Hospital-based Dermatopathology

Hospital-based Dermatopathology

Janis M. Taube, MDDirector of DermatopathologyJohns Hopkins University SOM

Overview• Drug-eruptions• Erythroderma• Manifestations of renal disease• Blistering disorders• Vasculitis/Vasculopathy

“There are some remedies worse than the disease.”

Publilius Syrus (c. 42 BC)

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

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%

“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.

Histopathologic features

Recognized histologically and drug etiology assigned:


Recognized histologically and drug etiology assigned: fixed drug eruption



Recognizable histologic pattern, causative role of drug not always apparent:



Recognizable histologic pattern, causative role of drug not always apparent: urticaria



Recognizable histologic pattern, causative role of drug not always apparent: urticaria

Histology is “non-specific”:



Recognizable histologic pattern: causative role of drug not always apparent: urticaria

Histology is “non-specific”: morbilliform

• 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

Clinical Features

• Erythematous macules and papules that coalesce

• Trunk is most common• +/- pruritis• Resemble viral exanthems

Gerson, et al. JAAD 2008

Histology in ~100 clinically morbilliform drug eruptions










Urticarial Drug Eruptions

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).

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

Neutrophilic Urticarial Dermatosis

Am J of Dermatopathol. 38(1):39-49, 2016

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%)

Fixed Drug Eruptions

Fixed drug eruption• Not a common cause of

biopsy• Face and male genitalia are

most common sites• Ampicillin, barbiturates,

NSAIDs• Resolves with residual

hyperpigmentation

EM/SJS/TEN

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.

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

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

Pustular Psoriasis

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

RAF activation of the MAPK/ERK pathway

Gibney GT, et al. Nat Rev Clin Oncol, 2013

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

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

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

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

Doyle and Sperling et al. Am J Dermpath, 2011

• 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

EGFR inhibitors

Brodell, et al. J Cutan Pathol, 2013

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

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

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

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

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

FDA approvals for multiple PD-L1 IHC assays

Taube JM, et al, Mod Path, 2017

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.

Lichenoid drug eruption

Curry, et al. J Cutan Pathol, Volume: 44, Issue: 2, Pages: 158-176

Curry, et al. J Cutan Pathol, Volume: 44, Issue: 2, Pages: 158-176

Anti-type IV collagen

Granulomatous dermatitis following anti-PD-1 therapy

Overview• Drug-eruptions• Erythroderma• Manifestations of renal disease• Blistering disorders• Vasculitis/Vasculopathy (another lecture)

Erythroderma• Otherwise healthy adult = drug-based

Drug-associated erythroderma

Curr Probl Dermatol 2002;14:117-146.

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)


Cutaneous Manifestations of Renal Disease

• Calciphylaxis• Nephrogenic systemic fibrosis/nephrogenic

fibrosing dermopathy (sclerotic bodies)

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

Adjacent areas of a wedge biopsy:

SubQ Throm VascCalciphylaxis

Nephrogenic Systemic Fibrosis

• Progressive, symmetric hardening of skin over extremities

• “woody induration”• Acute or chronic

renal disease with close relationship to gadolinium exposure


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

IgG

IgG

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

IgG

Overview• Drug-eruptions• Erythroderma• Manifestations of renal disease• Blistering disorders• Vasculitis/Vasculopathy

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

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

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

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

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

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.

Depth of biopsy

Carlson JA. Am J Dermatopathol 2005;27,504-28.

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

Additional findings pointing to a more specific diagnosis…

1. H&E2. DIF studies

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






LCV of upper dermis

• These findings favor localized cutaneous disease

• Other entities which commonly show this pattern in DDx include HSP, MPA.

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.

LCV secondary to infection

Increased frequency of subcorneal, intraepidermal, and subepidermal neutrophilic pustules.

Etiology may be visible on routine histology, e.g. HSV.






Extracutaneous disease involving the skin

“Pan dermal” or small + medium vessel disease

Connective tissue disease-associated vasculitis

ANCA+ primary systemic vasculitisCryoglobulinemic vasculitis

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

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

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

Additional findings pointing to a more specific diagnosis…

1. H&E2. DIF studies

Contribution of DIF

HSP CV or RV ANCA+

Negative

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)

Retiform purpura related to levamisole

Chung C., et al. JAAD, 2011

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

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?

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

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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Hospital-based Dermatopathology