Merkel-cell carcinoma

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Merkel-cell carcinoma
Merkel cell carcinoma - very high mag.jpg
Micrograph of a Merkel-cell carcinoma. H&E stain.
SpecialtyOncology

Merkel-cell carcinoma (MCC) is a rare and highly aggressive skin cancer, which, in most cases, is caused by the Merkel cell polyomavirus (MCPyV or MCV) discovered by scientists at the University of Pittsburgh in 2008.[1] It is also known as cutaneous APUDoma, primary neuroendocrine carcinoma of the skin, primary small cell carcinoma of the skin, and trabecular carcinoma of the skin.[2]

About 80% of Merkel-cell carcinomas are caused by MCPyV.[3] Indeed, DNA sequences of Merkel cell polyomavirus (MCPyV) were identified in this tumor [3] The virus is clonally integrated into the cancerous Merkel cells. In addition, the virus has a particular mutation only when found in cancer cells, but not when it is detected in healthy skin cells.[4] Direct evidence for this oncogenic mechanism comes from research showing that inhibition of production of MCPyV proteins causes MCV-infected Merkel carcinoma cells to die but has no effect on malignant Merkel cells that are not infected with this virus.[5][6] MCV-uninfected tumors, which account for about 20% of Merkel-cell carcinomas, appear to have a separate and as-yet unknown cause.[7] Those tend to have extremely high genome mutation rates, due to ultraviolet light exposure, whereas MCV-infected Merkel cell carcinomas have low rates of genome mutation.[8]

Signs[edit]

Small spot on the left arm is Merkel-cell cancer
Merkel-cell carcinoma. Gross pathology specimen

Merkel-cell carcinoma (MCC) usually presents as a firm, painless, nodule (up to 2 cm diameter) or mass (>2 cm diameter). These flesh-colored, red, or blue tumors typically vary in size from 0.5 cm (less than one-quarter of an inch) to more than 5 cm (2 inches) in diameter, and usually enlarge rapidly. Although MCC's may arise almost anywhere on the body, about half originate on sun-exposed areas of the head and neck, one-third on the legs, and about one-sixth on the arms. In about 12% of cases, no obvious anatomical site of origin ("primary site") can be identified.[9] The most significant clues in the diagnosis of MCC were summarized 2008 in the acronym AEIOU (Asymptomatic/lack of tenderness, Expanding rapidly, Immune suppression, Older than 50 years, and Ultraviolet-exposed site on a person with fair skin).[10] Ninety percent of MCC's have 3 or more of those features.[11] MCC is sometimes mistaken for other histological types of cancer, including basal cell carcinoma, squamous cell carcinoma, malignant melanoma, lymphoma, and small cell carcinoma, or as a benign cyst.[7] Merkel cell carcinomas have been described in children, however pediatric cases are very rare.[12]

Merkel-cell cancers tend to invade locally, infiltrating the underlying subcutaneous fat, fascia, and muscle, and typically metastasize early in their natural history, most often to the regional lymph nodes. MCCs also spread aggressively through the blood vessels to many organs, particularly to liver, lung, brain, and bone.[13]

Pathophysiology[edit]

Merkel-cell carcinoma (arrow) infiltrating skin tissue, stained brown for Merkel cell polyomavirus large T protein.[2]

Several factors are involved in the pathophysiology of MCC, including a virus called Merkel cell polyomavirus (MCV), ultraviolet radiation (UV) exposure, and weakened immune function.[3]

Merkel cell polyomavirus[edit]

MCV likely contributes to the development of the majority of MCC.[14] About 80% of MCC tumors are infected with MCV, with the virus integrated in a monoclonal pattern,[14] indicating that the infection was present in a precursor cell before it became cancerous. MCV, a polyomavirus, is the first polyomavirus strongly suspected to cause tumors in humans.[15] MCV is ubiquitous and is thought to be part of the human skin microbiome.[16] Intriguingly, most MCV viruses obtained so far from tumors have specific mutations that render the virus uninfectious.[4][17] MCC patients whose tumors contain MCV have higher antibody levels against the virus than similarly infected healthy adults.[18] A study of a large patient registry from Finland suggests that individuals with MCV-positive MCC's have better prognoses than do MCC patients without MCV infection.[19] Like other tumor viruses, most people who are infected with MCV do not develop MCC.[citation needed] As of 2008, it was unknown what other steps or co-factors were required for MCC-type cancers to develop.[20]

UV light[edit]

At least 20% of MCC tumors are not infected with MCV, suggesting that MCC may have other causes, especially sunlight or ultraviolet light as in a tanning beds. MCC can also occur together with other sun exposure-related skin cancers that are not infected with MCV (i.e. basal cell carcinoma, squamous cell carcinoma, melanoma). Ultraviolet radiation such as in sun exposure increases the risk in MCC development, consistent with the fact that MCCs occur more commonly in sun-exposed areas.[10][7]

Immunosuppression[edit]

The incidence of MCC is increased in conditions with defective immune functions such as malignancy, HIV infection, and organ transplant patients, etc.[1] Mutations in MCC occur more frequently than would otherwise be expected among immunosuppressed patients, such as transplant patients, AIDS patients, and the elderly, suggesting that the initiation and progression of the disease is modulated by the immune system.[10] While infection with MCV is common in humans,[21] In addition, a high incidence of this tumor has been observed in autoimmune disease affected patients treated with immunosuppressants, such as TNF inhibitors.[3]

Diagnosis[edit]

Photomicrographs of a typical Merkel-cell carcinoma at a 4x, b 40x, and c–d 100x objectives. Hematoxylin and eosin staining demonstrates small, undifferentiated cells with high N/C ratio and scanty cytoplasm. Typical immunopanel demonstrates positive staining with e cytokeratin AE1/AE3 (100x oil immersion), f CK 20 (100x oil immersion), and neuroendocrine markers such as g chromogranin (100x oil immersion).[22]

Definitive diagnosis of Merkel cell carcinoma (MCC) requires examination of biopsy tissue. An ideal biopsy specimen is either a punch biopsy or a full-thickness incisional biopsy of the skin including full-thickness dermis and subcutaneous fat. In addition to standard examination under light microscopy, immunohistochemistry (IHC) is also generally required to differentiate MCC from other morphologically similar tumors such as small cell lung cancer, the small cell variant of melanoma, various cutaneous leukemic/lymphoid neoplasms, and Ewing's sarcoma. Similarly, most experts recommend longitudinal imaging of the chest, typically a CT scan, to rule out that the possibility that the skin lesion is a skin metastasis of an underlying small cell carcinoma of the lung.[citation needed]

Prevention[edit]

Sunlight exposure is thought to be one of the causes of Merkel cell carcinoma (MCC). The World Health Organization, American Academy of Dermatology, and Skin Cancer Foundation recommend the following measures to prevent excessive UV exposure and skin cancer:[23][24][25]

  • Limiting sun exposure between the hours of 10am and 4pm, when UV rays are the strongest
  • Seeking shade when UV rays are most intense
  • Wearing sun-protective clothing including a wide brim hat, sunglasses, and tightly-woven, loose-fitting clothing
  • Using sunscreen
  • Avoiding tanning beds and artificial UV exposure

Treatment[edit]

Early diagnosis and treatment of Merkel-cell cancers are important factors in decreasing the chance of metastasis, after which it is exceptionally difficult to cure.

Surgery[edit]

Surgery is usually the first treatment that a patient undergoes for Merkel-cell cancer, given that surgeons perform the biopsy—however there is no evidence to suggest it is superior to treatment with radiation alone.[26] As with surgery for most other forms of cancer, it is normal for the surgeon to remove a border of healthy tissue surrounding the tumor. Complete excision is associated with significant higher survival rates.[27] Due to the capability of vertical growth that may extend into muscle in MCC, Mohs surgery may also be helpful to provide local control.[28][29] 

Radiation and chemotherapy[edit]

Because of MCC's aggressive local and regional metastatic behavior, radiotherapy is commonly used to treat Merkel-cell cancer. It can be used as definitive therapy or after surgery. It has been shown to be effective in reducing the rates of recurrence and in increasing the survival of patients with MCC.[30] Radiation therapy can also be an alternative if MCC patients are not surgical candidate.[31]

Chemotherapy may be used to treat both primary and metastatic MCC. Although the definitive role of chemotherapy is unknown chemotherapy plays a role in the treatment, especially in MCC of head and neck regions.[32]

Sentinel lymph node biopsy[edit]

Sentinel lymph node biopsy (SLNB) detects MCC spread in one third of patients whose tumors would have otherwise been clinically and radiologically understaged, and who may not have received treatment to the involved node bed. There was a significant benefit of adjuvant nodal therapy, but only when the SLNB was positive. Thus, SLNB is important for both prognosis and therapy and should be performed routinely for patients with MCC. In contrast, computed tomographic scans have poor sensitivity in detecting nodal disease as well as poor specificity in detecting distant disease.[33]

Drug therapy[edit]

As of 2013 there had been hope that new targeted anticancer therapy for patients with distant and systemic MCC disease would be available in the near future, particularly to target the MCV either to prevent infection or to inhibit viral-induced carcinogenesis.[34] In March 2017, the U.S. Food and Drug Administration granted accelerated approval to avelumab to treat adults and children above 12 years with metastatic MCC. Avelumab, a checkpoint-inhibitor targets the PD-1/PD-L1 pathway (proteins found on the body's immune cells and some cancer cells) to help the body's immune system attack cancer cells.[35] In December 2018, the U.S. Food and Drug Administration granted accelerated approval to pembrolizumab(KEYTRUDA®, Merck & Co. Inc.) for adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma. Keytruda (pembrolizumab), is another checkpoint-inhibitor targeting the PD-1/PD-L1 pathway.[36]

National Comprehensive Cancer Network guidelines recommend PD-1 inhibitors, either nivolumab, pembrolizumab or avelumab, for patients with disseminated MCC; systemic therapy is not recommended for early stage MCC.[11]

Prognosis[edit]

Overall, the 5-year survival rate for Merkel cell carcinoma is around 60%. It varies depending on the stages of the cancer. In general, a higher cancer stage correlates with a lower survival rate. For example, National Cancer Data Base has survival rates collected from nearly 3000 MCC patients from year 1996-2000 with 5-year survival rates listed as follows:[37] Stage IA: 80%. Stage IB: 60%. Stage IIA: 60%. Stage IIB: 50%. Stage IIC: 50%. Stage IIIA: 45%. Stage IIIB: 25%. Stage IV: 20%. 5 yr survival may be 51% among patients with localized disease, 35% for those with nodal disease, and 14% with metastases to a distant site.[11]

Several other features may also affect prognosis, independent of tumor stage. They include MCV viral status, histological features, and immune status. In viral status, MCV large tumor antigen (LT antigen) and retinoblastoma protein (RB protein) expression correlates with more favorable prognosis, while p63 expression correlates with a poorer prognosis.[38][39] Histological features such as intratumoral CD8+ T lymphocyte infiltration may be associated with a favorable prognosis, while lymphovascular infiltrative pattern may be associated with a poorer prognosis.[40][41] Immune status, especially T cell immunosuppression (e.g., organ transplant, HIV infection, certain malignancy) predicts poorer prognosis and higher mortality.[42]

The antibody titer in the blood to the Merkel cell polyomavirus oncoprotein can be used as a treatment response biomarker in people that have detectable antibodies at the time of diagnosis.[43][44]

Epidemiology[edit]

This skin cancer occurs most often in Caucasians between 60 and 80 years of age, and its rate of incidence is about twice as high in males as in females. MCC is not a very common skin cancer. In 2013, the annual incidence rate was around 0.7 per 100,000 persons in the U.S.[45] As of 2005, roughly 2,500 new cases of MCC have been diagnosed each year in the United States,[45] as compared to around 60,000 new cases of malignant melanoma and over 1 million new cases of nonmelanoma skin cancer.[46] Similar to melanoma, the incidence of MCC in the US is increasing rapidly.[7]

Since 2006, it has been known that other primary cancers increase the risk of MCC significantly, especially in those with the prior multiple myeloma, chronic lymphocytic leukemia, and malignant melanoma.[47]

Immunosuppression can profoundly increase the odds of developing MCC.[3] As of 2013, MCC occurred 30 times more often in people with chronic lymphocytic leukemia and 13.4 times more often in people with advanced HIV as compared to the general population; solid organ transplant recipients had a 10-fold increased risk compared to the general population.[30] A 2015 review of transplant recipients showed an up to 24-fold increased risk of MCC compared to the general population.[48] In addition a high incidence of this tumor has been observed in autoimmune disease affected patients treated with immunosuppressants, such as TNF inhibitors.[3]

Notable people who have had it[edit]

References[edit]

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External links[edit]

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