The histiocyte and it’s role in dermatology

Table of contents :
THE HISTIOCYTE AND IT’S ROLE IN DERMATOLOGY
INTRODUCTION
HISTIOCYTES
LANGERHANS CELLS
SITES
Slide 6
REGIONAL VARIATION
EMBRYOLOGY
SOURCE
HISTOLOGY
Slide 11
MARKERS
Slide 13
ELECTRON MICROSCOPY
Slide 15
FUNCTIONS
EVENTS DURING ANTIGEN TRAPPING
Slide 18
Slide 19
CLASSIFICATION OF HISTIOCYTOSIS: HISTIOCYTE SOCIETY
Slide 21
L GROUP
LANGERHANS CELL HISTIOCYTOSES (LCH)
AGE
Slide 25
GENETICS
Slide 27
Slide 28
Slide 29
Slide 30
Slide 34
Slide 35
PRESENTATION
Slide 37
Slide 38
Slide 39
Slide 40
SKIN LCH IN ADULTS
SKIN – ONLY LCH
SKIN LCH AS PART OF LOW RISK MS DISEASE
Slide 44
SKIN AS PART OF DISSEMINATED DISEASE
Slide 46
EXTRACUTANEOUS FINDINGS
Slide 48
DIFFERENTIAL DIAGNOSIS
Slide 50
Slide 51
Slide 52
Slide 53
Slide 54
Slide 55
Slide 56
Slide 57
Slide 58
Slide 59
Slide 60
Slide 61
JUVENILE XANTHOGRANULOMA (JXG)
Slide 63
CLINICAL FEATURES: JXG
Slide 65
CLINICAL FEATURES: JXG (2)
HISTOPATHOLOGY: JXG
Slide 68
IMMUNOHISTOCHEMISTRY
Slide 70
PROGNOSIS AND TREATMENT: JXG
RETICULOHISTIOCYTOMA
Slide 73
BENIGN CEPHALIC HISTIOCYTOSIS
Slide 75
GENERALISED ERUPTIVE HISTIOCYTOMA
Slide 77
PROGRESSIVE NODULAR HISTIOCYTOSIS
Slide 79
ROSAI-DORFMAN DISEASE
Slide 81
Slide 82
NECROBIOTIC XANTHOGRANULOMA
Slide 84
Slide 85
TREATMENT
XANTHOMA DISSEMINATUM
Slide 88
Slide 89
TREATMENT
MULTICENTRIC RETICULOHISTIOCYTOSIS
Slide 92
HISTOPATHOLOGY
Slide 94
PROGNOSIS AND TREATMENT
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS
Slide 97
TREATMENT (2)
DIFFUSE PLANE XANTHOMATOSIS
Slide 100
TREATMENT (3)
MALAKOPLAKIA
Slide 103
Slide 104
FAMILIAL SEA-BLUE HISTIOCYTOSIS
Slide 106
Slide 107
HEREDITARY PROGRESSIVE MUCINOUS HISTIOCYTOSIS
THANK YOU

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THE HISTIOCYTE AND IT’S ROLE IN DERMATOLOGY

INTRODUCTION • Histiocytoses

encompasses

group

of

diverse

disorders

resulting

from

accumulation and infiltration of histiocytes which include Langerhans cells, monocytes/macrophages and dendritic cells in affected tissues ranging from benign cases at one end to malignant ones at other.

• Three histiocytes of cutaneous importance are: • Langerhans cell • Mononuclear cell/ macrophage • Dermal dendrocyte

HISTIOCYTES • Represent cells of Mononuclear Phagocyte System • Share a common bone marrow progenitor – NeutrophilMacrophage Colony Forming Unit • Broadly divided into 2 functionally distinct cell populations 1. The professional Phagocyte 2. The Antigen presenting cell

LANGERHANS CELLS • Type of dendritic cells • Intraepidermal macrophages • Represent skin’s mononuclear phagocyte system • Concentration in epidermis: 460 to 1000/ mm square • First described by Paul Langerhans

SITES • Epidermis: all layers except Stratum corneum, mainly in Stratum spinosum • Papillary dermis especially perivascular • Oral mucosa, foreskin, vagina • Outer root sheath of human hair • Secretory duct of sebaceous gland • Epithelium of crypts of tonsil

REGIONAL VARIATION • Number decreases on repeated UV exposure • Less in trunk compared to extremity

EMBRYOLOGY • Week 7 : Appear in epidermis (ATPase +) • Week 8 – 12: Become CD1a + • Week 10-11: Identified by electron microscopy by Langerhans granules • S100 protein absent in fetal Langerhans cells, positive within 1 day after delivery

SOURCE • In contrast to other dendritic cells, Langerhans cells do not arise from bone marrow derived myeloid progenitor cells • Originate from fetal liver-derived monocyte precursors that populate skin prior to birth • Postnatally in steady state : repopulate directly from other skin LC cells • During inflammation : blood borne precursor (monocytes which differentiate into macrophages and other histiocytic lines)

HISTOLOGY • H&E : Clear cells in suprabasal epidermis • Difficult to detect in conventional section • Staining for : 1. ATPase 2. Aminopeptidase

• LCH cells – round to oval in shape • 20 – 25 μm in size (2-3 times as large as lymphocytes) • Found in aggregates, lacking dendritic morphology • Nucleus – lobulates, coffee bean/ boat shaped, complex angular and elaborate folds • Cytoplasm – generous, homogeneously pink

MARKERS • CD1a • CD207 or Langerin • HLA-DR antigen • S100 protein • CD45 • Membrane bound ATPase • Fc & C3 receptors

Identified by immunostaining, using antibody against these markers tagged by flourescent dyes or peroxidase

Langerhans cells immunoreactive for CD1a

ELECTRON MICROSCOPY • Lobulated nucleus • Relatively clear cytoplasm • No tonofilaments or desmosomes • Well developed organelles

• Rod or racquet shaped Birbeck granules • Granules form as a result of endocytotic invagination of cell membrane • Granules contain Langerin and CD1a

FUNCTIONS • Phagocytosis • Antigen processing • Antigen presentation to lymphocytes • Release cytokines like IL-1 • Regulate balance between immunity and peripheral tolerance

EVENTS DURING ANTIGEN TRAPPING • Exposure to antigen

• Processing by LCs within their lysosome

• Produce collagen degrading MMP enabling transdermal LC motility

• LCs migrate via lymphatics & reach regional lymph node

• Presents antigen to T lymphocyte

• T cell sensitization results in formation of memory T cells • Important in cutaneous immunosurveillance and contact hypersensitivity reaction

CLASSIFICATION OF HISTIOCYTOSIS: HISTIOCYTE SOCIETY • Class I: Langerhans Cell Histiocytosis • Class Iia: Dermal Dendritic Cell Histiocytosis • Class Iib: Non-langerhans Cell, Nondermal Dendritic Cell Histiocytoses • Class III: Malignant Histiocytoses

L GROUP • Langerhans cell Histiocytosis • Indeterminate cell histiocytosis – Erdheim-Chester disease

LANGERHANS CELL HISTIOCYTOSES (LCH) • LCH is a proliferative disease characterized by excess accumulation of CD1a+ Langerhans cells in various sites leading to tissue damage

• Rare disease affecting 2-5 children/million/year

• Could be underdiagnosed due to heterogeneity of manifestations, especially those with localized bone or skin disease, or undergo spontaneous resolution

AGE • LCH occurs worldwide, higher among whites • Male : female ratio= 2:1 • Most common- children aged 0-4 years • Single system (SS) disease – constitutes 70% of pediatric LCH • Bone – most commonly affected , skin – 10%

• In adults – mean age at diagnosis is 35 years • 69% of adults with LCH had Multisystem disease (MS) with lung and skin involvement being most common • In SS disease, 51% had lung involvement, bone had 38% and skin 14%

GENETICS • Etiology – unknown • Immune dysregulation and abnormal cytokine expression – potential mechanisms • Neoplastic disease – clonality of pathological LCH • BRAF V600E mutation in 57% - RAS pathway activation

ACTIVATION OF SIGNAL TRANSDUCTION (RAS PATHWAY)

CLONAL PROLIFERATION OF CD1a + CELLS

ACCUMULATION OF CELLS IN VARIOUS TISSUES/ORGANS

CLINICAL MANIFESTATIONS

HISTOPATHOLOGY OF LCH

EARLY LESIONS: Cellular and granulomatous components • Pathological Langerhans cells • Macrophages • Giant cells • T Lymphocytes • Giant histiocytes

OLDER LESIONS: • Cellularity and number of Langerhans cells decreased • Macrophages more in number • Fibrosis more prominent

HISTOPATHOLOGY OF LCH

LANGERIN

S100

CD1a

TRADITIONAL CLASSIFICATION Eosinophilic granuloma • Chronic unifocal LCH Hand -Schuller- Christian disease • Classic multifocal LCH Letterer- Siwe disease Acute disseminated LCH Congenital self healing reticulohistiocytosis Hashimoto -pritzker disease

LCH

SINGLE SYSTEM

UNIFOCAL

MULTIFOCA L

MULTISYST EM

LOW RISK

HIGH RISK

PRESENTATION • SS bone LCH – MC form • Skull vault – most frequent site of disease • Any bone can be involved except hands and feet • SS skin LCH – 2nd most common • MS LCH – involvement of any organ, kidney and gonads usually spared • High risk - involvement of hematopoietic system, liver and spleen

• Skin LCH – can occur at any age • Variable – macules, papules, plaques, scales, vesicles, pustules, crusts, bullous and ulcerative lesions • Most characteristic lesion in children – papulosquamous lesion with greasy scales affecting scalp • Other sites – gluteal cleft, midline of trunk

• Persistent eruption on scalp and skin flexures outside infancy – raise suspicion • Unusual persistence of cradle cap or nappy rash even in infancy – raise suspicion • Petechiae/ purpura + when platelet count reduced

● -

SD like eruptions

Rose-yellowish papules on abdomen

Candida intertrigo like lesions

• Involvement of external ear canal – associated with secondary pseudomonas infection • LCH of middle and inner ear – associated with temporal bone disease • Mucus membranes of mouth and genital tract – may be involved

SKIN LCH IN ADULTS • 14.3% of SS and 62% of MS LCH – skin involvement • Area of involvement similar to children • Ulceration of flexures, groin, perianal or vulvar area – common • Lesions – popular, pustular, nodular, erythematous, poikilodermatous, xanthomatous, polypoid and peduncular • May involve nails, mucosa • Asymptomatic, pruritic or burning

SKIN – ONLY LCH • Seen in very young child • May undergo spontaneous regression within weeks to months or progress to MS high risk disease • Infants (birth – 4 weeks) – Hashimoto – Pritzker disease or Congenital self-healing reticulohistiocytosis • Prolonged follow up – required • Generally good prognosis

SKIN LCH AS PART OF LOW RISK MS DISEASE • Hand-Schuller-Christian syndrome • Chronic multifocal form of LCH • Triad: Lytic bone lesions, exophthalmos, diabetes insipidus and skin lesions • Age of onset – 2-6 years

• Skin manifestations: nodules and tumors – yellowbrown, seborrhea like picture • Oral mucosa – gingival ulceration and hemorrhage • Premature tooth eruption – may be first manifestation

SKIN AS PART OF DISSEMINATED DISEASE • Letterer – Siwe disease • Most extensive and severe form • Usually < 2 years, often in neonates • Typical seborrhea-like pattern in scalp and nappy area

• Extensive ulceration, superinfection, petechia, purpura – may accompany • Multiple organs involved – bones, liver, spleen, lungs, CNS, bone marrow • Worst prognosis • Least likely to resolve spontaneously • Always requires systemic therapy

EXTRACUTANEOUS FINDINGS

● ● ● ● ● ●

BONE(77%) LYMPH NODES(19%) SPLEEN(13%) LIVER(16%) LUNG(10%) CNS(6%)

Loosening of teeth due to infiltration of the gingiva in LCH

Purpuric linear lesions of nail bed in LCH

DIFFERENTIAL DIAGNOSIS • Dermatophytosis, mastocytosis, scabies • Vesicular – herpes simplex, herpes zoster • Papulonodular lesions – neuroblastoma, leukemia, lymphoma • Seborrheic dermatitis • Adults – hidradenitis suppurativa, Paget disease, keratosis follicularis, STD

OTHER INVESTIGATIONS INVESTIGATIONS ON ALL PATIENTS • Complete blood count • Renal function test • Serum electrolytes • Liver function tests • Coagulation profile • ESR • C-reactive protein • Skeletal survey • Chest X ray

INVESTIGATIONS

• • • • • • •

TESTS INDICATED IN SOME PATIENTS MRI of brain-lytic bone lesions, diabetes insipidus, symptoms suggestive of CNS involvement Water deprivation test-polyuria, polydipsia HRCT thorax-respiratory symptoms, smoker Lung function test- tachypnoea,to assess before chemotherapy Bronchoalveolar lavage-to assess infiltration Lung biopsy-to exclude opportunistic infections Bone marrow biopsy-for cytopenias

INVESTIGATIONS • • • •

Abdominal ultrasound-abnormal LFT Liver biopsy-abnormal LFT, to evaluate infiltration Endoscopy and biopsy-for malabsorption Endocrine evaluation-growth hormone and TSH estimation • Audiology evaluation-deafness

MANAGEMENT

SKIN LCH IN CHILDREN SKIN ONLY LCH • OBSERVATION • TOPICAL MIDPOTENT STEROID • UVB/PUVA/TACROLIMUS • SYSTEMIC TREATMENT –SEVERE DISEASE

SKIN LCH IN CHILDREN SKIN AS A PART OF LOW RISK MS LCH • VINBLASTINE/PREDNISOLONE • VINCRISTINE/CYTARABINE WITH OR WITHOUT PREDNISLONE • CLADRIBINE MONOTHERAPY

SKIN LCH IN CHILDREN SKIN AS A PART OF HIGH RISK MS LCH • VINBLASTINE/PREDNISOLONE • CLADRIBINE WITH CYTARABINE OR CLOFARABINE • STEM CELL TRANSPLANTATION

SKIN LCH IN ADULTS SKIN ONLY LCH • TOPICAL OR INTRALESIONAL STEROID/TOPICAL IMIQUIMOD/NITROGEN MUSTARD/TACROLIMUS/SIROLIMUS • UVB/PUVA • SURGICAL EXCISION-for localised disease • RADIATION THERAPY • SYSTEMIC THERAPY

SKIN LCH IN ADULTS SKIN ONLY LCH UNRESPONSIVE TO TOPICAL THERAPY OR AS PART OF LOW RISK MS LCH • METHOTREXATE 20 MG /WEEK • AZATHIOPRINE 2mg/kg/day • THALIDOMIDE 100 mg (Prolonged therapy) • INTERFERON α6 mega units once daily(prolonged thearpy) • Combination of interferon αband thalidomide • ETOPOSIDE • ZOLINDRONIC ACID 4 mg IV every 1-6 months • Other options-cytarabine/vinblastine/prednisolone

SKIN LCH IN ADULTS SKIN AS A PART OF HIGH RISK MS LCH: • CLADRIBINE 6mg /m.sq SC/IV DAYS 1-5 EVERY 4 WEEKS • VINBLASTINE/PREDNISOLONE • CLOFARABINE 20mg-40mg/m.sq/day fpr 5 days every 4 weeks

TREATMENT OF BONE LCH • Unifocal-simple curettage/excision biopsy • Symptomatic bone disease- intralesional steroids • Optic nerve compression/spinal cord compromise-low dose radiation (6 to 10 Gy)

BRAF INHIBITORS IN LCH • Useful in those with BRAF V600 E mutation • Vemurafenib-showed to be useul in refractory cases with BRAF mutation • Experimental at present

PROGNOSIS • Single system disease-spontaneous regression/good response to therapy • SS disease and low risk MS –LCH  mortality low  Reactivations and long term sequelae  Commonest-diabetes insipidus  Serious-CNS disease • Multisystem high risk disease-poor prognosis with fatality

JUVENILE XANTHOGRANULOMA (JXG) • Benign proliferative disorder of histiocytes in early infancy and childhood

• Primarily a self-limited dermatologic disorder, rarely a/w systemic manifestations

• PATHOPHYSIOLOGY- Papules and nodules of JXG represent collections of non LC histiocytes

• Granulomatous reaction of histiocytes to an unidentified stimulus

• Arises most often in infancy (2cm

• Sites- face, head and neck, upper trunk, upper extremities • Skin lesions regress spontaneously within 3 -6 years in children. • Heal with hyperpigmentation, atrophy, anetoderma

CLINICAL FEATURES: JXG • Extracutaneous JXG rare (3.9%) • Most common- eye (iris) • Tumor, unilateral glaucoma, unilateral uveiitis, spontaneous hyphema, heterochromia iridis • Visceral involvement may occur in lung, liver, spleen, testes, pericardium, GI tract, kidney, deeper soft tissues, CNS • Café au lait macules (20%)

HISTOPATHOLOGY: JXG • Early biopsy - a dense monomorphous histiocytic infiltrate in dermis • Extension into s.c tissue, fascia and muscles in 1/3 cases. • Mature lesions- foam cells, Touton giant cells, foreign body

giant cells

• Touton giant cell – seen in 85% of JXG • Characteristic wreath of nuclei • Homogenous eosinophilic centre • Prominent xanthomatization in periphery

IMMUNOHISTOCHEMISTRY • Positive for • • • • •

Factor XIIIa, CD 68 CD 163 CD 14 Fascin

• Negative for

• S 100 protein • CD 1a

PROGNOSIS AND TREATMENT: JXG • Self healing disease • Resolves in 1-5 years • No treatment is required as disorder is self limiting • Surgery and radiotherapy for ocular and CNS lesions • CO₂ laser for multiple JXG • Visceral involvement requires systemic steroids with or without chemotherapy with vinca alkaloids • Patients with aggressive disease with visceral involvement treated with multiagent chemotherapy

RETICULOHISTIOCYTOMA • Histiocytic tumor of skin and soft tissue • Localized variant of multicentric reticulohistiocytosis • Generally solitary and asymptomatic papules or domeshaped nodules • Young adult males

• HPE: nodules of epithelioid histiocytes with abundant, glassy eosinophilic cytoplasm • Cells may have lacuna space-like clearing and scalloped cytoplasm • CD68 and CD163 positive, CD1a and S100 negative • Treatment: surgical excision

BENIGN CEPHALIC HISTIOCYTOSIS • Rare self limiting nonlipid non x histiocytoses • Variant of JXG without systemic involvement • Age: 2-66 months • Asymptomatic erythematous brown macules/ papules/ nodules • Face, earlobes, neck, upper trunk

• No mucosal involvement • Spontaneous regression may be 2-8yrs without scarring • IHC: Similar to JXG • Electron microscopy: wormlike cytoplasmic inclusions

GENERALISED ERUPTIVE HISTIOCYTOMA • Rare, mainly affects adults • Papular, nonxanthomatous, self healing • Asymptomatic symmetrical papules • Sites: face, trunk, proximal extremities (sparing flexures)

• Visceral and mucous involvement rare

• Characteristic feature: Rapid appearance of crop of lesions • Resolve spontaneously or leave a macular area of hyperpigmentation • Does not require treatment • Differential diagnosis: LCH, other forms of N-LCH, and urticaria pigmentosa

PROGRESSIVE NODULAR HISTIOCYTOSIS • Normolipemic histioxanthomatous condition • Hundreds of diffuse and symmetrical lesions • 2 different type of lesions: • Papules: 2-10 mm in size, yellow-orange coloured • Nodules: 1-5 cm , skin coloured or reddish orange due to overlying telengiectasia a/w pain and ulceration.

• Benign condition, but no tendency for spontaneous resolution • No systemic involvement • HPE: dermal disease • Early lesions: Xanthomatized and scalloped histiocytes • Older lesions: spindle shaped histiocytes in storiform pattern • Local excision may be used for symptomatic lesions

ROSAI-DORFMAN DISEASE • SINUS HISTIOCYTOSIS WITH MASSIVE LYMPHADENOPATHY

• Abdundant histiocytes in lymphnodes

• Children or young adults

• Self limiting benign disease

• Slightly more common in men and black people

• Massive B/L and painless cervical lymphadenopathy

• Fever, night sweats and weight loss

• Extranodal involvement(43%), skin is the most common

• Skin- yellow papules and nodules, macular erythema, scaling, telangiectasia

• Other sites: lung, GUT, breast, GIT, liver, pancreas

HISTOPATHOLOGY TREATMENT

• Lymph nodes – pericapsular fibrosis and dilated sinuses heavily infiltrated •

Benign course

with histiocytes, lymphocytes and plasma cells

• Treatment only necessary when vital organ is being compromised

• Emperipolesis + • Treatment • Systemic corticosteroids S100, CD2, factor XIIIa, CD68, CD163, • Cryotherapy • Surgical excision a1-antichymotrypsin, a1-antitrypsin,

• Immunocytochemistry: positive for

HAM-56

NECROBIOTIC XANTHOGRANULOMA • Rare, multisystem histiocytic disease

• Widespread infiltrated xanthomatous nodules and plaques

• Strongly associated with hematological malignancy

• Paraproteins – act as autoantibodies – fibroblast proliferation and dermal macrophage deposition

• MC site face- periorbital (85%) • Multiple reddish yellow nodular and ulcerative lesions with telengiactesia • Size: 0.5 – 20 cm • Half cases develop central atrophy and ulceration

• Eye manifestations (50-80%) : conjunctivitis, keratitis, scleritis, uveitis, iritis, ectropion or proptosis

• Systemic symptoms – nausea, vomiting, fatigue, epistaxis, back pain

• Others- Lymphadenopathy, Hepatosplenomegaly, Raynaud phenomenon

• Myocardial and pulmonary lesions

• 80-90% - monoclonal gammopathy, out of which half develop multiple myeloma

TREATMENT • Treat underlying paraproteinemia • Systemic And Intralesional Steroids • Chlorambucil • Cyclophosphamide • Azathioprine • IFN A • Plasmapheresis • Local Radiation Therapy • CO₂ Laser • Puva

XANTHOMA DISSEMINATUM • Rare, normolipemic, histiocytic proliferative disorder affecting skin, mucous membranes • Proliferation of histiocytes in which lipid deposition is secondary • Affects males in childhood or young adults • Involves skin, mucus membranes of eyes, upper respiratory tract and meninges • Frequently hypothalamus and pituitary involved

transient DI

• Reactive rather than neoplastic process • Lesional cell: inflammatory lipid laden macrophage with characteristic foamy appearance • Red-yellow discrete,disseminated papules and nodules soft plaques –symmetrically distributed on trunk, face eyelids, flexures • 50% involve mucosa of URT. Warty plaques in mouth • CNS(frequent) – Diabetes Insipidus, seizures and growth retardation

• Self-limiting, may be locally destructive • 3 forms 1. Self healing form 2. Chronic progressive form 3. Progressive multiorgan form (often fatal)

TREATMENT CUTANEOUS XANTHOMA DISSEMINATUM • CO2 laser • Surgical excision • Dermabrasion • Electrocoagulation

SYSTEMIC XANTHOMA DISSEMINATUM • Corticosteroids • Chlorambucil • Azathioprine • Cyclophosphamide • Cladribine • Statins

MULTICENTRIC RETICULOHISTIOCYTOSIS • Rare non-LCH disorder • Specific nodular lesions, mucosal lesions and destructive arthritis • Middle aged adults, predominantly female • 28% have associated malignancy (gastric, ovarian, breast uterine) • Considered a reactive histiocytosis

• Firm brown/ yellow papules and plaques, predominantly on extensors • Coral bead like lesions around nail folds – nail dystrophy • 2/3rds have symmetrical polyarthritis (hands) • Often remits spontaneously • Can progress to mutilating osteoarthropathy

HISTOPATHOLOGY • Giant multinucleated histiocytes with voluminous ground glass cytoplasm • Cells are PAS positive, diastase resistant • Type IV collagen inclusions + • IMMUNOCYTOCHEMISTRY: • Positive for • Acid phosphatase, ATPase, Lysozyme, Alpha1-antitrypsin • Factor XIIIa • Negative for : S100, CD1a, CD34

PROGNOSIS AND TREATMENT • Prognosis is good, disease becomes quiescent in 7-8 years if no malignancy • Can leave considerable morbidity with crippling arthropathy and scarred skin • Most children have self limiting disease and non deforming arthritis • No effective treatment • Methotrexate • Cyclophosphamide • Ciclosporin • Leflunomide • Bisphosphonates • Anti-TNF agents • Tocilizumab

HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS

• HLH – hyperinflammatory condition from uncontrolled ineffective immune response • Widespread infiltration of organs by lymphocytes and histiocytes • Children – EBV associated • Adults – lymphoma

• Primary HLH – underlying genetic defect • Secondary HLH - known stimulus (infectious, malignant, autoimmune)

TREATMENT • PRIMARY HLH • Dexamethasone, etoposide, ciclosporin A • Hematopoietic stem cell transplant • Antithymocyte globulin • Alemtuzumab

• SECONDARY HLH • Corticosteroids +/- IVIG • Etoposide • Ciclosporin A • Rituximab • TNF alpha inhibitors • Il-1 inhibitors

DIFFUSE PLANE XANTHOMATOSIS • Rare non-lipemic diseases characterized by xanthomatous skin lesions with paraproteinemia

• 3 major features- xanthelasma, diffuse plane xanthoma of head, neck, trunk and extremities and normal plasma lipid levels

• Symmetrical distributed, asymptomatic yellow to brown plaques involve flexural areas and scars.

• A/w myeloproliferative disorders: Multiple myeloma and Monoclonal gammopathy • Perivascular deposition of lipoprotein-immune complex deposition

TREATMENT • Treat underlying myeloproliferative disease • Plasma exchange • Limited involvement • Excision • Dermabrassion • Ablative laser therapy

MALAKOPLAKIA • Immunodeficiency disorder where macrophages fail to phagocytose bacteria • A/w: E-coli, proteus, M.tuberculosis, S.aureus • Commonly affects urinary and gastrointestinal tracts • Skin: draining abscesses, sinus, ulcer, mass, tender nodules, papules

• HPE: sheets of large histiocytes with abundant cytoplasm • Cells have fine eosinophilic granules in cytoplasm – Hansemann cells • Contain round basophilic inclusion bodies – MichaelisGutmann bodies • Stain with PAS, Von Kossa stain (calcium), Perls stain (ferric iron) • Represent abnormal degradation of bacteria with iron and calicum deposited on remaining glycolipid

• Benign self-limiting course • Fatal cases have been reported • Management – surgical excision, antibiotics

FAMILIAL SEA-BLUE HISTIOCYTOSIS • Rare inherited abnormality of lipid metabolism • May Gruenwald stain – stains cytoplasmic granules of histiocytes a deep azure blue • Also seen in Niemann-Pick disease, prolonged IV fat emulsion use, Sphingomyelinase deficiency and CML

• Presents in young adults with hepatosplenomegaly and thrombocytopenia • Storage disorder – glycolipid, phospholipid accumulate in histiocytic cells in bone marrow, liver and spleen • Skin, lungs, GIT, eye and nervous system may be involved • Skin: patchy and irregular brownish grey pigmentation and/or nodules • Face, upper chest and shoulders

• CNS: ataxia, epilepsy, dementia • Eye: white stippled deposits at margins of fovea/ macula • Usually benign, may disseminate • Death from heart, liver or lung involvement • Treatment of associated lipid disorder

HEREDITARY PROGRESSIVE MUCINOUS HISTIOCYTOSIS • Autosomal dominant genodermatosis • Skin coloured to red-brown papules on nose, hands, forearms and thighs • All cases in women • Appear in first decade and increases throughout life • No spontaneous resolution, no systemic involvement

THANK YOU