1. Monocyte/Macrophage Disorders
Northeast Regional Medical Center/KCOM

2. Granuloma Annulare Localized Generalized Macular Deep Perforating
In HIV
In Lymphoma

3. 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

4. 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.

5. 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

6. Interstitial GA NLD Upper dermis “Skip areas” Mucin Deep dermis, subQ
No “skip” areas
No mucin

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

19. 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.

23. 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.

25. 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.

27. 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

28. GA and Lymphoma Rare Atypical presentation: Facial or Palmar Painful
Any type of lymphoma can occur.
Lymphoma may occur before or after the GA.

29. 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.

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

31. AGOB – Photo- distribution, papules and plaques
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

32. Histo: Like GA, but with Giant Cells, Elastophagocytosis

33. Histo: Like GA, but with Giant Cells, Elastophagocytosis

34. Histo: Like GA, but with Giant Cells, Elastophago-cytosis

35. Photoexacerbated GA

36. 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.

37. Granuloma Mulitforme of Leiker

38. 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.

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

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

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

43. Asteroid Body inside a multinucleated giant cell

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

45. Sarcoidosis AKA…. Besnier-Boeck-Schaumann Disease Boeck’s sarcoid
Besnier’s lupus pernio
Schaumann’s benign lymphogranulomatosis

46. 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.

47. Sarcoid – like syphillis, mimics many other dz’s
Papules, nodules, plaques.
Subcutaneous nodules.
Scar sarcoid, erythroderma.
Ulcerations, verrucous.
Ichthyosiform, hypomelanotic

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

49. Papular Sarcoid

50. Papular Sarcoid

51. Papular Sarcoid

52. Papular Sarcoid

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

54. Annular Sarcoidosis

55. 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

56. Hypopigmented Sarcoid

57. Lupus Pernio Violaceous Nose, cheeks, lips Forehead, ears
43% associated with punched out bone lesions.
37% Ocular lesions
Nasal perforation

58. Punched-Out Lytic lesions, Bone Cysts

59. Ulcerative Sarcoidosis

60. Lupus Pernio

61. Lupus Pernio

62. Lupus Pernio

63. Lupus Pernio

64. Darier-Roussy Sarcoid
5% or fewer of patients with sarcoidosis have subcutaneous nodules.

65. Darier-Roussy (SubQ)

66. Scar Sarcoid

67. Scar Sarcoid

68. Erythrodermic Sarcoid
Extremely Rare
Begins as erythematous patches that become confluent.

69. Ichthyosiform Sarcoid
Legs
Arms
No palpable component

70. Ichthyosiform Sarcoid

71. 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

72. Morpheaform Sarcoid Rare Dermal Fibrosis Simulates Morphea
Antimalarials may help.

73. Morpheaform Sarcoid

74. Morpheaform Sarcoid

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

76. 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

77. 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.

78. Heerfort’s Syndrome Parotid gland enlargement
Lacrimal gland enlargement
Uveitis
Fever
Sarcoidosis

79. 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.

80. CXR- Hilar Adenopathy

81. Sarcoidosis in Fingers

82. Sarcoidosis in Fingers

83. CNS

84. Candle-wax drippings – granulomatous uveitis

85. Sarcoid - Treatment Systemic Corticosteroids Antimalarials
Methotrexate
Thalidomide

86. 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

87. 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

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

90. MULTINUCLEATED “FOAM” CELLS aka TOUTON GIANT CELLS ALONG WITH EOS, NEUTS, LYMPHS.
STAINS:
+ CD1
+ FACTOR
XIIIa
- S100

91. 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

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

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

94. Reticulohistiocytic Granuloma

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

96. 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

97. “Coral Bead” Paronychia

98. Classic Ground Glass Touton Giant Cells, PAS +

99. 90% Face & Hands

100. 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.

101. 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?

102. Generalized Eruptive Histiocytoma

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

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

105. 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.

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

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

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

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

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

111. NXG: Cholesterol Clefts

112. 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

113. 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

114. XD - Periorbital

115. XD - Axillary

116. XD - Pathology Xanthoma Cells Eosinophilic Histiocytes
Numerous Touton giant cells
Inflammatory cell infiltrate usually present.

117. 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.

118. Indeterminate Cell Histiocytosis
Dermal precursors of Langerhan’s cells
S-100 positive
CD1 positive
NO BIRBECK GRANULES!
Chronic without spontaneous involution
No systemic involvement

119. 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

120. 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

121. 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

122. 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

123. 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

124. 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…..

125. 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

126. RDD - Emperipolesis – Histiocytes engulf plasma cells and lymphocytes

127. RDD - Emperipolesis

128. RDD - Treatment Radiation Chemotherapy Systemic corticosteroids
Thalidomide

129. 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

130. 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

131. Sea-Blue Histiocytosis – Bone Marrow

132. X-type Histiocytoses Hashimoto-Pritzker Histiocytosis X
aka Congenital Self-Healing Reticulohistiocytois
Histiocytosis X
Aka Letterer-Siwe
Aka Hand-Schuller Christian
Aka Eosinophilic Granuloma

133. 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

134. Hashimoto-Pritzker

135. Hashimoto-Pritzker Before and After

136. Hashimoto-Pritzker

137. Hashimoto-Pritzker

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

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

140. HASHIMOTO-PRITZKER
S-100 stain
CD1a stain

141. 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.

142. 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

143. 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.

144. 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.

145. 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.

146. Histicytosis X - scalp

147. Often mistaken for SD, but focal hemorrhage is present

148. Often mistaken for SD, but focal hemorrhage is present

152. 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

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