Hospital-based Dermatopathology

Janis M. Taube, MDDirector of DermatopathologyJohns Hopkins University SOM

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

“ 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%)

Histopathologic features

Recognized histologically and drug etiology assigned:

Histopathologic features

Recognized histologically and drug etiology assigned: fixed drug eruption

Histopathologic features

Recognized histologically and drug etiology assigned: fixed drug eruption

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

Histopathologic features

Recognized histologically and drug etiology assigned: fixed drug eruption

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

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”:

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

• Most common eruptions produce non-specific findings– 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

Histology in ~100 clinically morbilliform drug eruptions

Gerson, et al. JAAD 2008

Morbilliform Drug Eruptions

• 82% of cases had inflammatory cells in superficial dermis

• 80% cases had perivascular and interstitial pattern

• 50% cases had eosinophils• 50% cases had the focal vacuolar interface

changes

Urticarial 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

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

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

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

• Skin and mucosal eruptions are irregular size and shape and are painful

• Clinical findings such as %BSA involvement are key

Histologic features

EARLY LATE

Newer classes of drugs

• Selective BRAF inhibitors• α-TNF in rheumatic diseases• Acneiform eruptions with EGFR-inhibitors• GM-CSF and G-CSF• Novel “checkpoint blockade” agents

RAF activation of the MAPK/ERK pathway

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

BRAF inhibitors

• Squamous lesions, ranging from verrucous keratoses to invasive SCC +/- KA-like features

• (24/47) 51% of patients developed 146 total cutaneous neoplasms

• 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, et al. Am J Dermpath, 2011

• Used to treat NSCLC, metastatic CRC, pancreatic cancer, advanced HNSCC

• EGFR is found on undifferentiated keratinocytes in 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

GM-CSF and G-CSF

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

“Checkpoint Blockade” of CTLA-4 or PD-1 Signaling

Ribas A. NEJM 2012

PD-1 blockade

Comparison of immune-mediated related dermatitis following checkpoint blockade

Phan GQ, et al. PNAS 2008

CTLA-4 blockade

58Mild eczematous dermatitisBlistering dermatitis

Taube JM, et al. unpublished data

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.

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.

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

Cutaneous Manifestations of Renal Disease

• Calciphylaxis• Nephrogenic systemic fibrosis/nephrogenic

fibrosing dermopathy

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

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

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

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

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

Retiform purpura related to levamisole

Chung C., et al. JAAD, 2011