Scientific and clinical developments in Merkel cell carcinoma: A polyomavirus-driven, often-lethal skin cancer

Abstract

Merkel cell carcinoma (MCC) is a primary neuroendocrine skin cancer that recurs in ~40% of cases. Merkel cell polyomavirus (MCPyV) and ultraviolet (UV)-induced mutations are two major causative factors of MCC. Virus-positive MCCs express polyomavirus oncoproteins that are highly immunogenic yet are required for ongoing tumor growth. Virus-negative MCCs have a high burden of UV-DNA mutations that encode tumor-specific UV-neoantigens. Thus, both UV- and virus-induced MCCs are highly immunogenic, enabling diverse T-cell targeted therapies. Optimal MCC management is challenging given its rarity, aggressive nature, rapidly evolving care guidelines, and fundamental differences in management compared to other skin cancers. MCC is often managed aggressively with extensive surgery, radiotherapy or systemic therapy, frequently leading to toxicities that might have been avoidable while still achieving optimal disease control. Thus, multi-disciplinary care is crucial for providing patients with the best possible outcomes. The outlook for many patients with advanced MCC has progressed remarkably over the past decade due to PD-1 pathway blocking agents that provide durable benefit for a substantial subset of MCC patients. The management of early-stage MCC has also improved due to better approaches to integrate surgery and radiotherapy. Prognostic accuracy and ongoing surveillance have advanced due to stage-specific recurrence data and sophisticated "liquid biopsies" that allow early detection of disease recurrence. Here we summarize both recent striking progress and pressing challenges such as PD-(L)1-refractory MCC, and management of MCC patients with immune dysfunction. We also highlight diverse resources to allow providers to take advantage of recent progress in this fast-moving field.

Keywords: Cutaneous neuroendocrine carcinoma; Immunotherapy; Merkel cell carcinoma; Merkel cell polyomavirus; Multidisciplinary care.

Figure 1

Clinical features of Merkel cell carcinoma Panel A A 92-year-old man who presented with a rapidly growing red nodule on the right earlobe. Panel B A 77-year-old woman who presented with a 2.0 x 1.6 cm raised lesion on the anterior lower extremity. Panel C-E Histopathology of typical Merkel cell carcinoma. Panel C There are numerous round basophilic cells with an increased nuclear/cytoplasmic ratio and nuclear molding that are crowding out the dermal stroma (Hematoxylin and eosin stain). Panel D Immunohistochemistry staining shows the classic dot-like perinuclear expression pattern of CK20. Panel E Anti-Merkel cell polyomavirus T antigen antibody (CM2B4 clone) shows nuclear expression of Merkel cell polyomavirus oncoprotein in a virus-positive Merkel cell carcinoma.

Figure 2

Kaplan-Meier curves of patients with advanced Merkel cell carcinoma who were treated with immunotherapy as compared to historical cohorts of patients who were treated with chemotherapy. Panel A Overall survival (OS) of patients with chemotherapy-refractory MCC who were treated either with avelumab (anti-PDL1; brown-upper line) or with additional chemotherapy (red & blue lines; from two historical cohorts from the literature; Becker 2017[23], Cowey 2017[22]). Adapted, with permission, from Nghiem et al, ASCO 2021[26] Panel B Overall survival of patients who were treated with first-line pembrolizumab (anti-PD1) as compared to historical cohorts of patients who received first-line chemotherapy. Numbers that align with 6-month time periods indicate survival percentage for each cohort. Adapted, with permission, from Nghiem et al, JCO 2019 [29]

Figure 3

Flow chart for Merkel cell carcinoma management # Consider baseline Merkel cell polyomavirus serology test for prognostic significance and to track disease † Whole body FDG-PET/CT (preferred) or CT of chest, abdomen, pelvis and/or neck with contrast; brain MRI if symptomatic * No pathologically enlarged nodes on physical examination and by imaging study ** Pathologically enlarged nodes on physical examination or by imaging study *** SLNB may not be indicated if a patient would not benefit from the prognostic information, if it would not alter management of the regional nodes, or if a patient is not a good candidate for surgery/anesthesia **** Adjuvant RT is often indicated unless the following low-risk features are present: primary lesion ≤1 cm, primary site not on head/neck, no lymphovascular invasion, widely negative pathologic margins, negative SLNB, and patient not immunosuppressed ^ Consider excisional biopsy primarily or after negative needle/core biopsy to exclude false-negative biopsy result ^^ Consider radiation therapy to the nodal basin in high-risk patients Adapted, with permission, from Park et al, Future Oncol 2021[50]