Merkel cell cancer pathophysiology

Merkel cell carcinoma (MCC) is an unusual cutaneous malignancy of neuroendocrine origin.Merkel nerve endings are mechanoreceptors in the skin.Merkel cells are normal components in the basal layer of the epidermis of the skin.

The normal physiology of merkel cells can be understood as follows:^[1]

• Merkel nerve ending are large, pale cells which function as mechanoreceptors in the skin.
• Merkel cells are usually derived from ectoderm and can be found in the mucosa and basal layer of the epidermis on the skin.
• Neuropeptides which are an integral part of cytoskeletal filaments can be positive for merkel cells.
• Large population of merkel cells can be found in the nerve terminal.
• The presence of merkel cells in the glabrous skin can be called as touch corpuscles and they function as mechanoreceptors.

• It is understood that merkel cell cancer is the result caused by either merkel cell polyomavirus, ultraviolet (UV), radiation exposure and immunosuppression.

• Out of 14 different strains of human polyomaviruses species, MCPyV(merkel cell polyomavirus) is know to cause merkel cell carcinoma in approximately 80% of the patients.^[2][3][4]
• Merkel cell polyomavirus belongs to DNA virus which has no envelop and it is double stranded.
• According to new research, specific deletion in the VP1 gene on MCPyV(merkel cell polyomavirus) may lead to merkel cell carcinoma.^[5]
• Large T antigen were found to be associated with MCPyV and development of merkel cell carcinoma.
• It is thought that MCPyV(merkel cell polyomavirus) is a normal flora of the skin and sheds chronically.^[6]
• Two major oncoproteins were encoded by MCPyV(merkel cell polyomavirus):
  • Large tumor (LT) antigen
  • Small tumor (ST) antigen
• Both large tumor (LT) antigen and small tumor (ST) antigen believed to be play a crucial role in the development of merkel cell carcinoma.
• MCPyV(merkel cell polyomavirus) pathogenesis in sequential order:
  1. Integration of viral genome into the host genome.
  2. Increased expression of small tumor (ST) antigen after integration.
  3. Gaining of mutations in the 3 end of large tumor (LT) antigen which results in the production of truncated molecule.
  4. And finally evade the immune response by the body.

UV radiation

• It is understood that merkel cell carcinoma is also caused by ultraviolet (UV) radiation exposure.^[7][8]
• Exposure to sun is one of the major source of ultraviolet (UV) radiation especially UVB.
• The risk of developing merkel cell carcinoma increases in fair skin individuals.^[9]
• Incidence is directly proportional to sun exposure in developing merkel cell carcinoma.^[10]
• Patients who are undergoing PUVA therapy have an inceased risk of developing merkel cell carcinoma.
• The exact pathogenesis of how ultraviolet (UV) radiation exposure leads to merkel cell carcinoma is not completely understood.

Immunosuppression

• Patients who underwent organ transplant are also very prone to developing merkel cell carcinoma due to immunosuppression.
• Patients who are suffering with HIV and malignancies especially B cell origin are also likely prone to develop merkel cell carcinoma due to immunosuppression.
• The exact pathogenesis of how immunosuppression leads to merkel cell carcinoma is not completely understood.

Genes involved in the pathogenesis of merkel cell carcinoma include:

• TP53 gene mutations
• Retinoblastoma (RB1) gene mutations
• NOTCH1
• PRUNE2
• HRAS
• PIK3CA
• KNSTRN
• PREX2
• RAC1

On gross pathology of merkel cell carcinoma

On microscopic histopathological analysis, trabecular pattern, monotonous round tumor cells, mitotic figures, atypical fibroxanthoma-like areas and dusty chromatin are characteristic findings of merkel cell carcinoma.