Merkel Cell Carcinoma Case Reports With Merkel Cell Polyomavirus Test and Review of the Literature
Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin cancer that occurs in the elderly and immunosuppressed people. The pathogenesis of MCC is still not fully clarified. It is known that the pathogenesis may be a multifactorial process, including immunosuppression, UV damage to the skin (virus negative), and Merkel cell polyomavirus (MCPyV) infection. MCC is often manifested as asymptomatic and rapidly growing red or purple nodules. Sentinel lymph node biopsy is recommended to detect whether MCC spreads to regional lymph nodes. Expand the resection of the local primary site and integrate radiotherapy according to tumor risk factors are recommended. Although the clinical manifestations are similar, the prognosis and genetic mutation of polyomavirus-associated MCC (MCCP) and nonviral MCC (MCCN) are significantly different. In this article, we reported 2 cases of MCC and reviewed relative literature.   Case 1 A 91-year-old woman presented with a half-year history of a brown papule on the left temple. The papule gradually increased from approximately 0.5 to 3.5 cm in diameter, which was soft without pain, accompanied by itching, ulcer, and pus. The boundary was clear. The cervical lymph nodes were not touched (Fig. A). Histopathological examination showed it was mainly located in the dermis. There is extensive and dense monocyte infiltration in the dermis, and there is no infiltration area between the dermis and epidermis. Small and round basophilic tumor cells are arranged in a solid pattern. Some cells differentiate like plasma cells. The nests of tumor cells are separated by fibrous connective tissue. Immunohistochemistry examination showed that CK20+, NSE+, CD56+, Merkel cell polyomavirus large T antigen (CM2B4)-, TTF-1-, Melan-A-, S-100-, CD3-, Bcl-2-, and Ki-67 were 50% (Fig. ). According to the clinical symptoms and pathological results, the patient was diagnosed with MCC. Extensive surgery was performed by enlarging 5 mm, and no recurrence was found after 2 years of follow-up. Case 2 A 76-year-old man presented to our outpatient department with a surgical scar on his right buttock. There was a papule that rapidly increased from approximately 3 mm to 1.5 cm in diameter in 1 month without pain and was surgically removed (Fig. A). The biopsy showed the epidermis is generally normal. Nodular-like tumor cell proliferation is present in the whole dermis. It is shown that the small and round basophilic tumor cells proliferation in the dermis were arranged in a solid pattern. Finely granular chromatin, inconspicuous nucleoli, scant cytoplasm, and mitoses are abundant. The tumor tissue invaded the subcutaneous adipose tissue. The nest of tumor cells was surrounded by fibrous connective tissue. There was a dense lymphocyte infiltration. Immunohistochemical results included CK20+, SYN+,NSE+, CM2B4+, CD56+, TTF-1-, S-100-, LCA-, CK7-, and Ki-67 local hot spots >60% (Fig. ). According to the clinical symptoms, histology, and immunohistochemistry tests, he was diagnosed with MCC. The patient refused extended surgical resection and sentinel lymph node biopsy for personal reasons. The patient underwent extensive surgery of enlarging 3 cm in another hospital. Two months after the operation, a recurrent tumor was found in the right hip, which was relieved after radiotherapy.   A 91-year-old woman presented with a half-year history of a brown papule on the left temple. The papule gradually increased from approximately 0.5 to 3.5 cm in diameter, which was soft without pain, accompanied by itching, ulcer, and pus. The boundary was clear. The cervical lymph nodes were not touched (Fig. A). Histopathological examination showed it was mainly located in the dermis. There is extensive and dense monocyte infiltration in the dermis, and there is no infiltration area between the dermis and epidermis. Small and round basophilic tumor cells are arranged in a solid pattern. Some cells differentiate like plasma cells. The nests of tumor cells are separated by fibrous connective tissue. Immunohistochemistry examination showed that CK20+, NSE+, CD56+, Merkel cell polyomavirus large T antigen (CM2B4)-, TTF-1-, Melan-A-, S-100-, CD3-, Bcl-2-, and Ki-67 were 50% (Fig. ). According to the clinical symptoms and pathological results, the patient was diagnosed with MCC. Extensive surgery was performed by enlarging 5 mm, and no recurrence was found after 2 years of follow-up.   A 76-year-old man presented to our outpatient department with a surgical scar on his right buttock. There was a papule that rapidly increased from approximately 3 mm to 1.5 cm in diameter in 1 month without pain and was surgically removed (Fig. A). The biopsy showed the epidermis is generally normal. Nodular-like tumor cell proliferation is present in the whole dermis. It is shown that the small and round basophilic tumor cells proliferation in the dermis were arranged in a solid pattern. Finely granular chromatin, inconspicuous nucleoli, scant cytoplasm, and mitoses are abundant. The tumor tissue invaded the subcutaneous adipose tissue. The nest of tumor cells was surrounded by fibrous connective tissue. There was a dense lymphocyte infiltration. Immunohistochemical results included CK20+, SYN+,NSE+, CM2B4+, CD56+, TTF-1-, S-100-, LCA-, CK7-, and Ki-67 local hot spots >60% (Fig. ). According to the clinical symptoms, histology, and immunohistochemistry tests, he was diagnosed with MCC. The patient refused extended surgical resection and sentinel lymph node biopsy for personal reasons. The patient underwent extensive surgery of enlarging 3 cm in another hospital. Two months after the operation, a recurrent tumor was found in the right hip, which was relieved after radiotherapy.   MCC is a rare and highly malignant neuroendocrine skin cancer, which was first described in the 1800s by Dr. Friedrich Merkel. There are an estimated 2000 cases of MCC in the United States each year according to the American Cancer Society. In Europe, it is found an annual incidence of 1.3 per million, with the highest incidence in people older than 65 years, according to results of the surveillance of rare cancers in Europe project. However, in Australia, with higher sunshine intensity, the incidence rate is relatively higher. Between 2006 and 2010, 340 cases of MCC were diagnosed in Queensland, and the incidence rate is 1.6 for every 100 thousand people. The most common body part of MCC was the sun-exposed head and neck (43%). Upper extremities and shoulders, lower extremities and hips, trunk, and other sites accounted for 24%, 15%, 11%, and 9%, respectively. MCC usually presents as painless, fast-growing red or purple skin nodules. Chronic exposure to ultraviolet (UV) radiation, immunosuppressant condition, and advanced age are risk factors of MCC. There is a simple way to describe the clinical features of MCC, which is the acronym AEIOU. Michelle Heath et al investigated 195 patients with MCC and summarized in an acronym AEIOU, which means asymptomatic, rapid expansion, immunosuppression, older than 50 years, and UV exposure of light skin. The clinical symptoms of MCC are not typical. Meanwhile, the histology is difficult to distinguish from other “small round blue cells” tumor groups, including metastasis of small cell lung carcinoma (TTF-1+), melanoma (S-100+, Melan-A+, CK−), lymphoma (LCA+, CK−), Ewing sarcoma (CD99+ and Fli-1+), and rhabdomyosarcoma (muscle-specific actin-, desmin- and myoglobin+). Therefore, immunohistochemical stains are key tools to identify the diagnosis of MCC. MCC showed quite distinctive immunostaining markers including the dot-like expression of CK20 and positive of NSE and negative of LCA and S100 protein. As for the pathogenesis of MCC, it is still not fully clarified. It is known that immunosuppression, UV damage to the skin (virus negative), and MCPyV might be involved in the pathogenesis of MCC. Among these oncogenesis factors, MCPyV plays a particularly important role. MCPyV, 1 of the polyomaviruses, is an unenveloped double-stranded DNA virus with a circular genome. Large T antigen (LT) and small T antigen (ST) are 2 important components. LT is essential for viral DNA replication and contains the retinoblastoma-associated protein (RB)-binding motif. LT directly binds to and inhibits RB, which is a transcriptional repressor that acts as a “guardian” of G1/S cell cycle checkpoints. RB inactivation is a key molecular event entering the S phase. Once a cell passes the G1/S checkpoint, it enters the cell cycle independent of the extracellular growth signal. Therefore, the inactivation of RB by LT enables MCCP tumor cells to avoid growth inhibition. ST encodes a unique region that is essential in mediating ST-host protein interactions. ST inhibits p53 to escape growth inhibitory factors and maintains proliferative signals by activating MYCL. , LT and ST played crucial roles in the MCPyV oncogenesis of MCC. However, MCPyV is a highly prevalent virus that can cause persistent, mostly harmless infections, and can be easily detected on the skin of healthy individuals. Healthy individuals rarely have antibodies to T antigens, but most patients with MCCP have detectable serum antibodies to LT and ST. The MCPyV oncogenic hypothesis requires 2 fundamental elements: integration of the viral genome into the host genome and truncation of LT so that the viral genome cannot replicate. In MCCP, the MCPyV gp3 mutations encoding LT disrupt the DNA-binding domain and the helicase domain away from the RB-binding motif. Therefore, LT is truncated, which can bind to RB and promote cell cycle progression but cannot mediate continued viral replication. The extremely low probability that the virus mutates and no longer replicates at the same time could explain why MCC is rare and MCPyV infection is common. It also explains how MCPyV viral proteins mimic genomic instability and high mutation burden as seen in MCCN in a relatively stable genomic context in MCCP. MCCP and MCCN not only have great differences in gene mutation but also have quite different prognoses. Studies have found that patients detected with antibodies to MCPyV oncoprotein had a better prognosis. The medium survival time of MCCP subgroups (6.6 years) was significantly longer ( P = 0.08) than polyomavirus-negative ones (1.2 years). There are several methods for the detection of MCPyV, including immunohistochemistry, PCR, RNA or DNA in situ hybridization, etc. Immunohistochemistry of large T-antigen protein is a common method to detect MCPyV. Antibody CM2B4 for the detection of MCPyV LT is most widely used with approximately 88% sensitivity and 94% specificity (compared with multimode methods combining PCR and immunohistochemistry). Anna-Stiina et al analyzed 180 MCC samples using antibody CM2B4 for immunohistochemical staining and RT-PCR for the detection of MCPyV DNA. They found the correlation between these 2 methods was highly statistically significant ( P < 0.0001). Immunohistochemistry technology, due to its relatively low technical threshold, is more feasible for implementation in underdeveloped regions.   To summarize, we reported 2 MCC cases with and without MCPyV LT antigen. The site of the lesion in case 1 is the exposed area on the face, which is consistent with the report in the literature that the MCCN cases may be related to sun exposure. Meanwhile, the lesion of case 2 is in the unexposed area of the buttock, which is rarely reported in patients with MCC. This might be associated with MCPyV infection instead of UV exposure. For clinicians, red and rapidly expanding but asymptomatic lesions should be of particular concern. Histopathological and immunohistochemical examinations are needed to confirm the diagnosis of the patient. Testing for the MCPyV at the onset of MCC is recommended, which is helpful in predicting the prognosis of patients. A larger number of patients and long-term follow-ups are needed. Although advances have been made in MCC biology, it remains unclear the cell origin of MCC. Although the clinical symptoms and pathological manifestations of MCCP and MCCN are similar, there are significant differences in their prognosis and gene mutations. Whether there is a common crucial tumorigenesis pathway between these 2 subgroups is worth studying. Further work is needed to research how LT and ST contributed to the development of carcinoma such as evading immune destruction.   