Iatrogenic Dermatopathology: When Therapy Goes Wrong Tammie Ferringer, MD Geisinger Medical Center, Danville, PA tferringer@geisinger.edu I do not have any relevant relationships with industry Targeted Therapies Modulate key molecular pathways essential in tumor growth or inflammation 1
mabs, NIBS, etc. Nomenclature end of the names of therapeutic agents conveys information about their structure "-cept" refers to fusion of a receptor to the Fc part of human immunoglobulin G1 (IgG1) "-mab" indicates a monoclonal antibody (mab) "-ximab" indicates a chimeric mab "-zumab" indicates a humanized mab -inib, enib indicates kinase inhibitors TNF-a EGFR MKI BRAF MEK CTLA-4 PD-1 Infliximab (Remicade ) Adalimumab (Humira ) Etanercept (Enbrel ) Golimumab (Simponi ) Certolizumab (Cimzia ) Cetuximab (Erbitux ) Erlotinib (Tarceva ) Gefitinib (Iressa ) Sorafenib (Nexavar ) Sunitinib (Sutent ) Vemurafenib (Zelboraf ) Dabrafenib (Tafinlar ) Trametinib (Mekinist ) Selumetinib Ipilimumab (Yervoy ) Nivolumab (Opdivo ) Pembrolizumab (Keytruda ) Targeted Therapy Inhibitors TNF-Inhibitors TNF-alpha is a proinflammatory cytokine All inhibitors are monoclonal ab except etanercept 2
TNF-Inhibitors Psoriasis TNF-Inhibitors Indications Arthritis (RA, JRA, psoriatic) Ankylosing spondylitis Inflammatory bowel disease Cutaneous SE of TNF- Inhibitors Infusion or injection site reaction Psoriasiform Interface Granulomatous Eczematous Vasculitis Alopecia Pseudolymphoma Panniculitis 3
Case 1 62 yo RA patient on etanercept Case 1 4
TNF-Inhibitor Injection Site Reactions Especially those on etanercept for RA Usually in first 2 months of therapy Can have recall reaction 1-2 days after injection and lasts 3-5 days Decreases in frequency and severity with time Injection Site Reactions Dermal edema, perivascular lymphocytic infiltrate with eosinophils Sparse neutrophils and macrophages can also be seen Rarely vasculitis Arch Dermatol. 2001;137(7):893-899. Injection Site Reaction 57 yo RA patient on adalimumab Winfield H. Arch Dermatol. 2006;142(7):218-220. 5
Case 2 45 yo Crohns patient on adalimumab for 6 mos Case 2 45 yo Crohns patient on adalimumab for 6 mos 6
TNF-Inhibitor Induced Psoriasiform Eruptions Most in RA, Crohns, or ankylosing spondylitis patients May not be recognized in patients being treated for psoriasis Most have no personal or family history of psoriasis Can occur many months after starting therapy Disruption of cytokine balance by TNF blockage allowing unopposed IFN-alpha production by PDC TNF-Inhibitor Induced Psoriasiform Eruptions Patterns Plaque psoriasis (48-57%) Palmoplantar pustulosis (29-45%) Guttate, scalp, pustular, erythrodermic, inverse McKee s Pathology of the Skin 4 th ed) TNF-Inhibitor Induced Psoriasiform Eruptions 61 yo RA patient on infliximab 7
TNF-Inhibitor Induced Psoriasiform Eruptions 78 yo RA patient on MTX and etanercept and recurred on certolizumab Pustular Guttate like Laga AC. Histopathologic spectrum of psoriasiform skin reactions associated with TNF-A inhibitor therapy. AJDP 2010;32:568. Plaque like TNF-Inhibitor Induced Psoriasiform Eruptions Can show Lichenoid Spongiotic Apoptotic keratinocytes Eosinophils Plasma cells May lack Tortuous blood vessels Suprapapillary plate thinning 8
Psoriasiform Drug Eruptions Other Drugs IFN-alpha Lithium Beta blockers Anticonvulsants Metformin Terbinafine Captopril Digoxin GM-CSF Case 3 60 yo RA patient on longterm adalumimab with mental status change 9
Case 3 ANA over 10,240 Positive antihistone ab Lupus cerebritis Improved with solumedrol and discontinuation of adalumimab TNF-Inhibitor Induced Lupus Like Reaction Not as frequent as psoriasiform ANA develops in up to 63% (esp with infliximab) Lupus like reaction occurs in less than 1% Most occur between 1 and 10 months after starting the drug Rarely in patients being treated for psoriasis May respond to change within the class TNF-Inhibitor Induced Lupus Like Reaction Skin findings in two-thirds SCLE, DLE, photosensitivity, malar rash, alopecia, pernio, oral ulcers SCLE may involve lower extremities and be bullous Arthritis may occur but CNS and renal involvement are very rare TAILS (TNF-A antagonist induced lupus like syndrome) 10
60 yo Crohns patient on infliximab for 3 years TNF-Inhibitor Induced Interface Reactions versus LP Symmetric trunk/extremities More necrotic keratinocytes and eosinophils Laga AC. AJDP 2010;32:568 11
Case 4 43 yo RA patient previously treated with MTX, Humira, Enbrel, Cimzia, now on Simponi which was started 6 mos ago 12
53yo RA patient treated with etanercept presented with violaceous nodules on the inner thighs 53yo RA patient treated with etanercept presented with violaceous nodules on the inner thighs Dermatol Clin 33 (2015)373-87. 13
Reactive Granulomatous Dermatitis Hematologic Disorders CTD Inflammatory Arthritis PNGD IGD IGDR TNF-Inhibitors CCG, BB, ACEi, statins TNF-Inhibitor Induced Non-Infectious Granulomatous Reactions Average latency 1 year Interstitial granulomatous dermatitis/pngd GA Sarcoid 58 yo UC patient treated with infliximab for 1 yr with these lesions that recur after each infusion 14
Case 5 32yo female with Crohn s on remicade with erythematous scalp with hair loss, fungal culture negative, Scarring alopecia? 15
Case 5 Case 5 Case 5 16
Case 5 TNF-Inhibitor Induced Alopecia Am J Dermatopathology 2011;33:161. TNF-Inhibitor Induced Alopecia Psoriasis + Alopecia Areata + Mixed Infiltrate Doyle LA, et al. Am J Dermatopathology 2011;33:161. 17
TNF-Inhibitor Induced Alopecia Am J Dermatopathology 2011;33:161. TNF-Inhibitor Induced Infection Disseminated VZV 18
Summary for Catnappers TNF-inhibitors Infliximab (Remicade ) Adalimumab (Humira ) Etanercept (Enbrel ) Golimumab (Simponi ) Certolizumab (Cimzia ) Summary for Catnappers TNF-I Reactions Injection site reaction DHR or Wells like +/- vasculitis Psoriasiform dermatitis Often with interface, spongiosis and mixed infiltrate Interface LE-like, lichenoid, or EM-like Granulomatous IGD/PGND, sarcoidal, GA-like Alopecia AA histology with psoriasis, mixed infiltrate and atrophic sebaceous glands TNF-a EGFR MKI BRAF MEK CTLA-4 PD-1 Infliximab (Remicade ) Adalimumab (Humira ) Etanercept (Enbrel ) Golimumab (Simponi ) Certolizumab (Cimzia ) Cetuximab (Erbitux ) Erlotinib (Tarceva ) Gefitinib (Iressa ) Sorafenib (Nexavar ) Sunitinib (Sutent ) Vemurafenib (Zelboraf ) Dabrafenib (Tafinlar ) Trametinib (Mekinist ) Selumetinib Ipilimumab (Yervoy ) Nivolumab (Opdivo ) Pembrolizumab (Keytruda ) Targeted Therapy Inhibitors 19
EGFR Inhibitors Monoclonal antibodies Cetuximab (Erbitux ) Small molecule tyrosine kinase inhibitors Gefitinib (Iressa ) Erlotinib (Tarceva ) EGFR in Malignancies Mutation or amplification in: Breast cancer Colon cancer Lung cancer Cervical cancer Etc... EGFR in Skin Expressed in Keratinocytes (esp basal and suprabasal) Follicular epithelium Eccrine glands Sebaceous cells Erlotinib (Tarceva ) Cetuximab (Erbitux ) Courtesy J. Lubbe, Geneva, R. Dummer, Zurich 20
Cutaneous Side Effects of EGFR Inhibitors Rash (follicular papulopustular) 50-90% Xerosis Paronychia 10-20% Hair changes- trichomegaly, curling, trichorrhexis, alopecia Mucositis Photosensitivity Cetuximab (Erbitux ) Erlotinib (Tarceva ) Courtesy J. Lubbe, Geneva, R. Dummer, Zurich Lacouture ME. Mechanisms of cutaneous toxicities to EGFR inhibitors Nat Rev Cancer, 2006. Acneiform Rash of EGFR Inhibitors First 1-2 weeks Seborrheic areas Follicular erythematous papules and pustules Belloni B. Chem Immunol Allergy. 2012 6 days after starting cetuximab for colon cancer Acneiform Eruption Unlike acne More monomorphic Pruritic No comedones Hoang MP. AJDP 2012 Drug Incidence Cetuximab 88-90% Gefitinib 25-30% Erlotinib 75% 21
Case 6 70 yo with rash that started during cetuximab treatment for metastatic rectal adenocarcimoma Case 6 Acneiform Rash of EGFR Inhibitors Hyperkeraotit Hyperkeratotic widened infundibulum Suppurative folliculitis 22
Prognostic Implications of Skin Toxicity with EGFR Inhibitors TNF-a EGFR MKI BRAF MEK CTLA-4 PD-1 Infliximab (Remicade ) Adalimumab (Humira ) Etanercept (Enbrel ) Golimumab (Simponi ) Certolizumab (Cimzia ) Cetuximab (Erbitux ) Erlotinib (Tarceva ) Gefitinib (Iressa ) Sorafenib (Nexavar ) Sunitinib (Sutent ) Vemurafenib (Zelboraf ) Dabrafenib (Tafinlar ) Trametinib (Mekinist ) Selumetinib Ipilimumab (Yervoy ) Nivolumab (Opdivo ) Pembrolizumab (Keytruda ) Targeted Therapy Inhibitors Sorafenib Multikinase Inhibitors Targets include: RAF, VEGFR-2 and 3, PDGFR-beta, FLT-3, c-kit, RET Sunitinib Targets include: VEGFR and PDGFR, c-kit, RET, FLT- 3, CSF-1 23
Cutaneous SE of Multikinase Inhibitors Hand-foot skin reaction Facial erythema Splinter hemorrhages Alopecia Curly hair Acneiform eruption Mucositis Skin and hair discoloration SCCs/KAs (sorafenib) SJS Autier J. Arch Dermatol2008 Hand-Foot Skin Reaction of Multikinase Inhibitors 2-3 weeks after initiation Palms and soles symmetrically Burning and pain precede clinical signs Discrete and associated with hyperkeratosis Drug Incidence Sorafenib 48% Sunitinib 36% Lee WJ et al. Br J Dermatol 2009. Multikinase Inhibitor HFSR Following increase in dose of sorafenib for metastatic RCC 24
Multikinase Inhibitor HFSR Yellow hyperkeratotic plaques Chemo Induced Acral Erythema Tingling/numbness Diffuse erythema Desquamation Autier. Arch Dermatol. 2008 Son HS, Yonsei Med. J. (2009) Hand-Foot Skin Reaction of Multikinase Inhibitors Vacuolar degeneration of keratinocytes Acanthosis Variable parakeratosis Hoang MP, et al. AJDP 2012. Tender bullae on feet after starting sorafenib for HCC Hand-Foot Skin Reaction of Multikinase Inhibitors Day 12 Day 30 Lacouture et al. Ann.Oncol. 2008 Day 45 25
TNF-a EGFR MKI BRAF MEK CTLA-4 PD-1 Infliximab (Remicade ) Adalimumab (Humira ) Etanercept (Enbrel ) Golimumab (Simponi ) Certolizumab (Cimzia ) Cetuximab (Erbitux ) Erlotinib (Tarceva ) Gefitinib (Iressa ) Sorafenib (Nexavar ) Sunitinib (Sutent ) Vemurafenib (Zelboraf ) Dabrafenib (Tafinlar ) Trametinib (Mekinist ) Selumetinib Ipilimumab (Yervoy ) Nivolumab (Opdivo ) Pembrolizumab (Keytruda ) Targeted Therapy Inhibitors BRAF Inhibitors and MM Ragini R, et al. Clinics in Dermatol, 2013. Vemurafenib BRAF Inhibitors FDA approval 8/17/2011 BRAF V600E inhibitor Dabrafenib FDA approval 5/29/2013 B-RAFV600E and B-RAFV600K inhibitor Up to 90% of patients under BRAF-inhibitor therapy have cutaneous side effects 26
63 yo woman 1 wk after starting vemurafenib Case 7 Case 7 Case 7 27
Case 7 BRAF Inhibitor Related Keratoacanthomas 77 yo with metastatic melanoma on vemurafenib 83 BRAF Inhibitor Related Keratoacanthomas 84 28
BRAF Inhibitor Related Keratoacanthomas 85 BRAF Inhibitor Induced Acantholytic Dyskeratosis 8 of 14 patients on BRAF inhibitors Warty dyskeratoma Grover-like rash Chu EY. JAAD 2012 29
Other BRAF Inhibitor Induced Side Effects Livingstone E, et al. Chin Clin Oncol;2014. Cutaneous SE of BRAF Inhibitors (93%) Cutaneous SCC/KA (26%) BRAF associated verrucoid keratoses (BAVK) Keratosis pilaris-like rash Photosensitivity Alopecia Hand foot skin reaction Seborrheic dermatitis-like hyperkeratosis of the face Neutrophilic panniculitis Acantholytic dyskeratosis Huang V. Arch Dermatol 2012. Modified from Anforth R, Fernandez-Peñas P, Long GV. Cutaneous toxicities of RAF inhibitors. Lancet Oncol. 2013 Jan;14(1):e11-8. 30
J Clin Oncol. 2012 May 21. 12/22 melanomas (0 BRAF, 1 NRAS) 9/22 dysplastic nevi (0 BRAF, 2 NRAS) Control group: 22 nevi (8 BRAF, 0 NRAS) JAAD 2015;73:491-9 31
BRAF Inhibitor Resistance Need to avoid resistance and paradoxical activation of MEK/ERK signaling in RAS mutant cells Combined dabrafenib and trametinib (MEK inhibitor) TNF-a EGFR MKI BRAF MEK CTLA-4 PD-1 Infliximab (Remicade ) Adalimumab (Humira ) Etanercept (Enbrel ) Golimumab (Simponi ) Certolizumab (Cimzia ) Cetuximab (Erbitux ) Erlotinib (Tarceva ) Gefitinib (Iressa ) Sorafenib (Nexavar ) Sunitinib (Sutent ) Vemurafenib (Zelboraf ) Dabrafenib (Tafinlar ) Trametinib (Mekinist ) Selumetinib Ipilimumab (Yervoy ) Nivolumab (Opdivo ) Pembrolizumab (Keytruda ) Targeted Therapy Inhibitors MEK Inhibitors Trametinib (Mekinist ) MEK 1 and 2 inhibitor EGFRI-like rash or acneiform dermatitis 82% No cutaneous SCC Livingstone E, et al. Chin Clin Oncol;2014. 32
MEK Inhibitors Balagula Y, Invest New Drugs, 2011 TNF-a EGFR MKI BRAF MEK CTLA-4 PD-1 Infliximab (Remicade ) Adalimumab (Humira ) Etanercept (Enbrel ) Golimumab (Simponi ) Certolizumab (Cimzia ) Cetuximab (Erbitux ) Erlotinib (Tarceva ) Gefitinib (Iressa ) Sorafenib (Nexavar ) Sunitinib (Sutent ) Vemurafenib (Zelboraf ) Dabrafenib (Tafinlar ) Trametinib (Mekinist ) Selumetinib Ipilimumab (Yervoy ) Nivolumab (Opdivo ) Pembrolizumab (Keytruda ) Targeted Therapy Inhibitors IMMUNE CHECKPOINT INHIBITORS https://www.cancer.gov/publis hedcontent/images/images/r esearch/science/immunecheckpoint-enlarge.jpg 33
Immune Checkpoint Inhibitors: Adverse Effects **Autoimmune side effects** Hypothyroidism >> Hyperthyroidism Pneumonitis Creatinine elevation Elevated AST, ALT Colitis & diarrhea Infusion related reactions Immune Checkpoint Inhibitors: Cutaneous Adverse Effects 10-15% and more so when treating melanoma and RCC rather than H&N SCC and NSCLC PD-1 inhibitors have less severe reactions with a later onset than ipilumimab Lichenoid reactions ** Psoriasiform spongiotic Urticarial reactions Grover disease BP Granulomatous dermatitis Panniculitis Vitiligo 62yo on Keytruda for colon cancer EGFR MKI BRAF MEK CTLA-4 PD-1 Cetuximab (Erbitux ) Erlotinib (Tarceva ) Gefitinib (Iressa ) Sorafenib (Nexavar ) Sunitinib (Sutent ) Vemurafenib (Zelboraf ) Dabrafenib (Tafinlar ) Trametinib (Mekinist ) Selumetinib Ipilimumab (Yervoy ) Nivolumab (Opdivo ) Pembrolizumab (Keytruda ) Summary Catnappers Papulopustular rash Hand-foot syndrome BRAF associated verrucoid keratoses (BAVK) Cutaneous SCC/KA Acantholytic dyskeratosis Neutrophilic lobular panniculitis Papulopustular rash Autoimmune AE Lichenoid 34
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