Merkel Cell Carcinoma: From Pathobiology to Clinical Management

Merkel cell carcinoma (MCC) is an infrequent, rapidly growing skin neoplasm that carries a greater probability of regional lymph node involvement, and a grim prognosis in advanced cases. While it is seen predominantly in old age in sun-exposed body parts, the prevalence varies among different races and geographical regions. Merkel cell polyomavirus and UV radiation-induced mutations contribute to its etiopathogenesis. The clinical presentation of MCC lacks pathognomonic features and is rarely considered highly at the time of presentation. Histopathological examination frequently reveals hyperchromatic nuclei with high mitotic activity, but immunohistochemistry is required to confirm the diagnosis. Sentinel lymph node biopsy (SLNB) and imaging are advised for effective staging of the disease. Multimodal management including surgery, radiation therapy, and/or immunotherapy are deployed. Traditional cytotoxic chemotherapies may result in an initial response, but do not result in a significant survival benefit. Checkpoint inhibitors have dramatically improved the prognosis of patients with metastatic MCC, and are recommended first-line in advanced cases. There is a need for well-tolerated agents with good safety profiles in patients who have failed immunotherapies.

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Management Recommendations for Merkel Cell Carcinoma—A Danish Perspective

Cancers ◽

10.3390/cancers12030554 ◽

2020 ◽

Vol 12 (3) ◽

pp. 554 ◽

Cited By ~ 1

Author(s):

Simon Naseri ◽

Torben Steiniche ◽

Morten Ladekarl ◽

Marie Louise Bønnelykke-Behrndtz ◽

Lisbet R. Hölmich ◽

...

Keyword(s):

Lymph Node ◽

Cell Carcinoma ◽

Merkel Cell Carcinoma ◽

Adjuvant Radiotherapy ◽

Checkpoint Inhibitors ◽

Regional Lymph Node ◽

Immune Therapy ◽

Patient Treatment ◽

Merkel Cell ◽

Management Recommendations

Merkel cell carcinoma (MCC) is a rare malignant neuroendocrine carcinoma of the skin with a poor prognosis and an apparent increase in incidence. Due to its rarity, evidence-based guidelines are limited, and there is a lack of awareness among clinicians. This review constitutes the consensus management recommendations developed by the Danish MCC expert group and is based on a systematic literature search. Patients with localized disease are recommended surgical excision and adjuvant radiotherapy to the primary site; however, this may be omitted in patients with MCC with low risk features. Patients with regional lymph node involvement are recommended complete lymph node removal and adjuvant radiotherapy in case of extracapsular disease. Metastatic disease was traditionally treated with chemotherapy, however, recent clinical trials with immune therapy have been promising. Immune checkpoint inhibitors targeting the programmed cell death protein 1(PD-1)/programmed death-ligand 1(PD-L1) axis should therefore be strongly considered as first-line treatment for fit patients. A 5-year follow-up period is recommended involving clinical exam every 3 months for 2 years and every 6 months for the following 3 years and PET-CT one to two times a year or if clinically indicated. These national recommendations are intended to offer uniform patient treatment and hopefully improve prognosis.

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Frequency and prognosis of metastasis to liver, lung, bone and brain from Merkel cell carcinoma

Future Oncology ◽

10.2217/fon-2020-0064 ◽

2020 ◽

Vol 16 (16) ◽

pp. 1101-1113 ◽

Cited By ~ 1

Author(s):

Yi-Jun Xia ◽

Dong-Sheng Cao ◽

Jun Zhao ◽

Bang-Zhong Zhu ◽

Juan Xie

Keyword(s):

Lymph Node ◽

Cell Carcinoma ◽

Merkel Cell Carcinoma ◽

Distant Metastasis ◽

Regional Lymph Node ◽

Distant Metastases ◽

Lymph Node Biopsy ◽

Merkel Cell ◽

Factors Affecting ◽

Node Removal

Aim: To describe the factors affecting distant metastasis of Merkel cell carcinoma (MCC) and the prognosis of metastatic MCC. Materials & methods: The MCC patient information was downloaded from the SEER database. Logistic regression and Cox proportional hazard models were conducted to screen for significant factors. Results: A total of 3449 patients were enrolled. Surgery and chemotherapy were significantly correlated with the occurrence of distant metastasis. In the cause-specific survival rate of MCC, regional lymph node removal, sentinel lymph node biopsy, radiation and chemotherapy can significantly reduce the prognostic risk of patients with distant metastases. Conclusion: Our study screened out the factors affecting the distant metastasis and prognosis of MCC and more prospective studies are needed to verify our findings.

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Features Predicting Sentinel Lymph Node Positivity in Merkel Cell Carcinoma

Journal of Clinical Oncology ◽

10.1200/jco.2010.33.4136 ◽

2011 ◽

Vol 29 (8) ◽

pp. 1036-1041 ◽

Cited By ~ 100

Author(s):

Jennifer L. Schwartz ◽

Kent A. Griffith ◽

Lori Lowe ◽

Sandra L. Wong ◽

Scott A. McLean ◽

...

Keyword(s):

Lymph Node ◽

Sentinel Lymph Node ◽

Cell Carcinoma ◽

Merkel Cell Carcinoma ◽

Growth Pattern ◽

Regional Lymph Node ◽

Mitotic Rate ◽

Tumor Thickness ◽

Merkel Cell ◽

Primary Tumors

Purpose Merkel cell carcinoma (MCC) is a relatively rare, potentially aggressive cutaneous malignancy. We examined the clinical and histologic features of primary MCC that may correlate with the probability of a positive sentinel lymph node (SLN). Methods Ninety-five patients with MCC who underwent SLN biopsy at the University of Michigan were identified. SLN biopsy was performed on 97 primary tumors, and an SLN was identified in 93 instances. These were reviewed for clinical and histologic features and associated SLN positivity. Univariate associations between these characteristics and a positive SLN were tested for by using either the χ2 or the Fisher's exact test. A backward elimination algorithm was used to help create a best multiple variable model to explain a positive SLN. Results SLN positivity was significantly associated with the clinical size of the lesion, greatest horizontal histologic dimension, tumor thickness, mitotic rate, and histologic growth pattern. Two competing multivariate models were generated to predict a positive SLN. The histologic growth pattern was present in both models and combined with either tumor thickness or mitotic rate. Conclusion Increasing clinical size, increasing tumor thickness, increasing mitotic rate, and infiltrative tumor growth pattern were significantly associated with a greater likelihood of a positive SLN. By using the growth pattern and tumor thickness model, no subgroup of patients was predicted to have a lower than 15% to 20% likelihood of a positive SLN. This suggests that all patients presenting with MCC without clinical evidence of regional lymph node disease should be considered for SLN biopsy.

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Immunotherapy with imiquimod and interferon alfa for metastasized Merkel cell carcinoma

Current Oncology ◽

10.3747/co.23.2878 ◽

2016 ◽

Vol 23 (2) ◽

pp. 150 ◽

Cited By ~ 8

Author(s):

R.U. Wahl ◽

T. Braunschweig ◽

A. Ghassemi ◽

A. Rübben

Keyword(s):

Lymph Node ◽

Cell Carcinoma ◽

Merkel Cell Carcinoma ◽

Lymph Node Metastases ◽

Neuroendocrine Tumour ◽

Regional Lymph Node ◽

Pegylated Interferon ◽

Interferon Alfa ◽

Merkel Cell ◽

Node Metastases

Merkel cell carcinoma (mcc) is a highly aggressive neuroendocrine tumour of the skin. Remission rates are high with chemotherapy in patients with metastasis, but without any improvement in overall survival.We present the case of a 90-year-old woman with facial mcc. After radiation and surgery, the mcc recurred with widespread cutaneous and regional lymph node metastases. The metastases were treated with weekly intralesional injections of 1–2×106 IU interferon alfa-2a, accompanied by topical imiquimod 5% cream 3 times weekly. After partial regression, subcutaneous pegylated interferon alfa-2b was added at a dose of 30 μg weekly, which was then increased to 50 μg weekly. At 4 months after the start of immunotherapy, all cutaneous metastases and the intralesionally treated lymph node metastases receded. Interruption or reduction of systemic interferon application resulted in locoregional relapses that were successfully treated with surgery or intralesional interferon injections. The patient remains alive 30 months after initiation of immunotherapy, suggesting that locally metastasized mcc might be able to be controlled with local and systemic immunotherapy.

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Patients With Merkel Cell Carcinoma Tumors ≤ 1.0 cm in Diameter Are Unlikely to Harbor Regional Lymph Node Metastasis

Journal of Clinical Oncology ◽

10.1200/jco.2008.20.8272 ◽

2009 ◽

Vol 27 (23) ◽

pp. 3772-3777 ◽

Cited By ~ 72

Author(s):

Jayme B. Stokes ◽

Katherine S. Graw ◽

Lynn T. Dengel ◽

Brian R. Swenson ◽

Todd W. Bauer ◽

...

Keyword(s):

Lymph Node ◽

Lymph Node Metastasis ◽

Cell Carcinoma ◽

Merkel Cell Carcinoma ◽

Regional Lymph Node ◽

Nodal Metastasis ◽

Regional Lymph Node Metastasis ◽

Tumor Diameter ◽

Merkel Cell ◽

Node Metastasis

Purpose Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine cutaneous malignancy. Current recommendations include offering regional lymph node evaluation by either sentinel lymph node biopsy (SLNB) or complete lymph node dissection (CLND) to all patients with MCC; however, we hypothesized a cohort of low-risk patients may exist for whom regional nodal metastasis would be unlikely. Methods A retrospective review of the Department of Veterans Affairs national health care database was performed. Patients undergoing resection of primary MCC were identified; and demographic, medical, and social history; tumor characteristics; nodal status; and recurrence events were recorded. Results Between 1995 and 2006, 346 patients were diagnosed with MCC. Of these, 213 underwent resection of the primary lesion and evaluation of the draining lymph node basin. Fifty-four patients (25%) had tumors ≤ 1.0 cm in diameter. Average tumor diameter was 0.7 cm, and 63% were located on the head or neck. Only two patients (4%) with tumors ≤ 1.0 cm had regional lymph node metastasis, compared with 51 (24%) of 213 patients with tumors more than 1.0 cm (P < .0001). Both patients had clinically evident nodal disease at presentation and underwent CLND. Both have remained recurrence-free for 40 months. Thirteen (25%) of 51 patients with nodal metastasis and tumors more than 1 cm had occult nodal metastasis. Conclusion In this series, patients with MCC ≤ 1.0 cm were unlikely to have regional lymph node metastasis, suggesting that regional nodal evaluation may reasonably be avoided in these patients. However, these data support SLNB for MCC more than 1 cm in diameter.

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Merkel Cell Carcinoma: A Review of Current Advances

Journal of the National Comprehensive Cancer Network ◽

10.6004/jnccn.2009.0025 ◽

2009 ◽

Vol 7 (3) ◽

pp. 333-339 ◽

Cited By ~ 28

Author(s):

Frank Qian Zhan ◽

Vathani Sharon Packianathan ◽

Nathalie Charlotte Zeitouni

Keyword(s):

Lymph Node ◽

Cell Carcinoma ◽

Merkel Cell Carcinoma ◽

Regional Lymph Node ◽

Multidisciplinary Treatment ◽

Treatment Algorithm ◽

Cancer Center ◽

Cytokeratin 20 ◽

Merkel Cell ◽

Neurofilament Protein

Merkel cell carcinoma (MCC) is a rare but aggressive cutaneous malignancy of neuroendocrine origin. Its incidence has tripled over the past 15 years. This article reviews the recent advancement in diagnosis, discoveries in pathogenesis, and updates in management. The acronym, AEIOU, has been proposed to aid in clinical identification. In addition to cytokeratin 20, newer immunohistochemical stains (in particular thyroid transcription factor-1 and neurofilament protein) have proven to be essential in pathologic diagnosis. Although immune suppression and ultraviolet radiation have long been associated with the MCC oncogenesis, recent studies also show involvement of a new polyomavirus and bcl-2. Several tumor classifications have been published in the literature, with the 4-tiered system from Memorial Sloan-Kettering Cancer Center the most widely used. A similar classification with additional distinctions among nodal disease is being constructed. A multidisciplinary treatment algorithm is recommended for MCC. Surgical excision with adjuvant radiotherapy (RT) is indicated for localized tumors. RT is favored over complete lymph node dissection and chemotherapy for regional lymph node involvement. For distant metastasis, management should be individualized with a combination of palliative surgery, RT, and chemotherapy.

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