Hospital-based Dermatopathology Janis M. Taube, MD Director of Dermatopathology Johns 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/maculopapular/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
Morbilliform (exanthematous) drug eruptions 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 viralinduced morbilliform 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 1 Sufficool 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
EGFR inhibitors 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 Brodell, et al. J Cutan Pathol, 2013
GM-CSF and G-CSF
Novel Immunotherapeutic Agents Signal 2 Two signal model to develop an antigenspecific T-cell response Multiple Accelerators and Brakes Signal 1 Pardoll D, 2012 Pardoll 2012 De novo vs. ongoing response in the periphery Tumors may co-opt checkpoint signals to turn off the host immune response
Checkpoint Blockade of CTLA-4 or PD-1 Signaling Ribas A. NEJM 2012
Comparison of immune-mediated related dermatitis following checkpoint blockade CTLA-4 blockade PD-1 blockade Phan GQ, et al. PNAS 2008 Blistering dermatitis Taube JM, et al. unpublished data Mild eczematous dermatitis 58
Complete regression of metastatic melanoma (anti- PD-1, 3 mg/kg) associated with vitiligo Pre Normal skin Boundary Post 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
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 Calciphylaxis
Adjacent areas of a wedge biopsy: Calciphylaxis SubQ Throm Vasc
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 and columnar 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 detectable antibodies 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