Monocyte/Macrophage Disorders

Northeast Regional Medical Center/KCOM

Granuloma Annulare

Localized Generalized Macular Deep Perforating In HIV In Lymphoma

Granuloma Annulare

Common, Idiopathic, all races 50% patients IgM and C3 in vessels LCV changes sometimes seen Suggests Ab mediated vasculitis Common in HIV patients EBV sometimes found Occurs in resolved lesions Zoster

GA - Histology

Classic – histiocytes palisading around “necrobiotic” collagen. Granulomas located in the upper dermis with perivascular lymphocytic infiltrate Necrobiosis – “altered” collagen, paler grayer hue, fragmented, haphazardly arranged, more compact.

Mucin prominent in older lesions.

GA- Histology

Interstitial – diffuse dermal infiltrate between collagen bundles consisting of histiocytes, monocytes, neutrophils.

“Skip” areas of normal dermis seen.

Interstitial mucin often seen.

May be adjacent to classic granulomas

Interstitial GA

Upper dermis “Skip areas” Mucin

NLD

Deep dermis, subQ No “skip” areas No mucin

Localized GA

Young adults Acral Annular, scalloped White or pink flat topped papules spread peripherally 75% clear in 2 yrs 25% last 8 yrs

Diffuse GA

MC women past middle age Diabetes reported in 20% cases MC neck, upper trunk, shoulders MC form of GA seen in HIV.

Clears spontaneously in 3-4 years.

Difficult to treat.

Subcutaneous GA

Aka Deep, Pseudorheumatoid Nodule MC children, boys > girls 2:1 MC ages 5-12.

Acral distribution History of trauma preceding lesion Asymptomatic but often an extensive workup is done to rule out JRA.

Perforating GA

MC dorsum of hands Papules with central keratotic core Core represents transdermal elimination of degenerated or “necrobiotic” material in center of palisaded histiocytes.

GA in HIV disease

GA may occur at all phases of HIV disease.

Typically papular lesions 60% Diffuse, 40% Localized Photodistributed and perforating lesions may occur

GA and Lymphoma

Rare Atypical presentation: Facial or Palmar Painful Any type of lymphoma can occur.

Lymphoma may occur before or after the GA.

GA- Treatment

Biopsy, IL, Cryo, topical Vit. E, Excision GENERALIZED: Problematic Oral steroids, high dose but high relapse rate – diabetes complicates Dapsone, Nicotinomide, SSKI, Cyclosporine, Accutane.

Annular Elastolytic Giant Cell Granuloma of Meischer/Actinic Granuloma of O’Brien

Annular Elastolytic Giant Cell Granuloma of Meischer/Actinic Granuloma of O’Brien

Variants of GA.

AEGCG – solitary atrophic thin yellow plaque on the forehead, NLD-like.

AGOB – Photo- distribution, papules and plaques

Histo: Like GA, but with Giant Cells, Elastophagocytosis

Histo: Like GA, but with Giant Cells, Elastophagocytosis

Histo: Like GA, but with Giant Cells, Elastophago cytosis

Photoexacerbated GA

Granuloma Mulitforme of Leiker

Similar histology to AEGCG & AGOB Only Central Africa, Adults > 40 yrs old.

Upper Trunk and Arms Begin as small papules, expand into round or oval plaques 15cm wide and as much as 4mm in height.

Must rule out tuberculoid leprosy.

Granuloma Mulitforme of Leiker

Sarcoidosis

Multisystem Disease Lungs, lymph nodes, skin and eyes MC.

10x more frequent in blacks in US Women under age 40 Irish, African, Afro-Caribbean.

Presence inversely proportional to the incidence of TB and/or Leprosy.

Sarcoidosis

Etiology unknown HLA-A1 – Lofgren’s syndrome HLA-B13 – Chronic & Persistent form HLA-B8 HLA-DR3 Final common pathway is granuloma formation

NON-CASEATING GRANULOMAS COMPOSED OF EPITHELIOID CELLS AND OCCASIONAL LANGERHAN’S GIANT CELLS

“NAKED” GRANULOMAS “NAKED” meanse a sparse rather than a dense infiltrate. Lymphocytes, macrophages & fibroblasts may occur

Asteroid Body inside a multinucleated giant cell

SCHAUMANN OR CONCHOIDAL BODIES ARE COMPOSED OF CALCIUM CARBONATE. THEY ARE EASILY MISSED (LEFT) IF NOT VIEWED UNDER POLARIZED LIGHT (RIGHT)

Sarcoidosis AKA….

Besnier-Boeck-Schaumann Disease Boeck’s sarcoid Besnier’s lupus pernio Schaumann’s benign lymphogranulomatosis

Sarcoid Skin Involvement

Anywhere from 9% to 37% of cases.

2 types: specific and non-specific Specific: granulomas on biopsy Non-Specific: reactive, Erythema Nodosum Skin findings may occur before, during or after systemic findings.

Sarcoid – like syphillis, mimics many other dz’s

Papules, nodules, plaques.

Subcutaneous nodules.

Scar sarcoid, erythroderma.

Ulcerations, verrucous.

Ichthyosiform, hypomelanotic

Papular Sarcoid

MC form AKA Miliary Sarcoid Face, eyelids, neck, shoulders May involute to macules Ddx: syringomas

Papular Sarcoid

Papular Sarcoid

Papular Sarcoid

Papular Sarcoid

Annular Sarcoidosis

Central clearing Hypo pigment ation Atrophy Scarring Favor head & neck Assoc. with chronic sarcoidosis

Annular Sarcoidosis

Hypopigmented Sarcoid

May be the earliest sign of sarcoidosis in blacks.

MC extremities Visually macular, but often have a palpable dermal or subQ component in center of lesion

Hypopigmented Sarcoid

Lupus Pernio

Violaceous Nose, cheeks, lips Forehead, ears 43% associated with punched out bone lesions.

37% Ocular lesions Nasal perforation

Punched-Out Lytic lesions, Bone Cysts

Ulcerative Sarcoidosis

Lupus Pernio

Lupus Pernio

Lupus Pernio

Lupus Pernio

Darier-Roussy Sarcoid

5% or fewer of patients with sarcoidosis have subcutaneous nodules.

Darier-Roussy (SubQ)

Scar Sarcoid

Scar Sarcoid

Erythrodermic Sarcoid

Extremely Rare Begins as erythematous patches that become confluent.

Ichthyosiform Sarcoid

Legs Arms No palpable component

Ichthyosiform Sarcoid

Alopecia

Occurs in 2 settings; 1) Existing plaques extend onto scalp.

--leads to permanent scarring.

2) Macular lesions appear on scalp resembling Alopecia Areata --may be permanent or reversible

Morpheaform Sarcoid

Rare Dermal Fibrosis Simulates Morphea Antimalarials may help.

Morpheaform Sarcoid

Morpheaform Sarcoid

Mucosal Sarcoid

Pinhead sized papules Grouped or fused together to form a plaque.

Erythema Nodosum in Sarcoid

MC nonspecific cutaneous finding in sarcoidosis Young females Anterior shins Good prognosis

Lofgren’s Syndrome

= fever, arthralgias, hilar adenopathy, fatigue, EN

Systemic Sarcoidosis

MC – Lungs Ocular 20-30% Bones & Liver 20%, elevated Alk Phos.

Renal, Hypercalcemia Heart, CNS, Spleen Elevated ACE levels to follow disease activity only.

Heerfort’s Syndrome

Parotid gland enlargement Lacrimal gland enlargement Uveitis Fever Sarcoidosis

Mikulicz’s Syndrome

Sarcoidosis with enlargement of the; Lacrimal glands Submaxillary and Parotid glands.

Problematic: numerous conditions involving enlarged partoid glands have since been named after Dr. Mikulicz.

CXR- Hilar Adenopathy

Sarcoidosis in Fingers

Sarcoidosis in Fingers

CNS

Candle-wax drippings – granulomatous uveitis

Sarcoid - Treatment

Systemic Corticosteroids Antimalarials Methotrexate Thalidomide

Non-X Histocytoses

Juvenile Xanthogranuloma Benign Cephalic Histiocytosis Solitary/Multicentric Reticulohistiocytosis Generalized Eruptive Histiocytoma Necrobiotic Xanthogranuloma Xanthoma Disseminatum Papular Xanthoma Indeterminate Cell Histiocytosis Progressive Nodular Histiocytoma Hereditary Progressive Mucinous Histiocytosis Rosai-Dorfman Disease Sea-Blue Histiocytosis

Juvenile Xanthogranuloma (JXG)

MC Non Langerhans’ histiocytosis 1 st year of life, usu. white males 80% are solitary, well demarcated, firm, rubbery red to pink with yellow tinge Regress in 3-6 years with atrophy.

Ocular involvement rare, MC iris Assoc. with NF-1 and JCML

JXG Histopathology

Non-encapsulated Infiltrate in the upper and mid reticular dermis Mononuclear cells with abundant amphophilic cytoplasm that is poorly lipidized or vacuolated.

MULTINUCLEATED “FOAM” CELLS aka TOUTON GIANT CELLS ALONG WITH EOS, NEUTS, LYMPHS.

STAINS: + CD1 + FACTOR XIIIa - S100

Benign Cephalic Histiocytosis

Rare Males 2:1, Onset 6-12 months of age Begins on head, cheeks, spreads to neck and upper trunk Multiple reddish yellow papules 2-3mm, may coalesce into a reticulate pattern.

Involute over 2 to 8 years with atrophy

BENIGN CEPHALIC HISTIOCYTOSIS DIFFUSE DERMAL INFILTRATION OF NON-LIPIDIZED HISTIOCYTIC CELLS, S-100 NEGATIVE

Reticulohistiocytosis

Solitary form – aka Reticulohistiocytic Granuloma or Reticulohistiocytoma Solitary form has no systemic involvement Multicentric form – aka Multicentric Reticulohistiocytosis Underlying malignancy in 30%

Reticulohistiocytic Granuloma

Reticulohistiocytic Granuloma: Multinucleate Giant Cells, Histiocytes, Lymphocytes with some stroma fibrosis

Multicentric Reticulohistiocytosis

Multisystem disease, 5 th decade, F>M.

90% Face & hands, red-brown papules and nodules Paronychia: “coral bead” appearance Joints symmetrically involved with mutilating arthritis, telescoping shortening of digits, doigts en lorgnette, opera-glass fingers, RF is negative 1/3 have high cholesterol, xanthelasma

“Coral Bead” Paronychia

Classic Ground Glass Touton Giant Cells, PAS +

90% Face & Hands

Tx: Multicentric Reticulohisticytosis

Treatment is problematic because mutilating arthritis requires immunosuppressive therapy.

Immunosuppressive therapy can worsen underlying malignancies Prednisone, Antimalarials, MTX, Cytoxan, PUVA, Nitrogen mustard.

Generalized Eruptive Histiocytoma

Widespread symmetric papules, trunk and proximal extremities, come in crops Progressive development of new lesions over several years with eventual spontaneous involution to hyper pigmented macules Flesh, brown or violaceous papules Controversy: is this just xanthoma disseminatum? MRH? Indeterminate cell histiocytosis ?

Generalized Eruptive Histiocytoma

GENERALIZED ERUPTIVE HISTIOCYTOMA: DERMAL INFILTRATE OF NON-LIPIDIZED MONONUCLEAR HISTIOCYTES, S-100 IS NEGATIVE

GENERALIZED ERUPTIVE HISTIOCYTOMA: DERMAL INFILTRATE OF NON-LIPIDIZED MONONUCLEAR HISTIOCYTES, S-100 IS NEGATIVE

Necrobiotic Xanthogranuloma (NXG)

Multisystem disease of older adults Characteristic periorbital yellow plaques that resemble xanthelasmas except that they are deep, firm, indurated and may extend into the orbit Trunk & proximal extremity lesions are orange-red plaques with an active red border and an atrophic border with superficial telangiectiasias.

NXG: Periorbital yellow plaques that resemble xanthelasmas except that they are deep, firm, indurated, may involve the orbit

NXG: Trunk & proximal extremity lesions are orange-red plaques w/ active red border & an atrophic border with superficial telangiectasias

NXG: conjunctivitis, keratitis, scleritis, uveitis, iritis, ectropion or proptosis

NXG: Process extends into the fat, obliterating fat lobules. Extensive zones of degenerated collagen or “necrobiosis” surrounded by palisaded macrophages.

NXG: Foam Cells with abundant infiltrate of lymphocytes, plasma cells

NXG: Cholesterol Clefts

NXG and Malignancy

80% IgG monoclonal paraproteinemia (Kappa) Bone marrow may show plasmacytosis, anemia, leukopenia, myeloma, myelodysplastic syndromes.

Cause unknown, course progressive Treat aimed at paraproteinemia: Melaphan, Chlorambucil, Corticosteroids, Plasmapheresis, Alpha Interferon-2b

Xanthoma Disseminatum

Serum lipids are normal, MC young males Mucocutaneous, discreet, disseminated Intertriginous distribution Diabetes Insipidus 40% due to xanthomatous infiltration of the pituitary gland.

Chronic and Benign, may persist, may involute spontaneously after some years

XD - Periorbital

XD - Axillary

XD - Pathology

Xanthoma Cells Eosinophilic Histiocytes Numerous Touton giant cells Inflammatory cell infiltrate usually present.

Papular Xanthoma

Small yellowish papules Localized or generalized No tendency to merge into plaques Aggregates of foam cells in the dermis without a cellular or histiocytic phase Absence of inflammatory cells.

Indeterminate Cell Histiocytosis

Dermal precursors of Langerhan’s cells S-100 positive CD1 positive NO BIRBECK GRANULES!

Chronic without spontaneous involution No systemic involvement

Progressive Nodular Histiocytosis

Superficial papules & deeper nodules Diffuse, symmetrical, non-flexural.

Larger lesions may ulcerate, become painful Face lesions may coalesce into leonine facies General health is good

Progressive Nodular Histiocytosis

Histo: DF-like, few Toutons, lacks the PAS+ ground glass giant cells of MRH.

Stains positive for Vimentin, CD68, Factor XIIIa Stains negative for S-100 and CD34

Hereditary Progressive Mucinous Histiocytosis in Women

AD or X-linked Few to numerous flesh to red-brown papules up to 5mm in diameter Face, arms, forearms, hands, legs Onset 2 nd decade Slow progression, no tendency to spontaneous involution, no systemic involvement

Hereditary Progressive Mucinous Histiocytosis in Women

May histologically differentiate from other non-X histiocytoses as follows: Familial pattern Abundant mucin + Alcian blue staining Lack of lipidized and multinucleated cells

Rosai-Dorfman Disease

Aka Sinus Histiocytosis with Massive Lymphadenopathy Onset 1 st or 2 nd decade of life Fever, massive cervical LAD, polyclonal hyperglobulinemia, leukocytosis, anemia, elevated SED rate.

Males and blacks MC.

Skin involvement in 43% of cases Most patients with skin lesions are > age 40

Rosai-Dorfman Disease

Isolated or disseminated yellow-brown papules or nodules, or macular erythema. Large annular lesions resembling GA may occur.

HHV-6 identified in numerous reports.

May clear spontaneously Skin biopsy non-specific unless emperipolesis is present but lymph node pathology is characteristic…..

Rosai-Dorfman Disease – LN Biopsy

Expansion of the sinuses by large foamy histiocytes admixed with plasma cells CD4, Factor XIIIa and S-100 positive No Birbeck granules

RDD - Emperipolesis – Histiocytes engulf plasma cells and lymphocytes

RDD - Emperipolesis

RDD - Treatment

Radiation Chemotherapy Systemic corticosteroids Thalidomide

Sea-Blue Histiocytosis

Familial or Acquired Characteristic and diagnostic cell is a histiocyte containing cytoplasmic granules that stain as follows: Blue-green with Geimsa Blue with May-Gruenwald

Sea-Blue Histiocytosis

Lesions include papules, eyelid swelling and patchy gray pigmentation of the face and upper trunk.

Infiltrates marrow, spleen, liver, lymph nodes, lungs and skin in some cases.

Similar findings seen in patients with Myelogenous leukemia and Neimann-Pick Disease, and following prolonged use of IV fat supplementation

Sea-Blue Histiocytosis – Bone Marrow

X-type Histiocytoses

Hashimoto-Pritzker  aka Congenital Self-Healing Reticulohistiocytois Histiocytosis X  Aka Letterer-Siwe  Aka Hand-Schuller Christian  Aka Eosinophilic Granuloma

Hashimoto-Pritzker

Onset: birth or very soon thereafter Solitary or multinodular Red, brown, pink or dusky Lesions > 1 cm characteristically ulcerate as they resolve Asymptomatic, resolves in 8 to 24 weeks

Hashimoto-Pritzker

Hashimoto-Pritzker Before and After

Hashimoto-Pritzker

Hashimoto-Pritzker

EM: 10-25% of cells have Langerhans’ cell granules, but this does not distinguish Hashimoto-Pritzker from Histiocytosis X.

H&E: large mononuclear cells & multinucleated giant cells with ground glass or foamy cytoplasm

HASHIMOTO-PRITZKER

S-100 stain CD1a stain

H-P MANAGEMENT

Must rule out Histiocytosis-X as both present similarly Rule out systemic involvement with physical exam, CBC, LFT, Bone survey.

If any of the above are abnormal, consider liver-spleen scan and bone marrow biopsy.

Histiocytosis X

Proliferation of Langerhans’ cells MC-Bone, Skin, Lymph, Lungs, Liver and Spleen, Endocrine glands, CNS.

Children age 1-4 years old Lymphs are clonal, but not as atypical appearing as lymphoma cells – debate as to whether this is neoplastic v. reactive

Histiocytosis X

RESTRICTED TYPES:  A) Biopsy proven skin rash without other involvement  B) Monostotic lesions, with or without diabetes insipidus, LAD or rash  C) Polyostotic lesions with or without diabetes insipidus, LAD or rash.

Histiocytosis X

EXTENSIVE TYPE:  A) Visceral involvement with or without bone lesions, diabetes insipidus, LAD or rash but WITHOUTsigns of organ dysfunction of lung, liver or hematopoetic system  B) Visceral involvement with or without bone lesions, diabetes insipidus, LAD or rash but WITH signs of organ dysfunction.

Histiocytosis X Distribution

MC is Letterer-Siwe: Tiny red, red brown or yellow papules that are widespread but favor the intertriginous areas, behind ears and scalp.

Lesions may erode or weep.

In children, LS distribution is assoc. with multisystem disease, but in adults 25% have disease limited to skin only.

Histicytosis X - scalp

Often mistaken for SD, but focal hemorrhage is present

Often mistaken for SD, but focal hemorrhage is present

Histiocytosis X - TX

Skin only: topical steroids, nitrogen mustard, PUVA, Interferon Alpha.

extensive disease but without organ dysfunction: oral corticosteroids Extensive disease with orgain dysfunction: Vinblastine, Cyclosporine, Radiation. Refractory: 2-chlorodeoxyadenosine

THE END SLICK RICK SAYS: “DON’T FORGET TO TURN IN YOUR TEST QUESTIONS”