targeted therapies - pathology...may 04, 2018 · plaque psoriasis (48-57%) palmoplantar pustulosis...

5/21/2018

1

Iatrogenic Dermatopathology: When Therapy Goes Wrong

Tammie Ferringer, MDGeisinger Medical Center,

Danville, [email protected]

I do not have any relevant relationships with industry

Targeted Therapies

◼ Modulate key molecular pathways essential in tumor growth or inflammation

http://ib.bioninja.com.au/standard-level/topic-5-evolution-and-biodi/51-evidence-for-evolution/evolution.html

5/21/2018

2

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

Targeted Therapy

Inhibitors

TNF-a Infliximab (Remicade®)Adalimumab (Humira®)Etanercept (Enbrel®)Golimumab (Simponi®)Certolizumab (Cimzia®)

EGFR Cetuximab (Erbitux®)Erlotinib (Tarceva®)Gefitinib (Iressa®)

MKI Sorafenib (Nexavar®)Sunitinib (Sutent®)

BRAF Vemurafenib (Zelboraf®)Dabrafenib (Tafinlar®)

MEK Trametinib (Mekinist®)Selumetinib

CTLA-4PD-1

Ipilimumab (Yervoy®)Nivolumab (Opdivo®)Pembrolizumab (Keytruda®)

TNF-Inhibitors

◼ TNF-alpha is a proinflammatory cytokine

◼ All inhibitors are monoclonal ab except etanercept

5/21/2018

3

TNF-Inhibitors

TNF-Inhibitors

Indications

◼ Psoriasis

◼ 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

5/21/2018

4

Case 1

62 yo RA patient on etanercept

Case 1

5/21/2018

5

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

Arch Dermatol. 2001;137(7):893-899.

Injection Site Reactions◼ Dermal edema,

perivascular lymphocytic infiltrate with eosinophils

◼ Sparse neutrophils and macrophages can also be seen

◼ Rarely vasculitis

Injection Site Reaction

Winfield H. Arch Dermatol. 2006;142(7):218-220.

57 yo RA patient on adalimumab

5/21/2018

6

Case 2

45 yo Crohns patient on adalimumab for 6 mos

Case 2

45 yo Crohns patient on adalimumab for 6 mos

5/21/2018

7

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


◼ Patterns

◼ Plaque psoriasis (48-57%)

◼ Palmoplantar pustulosis (29-45%)

◼ Guttate, scalp, pustular, erythrodermic, inverse

McKee’s Pathology of the Skin 4th ed)

61 yo RA patient on infliximab


5/21/2018

8

78 yo RA patient on MTX and etanercept and recurred on certolizumab


Guttate like

Plaque like

Pustular

Laga AC. Histopathologic spectrum of psoriasiform skin reactions associated with TNF-A inhibitor therapy. AJDP 2010;32:568.


◼ Can show◼ Lichenoid

◼ Spongiotic

◼ Apoptotic keratinocytes

◼ Eosinophils

◼ Plasma cells

◼ May lack◼ Tortuous blood vessels

◼ Suprapapillary plate thinning

5/21/2018

9

Psoriasiform Drug EruptionsOther Drugs

◼ IFN-alpha

◼ Lithium

◼ Beta blockers

◼ Anticonvulsants

◼ Metformin

◼ Terbinafine

◼ Captopril

◼ Digoxin

◼ GM-CSF

Case 3

60 yo RA patient on long-term adalumimab with mental status change

5/21/2018

10

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

◼ 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)

TNF-Inhibitor Induced Lupus Like Reaction

5/21/2018

11

60 yo Crohns patient on infliximab for 3 years

versus LP

◼ Symmetric trunk/extremities

◼ More necrotic keratinocytes and eosinophils

TNF-Inhibitor Induced Interface Reactions

Laga AC. AJDP 2010;32:568

5/21/2018

12

Case 4

43 yo RA patient previously treated with MTX, Humira, Enbrel, Cimzia, now on Simponiwhich was started 6 mos ago

5/21/2018

13

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.

5/21/2018

14

Reactive Granulomatous Dermatitis

IGDPNGD

IGDRTNF-Inhibitors

CCG, BB, ACEi, statins

CTDInflammatory Arthritis

Hematologic Disorders

◼ Average latency 1 year

◼ Interstitial granulomatous dermatitis/PNGD

◼ GA

◼ Sarcoid

TNF-Inhibitor Induced Non-Infectious Granulomatous Reactions

58 yo UC patient treated with infliximab for 1 yrwith these lesions that recur after each infusion

5/21/2018

15

Case 5

32yo female with Crohn’s on remicade with erythematous scalp with hair loss, fungal culture negative, Scarring alopecia?

5/21/2018

16

Case 5

Case 5

Case 5

5/21/2018

17

Case 5

TNF-Inhibitor Induced Alopecia

Am J Dermatopathology 2011;33:161.


Doyle LA, et al. Am J Dermatopathology 2011;33:161.

Psoriasis + Alopecia Areata + Mixed Infiltrate

5/21/2018

18


Am J Dermatopathology 2011;33:161.

Disseminated VZV

TNF-Inhibitor Induced Infection

5/21/2018

19

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

Targeted Therapy

Inhibitors






CTLA-4PD-1


5/21/2018

20

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 (espbasal and suprabasal)

◼ Follicular epithelium

◼ Eccrine glands

◼ Sebaceous cells

Cetuximab (Erbitux®)

Erlotinib (Tarceva®)

Courtesy J. Lubbe, Geneva, R. Dummer, Zurich

5/21/2018

21

Erlotinib (Tarceva®)Cetuximab (Erbitux®)

Courtesy J. Lubbe, Geneva, R. Dummer, Zurich

Cutaneous Side Effects of EGFR Inhibitors• Rash (follicular papulopustular) 50-90%

• Xerosis

• Paronychia 10-20%

• Hair changes- trichomegaly, curling, trichorrhexis, alopecia

• Mucositis

• Photosensitivity

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 comedonesDrug Incidence

Cetuximab 88-90%

Gefitinib 25-30%

Erlotinib 75%

Hoang MP. AJDP 2012

5/21/2018

22

70 yo with rash that started during cetuximab treatment for metastatic rectal adenocarcimoma

Case 6

Case 6

Acneiform Rash of EGFR Inhibitors

◼ Hyperkeraotit◼ Hyperkeratotic

widened infundibulum

◼ Suppurative folliculitis

5/21/2018

23

Prognostic Implications of Skin Toxicitywith EGFR Inhibitors

Targeted Therapy

Inhibitors






CTLA-4PD-1


Multikinase Inhibitors

◼ Sorafenib◼ 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

5/21/2018

24

Cutaneous SE of MultikinaseInhibitors

◼ 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.

MultikinaseInhibitor HFSR

Following increase in dose of sorafenib for metastatic RCC

5/21/2018

25

Multikinase Inhibitor HFSR

◼ Yellow hyperkeratotic plaques

Chemo Induced Acral Erythema

◼ Tingling/numbness

◼ Diffuse erythema

◼ Desquamation

Son HS, Yonsei Med. J. (2009)Autier . Arch Dermatol. 2008

◼ Vacuolar degeneration of keratinocytes

◼ Acanthosis

◼ Variable parakeratosis


Tender bullae on feet after starting sorafenib for HCC

Hoang MP, et al. AJDP 2012.

Lacouture et al. Ann.Oncol. 2008


Day 12

Day 30

Day 45

5/21/2018

26

Targeted Therapy

Inhibitors






CTLA-4PD-1


BRAF Inhibitors and MM

Ragini R, et al. Clinics in Dermatol, 2013.

BRAF Inhibitors◼ Vemurafenib

◼ 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

5/21/2018

27

63 yo woman 1 wk after starting vemurafenib Case 7

Case 7

Case 7

5/21/2018

28

Case 7

BRAF Inhibitor Related Keratoacanthomas

83|

77 yo with metastatic melanoma on vemurafenib


84|

5/21/2018

29

| 85


BRAF Inhibitor Induced Acantholytic Dyskeratosis

◼ 8 of 14 patients on BRAF inhibitors

◼ Warty dyskeratoma

◼ Grover-like rash

Chu EY. JAAD 2012

5/21/2018

30

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 dyskeratosisHuang 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.

5/21/2018

31

◼ 12/22 melanomas (0 BRAF, 1 NRAS)

◼ 9/22 dysplastic nevi (0 BRAF, 2 NRAS)

◼ Control group: 22 nevi (8 BRAF, 0 NRAS)

J Clin Oncol. 2012 May 21.

JAAD 2015;73:491-9

5/21/2018

32

BRAF Inhibitor Resistance

◼ Need to avoid resistance and paradoxical activation of MEK/ERK signaling in RAS mutant cells…

◼ Combined dabrafenib and trametinib (MEK inhibitor)

Targeted Therapy

Inhibitors






CTLA-4PD-1


MEK Inhibitors

◼ Trametinib (Mekinist®)

◼ MEK 1 and 2 inhibitor

◼ EGFRI-like rash or acneiform dermatitis 82%

◼ No cutaneous SCC

Livingstone E, et al. Chin ClinOncol;2014.

5/21/2018

33

MEK Inhibitors

Balagula Y, Invest New Drugs, 2011

Targeted Therapy

Inhibitors






CTLA-4PD-1


https://www.cancer.gov/PublishedContent/Images/images/r

esearch/science/immune-

checkpoint-enlarge.jpg

IMMUNE CHECKPOINT INHIBITORS

5/21/2018

34

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 Keytrudafor colon cancer

Summary

CatnappersEGFR Cetuximab (Erbitux®)Erlotinib (Tarceva®)Gefitinib (Iressa®)

• Papulopustular rash


• Hand-foot syndrome


• BRAF associated verrucoid keratoses(BAVK)

• Cutaneous SCC/KA • Acantholytic dyskeratosis

• Neutrophilic lobular panniculitis


• Papulopustular rash

CTLA-4PD-1


• Autoimmune AE• Lichenoid

5/21/2018

35

targeted therapies - pathology...may 04, 2018 · plaque psoriasis (48-57%) palmoplantar pustulosis...

Documents