Download - Hospital-based Dermatopathology
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Hospital-based Dermatopathology
Janis M. Taube, MDDirector of DermatopathologyJohns Hopkins University SOM
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Overview• Drug-eruptions• Erythroderma• Manifestations of renal disease• Blistering disorders• Vasculitis/Vasculopathy
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“There are some remedies worse than the disease.”
Publilius Syrus (c. 42 BC)
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Drug eruptions
• Cutaneous reactions to drug are the most common adverse reaction to drugs
• Most common cause of skin biopsies in hospital setting– 2% of all hospital consultations– Approximately 2% are considered “serious”
• Predisposing factors: age, female gender, and immunosuppression
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Historical data
• Boston Collaborative Drug Surveillance Program 1996– 22,247 inpatients with 565 drug-related skin
eruptions (2.5%)
• Outpatient estimates also from 1-3%
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“Classic” Drug eruptions
• Exanthematous/maculo-papular/morbilliform (46%)• Urticarial (23%)• Fixed drug (10%)• EM/SJS/TEN (5%)• Other (16%), AGEP, reactions specific to new
targeted agents or checkpoint blockade, etc.
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Histopathologic features
Recognized histologically and drug etiology assigned:
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Histopathologic features
Recognized histologically and drug etiology assigned: fixed drug eruption
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Histopathologic features
Recognized histologically and drug etiology assigned: fixed drug eruption
Recognizable histologic pattern, causative role of drug not always apparent:
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Histopathologic features
Recognized histologically and drug etiology assigned: fixed drug eruption
Recognizable histologic pattern, causative role of drug not always apparent: urticaria
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Histopathologic features
Recognized histologically and drug etiology assigned: fixed drug eruption
Recognizable histologic pattern, causative role of drug not always apparent: urticaria
Histology is “non-specific”:
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Histopathologic features
Recognized histologically and drug etiology assigned: fixed drug eruption
Recognizable histologic pattern: causative role of drug not always apparent: urticaria
Histology is “non-specific”: morbilliform
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• Up to 50% of drug eruptions– List of over 100 medications causing it– Amoxicillin, ampicillin, miconazole, and
streptomycin in >5% of patients receiving drug
• Proposed to be immunologically-mediated reactions
• Clinically, very difficult to differentiate from viral-induced morbilliform eruptions
Morbilliform (exanthematous) drug eruptions
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Clinical Features
• Erythematous macules and papules that coalesce
• Trunk is most common• +/- pruritis• Resemble viral exanthems
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Gerson, et al. JAAD 2008
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Histology in ~100 clinically morbilliform drug eruptions
Gerson, et al. JAAD 2008
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Histology in ~100 clinically morbilliform drug eruptions
Gerson, et al. JAAD 2008
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Histology in ~100 clinically morbilliform drug eruptions
Gerson, et al. JAAD 2008
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Histology in ~100 clinically morbilliform drug eruptions
Gerson, et al. JAAD 2008
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Histology in ~100 clinically morbilliform drug eruptions
Gerson, et al. JAAD 2008
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Urticarial Drug Eruptions
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Biopsies can be useful:
• Urticaria vs. urticarial vasculitis• Neutrophilic vs. eosinophilic predominance
• Neutrophilic urticarial dermatosis typically has an associated inflammatory disorder (Still’s dz, SLE, Schnitzler syndrome).
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Urticarial vasculitis = Type III hypersensitivity reaction
• Antibodies target drug-related haptens
• Antigen-antibody complex formation
• Immune complexes deposit in post-capillary venules
• Activation of complement, and vascular damage
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Neutrophilic Urticarial Dermatosis
Am J of Dermatopathol. 38(1):39-49, 2016
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2
Neutrophilic Epitheliotropism Is a Histopathological Clue to Neutrophilic Urticarial Dermatosis.Broekaert, Sigrid; Boer-Auer, Almut; Kerl, Katrin; Herrgott, Ilka; Schulz, Xenia; Bonsmann, Gisela; Brehler, Randolf; Metze, Dieter
Am J of Dermatopathol. 38(1):39-49, January 2016.
MPO
Systemic inflammation NOS
Adult onset Still’s disease Lupus erythematosus
Neutrophilic epitheliotropismsensitivity (83.1%)specificity (74.3%)
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Fixed Drug Eruptions
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Fixed drug eruption• Not a common cause of
biopsy• Face and male genitalia are
most common sites• Ampicillin, barbiturates,
NSAIDs• Resolves with residual
hyperpigmentation
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EM/SJS/TEN
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Histologic featuresEARLY LATE
Example signout:
DIAGNOSIS: erythema-multiforme-like reaction pattern (See Note):
NOTE: Findings such as these may be seen in erythema multiforme, Stevens Johnson Syndrome, and toxic epidermal necrolysis. Clinical correlation is essential in making this distinction.
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Toxic Epidermal Necrolysis
• Mortality rate is 25-30%• Can resemble nonspecific
drug reactions characterized by morbilliform eruption
• Spreads symmetrically from face and trunk to extremities
• Biopsy is useful for ruling out other bullous disorders
• Clinical findings such as %BSA involvement are key
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Acute Generalized Exanthematous Pustulosis (AGEP)
• Within 10 days of starting drug• High fevers and malaise• Generalized toxic erythema studded with
non-small non-follicular pustules• Cephalosporins, Bactrim, furosemide,
hydroxychloroquine
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Pustular Psoriasis
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Newer classes of drugs
• Selective BRAF inhibitors• α-TNF in rheumatic diseases• Acneiform eruptions with EGFR-inhibitors• GM-CSF and G-CSF• Immune checkpoint blockade agents, e.g. anti-
PD-(L)1
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RAF activation of the MAPK/ERK pathway
Gibney GT, et al. Nat Rev Clin Oncol, 2013
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BRAF inhibitors
• Review of single academic institution archives (24/47) 51% of patients developed 146 total cutaneous neoplasms
• Squamous lesions, ranging from verrucous keratoses to invasive SCC +/- KA-like features
• Secondary melanomas have also been reported
• Other malignancies include RAS-mutant leukemia and colon cancer
1Sufficool KE, et al J Cutan Pathol 2014
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Selective BRAF inhibitors
• Activating BRAF mutations in up to 60% of melanomas
• BRAF inhibitors have been associated with SCC
• New melanocytic lesions have also been reported
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Management of lesions in this setting:
1) Combination therapies with BRAF and MEK inhibitors
2) Use of retinoids, topical 5-FU
3) Frequent skin checks
4) Complete resection of lesions, when possible
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α-TNF in rheumatic diseases• ¼ of patients experience cutaneous side effects• Psoriasis and eczema-like (>1/2)• Viral, bacterial, an fungal infections (1/3 cases)• Other:
– Dermatitis herpetiformis– Lichenoid reactions– Leukocytoclastic vasculitis– Alopecia
Pathogenesis: unopposed IFN-alpha by plamacytoid dendritic cells in genetically predisposed
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Doyle and Sperling et al. Am J Dermpath, 2011
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• Used to treat NSCLC, metastatic CRC, pancreatic cancer, advanced HNSCC
• EGFR is found on undifferentiated keratinocytesin the epidermis, follicular keratinocytes and sebocytes of the pilosebaceous unit, and cells in outer root sheath of hair follicle
• Cutaneous reactions in 90% of patients
EGFR inhibitors
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EGFR inhibitors
Brodell, et al. J Cutan Pathol, 2013
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Pardoll 2012
Novel Immunotherapeutic Agents
Signal 2
•Two signal model to develop an antigen-specific T-cell response
•Multiple “Accelerators” and “Brakes”
•De novo vs. ongoing response in the periphery
•Tumors may co-opt ”checkpoint” signals to turn off the host immune response
Signal 1
Pardoll D, 2012
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T cell
T cell
Macrophage
MelanomaCell
Anti-PD-1/PD-L1 therapy blocksPD-L1 mediated adaptive immune resistance
PD-1
IFNγ(AND OTHER SIGNALS)
PD-L1
PD-L1
Taube JM, et al. Sci Transl Med 2012
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T cell
T cell
Macrophage
MelanomaCell
Anti-PD-1/PD-L1 therapy blocksPD-L1 mediated adaptive immune resistance
PD-1
IFNγ(AND OTHER SIGNALS)
PD-L1
PD-L1
Taube JM, et al. Sci Transl Med 2012, Tumeh, et al Nature 2014
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0
0.2
0.4
0.6
0.8
1
PD-L1(+) PD-L1(-)
PD-L1(+)PD-L1(-)CR/PRNR
Prop
ortio
nof
pat
ient
s
p=0.006
Correlation of PD-L1 expression in pretreatment tumor biopsies with clinical outcomes
NSCLC
Melanoma
RCC
9/25
16*/25
17/17
0/17
*2 pts still under evaluation
42 pts include 18 MEL, 10 NSCLC, 7 CRC, 5 RCC, and 2 CRPC.
Topalian ST, et al NEJM 2012
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Correlation of pre-treatment tumor PD-L1 expression with objective response to PD-1/PD-L1 pathway blockade
Nivolumab(anti-PD-1)
Pembrolizumab(anti-PD-1)
MEDI4736 (anti-PD-L1)
MPDL3280A (anti-PD-L1)
0
10
20
30
40
50
60
70
80
PD-L1+PD-L1-
Modified from J. Sunshine and J.M. Taube, Curr Opin Pharma, 2015
Unselectedpatients
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FDA approvals for multiple PD-L1 IHC assays
Taube JM, et al, Mod Path, 2017
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Complete regression of metastatic melanoma (anti-PD-1, 3 mg/kg) associated with vitiligo
Pre
Post
Normal skin
Boundary
Vitiligo
History: 62-year-old male had previously developed PD following IL-2, temozolomide, and multiple surgeries.
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Lichenoid drug eruption
Curry, et al. J Cutan Pathol, Volume: 44, Issue: 2, Pages: 158-176
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Curry, et al. J Cutan Pathol, Volume: 44, Issue: 2, Pages: 158-176
Anti-type IV collagen
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Granulomatous dermatitis following anti-PD-1 therapy
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Overview• Drug-eruptions• Erythroderma• Manifestations of renal disease• Blistering disorders• Vasculitis/Vasculopathy (another lecture)
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Erythroderma• Otherwise healthy adult = drug-based
Drug-associated erythroderma
Curr Probl Dermatol 2002;14:117-146.
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Loss of granular cell layer,
variable parakeratotic scale
Look for: 1) neutrophils (psoriasis or seb derm)2) lymphocytes (mycosis fungoides)3) necrotic keratinocytes, keratinocyte necrosis (drug)
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Overview• Drug-eruptions• Erythroderma• Manifestations of renal disease• Blistering disorders• Vasculitis/Vasculopathy (another lecture)
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Cutaneous Manifestations of Renal Disease
• Calciphylaxis• Nephrogenic systemic fibrosis/nephrogenic
fibrosing dermopathy (sclerotic bodies)
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Calciphylaxis
• Frequently lethal• Most commonly, but not
always ESRD• Deep stellate ulcerations
with eschar formation• Intimal hyperplasia and
medial calcification of small dermal and subcutaneous arterioles and arteries
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Adjacent areas of a wedge biopsy:
SubQ Throm VascCalciphylaxis
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Nephrogenic Systemic Fibrosis
• Progressive, symmetric hardening of skin over extremities
• “woody induration”• Acute or chronic
renal disease with close relationship to gadolinium exposure
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Overview• Drug-eruptions• Erythroderma• Manifestations of renal disease• Blistering disorders• Vasculitis/Vasculopathy (another lecture)
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Paraneoplastic pemphigus
• Most often associated with CLL, NHL, Castleman’s disease
• involves stratified squamous epithelium andcolumnar epithelium of lungs, resulting in progressive bronchiolitis obliterans
• Variable presentation: some PV-like and many with T-cell mediated disease phenotype, e.g. EM
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IgG
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IgG
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Paraneoplastic Pemphigus in absence of detectableantibodies
• Patients treated with Retuximab
• Lack autoantibodies detected by DIF, IIF, or immunoprecipitation
• Lack features of acantholysis on H&E
• Indicates that PNP may be mediated by cytotoxic T-cells rather than autoantibodies
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IgG
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Overview• Drug-eruptions• Erythroderma• Manifestations of renal disease• Blistering disorders• Vasculitis/Vasculopathy
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Cutaneous Vasculitis
• Approximately 90% of cutaneous vasculitis cases are associated with immune complex deposition or ANCAs and show neutrophilic small vessel vasculitis on histology
• Etiologic non-specificity of these neutrophilic lesions is potentially limiting– Step 1: recognize vasculitis is present– Step 2: determine the specific type of the disease
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Cutaneous Vasculitis Epidemiology• 15-30 cases per million per year• Adults more often than children• Fatal disease occurs in <7% of patients
40-50% Localized disease, idiopathic and self-limited
15-20% Localized disease secondary to recent infection
15-20% Localized disease secondary to drug hypersensitivity
15-20% Extracutaneous inflammatory/rheumatologic or ANCA+ disease secondarily involving skin
<5% Malignancy/paraneoplastic associated
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Terminology• “leukocytoclastic vasculitis (LCV)” is
pathologic terminology, and in the skin, it means small vessel disease
• “cutaneous leukocytoclastic angiitis (CLA)” is the predominant clinical term for disease confined to the skin
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Classification• On histology, cutaneous vasculitis is classified by:
– Vessel size (small vessel and/or muscular arteries)– Extent of involvement (superficial dermal vs. pandermal vs. subcutaneous)– Predominant cellular infiltrate (neutrophilic, eosinophilic, granulomatous,
lymphocytic)
Small vessel Medium vessel
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Diagnostic biopsies
• Skin biopsy is the gold standard for the diagnosis of cutaneous vasculitis
• Obtain one biopsy for H&E and one for DIF
• Obtain biopsies from non-ulcerated sites
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Timing of biopsy
Carlson JA. Histopathology 2010;56,3-23.
• Earliest, most symptomatic, reddest lesions have the highest yield (usually 12-48 hours after appearance of lesion)
• DIF biopsy time frame is similar.
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Depth of biopsy
Carlson JA. Am J Dermatopathol 2005;27,504-28.
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Histologic diagnostic criteria
2 of the following 3 criteria are necessary for small vessels:
1) Angiocentric and/or angioinvasive inflammatory infiltrates
2) Disruption and/or destruction of vessel wall (surrogate measures are leukocytoclasis or onion-skinning fibrosis)
3) Fibrinoid necrosis-intramural fibrin deposition
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Additional findings pointing to a more specific diagnosis…
1. H&E2. DIF studies
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LCV of upper dermis
•On biopsy, 60% of patients presenting with localized cutaneous vasculitis will have small vessel vasculitis restricted to the upper dermis.
•DIF shows small granular IgG, IgM and C3 in vessel walls
40-50% Localized disease, idiopathic and self-limited
15-20% Localized disease secondary to recent infection
15-20% Localized disease secondary to drug hypersensitivity
15-20% Extracutaneous inflammatory/rheumatologic or ANCA+ disease secondarily involving skin
<5% Malignancy/paraneoplastic associated
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LCV of upper dermis
• These findings favor localized cutaneous disease
• Other entities which commonly show this pattern in DDx include HSP, MPA.
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LCV secondary to drugsTissue eosinophilia is a clue to a drug
etiology.
Established clinically by temporal relationship of drug intake to eruption, effect of withdrawl and re-challenge, and knowledge of drugs likely to cause.
Bahrami S, et al. Arch Derm 2006;142,155-61.
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LCV secondary to infection
Increased frequency of subcorneal, intraepidermal, and subepidermal neutrophilic pustules.
Etiology may be visible on routine histology, e.g. HSV.
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40-50% Localized disease, idiopathic and self-limited
15-20% Localized disease secondary to recent infection
15-20% Localized disease secondary to drug hypersensitivity
15-20% Extracutaneous inflammatory/rheumatologic or ANCA+ disease secondarily involving skin
<5% Malignancy/paraneoplastic associated
Extracutaneous disease involving the skin
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“Pan dermal” or small + medium vessel disease
Connective tissue disease-associated vasculitis
ANCA+ primary systemic vasculitisCryoglobulinemic vasculitis
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CTD vasculitis
• Co-existence of small and medium vessel vasculitis is characteristic
• Most frequently in patients with SLE, RA, Sjogren’ssyndrome, and less likely DM
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ANCA+ primary systemic vasculitis
Carlson JA. Histopathology 2010;56,3-23.
Wegner’s granulomatosis Churg Strauss Disease
Granlomatous dermatitis seen in <20% of Wegners and Churg Strauss skin bx
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ANCA+ primary systemic vasculitis
• LCV is the most common pattern identified (seen in 50-70% of skin biopsies)• Churg Strauss does show tissue eosinophilia in >50% of skin biopsies
LCV
Early granuloma
Wegner’s granulomatosis Churg Strauss Disease
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Additional findings pointing to a more specific diagnosis…
1. H&E2. DIF studies
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Contribution of DIF
HSP CV or RV ANCA+
Negative
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Contribution of DIF (cont)IgG and/or IgM basement membrane zone (60% of cases) or keratinocyte nuclear
reactants can be found in CTD vasculitis (such as lupus vasculitis)
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Retiform purpura related to levamisole
Chung C., et al. JAAD, 2011
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Vasculitis summary
• Histologic examination focuses on:1) Whether vasculitis is present2) Size and extent of vessel involved3) Type of inflammatory infiltrate
• Additional studies such as DIF and ANCA status may allow for a more specific diagnosis
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Example signout
DIAGNOSIS: Leukocytoclastic vasculitis (see note)
Note: Correlation with a biopsy for DIF and additional laboratory studies may allow for a more specific diagnosis.
No supplementary information:
Is vasculitis present or absent?
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DRESS syndrome
• Drug reaction with eosinophilia and systemic symptoms (DRESS) has an estimated mortality of 10%
• Most frequent skin finding: morbilliform rash• Systemic involvement includes hematologic,
hepatic, renal, pulmonary, cardiac, neurologic GI and endocrine abnormalities
• Currently no universally recognized diagnostic criteria
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Etiology• Many agents, but
carbamazepine is most frequent
• 2-6 weeks after drug administration
• Associations include: – Drug detoxification enzyme
abnormalities– Possible reactivation of
herpes viruses– Certain HLA alleles
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