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 infiltrateNecrobiosis – “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

Deep dermis, subQ

No “skip” areas

No mucin

NLD

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’sPapules, 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 SarcoidosisCentral clearing Hypo-pigment-ationAtrophyScarringFavor head & neckAssoc. 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 Sarcoid5% 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 HistocytosesJuvenile 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

1st 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-encapsulatedInfiltrate in the upper and mid reticular dermisMononuclear 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, 5th 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 cropsProgressive development of new lesions over several years with eventual spontaneous involution to hyper-pigmented maculesFlesh, brown or violaceous papulesControversy: 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 malesMucocutaneous, discreet, disseminatedIntertriginous distributionDiabetes 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

WomenAD or X-linkedFew to numerous flesh to red-brown papules up to 5mm in diameterFace, arms, forearms, hands, legsOnset 2nd decadeSlow 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 LymphadenopathyOnset 1st or 2nd decade of lifeFever, massive cervical LAD, polyclonal hyperglobulinemia, leukocytosis, anemia, elevated SED rate.Males and blacks MC.Skin involvement in 43% of casesMost 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 spontaneouslySkin 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 cellsCD4, Factor XIIIa and S-100 positiveNo 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-SiweAka Hand-Schuller ChristianAka 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

S-100 stain CD1a stain

HASHIMOTO-PRITZKER

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’ cellsMC-Bone, Skin, Lymph, Lungs, Liver and Spleen, Endocrine glands, CNS.Children age 1-4 years oldLymphs 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

involvementB) Monostotic lesions, with or without

diabetes insipidus, LAD or rashC) 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

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

THE END