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Transcript of Non infectious granulomatous dermatosespathology.massgeneral.org/HMS/Poznan/pdf/Piris...
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Non‐infectious granulomatousdermatoses
Adriano Piris, MD• Co‐director, Mihm Cutaneous Pathology Consultative ServiceCo director, Mihm Cutaneous Pathology Consultative Service
Department of Dermatology, Brigham & Women’s Hospital • Stewart Rahr‐MRA Young InvestigatorMelanoma Research Alliance, Washington, D.C.
• Consultant Staff Department of Pathology, Dana Farber Cancer Institute
NonNon--infectious granulomasinfectious granulomas
SarcoidosisSarcoidosis
Granuloma annulareGranuloma annulare
Rheumatoid noduleRheumatoid nodule
Palisaded neutrophilic Palisaded neutrophilic
and granulomatous and granulomatous Necrobiosis lipoidicaNecrobiosis lipoidica
Elastolytic granulomaElastolytic granuloma
Necrobiotic Necrobiotic
xanthogranulomaxanthogranuloma
gg
dermatitisdermatitis
Crohn’s diseaseCrohn’s disease
SarcoidosisSarcoidosis
• Systemic disease of unknown etiology
• Non-caseating granulomasNon caseating granulomas
Third and fourth decadesThird and fourth decades
Female predominanceFemale predominance
African americansAfrican americans
Cutaneous lesions in sarcoidosisCutaneous lesions in sarcoidosis
•• Papules, plaques and nodulesPapules, plaques and nodules
•• Lupus pernioLupus pernio
•• VerrucousVerrucous
•• HypopigmentedHypopigmented
Al iAl i•• Subcutaneous nodulesSubcutaneous nodules
•• LichenoidLichenoid
•• ErythrodermicErythrodermic
•• Vasculitic (rare variant)Vasculitic (rare variant)
•• AlopecicAlopecic
•• MorpheaphormMorpheaphorm
•• IchthyosiformIchthyosiform
•• AtrophicAtrophic
•• UlcerativeUlcerative
Courtesy of Dr Linda WangCourtesy of Dr Linda Wang Courtesy of Dr Linda WangCourtesy of Dr Linda Wang
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Systemic lesions in sarcoidosis
• Hilar lymph nodes (70-90%)
• Lungs (50-90%)
• Peripheral lymphadenopathy (30%)• Peripheral lymphadenopathy (30%)
• Ocular lesions(25%)
• Chronic iridocyclitis
• Hepatomegaly (20%)
• Splenomegaly (17%)
Systemic lesions in sarcoidosis• Bone lesions (15%)
• phalanges (sausage-shaped)
• Large salivary glands (8%)
• Neurosarcoidosis (5%)
• hypothalamus, pituitary gland, leptomeninges,
and cranial nerves particularly facial nerve
• Cardiac involvement, uncommon
• granulomas in conduction system
SarcoidosisSarcoidosis
• Usually benign disease
F l i 5% f • Fatal in 5% of cases
• Cardiac involvement
• Respiratory or renal failure
PathogenesisPathogenesis
Antigen-driven disorder in which the
helper/inducer T cell arm of the immune
SarcoidosisSarcoidosis
helper/inducer T cell arm of the immune
system reacts in an exaggerated fashion to a
yet undetermined antigen
(? Mycobacteria).
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Asteroid bodiesAsteroid bodies
McKee, Calonje, Granter;McKee, Calonje, Granter;Pathology of the SkinPathology of the Skin, 3, 3
rdrdEdEd
Asteroid bodiesAsteroid bodies
Schaumann bodiesSchaumann bodies
Lupus pernio
• Chronic variant of sarcoidosis
• Nose and central face
• May be locally destructive
Gary M. White & Neil H.Cox
Diseases of the Skin
W.B Saunders
Lupus pernioLupus pernio(Sarcoidosis)(Sarcoidosis)
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Sarcoidosis: Diagnosis of exclusion
• Histology
• Imaging studies
• ACE (angiotensin converting enzyme) levels
• CD4/CD8 in bronchoalveolar lavage
• Negative work up for infectious etiology
• Presence of foreign bodies does not rule out the diagnosis
Differential diagnosis
Infectious granulomata
(use special stains!)
Foreign body granulomata
Crohn’s disease
(it may be the first manifestation)
Interstitial and Palisading Granulomatous Dermatitis
Group of disorders in which the unifying histiologic feature is histiocytic infiltrationhistiologic feature is histiocytic infiltration with variable alteration of the connective tissue framework
NecrobiosisNecrobiosis
Areas of altered dermal connectiveAreas of altered dermal connectivetissue with loss of definition of tissue with loss of definition of collagen bundles and alteration in collagen bundles and alteration in st i i (H&E)st i i (H&E)staining (H&E)staining (H&E)
Degeneration and loss of collagen/elasticDegeneration and loss of collagen/elasticfibers and connective tissue cellsfibers and connective tissue cells
Replacement by mucin, fibrin, lipids, sclerosisReplacement by mucin, fibrin, lipids, sclerosis
Interstitial and Palisading Granulomatous Dermatitis
• Granuloma annulare
• Elastolytic granuloma
• Necrobiosis lipoidica
• Rh t id d l• Rheumatoid nodule
• Necrobiotic xanthogranuloma
• Palisaded neutrophilic and granulomatous dermatitis
• Crohn’s disease
Granuloma annulareGranuloma annulare
•• Frequent palisaded granulomatous Frequent palisaded granulomatous
condition of unknown etiologycondition of unknown etiology
•• Benign, selfBenign, self--limitedlimited
•• Children and young adultsChildren and young adults
•• FemalesFemales
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Distribution of Lesions
• GA : hands, feet and wrists, most commonly
• Also on elbow or trunk
Clinical variantsClinical variants•• LocalizedLocalized•• GeneralizedGeneralized•• PerforatingPerforating•• SubcutaneousSubcutaneous
Granuloma annulareGranuloma annulare
•• SubcutaneousSubcutaneous•• PapularPapular•• LinearLinear
Granuloma Annulare Granuloma Annulare
Histopathological variantsHistopathological variants
•• InterstitialInterstitial
•• SarcoidalSarcoidal
Granuloma annulareGranuloma annulare
•• SarcoidalSarcoidal
•• PerforatingPerforating
•• DiffuseDiffuse•• Subcutaneous Subcutaneous (Pseudorheumatoid nodule)(Pseudorheumatoid nodule)
Histologic considerations: Granuloma annulare
• Three phases in evolution:
1. Interstitial histiocytic infiltration
2 Mucin deposition2. Mucin deposition
3. Areas of necrobiosis with fibrin deposition
• Tissue eosinophilia in up to 2/3 of biopsies
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Subcutaneous granuloma annulare
• Disorder of childhood
• Mean age of presentation: 4.3 years
• Sites: extremities and scalp
• No patients have developed systemic disease in 26 years of follow‐up
Subcutaneous granuloma annulare
• Associated with large zones of necrobiosis and fibrin resembling rheumatoid nodule
• Eosinophils may be prominent
Deep GADeep GA“Pseudorheumatoid “Pseudorheumatoid
Nodule”Nodule”
Granuloma Annulare Tissue Reactions Associated with Systemic Disease
• Granuloma annulare has an atypical presentation(unusual sites like elbow) or multiple lesions
• I t titi l t hili• Interstitial neutrophilia
• Plasma cells
• Thrombosis
• Neutrophils in vessel wall with fibrin
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• Infections: Parvovirus B19, CMV, HIV, and hepatitis C
• Collagen vascular disease: Rheumatoid arthritis
Atypical GA as a manifestationof underlying systemic disease
arthritis
• Diabetes Mellitus
• Thyroid disease
• Low grade B cell malignancy (Paraproteinemia)
Generalized GA in the setting ofHIV disease
Atypical GA Tissue ReactionIn the setting of IBD
Granulomatous VasculitisHepatitis C associated GA tissue reaction
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Clue to the Atypical GA tissueReaction: Vasculopathy
Differential diagnosisDifferential diagnosis
•• Necrobiosis lipoidicaNecrobiosis lipoidica•• Actinic granulomaActinic granuloma
•• XanthomasXanthomas•• Rheumatoid noduleRheumatoid nodule
Granuloma annulareGranuloma annulare
gg•• Infectious Infectious
granulomasgranulomas•• Mycobacterium marinumMycobacterium marinum
•• Epithelioid sarcomaEpithelioid sarcoma•• Palisaded Palisaded
neutrophilic and neutrophilic and granulomatous granulomatous dermatitisdermatitis
Annular elastolytic giantAnnular elastolytic giant--cell granulomacell granuloma
•• Actinic granulomaActinic granuloma
•• SunSun--exposed skinexposed skin
•• Granuloma annulare variant?Granuloma annulare variant?
•• Clinically similar to GAClinically similar to GA
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Necrobiosis lipoidicaNecrobiosis lipoidica
•• Idiopathic disorderIdiopathic disorder
•• Indurated plaques on the shinsIndurated plaques on the shinsp qp q
•• Associated with diabetes mellitus (DM)Associated with diabetes mellitus (DM)Prevalence in DM 3/1000Prevalence in DM 3/1000
•• Female preponderance (3:1)Female preponderance (3:1)
Necrobiosis lipoidica
• Circumscribed plaque
• Bilateral
• Symmetrical
• Pretibial location
Necrobiosis Lipoidica
Courtesy of Dr Linda WangCourtesy of Dr Linda Wang
Patient BH
A 74 year old woman with arterial hypertension on an ACE inhibitor developed a plaque on the ankle
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Necrobiosis lipoidica
• Entire dermis usually involved by zones or layers
• Layers include fibrosis alternating with areas of altered collagen, with scattered lymphocytes and histiocytes, and cellular debris, especially around altered collagen
• Multinucleate giant cells and foamy macrophages scattered throughout lesion
• 20% show necrobiosis of the subcutaneous septa, a form of panniculitis
• Foci of mucin not present
• NL diffuse, involving entire dermis; GA focal or multifocal
Histopathological variantsHistopathological variants
•• DiffuseDiffuse
Necrobiosis lipoidicaNecrobiosis lipoidica
•• SarcoidalSarcoidal
•• PerforatingPerforating•• Subcutaneous Subcutaneous
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Necrobiosis Lipoidica Tissue Reactions associated with systemic disease
• Sarcoidal granulomas seen in sarcoidosis, autoimmune thyroid disease and diabetes
• Thrombosis seen in diabetes, rheumatoid arthritis, and low grade B cell malignancyg g y
• Neutrophilia in rheumatoid arthritis
• Clonal plasma cell infiltrates in the setting of myeloma
5 year history of facial plaques compatibleWith a sarcoidal diathesis
Subsequently developed NL like plaques on legs
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KappaLambda
Subsequent evaluation revealed a monoclonal marrow plasmacyticInfiltrate consistent with myeloma
Differential diagnosisDifferential diagnosis
•• Granuloma annulareGranuloma annulare•• Infectious Infectious
•• Rheumatoid noduleRheumatoid nodule•• SarcoidosisSarcoidosis
Necrobiosis lipoidicaNecrobiosis lipoidica
granulomasgranulomas•• Necrobiotic Necrobiotic
xanthogranulomaxanthogranuloma
Sarco dos sSarco dos s•• Crohn’s diseaseCrohn’s disease•• Epithelioid sarcomaEpithelioid sarcoma
Rheumatoid nodule
• Subcutaneous
• Sites of trauma or at pressure points
• Adults with rheumatoid arthritis (30%)• Adults with rheumatoid arthritis (30%)
• severe disease
• high titer of rheumatoid factor
• joint erosions
• increased incidence of rheumatoid vasculitis
Rheumatoid nodule• Extensor aspect of
forearms and elbows,
knuckles, feet, knees,
buttocks scalp back buttocks, scalp, back
etc
• Extracutaneous sites
(heart, larynx, lungs,
pleura, etc)
Courtesy of Dr Linda WangCourtesy of Dr Linda Wang
Courtesy of Dr Linda WangCourtesy of Dr Linda Wang
Rheumatoid nodules
• Lesions appear in subcutaneous tissue and extending into dermis
• Irregular‐shaped, broad zones and necrobiosis with hypereosinophilic appearance due to fibrin depositiondeposition
• Peripheral palisade of histiocytes
• Vessels show endothelial necrosis and fibrin thrombi in necrobiotic zones
• Peripheral to palisading areas is granulation tissue‐like appearance
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Pathogenesis:
• Trauma
• Immune complex mediated: IgG and IgM in vessels surrounding nodules
• Rheumatoid factor and complement in nodules
• Cytokine and cell adhesion molecules
• Vasculitis
• Deep granuloma annulare
(pseudorheumatoid nodule)
Differential diagnosis
• Foreign body granulomas
• Infectious granulomas
• Epithelioid sarcoma
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Necrobiotic xanthogranuloma (NXG) with paraproteinemia
• Described by Kossard + Winkelmann (1980)
• A progressive periorbital dermatosis associated with paraproteinemia or a myeloproliferative disorderdisorder
• Rare disorder• Large, yellow plaques• Paraproteinemia
(IgG kappa type)
Pathogenesis
Both the pathogenesis of NXG and its link to paraproteinemia are unclear
DIF: IgM, C3 and fibrinogen in blood vessel walls
NECROBIOTIC XANTHOGRANULOMA:clinical features
• Asymptomatic, itchy or painful indurated yellow, red‐orange or violaceous plaques and nodules involving head and neck, trunk, proximal limbsp
• Lead to scarring, atrophy, local infection
• Hepatosplenomegaly, uveitis, iritis, proptosis, periorbital ulceration
• No gender preference
75 y/o male with myeloma developed papules and plaques on abdomen with periorbital pxanthomas
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NECROBIOTIC XANTHOGRANULOMA:histopathology
• A necrotizing granulomatous dermatitis with cholesterol clefts and lipidized histiocytes including Touton giant cell forms
• Unlike plane xanthoma, foamy histiocytes are not predominant
• Lymphoid follicles, plasma cells, occasional eosinophils may be seen
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NECROBIOTIC XANTHOGRANULOMA :systemic disease associations
• Associated in 80% of cases with myeloma, typically of IgGκ‐restricted plasma cells
• Al d ib d i ti t ith• Also described in patients with
• Scleroderma (Russo. Cutis, 2002)
• Asthma
• Systemic amyloidosis (Westermann et al. Med Clin 2001)
• Necrobiosis lipoidica
• Granuloma annulare
Differential diagnosis
• Rheumatoid nodule
Massive necrobiosisMassive necrobiosisCholesterol cleftsCholesterol cleftsBizarre multinucleated giant cellsBizarre multinucleated giant cellsTouton giant cellsTouton giant cells
Palisaded neutrophilic and granulomatous dermatitis Palisaded neutrophilic and granulomatous dermatitis associated with systemic diseasesassociated with systemic diseases
•• Connective tissue disordersConnective tissue disorders•• Rheumatoid arthritisRheumatoid arthritis
•• Sjögren’s syndromeSjögren’s syndrome•• Vasculitis (ChurgVasculitis (Churg--Strauss, Wegener’s etc)Strauss, Wegener’s etc)
•• Inflammatory bowel diseaseInflammatory bowel disease•• InfectionInfectionInfectionInfection•• CarcinomasCarcinomas•• Endocrine disorders:Endocrine disorders:
•• ThyroiditisThyroiditis•• DiabetesDiabetes
•• Drug reactionsDrug reactions•• Immunodysregulatory drugs: ACE inh, BImmunodysregulatory drugs: ACE inh, B--blockers, Cablockers, Ca--channel channel
Blockers, Lipid lowering agents, antihistaminics.Blockers, Lipid lowering agents, antihistaminics.•• Sulfonamides, MethotrexateSulfonamides, Methotrexate
Palisaded neutrophilic and Palisaded neutrophilic and granulomatous dermatitisgranulomatous dermatitis
UrticarialUrticarialLivedoidLivedoidP l P l
Clinical featuresClinical features
Papules Papules PlaquesPlaquesNodulesNodulesIndurated linear bandsIndurated linear bands
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Palisaded neutrophilic and Palisaded neutrophilic and granulomatous dermatitisgranulomatous dermatitis
•• UrticariaUrticaria--like lesionslike lesions
Histological featuresHistological features
•• Leukocytoclastic vasculitisLeukocytoclastic vasculitis
•• Palisaded granulomatous reactionPalisaded granulomatous reaction
•• Dermal fibrosis/NLDDermal fibrosis/NLD--like lesionslike lesionsCourtesy of Dr Linda WangCourtesy of Dr Linda Wang
NYU Dermatology ClnicNYU Dermatology Clnic
Palisaded neutrophilic and Palisaded neutrophilic and granulomatous dermatitisgranulomatous dermatitis
Neutrophils and nuclear dustNeutrophils and nuclear dust
VasculitisVasculitis
ThrombosisThrombosis
Atypical clinical presentationAtypical clinical presentation
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• Large bowel involvement (80%)
• No correlation with activity of the disease
Cutaneous granulomatous Crohn’s disease
• Perianal, genitalia, perineum, lips, lower extremities, colostomy sites
• Contiguous or not (‘metastatic’ Crohn’s dx)
• May precede bowel involvement
• Single or multiple
• Papules, plaques, skin tags,
Cutaneous granulomatous Crohn’s disease
nodules, ulcers, edema,
deep fissures, abscesses,
fistula formation
• Non-caseating granulomas
• Necrobiosis
Cutaneous granulomatous Crohn’s disease
Histological features
Necrobiosis
• Granulomatous vasculitis• Granulomas in lymphatics
(diagnostic)
• Palisading neutrophilic and granulomatous dermatitis
D Els V l quD Els V l qu
AcknowledgementsAcknowledgements
•• Dr. Elsa Velazquez.Dr. Elsa Velazquez.
•• Dr. Martin Mihm.Dr. Martin Mihm.
•• Dr. Cynthia Magro Dr. Cynthia Magro
•• Dr. Neil CrowsonDr. Neil Crowson