Evaluation and Management of Merkel Cell Carcinoma

By Mandy Frith, DMSc, MPAS, PA-C

Abstract
Merkel cell carcinoma is a rare, but aggressive cutaneous neuroendocrine neoplasm that can be difficult to diagnose due to the absence of many distinctive clinical features. It is often confused with other skin tumors, benign and malignant. Over 50 percent of Merkel cell carcinomas occur on the head and neck in people over the age of 50, especially in areas of actinically damaged skin. Local and distant metastases occur in many patients, and the recurrence rate is high. The mortality rate rivals that of malignant melanoma. Early diagnosis and appropriate treatment are key to preventing metastasis and death.

INTRODUCTION
Merkel cell carcinoma (MCC) is an aggressive neuroendocrine tumor that most often presents as a single cutaneous or subcutaneous nodule. It most commonly occurs in individuals over the age of 50, typically arising in sun-exposed areas of the body, such as the head and neck. Individuals that are immunosuppressed, such as organ transplant patients, those that are human immunodeficiency virus (HIV) positive or that suffer from hematologic malignancies are at greater risk of developing MCC.1-8,10 Heath et al coined the acronym AEIOU to aid in remembering the common clinical features of MCC and the patient population that is affected. AEIOU stands for the following: Asymptomatic, Expanding rapidly, Immunosuppressed, Over 50 years of age, and UV-exposed.2,3,8 MCC has a high incidence of metastasis, typically occurring in the draining nodal basin first, then followed by distant skin, lung, central nervous system, bone, and liver.1,6

Cyril Toker first described MCC in 1972 as “trabecular carcinoma of the skin.” The name was later changed to “Merkel cell carcinoma” because of the resemblance of the tumor cells to Merkel cells, which are normally occurring cells found in the basal layer of the epidermis, especially around hair follicles.1 The cell of origin is still not known. Pathogenesis of MCC has been linked to both chronic exposure to ultraviolet light (UV) and the presence of Merkel cell polyomavirus (MCPyV).1-3,6 MCPyV is thought to be an asymptomatic childhood virus and is commonly found in the general population.2,5 An estimated 80 percent of MCC are thought to be MCPyV positive.2,5 One study suggested that the majority of MCC diagnosed in the Northern hemisphere were associated with the virus; whereas, in areas with high levels of UV exposure, UV-mediated carcinogenesis is a prevalent causative factor.1 The role of MCPyV is currently being investigated, but both the MCPyV virus and high levels of UV exposure factors cause the genetic mutations that lead to the development of MCC. These findings have opened an area of research that may lead to improved monitoring and immune therapies.3

Incidence
It has been difficult to estimate the incidence of MCC due to the previous lack of consistent reporting. The addition in MCC monitoring and changes in cancer registry has led to improved statistics and it is thought that there has been an overall increase in the incidence of MCC over the last 30 years.1 It has been estimated that since the early 1990s, there has been a 5 to 10 percent increase each year.4 Between 2000 and 2013, there has been a reported 95-percent increase in the diagnosis of MCC.2 In 2011, the incidence of MCC in the United States increased from 0.6 in 2009 to 0.79 per 100,000 people per year.1,3

DIAGNOSIS
Characteristics
Clinical Presentation. MCC presents as rapidly growing, red-to-violet nodules, most often located on sun-exposed areas, such as the head and neck. These lesions are typically asymptomatic and are often misdiagnosed as benign cysts or malignant lesions, such as cutaneous squamous cell carcinoma. Ulceration is not typically present.1-8,10
Histology. Histologically, MCC appears on hematoxylin-eosin (H&E) stains as small, monomorphic, round to oval, blue cells with hyperchromatic nuclei, scant cytoplasm, and high mitotic activity.1 Three histologic subtypes have been described. These include small cell, trabecular, and intermediate. Most tumors have overlapping features of each subtype.1,3-5,7-8,10 MCC can be difficult to diagnose with H&E stains alone and requires a high level of suspicion as well as experience distinguishing it from other tumors. Differentiating between primary MCC and metastatic small cell carcinoma of the lung (SCLC) is often challenging. Immunostains are important in confirming the diagnosis. Cytokeratin 20 (CK-20) and thyroid transcription factor 1 (TTF-1) are the most sensitive and specific and can be used to differentiate between small cell lung cancer. CK-20 is positive in 75 to 100 percent of primary MCCs but is seldom positive in SCLC. TTF-1 will not be positive in MCC but is positive in more than 80 percent of SCLC.4

Evaluation
Careful vigilance and a high level of suspicion are required to diagnose MCC. Regular skin examinations in patients at risk are critical. These patients often have a history of actinic keratoses and other non-melanoma skin cancers.1,10 The 2018 National Comprehensive Cancer Network (NCCN) Guidelines for MCC include detailed information about the management of these tumors, including surgical treatment of the primary lesion and draining nodal basin; radiation therapy, as primary treatment and adjuvant therapy; and management of recurrence.4

Lab studies. Suspicious lesions should be biopsied using either shave, punch, incisional, or excisional biopsy. The particular technique used will be dependent on the location of the tumor on the body, the size of the tumor, and depth of the tumor.4, 10 Diagnosis is made by analyses of histological features on H&E stains and confirmed by immunostains. Once diagnosis is confirmed, further work-up including full body skin examination and lymph node examination is necessary to rule out metastatic disease.4-5

Staging. The staging system most often used for MCC is the American Joint Committee on Cancer (AJCC) TNM system, which is based on three key prognostic factors: “tumor size greater or less than 2 cm; invasion to underlying structures; lymph node involvement, with a distinction between clinical and pathological node status; and the presence of metastases.”4 The 2017 AJCC staging system, 8th Edition uses four clinical stages: stage 0 (in situ), stage I (localized disease, primary lesion ≤2 cm), stage II (localized disease, primary lesion >2 cm), stage III (nodal spread), and stage IV (metastatic disease beyond the local nodes).4,10

Imaging studies. At the time of primary diagnosis, 25 to 30 percent of patients will already have locoregional metastases present.1,11 This high incidence of lymph node metastasis warrants the use of sentinel lymph node biopsy (SLNB) to help identify subclinical nodal disease in patients without clinically suspicious lymph nodes.10-11 SLNB can also be used to determine which patients may need complete lymph node dissection (CLND) or radiation for regional control. SLNB should be done prior to surgical intervention since surgical removal prior to SLNB may change the drainage patterns lymph system in that area and compromise the accuracy of the test.11 Those patients found to have clinically suspicious lymph nodes should undergo biopsy of the suspicious node using fine needle aspiration (FNA) or core biopsy with the proper immunohistologic panels.4,10-11 Negative results may merit the need for open biopsy.

Further imaging is warranted in those patients found to have positive nodes. NCCN guidelines recommend whole body positron emission tomography(PET)/computed tomography (CT) scanning as the modality of choice for diagnostic imaging of MCC. If that is not an option, magnetic resonance imaging (MRI) with contrast of the brain and neck/chest/abdomen/pelvis CT with contrast is also an option.4 See Figure 2 for a simplified algorithm for evaluation of possible MCC.

TREATMENT
Histopathologic reading and staging of the primary lesion help determine the most appropriate treatment course.6 Due to the complexity of this disease, a multispecialty approach with dermatology, surgical oncology, radiation oncology and others is recommended in managing these patients.

Surgical Intervention
Surgical excision of the tumor with negative margins is the first choice in therapy for patients with primary MCCs.1-11 Wide local excision with 1 to 3 cm of clinically free margins is recommended. If positive margins are found, then the area should undergo re-excision until free margins are obtained.

Because these tumors are frequently located on the head and neck (areas where tissue sparing is critical), Mohs micrographic surgery (MMS) is an alternative to traditional wide local excision.9 MMS provides complete margin control using frozen horizontal sections while also sparing healthy tissue, although more research is needed to determine the local recurrence rate for MMS versus wide local excision. Locoregional recurrence typically presents as satellite and in-transit metastases. Therefore, it is typically suggested that the center section of the tumor is sent for permanent sections due to the concern that Mohs surgery may contribute to recurrence via continuitatem invasion, or the theory that cancer cells can spread throughout the body by direct invasion of surrounding tissues.5
In patients who have biopsy proven positive sentinel nodes, complete lymph node dissection should be done followed by adjuvant radiation therapy to the draining nodal basin.6,11

Adjuvant Therapy
Radiation therapy. MCC tends to be responsive to radiation therapy.1 In patients without nodal involvement, wide-field adjuvant radiation therapy to the primary tumor site is frequently recommended following surgery, especially in high-risk patients.4,11 In some cases, radiation to the draining lymph node basin is also recommended, especially in high-risk patients. Radiation therapy is also used in patients with nodal disease, either in combination with complete lymph node dissection or alone.11 Radiation therapy can also be used as palliative treatment for inoperable cases of MCC.6 In 75 to 85 percent of cases, radiation therapy can control the disease.1,8

Chemotherapy. Chemotherapy is being used less frequently due to the recent introduction of immunotherapy in the treatment of MCC. Previously, chemotherapeutic regimens were the most frequent treatments for metastatic inoperable MCC. These included platinum-based regimens, such as etoposide, taxanes and anthracyclines, alone or in combination.8 These regimens are highly toxic with many side effects, and only short-term control is usually seen. Currently, the usefulness of chemotherapy is controversial and typically only used for advanced‐stage MCC and palliative therapy not responsive to radiotherapy.3,11

Immunotherapy. MCC, like other types of cancers, produces antigens that can be recognized by the immune system. However, many tumors will develop other features that will allow them to locally evade the immune system, rendering the immune system less effective. Immune therapy is a new area of research being investigated that is developing new medications to target these mechanisms. One such class of medications is immune checkpoint inhibitors (CPI). In 2016, the United States Food and Drug Administration (FDA) approved avelumab, the first drug used for the treatment of MCC. Avelumab, along with nivolumab and pembrolizumab, are immune CPIs.5 These medications disable the PD-L1 (programmed cell death-ligand 1) protein on cancer cells by stimulating T cells and activating an anti-tumor response. This causes the immune system to attack the cancer cells.11 NCCN guidelines for immunotherapy recommends avelumab, nivolumab, or pembrolizumab in patients with metastatic MCC.2 These medications are not without risk. Serious adverse effects include acute kidney injury, anemia, abdominal pain, ileus, asthenia, and cellulitis. These complications are of increased concern in patients with solid organ transplants, as CPIs have been shown to have an increased incidence of organ rejection in these patients.12

Other areas of research. Other immunotherapies are currently in clinical trials. These include adoptive T cell transfer, intratumoral interferon, interleukin-12 DNA electroporation, and Toll-like receptor-4 agonists. Potential therapeutic targets for somatostatin analogs, tyrosine kinase inhibitors, and mammalian target of rapamycin inhibitors have been found in MCPyV positive tumors, allowing for targeted molecular therapy that can be used in the treatment MCC.11

POST DIAGNOSIS
Follow up
Due to the high risk of recurrence, metastasis, and death, follow up is a vital part of improving long-term survival. Immediately after diagnosis and following the completion of treatment, careful follow-up including full body skin exam and lymph node exam should occur every 3 to 6 months for two years, then every 6 to 12 months thereafter.4 The frequency of these exams should be adjusted depending on the patient’s risk of recurrence, stage of disease, and other risk factors, like continued sun exposure, that might increase the patient’s chance of recurrence. Patients should also be educated about the importance of regular self-examination of the skin to aid in early detection of new MCC, as well as other non-melanoma skin cancers.

Surveillance imaging may or may not be recommended and should only be performed if clinically warranted. These would include new onset adenopathy or organomegaly, changes in liver function tests or other bloodwork, or the development of other new symptoms. For high-risk patients such as those with stage IIIB or higher disease or patients that are immunosuppressed, routine imaging with the same imaging modalities recommended in initial clinical workup should be considered.2 Suggested imaging includes brain MRI with contrast and neck/chest/abdomen/pelvis CT with contrast or whole-body PET/CT.

Prognosis
MCC has a mortality rate of 33 to 46 percent, even higher than malignant melanoma.6 Survival rates depend on the stage at diagnosis with five-year survival rates of 62.8 percent in patients with stage I disease, 34.8 to 54.6 percent with stage II, 26.8 to 40.3 percent with stage III, and 13.5 percent with stage IV.6

Recurrence, either local or distant, typically happens within the first 2 to 3 years after initial diagnosis. Localized MCC treated with wide local excision has a recurrence rate of 25 to 40 percent.11 Metastasis happens most frequently in the draining lymph node basin. Other areas include distant skin metastases, lung, central nervous system, bone, and liver.

CONCLUSION
MCC is a difficult tumor to diagnose, both clinically and pathologically. It can require a high level of suspicion, making a thorough history and physical examination a key part of every visit in order to recognize some of the subtle signs that may be present. The apparent increasing incidence, along with the poor prognosis when left untreated, makes it a tumor that you don’t want to misdiagnose.

References:

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11. Coggshall K, Tello TL, North JP, Yu SS. Merkel cell carcinoma: An update and review: Pathogenesis, diagnosis, and staging. Journal of the American Academy of Dermatology. 2018;78(3):433-442. http://www.sciencedirect.com.ezproxy.lynchburg.edu/science/article/pii/S019096221732755X. doi: //doi.org/10.1016/j.jaad.2017.12.001.
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Mandy Frith, DMSc, MPAS, PA-C, is from Birmingham, Alabama.

Disclosures: The author has disclosed no potential conflicts of interest, financial or otherwise, relating to the content of this article.