Merkel cell cancer

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2] Ahmad Al Maradni, M.D. [3]

Merkel cell carcinoma is a very rare and highly aggressive cutaneous cancer. This cancer is a type of neuroendocrine tumor, like small cell lung cancer. Merkel cell carcinoma is the most serious form of skin cancer. when merkel cell carcinoma metastasized to the lymph nodes, the average 5-year survival rate for a patient with merkel cell carcinoma is less than 50 percent. Recurrence may occur in up to half of all the patients with merkel cell carcinoma. Merkel cell cancer usually occurs on either the face, head, or neck. Patients with merkel cell carcinoma usually present with a rapid growing, firm, painless, red/violaceous skin lesion. Merkel cell carcinoma usually metastasizes first to regional lymph nodes and then to other organs, and spreads to other parts of the body, especially the liver, lungs, brain and bones. The predominant therapy for merkel cell carcinoma is surgical resection, but chemoradiation may also be required in more advanced disease.

Merkel cell was first discovered by Freidrich Sigmund Merkel and also mentioned by Cyril Toker, in 1972.Merkel cell polyomavirus, the pathogen responsible for Merkel cell cancer, was first discovered in 2008.

Merkel cell carcinoma is classified into 3 subgroups: Trabecular, intermediate, and small cell.

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

Common causes of merkel cell carcinoma include merkel cell polyomavirus, age, skin tone, exposure to sunlight and history of immunosuppression.

Merkel cell cancer must be differentiated from other skin lesions, such as basal cell carcinoma, squamous cell carcinoma, malignant melanoma, lymphoma, vascular tumors, and other benign skin tumors.

The incidence of merkel cell carcinoma ranges from 0.15 to 0.44 per 100,000 individuals. The median age at diagnosis is approximately 65 years. Merkel cell carcinoma is more common among males and individuals of Caucasian race.

Risk factors for the development of merkel cell cancer include old age, male gender, caucasian race, chronic exposure to sunlight, immunodeficiency, and personal history of cancer.

According to the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for skin cancers, including merkel cell cancer.

Merkel cell cancer is an aggressive cutaneous cancer that grows very rapidly. Merkel cell cancer usually metastasizes first to regional lymph nodes. Merkel cell cancer is a highly aggressive tumor with a mortality rate that approaches 30% to 40% within 3 years of diagnosis.

The staging of merkel cell cancer is based on the TNM staging system.

Patients with merkel cell carcinoma usually present with a rapid growing, painless, small mass that is typically located on sun exposed area of the body.

Physical exam findings of merkel cell cancer include red/violaceous skin mass that appear in sun exposed areas.

Laboratory findings consistent with the diagnosis of merkel cell cancer include immunohistochemistry, cytogenetic and molecular analysis, and lymph node biopsy. .

CT scan is useful in detecting metastasis to organs and regional lymph nodes in merkel cell carcinoma.

Positron emission tomography (PET) imaging may be used for the staging of merkel cell cancer.

Other diagnostic studies for merkel cell cancer include skin biopsy, which demonstrates positive cytokeratin-20 , and electron microscopy, which demonstrates granules, and cytoplasmic extensions.

The predominant therapy for Merkel cell cancer is surgical resection. Adjunctive chemoradiation and adjuvant immunotherapy may also be required in more advanced disease.

The majority of cases of Merkel cell cancer are treated with surgery.

Primary prevention of merkel cell cancer includes avoidance of excessive sun exposure and use of sunscreen.

There are no established measures for the secondary prevention of merkel cell cancer.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2]

Merkel cell carcinoma is classified into 3 subgroups: trabecular, intermediate, and small cell.

Histologically, MCC has been classified into three distinct subtypes:^[1][2][3]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2] Ahmad Al Maradni, M.D. [3]

Merkel cell was first discovered by Freidrich Sigmund Merkel and also mentioned by Cyril Toker, in 1972.

• Merkel cell was first discovered by Freidrich Sigmund Merkel, a German histopathologist, in 1875.^[1][2]
• Merkel cell carcinoma was first discovered by Cyril Toker, in 1972.^[3]

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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.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2]

Common causes of merkel cell carcinoma include merkel cell polyomavirus, age, skin tone, exposure to sunlight and history of immunosuppression.

Common causes of merkel cell carcinoma may include:^[1][2]

• Merkel cell polyomavirus^[3]
  • Especially MCPvy
• Sunlight^[4]
  • Ultraviolet radiation especially UVB plays an important role in the developing merkel cell carcinoma.
• Skin tone^[5]
  • Fair skin people are more prone to merkel cell carcinoma.
• Immunosuppression: Especially patients with ^[6][7][8][9]
  • HIV positive patients
  • Organ transplant patients
  • Chronic lymphocytic leukemia (CLL)
  • Lymphoproliferative disorders

Less common causes of merkel cell carcinoma include:

• Age
  • The risk increases with the age and the median age is around 65 years or above.

• Location in the body from decreasing order
  • Head > Upper limb > Lower Limb > and Trunk

• Merkel cell carcinoma is caused most commonly by mutation in
  • TP53 gene mutations
  • Retinoblastoma (RB1) gene mutations

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ahmad Al Maradni, M.D. [2]

Merkel cell cancer must be differentiated from other skin lesions, such as basal cell carcinoma, squamous cell carcinoma, malignant melanoma, lymphoma, vascular tumors, and other benign skin tumors.

Merkel cell cancer must be differentiated from other skin lesions, such as:^[1]

• Basal cell carcinoma
• Squamous cell carcinoma
• Malignant melanoma
• Lymphoma
• Metastatic carcinoma
• Sarcoma
• Benign cyst
• Acneiform lesion
• Lipoma
• Dermatofibroma
• Vascular lesion

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2] Ahmad Al Maradni, M.D. [3]

The incidence of merkel cell carcinoma ranges from 0.5 per 100,000 individuals. The median age at diagnosis is approximately 65 years. Merkel cell carcinoma is more common among males and individuals of the caucasian race.

• The incidence of merkel cell carcinoma ranges from 0.5 per 100,000 individuals.^[1][2]
• The incidence is thought to have tripled between 1986 and 2001.
• According to the new research incidence rates are reportedly increasing in Australia and New Zealand.^[3][4]
• By 2020, the incidence of merkel cell carcinoma was estimated to be 2835 cases in the United States.^[5]
• By 2035, the incidence of merkel cell carcinoma was estimated to be 3284 cases in the United States.^[6]

• Merkel cell carcinoma incidence increases progressively with age.^[7]
• The majority of patients with merkel cell carcinoma are diagnosed at age > 50 years.^[7]
• The median age at diagnosis is approximately 65 years.^[8]

• Merkel cell carcinoma is slightly more common among males than females.^[7]

• Merkel cell carcinoma is much more common among individuals of the caucasian race compared to individuals of other ethnicities.^[7]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ahmad Al Maradni, M.D. [2]

Risk factors for the development of merkel cell cancer include old age, male gender, caucasian race, chronic exposure to sunlight, immunodeficiency, and personal history of cancer.

• Common risk factors in the development of merkel cell cancer may be occupational, environmental, genetic, and viral.

• Common risk factors for the development of merkel cell cancer include:^[1][2][3]
  • Mutations in the DNA due to polyomaviruses
  • Chronic exposure to sunlight
  • Immunodeficiency or administration of immunosuppressive pharmacologic agents

• Less common risk factors in the development of merkel cell cancer include:^[4][5][6]
  • Old age > 70 years
  • Male gender
  • Fair skin
  • Personal history of cancers
  • Caucasian race

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2] Ahmad Al Maradni, M.D. [3]

According to the United states preventive services task force recommendations scheme (USPSTF), there is insufficient evidence to recommend routine screening for skin cancers, including merkel cell cancer.

According to the United states preventive services task force recommendations scheme (USPSTF), there is insufficient evidence to recommend routine screening for skin cancers, including merkel cell cancer.^[1]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2] Ahmad Al Maradni, M.D. [3]

Merkel cell cancer is an aggressive cutaneous cancer that grows very rapidly. Merkel cell cancer usually metastasizes first to regional lymph nodes. Merkel cell cancer is a highly aggressive tumor with a mortality rate that approaches 30% to 40% within 3 years of diagnosis.

• Merkel cell cancer is an aggressive cutaneous tumor that grows rapidly.
• Merkel cell cancer usually metastasizes to:
  • Lymph nodes
  • Liver
  • Lungs
  • Brain
  • Bones

Common complications of merkel cell carcinoma include:^[1]

• Neurologic complications which include:^[2]
  • Seizures
  • Bilateral radiculopathies
  • Myoclonus
  • Cauda equina syndrome
  • Altered mental status
• Leptomeningeal carcinomatosis

• Merkel cell cancer is a highly aggressive tumor with a mortality rate that approaches 30% to 40% within 3 years of diagnosis.
• If diagnosed early, merkel cell carcinoma has a good prognosis with a 5-year survival rate of approximately 90%.
• The prognosis depend on the following:^[3][4][5][6]
  • Stage at diagnosis (1st most potent prognostic factor).
  • Lymph node involvement (2nd most important prognostic factor).
  • Merkel cell polyomavirus (MCPyV) viral load also play an significant role in prognosis of merkel cell cancer.
  • Cancer location
  • Cancer depth
  • Primary vs recurrent
• Lymphovascular invasion in merkel cell cancer patients associated with poor prognosis.
• Intratumoral lymphocyte infiltration in merkel cell cancer patients associated with good prognosis due to presence of CD8+ lymphocyte infiltration.^[7]
• p63 expression in merkel cell cancer patients associated with poor prognosis.