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 aggressive skin cancer occurring in about 3 per 1,000,000 population.[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] Factors involved in the development of MCC include the Merkel cell polyomavirus (MCPyV or MCV), a weakened immune system, and exposure to ultraviolet radiation.[3][4] Merkel-cell carcinoma usually arises on the head, neck, and extremities, as well as on the perianal and eyelid.[5] It is more common in elderly people, people who have a weakened immune system, and people who were exposed to UV radiation. MCC is less common in children.[1][5]

Signs and symptoms[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.[6] 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).[7] Ninety percent of MCC's have 3 or more of those features.[8] 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.[9] Merkel cell carcinomas have been described in children, however pediatric cases are very rare.[10]

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.[11]

Pathophysiology[edit]

Merkel-cell carcinoma (arrow) infiltrating skin tissue, stained brown for Merkel cell polyomavirus large T protein.[12]

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.[4]

Merkel cell polyomavirus[edit]

MCV likely contributes to the development of the majority of MCC.[13] About 80% of MCC tumors are infected with MCV, with the virus integrated in a monoclonal pattern,[13] indicating that the infection was present in a precursor cell before it became cancerous. MCV, a polyomavirus, is often present in MCC but no clear evidence suggests that the relationship is causal.[3] MCV is ubiquitous and is thought to be part of the human skin microbiome.[14] Intriguingly, most MCV viruses obtained so far from tumors have specific mutations that render the virus uninfectious.[15][16] People with MCC whose tumors contain MCV have higher antibody levels against the virus than similarly infected healthy adults.[17] A study of a large patient registry from Finland suggests that individuals with MCV-positive MCC's have better prognoses than do people with MCC who do not have a MCV infection.[18] 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.[19]

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.[7][9]

Immunosuppression[edit]

The incidence of MCC is increased in conditions with defective immune functions such as malignancy, HIV infection, and organ transplant patients, etc.[20] Mutations in MCC occur more frequently than would otherwise be expected among people who are immunosuppressed, such as people who have undergone an organ transplant, people with AIDS, and elderly people, suggesting that the initiation and progression of the disease is modulated by the immune system.[7] While infection with MCV is common in humans,[21] In addition, a high incidence of this tumor has been observed in people who are affected by autoimmune disease who are being treated with immunosuppressants, such as TNF inhibitors.[4]

RNA modifications[edit]

A recent study demonstrates the presence of m6A in the small T antigen of Merkel cell polyomavirus (MCPyV) in Merkel cell carcinoma, a fatal skin cancer.[22]

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).[23]

Diagnosis of MCC begins with a clinical examination of the skin and lymph nodes.[24] Following, definitive diagnosis of Merkel cell carcinoma (MCC) requires examination of biopsy tissue to identify its histopathologic features.[24][25] 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. On light microscopy, MCC shows basaloid tumor nests with neuroendocrine features ("salt and pepper" chromatin, scarce cytoplasm, and brisk mitotic activity).[24][25] 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. Once an MCC diagnosis is made, a sentinel lymph node biopsy is recommended as a part of the staging work-up needed to determine prognosis and subsequent treatment options.[24][25]

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:[26][27][28]

  • 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]

The goal of surgical excision is to remove the MCC with negative resection margin, meaning the tumour has been excised completely with a surrounding border of healthy tissue.[29] Complete excision is associated with significantly higher survival rates.[29] Surgical margins should extend 1 to 2 cm beyond the border of the MCC and may include underlaying fascia and muscle if the MCC has invaded deeper than the dermis.[29] Surgical excision should be coordinated with the sentinel lymph node biopsy (SNLB).[29] Reconstruction may also be needed if the surgical treatment requires extensive tissue removal.[29] However, reconstruction should not occur until negative margins and a negative SLNB have been confirmed.[29]

Radiation and Chemotherapy[edit]

Radiation therapy is the primary management of Merkel cell carcinoma (MCC). The largest series we have are from Australia and have demonstrated that radiotherapy alone achieves equal outcomes to upfront or neoadjuvant surgery followed by radiation therapy.[30][31] The role of surgery is largely historical and relegated to biopsy, and its exact role remains unclear. There have been no head to head, prospective trials comparing the two treatment modalities, and in the absence of this, the most common approach tends to be excisional biopsy prior to referring for radiation therapy to eradicate MCC, given the rarity of the disease. A key concern regarding MCC is that MCC has a predilection for the head and neck region, a site in which surgery leads to unacceptably poor cosmetic outcomes and reduced local control, ultimately necessitating larger radiation therapy treatment fields (similar to squamous cell carcinomas arising in the head and neck region); as such, surgery should ideally never be attempted in the head and neck region for MCC.[30]

MCC is exquisitely radiosensitive.[32] The conclusion amongst published studies in the Radiation Oncology community is that MCC should be managed ideally with radiation therapy alone[31] including the eviQ guidelines for MCC[33] in Australia, where MCC is significantly more common than in the remainder of the world and where the most relevant clinical experience, research, and body of evidence exists.[citation needed]

Sentinel lymph node biopsy[edit]

Sentinel lymph node biopsy (SLNB) detects MCC spread in one third of people with MCC 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.[34]

Drug therapy[edit]

Immunotherapies, namely inhibitors of the PD1-PDL1 checkpoint signalling pathway, are novel anticancer agents that have shown benefit in advanced-stage MCC or chemotherapy-resistant MCC.[35][36][37] These checkpoint inhibitors reactivate the immune response, enabling the immune system to target cancer cells for destruction.[38]

In March 2017, the U.S. Food and Drug Administration granted accelerated approval to avelumab, a PDL1 inhibitor, 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.[39] In December 2018, the U.S. Food and Drug Administration granted accelerated approval to pembrolizumab(KEYTRUDA®, Merck & Co. Inc.) for all ages (adults and pediatrics) with recurrent locally advanced or metastatic Merkel cell carcinoma. Keytruda (pembrolizumab), is another checkpoint-inhibitor targeting the PD-1/PD-L1 pathway.[40] Other than immunotherapies, there has been hope that new targeted anticancer therapy for people with distant and systemic MCC disease would be available in the near future, by targeting the MCV either to prevent infection or to inhibit viral-induced carcinogenesis.[41]

National Comprehensive Cancer Network guidelines recommend PD-1 inhibitors, either nivolumab, pembrolizumab or avelumab, for people with disseminated MCC; systemic therapy is not recommended for early stage MCC.[8]

Prognosis[edit]

According to the American Joint Committee on Cancer (AJCC), the natural course of MCC is “variable and depends heavily on the stage at diagnosis".[42] Staging of MCC is classified according to the TNM staging system, a notation system that describes the stage of cancer according to the size of the primary tumor (T), the degree of spread to regional lymph nodes (N), and the presence of distant metastasis (M).[42] A combination of T, N, and M stages dictate the final clinical stage group (0, I, IIA, IIB, IIIA, IIIB, IV).[43] Advanced stage (i.e. increased size of the tumor, spreading of the tumor into surrounding and/or distant tissue, and involvement of lymph nodes) is associated with lower survival rates.[44]

The 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:[45] 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 people with localized disease, 35% for those with nodal disease, and 14% with metastases to a distant site.[8]

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.[46][47] 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.[48][49] Immune status, especially T cell immunosuppression (e.g., organ transplant, HIV infection, certain malignancy) predicts poorer prognosis and higher mortality.[50]

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.[51][52]

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.[53] As of 2005, roughly 2,500 new cases of MCC have been diagnosed each year in the United States,[53] as compared to around 60,000 new cases of malignant melanoma and over 1 million new cases of nonmelanoma skin cancer.[54] Similar to melanoma, the incidence of MCC in the US is increasing rapidly.[9]

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.[55]

Immunosuppression can profoundly increase the odds of developing MCC.[4] 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.[56] A 2015 review of transplant recipients showed an up to 24-fold increased risk of MCC compared to the general population.[57] In addition a high incidence of this tumor has been observed in autoimmune disease affected patients treated with immunosuppressants, such as TNF inhibitors.[4]

History[edit]

Friedrich Sigmund Merkel (1845-1919) was a German anatomist and histopathologist who first described the Tastzellen (touch cells) in the skin in 1875.[58] In 1878 the term Merkel cell was coined by the anatomist Robert Bonnet (1851–1921).

Merkel-cell carcinoma was first described in 1972 by Cyril Toker.[59] He reported five cases of 'trabecular carcinoma of the skin'.

Famous persons afflicted[edit]

References[edit]

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