Obstetrics and Gynecology, Vol 196, Issue 2. Goldstein AT, Burrows LJ. Surgical treatment of clitoral phimosis caused by lichen sclerosus, 126.e1-4, 2007, with permission from Elsevier)

Lichen sclerosus is associated with a nearly 300 times increased risk of development of vulvar squamous cell carcinoma, with a period of 4–10 years between diagnosis of lichen sclerosus and diagnosis of vulvar squamous cell carcinoma. It is unclear if successful treatment of vulvar lichen sclerosus decreases the risk of vulvar squamous cell carcinoma; however, carcinoma is seen typically in elderly patients and has not been reported in pediatric patients. Age greater than 70 years has been associated with treatment failure and disease recurrence (Carli et al. 1995; Schlosser and Microwski 2015). Topical treatments in ointment formulations are preferable as they have improved potency and absorption. Ointment formulations also have emollient properties and are less likely to contain vulvar irritants including preservatives, alcohol, and propylene glycol. Topical superpotent corticosteroids are the mainstay of therapy for vulvar lichen sclerosus, and clobetasol propionate 0.05 % ointment has demonstrated significant efficacy in randomized trials (Schlosser and

Benign Diseases of the Vulva

Microwski 2015). An initial twice-daily application is recommended. As symptoms improve, the application can be tapered and a less potent corticosteroid can be used. Maintenance therapy over a period of 6–12 months is commonly recommended. Side effects of long-term topical corticosteroid therapy include atrophy and thinning of the skin as well as development of striae and telangiectasias. Long term use can also increase susceptibility to superimposed candida infections and can be associated with reactivation of herpes simplex viral infection (Schlosser and Microwski 2015). Topical estrogen therapy may be beneficial in postmenopausal patients who experience significant atrophy with topical corticosteroid use. In addition, oral antifungals and antihistamines can be used to combat side effects rather than utilizing their topical formulations. Topical creams may exacerbate symptoms due to their potential to act as topical irritants. Second-line therapy includes a twice-daily application of topical calcineurin inhibitors, such as tacrolimus 0.1 % ointment, which may be chosen for use in cases which demonstrate a lack of response to topical corticosteroids or in patients who develop side effects from corticosteroid therapy; however, their use has been associated with a reportedly increased risk of dermatologic malignancies (Fischer and Bradford 2007; Schlosser and Microwski 2015). Systemic retinoid therapy such as acitretin can be useful for patients with hyperkeratotic or hypertrophic vulvovaginal lichen sclerosus refractory to superpotent topical corticosteroids. Oral acitretin regimens of 20–30 mg per day over a course of 16 weeks have been studied; however, as retinoids are teratogenic, they should not be used in women who might become pregnant. There is evidence that acitretin can reduce the incidence of squamous cell carcinoma in at-risk patients such as those who have undergone organ transplantation. It is suggested that there may also be a similar protective effect against squamous cell carcinoma in patients with lichen sclerosus; however, further study into this area is necessary (Bousema et al. 1994; Schlosser and Microwski 2015).

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Surgical therapy for severe vulvar and introital scarring affecting function should only be undertaken after resolution of inflammation with at least a 6-month, disease-free period. Superpotent topical corticosteroids must be used to prevent a postoperative lichen sclerosus recurrence due to the Koebner phenomenon (the development of new lesion areas secondary to trauma) as well as to prevent recurrence of labial agglutination and stenosis of the introitus (Schlosser and Microwski 2015). Additional supportive measures can be undertaken to help manage the pruritus, pain, and irritation. Patients should wash the vulvar area with water only, then pat dry and avoid rubbing. Sitz baths as well as ice packs and cool compresses can be utilized to ease burning symptoms. Petroleum jelly or A and D ointment can act as soothing emollients and decreases friction in the affected areas. Some patients develop a secondary vulvodynia which may be treated with topical 5 % lidocaine ointment, while other patients may benefit from systemic treatments for neuropathic pain including amitriptyline and gabapentin (Schlosser and Microwski 2015). In most patients disease control should be attained within 3–4 months. Patients should then be followed every 6–12 months to monitor for disease recurrence as well as for the development of atrophy, scarring, or potential malignant changes. Cases that do not improve despite appropriate therapy should be reassessed, and alternate diagnoses such as contact dermatitis, a superimposed infectious process, or undiagnosed malignancy should be considered and further evaluated. Suspicious or unresponsive areas must be biopsied. A multidisciplinary approach should be considered for patients with refractory or multifocal disease as well as to help manage common psychological effects secondary to severe or persistent disease (Schlosser and Microwski 2015).

2.5

Psoriasis

Vulvar psoriasis affects approximately 5 % of women and 15 % of girls with vulvar dermatosis.

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This chronic dermatosis is generally diagnosed clinically and has several presentations, including the classic form with well-demarcated thick scaly plaques, discrete pustules in the pustular form, or as erythema with minimal scaling in the inverse form which presents predominantly in the anogenital area and in flexural folds. Vulvar psoriasis affects the hair-bearing cutaneous regions of the vulva, especially the mons pubis and labia majora, and generally spares the mucosa (Hoang et al. 2014; Kapila et al. 2012). Biopsy frequently is nondiagnostic, however areas of parakeratosis with neutrophils, known as Munro’s microabscesses, as well as spongiosis are a common finding (Hoang et al. 2014). Treatment of vulvar psoriasis should focus on relief of symptoms and the minimization of Koebnerization. Use of soothing emollients and avoidance of topical irritants is recommended. Flares can be managed with topical mid- to highpotency topical corticosteroids. Topical corticosteroid therapy can then be followed with topical tar preparations, retinoids, calcineurin inhibitors, and low potency topical corticosteroids for maintenance therapy. In rare cases of severe refractory disease, systemic therapy with methotrexate may be considered; however limited efficacy has been demonstrated with this treatment (Kapila et al. 2012).

3

Neoplasms

3.1

Vulvar Intraepithelial Neoplasia

Vulvar intraepithelial neoplasia (VIN) is a premalignant squamous lesion with a peak incidence of 5 per 100,000 women which is observed primarily in Caucasian women in their forties (Preti et al. 2014). VIN was historically divided into three grades. However, after studies revealed that VIN 1 was predominantly a self-limited disease due to human papillomavirus (HPV) infection, the International Society for the Study of Vulvovaginal Disease (ISSVD) revised the classification system in 2004 such that now only a high-grade disease is classified as VIN, and what was previously called VIN 1 is now classed and

treated as condyloma (Sideri et al. 2005). VIN is now subdivided into usual-type VIN and differentiated VIN. Usual-type VIN is the most common type and is linked to carcinogenic HPV genotypes as well as states associated with persistent HPV infection including being immunocompromised and smoking. This grouping includes warty, basaloid, and mixed VIN. Differentiated VIN accounts for only 2–5 % of cases of VIN. It is more commonly associated with vulvar dermatoses such as lichen sclerosus, a risk factor for squamous cell carcinoma, and is not associated with HPV infection (Preti et al. 2014; Sideri et al. 2005). There is no screening test specifically for VIN, which is diagnosed clinically. VIN has a variable presentation. Color can range from gray or white to red, brown, or even black. The majority of lesions are raised (Fig. 3); however, they can be flat as well. Vulvar colposcopy can be used to aid visual inspection of the area after applying cotton pads soaked with 3–5 % acetic acid. Any suspicious or pigmented lesion, any areas refractory to treatment, or lesions found in a postmenopausal woman should be biopsied (ACOG 2011; Preti et al. 2014). All cases of VIN should be treated. If malignancy is suspected, VIN lesions should be surgically managed with wide local excision, using either a cold knife or loop electrode excision. In rare cases, such as in immunocompromised women with extensive disease, a skinning vulvectomy may be considered. Gross margins of 0.5–1 cm are preferred when performing wide local excision, though adjustments can be made to avoid structures such as the urethra, clitoris, and anus. Negative margins on pathologic examination are preferred, however risk of recurrence remains. If suspicion for malignancy is low, CO2 laser ablation or topical therapy with imiquimod 5 % for 12–20 weeks, cidofovir 1 %, or photodynamic therapy in conjunction with the photosensitizing agent 5-aminolevulinic acid (ALA) can be utilized (ACOG 2011; Preti et al. 2014). The quadrivalent HPV vaccine reduces the risk of developing VIN as it confers protection from HPV genotypes 6, 11, 16, and 18 (Muñoz et al. 2010). Smoking cessation should be

Benign Diseases of the Vulva

9

Fig. 3 (a) Vulvar SCC on the left labium minus, 9 mm diameter and with a depth of invasion of 4 mm. (b) Lesion on the right labium minus, which turned out to be VIN on histologic examination. (Reprinted from American Journal of Obstetrics and Gynecology, Vol 203, Issue 2, Simons M,

Van De Nieuwenhof HP, Van Der Avoort IA, Bulten J, De Hullu JA, A patient with lichen sclerosus, Langerhans cell histiocytosis, and invasive squamous cell carcinoma of the vulva, e7-10, 2010, with permission from Elsevier)

stressed, as it is associated with usual-type VIN, and the diagnosis and treatment of vulvar dermatoses may reduce the risk of differentiated VIN and development of squamous cell carcinoma (ACOG 2011). Despite treatment, recurrence rates can be as high as 30–50 %, and rates are even higher if positive margins were noted on excision. After treatment, patients should be re-examined at 6 months and 1 year and can then resume yearly monitoring if no new lesions are noted (ACOG 2011), though some studies suggest following patients more closely, with follow-up every 3 months for the first 2–3 years, then every 6 months subsequently (Preti et al. 2014).

examination are essential, as well as an awareness of the wide range of potential diagnoses. The first steps in evaluation often involve assessment for and removal of potential irritants as well as testing for suspected infections. Discontinuation of topical products is often a crucial component in the management of symptoms, as nearly any product in contact with the vulvovaginal region has the potential to cause irritation. The common dermatoses reviewed in this chapter, including contact dermatitis, lichen simplex chronicus, lichen planus, lichen sclerosus, and psoriasis, are often treated with topical corticosteroids as a first-line therapy. However, providers should have a low threshold to obtain a biopsy for tissue diagnosis in refractory cases or unusual presentations in order to rule out underlying malignancy or alternate diagnoses. In severe and chronic cases of vulvar dermatoses, a long-term follow-up is often indicated to monitor for disease recurrence or progression, potential malignant transformation, as well as

4

Conclusion

As reviewed above, numerous conditions can manifest as vulvar disease. When evaluating vulvar complaints, a thorough history and physical

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S. Cahoon

vulvovaginal scarring, labial agglutination, or introital stenosis. Cases of VIN must be monitored closely due to high rates of recurrence as well as risk of malignancy. Depending on the etiology of the vulvar disease, patients may have multifocal disease affecting more than one organ system. As such, a multidisciplinary approach should be taken to coordinate therapy. Additionally, patients can experience significant morbidity from vulvar dermatoses, which may have wide impacts on various activities ranging from normal sexual activity to basic voiding function. These morbidities can have significant psychological impacts on patients which should be addressed as a component of comprehensive gynecologic care.

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Cross-References

▶ Benign Vulvar and Vaginal Pathology ▶ Diagnosis and Treatment of Vulvovaginitis ▶ Management of Chronic Recurrent Vulvovaginitis ▶ Management of Vaginal and Vulvar Lesions in the Older Woman ▶ Pre-invasive Epithelial Disease of the Vulvar

References American College of Obstetricians and Gynecologists. Diagnosis and management of vulvar skin disorders. ACOG Practice Bulletin No. 93. Obstet Gynecol. 2008;111:1243–53. American College of Obstetricians and Gynecologists. Management of vulvar intraepithelial neoplasia. ACOG Committee Opinion No. 509. Obstet Gynecol. 2011;118:1192–4. Anderson M, Kutzner S, Kaufman RH. Treatment of vulvovaginal lichen planus with vaginal hydrocortisone suppositories. Obstet Gynecol. 2002;100:359–62. Belfiore P, Di Fede O, Cabibi D, Campisi G, Amarù GS, De Cantis S, Maresi E. Prevalence of vulval lichen planus in a cohort of women with oral lichen planus: an interdisciplinary study. Br J Dermatol. 2006;155(5):994–8. Bousema MT, Romppanen U, Geiger JM, Baudin M, Vähä-Eskeli K, Vartiainen J, Vuopala S. Acitretin in the treatment of severe lichen sclerosus et atrophicus of the vulva: a double-blind, placebo-controlled study. J Am Acad Dermatol. 1994;30(2 Pt 1):225–31.

Carli P, Cattaneo A, De Magnis A, Biggeri A, Taddei G, Giannotti B. Squamous cell carcinoma arising in vulval lichen sclerosus: a longitudinal cohort study. Eur J Cancer Prev. 1995;4:491–5. Cooper SM, Gao XH, Powell JJ, Wojnarowska F. Does treatment of vulvar lichen sclerosus influence its prognosis? Arch Dermatol. 2004;140(6):702–6. Crone AM, Stewart EJC, Wojnarowska F, Powell SM. Aetiological factors in vulvar dermatitis. J Eur Acad Dermatol Venereol. 2000;14(3):181–6. Eisen D. The evaluation of cutaneous, genital, scalp, nail, esophageal, and ocular involvement in patients with oral lichen planus. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1999;88(4):431–6. Fairchild PS, Haefner HK. Surgical management of vulvovaginal agglutination due to lichen planus. Am J Obstet Gynecol. 2016;214(2):289.e1–2. Fischer G, Bradford J. Topical immunosuppressants, genital lichen sclerosus and the risk of squamous cell carcinoma: a case report. J Reprod Med. 2007;52:329–31. Fischer G, Spurrett B, Fischer A. The chronically symptomatic vulva: aetiology and management. Br J Obstet Gynaecol. 1995;102:773–9. Fung MA. Inflammatory diseases of the dermis and epidermis. In: Busam KJ, editor. Dermatopathology. 2nd ed. Philadelphia: Saunders Elsevier; 2016. p. 11–78. Goldstein AT, Burrows LJ. Surgical treatment of clitoral phimosis caused by lichen sclerosus. Am J Obstet Gynecol. 2007;196(2):126.e1–4. Goldstein AT, Parneix-Spake A, McCormick CL, Burrows LJ. Pimecrolimus cream 1% for treatment of vulvar lichen simplex chronicus: an open-label, preliminary trial. Gynecol Obstet Invest. 2007;64:180–6. Gorouhi F, Davari P, Fazel N. Cutaneous and mucosal lichen planus: a comprehensive review of clinical subtypes, risk factors, diagnosis, and prognosis. Scientific World Journal. 2014;2014(2):1–22. Hoang MP, Reuter J, Papalas J, Edwards L, Selim M. Vulvar inflammatory dermatoses: an update and review. Am J Dermatopathol. 2014;36(9):689–704. Kapila S, Bradford J, Fischer G. Vulvar psoriasis in adults and children: a clinical audit of 194 cases and review of the literature. J Low Genit Tract Dis. 2012;16:364–71. Kortekangas-Savolainen O, Kiilholma P. Treatment of vulvovaginal erosive and stenosing lichen planus by surgical dilatation and methotrexate. Acta Obstet Gynecol Scand. 2007;86(3):339–43. Lazar AJF, Murphy GF. The Skin. In: Kumar V, Abbas A, Aster J, editors. Robbins & Cotran pathologic basis of disease. 8th ed. Philadelphia: Saunders; 2009. p. 1141–78. Lewis FM. Vulval lichen planus. Br J Dermatol. 1998;138 (4):569–75. Lotery HE, Galask RP. Erosive lichen planus of the vulva and vagina. Obstet Gynecol. 2003;101(5):1121–5. Lynch P. Lichen simplex chronicus (atopic/ neurodermatitis) of the anogenital region. Dermatol Ther. 2004;17:8–19.

Benign Diseases of the Vulva Margesson LJ. Contact dermatitis of the vulva. Dermatol Ther. 2004;17(1):20–7. Marren P, Wojnarowska F, Powell S. Allergic contact dermatitis and vulvar dermatoses. Br J Dermatol. 1992;126(1):52–6. McPherson T, Cooper S. Vulval lichen sclerosus and lichen planus. Dermatol Ther. 2010;23(5):523–32. Meyrick TRH, Ridley CM, McGibbon DH, Black MM. Lichen sclerosus et atrophicus and autoimmunity – a study of 350 women. Br J Dermatol. 1988;118 (1):41–6. Moyal-Barracco M, Wendling J. Vulvar dermatosis. Best practice and research. Clin Obstet Gynaecol. 2014;28 (7):946–58. Muñoz N, Kjaer SK, Sigurdsson K, Iversen OE, Hernandez-Avila M, Wheeler CM, Perez G, Brown DR, Koutsky LA, Tay EH, Garcia PJ, Ault KA, Garland SM, Leodolter S, Olsson SE, Tang GW, Ferris DG, Paavonen J, Steben M, Bosch FX, Dillner J, Huh WK, Joura EA, Kurman RJ, Majewski S, Myers ER, Villa LL, Taddeo FJ, Roberts C, Tadesse A, Bryan JT, Lupinacci LC, Giacoletti KE, Sings HL, James MK, Hesley TM, Barr E, Haupt RM. Impact of human papillomavirus (HPV)-6/11/16/18 vaccine on all HPV-associated genital diseases in young women. J Natl Cancer Inst. 2010;102:325–39. O Gorman SM, Torgerson RR. Allergic contact dermatitis of the vulva. Dermatitis. 2013;24(2):64–72. Powell J, Wojnarowska F. Childhood vulvar lichen sclerosus: an increasingly common problem. J Am Acad Dermatol. 2001;44:803–6. Preti M, Scurry J, Marchitelli CE, Micheletti L. Vulvar intraepithelial neoplasia. Best Pract Res Clin Obstet Gynaecol. 2014;28(7):1051–62. Ramer MA, Altchek A, Deligdisch L, Phelps R, Montazem A, Buonocore PM. Lichen planus and the vulvovaginal-gingival syndrome. J Periodontol. 2003;74(9):1385–93. Rogers 3rd RS, Eisen D. Erosive oral lichen planus with genital lesions: the vulvovaginal-gingival syndrome and the peno-gingival syndrome. Dermatol Clin. 2003;21(1):91–8. Schlosser BJ, Microwski GW. Lichen sclerosus and lichen planus in women and girls. Clin Obstet Gynecol. 2015;58(1):125–42. Shengyuan L, Songpo Y, Wen W, Wenjing T, Haitao Z, Binyou W. Hepatitis C virus and lichen planus: a

11 reciprocal association determined by a meta-analysis. Arch Dermatol. 2009;145(9):1040–7. Shiohara T, Kano Y. Lichen planus and lichenoid dermatoses. In: Bolognia JL, Jorizzo J, Rapini RP, editors. Dermatology. 3rd ed. New York: Mosby Elsevier; 2008. p. 183–202. Sideri M, Jones RW, Wilkinson EJ, Preti M, Heller DS, Scurry J, Haefner H, Neill S. Squamous vulvar intraepithelial neoplasia: 2004 modified terminology, ISSVD Vulvar Oncology Subcommittee. J Reprod Med. 2005;50(11):807–10. Simons M, Van De Nieuwenhof HP, Van Der Avoort IA, Bulten J, De Hullu JA. A patient with lichen sclerosus, Langerhans cell histiocytosis, and invasive squamous cell carcinoma of the vulva. Am J Obstet Gynecol. 2010;203(2):e7–10. Simpson RC, Littlewood SM, Cooper SM, Cruickshank ME, Green CM, Derrick E, Yell J, Chiang N, Bell H, Owen C, Javed A, Wilson CL, McLelland J, Murphy R. Real-life experience of managing vulval erosive lichen planus: a case-based review and U.K. multicentre case note audit. Br J Dermatol. 2012;167(1):85–91. Stewart K. Clinical care of vulvar pruritus, with emphasis on one common cause, lichen simplex chronicus, dermatologic clinic, 2010:28(4):669–680. Taylor AH, Guzail M, Al-Azzawi F. Differential expression of oestrogen receptor isoforms and androgen receptor in the normal vulva and vagina compared with vulval lichen sclerosus and chronic vaginitis. Br J Dermatol. 2008;158:319–28. Vallejo MJ, Huerta G, Cerero R, Seoane JM. Anxiety and depression as risk factors for oral lichen planus. Dermatology. 2001;203(4):303–7. Virgili A, Corazza M, Bacilieri S, Califano A. Contact sensitivity in vulval lichen simplex chronicus. Contact Dermatitis. 1997;37(6):296–7. Virgili A, Bacilieri S, Corazza M. Managing vulvar lichen simplex chronicus. J Reprod Med. 2001;46:343–6. Virgili A, Borghi A, Toni G, Minghetti S, Corazza M. Prospective clinical and epidemiologic study of vulvar lichen sclerosus: analysis of prevalence and severity of clinical features, together with historical and demographic associations. Dermatology. 2014;228(2):145–51.

Management of Vulvodynia Martha Goetsch

Abstract

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2

2 Nomenclature of Vulvodynia . . . . . . . . . . . . . . . . . . 2.1 Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2 2

3

Taking a Patient History . . . . . . . . . . . . . . . . . . . . . .

4

4

Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . .

4

5

Physical Examination of Vulvodynia . . . . . . . . .

5

6

Histology and Physiology of Vulvodynia . . . . .

6

7

Population Findings in Vulvodynia . . . . . . . . . .

6

Theories of Causation of Localized Provoked Vulvodynia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.1 Low Estrogen as a Cause of Vestibulodynia . . .

7 8

1

8

9

Vulvodynia’s Place in the History of Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

9

10

Comorbidities with Vulvodynia . . . . . . . . . . . . . . . 10

11

Therapeutic Efforts: General Points . . . . . . . . . 11

12

Specific Therapies for Vulvodynia . . . . . . . . . . . . 11

13

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

14

Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

M. Goetsch (*) Center for Women’s Health, Oregon Health & Science University, Portland, OR, USA e-mail: [email protected] # Springer International Publishing Switzerland 2016 D. Shoupe (ed.), Handbook of Gynecology, DOI 10.1007/978-3-319-17002-2_76-1

Vulvodynia is the term assigned when a woman has a chronic condition of pain in the inner or outer vulva that has lasted longer than 6 months and cannot be explained by a chronic skin condition or infection. The general diagnostic term vulvodynia is used to describe two subtypes of vulvar pain. One is localized to the vestibule of the vulva, generally is painful only when touched, and is the most common explanation for repeated pain at initial vaginal penetration. It is the most common form of vulvodynia, termed localized provoked vulvodynia (LPV). The second form of vulvodynia causes a constant burning sensation in areas of the outer vulva, whether touched or not, and is less common. Vestibular vulvodynia is often associated with tight pelvic floor muscles and was initially described in 1861 by Marion Sims and named vaginismus. Localized provoked vulvodynia has characteristic histologic findings of nerve hyperplasia and an infiltrate of lymphocytes and mast cells. A multitude of therapies has been tried for both types of vulvodynia, but careful comparative studies have been few. Because of the significant associated problem of dyspareunia, this condition has very deleterious effects on intimacy, development of relationships, and self-image. Therapeutic efforts should be multidisciplinary, including gynecologic assessment and treatment of local skin pain, physical therapy to retrain tight pelvic floor 1

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muscles, and skilled mental health counseling for emotional difficulties. Keywords

Vulvodynia • Localized provoked vulvodynia • Generalized vulvodynia • Dyspareunia • Female sexual pain • Chronic vulvar pain condition

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Introduction

Vulvodynia has been a puzzling disorder with a checkered history of varying understandings, explanations, therapies, and research initiatives. It may be one of the most interesting of misunderstood medical conditions. Because localized provoked vulvodynia is a cause of repeatedly painful sexual intercourse affecting 12–14 % of women in the premenopausal population, all care practitioners who see women should be conversant about vulvodynia and vulvar conditions in general. With steadily increasing ease of finding information using electronic search engines, more and more women are assigning a potential name to their own pain condition and then requesting help from their gynecologist. Additionally, pressure at the National Institutes of Health (NIH) to increase vulvodynia research funding has been increasing. Finally, as the population bubble of older women swells and as women have increasingly stopped using supplemental estrogen in postmenopause, there is evidence that the very prevalent problem of postmenopausal dyspareunia is a form of localized provoked vulvodynia.

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Nomenclature of Vulvodynia

In 2015 three specialty organizations produced a consensus document of terminology and classifications of persistent vulvar pain. The organizations were the International Society for the Study of Vulvovaginal Disease (ISSVD), the International Society for the Study of Women’s Sexual Health (ISSWSH), and the International Pelvic Pain Society (IPPS).

“Vulvodynia is vulvar pain of at least 3-month duration, without clear identifiable cause, which may have potential associated factors.” Categories are further defined by descriptors: • Localized (e.g., vestibulodynia, clitorodynia) or generalized or mixed (localized and generalized) • Provoked (e.g., insertional, contact) or spontaneous or mixed (provoked and spontaneous) • Onset (primary or secondary) • Temporal pattern (intermittent, persistent, constant, immediate, delayed) Associated factors are often “musculoskeletal,” such as pelvic floor myalgia; “psychosocial,” with feelings of inadequacy, grief, anxiety; or “comorbidities” such as painful bladder syndrome or fibromyalgia. Allodynia is a painful sensation from a stimulus that should be painless. This is in contrast to hyperalgesia, which is enhanced intensity of a pain sensation. The most common form of vulvodynia is localized provoked, and it is often referred to as vestibulodynia since it is localized to the vulvar vestibule. Studies have suggested that this form occurs in 90 % of those diagnosed with vulvodynia. The less common form of vulvodynia is generalized vulvodynia, which usually has a spontaneous and constant level of pain and describes 10 % of those with vulvodynia (Lamvu et al. 2015).

2.1

Anatomy

The vulva has distinct zones because of embryologic origins. The tissues comprising labia majora and minora are derived from ectodermal tissues and have an array of potential problems that must be ruled out in an assessment of vulvar pain. For instance, the dermatosis of lichen sclerosus is an inflammatory disorder that affects the ectodermal skin primarily. The vulvar vestibule is a second distinct zone comprising mucosa from the inner labia minora to

Management of Vulvodynia

Fig. 1 The vestibule is the area medial to Hart’s line, seen here as the demarcation between somewhat ruddy coloration and a pale zone along the inner surface of the labia minora. The lateral labial tissue is of ectodermal origin and the pale zone is endodermal in origin. The vestibule extends from Hart’s line to hymen and fourchette to clitoris (Goetsch 1996)

the hymen and from just under the clitoris to the fourchette. This introital zone is endodermal in embryologic origin, perforated by the urethra and related to the bladder in development. The demarcation of the ectodermal and endodermal zones is Hart’s line, named after an Edinburgh gynecologist in the 1880s who noted the visual landmarks. Figure 1 shows these landmarks with Hart’s line visible midway along the inner aspect of the labia minora. This vestibular zone of mucosa forms the entryway to the vagina, and the vestibule is supposed to be sensitive in a positive way, but has a capacity to develop localized exquisite tenderness, i.e., vulvar vestibulodynia, or become very symptomatic from an inflammatory trigger such as Candida. The structure representing the innermost point of the vulva is the hymen where the vaginal mucosa begins, and the vaginal mucosa is mesodermal in origin. Therefore, within about 1.5 in., three embryologic layers are represented. Each zone has different and unique tissue properties including different nerve sensitivities. Some systems of nomenclature refer to vulvar pain as a subcategory of pelvic pain. This can be confusing since the common clinical problem associated with vulvodynia is pain with intercourse and specifically pain at first penetration. Vulvodynia is vulvar pain, not deeper pain from

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the pelvis. Dyspareunia is a term derived from the Greek words for “badly mated”. It is important to distinguish entry dyspareunia, which is pain occurring at initial penetration, from deep dyspareunia, associated with deep penetration of the vagina. The vagina itself does not usually account for pain in various female genital pain syndromes. Compared to the severity of typical introital symptoms of pain or itching or the severity of upper tract pain from uterine/tubal/abdominal structures, the vagina is relatively nontender. Structures just deep to the vaginal walls can be tender and will be discussed below. Causes of deep pelvic pain can be conditions such as adenomyosis, endometriosis, or pelvic scarring from prior infections or surgery. Vulvar pain might reasonably be segregated from pelvic pain in pain classifications. Another consideration regarding nomenclature is the difference between “chronic pain” and a “chronic condition” that causes intermittent pain. Localized provoked vulvodynia is a cause of exquisite pain on touch, as, for example, with repeated penetrative activity of intercourse. However, if a woman with this chronic condition refrains from intercourse, she may well have no pain. Generalized vulvodynia, on the other hand, is a condition of persistent spontaneous pain that is sometimes completely unremitting. The origin of -dynia is from the Greek oδύνη (odunē, “sorrow, grief, anguish, unhappiness”), which is used as a term meaning “painful.” Women’s descriptions of vulvodynia are usually those of a thermal nature. Generalized vulvodynia usually has a burning or stinging sensation, and localized vulvodynia has a burning, raw, or tearing sensation provoked by entry penetration. Generalized vulvodynia is an acquired condition. In contrast, the more common condition, localized provoked vulvodynia (LPV), is categorized by onset as either primary or secondary. The primary type will have been present with penetrative attempts for as long as the patient can recall – often from the first attempt to place a tampon, the first attempt at coitus, and the first speculum examination. This implies a presence before recognition, perhaps even since childhood, but there is not a body of information about prepubertal

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girls since genital examinations are restricted in this age group so as not to cause emotional harm. Secondary vestibulodynia is a penetrative pain that has been acquired after there has been no prior pain with penetration.

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Taking a Patient History

For localized provoked vulvodynia (LPV), the usual patient complaint is pain with penetration. On taking a history, it is useful to ask about qualities of pain, timing of onset, and other associated issues. The pain is usually described as burning or tearing in nature. If milder, it is described as an irritation as if tissues are dry. The use of a lubricant can help in more minor cases but does not correct severe tenderness. Ask patients when they first experienced pain with sex, but questions about other examples of penetration are useful. Attempts with tampons usually antedate the first speculum examination or first coital attempts by years indicating early presence of the disorder. Removal of an engorged tampon is often more painful than insertion. Those with severe LPV often cannot use tampons due to pain. A clinical history should allow an assignment to primary versus secondary status, although the plan of therapy does not depend on the LPV type. Comorbidities such as psychosocial impairment are more common in women with primary LPV who have never known painless intimacy and often come to attention later than women with secondary LPV. The duration of time women have been suffering pain and continuing to have intercourse will also affect the likelihood that they have developed the secondary problem of pelvic floor myalgia as a reaction to entry pain. A family history may reveal a mother or sisters who have had a similar pain condition, but this very private information may not have been shared. Finally, it is useful to ask about bladder issues such as frequency, urgency, and nocturia as patterns that may reveal the comorbidity of bladder involvement either because of mucosal inflammation or due to tight pelvic muscles reducing filling capacity.

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Differential Diagnosis

Vulvar pain and dyspareunia can be caused by other vulvar or genital problems than vulvodynia. Infections should be ruled out before the diagnosis of vulvar vestibulodynia is assigned. Such problems can also be comorbidities with vulvodynia, however, so if treatment of the obvious problem does not return a patient to normal, the differential diagnosis should be expanded with a consideration of vulvodynia. Many vulvar pain sufferers have been to multiple practitioners before they get an accurate diagnosis, and they often give histories of having been treated multiple times with antifungals or antibiotics for a presumed vaginitis. Whereas it is true that a vaginitis such as candidiasis or an irritative bacterial vaginitis (desquamative inflammatory vaginitis) creates acute symptoms in the introitus, these symptoms will clear with appropriate therapy. Without evidence of a vaginitis on visual or microscopic examination, vaginal pathogens are an unlikely cause of introital pain symptoms. Of note, bacterial vaginosis (BV) is an imbalance of vaginal bacteria and not a cause of pain, typically causing just an odor (“halitosis” of the vagina?) and/or discharge. BV is too often blamed for the pain condition of vulvodynia, leading to inappropriate and ineffectual antibiotic use and delay in accurate diagnosis. An exception to the accuracy of standard office microscopy is subclinical Candida albicans or Candida glabrata, due to vaginal colonization which causes vestibular symptoms. These pathogens can be diagnosed with the DNA probe or vaginal culture. In the case of candida, oral antifungal treatment for a series of a few weeks can reestablish a baseline of normal vulvar sensations to assess that there is not a component of vulvodynia that is present. Dermatologic conditions of the vulva and vagina (lichen planus, LP, and lichen sclerosus, LS) can cause pain with intercourse. If vulvar scarring is noted, an inflammatory process is to blame, not vulvodynia or atrophy. In the setting of visual changes in the vulva, a biopsy may be indicated. A routine biopsy (with LS) or

Management of Vulvodynia

immunohistochemical staining (with LP) can establish the diagnosis unless the physical appearance is sufficient to classify the dermatosis. These inflammatory processes require steroid therapy for control.

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Physical Examination of Vulvodynia

Vulvodynia is often described as a diagnosis of exclusion with no physical findings. This is the case with generalized vulvodynia, but not with localized provoked V. Care in doing a focused examination of the external vulva and vestibule is primary. First, the patient should be asked to clarify where she feels pain, pointing and touching the specific areas. A simple examination of the external vulva employs light probing touch by the examiner’s finger and can ascertain whether pain is elicited. A swab touch test of the vestibule can then be performed, mapping the degrees of pain in specific zones. Findings in generalized vulvodynia: Pain is usually in areas outside the vestibule, thereby distinguishing it from vestibulodynia. Locations can be confirmed by touch, but touch does not always provoke more pain during the examination process. There are no visual skin changes. Findings in localized provoked vulvodynia: The labial tissues must be gently but firmly drawn far enough apart to examine the entire vestibule including the crypts next to the hymen, especially at each Bartholin’s duct orifice. In normal settings light touch in this zone is not tender. Allodynia is tenderness to types of touch that should not be painful, and this characterizes vestibulodynia. A physical finding of erythema is usually evident in portions of the vestibule. Redness can be very specific to the zone of allodynia, for instance, forming a U-shape from 3 to 9:00, as if the hymen were a clock face. The most pronounced redness is often around each Bartholin’s duct orifice. Reddened spots can exist at tiny vestibular gland openings in the anterior vestibule. The erythema is not an erosion or ulcer but is from dilation of fine capillaries. General redness without

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tenderness is a physiologic variant and not of concern. The “swab test” utilizes a small cotton-tipped applicator moistened with water. The locations of pain are mapped using light rolling touch checking all surfaces of the vestibular mucosa. This technique reflects observations about this condition from an old text from 1885 stating that “the touch of a feather is insupportable.” The scoring can be 0–3: 0 = nontender, 1 = annoying touch, 2 = stinging or burning sensation, and 3 = very painful touch causing patient to flinch. Some authors have utilized an algesiometer in research settings (Pukall et al. 2003). It measures the threshold of pain using calibrated swab pressure or calibrated touch with von Frey hairs. It should be noted that prodding actions will also impact submucosal tissue layers; poking maneuvers may inadvertently elicit pain from superficial submucosal structures like muscles. Therefore light, rolling touch of a cotton swab may be preferable and sufficient to examine mucosa. Algesiometers or vulvalgesiometers are not readily available and the cotton swab therefore provides a simple tool for all practitioners to use. The “lidocaine test” helps to establish the mucosal nature of LPV because the application of aqueous 4 % lidocaine for 1–3 min can extinguish the mucosal pain of LPV but does not ablate the pain of aberrant nerve function in centrally mediated generalized vulvodynia (see “Histology and Theories”). Both localized vulvodynia (vestibulodynia) and generalized vulvodynia can be present in a mixed form in the vestibule and outer vulva, although this is not the usual circumstance. Some women are so avoidant of an exam of the vestibule that touch is not possible on the first visit. This has confounded the elucidation of “vaginismus,” since women have been entered into studies without having undergone full examinations for the mucosal pain condition of LPV (Reissing et al. 2004). Lidocaine is extremely helpful in examining women with other causes of mucosal tenderness, like vulvitis or a lichenoid dermatosis. Quelling introital tenderness makes it possible to accurately examine upper genital structures without eliciting

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pain from the introitus from touch with fingers or a speculum.

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Histology and Physiology of Vulvodynia

No histologic changes have been documented in generalized vulvodynia. It is considered a condition of aberrant nerve function with central sensitization with no specific nerve abnormalities at the peripheral skin level. Biopsies are negative for pathology. Histologic studies of vestibulodynia (localized provoked vulvodynia) have found an excessive number of nerve endings in the vestibule mucosa and submucosa (Bohm-Starke et al. 1999). These nerves are pain nerves (nociceptors) that are the type targeted by local anesthetic agents such as lidocaine that block sodium channels. Additionally, the local neural hyperplasia is accompanied by an infiltrate of lymphocytes and mast cells. The lymphocytes have been characterized as T-cells, and the inflammation is not the type responsive to therapy with topical steroids (Bohm-Starke et al. 2001). Differences in degree of neural hyperplasia and lymphocytic infiltrate have been noted in different types of vestibulodynia. Nerve trunks and mucosal branches are most pronounced in tissues from women with primary LPV (Leclair et al. 2011). The lymphocytes are more numerous in tissues from women with secondary LPV, with the most marked lymphocyte infiltrates in postmenopausal women’s tissues (Leclair et al. 2013). Vulvodynia does not predispose to cancer and is not contagious.

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Population Findings in Vulvodynia

Premenopausal vulvar vestibulodynia: Several prevalence studies have established that 12–14 % of young premenopausal women have LPV (Harlow et al. 2014). There are an equal proportion of sufferers in primary and secondary categories. Localized provoked type comprises 90 % of

cases of vulvodynia (Lamvu et al. 2015). Women have typically consulted five clinicians about their problem before receiving an accurate diagnosis. Postpartum vulvar vestibulodynia: Postpartum dyspareunia is a poorly studied phenomenon, but one prospective study found that 37 % of women delivering babies developed introital pain with penetration in association with lowered hormones after delivery and during lactation (Goetsch 1999). The women’s complaints were similar whether their delivery had been vaginal or abdominal. The severity was equally apportioned between mild, moderate, or severe pain, and median duration was 5 months. For some women postpartum dyspareunia does not resolve with the return of natural estrogen and periods. Two prevalence studies have found that 25 % of women with vestibulodynia described the onset as postpartum. It is unknown how many women need to deliver for one to develop chronic longterm vestibulodynia. Generalized vulvodynia: Population studies indicate that there is a stable prevalence of 8.3 % of vulvodynia through age 70. For about 17 %, however, symptoms may begin or remit spontaneously (Reed et al. 2012). Early studies termed this condition “essential vulvodynia” and described it as a complaint of postmenopausal women with constant sensations of irritation or stinging. It can be a comorbidity in younger women with LPV and can develop rarely after a vestibulectomy. A large clinical study indicated that 10 % of women with vulvodynia have generalized type (Lamvu et al. 2015). Postmenopausal pain with sex: Dyspareunia is very common in postmenopause and has suffered from a lack of research (Kao et al. 2008). There has been a hesitation to consider postmenopausal dyspareunia to be vulvodynia since the definition states “without another identifiable cause,” and in this age group, pain has commonly been ascribed to atrophy causing vaginal dryness. The newer term is genitourinary syndrome of menopause (GSM) and replaces the term “vulvovaginal atrophy” (Portman and Gass. 2014). GSM includes symptoms of dyspareunia, sensations of dryness, and urinary and vulvar irritation. Atrophy is a condition of thinned genital

Management of Vulvodynia

tissues from the lack of estrogen that characterizes menopause. Without estrogen, the uterus and cervix shrink, and vaginal, vestibular, and outer vulvar tissues thin. A problem with attributing menopausal dyspareunia to atrophy is that the intimacy tenderness is localized to the vestibule and not the vagina, despite both having developed atrophy (Goetsch et al. 2014). Additionally, not all women with genital atrophy have dyspareunia. Finally, in other circumstances of physiologic atrophy, such as muscle atrophy, there is no associated pain condition. For these reasons there is pressure to reconsider the definitional injunction against labeling a condition vulvodynia if the “clear identifiable” associated cause is atrophy (Kao et al. 2008). In women with menopausal dyspareunia, an examination indicates that the pain is at the entryway and is tenderness, not dryness. The use of lubricants can temper the sensation of irritation or pain, but they do not remove pain as should be expected if this were simply dryness. The use of lubricants is a good idea in menopause generally, for reasons of less natural lubrication, and a silicone lubricant is a good option. Postmenopausal dyspareunia fulfills the criteria of being localized to the vestibule and only painful when provoked, similar to the condition of vestibulodynia found in younger women. Menopausal vulvar vestibulodynia can be diagnosed with the cotton swab and lidocaine tests, demonstrating that there is extinguishable mucosal pain and no other cause of penetrative tenderness as demonstrated by a painless speculum examination. The lack of estrogen in menopause can therefore cause two concomitant problems: vestibulodynia and general genital atrophy. Estrogen therapy usually corrects both conditions, but not uniformly. For localized therapy the instructions are to apply estrogen into the vagina. However, this does not directly treat the important location of the vestibule, and low-dose vaginal therapy may not be strong enough to correct vestibular tenderness. Another example of chronic vulvar pain may be emerging now that years have passed after women were urged in national guidelines to

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forego postmenopausal estrogen. Women are presenting in the later years of menopause who have constant burning pain arising from the vestibule. These women often have not used estrogen for years or they have used special antiestrogen medications (such as aromatase inhibitors) as treatment for breast cancer. Their burning pain is constant and debilitating. It is a very severe example of vestibulodynia and responds to estrogen therapy directed to the vestibule (Goetsch 2012).

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Theories of Causation of Localized Provoked Vulvodynia

Current research is pursuing various possible triggers for both primary and secondary vulvar vestibulodynia. Scarring was an early theory to explain dyspareunia. It was proposed by Woodruff, who suggested that submucosal scarring from childbirth was causative. He demonstrated that a surgical procedure could be quite palliative, but because he believed scars to be the cause, his procedure advanced vaginal tissues out over the fourchette and down to mid-perineum so that there would not be a scar where penetration would occur. This prototype surgery has influenced surgical approaches since, although scarring is no longer the operant theory of causation. A counter to this theory of causative introital scarring is the fact that millions of women sustain tears around the introitus during vaginal childbirth, and these heal with only rare sequelae of tenderness and dyspareunia. In fact, keloids, which arise from pathologic thickening of scars in ectodermal skin, never involve the vestibule, which is endodermal. Psychological etiologies: By the early 1900s, with the new field of psychology experiencing increasing popularity, dyspareunia shifted from the category of a physical problem to being a sign of neurosis. See the “History” section below. This conceptualization meant that for much of the twentieth century, women with dyspareunia were referred to psychologists or psychiatrists for mental health therapy about

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maladjustment to being sexual. Modern psychologists have refined the research on etiologic psychological factors. Studies have reported mixed findings about the prevalence of antecedent depression or sexual abuse. One study found that severe childhood physical or sexual insecurity was associated with a threefold increase in vulvovaginal pain. Sexual pain is acknowledged to be a complex cause of distress (Bergeron et al. 2015). Irritant exposure: Many patients’ first symptoms are assumed to be from a yeast vulvovaginitis, and research is ongoing to assess a relationship between candida exposure and LPV. Clinically, episodes of severe vaginitis or a reaction to overthe-counter antifungals is a feature of some women’s histories of vestibulodynia. Episodes and treatments are common enough that cause and effect are hard to prove. The use of immune modulators such as imiquimod in the fourchette/vestibule area can elevate the risk that LPV will be triggered.

8.1

Low Estrogen as a Cause of Vestibulodynia

Low estrogen levels have been found to provoke growth of genital tract nociceptive nerves in animal studies. Additionally, lower and higher estrogen levels during estrus cycles are associated with repetitive proliferation and thinning of genital nerve density, respectively. The accompanying infiltrate of T-cells and mast cells may be responsible for recognizing low estrogen levels and releasing neurogenic messengers such as angiotensin II (Brauer and Smith 2015). The low-estrogen theory of causation holds that since vestibular tenderness is so specific to intercourse, it might be considered a strategic contraceptive condition. LPV makes intercourse intolerably painful in women who are otherwise healthy. Considering that species survival is a major rule of nature, dyspareunia during one period of reproductive life, lactation, could selectively increase survival of a newborn by postponing a next pregnancy. After high placental estrogen levels plummet with delivery, and

ovarian function is suppressed during the period of lactation, low estrogen may constitute a trigger for temporary vestibular pain. Postpartum dyspareunia is common after ovarian estrogen levels fall. In a 1996 study, dyspareunia occurred in 38 % of parturients, and if it continued beyond 5 months, its resolution was specifically associated with resumption of menses (Goetsch 1999). All cases resolved by 1 year, but this provided a painful disincentive to have intercourse, thereby acting as a contraceptive by virtue of pain. Two early prevalence studies of vestibulitis (the old term for vestibulodynia) found that 25 % of patients had first noted their dyspareunia postpartum, and it had not resolved. This is a useful piece of patient history to assess. Postmenopausal dyspareunia is also common after estrogen levels fall. Although this problem is usually attributed to vaginal atrophy, a new interpretation holds that both atrophy and vestibulodynia develop side by side, and the location of pain in patients with severe untreated vulvovaginal atrophy is the vestibule, not the vagina (Goetsch et al. 2015). A histologic study in this population has found the condition to be consistent with vestibulodynia (Leclair et al. 2013). Figure 2 shows an example of severe vestibulodynia in postmenopause. The theory of low-estrogen causation does not immediately seem to apply to premenopausal women, as this population has a 12–14 % prevalence of LPV despite generous levels of estrogen. The theory holds that if the introital zone is genetically primed to become tender, nonhormonal triggers may be capable of setting the neurogenic process in motion. This would explain vestibulodynia that arises after bladder infections or topical irritant use. The theory of an estrogen trigger may also explain primary vulvar vestibulodynia (pain since first attempt at vaginal penetration in young women.) Girls have scant estrogen until puberty. Many girls may be asymptomatic but have tender vestibules, something we don’t know since genital examinations are restricted in girls. Tenderness would then disappear with the rise of estrogen in puberty, only to return

Management of Vulvodynia

Fig 2 Severe vestibulodynia in a 64-year-old who has been without estrogen for 10 years and for whom estrogen is contraindicated due to a history of breast cancer for 3 years (Goetsch 2013)

postpartum. If, for some girls, the hormone receptor mechanism in the vestibule is faulty and the tenderness does not resolve with puberty, they are left with primary vulvar vestibulodynia despite normal estrogen levels. Primary vulvar vestibulodynia is present in 7 % of young women and may represent nature’s “error” rate, so to speak. Progesterone effect: Some researchers suggest that newer progestins with an androgenic nature be avoided. Genetic predisposition: Data show that there are genetic variants that cluster in women with LPV, and these relate to pro-inflammatory pathways, T-cell regulators, and serotonin and androgen receptors. Findings utilizing the Utah Population Database showed shared ancestry out to seven meioses among a set of women who had undergone corrective procedures for severe LPV (Morgan et al. 2016). Relationship to bladder pain syndromes: Not uncommonly, the clinical history in women with secondary vestibulodynia points to a bad bladder infection as a trigger. The bladder and

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the vulvar vestibule are both derived embryologically from the endodermal layer. A flare of symptoms in one of the two tissues can be reflected in symptoms in the other. Triggering by human papilloma virus (HPV): Investigators initially suspected HPV to be a causative agent of secondary vestibulodynia. However, there is rarely histologic or DNA evidence of the virus at biopsy, and academic consensus is that it is not causative. Patients can give a history of pain a few months into a new relationship, however, implicating a transmissible agent. HPV may therefore be acting as a “hit and run” actor. Therapeutic approaches are not altered even if HPV seems to have been a trigger. The early popularity of interferon injections for vestibulodynia faded when efficacy was questioned. Neuropathic pain with central mediation: Many researchers consider that both types of vulvodynia, localized and generalized, exhibit evidence of amplification of peripheral nerve impulses by intermediate synapses before they reach the brain and are perceived as pain (Zolnoun et al. 2006). Several studies have demonstrated heightened sensitivity to noxious stimuli in anatomic sites distant from the vulva in women with LPV. Whether in LPV this reflects a genetically determined variation in pain sensitivity, or a product of the peripheral LPV pain with development of central sensitization is not clear. Generalized vulvodynia is best described as a disorder with central sensitization and is most successfully treated with neuromodulators effective for peripheral neuropathy.

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Vulvodynia’s Place in the History of Medicine

Textbooks of gynecology over one hundred years ago described and offered treatments for what is now realized to be vulvar vestibulodynia and pelvic muscle hypertonus. “Vaginismus” was the original name given to this condition by Marion Sims when he presented a descriptive paper to the Obstetrical Society of London in 1861. The term “vaginismus” included both mucosal and muscle

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problems. He described five patients with severe dyspareunia that prohibited coitus, noting this to be a moral issue because they had never been able to consummate holy matrimony due to their severe conditions. His term “vaginismus” would today be considered the duo of vestibulodynia with pelvic floor myalgia. He published a description of a minor surgery that revised the tissues of the introitus, and he instructed patients to follow this with the use of vaginal dilators. Over the next decades of the nineteenth century, authors of gynecologic textbooks such as Simpson, Skene, Huhner, and Kelly described this condition. When psychological diagnoses became popular in the 1880s, textbooks began introducing the consideration that women with dyspareunia were hysterical and neurotic. The description of mucosal hypersensitivity dropped out of the writings by the 1930s, and women were treated by psychologists for neuroses and by physical therapists offering dilator training. “Vaginismus” held on as a psychiatric diagnosis in the Diagnostic and Statistical Manual of Mental Disorders (DSM) until the newest version, 5. Before edition 5, “vaginismus” was characterized as a severe aversion to penetration without a mention of pain, noting only tight muscle spasms sufficient to obstruct penile entry. The latest DSM-5 edition has eliminated “vaginismus” in favor of “genito-pelvic pain/penetration disorder” and emphasizes the distress that it causes.

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Comorbidities with Vulvodynia

Pelvic floor myalgia: Pelvic floor muscle tightness is usually present in LPV and can be a source of pain with penetration. Repeated, protective contractions of pelvic floor muscles can easily develop as a response to exquisite vulvar tenderness and/or deeper pelvic pain. Patients with myalgia have lost the capacity to fully relax these muscles, and there is relative weakness of the muscles despite the constant contracted state. Physical therapy is very important to help patients train these pelvic floor muscles. The American Physical Therapy Association has special certification for members who complete training in

therapy to the pelvic floor. These practitioners provide expertise for issues of pelvic floor tightness and pain as well as for other problems such as pelvic relaxation and associated urinary incontinence. Bladder issues: There are two ways that localized vulvodynia patients can develop symptoms that relate to their bladder function. In the simpler example, the increased muscle tension described above elevates the hammock of muscles thereby reducing filling capacity of the bladder and causing urinary frequency and urgency. Patients may have multiple episodes of nocturia and may complain of having a small bladder capacity. They don’t have bladder pain. As a second reason to develop bladder symptoms, there is a significant association between localized provoked vulvodynia and interstitial cystitis. Interstitial cystitis is a poorly understood problem of nonspecific bladder inflammation with intermittent symptoms of voiding pain, frequency, and urgency. These symptoms mimic bladder infections but patients are negative for bacteriuria. Just as occurred with vulvar pain, the terminology of bladder pain has evolved. It is now usually termed “interstitial cystitis/bladder pain syndrome.” The bladder and the vestibule derive from the same embryologic layer, the endoderm. Therefore it is not uncommon to elicit a history that there is a relationship between the symptoms of the two zones. For instance, women may relate the onset of vulvar pain to a bad bladder infection. And women with both conditions may note that when the bladder condition is worse, the vestibule has a flare of pain and vice versa. Both in vestibulodynia and interstitial cystitis, 17–20 % of sufferers have both conditions. It is useful to become conversant in both conditions. A helpful measure is dietary restriction of bladder irritants such as caffeine, alcohol, citric acid foods such as cranberries, spicy foods, and artificial sweeteners. The Interstitial Cystitis Association has an informative website. Psychosocial issues: As can be expected, sexual pain has many difficult emotional consequences for women who experience it, and it affects their partners as well. Women with sexual pain have increased levels of anxiety and

Management of Vulvodynia

depression, catastrophizing, and lower levels of self-efficacy. Sex therapists are specialists in this area and can help with the complicated emotions and difficult communication that is so common with these pain problems. All aspects of sexuality are affected by sexual pain, including arousal and lubrication, desire, orgasmic success, and the ability to have penetration itself. Many women continue to have intercourse despite pain because the risk to their relationship seems too great if they abstain. Continued penetrative activity despite pain will likely cause and worsen pelvic floor myalgia. Atrophy after menopause: Although for decades the problem of postmenopausal dyspareunia has been assumed to be a symptom of atrophy, recent publications have concluded that this pain condition has more in common with LPV (Kao et al. 2012) and is located in the vestibule rather than the vagina. Atrophy in other organ systems is not a cause of pain (atrophied muscles, aged skin). Specialists in menopause and vulvar pain have not aligned their concepts, but acknowledgment that neural hypertrophy is not a usual finding in atrophy will allow research to proceed regarding neurogenic vestibular inflammation of GSM that affects millions of women. Chronic pain conditions: Vulvodynia is considered by many pain researchers to be one of several conditions that exhibit central mediation and upregulation of pain processing. Other conditions often mentioned in this list are fibromyalgia, bladder pain syndrome, irritable bowel syndrome, and migraine syndrome. One confusion about research into such groupings of pain conditions is that often no distinction is made between generalized vulvodynia, probably a centrally mediated pain process, and localized provoked vulvodynia, felt by some vulvar researchers to be a chronic but peripheral condition.

11

therapeutic efficacy. This has resulted in a frustrating accumulation of anecdotal reports without rigorous science. Additionally, it is common that studies have failed to assign women to specific categories of generalized versus localized vulvodynia, and they have failed to group women into categories of primary versus secondary vestibulodynia. All of these factors mean that there are many answers awaiting elucidation. Treatment of the general problem of entry dyspareunia: When this complaint has become chronic, it is usually multifactorial. The triad of factors are mucosal allodynia, secondary tightening of pelvic floor muscles, and psychic stress. Therapeutic initiatives are required for each for full treatment. Despite acknowledgment that dyspareunia requires multimodal therapy, there is no full agreement about how to evaluate success. Researchers in the field have not established a uniform set of outcome measures. Using “dyspareunia” as an outcome, for instance, may be significant but still not be complete (i.e., intercourse is now possible but shouldn’t intercourse be comfortable and enjoyable?). The IMMPACT group that has published criteria for evaluating improvement in chronic pain conditions suggests that a pain reduction of 50 % is probably of clinical significance. However, for dyspareunia, an intolerable pain that is reduced 50 % may still be unacceptable. Proportional improvement may need clarification by assessing features like the consistency of relief and the confidence associated with sexual function. As another general point, only in menopause is estrogen therapy really helpful; pain may be ameliorated in some younger women, but the effect is not dramatic.

12 11

Therapeutic Efforts: General Points

Many therapies have been tried for vulvodynia. A criticism of most intervention studies is that they lack controls and randomization to compare

Specific Therapies for Vulvodynia

General suggestions for vulvar hygiene: Most reviews of vulvodynia emphasize reduction of local exposure to irritants, whether the irritants be sweat, soap residues in clothing, irritating body soaps or over-the-counter genital products.

12

Commonly used over-the-counter “intimacy” products like anti-itch or numbing benzocaine can be problematic because of skin hypersensitivity reactions and should be avoided. The use of an effective sexual lubricant is important to reduce friction across tender mucosal surfaces. Waterbased lubricants are recommended when condoms are being used, but silicone lubricants can provide longer-lasting lubrication. Multiple empiric therapies: Many pill and cream therapies have been tried empirically for all vulvodynias without scientific proof of efficacy. These include cortisone creams, hormone creams, anti-herpes therapies, antifungals, topical use of hot red pepper extract (capsaicin), and therapies used for shingles. A common impulse in response to seeing redness in the vestibule is to prescribe a course of topical steroids to the area. The inflammation of vestibulodynia, however, has been shown to be neurogenic and not a classic inflammation and is unresponsive to topical steroids. One study combined injections of steroid and anesthetic and showed efficacy in a year follow-up, but further studies were not forthcoming. A prolonged empiric course of an oral antifungal for several weeks is standard in some approaches to vulvodynia. Topical lidocaine therapy: For symptom relief of LPV, the most helpful therapy is topical lidocaine applied just before intercourse. Such therapy is not intuitive, as numbing a potentially erogenous area seems counterproductive. However, the numbing removes the burning allodynia and is only mucosal, so touch sensation remains. (It could be compared to the difference between a facial nerve block at the dentist’s and a rinse of oral lidocaine solution.) If mucosal pain is prevented, women with this condition can learn to relax their pelvic floor muscles, thereby further reducing discomfort. Choices of product include a gel formulation with 2 % lidocaine, an aqueous formulation with 4 % lidocaine, and an ointment with 5 % lidocaine. The benefits of the aqueous solution are its relative strength combined with a single preservative, making it less likely to sting on first application. Additionally, the liquid does not

M. Goetsch

smear widely and risk numbing the partner. Patients must be shown with a mirror just where the tender zones are, and they avoid numbing the clitoris. Pretreatment with lidocaine for several minutes immediately before intimacy, plus the use of an effective lubricant, can help many who have mild, and even severe vulvar vestibulodynia have comfortable intercourse. Clinically, premenopausal women find lidocaine use instructive to confirm the diagnosis, but unacceptable as an indefinite strategy. Lidocaine for those who cannot use estrogen in postmenopause: Breast cancer survivors who cannot use estrogen products can get excellent results for severe dyspareunia by learning to use a compress of liquid lidocaine anesthetic applied for 3 min to the painful area (followed by lubricant) just before intimacy (Goetsch et al. 2015), Ninety-five percent of affected women in a randomized trial were able to have comfortable intercourse after preventing entry dyspareunia with lidocaine. Half of the group had been abstaining because of the severity of pain. All aspects of sexual function improved when pain was prevented, independent of the length of time the couples had had to abstain, indicating that the adage “use it or lose it” is not an appropriate exhortation. In the 2015 randomized controlled trial, postmenopausal breast cancer survivors embraced liquid lidocaine as a long-term therapy, having previously found that the prohibition against estrogen gave them no other effective therapy for severe genital pain of menopause. Treatment of the vestibule mucosa: The most effective corrective therapy for LPV is superficial local excision of the affected mucosa (Tommola et al. 2010). More than 20 outcome series and one randomized comparative study show excision to be a successful and acceptable treatment for this condition. There has been great hesitation, however, to list this intervention as most indicated. Review publications and specialty committee reports continue to suggest that it be offered as a last resort, only after other therapies have been exhausted. Delay, however, has been shown to increase the difficulty of treating associated muscle and emotional problems. Pain for 5 or more

Management of Vulvodynia

Fig. 3 This shows the mapped area of vestibulodynia before the procedure of localized mucosal removal in a patient with tenderness from 3 to 9:00. The hymen will be used as a flap to close the resected zone without advancing the vaginal tissues (Goetsch 2007)

years prior to effective mucosal therapy has been associated with a worse prognosis for cure of dyspareunia. Early diagnosis and symptom relief are important to prevent sexual comorbidities. LPV may be a singular example of a focal unremitting inflammatory pain that is amenable to local excision. The procedures vary from uniform to individualized, the latter superficially removing only painful areas. Some techniques remove the hymen and advance vaginal wall tissue down to the perineum (vaginal advancement). Others leave the hymen and use it as a flap to close the resected zone of affected vestibule. Figure 3 shows an example prior to excision. The extent of surgery will determine the time needed to heal and the associated disfigurement to the vulva. Techniques have not been directly compared to assess morbidity and rates of cure. Since all surgeries excise the apertures of the Bartholin’s ducts and cover them with a flap, there is a risk of developing Bartholin’s duct cysts at a future time, but this occurs in only 10 % of cases and may not be apparent to patients. Postoperative physical therapy and dilator use help with the relaxation of tense muscles and the transition to comfortable sex. Another noninvasive therapy has employed the NgYag laser. It is a laser used by dermatologists for remodeling of skin collagen related to aging in nongenital areas. It is not clear what it targets in LPV, but there has been success in treating the

13

anterior vestibule where surgical excision is not feasible by directing multiple pulses of laser energy during 1–3 treatment sessions. NgYag laser is not a destructive laser. The classic vaporizing CO2 laser was found to have a low success rate and risked worsening the LPV; it was quickly abandoned. Treatment of pelvic floor myalgia: Physical therapy is an important adjunct in the treatment of LPV (Bergeron et al. 2008). It addresses muscle pain (pelvic floor myalgia) and tight introital muscles that heighten penetrative friction. Physical therapy may be less important for generalized vulvodynia, as this pain condition results less often in muscle tightening. Also, generalized V often affects older women who are more likely to be multiparas with laxer muscles compared to nulliparas who constitute a significant portion of LPV patients. The physical therapist must be specifically trained in pelvic floor muscle work. Techniques vary, and the consistent feature is to train women to recognize when muscles are tight and learn to relax them volitionally. On evaluation, muscles are usually in hypertonus but are actually weak. Biofeedback is provided either by digital monitoring by the therapist or with a vaginal sensor that assesses electromyographic (EMG) data. The goal is muscle relaxation, increased blood circulation, and enlargement of the vaginal caliber. Successful physical therapy of myalgia can reduce the degree of dyspareunia by 50 % even without addressing the vestibule tenderness. Soft or firm vaginal dilators of varying sizes can be helpful for home use so that therapy can continue for each woman independently. The ability to easily insert successive sizes of dilators confirms increasing success with relaxation. Physical therapists are a source of emotional support and patient education about anatomy and touch. Some use topical lidocaine to treat the mucosal pain of LPV in order to focus on muscle work. They can be effective teachers of home lidocaine use. Psychosocial therapy: Sexual pain, by its nature, complicates a woman’s sense of personal normalcy and sexual confidence. Professional counseling can be critical for patients and their partners, improving specific dysfunctions in

14

addition to the pain itself. Researchers are exploring various approaches to therapy more specific than simple supportive therapy. Cognitive behavioral therapy (CBT) has successfully focused on pain management and sexual functioning with improvements maintained at a 2.5-year followup (Bergeron et al. 2008). Mindfulness is being proven valuable as well, in changing perceived intensities of pain and benefiting muscle relaxation in series of group sessions. A sex counselor can be helpful by suggesting to couples a range of non-painful options for intimacy. Both parties are affected, and couples’ sex therapy is important to address the shared issues of guilt, inadequacy, and shame. Only a few studies report on therapeutic interventions that include the sexual partner. Hormone therapies: Generalized V is not considered to be hormonally sensitive. There is not a consensus about the benefit of manipulating the hormone milieu in patients with LPV. Researchers in Sweden have concluded that one in five patients with LPV is benefited to some degree by stopping their combined oral contraceptives. Some believe that the second-generation progestin drospirenone can trigger or worsen LPV and should be discontinued. Research is ongoing about the benefit of topical estradiol/testosterone cream. The one clear setting where estrogen therapy is definitely effective and appropriate is in menopausal dyspareunia. The therapy may need to be applied directly to the vestibule, but research lags in this area, as the general understanding of GSM assumes that the pain is from vaginal thinning. Efficacy of vaginal estrogen regimens is the subject of a Cochrane review. A synthetic estrogen receptor modulator, oral ospemifene, is available as an alternative to standard estradiol products for menopausal dyspareunia. Diet therapy, particularly a low oxalate diet, has never been shown to have benefit in vestibulodynia. A diet restricting bladder irritants can help with bladder pain and urgency. Extreme adherence to a low oxalate diet does not provide healthy nutrition. Neuromodulators: Oral medicines to treat the nervous system are commonly

M. Goetsch

offered by many vulvar practitioners across the country, although results vary and good comparative studies are few (Foster et al. 2010). These classes of medications include the tricyclic medicines (amitriptyline, desipramine, nortriptyline) and neuromodulators (gabapentin, pregabalin, and duloxetine). Some of these medicines have also been mixed into a cream and applied directly to the painful vestibule (Boardman et al. 2008). There are studies supporting the use of topical 5 % lidocaine, 2 % amitriptyline cream, and 6 % gabapentin cream as helpful for some patients. Baclofen or valium has been offered as vaginal suppositories. Generalized vulvodynia: This disorder, characterized by aberrant nerve messaging, is not appropriately treated by surgery. Medical management is with neuromodulators.

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Conclusion

Vulvar pain is a complicated sexual pain disorder affecting 8–15 % of all young women and at least 50 % of postmenopausal women, with even higher percentages in women who are not using supplemental estrogens after menopause such as women with a history of breast cancer. Although what we know to be vulvodynia was described in early gynecologic textbooks, it was misunderstood for decades and then “rediscovered” in the 1980s. Research is ongoing to understand the physiology and why this affects so many women. Clinicians in many specialties should be familiar with this condition and its variations in order to offer accurate diagnoses and referral for treatment. Those whose practices include genital examinations should know how to pretreat with lidocaine in order to assess upper and lower tract conditions most accurately. Therapies for vulvodynia must address not only the physical pain but the emotional and psychological distress that results. An integrated multidisciplinary approach provides the best strategy for success.

Management of Vulvodynia

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Cross-References

▶ Benign Diseases of the Vulva ▶ Benign Vulvar and Vaginal Pathology ▶ Management of Menopausal Symptoms ▶ Management of Pelvic Pain, Dyspareunia, and Endometriosis ▶ Management of Sexual Dysfunction ▶ Management of Vaginal and Vulvar Lesions in the Older Woman

References Bergeron S, Khalife S, Glazer H, Binik Y. Surgical and behavioral treatments for vestibulodynia: two-and-onehalf–year follow-up and predictors of outcome. Obstet Gynecol. 2008;111:159–66. Bergeron S, Corsini-Munt S, Aerts L, Rancourt K, Rosen N. Female sexual pain disorders: a review of the literature on etiology and treatment. Curr Sex Health Rep. 2015;7(3):159–69. doi:10.1007/s11930-015-0053-y. Boardman LA, Cooper AS, Blais LR, Raker CA. Topical gabapentin in the treatment of localized and generalized vulvodynia. Obstet Gynecol. 2008;112 (3):579–85. Bohm-Starke N, Hilliges M, Falconer C, Rylander E. Neurochemical characterization of the vestibular nerves in women with vulvar vestibulitis syndrome. Gynecol Obstet Invest. 1999;48:270–5. Bohm-Starke N, Falconer C, Rylander E, Hilliges M. The expression of cyclooxygenase 2 and inducible nitric oxide synthase indicates no active inflammation in vulvar viestibulitis. Acta Obstet Gynecol Scand. 2001;80:638–44. Brauer MM, Smith P. Estrogen and female reproductive tract innervation: cellular and molecular mechanisms of autonomic neuroplasticity. Auton Neurosci. 2015;187:1–17. Foster D, Kotok M, Huang L, Watts A, Oakes D, Howard F, et al. Oral desipramine and topical lidocaine for vulvodynia: a randomized controlled study. Obstet Gynecol. 2010;116(3):583–93. Goetsch M. Postpartum dyspareunia – an unexplored problem. J Reprod Med. 1999;44(11):963–8. Goetsch M. Unprovoked vestibular burning in late estrogen-deprived menopause: a case series. J Low Genit Tract Dis. 2012;16(4):442–6. Goetsch MF, Lim JY, Caughey AB. Locating pain in breast cancer survivors experiencing dyspareunia: a randomized controlled trial. Obstet Gynecol. 2014;123 (6):1231–6.

15 Goetsch MF, Lim JY, Caughey AB. A practical solution for dyspareunia in breast cancer survivors: a randomized controlled trial. J Clin Oncol. 2015;33(30):3394–400. Harlow B, Kunitz C, Nguyen R, Rydell S, Turner R, MacLehose R. Prevalence of symptoms consistent with a diagnosis of vulvodynia: population-based estimates from 2 geographic regions. Am J Obstet Gynecol. 2014;210:40.e1–8. Kao A, Binik Y, Kapuschinski A, Khalife S. Dyspareunia in postmenopausal women: a critical review. Pain Res Manag. 2008;13(3):243–54. Kao A, Binik Y, Amsel R, Funaro D, Leroux N, Khalife S. Challenging atrophied perspectives on postmenopausal dyspareunia: a systematic description and synthesis of pain characteristics. J Sex Marital Ther. 2012;38:128–50. Lamvu G, Nguyen R, Burrows L, Rapkin A, Witzeman K, Marvel RP, Hutchins D, et al. The evidence-based vulvodynia assessment project. a national registry for the study of vulvodynia. J Reprod Med. 2015;60 (5–6):223–35. Leclair C, Goetsch M, Korcheva V, Anderson R, Peters D, Morgan T. Differences in primary compared with secondary vestibulodynia by immunohistochemistry. Obstet Gynecol. 2011;117(6):1307–13. Leclair CM, Goetsch MF, Li H, Morgan TK. Histopathologic characteristics of menopausal vestibulodynia. Obstet Gynecol. 2013;122(4):787–93. Morgan TK, Allen-Brady KL, Monson MA. Familiality analysis of provoked vestibulodynia treated by vestibulectomy supports genetic predisposition. Am J Obstet Gynecol. 2016;214(5):609.e1–e7. Portman D, Gass M. Geintourinary syndrome of menopause: new terminology for vulvovaginal atrophy from the International Society for the Study of Women’s Sexual Health and The North American Menopause Society. Menopause. 2014;21(10):1–6. Pukall C, Payne K, Binik Y, Khalife Y. Pain measurement in vulvodynia. J Sex Marital Ther. 2003;29(1):111–20. Reed B, Harlow S, Sen A, Legocki L, Edwards R, Arato N, et al. Prevalence and demographic characteristics of vulvodynia in a population-based sample. Am J Obstet Gynecol. 2012;206:170.e1–9. Reissing E, Binik Y, Khalife S, Cohen D, Amsel R. Vaginal spasm, pain, and behavior: an empirical investigation of the diagnosis of vaginismus. Arch Sex Behav. 2004;33(1):5–17. Tommola P, Unkila-Kallio L, Paavonen J. Surgical treatment of vulvar vestibulitis: a review. Acta Obstet Gynecol Scand. 2010;89:1385–95. Zolnoun D, Hartmann K, Lamvu G, As-Sanie S, Maixner W, Steege J. A conceptual model for the pathophysiology of vulvar vestibulitis syndrome. Obstet Gynecol Surv. 2006;61(6):395–401.

Management of Pelvic Pain, Dyspareunia, and Endometriosis Judy Hall Chen

Abstract

Pelvic pain is an enigmatic diagnosis which often brings frustrations to both patient and practitioner. Within this chapter an introduction to the changing categorization of pain, a review of pain pathophysiology, and clinical approaches to three presentations of pelvic pain (general pelvic pain, dyspareunia, and endometriosis) are highlighted. Dives into the clinical approach for general pelvic pain, dyspareunia, and endometriosis stress the need for thorough interview, history documentation, and detailed physical exam findings. If these parameters fail to give a clear explanation of the etiology, other techniques may be useful to elicit other common findings associated with pelvic pain, dyspareunia, or endometriosis. Despite the trend toward algorithmic clinical practice for many disease assessments, the diversity of diagnoses related to pelvic pain limits the effectiveness of an algorithmic approach. A focus on the reproductive status of the patient impact may help to guide both diagnosis and therapeutic options.

Keywords

Pelvic pain • Dyspareunia • Endometriosis • Pain • Pain syndromes • Sensitization • Convergence • Neuronal cross-talk

Contents 1 1.1

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Terminology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2 2

2 2.1 2.2 2.3 2.4 2.5

Pain Physiology: Basic Concepts . . . . . . . . . . . . Sensitization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Convergence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Modulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Neuropathic Pain and Nociceptors . . . . . . . . . . . . Understanding Pain Physiology: Summary . . .

3 3 5 5 6 6

3 3.1 3.2 3.3 3.4 3.5

7 8 10 10 12

3.6 3.7 3.8 3.9 3.10 3.11

Pelvic Pain Management . . . . . . . . . . . . . . . . . . . . . Pelvic Pain Story . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Confirming Suspicion with Objective Data . . . Management and Treatment Options . . . . . . . . . . Dyspareunia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Sexual Stages and Categories of Sexual Dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Management of Dyspareunia . . . . . . . . . . . . . . . . . . Endometriosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Management of Endometriosis: Pelvic Pain . . Management of Endometriosis: Infertility . . . . Reassessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

12 14 15 16 18 20 21

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

J.H. Chen (*) Department of Health Services, Los Angeles County, Keck School of Medicine, Los Angeles, CA, USA e-mail: [email protected] # Springer International Publishing AG 2017 D. Shoupe (ed.), Handbook of Gynecology, DOI 10.1007/978-3-319-17002-2_78-1

1

2

1

J.H. Chen

Introduction

Pain is the one symptom which provokes strong responses and emotions in both patients and physicians. Since the pain is often generated as a complex symptom arising out of activation of multiple levels of neural feedback loops modified by both physiologic and psychological factors, there is often difficulty in exactly isolating the exact location of the physiologic process involved in the disease. Beyond the complexity of the pain response lies the complexity of the female pelvis and reproductive system. The cyclic and systemic nature of reproductive hormones adds not only endocrine modulation of the disease process but may also affect the psychologic status of the patient. Added to this are stress factors related to fertility desire and potential. Although scientific investigation continues to unveil new understandings related to these processes, the interplay and overlap which occurs in patients with chronic pelvic pain continues to be an area that demands individual customization. Much of this chapter focuses upon the general accepted physiology of pain perception and on areas that often cause confusion for patients and physician. The goal, ultimately, is to provide clinicians with workup and management protocols based in a firm understanding of the underlying basic pathophysiology of female pelvic pain. Although there are some innovative diagnostic tools and/or therapies that are under investigation, they often require a more in depth pursuit on behalf of the reader and thus will not be the focus of this chapter.

1.1

Terminology

Before diving into the aspects of pelvic pain related to women specifically, there is a need to outline the source of difficulty within this area: nomenclature and physiology. Prior terminology grouped much of pelvic pain into merely time constraints: less than 6 months (acute) versus more than 6 months (chronic). However, as the understanding of the different causes of pain has evolved so has the nomenclature of pelvic pain.

No longer does a general diagnosis of chronic pelvic pain suffice to guide treatment. It is now important to specifying source, progression, cyclic changes and effect of medications. “Chronic pelvic pain” today as a term has evolved from merely a diagnosis to a symptom requiring further investigation and delineation. This change in definition requires the language used to detail the symptom of chronic pelvic pain to become richer and more specific. Without modification in physician language the cognitive process of forming a differential diagnosis remains limited. The past combination of imprecise language and static understanding of pain pathology gave rise to a frustrating cycle of generalized history taking, imprecise differential diagnosis lists, indeterminate results, and failed empiric therapy. These factors potentially give rise to a gradual split between patient and physician often leading to a change in healthcare providers with the possibility of repeating a similar experience. Repeated cycles of these events often lead to frustration and distrust on both sides of the clinical experience: patients and clinicians. Using a more precise nomenclature assists in increased diagnostic accuracy, therapeutic precision and in rebuilding patient rapport and professional communication. Baranowski gives good scope to untangling the complexity of the current vague terminology by introducing the concept of classifying CPP into three conditions of medical understanding: phenotyping, terminology, and taxonomy (Baranowski 2009). Phenotyping is the process of identifying the pathophysiologic changes in order to understand the cause of the pain symptoms. Terminology highlights the gap between the true definition of words and the varied use of practitioners when selecting words to describe both the cause and symptoms of pelvic pain. Lastly, taxonomy separates terminology into two categories: known pathologic causes of pelvic pain versus syndromes of pain which have consistent symptom presentations but no know associated pathologic process. Expanding our understanding from a symptom, chronic pelvic

Management of Pelvic Pain, Dyspareunia, and Endometriosis

pain is now a starting point in a process to identifying diseases and syndromes as separate entities. In 2004, the American College of gynecologists (ACOG) defined chronic pelvic pain, CPP, as noncyclical pain of at least 6 months’ duration, involving the pelvis, anterior abdominal wall, lower back, and/or buttocks, serious enough to cause disability or to necessitate medical care. Similarly the World Health Organization defined CPP as constant or intermittent, cyclical or noncyclical pain that persists for 3 months or more (Latthe et al. 2006). In contrast, the European Association of Urology (EAU) and the International Association for the Study of Pain (IASP) laid aside to catch all diagnosis of “chronic pelvic pain” in favor of separating out pelvic pain with a clear attributable cause from the syndromes of pain within the pelvic area. Specifically the EAU states: Chronic pelvic pain is chronic or persistent pain perceived* in structures related to the pelvis of either men or women. It is often associated with negative cognitive, behavioral, sexual and emotional consequences as well as with symptoms suggestive of lower urinary tract, sexual, bowel, pelvic floor or gynecological dysfunction. *where perceived indicates that the patient and clinician, to the best of their ability from the history, examination and investigations (where appropriate) has localized the pain as being perceived in the specified anatomical pelvic area. In this chapter, we will step away from older definitions of CPP and adopt the view of the EAU and IASP with the intention to give a broader systematic categorization of pelvic pain within women. Table 1 should illicit a list of the different chief complaints of pelvic pain in women.

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3

Pain Physiology: Basic Concepts

Understanding the physiology of pain assists with whittling down the list of potential diagnoses. Pain as a symptom has two components. The first is concrete and has its basis within the anatomy of the nervous system. The second is more amorphous and incompletely defined and involves inflammatory protein peptides and neurotransmitters that often modify perception of pain. The anatomy of pain begins within the peripheral nerves that contain primary afferent nociceptors and pain receptors also known as primary sensory afferents. While the largest diameter peripheral nerve fibers are the A-beta (Aβ) fibers, it is the small-diameter myelinated A-delta (Aδ) fibers and the unmyelinated axons (C) fibers which contribute the most to the detection and relay of pain signals to the central sensory cortex. These two fibers innervate skin, deep somatic structures, and visceral structures. Activation of these primary sensory afferents (pain receptors) requires the presence of a noxious stimulus or a combination of stimuli such as heat, intense mechanical pressure, or chemical irritants. Once activated these primary afferents transmit their signal to the central nervous system through the dorsal root ganglion in the spinal cord to the brain. The integration of pelvic anatomy, inflammatory responses, and psychiatric modulation may help to obscure the primary stimulant of the symptoms as well as significant changes of symptoms over time. The changing and confusing presentation of pain symptoms occurs due to the phenomena of sensitization, convergence, and modulation.

2.1

Sensitization

Sensitization is a learning process where repeated stimuli result in a progressive amplification of a response. It is the process by which pain receptors alter the transmission of the original stimuli secondary to inflammation. Enhancing the signal transmission of the peripheral nerves are the

Muscular e.g., Neurologic e.g., Urologic

Anorectal Neurologic

e.g., Pudendal neuralgia

e.g., Pudendal pain syndrome

Generalized vulvar pain syndrome Localized vulvar pain syndrome

Vaginal pain syndrome Vulvar pain syndrome

Gynaecologic

Axis V temporal characteristics Onset Acute Chronic Ongoing Sporadic Cyclical Continuous Time Filling Emptying Immediate post Late post

Provoked

Axis IV referral characteristics Suprapubic Inguinal Urethral Penile/clitoral Perineal Rectal Back Buttocks

Vestibular pain syndrome Clitoral pain syndrome

Axis VI character Aching Burning Stabbing Electric Other

Hx history, Ex examination, Ix investigation, ESSIC European Society for the Study of IC/PBS, PTSD posttraumatic stress disorder

Nonpelvic pain syndromes

Axis I region Chronic pelvic pain pelvic syndrome pain

Axis III end organ as pain syndrome as identified from Hx, Ex, and Ix Bladder pain (See Table 5 on syndrome ESSIC Urethral pain classification) syndrome Type A Prostate pain inflammatory syndrome Type B Scrotal pain noninflammatory syndrome Testicular pain Penile pain syndrome syndrome Epididymal pain Endometriosis syndrome associated pain Post-vasectomy syndrome pain syndrome

Axis II system Urologic

Cutaneous Allodynia

Gastrointestinal *** Muscular Hyperalgesia

Sexual e.g., Female dyspareunia impotence

Axis VII associated symptoms Urinary Frequency Nocturia Hesitance Poor flow Pis en deux Urge Urgency Incontinence Other Gynecological e.g., Menstrual

Table 1 European Association of Urology classification of chronic urogenital pain syndromes (Reprinted with permission Fall et al. 2009) Axis III psychological symptoms Anxiety About pain or putative cause of pain Other Depression Attributed to pain/ impact of pain Attributed to other causes or unattributed Shame, Guilt related to disclosed or undisclosed sexual experience/s PTSD symptoms Reexperiencing Avoidance Hyperarousal Monosymptomatic delusions

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Management of Pelvic Pain, Dyspareunia, and Endometriosis

inflammatory markers produced during tissue injury including bradykinin, prostaglandins, and leukotrienes. The threshold for activating the afferent nociceptors and pain receptors is lessened and the frequency of firing is increased when intense, repeated, or prolonged stimuli are applied to damaged or inflamed tissue. This may result in innocuous stimuli to become noxious (Fields and Martin 2001). Sensitization can be triggered in an autocrine fashion via the pain receptor itself. Once triggered, pain receptors produce inflammatory factors which then can alter the original response. Sensitization contributes to the sensation of tenderness, soreness, and hyperalgesia. Frequently, the repetitive occurrence of tissue injury can further shape the response of pain receptors to cause a new response not previously associated with such stimulation. This process causes an evolution of neuronal response to persistent stimulation (Jones 2001). Primary afferent nociceptors may also activate an autocrine response through the production of substance P, a neuropeptide unique to neuronal tissue. Substance P impacts the transmission of pain signals by increasing vasodilation, degranulation of mast cells, release of leukocytes, and even production of inflammatory markers. This multimodal process increases sensitivity of pain signaling and interpretation and may contribute to evolving pain complaints and triggers.

2.2

Convergence

There are several theories describing the mechanisms behind referred pain. Convergence is where multiple primary afferent axons connect with multiple different central spinal neurons (the dorsal root ganglion) that in turn may also contact multiple different afferent axons. This “mixing” of transmitters and receptors within the nervous system leads to the phenomenon known as referred pain. The most common example of referred pain is the irritation of the diaphragm being perceived as shoulder pain. While each dorsal root ganglion

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is associated with a dermatomal section for skin innervation, it also receives signals from internal organs and/or deeper musculoskeletal structures. While sensitization can modulate an individual’s response to an activated pain receptor, convergence can obscure the origin of the pain receptor. Convergence and sensitization within the pelvis have also been referred to as “neuronal cross talk,” where the activation of the neuronal system by one organ system within the pelvis alters the threshold as well as response of another organ system (Pezzone et al. 2005). Both the overlapping nature of the autonomic sacral plexus and the inflammatory markers of the paracrine system function to produce a “neuronal cross talk” within the pelvis. This cross talk effectively functions both as a modulator of primary afferents to all the pain receptors within the pelvis and also as unique triggers in themselves.

2.3

Modulation

Pain modulation is an increase or decrease in the sensation of pain due to outside stimuli. The “Gate Control” theory postulates that nonpainful input “closes the gates” to painful stimuli, thus blocking pain sensation from reaching the CNS. The “Gate Control” theory or the “Gate Theory” has led to development of transcutaneous electrical nerve stimulation (TENS) for pain relief. There is also the well-known phenomena called “stress induced analgesia” linked to situations on the battlefield or arena where wounded soldiers or injured athletes report that they feel no pain. Pain information heading to the CNS may be modulated by ascending and descending inhibitory systems through endogenous opioids, endogenous serotonin, spinal cord inhibition, peripheral nerve stimulation, or exogenous analgesics.

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There is a complex response to pain stimuli that varies greatly from subject to subject. The perceived pain sensation is often heavily influenced by the emotional state. Neural pathways that are often associated with modulation of chronic pelvic pain are those associated with mood and emotion. Mood and emotions can strongly modulate how pain is perceived. In healthy volunteers, positive affect was associated with reduced pain, while negative mood was associated with amplification of pain sensations (Meagher et al. 2001). Psychiatric disorders have a good correlation with increased pain symptoms with depression occurring as a comorbidity about 30-40% of the time (Holdcroft and Jaggar 2005).

The exact molecular mechanisms in which psychiatric disorders modulate pain perception have yet to be delineated. However, evidence indicates that psychological variables such as expectation and anticipation influence “pain-modulating circuits” between the brain and paintransmission pathways. One such “pain-modulating circuit” links the hypothalamus, midbrain, and medulla with the spinothalamic and spinoreticulothalamic pathways (Jones 2001). In this circuit, the opioid receptors are responsible for both inhibiting pain responses as well as enhancing pain responses. This is possibly one of many contributors to the phenomenon of opioidinduced hyperalgesia (Jones 2001).

2.4

Neuropathic Pain and Nociceptors

Direct damage to the somatosensory nervous system may result in a type of pain called neuropathic pain. Neuropathic pain may include dysesthesia (abnormal sensations) or allodynia (normally nonpainful stimuli). Common qualities of neuropathic pain include burning or coldness, “pins and needles” sensations, tingling, numbness, and itching. In addition to nerve damage, however, these sensations can also be triggered by strong

nociceptive stimulation (Berkley 2005). Nociceptors are nerve endings that are found in the high numbers in the skin, but also on internal surfaces as the periosteum, joint surfaces, and some internal organs. They are stimulated by damaging mechanical, thermal, and chemical stimuli. The differentiation between the two sources of neuropathic pain [direct nerve damage or activation of nociceptors] currently requires direct testing of nerve conduction of the specific nerve in question. This becomes difficult when the specific nerve in question lies with a visceral organ and as is often the case, within the pelvis. Assessing neuropathic pain relies upon detailed, careful descriptions of pain complaints and the clinician may find useful available pain scales. The Leeds assessment of neuropathic symptoms and signs scale (LANSS) may assist with teasing out the elements of history that increase the likelihood that there is true tissue damage. However, a clear separation of the overlap between the effects of persistently stimulated nociceptors versus true neuronal damage is sometimes very difficult.

2.5

Understanding Pain Physiology: Summary

Overall, an understanding how sensitization, convergence, modulation, and neuropathic pain influence pain acuity and chronicity plays a vital role in guiding clinical evaluation. Accurate and detailed descriptions of pain symptoms, intensity, duration, site, modulating factors, type of pain, and response to medication coupled with a documentation of the changes in these parameters over time provide an optimal base for accurate evaluation. The process of sensitization and neuroplasticity (changes in the brain throughout a person’s life) may cause confusing and changing patterns of complaints. Perceiving pain as a syndrome, which allows for evolution of a neuroplastic response, rather than an isolated injury process assists in both the process of patient education as well as treatment selection.

Management of Pelvic Pain, Dyspareunia, and Endometriosis

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Fig. 1 Female pelvis with relation of major organs (Gray’s anatomy. 1918, www.bartleby.com/107/, plate 829)

3

Pelvic Pain Management

Now armed with an understanding of the physiologic pain response at the neuronal level, the clinician can better evaluate and manage female pelvic pain. Consistent with the overlapping of the neuronal response of pain, the female pelvis has multiple levels of overlap between organs, innervation, and hormonal cycling. The complexity of the anatomic structures and their neuronal innervation in the female pelvis coupled with the impact of hormonal changes plays a central role in many common pelvic pain syndromes in women including dyspareunia and endometriosis. Complaints of pain within the female pelvic region are common. The prevalence of chronic pelvic pain worldwide has been estimated to be about 16–82% for dysmenorrhea, 8–21% for dyspareunia, and 2–24% for noncyclical pain (Latthe et al. 2006). The wide range of prevalence

speaks to the difficulties of consistent diagnostic criteria and the underlying complexities affecting pain symptoms (Berkley 2005; Winnard et al. 2006). Within the pelvis, pain stimuli may arise from any of the following: the bony pelvis, the musculature of pelvic floor and abdominal wall, vasculature, nerves, reproductive organs, bowel, ureter, and bladder (see Fig. 1). Rat models have demonstrated both mechanical as well as chemical “sensitization” of the urinary tract in response to colonic irritation. The frequency of bladder contractions increased and threshold of firing decreased when exposed to inflammatory markers (Ustinova et al. 2006). Studies highlight how pain perceptions may inaccurately point to the true physiologic process that is occurring at the visceral level. In other words, disease within one pelvic organ system may be the source of afferent nociception in a separate pelvic organ thus the pain perceived.

Confounding the complexity of both the pelvic anatomy and neurophysiology, female patients

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have an added modulator of pain, the influence and fluctuation of reproductive hormones. Dr. Berkley and her team demonstrated in a rat model that the spread of inflammatory markers to the colon, uterus, bladder fluctuated with the cycling of progesterone (Winnard et al. 2006). Particularly, they demonstrated that cross-organ interaction increased during the proestrus stage (presence of progesterone), lending evidence to the difference between pain descriptions of women and of men – particularly the cyclic nature of pain.

While these studies do not delineate the entire physiologic process behind cyclic pain, it does offer insight into the factors influencing how pain changes in women. Integrating an understanding of fluctuating inflammatory markers secondary to reproductive hormones into the concept of “neuronal cross talk” adds insight to the confusing and often changing pattern of chronic pelvic pain in cycling women. Since female pelvic pain may vary within ovulatory cycles, the clinician should consider closely the changes of complaints during the menstrual cycle. Establishing the status of patients as premenarchal, peri-menarcheal, reproductive age ovulatory, reproductive age nonovulatory, perimenopausal, and postmenopausal is important. As patients progress through stages of their reproductive status, their pain will likely change and require different treatment plans. The causes of pain in the menarcheal teenager not only differ from the postmenopausal woman but often differ from their closer peers in the early reproductive years. Thus, determining the ovulatory status of a patient should impact not only patients with complaints of infertility but also patients with pelvic pain.

3.1

Pelvic Pain Story

Of primary importance to the clinician is an understanding of the “story” each patient with pelvic pain tells. Particularly at the first visit.

In no other diagnostic process (with possibly the exception of a psychiatric history) is the history intake so vitally essential and pivotal. Many patients with pelvic pain have been seen multiple times by healthcare providers and tell stories of multiple diagnosis and treatment failures. They often bring with them not only the physiologic pain issue but also the emotional complexity related to a cycles of hope and failure. A primary key in caring for patients with pelvic pain is patience, particularly during the first visit. At his time the opportunity to build trust and cooperation with the patient becomes the cornerstone for all subsequent interactions. From this point on, the ability to negotiate a patient alliance in the process of investigation and therapeutic trials has often been set. The complex nature of the neuronal response, pelvic anatomy, and female hormonal status does not lend itself to quick and clear diagnoses within a few visits. Rather these complexities require the clinician and patient to commit to a long-term cooperative relationship. Chronic pelvic pain should be viewed in the same manner as that of other chronic morbidities like hypertension or diabetes. This view of chronic pelvic pain when established at the initial visit not only manages patient expectations but also physician expectations as the patient evolves through a cycle of success and failure under their care. Given the dual nature of pain as both a physiologic reaction and a psychiatric response, the goal of the first interview should be to first understand the contributing physiologic factors as well as the psychologic factors before determining the needed diagnostic exams or therapeutic interventions. Frequently the best care models for these patients are ones which approach the management of pelvic pain from a team perspective. Depending upon the resources available to a clinic, the medical team should not only include the primary physician and nurse evaluating the patient but also extend to other physician specialists, physical therapists, and mental health support (Chaitow

Management of Pelvic Pain, Dyspareunia, and Endometriosis

and Jones 2012). Novel models may even extend the mental health support team to include social service support depending upon the nonmedical needs of the patient. During the initial visit, the history of present illness (HPI) should have three sections of focus: the classical description of the nature of the pain, the time course or evolution of the pain, and finally the history of the different assessments and prior treatments. Sufficient inquiry should be made to maximize the clinician’s understanding of the patient’s perception related to each of the above three areas. It is particularly helpful to note the emotional response of the patient as they describe each component in detail. The emotional response becomes an indicator as to severity of each symptom and the overall impact on her life style. The classical process of investigating the “seven attributes of a symptom” has no greater relevance than with pain. Detailing the location, quality, severity, timing, remitting/exacerbating factors, associated manifestations, and environmental influences of the patient’s pain complaints is critical (Bickley and Szilagyi 2012). Pointed questions to specific known events (either physiologic – i.e., ovulation – or psychologic – i.e., a loss of a loved one) and any change in the “seven attributes” of the pain will lead to improved differentiation between the three influences of pain (primary source, pain physiology, hormonal). Lastly, documenting results of past medical treatments adds information as to the primary source of the original injury, the influences of hormonal changes, and the possible presence of multiple diagnoses. The patient’s medical history becomes the second most influence portion in the initial interview. While this portion of history taking may appear routine and basic, the additional information obtained clarifies current diagnoses and may expand investigational and treatment options. Specific medical problems that may modulate pain responses include diabetes, rheumatologic

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diseases, inflammatory diseases, or prior surgeries. Reviewing medication history is also important and may add information such as highlighting pain modulation and behavior related to current or past medications. Importantly for female patients, a thorough gynecologic history cannot be avoided. The elements of the last menstrual period, menarche, dysmenorrhea [now and in past], number of pregnancies, types of deliveries or terminations, delivery complications, regularity of cycle length, bleeding duration, flow of bleeding, prior sexual infection exposure and treatment courses, and current and past contraceptive usage. An additional element of the gynecologic history requires a review of pap smear screening. While it usually does not directly add insight into the patient’s pain history, it may provide further information of the patient’s awareness of their own health status and needs. Lastly, it is worthwhile to spend some time understanding the patient’s psychiatric history. Finally, the last element is a complete and careful physical and pelvic exam. Specific recommendations are as follows: 1. Go slow. This cannot be stressed enough. Much of the “pain” reaction of patients during this exam is provoked by clinicians who perform this exam without much warning and with extreme rapidity or roughness. 2. Limit the amount of palpation to directive, purposeful movements. a. Directive palpation of the external genitalia, vaginal entrance (hymenal ring), vaginal walls (anterior, posterior, lateral), levator ani muscles, cervix, uterus, and adnexa may help to identify a precise area of provocation. b. Usage of a single digit or q-tip may help to further elicit a precise pain response and thus a specific diagnosis. c. Bimanual assessment of uterus should focus on assessment of size, mobility, and position within the pelvic cavity. Cervical motion tenderness is noted. Ovarian assessment is primarily focused upon the presence or absence of fullness from a mass, not on the presence or absence of normal ovaries.

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d. Rectovaginal assessment allows for assessment of abnormal tissue growth (whether a mass or disease invasion), mobility of organs in contrast to bony pelvis, tenderness, and cul-de-sac disease. 3. Speculum assessment requires the proper size speculum a. Standard metal speculums have a Grave’s speculum design which has a wider nose and thus more useful in parous women. b. Standard plastic speculums have a Peterson’s design which has a narrow nose and thus more useful in patients with narrow or tight introituses.

3.2

Confirming Suspicion with Objective Data

The approaches to lab work and radiologic investigation mirror two philosophies within medicine: investigate based upon ordered differential diagnosis list and investigate based upon anticipated “worst” outcome priority. Frequently blood work will include a complete blood count and a comprehensive metabolic panel. Additional laboratories include inflammatory markers, sedimentation rate or (hs)CRP or Ca-125 when endometriosis is suspected. Rheumatologic disease screening is particularly good in patients with systemic pain complaints. A pelvic ultrasound confirms findings of enlarged pelvic organs or masses found on physical exam or on ovarian masses or tubal pathology. It is also the best imaging option to delineate the pelvic organs as it offers the least amount of radiation exposure. The role of a CT scan or a MRI in the setting of chronic pelvic pain is to assist with diagnosis and surgical planning or to rule out suspected or unsuspected malignancy.

3.3

Management and Treatment Options

• Risk factors for endometriosis include heavy monthly menstrual flow, menstrual outflow obstruction, and family history. Common symptoms include cyclic pelvic, lower back or rectal pain, severe menstrual cramps, deep dysmenorrhea, painful bowel movement, and primary infertility. The Ca-125 is often elevated. Pelvic ultrasound or MRI may show an endometrioma if present but will not show endometrial implants. Laparoscopic confirmation of endometriosis is rarely recommended as the first line treatments are Mirena IUD, progestin dominant oral contraceptive pills, and cyclic NSADs. Second line treatments include gonadotropin agonists and contraceptive implants. [see below] • Dyspareunia on entry and/or deep penetration can be due vulvovaginitis, STDs, herpetic lesion, injury to vulva or vagina, atrophic vaginitis, vaginal inlet obstruction, vaginismus, lichens sclerosis, or vulvodynia [chronic pain affecting the vulva]. Dyspareunia on deep penetration may be caused by uterine fibroid or mass, pelvic endometriosis, ovarian cyst, ectopic pregnancy, pelvic adhesions. Evaluation of vulva or vaginal discharge, redness, injury, lesion, pregnancy test, ultrasound findings, menopausal status along with detailed description of the complaint generally leads to the correct treatment option. [See below] (Table 2) • Systemic complaints, complaints that present across multiple organ systems, require a thorough investigation of diseases which present in a systemic fashion (i.e., rheumatologic pathologies, immunologic pathologies). Treatments targeting only the pain will palliate but not treat many systemic disease presentations. • Musculoskeletal complaints of the pelvic floor (ranging from spasms of vulvovaginal area to dyspareunia to incontinence) require a systematic and detailed physical exam. Through the combination of a thorough history and precise pelvic exam one can often consult with a physical therapist with a specialty in pelvic floor

Management of Pelvic Pain, Dyspareunia, and Endometriosis

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Table 2 Factors associated with either deep or superficial dyspareunia (Reprinted with permission, Meana and Binik 2011). ainconsistently associated with deep dyspareunia Conditionsa associated with deep dyspareunia Lack of arousal necessary for vaginal lengthening or lubrication Chronic cervicitis Repeated cervical trauma Bowel disorders (i.e., IBS) Endometriosis Ectopic pregnancy Vulvovaginitis Pelvic adhesions (secondary to infection or surgery) Uterine fibroids Pelvic inflammatory disease Pelvic congestion Pelvic organ prolapse Urologic disorders (i.e., painful bladder syndromes) Fibroids, pelvic mass, ovarian neoplasm, cyst

function to develop a treatment plan which have durable efficacy. Surgical corrections are available in some instances. Use of NSAIDs can also be effective. • Myofascial trigger points have been associated with increased sensitization and crossactivation of other pain syndromes within the pelvis – particularly those related to urinary complaints, sexual dysfunction, and vulvovaginal pain (Chaitow 2007). Deactivation of these sites often impacted the pain perceived from the above related sites. Manual deactivation lies within the realm of the rehabilitation therapist; however, clinicians may also rely upon trigger point injections at sites of extreme tenderness. • Bulk symptoms (ranging from pressure to increasing abdominal girth) should also include a thorough investigation of associated gastrointestinal complaints, radiologic investigations, as well as consideration of a risk profile for carcinoma. Ultimately, treatment may involve surgical excision and a referral to a gynecologic surgeon. • Perimenopausal complaints require an understanding of the perimenopausal period. Perimenopause is defined as the 4–5 years before the onset of menopause punctuated by

Conditions associated with superficial dyspareunia Vestibulodynia Vulvovaginitis Sexually transmitted infections Vulvodynia Vaginismus Vulvar dermatoses Congenital anomalies Obstetrical sequelae (i.e., episiotomy scars) Bowel disorders (i.e., IBS) Vulvovaginal atrophy Neurologic disorders Muscular abnormalities (i.e., pelvic floor hyper- or hypotonicity Neoplastic vulvar lesions Urologic disorders

symptoms of hormonal fluctuations: irregular cycles, hot flashes, vaginal dryness, dyspareunia headaches, mood and sleep disturbances. As previously mentioned, the process of sensitization is modulated by the cyclic nature of estrogen and progesterone, thus any changes to this cycling may modify pain sensation. Low dose hormonal replacement often has efficacy. • Mental health and mood disorders can modify the perception of the severity of their disease. Descriptions of pain symptoms which appear out of proportion of believed triggers; persistent pain which does not fit a generalizable physiologic pattern may require inquiries into the state of the patient’s mental health. Again, having a therapeutic team available to assess these patients not only provides comprehensive care for difficult diagnoses and assists in managing efficiencies within the medical system. • Neuropathic pain as mentioned previously may not be easily identified as true neuronal damage versus persistent stimulation of the neuronal tissue, but idiopathic modulation of the neuronal tissue can be done through the usage of both tricyclic antidepressants and neuromodulators such as gabapentin. Such

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usage may not elicit the true pathophysiology, and a thorough work up of the pain should be pursued. Consultations with physical therapy and neurology may enhance the therapeutic process. • All facets of the inflammatory processes can be applied to basic nociceptive triggers and often are difficult in isolating the original source of the inflammation. Thus, not all NSAIDs are effective and not all antibiotics treat pelvic pain. • Given the potential severity of pelvic inflammatory disease it is always reasonable to treat for suspected PID, first, but close follow-up should be practiced to elicit any changes or persistence of pain which will require further investigation into the proper diagnosis.

3.4

Dyspareunia

Dyspareunia is considered a part of the spectrum of female sexual dysfunction though generally is described as pain with intercourse. It spans the spectrum of pain during any portion of the sexual response cycle. The International Classification of Disease 10th revision attempts to attribute dyspareunia to either organic or nonorganic causes, and the Diagnostic and Statistical Manual of Mental Disorders 4th revision separates the origin of dyspareunia into psychologic factors versus combined factors (Meana and Binik 2011). While the terminology and the complexity of neuron physiology plague both chronic pelvic pain and dyspareunia, other factors such as culture, personal opinions of morality and ethics, and societal perceptions influence the patientphysician interaction and subsequently clinical investigation and treatment further complicate the process of diagnosis and treatment in patients with complaints of dyspareunia. As women continue to delay reproductive activity but maintain an active sexual life, questions surrounding sexual activity and capacity have become more common place. The World Health Organization in 2006 estimated that about 8–22% of sexually active female reporting painful

intercourse with 26% attributing their sexual difficulties to dyspareunia (Meana and Binik 2011). The variety in the reported prevalence of dyspareunia arises from differing definitions used to define dyspareunia and characteristics of the target study group: age, educational level, socioeconomic standing, and comorbid conditions, particularly urinary complaints (Palacios et al. 2009). Estimates of dyspareunia prevalence increase when the study population is composed of “high risk” populations such as chronic pelvic pain patients or patients with reported female sexual dysfunction. In contrast to chronic pelvic pain, well-defined approaches to history taking, physical exam, and diagnostic investigation have not been a part of the educational standard within women’s health. While scientific literature and experts within the field exist, clinicians continue to struggle with caring for women with sexual complaints. As dealing with chronic pelvic pain, patients with dyspareunia require clinicians to understand the overlap and integration between pathology and psychological symptoms. The DSM IV defines dyspareunia as recurrent or persistent genital pain associated with sexual intercourse which causes personal distress (Mimoun and Wylie 2009). In approaching patients with these complaints, often the first hurdle is managing the patient’s distress surrounding her pain.

3.5

The Sexual Stages and Categories of Sexual Dysfunction

Beginning with the stages of the sexual response cycle in women, two models have been described. Masters and Johnson described a cycle of four stages: stimulation leads to excitement – plateau – orgasm – resolution. Kaplan describes the sexual cycle as stages of desire, arousal, orgasm, and resolution. In contrast, Basson adds a layer of complexity by acknowledging the psychosocial aspects and influences of emotional intimacy (Clayton and Hamilton 2010). Satisfaction in an individual’s sexual response does not depend upon the completion of all these aspects. A lack

Management of Pelvic Pain, Dyspareunia, and Endometriosis

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Fig. 2 Central effects on sexual function. + indicates a positive effect; indicates a negative effect (Reprinted with permission Clayton and Hamilton 2010)

in any of these four areas may cause disruption in a patient’s sexual satisfaction. The 2017 ICD-10-CM R37 clinical describes sexual dysfunction, unspecified as “a change in sexual function that is viewed as unsatisfying, unrewarding, inadequate or deleterious.” This category is further divided into multiple specific causes. In the largest and most diverse crosssectional studies on menopausal women in the United States, SWAN (Study of Women’s health Across the Nation) describes six variables related to sexual outcomes in menopausal women (Avis and Green 2011): Importance of sex, sexual desire, frequency of activities and physical pleasure (both intercourse and masturbation), emotional satisfaction with partner, arousal, and pain. The diagnostic criteria of sexual dysfunction used by the DSM IV-TR is divided into multiple categories including sexual desire disorders, sexual arousal disorders, and orgasmic disorders sexual pain disorders. The categories and criteria of sexual pain disorders are listed below. DSM IV-TR: Sexual pain disorders are divided into two sections. • Dyspareunia – Recurrent or persistent genital pain associated with sexual intercourse causing

marked distress of interpersonal difficulty. • Vaginismus – Recurrent or persistent involuntary spasm of the musculature of the outer third of the vagina that interferes with vaginal intercourse causing marked distress or interpersonal difficulty. A discussion between clinician and patient regarding the level of distress is important. A conversation defining the goals of sexual function may have more impact than anticipated within the context of managing dyspareunia. Hormonally, current understanding has defined roles for both sex hormones and neurotransmitters within the stages of sexual desire/excitement and sexual arousal (Fig. 2). While specific female hormone–receptor combinations and cellular cascades have not been fully delineated, all the sexual hormones (testosterone, estrogen, progesterone) play a part in increasing sexual desire and maintaining organs during arousal (Fig. 3). How each hormone interacts with the other and in which manner continues to be an area of study. While no direct association has been made

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Fig. 3 Peripheral effects on sexual function. + indicates a positive effect; indicates a negative effect (Reprinted with permission Clayton and Hamilton 2010)

between changing levels of estrogen and decreasing sexual outcomes, there does appear to be an association between increasing vaginal dryness and increasing complaints of dyspareunia. Dyspareunia can occur during the early stages of the perimenopausal period or late stages. Studies show effectiveness of vaginal or systemic estrogen replacement with decreasing dyspareunia. Animal studies demonstrate a role for dopamine in the stimulation of sexual desire, arousal, and drive (Hull et al. 1993). In drilling down to individual stages of the sexual cycle, norepinephrine is known to play a role in arousal while oxytocin is known to play a role in orgasms.

3.6

Management of Dyspareunia

With complaints of dyspareunia there is a need to differentiate between the two biggest categories of pain with intercourse: dyspareunia versus vestibulodynia. More general terminology divides dyspareunia into deep dyspareunia and superficial dyspareunia (Meana and Binik 2011). Often deep dyspareunia is associated with pathology deeper within the vaginal canal, cervix, and pelvic cavity. Superficial dyspareunia is associated more with the external genitalia and vaginal entrance (hymen). Meana et al. describe a list of factors associated with either deep or superficial dyspareunia in their publication on chronic pelvic pain (Table 2) (Meana and Binik 2011).

While the factors related to superficial dyspareunia tend to be more consistent in their presentation, the exam associated with delineating between deep and superficial is more detailed and extensive than a routine pelvic exam. Examining these patients requires a pre-exam suspicion leading to a detailed exam of the external genitalia occasionally utilizing a q-tip or finger for localization of pain responses along individual portions of the external genitalia. The portions of the external genitalia examined include mons pubis, labia majora, labia minora, clitoral hood, urethra, skene’s glands, hymen, bartholin’s glands, introitus, and vulva. Special attention should be given to the specific areas of complaint by the patient. Evidence of infection, lesions, erythema, swelling, color changes, and differential texture should also be noted. As the exam progresses to the vaginal canal, usage of a single digit at the beginning of the bimanual portion of the pelvic exam is recommended. The bimanual exam includes a directive palpation of the vaginal canal along the anterior, lateral, and posterior walls in a sequential manner. Palpation of the cervix should be done in a manner to isolate the cervix from the vaginal walls thus decreasing any confounding response from vaginal tenderness. Assessment of the uterus and adnexa should proceed noting any masses and/or tenderness. Attention is paid to abdominal findings of guarding or distention. Often the smallest Peterson billed

Management of Pelvic Pain, Dyspareunia, and Endometriosis

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Table 3 Therapeutic options for the listed conditions contributing to complaints of superficial dyspareunia Conditions associated with superficial dyspareunia Vestibulodynia

Cyclical vulvovaginitis Sexually transmitted infections Vulvar dermatoses Congenital anomalies Obstetrical sequelae (i.e., episiotomy scars) Vulvovaginal atrophy Neurologic disorders Muscular abnormalities (i.e., pelvic floor hyper- or hypotonicity Neoplastic vulvar lesions Urologic disorders Bowel disorders

Therapeutic options Lidocaine gel prior to intercourse, capsaicin cream, anti-tricyclics (either oral or vaginal), severe symptoms may benefit from trigger point injections, as a last resort – surgery may be indicated Suppression of cause of vulvovaginitis if infective versus steroidal creams for systemic inflammatory complaints Appropriate antibiotic/parasitic treatment Therapy should target pathology results Depending upon diagnosis: surgical intervention, vaginal dilators, hormonal therapy, etc. Vaginal dilators versus surgical intervention Vaginal estradiol preparations versus Premarin ®, systemic hormone replacement Consultation with neurologist for systemic manifestations is recommended Vaginal dilators, muscle relaxants via a vaginal route, relaxation techniques, pelvic floor physiotherapy, antidepressants versus antipsychotics Treatment according to pathologic diagnosis Kegels, pelvic floor physiotherapy, vaginal estrogen may consider comanagement with a urogynecologist depending on the diagnosis Treatment for constipation, consideration of comanagement with a gastroenterologist depending upon diagnosis

speculum is better tolerated than a typical Graves speculum. One should not shy from frequent exams as they may be necessary to narrow down the differential as complaints persist or alter. During this pelvic exam, attention should be paid to any area of chronic skin changes or abnormal growths within the vagina or cervix which necessitates a biopsy for complete assessment. Cultures for sexually transmitted infections or wet mount can be performed to help differentiate possible infectious contributors to the complaints of dyspareunia. Vaginal smears can be used to assess for atrophy. Other laboratory investigations vary based on suspected systemic disease (such as diabetes). Radiologic investigations starting with pelvic ultrasound may be useful to confirm physical exam findings during the bimanual exam but are not mandatory in the process of evaluating dyspareunia. Treatment should be targeted as suspicion for particular diagnoses arises whether for an infection, neoplasm, atrophy, etc. In Table 3 is a list of therapeutic options for the listed conditions contributing to complaints of superficial dyspareunia.

Conditions and therapeutic options associated with deep dyspareunia are shown in (Table 4).

3.7

Endometriosis

The incidence of endometriosis in premenopausal patients with chronic pelvic pain symptoms ranges from 35 to 50%, while the overall incidence in all women is about 10% (Burney and Giudice 2012). The two complaints most often associated with the presentation of endometriosis in premenopausal reproductive aged women are pelvic pain or infertility. It is suggested that about 20–50% of patients with infertility have endometriosis and that about 30–50% of patients with endometriosis have infertility (The Practice Committee of the American Society for Reproductive Medicine 2006). In a comparison to fertile women, infertile women have up to a 6-to 8-fold increased risk for endometriosis. Given the variable pain presentation of patients with endometriosis, a complaint of infertility triggers considerations of endometriosis. When the chief

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Table 4 Treatment options for deep dyspareunia complaints Conditions* associated with deep dyspareunia Lack of arousal necessary for vaginal lengthening Chronic cervicitis Repeated cervical trauma Pelvic endometriosis Pelvic adhesions (secondary to infection or surgery) Uterine fibroids Pelvic inflammatory disease Pelvic congestion Pelvic organ prolapse Urologic disorders (i.e., painful bladder syndromes) Bowel disorders (i.e., IBS)

Therapeutic options Counseling, self-experimentation with arousal techniques, vaginal dilators, vibrators Treatment as dictated by the CDC Surgical options for excision Hormonal suppression (oral vs. injection), surgical excision Appropriate treatment if infective, surgical excision Medical therapy to decrease size, surgical excision, ultrasonic options in certain institutions Treatment as dictated by the CDC, interventional drainage if abscess is present, surgical excision Hormonal suppression, surgical excision Kegels, pessary, surgical excision with repair Kegels, targeted medical therapy depending upon diagnosis, pelvic physiotherapy, surgical interventions per urogynecologic recommendations Treatment targeting constipation, consultation of a gasteroenterologist

*Inconsistently associated with deep dyspareunia

complaint of a patient is infertility, the clinical investigation process must expand to include the appropriate overall infertility testing. Despite the high incidence of endometriosis among symptomatic patients in their reproductive life, an average 6.7 years often pass before a diagnosis of endometriosis is determined (Nnoaham et al. 2011). Evaluation of ovaries by transvaginal ultrasound is often first line treatment for patients presenting with ultrasound especially when complaints on dysmenorrhea or dyspareunia or pelvic pain.

3.8

Pathophysiology

Burney et al. give a thorough and well written summary “Pathogenesis and pathophysiology of endometriosis” from Fertility and Sterility Vol 98. No3. September 2012. They define endometriosis as “an inflammatory, estrogen-dependent condition associated with pelvic pain and infertility” with multiple theories related to the “origin and molecular basis” of its disease process. Taken from their article, Fig. 4 demonstrates most of the current theories on the pathogenesis of endometriosis, the most well-known being Sampson’s theory of retrograde menstruation. Support for

this therapy lies not only in laparoscopic studies of healthy women with patent fallopian tubes identifying retrograde menstruation in 90% of these patients, but also from observed correlations between women with mullerian malformations and the increased prevalence of endometriosis among them. Obstructive outflow pathology of mullerian malformations leads to “back flow” of endometrial tissue through the fallopian tubes into the intraabdominal peritoneal cavity. The observed areas of implantation of likely retrograde endometriotic tissues presents commonly in the posterior cul-de-sac, ovaries, and tubes. Additionally, there are other factors include genetic susceptibilities, endocrine responses, immune system activation, epigenetic modifications, and a emybrologic origin of endometriosis (Signorile and Baldi 2010). Proliferation of endometrial cells in the peritoneal environment causes not only an activation of inflammatory markers but also a change in both the nature of the endometrial cells and the surrounding peritoneal cells. Physical evidence of these changes correlates to various scar tissues on the peritoneum that are seen during surgical visualizations. These lesions are often described by their coloring – black, red, white or by the

Management of Pelvic Pain, Dyspareunia, and Endometriosis

17

Fig. 4 Theories regarding endometriosis pathogenesis (Reprinted with permission Burney and Giudice 2012)

presence of adhesive tissue between pelvic organs. Infertility in patients with endometriosis is thought to be due to several factors including tubal scarring and blockage leading to the interrupted passage of a mature ovum and unfavorable hormonal/inflammatory environment for either fertilization or implantation. De Ziegler et al. break up the pathophysiology of infertility secondary to endometriosis into three categories (Fig. 5): pelvic fluid within the pelvic cavity, ovarian function at the level of the ovary, and the endometrium (De Ziegler et al. 2010). Activation of inflammatory markers leads to a change in the peritoneal fluid which baths the reproductive organs. The most favorable location of fertilization is the ampullary region of the fallopian tube, an area that is open to the exposure of free peritoneal fluid. Altered ovarian function specific to endometriosis patients has yet to have an explanation or description of a specific pathologic process. Scientists have reported that endometriosis increased production of estradiol through prostaglandins as well as an abnormal response to progesterone. Endometriosis often has a misalignment between disease severity and symptom complaint. A disease state found in an individual may be

replicated in another individual but it may not confer the same or even similar symptoms. This divergence between pathophysiology and clinical presentation is reflected within the multiple efforts to create a staging system for endometriosis similar to a cancer staging system. Although the American Society of Reproductive Medicine (ASRM) has the longest standing staging system for endometriosis, it has been fraught with limitations because of the noncorrelation between disease stage and symptom presentation (Pearce et al. 2012). In addition, there is a lack of prognostic value. The primary benefit to the ASRM system has been within the realm of research and repeat surgical assessments. In 2010 Adamson and Pasta introduced a validated revision of the ASRM endometriosis staging system that is designed to correlate with nonin-vitro fertility treatment outcomes and give clinicians an opportunity to counsel patients on possible anticipated outcomes (Adamson and Pasta 2010). They describe a scoring system where an endometriosis fertility index, using history, surgical findings and functional assessment of tubes and ovaries is calculated. This index is then used to correlate with non-in-vitro fertility treatment outcomes (Fig. 6).

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J.H. Chen

Fig. 5 Effects of endometriosis on human reproduction (Reprinted with permission De Ziegler et al. 2010). ART: assisted reproductive technologies

3.9

Management of Endometriosis: Pelvic Pain

The two complaints associated with endometriosis, pelvic pain and infertility, usually require a different approach during the initial patient interview and assessment. To begin, it may be more approachable to start with those patients who have complaints of pain and then move to those who present with infertility. While the emotional carriage which will accompany both complaints may be similar, the details of history and eventual

investigations will vary based upon the patient’s primary complaint and goals. The defining pain description of endometriosis is cyclic pelvic pain, otherwise traditionally known as dysmenorrhea. Dysmenorrhea is pain associated with menses and can be separated into two categories: primary versus secondary. Primary dysmenorrhea occurs in about 40% of menstruating teenagers and is not consistently related to endometriosis. The pathophysiology linked to primary dysmenorrhea focuses on the prostaglandin pathway stimulated by the shedding of the

Management of Pelvic Pain, Dyspareunia, and Endometriosis

19

ENDOMETRIOSIS FERTILITY INDEX (EFI) SURGERY FORM LEAST FUNCTION (LF) SCORE AT CONCLUSION OF SURGERY Score

Left

Description

4 3

= =

Normal Mild Dysfunction

Fallopian Tube

2

=

Moderate Dysfunction

Fimbria

1 0

= =

Severe Dysfunction Absent or Nonfunctional

Ovary

To calculate the LF score, add together the lowest score for the left side and the lowest score for the right side. If an ovary is absent on one side, the LF score is obtained by doubling the lowest score on the side with the ovary.

Right

Lowest Score

+ Left

= Right

LF Score

ENDOMETRIOSIS FERTILITY INDEX (EFI) Historical Factors Factor Description Age

If age is ≤ 35 years If age is 36 to 39 years If age is ≥ 40 years

Surgical Factors Points

Factor Description

Points

LF Score 2 1 0

If LF Score = 7 to 8 (high score) If LF Score = 4 to 6 (moderate score) If LF Score = 1 to 3 (low score)

3 2 0

Years Infertile If years infertile is ≤ 3 If years infertile is > 3

2 0

AFS Endometriosis Score If AFS Endometriosis Lesion Score is < 16 If AFS Endometriosis Lesion Score is ≥ 16

1 0

Prior Pregnancy If there is a history of a prior pregnancy If there is no history of prior pregnancy Total Historical Factors

1 0

AFS Total Score If AFS total Score is < 71 If AFS total Score is ≥ 71 Total Surgical Factors

1 0

+

EFI = TOTAL HISTORICAL FACTORS + TOTAL SURGICAL FACTORS:

Historical

= Surgical

EFI Score

Fig. 6 Endometriosis fertility index surgery form (Reprinted with permission Adamson and Pasta 2010)

endometrial lining rather than the implantation of ectopic endometrial tissue. The cyclic pelvic pain most consistently correlated with endometriosis falls into the category of secondary dysmenorrhea, implying that there was a period in which the patient had menses without pain. This detail becomes essential in differentiating between treatment options and diagnostic options from an empiric approach. Traditionally it is thought that pain associated with endometriosis occurs a day or two prior to the start of menstruation; however, it is not consistently demonstrative of endometriosis highlighting the variation between pathology and clinical manifestation. Other descriptions of pain associated with a disease process suggestive of endometriosis are

pain with defecation particularly if it worsens during menses and dyspareunia. This pain may or may not be cyclic but usually worsen during menses, the most symptomatic time of the endometriotic implants. Some endometriosis presents with variable or constant, noncyclic, generalized or localized pelvic pain. Since endometriotic tissue responds to hormonal changes, hormonal modulation is the primary medical therapy. The Mirena IUD or progestin dominant OCPs are the primary first line medical agents used to suppress pain symptoms. Gonadotropin agonists or antagonists, NSAIDs, progestin only pills, depo-provera, contraceptive implants, surgical resection are also options (Table 5).

20

J.H. Chen

Table 5 Review of standard medical therapeutic recommendations, their benefits, and common concerns (Vercellini et al. 2011) Medical therapy options Combined oral contraceptives

Levonorgestrel-releasing intra-uterine devices Progesterone only oral therapy (i.e., norethindrone acetate) Progesterone-based intramuscular injections GnRH analogues Danazol

3.10

Benefits Ease of prescribing, prevalent, effective in both cyclic and continuous fashion, diversity of hormonal combination to assist with side effect control One time administration, long duration of effectiveness, may induce amenorrheic state Ease of prescribing, minimal interaction with other medications, minimal estrogenic side effects Three-month administration, very effective suppressor of endometrial gland proliferation Three-month administration, very effective suppressor of endometrial gland proliferation Very effective suppressor of endometrial gland proliferation

Management of Endometriosis: Infertility

When investigating complaints of infertility, a review of definitions is beneficial. Infertility in patients less than 35 years of age is a period of greater than 12 months of regular timed intercourse without contraception that is not marked by pregnancy (note that it is merely pregnancy and not delivery that drives this definition). While a patient who is 35 years of age or greater may be considered to have issues of infertility if that period is greater than 6 months. The urgency of investigation and exploration of patients presenting with infertility complaints increases as they age (refer to the chapter on infertility for details). The physical examination in a patient with a suspicion for endometriosis does not vary greatly from the physical exam of a patient with general complaints of chronic pelvic pain. On the bimanual assessment, attention should be paid to the mobility of the uterus in comparison to the anterior abdominal well, adnexas, and rectum. Rectovaginal assessment may add information related to obliteration of the posterior cul-de-sac and/or dissection of the endopelvic fascia between the rectum and vagina.

Limitations/concerns Cannot be used when estrogen is contraindicated

Requires trained personal to place, implant within body Daily dosing required

Office based administration required, bone density changes occur during therapy Prominent hypoestrogenic side effects Prominent androgenic side-effects: acne, hirsutism, etc.

• Thus far serum markers for endometriosis have been more experimental rather than practical (Burney and Giudice 2012). Clinically, the most common serum marker has been CA 125 in the setting of an endometrioma (endometriotic mass of the ovary). As often noted in the literature specific to CA 125, this is a serum marker which is nonspecific and thus frequently elevated in cases of endometriosis in general. Still there appears to be a role not only serially as with the cases of concurrent ovarian malignancies (Pearce et al. 2012) but also possibly for disease monitoring and therapy (Mol et al. 1998). • Ultrasonography has had more clinical impact than the investigations into serum markers. General pelvic assessment with ultrasound for ovarian masses, endometriomas, has become undisputed in the initial investigation and assessment of patients for which suspicion for endometriosis is high. – Clinicians who specialize in endometriosis often recommend transvaginal ultrasonography to assess for invasive endometriotic lesions on the bladder and bowel allowing for a noninvasive manner of confirming a diagnosis of severe endometriotic disease as well as monitoring disease progression (Young 2014).

Management of Pelvic Pain, Dyspareunia, and Endometriosis

• CT or MRI may be useful to assess local tissue invasion but are not necessary for the initial assessment of endometriosis. Medical therapy primarily utilizes the pathophysiologic understanding that endometriosis is a disease that responds to hormonal fluctuations. Thus if the cyclic nature of estrogen and progesterone can be controlled, it is assumed that the disease progression and impact of endometriosis can also be controlled. Standard medical therapeutic recommendations, their benefits, and common concerns are reviewed in Table 5 (Vercellini et al. 2011). Other medical options have demonstrated potential in managing endometriosis through other molecular pathways: aromatase inhibitors (decreasing conversion of sex steroids to estrogen), immunomodulators and anti-inflammatory drugs (decreasing immune response and cytokine stimulation of pain pathways), anti-angiogenic therapies (blocking vascular endothelial growth factor in order to limit the invasive growth of ectopic endometrial tissue), and selective progesterone receptor modulators (blocking the effect of progesterone, primarily, and estrogen, secondarily, on reproductive tissue). All these options while available are generally considered after standard hormonal modulatory therapy has been exhausted. Surgical intervention can be divided into two aspects: conservative, implying fertility preservation, versus radical with complete removal of all reproductive organs. With the advancement of minimally invasive techniques (laparoscopic and robotic) and instruments, the ability to offer fertility preserving surgery has increased and become more ubiquitous. Complete removal of uterus with ovaries and tubes is reserved for those not seeking fertility. While it has a high success rate in relieving pain complaints, surgically induced menopause is associated with adverse changes in the vagina, bladder, brain, joints, vascular system, and bone. Postoperative problems with menopausal symptoms, mood disorders, bladder problems, vaginal atrophy, and sexual problems, along

21

with higher rates of cardiovascular disease, osteoporotic fractures, CNS diseases, and death rates in women with premenopausal removal of ovaries are reported. Some individuals who have undergone radical therapy may still have microscopic disease that is symptomatic requiring further therapy. Extensive counseling.

3.11

Reassessment

Chronic pelvic pain patients require close monitoring during early treatment and any period of uncertainty. While the frequency of close monitoring may differ depending upon overall assessment and treatment plan, a monthly follow-up for the first couple of months adds an early reassessment of treatment effectiveness and importantly adds to patient rapport and trust. At the point in the therapeutic process that the patient’s pain symptoms have improved or are resolved, lengthening of the interval of followup is appropriate. However, if the patient’s symptoms continue, worsen, or change in nature, a reassessment process mirroring the initial visit inquiry should be utilized and follow-up shortened and maintained appropriately.

4

Conclusion

The changing course of terminology and understanding of pain physiology cannot be stressed sufficiently. As terminology becomes more precise, the need increases to accurately specify a more specific etiology of pelvic pain based on this terminology. Matching clinical findings with a detailed history, directed physical and pelvic exam, appropriate laboratory, or radiologic assessment facilitates this process. Such a transition in describing and diagnosing pelvic pain will allow for more systematic and algorithmic approaches to treatment.

22

References Adamson GD, Pasta DJ. Endometriosis fertility index: the new, validated endometriosis staging system. Fertil Steril. 2010;94(5):1609–15. Avis NE, Green R. The perimenopause and sexual functioning. Obstet Gynecol Clin N Am. 2011;38 (3):587–94. Baranowski AP. Chronic pelvic pain. Best Pract Res Clin Gastroenterol. 2009;23(4):593–610. Berkley KJ. A life of pelvic pain. Physiol Behav. 2005;86 (3):272–80. Bickley L, Szilagyi PG. Bates’ guide to physical examination and history-taking. Philadelphia, Lippincott Williams & Wilkins; 2012. Burney RO, Giudice LC. Pathogenesis and pathophysiology of endometriosis. Fertil Steril. 2012;98(3):511–9. Chaitow L. Chronic pelvic pain: pelvic floor problems, sacro-iliac dysfunction and the trigger point connection. J Bodyw Mov Ther. 2007;11(4):327–39. Chaitow L, Jones R. Chronic pelvic pain and dysfunction: practical physical medicine. London, Elsevier Health Sciences; 2012. Clayton AH, Hamilton DV. Female sexual dysfunction. Psychiatr Clin N Am. 2010;33(2):323–38. De Ziegler D, Borghese B, Chapron C. Endometriosis and infertility: pathophysiology and management. Lancet. 2010;376(9742):730–8. Fall M, Baranowski AP, Elneil S, Engeler D, Hughes J, Messelink EJ, Oberpenning F, de C. Williams AC. EAU guidelines on chronic pelvic pain. Eur Urol. 2009; doi:10.1016/j.eururo.2009.08.020. Fields HL, Martin JB. Pain: pathophysiology and management. In: Braunwald E, Fauci AS, Kasper DL, Hauser SL, Longo DL, Jameson JL, editors. Harrison’s principles of internal medicine. 15th ed. New York: McGrawHill Medical Publishing Division; 2001. Holdcroft A, Jaggar S, editors. Core topics in pain. Cambridge, UK: Cambridge University Press; 2005. Hull EM, Eaton RC, Moses J, Lorrain D. Copulation increases dopamine activity in the medial preoptic area of male rats. Life Sci. 1993;52(11):935–40. Jones JB. Pathophysiology of acute pain: implications for clinical management. Emerg Med. 2001;13(3):288–92. Latthe P, Latthe M, Say L, Gülmezoglu M, Khan KS. WHO systematic review of prevalence of chronic pelvic pain: a neglected reproductive health morbidity. BMC Public Health. 2006;6(1):177. Meagher MW, Arnau RC, Rhudy JL. Pain and emotion: effects of affective picture modulation. Psychosom Med. 2001;63(1):79–90. Meana M, Binik YM. Dyspareunia: causes and treatments (including provoked vestibulodynia). In: Chronic pelvic pain. Oxford: Blackwell; 2011. p. 125–36.

J.H. Chen Mimoun S, Wylie K. Female sexual dysfunctions: definitions and classification. Maturitas. 2009;63(2):116–8. Mol BW, Bayram N, Lijmer JG, Wiegerinck MA, Bongers MY, van der Veen F, Bossuyt PM. The performance of CA-125 measurement in the detection of endometriosis: a meta-analysis. Fertil Steril. 1998;70(6):1101–8. Nnoaham KE, Hummelshoj L, Webster P, d’Hooghe T, de Cicco NF, de Cicco NC, Jenkinson C, Kennedy SH, Zondervan KT, Study WE. Impact of endometriosis on quality of life and work productivity: a multicenter study across ten countries. Fertil Steril. 2011;96 (2):366–73. Palacios S, Castaño R, Grazziotin A. Epidemiology of female sexual dysfunction. Maturitas. 2009;63 (2):119–23. Pearce CL, Templeman C, Rossing MA, Lee A, Near AM, Webb PM, Nagle CM, Doherty JA, Cushing-Haugen KL, Wicklund KG, Chang-Claude J. Association between endometriosis and risk of histological subtypes of ovarian cancer: a pooled analysis of case–control studies. Lancet Oncol. 2012;13 (4):385–94. Pezzone MA, Liang R, Fraser MO. A model of neural cross-talk and irritation in the pelvis: implications for the overlap of chronic pelvic pain disorders. Gastroenterology. 2005;128(7):1953–64. Signorile PG, Baldi A. Endometriosis: new concepts in the pathogenesis. Int J Biochem Cell Biol. 2010;42 (6):778–80. The Practice Committee of the American Society for Reproductive Medicine. Endometriosis and infertility. Fertil Steril. 2006;86(supplement 4):S156–60. Ustinova EE, Fraser MO, Pezzone MA. Colonic irritation in the rat sensitizes urinary bladder afferents to mechanical and chemical stimuli: an afferent origin of pelvic organ cross-sensitization. Am J Physiol Ren Physiol. 2006;290(6):F1478–87. Vercellini P, Eskenazi B, Consonni D, Somigliana E, Parazzini F, Abbiati A, Fedele L. Oral contraceptives and risk of endometriosis: a systematic review and meta-analysis. Hum Reprod Update. 2011;17 (2):159–70. Winnard KP, Dmitrieva N, Berkley KJ. Cross-organ interactions between reproductive, gastrointestinal, and urinary tracts: modulation by estrous stage and involvement of the hypogastric nerve. Am J Phys Regul Integr Comp Phys. 2006;291(6):R1592–601. Young SW. Imaging as the gold standard for diagnosis of endometriosis: TVUS techniques for deep endometriosis. 43rd AAGL Global Congress on Minimally Invasive Gynecology; 2014 Nov 17–21; ENDO604:12–36.

Management of Benign Breast Disease Heather R. Macdonald

Abstract

Contents 1 1.1 1.2 1.3

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical Breast Exam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Palpable Mass . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mastitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2 2 2 7

2

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

H.R. Macdonald (*) Keck School of Medicine, University of Southern California, Los Angeles, CA, USA e-mail: [email protected]; hmacdona@med. usc.edu # Springer International Publishing AG 2016 D. Shoupe (ed.), Handbook of Gynecology, DOI 10.1007/978-3-319-17002-2_79-1

The purpose of identifying and treating benign breast disease is twofold: to identify underlying breast cancer or exclude its presence and treat symptoms. The most common breast complaints are breast masses, breast pain, nipple discharge, and breast infections. A palpable breast mass should be evaluated by the triad of clinical breast exam (CBE), imaging (ultrasound in all patients with the addition of mammogram in patients over 30), and biopsy. Mastalgia is the most common breast complaint. A thorough evaluation should be performed to exclude malignancy. Nipple discharge may be physiologic, especially if bilateral, multiple ducts, seen only with expression and clear, green, or black. Medications, especially centrally acting or psychotropic drugs, and nipple stimulation are potential causes of non-pathologic discharge. Nipple discharge that is spontaneous, unilateral, single duct, clear or bloody, or associated with a palpable mass is especially concerning for underlying malignancy. Mastitis is a common occurrence even in non-lactating women. Inflammatory cancer must be ruled out, especially in an inflammation not responding to antibiotics and supportive measures. Lactating women with a breast infection must drain the breast regularly to prevent milk stasis that encourages bacterial growth. Antibiotic therapy should be guided by what is safe for the nursing infant. Skin flora is the most common pathogen. 1

2

H.R. Macdonald

Referral for specialty services should be provided to patients with atypical biopsies, discordant biopsies, breast cancer, biopsy findings that require excision, nonhealing abscesses, and hereditary breast and ovarian cancer syndromes.

Keywords

Clinical breast exam • Breast mass • Fibroadenoma • Mastalgia • Nipple discharge • Mastitis • Galactorrhea

1

Introduction

The purpose of identifying and treating benign breast disease is twofold: to identify underlying breast cancer or exclude its presence and treat symptoms. Breast complaints are common in gynecologic practice, and benign breast conditions are within the scope of practice of a general ob-gyn. Referral for specialty services should be provided to patients with atypical biopsies, discordant biopsies, breast cancer, biopsy findings that require excision, nonhealing abscesses, and hereditary breast and ovarian cancer syndromes. Elsewhere in this book, breast cancer screening in the asymptomatic woman is described. This chapter will focus on the evaluation and treatment of the symptomatic patient. Focus will be on the most common breast complaints: breast masses, breast pain, nipple discharge, and breast infections. Table 1 lists conditions for which specialty care is required, and the patient should be referred.

Table 1 Indications for referral to a breast specialist Indications for referral to a breast specialist Atypical breast biopsy Malignancy Histologic findings on biopsy that require excision Nonhealing breast abscess or inflammation Familial breast cancer syndromes Discordant breast biopsy results

1.1

Clinical Breast Exam

Clinical breast exam (CBE) should be part of a well woman health evaluation. The American College of Obstetricians and Gynecologists recommends women undergo CBE every 1–3 years between ages 20 and 39 and every year after age 40. If the patient is still menstrual, the ideal time to perform the exam is immediately after menses when breast tissue is most quiescent. The clinical breast exam should encompass all breast tissue from the clavicles to the inframammary folds and from the midaxillary lines to the sternal borders. Axillary and supraclavicular lymph nodes should be included in the field of examination. On clinical breast exam, dominant masses should be described by size, position on the clockface (with the nipple at the center, 12 o’clock superior, 6 o’clock inferior, etc.), and distance from the nipple (e.g., 2 cm mass at 4:00 3 cm from the nipple). The mobility of the lesion or lack thereof should be described as well as any overlying skin changes. The presence or absence of lymphadenopathy in the axillary or supraclavicular beds should be noted. Findings on clinical breast exam concerning for malignancy include tethering to the skin or underlying muscle, relative immobility of the mass, irregular or indistinct borders of a dominant mass, the presence of a mass with single duct bloody nipple discharge, overlying skin changes including erythema or induration, and the presence of axillary or supraclavicular adenopathy.

1.2

Palpable Mass

A palpable mass is a three-dimensional finding distinct from the surrounding breast tissue and is a common breast complaint. When a patient presents with suspicions of a palpable mass, she should be asked to describe when and how it was first discovered, how long it has been present, and if it is still palpable, does it change with her menstrual cycle, has she appreciated it before (i.e., does it come and go), is it painful, are there skin changes or nipple discharge, and has she had a breast mass previously in either breast. Masses

Management of Benign Breast Disease Table 2 Pertinent findings when documenting a breast mass Pertinent findings when documenting a breast mass Laterality Location expressed as clockface position and distance from the nipple Size Associated skin changes (edema, erythema, retraction) Fixation Texture (smooth, lobulated) Tenderness Presence or absence of axillary or supraclavicular lymphadenopathy

that wax and wane with menstrual cycles are consistent with fibrocystic changes and are rarely pathologic. History of a previous breast cyst or fibroadenoma may be informative as patients are at risk for additional lesions. Alternatively a palpable mass in conjunction with bloody nipple discharge is highly concerning for carcinoma. Overlying skin changes indicate an inflammatory process but can also be concerning for inflammatory carcinoma. Table 2 describes what should be documented when examination reveals a mass distinct from the surrounding breast tissue. A palpable breast mass should be evaluated by the triad of clinical breast exam (CBE), imaging (ultrasound in all patients with the addition of mammogram in patients over 30), and biopsy. Even in recent series, between 9% and 22% of palpable breast cancers were not apparent on breast imaging (Morrow 2000). In young patients with a benign clinical breast exam and benign appearing imaging (BIRADS 2), tissue sampling may be omitted, but as breast carcinoma or cancerous lesions metastasizing to the breast (lymphoma, sarcoma) can present in teenaged patients, careful consideration should be given to securing a definitive diagnosis of any dominant mass with tissue sampling. Tissue sampling should be accomplished with a needle wherever possible (Silverstein et al. 2009). Surgical excision of a previously unsampled breast mass should be rare. The majority of lesions will be benign and unlikely to need excision. The uncommon malignant lesion will not be completely treated by simple excision (if breast cancer) or

3

may not be treated surgically at all (if lymphoma or metastatic sarcoma). A concordant diagnostic triad of benign CBE, benign imaging, and benign biopsy carries a false-negative rate (or the chance that an underlying cancer may be missed) of less than 1% (Ariqa et al. 2002). Concordance of all three elements of the diagnostic triad is key. Any discordance between the clinical exam, imaging impression, and biopsy results should trigger a second biopsy or surgical excision. Management of the lesion is guided by the biopsy results. Asymptomatic benign masses less than 3 cm in size can be followed with ultrasounds to demonstrate stability every 6 months for 2 years. Any patient who is bothered by the sensation or presence of a mass should be offered excision. Surgical excision should be considered for lesions larger than 5 cm due to sampling concerns as breast lesions can be heterogeneous. Additionally, larger lesions can be cosmetically destructive even if benign and are better excised before they require more extensive if not reconstructive surgery. If atypia is identified within any lesion, surgical excision is warranted for definitive diagnosis and cancer risk reduction. Table 3 summarizes benign breast histology by risk of breast cancer as well as treatment considerations. Not all lesions listed will present as a palpable mass. For example, radial scar is most often identified by stereotactic core biopsy after a mammographic finding. However they are including Table 3 as a reference for interpreting breast biopsy results. Table 4 includes benign causes of palpable breast abnormalities and recommendations for management. Common benign causes of palpable breast masses include simple cysts and fibroadenomas. Cysts appear as empty black circles on ultrasound as cyst fluid allows free passage of ultrasound waves without reverberating back to the transducer. They often grow suddenly and are painful at first detection. They may be symptomatic with menses. They may be aspirated to alleviate tenderness. Cyst fluid should only be sent for cytology only if it is frankly bloody, as analysis of cyst aspirate has not been shown to be sensitive or specific for malignancy (Ciatto et al. 1987). Green, black, dark brown, yellow, and clear fluid

4

H.R. Macdonald

Table 3 Breast histology stratified by risk of breast cancer

Breast histology Carcinoma in situ (DCIS, LCIS) Proliferative lesions with atypia Atypical ductal hyperplasia Atypical lobular Proliferative lesions without atypia Fibroadenoma Moderate/ florid ductal hyperplasia of the usual type Radial scar/ complex sclerosing lesion Papilloma Papillomatosis Sclerosing adenosis Flat epithelial atypia Nonproliferative lesions (cysts) Duct ectasia

Papillary apocrine changes Nonsclerosing adenosis Periductal fibrosis Mild epithelial hyperplasia of the usual type Lipoma

Lifetime risk of breast cancer High risk 30–50% Intermediate risk

Therapeutic considerations Breast oncologic care

Consider chemoprevention

Low risk

Annual mammography may consider surgical excision; excise if symptomatic, biopsy discordant, or diagnosis in doubt

Minimal to no increase risk

Histology Breast cyst Fibroadenoma

Surgical excision

15–30%

5 cm

may be discarded. After cyst aspiration if any mass remains, it should be biopsied to avoid missing the solid component of a complex cyst. Cysts should only be surgically excised if they recur after multiple aspirations.

Fibrocystic change Proliferative fibroepithelial lesion

Management Observation; aspiration if painful Observation if asymptomatic 3 cm Observation Repeat sampling with needle biopsy or excision to rule out phyllodes tumor

Fibroadenomas are the most common solid benign mass, occurring in up to 25% of asymptomatic patients (El-Wakeel and Umpleby 2003). Fibroadenomas are biphasic lesions with both epithelial and stromal components. They belong to a family of lesions that include benign phyllodes tumors and cystosarcoma phyllodes. They frequently are nontender, firm, and very mobile and do not change with menses. Lesions less than 3 cm may be followed expectantly or excised based on patient preference. Many patients with fibroadenoma will form more than one lesion and may not desire multiple excisions. Fibroadenomas larger than 5 cm raise the suspicion of a phyllodes tumor. Larger lesions may be undersampled by needle biopsy and should be excised. Preoperative needle biopsy remains important however because a known phyllodes tumor is excised with a 1 cm margin to minimize recurrence, whereas a known fibroadenoma is not. In fact the compressed pseudocapsule of breast tissue that surrounds a fibroadenoma is carefully preserved at excision as it will decompress, often by the time the skin is closed, to fill in the defect left by the excised lesion. Phyllodes tumors even if benign are always excised as they are locally aggressive and cosmetically destructive. The management of breast cancers, carcinomas or sarcomas, is beyond this chapter.

1.2.1 Breast Pain Mastalgia is the most common breast complaint (Morrow 2000). It is more common among premenopausal patients than postmenopausal. Association with an underlying cancer is unusual but

Management of Benign Breast Disease

not impossible: in one series 16% of 240 patients with breast cancer presented with pain alone as an initial symptom (Preece et al. 1982). Concern for an underlying cancer may be what prompts the patient to seek medical attention, and a thorough evaluation should be performed to exclude malignancy. Cyclic mastalgia is generally described as a dull heaviness, worsened with pressure and movement and poorly localized. It may radiate to the axilla or shoulder. It may be alleviated with antiinflammatory medications. Noncyclic mastalgia is unrelated to timing of the menstrual cycle and is more common in the 40s and 50s. It may also be poorly localized and may not respond to over-thecounter medications. The underlying cause of breast pain is unknown. Premenstrual mastalgia suggests a hormonal cause, but no fluctuations or abnormalities of serum estrogen or progesterone levels have been shown to be associated with breast pain. Overuse of caffeine has also been postulated, but three studies looking at caffeine exposure and restriction in response to breast pain, including randomized control trials, have not demonstrated an association (Allen and Froberg 1987). In eliciting a history from a patient with breast pain, the duration and character of the pain should be characterized, as well as its location and relationship to the menstrual cycle. Any patient with recently missed menses should be evaluated for pregnancy as breast pain can be an initial symptom of a recently pregnant patient. The evaluation of mastalgia includes a clinical breast exam and a screening mammogram if the patient is over 35. Younger women may be appropriately evaluated with clinical breast exam alone without imaging if the exam is normal. Any palpable abnormality should be evaluated with ultrasound and possibly biopsy. Focal areas of tenderness may be ultrasounded to detect an underlying cyst too deep to appreciate on exam. Mastalgia is often selflimiting, resolving spontaneously in 3–6 months up to 80% of cases (Orr and Kelley 2016). Patients for whom the pain is severe enough to interfere with daily life and for whom it has persisted beyond the 3–6-month window expected for spontaneous resolution are candidates for

5 Table 5 Treatments for breast pain Agent NSAIDs Evening primrose oil Danazol

Bromocriptine

Tamoxifen

Comments and side effects Short-term efficacy Equivalent to placebo in randomized control trials Only FDA-approved medication for mastalgia Side effects: acne, androgenic (malepattern weight gain and hair growth and loss, deepening voice) Off-label use Decrease prolactin and stimulation of the breast Side effects: dizziness, potential for seizure if stopped suddenly Off-label use Estrogen antagonist at the breast Off-label use Side effects: menopausal symptoms, irregular vaginal bleeding due to endometrial stimulation; rare (VTE, cataracts, uterine cancers)

intervention. Table 5 outlines treatment options for mastalgia. The only FDA-approved medication for breast pain is danazol, an antigonadotropin. Response rates in clinical trials approached 75% for both cyclic and noncyclic breast pain at doses of 100–400 mg/day, with a slightly better rate seen in noncyclic pain patients (Mansel et al. 1982). Side effects include virilizing symptoms including deepening voice, weight gain, acne, and male-pattern hair loss and hair growth and limit its acceptability to patients. Tamoxifen a mixed estrogen receptor agonist/ antagonist can be tried in an off-label manner for 3–6 months. It blocks estrogen stimulation of the breast. Small studies of 10–20 mg daily have demonstrated pain relief (Fentiman et al. 1986; Messinis and Lolis 1988). Side effects include vaginal discharge, irregular uterine bleeding, and hot flushes. Long-term use has been associated with increased thromboembolic events, endometrial stimulation including hyperplasia and cancer, and cataracts. For patients wanting to try a herbal approach, evening primrose oil has been studied to treat breast pain with mixed results that mimic placebo effect; however, side effects were rare (Morrow

6

H.R. Macdonald

2000). Studies investigating caffeine restriction and vitamin E supplementation showed no benefit. Surgery has no role in the treatment of breast pain outside the excision of a tender mass.

1.2.2 Nipple Discharge Nipple discharge can be divided into physiologic discharge, potentially pathologic discharge, and discharge due to an underlying endocrine disorder or medication use. Single duct spontaneous clear or bloody nipple discharge is concerning for underlying breast pathology and should be worked up rigorously. The most common cause of spontaneous bloody nipple discharge is a benign intraductal papilloma, but an underlying ductal carcinoma must be ruled out. Key questions to ask when taking the history of a patient complaining of nipple discharge include the color of the discharge, with bloody or clear being most concerning and black or green being most likely physiologic. The patient should be asked to describe whether it is spontaneous or seen only with expression or manipulation of the nipple. If the patient has seen the discharge as it exists the nipple, she should be asked if it extrudes from one duct or several, with physiologic discharge seen at multiple points on the nipple. Single duct spontaneous discharge is most concerning. Table 6 describes pertinent characteristics that discern physiologic discharge from pathologic.

Table 6 Characteristics of nipple discharge Likely physiologic discharge Bilateral Multi-duct Seen with expression only Clear, green, brown, black History of nipple stimulation

Likely breast pathology Unilateral Single duct Spontaneous

Clear or bloody No history of nipple stimulation Presence of a palpable mass

Consider endocrinopathy or medication cause Unilateral or bilateral Multi-duct Spontaneous

Milky No history of nipple stimulation Menstrual irregularities

On clinical breast exam, the examiner should perform the exam as usual but then sweep all four breast quadrants with an eye on the nipple to note where pressure on the breast elicits the discharge. If discharge is expressed, the area of the breast being examined when the discharge was seen should be noted, as well as the color and how many ducts it involves. In the past, discharge has been sent for cytology. Studies have shown low sensitivity and specificity of cytologic studies of nipple discharge, so the test should no longer be ordered. Nipple discharge most concerning for underlying malignancy is single duct spontaneous clear or sanguineous discharge associated with a palpable mass. Workup includes diagnostic mammography, retroareolar ultrasound on the affected side, and biopsy of any identified lesions. If exam, mammogram, and ultrasound fail to identify a source, a ductogram may be considered. By injecting a radiopaque dye into the affected ductal system, a filling defect on subsequent mammogram may identify an intraductal mass. The ductogram is limited in its ability to localize and biopsy a lesion however. In the past decade, ductogram has largely been replaced by breast MRI with and without contrast, as lesions can be localized and biopsied with MRI guidance. Physiologic nipple discharge is common with repeated nipple stimulation, for example, with rigorous routine self breast exam, sexual activity, or nipple piercing or accessories. Once discharge is seen, some patients may feel a sensation of fullness behind the nipple that is alleviated by expressing the discharge, and others may feel compelled to express discharge in an effort to keep the area clean. By repeatedly expressing or checking for discharge, they are reinforcing its production and increasing its occurrence. The color is often black, brown, green, creamy, or clear and usually is elicited from more than one duct in the nipple. Retroareolar ultrasound may identify dilated ducts or duct ectasia. Green or black multi-duct nipple discharge that is seen only with expression from the nipple is not pathogenic but may be unnerving for the patient. Careful explanation of the mechanism of nipple stimulation to increase fluid production from the

Management of Benign Breast Disease

nipple and breast is important for patient reassurance, and treatment is cessation of nipple stimulation to diminish fluid production. Galactorrhea, or bilateral milky or creamy nipple discharge, usually identified in the absence of breast stimulation and coming from multiple ducts in both breasts is suggestive of an underlying endocrine disorder. Both prolactin-secreting tumors and hypothyroid disorders can present with galactorrhea. Please see the chapter entitled “▶ Hyperprolactinemia, Galactorrhea, and Pituitary Adenomas” for a more detailed discussion of galactorrhea. History and physical should focus on symptoms and signs of endocrinopathy including infrequent or absent menses, headaches, bitemporal vision loss, changes in appetite and weight, dryness of the hair and skin, and depressed energy and mood. Lab studies should include TSH and prolactin. If prolactin is elevated, a brain MRI focused on the sella turcica for pituitary lesions should be obtained and the patient referred for specialty care. Treatment may involve resection or medical therapy with antiprolactin medication like bromocriptine. Nipple discharge may also be related to medication use, particularly psychotropic medications. A careful medication history should be taken with attention paid to medications started or stopped in coincidence with onset of discharge.

1.3

Mastitis

Mastitis or inflammation of the breast can be due to several underlying causes: an acute peripheral abscess, a subareolar or periareolar abscess or fistula, granulomatous mastitis most commonly idiopathic in this country, or inflammatory breast cancer. Each has distinct presentation, treatment, recurrence risks, and workup. Mastitis is most commonly due to a bacterial infection. The most common pathogen is Staphylococcus aureus or skin flora. Antibiotic treatment is often initiated after a presumptive diagnosis of bacterial infection is made, but careful follow-up within 1 week is warranted to exclude a missed diagnosis of breast cancer. Risk factors for breast infections and abscesses in non-lactating women

7 Table 7 First-line antibiotic therapy for mastitis Condition Mastitis If penicillin allergic If MRSA is suspected or confirmed

Therapy Dicloxacillin, cephalexin Clindamycin, erythromycin Trimethoprimsulfamethoxazole double strength, clindamycin

include diabetes, smoking, and obesity. Common presenting symptoms are pain, redness, warmth, and fever. On physical exam, the affected breast is warm to touch, erythematous, and tender. An associated mass suggests an underlying abscess, and a breast ultrasound should be ordered for further evaluation. Abscesses smaller than 5 cm are often amenable to needle drainage; larger abscesses may require surgical incision and drainage. Antibiotic coverage should vary by local sensitivities, but Table 7 lists suggested targeted therapies to common pathogens. Patients should be followed closely for several weeks to ensure response to treatment. A clinical diagnosis of mastitis that does not respond to appropriate antibiotic treatment should be reevaluated for underlying malignancy. Ultrasound may be used to identify an underlying mass or lymph node for needle biopsy. If pus is encountered, it should be cultured for pathogen and sensitivities as antibiotic resistance is a growing problem. Bacterial infections of the breast are common in 10–20% of patients who are postpartum or nursing but may occur in otherwise healthy non-lactating women. Risk factors include milk stasis, blocked ducts, ineffectual infant feeding due to latch issues or poor suck, stress, tightfitting clothes or bras, or skin irritation and breakdown. Clinical presentation is similar to breast infections in non-lactating women. Treatment includes antibiotics, warm compresses to encourage milk expression, and aggressive massage and nursing (or pumping) to alleviate milk stasis. Antibiotic therapy should include aerobic and anaerobic coverage and should be with an agent safe for breastfeeding (see Table 7). Continuation of breastfeeding should be encouraged as prevention of milk stasis is of paramount importance to clear the infection. Infants are

8

more effective at draining the breast than pumps. Mothers can be reassured the breast infection does not pose a risk to her infant due to mother’s immunity present in the milk, antibiotic present in the milk, and an infant’s gastrointestinal immune defenses. If the mother chooses to stop breastfeeding, often due to discomfort, she should be educated she needs to continue to drain the breast with hand expression or a pump until the infection resolves. If an abscess is present, it should be treated similarly to that in a non-lactating patient. She should be counseled regarding the rare risk of milk fistula formation but be reassured most spontaneously resolve with cessation of breastfeeding. Peri- or subareolar abscesses are a distinct entity from peripheral breast abscesses. Patients will present with a painful subareolar infection that commonly fistulizes with drainage of pus from a defect at the periareolar border. They are frequently recurrent. Smoking is an important risk factor (Orr and Kelley 2016). The pathogenesis is thought to be squamous metaplasia of the terminal ductal epithelium with intussusception of secretions leading to infection and abscess formation. Acute abscesses should be treated with drainage if not draining already and antibiotics. When the inflammation has subsided, a duct excision via a radial incision is indicated to remove the occluded duct and excise the fistulous tract to prevent or treat a chronic fistula. Every nonhealing abscess should be evaluated with biopsy of the abscess wall to rule out inflammatory breast cancer. If no breast mass is identifiable by exam or imaging, the leading edge of skin erythema should be sampled with a punch biopsy. Inflammatory breast cancer can be readily identified by tumor cells in the dermal lymphatic system, creating the classic peau d’orange skin appearance of thickened erythematous skin with dimpled appearance. Inflammatory breast cancer is a poorly differentiated aggressive breast cancer that is systemic at its inception and carries a poor prognosis. The patient should be referred immediately to oncology for chemotherapy.

H.R. Macdonald

Rarely biopsy may reveal granulomatous mastitis, caused by either fungal or tuberculosis infections in the developing world but more commonly idiopathic granulomatous mastitis (IGM) in the USA. IGM describes an even more rare condition that presents with acute inflammatory changes and abscesses in the absence of infection or malignancy. It is a diagnosis of exclusion with granulomas seen on biopsy but no TB or fungal infections identified on special staining. The natural history is that of spontaneously occurring and resolving breast abscesses. Effective treatment is unknown although short courses of steroids are often used to diminish inflammation.

2

Conclusion

Breast complaints are common and distressing to patients, both due to their symptomatology and an underlying cancer-related anxiety. The evaluation of a breast complaint should be thorough to detect or rule out breast cancer and if appropriate reassuring to the patient. We have discussed the most common causes of benign breast disease. Patient education regarding normal breast health and abnormal breast findings is important.

References Allen SS, Froberg DG. The effect of decreased caffeine consumption on benign proliferative breast disease: a randomized clinical trial. Surgery. 1987;101:720–30. Ariqa A, Bloom K, Reddy VB, Kluskens L, Francescatti D, Dowlat K, Sizipikou P, Gattuso P. Fine-needle aspiration of clinically suspicious palpable breast masses with histopathologic correlation. Am J Surg. 2002;184(5):410–3. Ciatto S, Cariaggi P, Bulgaresi P. The value of routine cytologic examination of breast cyst fluids. Acta Cytol. 1987;32:301–4. El-Wakeel H, Umpleby HC. Systematic review of fibroadenoma as a risk factor for breast cancer. Breast. 2003;12:302–7. Fentiman IS, Brame K, Caleffi M, Chaudary MA, Hayward JL. Double blind controlled trial of tamoxifen therapy for mastalgia. Lancet. 1986;1:287–8.

Management of Benign Breast Disease Mansel RE, Wisbey JR, Hughes LE. Controlled trial of the antigonadotropin danazol in painful nodular benign breast disease. Lancet. 1982;1:928–30. Messinis IE, Lolis D. Treatment of premenstrual mastalgia with tamoxifen. Acta Obstet Gynecol Scand. 1988;67:307–9. Morrow M. The evaluation of common breast problems. Am Fam Physician. 2000;61(8):2371–8. Orr B, Kelley JL. Benign breast diseases: evaluation and management. Clin Obstet Gynaecol. 2016;59 (4):710–26.

9 Preece PR, Baum M, Mansel RE, Webster DJ, Fortt RW, Gravelle IH. Importance of mastalgia in operable breast cancer. Br Med J. 1982;284:1299–300. Silverstein MJ, REcht A, Lagios MD, Bleiweiss IJ, Blumencranz PW, Gizienski T, Harms SE, Harness J, Jackman RJ, Klimberg VS, Kuske R, Levine GM, Linver MN, Rafferty EA, Rugo H, Schilling K, Tripathy D, Whitworth PW, Willey S. Image-detected breast cancer: state-of-th-art diagnosis and treatment. J Am Coll Surg. 2009;209(4):504–20.

Management of Uterine Fibroids Valentina M. Rodriguez-Triana and William H. Parker

Abstract

Contents 1 1.1 1.2 1.3 1.4

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathology and Epidemiology . . . . . . . . . . . . . . . . . . . Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Oncogenic Potential . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Effects on Fertility and Pregnancy . . . . . . . . . . . . . .

2 2 2 2 3

2 2.1 2.2 2.3 2.4 2.5

Management of Uterine Fibroids . . . . . . . . . . . . . 3 Clinical Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Expectant Management . . . . . . . . . . . . . . . . . . . . . . . . . 5 Medical Management . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Surgical Management . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Radiologic Management . . . . . . . . . . . . . . . . . . . . . . . . 10

3

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

V.M. Rodriguez-Triana (*) • W.H. Parker (*) University of California Los Angeles, Los Angeles, CA, USA e-mail: [email protected]; [email protected]; [email protected] # Springer International Publishing Switzerland 2016 D. Shoupe (ed.), Handbook of Gynecology, DOI 10.1007/978-3-319-17002-2_80-1

Uterine fibroids are the most common tumors of the female reproductive tract. It is estimated that the incidence of fibroids by age 35 reaches 40 % for Caucasian women and 60 % for African American women (Baird and Dunson 2003). Most women with fibroids are asymptomatic; however, symptomatic fibroids remain the most common indication for hysterectomy. In 2010, approximately 196,735 hysterectomies were performed for fibroids in the United States (Wright et al., Obstet Gynecol 122 (2 Pt 1):233–241, 2013). The location of fibroids in the uterus will often determine the type and severity of symptoms a woman will experience. The most common presenting symptoms include infertility, heavy menstrual bleeding, bladder pressure, and pelvic pressure. A thorough history and physical examination along with appropriate imaging can help the clinician tailor the treatment options to improve a patient’s symptoms. As such, the management of fibroids is highly variable. Expectant management of fibroids is a reasonable option for women who are asymptomatic or not bothered by their symptoms. Medical management can be used for patients desiring to avoid surgery or in preparation for surgery. The surgical management of symptomatic fibroids is broad and includes endometrial ablation, laparoscopic cryomyolysis, laparoscopic uterine artery occlusion, 1

2

V.M. Rodriguez-Triana and W.H. Parker

laparoscopic radiofrequency volumetric thermal ablation (LRVTA), myomectomy (abdominal, laparoscopic, or hysteroscopic), and hysterectomy. Radiology-based management options include uterine artery embolization (UAE) and MRI-guided focused ultrasound. Both the UAE and the MRI-guided focused ultrasound require consultation with radiologists. Despite treatment options available, it is important for the clinician to recognize that not all fibroids require intervention. Counseling patients that fibroids do not have oncogenic potential may also help reassure them and guide their decision-making. Expectant management of fibroids in a stable woman is often an acceptable choice. Keywords

Fibroids • GnRH agonist • Levonorgestrel intrauterine device • Mifepristone • Myomectomy • Morcellation • Hysterectomy • Endometrial ablation • Hysteroscopy • Uterine artery occlusion • Laparoscopic radiofrequency volumetric thermal ablation • Uterine artery embolization • MRI-guided focused ultrasound

1

Introduction

1.1

Pathology and Epidemiology

Increasing age is associated with increased probability of developing fibroids. It is estimated that the incidence of fibroids by age 35 reaches 40 % for Caucasian women and 60 % for African American women. By age 50, the incidence reaches 70 % for Caucasian women and 80 % for African American women (Baird and Dunson 2003). Race also plays a role in the development of fibroids, as African American women are more likely to be diagnosed with fibroids approximately 5 years earlier than white women (Huyck et al. 2008). The exact mechanism is still unknown, although it could be related to differences in estrogen levels, diet, and environmental exposures (Marshall et al. 1997). Family history also plays a role in the development of fibroids, as women with a first degree relative with fibroids have a 2.5 times increased risk of developing fibroids themselves (Vikhlyaeva et al. 1995). Overweight women have a 21 % increased risk of having fibroids for every 10 kg increase in body weight (Ross et al. 1986). Certain factors are thought to be protective from the development of fibroids and include late menarche, exercise of 7 h per week, increasing parity, and tobacco use (Baird et al. 2003, 2007; Lumbiganon et al. 1996; Marshall et al. 1998; Michnovicz et al. 1986; Parazzini et al. 1996).

1.3 Fibroids are benign tumors of the myometrium. They are comprised of smooth muscle and contain large amounts of collagen, fibronectin, elastin, and proteoglycan (Leppert et al. 2006). They are surrounded by a pseudocapsule made of compressed smooth muscle and areolar connective tissue. In certain studies, fibroids have been detected in up to 77 % of all uteri removed during hysterectomy (Cramer and Patel 1990).

1.2

Risk Factors

Epidemiological studies have demonstrated certain risk factors for fibroid development.

Oncogenic Potential

Fibroids do not have oncogenic potential. They are monoclonal tumors that arise from myometrial smooth muscle and are genetically different from sarcomas. Genomic hybridization studies comparing sarcomas and fibroids have not found any shared anomalies between the two (Quade et al. 2004). There are certain leiomyoma variants that can demonstrate atypical behavior, but these tumors have a distinct histology and are not thought to originate from benign, typical fibroids. This becomes particularly relevant for women who opt for expectant management of their fibroids, as they should be counseled that their fibroids would not become cancerous if left untreated.

Management of Uterine Fibroids

1.4

Effects on Fertility and Pregnancy

Intramural and subserosal fibroids have not been shown to adversely affect fertility. In a study examining the use of hysteroscopy to assess cavity distortion from intramural and subserosal fibroids, there was no improvement in ongoing pregnancy rates or live birth rates after removal of intramural and subserosal fibroids (Pritts et al. 2009). In this same study, however, women with submucous fibroids had a 70 % decrease in pregnancy and live birth rates, which slightly improved after resection. This data is important to consider when counseling patients who desire fertility and have a fibroid uterus, as improvement in fertility rates remains contingent upon the location of the fibroids. Currently, there is no high-quality data to confirm the effects of fibroids on pregnancy; however, available data suggests that most women with fibroids will have normal pregnancy outcomes (Segars et al. 2014). Because of the relative paucity of data, it is not recommended that women with incidentally discovered fibroids undergo a myomectomy as part of preconception preparation.

2

Management of Uterine Fibroids

2.1

Clinical Evaluation

The goal of fibroid management and treatment is to improve overall quality of life, as their presence is rarely associated with any life-threatening emergencies. As such, a thorough evaluation of each patient will allow the clinician to provide treatment specific to a woman’s symptoms and goals.

2.1.1 Patient History Evaluation of fibroids begins with evaluation of symptoms, which can often give clues as to the location of the fibroids. The most common presenting symptom for women with fibroids is heavy menstrual bleeding. The degree to which

3

the patient has heavy bleeding is typically related to the location of the fibroids. Submucosal fibroids are the most highly associated with heavy bleeding and are also more likely to cause symptomatic anemia (Puri et al. 2014). The mechanism for this is likely due to fibroid deregulation of certain factors that affect angiogenesis, which in turn leads to the formation of abnormal vasculature that is more likely to cause bleeding (Stewart and Nowak 1996). Fibroids may also cause disrupted uterine contractions and impaired clotting mechanisms. Because the relationship between fibroids and heavy bleeding is variable, however, it is recommended that all women who present with abnormal uterine bleeding receive a full work-up, including screening for coagulopathies and other endocrinopathies. Because fibroids are not often associated with inter- menstrual and postmenopausal bleeding, women with these symptoms should undergo evaluation for underlying malignancies. The relationship of fibroids to pain has not been clearly established in the literature. In a study evaluating 635 asymptomatic women to determine the presence of fibroids via transvaginal ultrasound, the 96 women who had fibroids were only slightly more likely to complain of cyclic pelvic pain and dyspareunia compared to those without fibroids (Lippman et al. 2003). The women with fibroids were also no more likely to have dysmenorrhea than women without fibroids. Pedunculated fibroids that have torsed on their stalk can cause acute pain, which often requires surgical intervention. Fibroid degeneration is also associated with pelvic pain. Enlarging fibroids may outgrow their blood supply, which leads to cell necrosis and death. This process can often be successfully managed with NSAIDS and expectant management. Fibroids can be associated with pelvic pressure, bladder symptoms, and bowel complaints. Data looking at the effects of uterine artery embolization (UAE) on bladder symptoms demonstrated a 35 % reduction in mean uterine volume with a 86 % improvement in urinary frequency and urgency (Pron 2003). A separate study looking at women treated with GnRH agonist for 6 months demonstrated a 55 % decrease in uterine

4

volume with an additional decrease in urinary frequency, urgency, and nocturia (Langer et al. 1990). It is unclear from this data, if the symptom improvements were related to the medication or reduction in fibroid size. As mentioned earlier, patients with submucous fibroids can present with infertility. Thus, women presenting with infertility as a complaint should be evaluated for intracavitary pathology with saline sonohysterogram, MRI, or hysteroscopy as part of their work-up. There is no evidence to show that “rapid uterine growth,” defined by uterine growth of 6-week size in 1 year, correlates with the presence of sarcoma. In one study evaluating the incidence of sarcoma in patients presenting with rapid growth, one of 371 patients were found to have sarcoma (Parker et al. 1994). A reanalysis of the pathologic criteria used for this study found that this one patient had, in fact, an atypical leiomyoma rather than a leiomyosarcoma. Patients presenting with “rapid uterine growth” merit thorough evaluation, but this finding does not imply cancer.

2.1.2 Physical Examination Physical examination of patients with fibroids can often reveal size and location of fibroids and is essential when considering treatment options and planning a surgical approach. Even for women with a BMI >30 cm/kg, a bimanual exam to assess uterine size has been shown to correlate well with the actual pathologic size and weight of the uterus (Cantuaria et al. 1998). Most clinically significant subserosal and intramural fibroids will be detected as bulky and irregularly shaped on physical examination (ACOG 2000). As part of the evaluation, the clinician should assess the location of the top of the fundus. This will help determine the type of skin incision that is used for laparotomy or whether placement of an umbilical port would be feasible during laparoscopy. It is also important to determine how broad the uterus palpates in relationship to the pelvic sidewall. If the fibroid uterus feels very broad and difficult to be elevated off the sidewall, laparoscopic surgery may be more technically difficult.

V.M. Rodriguez-Triana and W.H. Parker

2.1.3 Imaging Imaging should be included as part of the evaluation of uterine fibroids. The most commonly used imaging modalities for fibroids are transvaginal ultrasound, salinesonohysterography (SSH), and magnetic resonance imaging (MRI). In one study evaluating the preoperative use of transvaginal ultrasound, SSH, hysteroscopy, and MRI in patients who were scheduled to undergo hysterectomy for symptomatic fibroids, MRI was 100 % sensitive and 91 % specific at detecting submucosal fibroids (Dueholm et al. 2001). Transvaginal ultrasound had 83 % sensitivity and 90 % specificity, SSH had 90 % sensitivity and 89 % specificity, and hysteroscopy had 82 % sensitivity and 87 % specificity. MRI provides the additional benefit of identifying adenomyosis and adenomyomas (Dueholm et al. 2002a, b). Focal areas that appear not well delineated and that have high or low intensity signals within the myometrium are very characteristic of adenomyosis. Of the above imaging modalities available for evaluation of fibroids, ultrasound continues to be the least expensive and most accessible. Fibroids on ultrasound appear as regularly shaped, hypoechoic masses. For uteri 1.5 cm, history of hypertension, and tamoxifen use (Di Spiezio et al. 2015; Lieng et al. 2010; Ben-Arie et al. 2004). 2.1.2 Diagnostics Transvaginal ultrasound (TVUS) is the first-line imaging modality for patients with AUB (American College of Ob/Gyn 2012). Polyps are typically hyperechoic lesions with regular contours within the endometrial cavity surrounded by a thin hyperechoic halo (Martinez-Perez et al. 2003). These findings are not specific to polyps and can be seen in other uterine abnormalities, like submucosal myomas. To further characterize the polyp or for patients with uncertain ultrasound findings, a saline infusion sonogram (SIS)

(ACOG 2012) or diagnostic hysteroscopy is recommended. SIS increases sonographic contrast of the uterine cavity to better evaluate the polyp and its features. SIS also allows detection of smaller lesions that were unable to be visualized on TVUS. Hysteroscopy with guided biopsy is the gold standard for the diagnosis of uterine polyps. It gives the ability to both directly visualize and to biopsy or remove the lesion. Other diagnostic methods that are less commonly utilized are blind dilation and curettage (D&C) for pathological diagnosis, hysterosalpingography (HSG), and pelvic MRI. If fertility is being evaluated, HSG is a good option to evaluate both the endometrial cavity and fallopian tubes. Three-dimensional ultrasound (3D US) is a noninvasive imaging technique with the ability to generate multiplanar reconstructed images through the uterus. 3D US allows the uterus to be visualized in coronal view, which allows for superior diagnostic accuracy (Ahmad et al. 2011).

2.1.3 Treatment Conservative medical management is an option, though the efficacy compared to low-risk surgical procedures, the cost-effectiveness, and the risk/ benefit ratio must be considered. GnRH agonists have been shown to give short-term relief from polyps though symptom recurrence is common (Vercellini et al. 1994). Combined hormone replacement therapies and levonorgestrelreleasing intrauterine system (LNG-IUS) have also been studied with limited data (Lieng et al. 2010; Gardner et al. 2009). Conservative surgical management, including blind D&C and TVUSguided polypectomy, has been commonly used but not recommended. However, given low risk of hysteroscopic resection, hysteroscopic methods are preferred (Munro et al. 2011). The most effective and safe method of diagnosis and treatment of endometrial polyps is hysteroscopy and polypectomy. The polypectomy can be performed via polyp forceps, polyp morcellation, or removal via electroloop. Recurrence rate is low, about 3.7%, and only 1.7% of patients undergoing hysteroscopic resection required repeat hysteroscopic resection (Preutthipan and Herabutya 2005). The most aggressive management option

Management of Abnormal Uterine Bleeding: Later Reproductive Years

is a hysterectomy for definitive treatment. It is the treatment of choice for polyps associated with malignancy or neoplasia.

2.2

Adenomyosis

2.2.1 Clinical Manifestations Adenomyosis is a condition in which the endometrial glands and stroma are located haphazardly within the myometrium (Reinhold et al. 1999). The ectopic endometrial proliferation within the myometrium causes reactive changes, including smooth muscle cell hyperplasia and hypertrophy, leading to a diffusely enlarged uterus (Ferenczy 1998). Adenomyosis is most frequently seen in parous women in their mid to late 40s (Azziz 1989). The prevalence ranges from 5% to 70%, likely due to inconsistent diagnostic criteria (McElin and Bird 1974). The relationship between adenomyosis and AUB is unclear. Adenomyosis is asymptomatic in up to half of all cases, but patients can present with various symptoms including AUB, dysmenorrhea, dyspareunia, and chronic pelvic pain. 2.2.2 Diagnostics Definitive diagnosis is made by histopathological examination of a uterine specimen; however, TVUS and magnetic resonance imaging (MRI) have been frequently used for accurate, noninvasive diagnosis. Adenomyosis may also be incidentally noted on hysterosalpingogram in patients undergoing fertility evaluation. The sensitivity and specificity for TVUS are 72% and 81%, respectively, while the sensitivity and specificity for MRI are 77% and 89%, respectively (Champaneria et al. 2010). The characteristics seen in adenomyosis on both imaging modalities are increased heterogeneity of the myometrium, linear striations radiating from the endometrium, myometrial cysts, poor definition of the endomyometrial junction, poor definition of lesion borders, and elliptical myometrial abnormality (Reinhold et al. 1999).

3

2.2.3 Treatment Hysterectomy is the definitive treatment for adenomyosis. There is limited data on the efficacy of conservative management in adenomyosis. Though studies are limited, combined oral contraceptives, danazol, and GnRH agonists, commonly used in treatment for dysmenorrhea and endometriosis, can be used (Kitawaki 2006). The LNG-IUD has been studied in adenomyosis, showing reduction in pain and AUB, as well as reduction in junctional zone thickness on MRI. The overall satisfaction after 36 months with the LNG-IUS for management of dysmenorrhea was 72.5% (Fedele et al. 1997; Bragheto et al. 2007; Sheng et al. 2009). Long-term follow-up for management of AUB has not been studied. Uterine artery embolization (UAE) has been shown to be successful in reduction in uterine size and improvement in dysmenorrhea and AUB. 57.4% of women had success at long-term follow-up at 3 years or longer and a mean reduction in uterine volume of 27.4% at long-term follow-up. Seventy percent of women were satisfied at their long-term follow-up even with a symptom recurrence rate of 38% (Kim et al. 2007).

2.3

Leiomyoma

2.3.1 Clinical Manifestations Uterine leiomyomata are the most common gynecologic tumor in women and the leading cause of hysterectomy in the United States. The incidence of fibroids has been shown to be as high as >80% in African-American women and almost 70% in white women (Baird et al. 2003). AfricanAmerican women are diagnosed at a younger age compared to Caucasian women, 37.5 years versus 41.6 years. African-American women were also found to have a greater number of leiomyomas, higher incidence of anemia, and more likely to report severe pelvic pain (Kjerulff et al. 1996b). Other risk factors include increasing parity, early menarche, and use of oral contraceptives before 16 years of age (Stewart 2015; Marshall et al. 1998). Symptomatology varies based on size, number, and location of fibroids. The

4

Y. Takashima et al.

Coagulopathy

Polyp

Ovulatory dysfunction

Adenomyosis

Submucosal

Leiomyoma

Other

Endometrial Iatrogenic

Malignancy & hyperplasia

Not yet classified

Leiomyoma subclassification system 3

2-5

5

O - Other

4 1

0 6

SM - Submucosal

2 7 Hybrid leiomyomas (impact both endometrium and serosa)

0

Pedunculated intracavitary

1