Radiation Therapy in Merkel Cell Carcinoma

Abstract

Merkel cell carcinoma (MCC) is an aggressive but rare cutaneous neuroendocrine malignancy arising predominantly in older Caucasians. Many (30–40%) will die from MCC despite treatment, usually from distant metastases. The incidence is increasing and lesions can arise anywhere on the body and are not just confined to the sun-exposed head and neck or extremities. The etiology of MCC is associated with a highly prevalent virus, the Merkel cell polyomavirus (MCPyV). The prevalence of MCPyV varies in distinct populations, with Australians experiencing less viral-associated MCC, and a more chronic ultraviolet radiation-induced pathway, compared with their European counterparts. The rarity of MCC makes it difficult to diagnosis clinically and lesions require biopsy confirmation. Histopathology is that of a population of small monomorphous round cells that belong to the family of so-called small blue round cell tumours. Most MCC will stain positive for cytokeratin 20 often in a perinuclear dot-like distribution. Extent of disease at diagnosis is highly prognostic of outcome. Most (50–60%) patients present with a primary lesion, but there is a need to investigate and/or treat draining lymph nodes as the incidence of subclinical spread is high (30–50%). Sentinel lymph node biopsy represents an effective and minimally morbid technique to establish nodal status with micrometastatic lymph node involvement, with evidence that patients with a negative biopsy can avoid regional treatment. There is an extensive body of evidence supporting the addition of adjuvant radiotherapy in improving locoregional control and survival. In many patients, however, the extent of disease at presentation is technically or medically inoperable. The unique radioresponsiveness of MCC provides the option of RT alone achieving 80–90% in-field control rates using doses in the range of 45–60 Gy, even in the setting of large primary lesions and/or nodal metastasis, with 40–60% cured. The role of surgery alone in this radiosensitive malignancy is controversial. Many patients will undergo an excision biopsy to confirm a diagnosis of MCC, and invariably excision margins will be close or positive with management following this controversial. Patients are often not suitable for wide excisions especially for lesions located on the head and neck. Noting the excellent results obtained with irradiating macroscopic MCC, patients with close and/or positive excision margins obtain excellent control rates following adjuvant radiotherapy. The role of systemic therapy in MCC is predominantly palliative. Various combinations of cytotoxic chemotherapy have been documented; however the results of chemotherapy have been disappointing with response rates of 40–60% (complete response rates 10–15%) but usually of short duration (6–9 months). The recent discovery of targeted immunomodulators that enhance a patient’s immune response carries great promise in patients previously considered incurable with future trials likely to incorporate these as adjuvant therapies along with radiotherapy and/or surgery.