This document provides an overview of Merkel cell carcinoma, including its histogenesis, pathogenesis, epidemiology, clinical features, diagnosis, staging, treatment options for both localized and metastatic disease, and prognosis. Key points discussed are the role of Merkel cell polyomavirus in pathogenesis, increasing incidence with age and sun exposure, diagnosis through biopsy and immunohistochemistry, standard treatment involving surgery and/or radiation for localized disease and chemotherapy or immunotherapy for advanced stages, and generally poor prognosis especially for metastatic or recurrent disease.

1. Merkel Cell Carcinoma
From Diagnosis to Treatment
Save Your Skin Webinar
Marco Iafolla, MSc, MD, FRCPC
William Osler Health System
Medical Oncologist
November 27, 2019

2. Disclosures
• Honorarium
• Merck & Co.

3. Agenda
• Histogeneis
• Pathogenesis
• Epidemiology
• Clinical Features
• Diagnosis
• Staging
• Treatment: standard of care and clinical trials
• Prognosis

4. Histogenesis
• Controversial histogenesis
• Merkel cells
• Immature totipotential stem cell
• Dermal fibroblasts vs epidermal keratinocytes
J Am Acad Dermatol. 1993 Aug;29(2 Pt 1):143-56. Oncogene. 2018 Mar;37(11):1409-1416.
J Skin Cancer. 2012;2012:680410. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/merkel-

5. Pathogenesis
• Merkel cell polyomavirus
• A nonenveloped, double-stranded DNA virus
• 5 genotypic variants
• Query part of human dermal microbiota
• Viral DNA found in tumor genome
• Expresses oncoproteins, immune evasion
• Present in 60-80% of Merkel Cell Carcinoma (MCC)
• Viral negative: mutations in TP52, RB1, HRAS, PIK3CA,
KNSTRN, PREX2, RAC1, NOTCH1; epigenetic changes
https://dktk.dkfz.de/en/about-us/news/dktk-essen-dangerous-merkel-cell-skin-carcinoma-exposed Hum Pathol. 2015 Mar;46(3):443-53.
Science. 2008 Feb 22;319(5866):1096-100. J Clin Microbiol. 2014 May;52(5):1687-90.
Cell Host Microbe. 2010 Jun 25;7(6):509-15. J Invest Dermatol. 2015 May;135(5):1221-1224.
Cancer Res. 2015 Sep 15;75(18):3720-3727. Hum Pathol. 2012 Dec;43(12):2282-91.

6. Pathogenesis
• UV exposure
• MCC likely to occur in sun-exposed areas
• Increased incidence with increased sun-
exposure
• Likely the etiology behind viral-negative MCC
• Increased risk for light skin people
J Am Acad Dermatol. 2008 Mar;58(3):375-81. Br J Dermatol. 2011 Nov;165(5):1051-7.
Pathology. 2014 Apr;46(3):205-10. https://www.cdc.gov/features/uv-radiation-safety/index.html
J Cutan Pathol. 2010 Jan;37(1):20-7.

7. Pathogenesis
• Immunosuppression
• Organ transplant recipients (24-fold risk)
• HIV positive
• B-cell malignancies
• Etiology (theory)
• Augmented immunity to Merkel cell polyomavirus
• Atypical cell immune evasion
• Synergistic mutagenesis between UV light and immunosuppressive drugs
Ann Oncol. 2011 Feb;22(2):250-6. J Natl Cancer Inst. 2015 Jan 8;107(2).
Lancet. 2002 Feb 9;359(9305):497-8. Cancer Epidemiol Biomarkers Prev. 2006 Aug;15(8):1545-9.

8. Epidemiology
• First described in 1972
• Males > females
• 1.7-7 cases per 1,000,000 persons
• Increase risk with increased age (mean age 74-76 years)
• Elderly (≥85 years) in Australia or New Zealand: 150-176 cases per
1,000,000 persons
Arch Dermatol. 1972 Jan;105(1):107-10. J Am Acad Dermatol. 2018 Mar;78(3):457-463.e2.
Eur J Cancer. 2011 Mar;47(4):579-85. Br J Dermatol. 2011 Nov;165(5):1051-7.
Br J Dermatol. 2015 Sep;173(3):835-7. J Cutan Pathol. 2010 Jan;37(1):20-7.

9. Clinical features
• Nodule: painless, firm, nontender, shiny, flesh-
colored or bluish-red, rapidly growing
• Rare ulceration or crusting
• Sun-exposed areas
• Head and neck 43%
• Upper extremities and shoulder 24%
• Lower limbs and hip 15%
• Initial presentation
• Local 65%
• Regional lymph node metastasis 26%
• Distant metastases 8%
https://skincancer.org/skin-cancer-information/merkel-cell-carcinoma/ Ann Surg Oncol. 2016 Oct;23(11):3564-3571.

10. Diagnosis
• Often misdiagnosed
• Differential diagnoses: basal cell carcinoma, squamous cell carcinoma,
keratoacanthoma, amelanotic melanoma
• Increased suspicion for patients with “AEIOU”
• Asymptomatic – 88%
• Expanding rapidly in ≤ 3 months – 63%
• Immune suppression – 8%
• Older than 50 years – 90%
• UV-exposed area in a fair-skinned person – 81%
• Sometimes: only lymph node or metastasis, no skin tumor found
• Need biopsy and immunohistochemistry to confirm diagnosis
J Am Acad Dermatol. 2008 Mar;58(3):375-81. Cancer. 1983 Jul 15;52(2):238-45.

11. Staging
• Stage I: tumor ≤ 2 cm in maximum dimension; no lymph node
involvement
• Stage II: tumors > 2 cm or tumor invading into bone, muscle, fascia, or
cartilage; no lymph node involvement
• Stage II is divided into two subgroups based upon the tumor size and depth of
invasion
• Stage III: any tumor with regional lymph node involvement or in-
transit dermal metastasis
• Stage III is divided into subgroups based upon the extent of regional lymph
node involvement
• Stage IV: metastasis beyond the regional lymph nodes
Merkel Cell Carcinoma. In: AJCC Staging Manual, Springer, New York 2010. p.315.

12. Staging
• Complete examination of skin and regional lymph nodes
• Local disease (Stage I and II)
• PET/CT and/or MRI
• Wide local excision (1-2 cm of normal skin margin)
• Sentinel lymph node biopsy
• 1/3 patients with clinically neg lymph nodes will have positive
pathology
• Less clear for MCC in the head and neck region
• Consider baseline Merkel virus oncoprotein antibody titer
• Advanced disease (Stage III and IV)
• Biopsy of metastatic lymph node or distant metastasis
Am J Clin Dermatol. 2013 Dec;14(6):437-47. Cancer. 2017 Apr 15;123(8):1464-1474.
https://www.cancer.gov/about-cancer/diagnosis-staging/staging/sentinel-node-biopsy-fact-sheet J Am Acad Dermatol. 2010 Nov;63(5):751-61.

13. Treatment – surgery and radiotherapy
• Stage I + II
• Definition: only primary tumor; negative sentinel lymph node biopsy
• Wide local excision of primary tumor +/- radiotherapy (to skin and lymph nodes)
• If surgery not possible, then radiotherapy
• Stage III
• Definition: local regional lymph node involvement or in-transit dermal
metastasis; positive sentinel lymph node biopsy
• Skin: wide local excision of primary tumor +/- radiotherapy
• Lymph nodes: regional lymph node dissection, or definitive radiotherapy, or both
dissection and radiotherapy.
• If sentinel lymph node assessment not possible, then radiotherapy
Ann Surg Oncol. 2014 Oct;21(11):3401-5. Ann Surg Oncol. 2014 Oct;21(11):3401-5.
Ann Oncol. 2012 Apr;23(4):1074-80.

14. Treatment – systemic therapy
• Stage I + II + III
• Chemotherapy
• After surgery +/- radiotherapy (adjuvant): no role for chemotherapy
• No randomized controlled trials to assess adjuvant chemotherapy
• 1/3 studies showed possible benefit for chemoradiotherapy after surgery if positive margins
or tumor ≥ 3.0 cm
• Concern for lower response to immunotherapy if prior chemotherapy
• Immunotherapy
• Not (yet) standard of care
• After surgery +/- radiotherapy
• Avelumab (anti-PD-L1): Phase 2 clinical trial (NCT03271372)
• Nivolumab (anti-PD-L): Phase 2 clinical trial (NCT02196961)
• Prior to surgery +/- radiotherapy
• Nivolumab (Phase 1+2 trial) induced major response in 65% of patients
JAMA Otolaryngol Head Neck Surg. 2015 Feb;141(2):137-41. J Natl Cancer Inst. 2016 May 31;108(9).
Int J Radiat Oncol Biol Phys. 2006 Jan 1;64(1):114-9. Lancet Oncol. 2016 Oct;17(10):1374-1385.
JAMA Oncol. 2018 Sep 1;4(9):e180077. J Clin Oncol. 2018;36S:ASCO #9506.

15. Surveillance after local treatment
• No recommendations on the type and/or frequency of imaging studies
• Follow-up is individualized
• As per National Comprehensive Cancer Network
• Physical exam: every 3-6 months x 3 years, then every 6-12 months
• Imaging: as clinically indicated, routine imaging if high-risk features
• Recurrence
• Usually within 1st year of treatment
• Local 29%
• Lymph node 33%
• Distant metastasis 33%
https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf J Cutan Med Surg. 2000 Oct;4(4):186-95.
J Clin Oncol. 2000 Jun;18(12):2493-9. J Clin Oncol. 2005 Apr 1;23(10):2300-9.

16. Treatment – metastatic disease
• Chemotherapy
• No randomized trials or prospective studies; retrospective data only
• Chemo regimens:
• Carboplatin/cisplatin plus etoposide
• 60% overall response rate, 36% complete response
• Cyclophosphamide plus doxorubicin plus vincristine
• 76% overall response rate, 35% complete response
• 50% alive at 9.5 months
• Side effects: 3.4% toxic deaths
J Clin Oncol. 2000 Jun;18(12):2493-9. Cancer Med. 2016 Sep;5(9):2294-301.

17. Treatment – metastatic disease
• Immunotherapy
• Avelumab (anti-PD-L1)
• Phase 2 trial called JAVELIN Merkel 200
• Part A: Patients with prior chemo
• 33% response overall rate, 10% complete
response
• 36% alive at 2 years
• Part B: Patients without prior chemo
• 62% overall response rate
• Data collection ongoing
• Side effects: 17% with infusion reaction, 5% with
serious side effects
https://www.acrobiosystems.com/A1066-PD-1-Pathway-Recombinant-Protein-Collection.html J Immunother Cancer. 2018 Jan 19;6(1):7.
JAMA Oncol. 2018 Sep 1;4(9):e180077.

18. Treatment – metastatic disease
• Immunotherapy: Avelumab (anti-PD-L1) after chemo
J Immunother Cancer. 2018;6(1):7.

19. Treatment – metastatic disease
• Immunotherapy: Avelumab (anti-PD-L1) after chemo
International Symposium on Merkel Cell Carcinoma, 2019

20. Treatment – metastatic disease
• Immunotherapy: Avelumab (anti-PD-L1): 2nd line “real world” data
JAMA Oncol. 2018 May;36(15_suppl):9537-9537
DCR, disease control rate
* Response was reported according to treating-physician assessment of follow-up scans at the time of resupply
† Patients with PD or AEs that required treatment discontinuation within the first 90 days were never resupplied and did not
a follow-up response evaluation; thus, these values may be underreported
‡ As of April 2018: 33 patients with response remain on treatment in the EAP; 20 patients with response were transferred to
commercial supply and no longer followed for outcomes

21. Treatment – metastatic disease
• 1st and 2nd line (combined) immunotherapy
• Nivolumab (anti-PD-1)
• Phase 1+2 trial called CheckMate 358
• 68% overall response rate, 14% complete response
• 71% response in 1st line, 63% response in 2nd line
• 92% alive at 3 months
• Side effects: 20% with serious side effects
Cancer Res. 2017;77S:AACR #CT074.

22. Treatment – metastatic disease
• 1st line Immunotherapy
• Pembrolizumab (anti-PD-1)
• Phase 2 trial called Cancer Immunotherapy Trials Network-09/Keynote-017
• 56% overall response rate, 24% complete response
• Similar response between viral-positive and viral-negative disease
• 69% alive at 2 years
• Side effects: 28% with serious side effects
J Clin Oncol. 2019 Mar 20;37(9):693-702.

23. Treatment – metastatic disease
• Targeted therapy
• Pazopanib (multiple tyrosine kinase inhibitor)
• Phase 2 trial called UKMCC-01
• 19% overall response rate, no complete responses
• Somatostatin analogs
• Case reports of remission
• No clinical trials yet reported
J Clin Oncol. 2016;34S:ASCO #9542. Minerva Chir. 1997 Nov;52(11):1359-65.
J Cancer Res Ther. 2010 Jul-Sep;6(3):382-4

24. Prognosis
Ann Surg Oncol. 2016 Oct;23(11):3564-3571.
Initial presentation
• Local 65%
• Regional lymph node metastasis 26%
• Distant metastases 8%

25. Prognosis
Ann Surg Oncol. 2016 Oct;23(11):3564-3571.

26. Prognosis
• Favorable prognostic factors for survival
• Initial localized disease
• Female sex
• Age < 65 years
• Immune competence
• No other major medical conditions
• Unfavorable prognostic factors for survival
• MCC arising from the head and neck region
• Difficult to treat
• MCC arising from the vulva or perianal region
• Late detection
• MCC arising from the legs
• Poor blood supply in the elderly, difficult surgery and radiotherapy
J Cutan Med Surg. 2000 Oct;4(4):186-95. Am J Clin Oncol. 2004 Oct;27(5):510-5.
J Clin Oncol. 2000;18(12):2493-9. Lancet Oncol. 2004 Oct;5(10):593-9.

27. Prognosis
• Clinicopathologic features with possible influence (small studies)
• Lymphovascular invasion: Odds Ratio for death 3.8
• Intratumoral CD8+ lymphocyte infiltration: Hazard Ratio (HR) for death 0.5
• p63 expression: HR for death 7.26 (95% CI 2.069-25.506) to 2.05 (95% CI 1.1-
3.8)
• Merkel cell polyomavirus
• Large tumor antigen: HR for MCC survival 0.22 (95% CI 0.09-0.52)
• Antibodies against virus: HR for recurrence 0.58 (95% CI 0.36-0.97)
• Virus negative: HR for death 1.85 (95% CI 1.19-2.89)
• Immunosuppression: HR for death 1.9 (95% CI 0.9-4)
Cancer. 2008 Nov 1;113(9):2549-58. J Clin Oncol. 2011 Apr 20;29(12):1539-46.
Mod Pathol. 2011 Nov;24(11):1451-61. Am J Clin Pathol. 2013 Dec;140(6):838-44.
Clin Cancer Res. 2011 Jul 15;17(14):4806-13. J Invest Dermatol. 2017 Apr;137(4):819-827.
Cancer. 2017 Apr 15;123(8):1464-1474. JAMA Dermatol. 2014 Jul;150(7):716-23.

28. Summary
• Merkel Cell Carcinoma (MCC)
• Is rare
• Aggressive; grows and spreads fast
• Most MCC is caused by Merkel cell polyomavirus
• Often misdiagnosed
• Local disease: surgery +/- radiotherapy
• Metastatic disease: new hope with immunotherapies