Hospital-based Dermatopathology · 2019-01-24 · Publilius Syrus (c. 42 BC) Drug eruptions •...
Transcript of Hospital-based Dermatopathology · 2019-01-24 · Publilius Syrus (c. 42 BC) Drug eruptions •...
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