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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

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monocyte macrophage disorders

Monocyte/Macrophage Disorders

Northeast Regional Medical Center/KCOM

granuloma annulare
Granuloma Annulare
  • Localized
  • Generalized
  • Macular
  • Deep
  • Perforating
  • In HIV
  • In Lymphoma
granuloma annulare3
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
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 histology5
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

Interstitial GA

NLD

localized ga
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
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
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
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 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
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
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 brien31
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
granuloma mulitforme of leiker
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.
sarcoidosis
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.
sarcoidosis39
Sarcoidosis
  • Etiology unknown
  • HLA-A1 – Lofgren’s syndrome
  • HLA-B13 – Chronic & Persistent form
  • HLA-B8
  • HLA-DR3
  • Final common pathway is granuloma formation
slide41

“NAKED” GRANULOMAS

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

slide44

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

sarcoidosis aka
Sarcoidosis AKA….
  • Besnier-Boeck-Schaumann Disease
  • Boeck’s sarcoid
  • Besnier’s lupus pernio
  • Schaumann’s benign lymphogranulomatosis
sarcoid skin involvement
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
Sarcoid – like syphillis, mimics many other dz’s
  • Papules, nodules, plaques.
  • Subcutaneous nodules.
  • Scar sarcoid, erythroderma.
  • Ulcerations, verrucous.
  • Ichthyosiform, hypomelanotic
papular sarcoid
Papular Sarcoid
  • MC form
  • AKA Miliary Sarcoid
  • Face, eyelids, neck, shoulders
  • May involute to macules
  • Ddx: syringomas
annular sarcoidosis
Annular Sarcoidosis
  • Central clearing
  • Hypo-pigment-ation
  • Atrophy
  • Scarring
  • Favor head & neck
  • Assoc. with chronic sarcoidosis
hypopigmented sarcoid
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
lupus pernio
Lupus Pernio
  • Violaceous
  • Nose, cheeks, lips
  • Forehead, ears
  • 43% associated with punched out bone lesions.
  • 37% Ocular lesions
  • Nasal perforation
darier roussy sarcoid
Darier-Roussy Sarcoid
  • 5% or fewer of patients with sarcoidosis have subcutaneous nodules.
erythrodermic sarcoid
Erythrodermic Sarcoid
  • Extremely Rare
  • Begins as erythematous patches that become confluent.
ichthyosiform sarcoid
Ichthyosiform Sarcoid
  • Legs
  • Arms
  • No palpable component
alopecia
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
Morpheaform Sarcoid
  • Rare
  • Dermal Fibrosis
  • Simulates Morphea
  • Antimalarials may help.
mucosal sarcoid
Mucosal Sarcoid
  • Pinhead sized papules
  • Grouped or fused together to form a plaque.
erythema nodosum in sarcoid
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
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
Heerfort’s Syndrome
  • Parotid gland enlargement
  • Lacrimal gland enlargement
  • Uveitis
  • Fever
  • Sarcoidosis
mikulicz s syndrome
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.
sarcoid treatment
Sarcoid - Treatment
  • Systemic Corticosteroids
  • Antimalarials
  • Methotrexate
  • Thalidomide
non x histocytoses
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
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
JXG Histopathology
  • Non-encapsulated
  • Infiltrate in the upper and mid reticular dermis
  • Mononuclear cells with abundant amphophilic cytoplasm that is poorly lipidized or vacuolated.
slide90

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

STAINS:

+ CD1

+ FACTOR

XIIIa

- S100

benign cephalic histiocytosis
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
slide92

BENIGN CEPHALIC HISTIOCYTOSIS

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

reticulohistiocytosis
Reticulohistiocytosis
  • Solitary form – aka Reticulohistiocytic Granuloma or Reticulohistiocytoma
  • Solitary form has no systemic involvement
  • Multicentric form – aka Multicentric Reticulohistiocytosis
  • Underlying malignancy in 30%
slide95
Reticulohistiocytic Granuloma: Multinucleate Giant Cells, Histiocytes, Lymphocytes with some stroma fibrosis
multicentric reticulohistiocytosis
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
tx multicentric reticulohisticytosis
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
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?
slide103

GENERALIZED ERUPTIVE HISTIOCYTOMA:

DERMAL INFILTRATE OF NON-LIPIDIZED MONONUCLEAR HISTIOCYTES, S-100 IS NEGATIVE

slide104

GENERALIZED ERUPTIVE HISTIOCYTOMA:

DERMAL INFILTRATE OF NON-LIPIDIZED MONONUCLEAR HISTIOCYTES, S-100 IS NEGATIVE

necrobiotic xanthogranuloma nxg
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.
slide106
NXG: Periorbital yellow plaques that resemble xanthelasmas except that they are deep, firm, indurated, may involve the orbit
slide107
NXG: Trunk & proximal extremity lesions are orange-red plaques w/ active red border & an atrophic border with superficial telangiectasias
slide109

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

nxg and malignancy
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
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 pathology
XD - Pathology
  • Xanthoma Cells
  • Eosinophilic Histiocytes
  • Numerous Touton giant cells
  • Inflammatory cell infiltrate usually present.
papular xanthoma
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
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
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 histiocytosis120
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
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 2nd decade
  • Slow progression, no tendency to spontaneous involution, no systemic involvement
hereditary progressive mucinous histiocytosis in women122
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
Rosai-Dorfman Disease
  • Aka Sinus Histiocytosis with Massive Lymphadenopathy
  • Onset 1st or 2nd 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 disease124
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
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 treatment
RDD - Treatment
  • Radiation
  • Chemotherapy
  • Systemic corticosteroids
  • Thalidomide
sea blue histiocytosis
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 histiocytosis130
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
x type histiocytoses
X-type Histiocytoses
  • Hashimoto-Pritzker
    • aka Congenital Self-Healing Reticulohistiocytois
  • Histiocytosis X
    • Aka Letterer-Siwe
    • Aka Hand-Schuller Christian
    • Aka Eosinophilic Granuloma
hashimoto pritzker
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
slide138
EM: 10-25% of cells have Langerhans’ cell granules, but this does not distinguish Hashimoto-Pritzker from Histiocytosis X.
slide140

HASHIMOTO-PRITZKER

S-100 stain

CD1a stain

h p management
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
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 x143
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 x144
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
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.
histiocytosis x tx
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