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Merkel cell carcinoma (neuroendocrine cancer of skin, trabecular cancer)

Rare aggressive cutaneous neoplasm. Etiology: 1) polyomavirus [4] (Merkel cell virus) 2) risk factors a) exposure to sunlight b) immunosuppression c) exposure to arsenic d) older age Epidemiology: 1) rare, 2000 cases in the U.S. yearly 2) occurs mostly in people after age 70 3) majority of patients are white 4) occurs more often in men than women 5) cause of death of Jimmy Buffet September 1, 2023 Pathology: 1) Merkel cells located in the basal layer of the epidermis & hair follicle or 2) immature totipotential stem cells that acquire neuroendocrine features during transformation 3) majority of tumors are intradermal as opposed to epidermal 4) frequent metastases to regional lymph nodes - commonly involved metastatic sites include liver, bone, brain & skin Microscopic pathology: 1) histologically similar to other poorly differentiated neoplasms 2) histologic patterns a) trabecular type b) small cell type c) intermediate type (most common) Immunohistochemistry: - cytokeratin: + - CK20: + 97% - CK7: -/+ (23% positive [3]) - Ber-EP4: + - EMA: + 78% - thyroid transcription factor 1: - - neuroendocrine markers: + - S100: - - high molecular weight cytokeratins: - - NSE: - - chromogranin A: + 72% - chromogranin B: + 100% - synaptophysin: + 39% - CD99: +/- Electron microscopy: 1) dense core granules 2) 10 nm filaments 3) desmosomes Genetics: - chromosome 1p abnormalities in ~40% - p53 mutations - p73 mutations - loss of heterozygosity 3p21 - genomic integration of Merkel cell polyomavirus (80%) * Merkel cell polyomavirus does not always lead to Merkel cell carcinoma Clinical manifestations: 1) rapidly growing painless firm nontender nodule 2) red, pink, or blue nodules 3) variable size from < 1/4 inch to > 2 inches 4) ~2% present with nodal or metastatic disease without apparent skin primary 5) ~1/3 - 1/2 eventually develop systemic disease - weight loss, night sweats, lymphadenopathy 6) predilection for sun-exposed areas a) head & neck 47% b) extremities 33% c) trunk 10% d) vulva 2% e) other < 1% * image [8] Laboratory: 1) tumor biopsy & sentinel lymph node biopsy 2) complete blood count 3) liver function tests Radiology: - CT scan to rule out metastases Management: 1) surgical resection - sentinel lymph node biopsy - for early stage disease with negative sentinel lymph node biopsy Mohs micrographic surgery is associated with significantly improved overall survival compared with wide local excision [11] 2) adjunctive radiation therapy may be useful [6] 3) chemotherapy NOT curative [4] - avelumab (Bavencio) FDA-approved for metastatic Merkel cell carcinoma March 2017 [7] - pembrolizumab (Keytruda) for metastatic Merkel cell [1]; FDA-approved [10] - neoadjuvant nivolumab may reduced extent of surgical resection needed [9] 4) prognosis - 5-year survival is 75% if localized, 61% if regional, 24% if metastatic

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disease interactions

General

neuroendocrine carcinoma skin cancer

References

  1. UpToDate http://uptodateonline.com/application/topic.asp?file=skin_can/7766&type=A&selectedTitle=24~42
  2. Dabbs. Diagnostic Immunohistochemistry. Churchill-Livingstone, 2002. page 233.
  3. Jensen et al. Appl Immunohisstochem Mol Morphol 8:310-5, 2000 PMID: 11127923
  4. Feng H et al, Clonal integration of a polyoma virus in human Merkel cell carcinoma. Science 2008, Jan 17 ePub PMID: 18202256
  5. Touze A et al. High levels of antibodies against Merkel cell polyomavirus identify a subset of patients with Merkel cell carcinoma with better clinical outcome. J Clin Oncol 2011 Apr 20; 29:1612. PMID: 21422439 - Paulson KG et al. Transcriptome-wide studies of Merkel cell carcinoma and validation of intratumoral CD8+ lymphocyte invasion as an independent predictor of survival. J Clin Oncol 2011 Apr 20; 29:1539. PMID: 21422430
  6. Kim JA and Choi AH. Effect of radiation therapy on survival in patients with resected Merkel cell carcinoma: A propensity score surveillance, epidemiology, and end results database analysis. JAMA Dermatol 2013 Jul; 149:831 PMID: 23864085
  7. Bankhead C FDA Approves Drug for Rare Skin Cancer. - Avelumab active in Merkel cell carcinoma. MedPage Today. March 23, 2017 https://www.medpagetoday.com/Dermatology/SkinCancer/64096
  8. Stokowsk LA Merkel Cell Carcinoma: Not Just Another Skin Cancer. An Interview With Paul Nghiem, MD, PhD Medscape. Oct 27, 2017. https://www.medscape.com/viewarticle/886140
  9. Kuznar W with expert critique by Klil-Drori AJ Neoadjuvant Nivolumab Tames Resectable Merkel Cell Carcinoma. May reduce the extent of surgery required. MedPage Today. ASCO Reading Room 11.24.2018 https://www.medpagetoday.com/reading-room/asco/skin-cancer/76465
  10. Kuznar W with critique by Hermel D Pembrolizumab Approved in Merkel Cell Carcinoma: Higher Response Rates, Less Toxicity Compared With Chemotherapy. Accelerated approval for both adults and children with recurrent locally advanced or metastatic disease. MedPage Today. ASCO Reading Room 01.26.2019 https://www.medpagetoday.com/reading-room/asco/skin-cancer/77620
  11. Cheraghlou S, Doudican NA, Criscito MC et al Overall Survival After Mohs Surgery for Early-Stage Merkel Cell Carcinoma. JAMA Dermatol. Published online August 23, 2023. PMID: 37610773 PMCID: PMC10448369 Free PMC article https://jamanetwork.com/journals/jamadermatology/fullarticle/2808884
  12. Wikipedia: Jimmy Buffett https://en.wikipedia.org/wiki/Jimmy_Buffett
  13. Merkel Cell Cancer http://cis.nci.nih.gov/fact/6_11.htm
  14. Merkel Cell Carcinoma (PDQ): Treatment http://www.nci.nih.gov/cancerinfo/pdq/treatment/merkelcell/patient/