Second cancers following the diagnosis of Merkel cell carcinoma: A nationwide cohort study
Introduction
Merkel cell carcinoma (MCC) is a rare and often highly malignant neuroendocrine tumour of the skin, first described by Toker in 1972 [1]. According to the surveillance, epidemiology, and end results (SEER) program registry of the United States statistics, the annual incidence of MCC increased from 1.5 cases per million to 4.4 cases per million in 15 years [2].
A marked proportion of primary MCCs has been reported to occur in an intimate association with a malignant epithelial neoplasm, mainly squamous cell carcinoma of the skin or of the head and neck [3], [4]. Besides other skin tumours, MCCs have been reported to be associated with haematological B-cell malignancies [5], [6] adenocarcinomas of the breast and the ovaries [4] and cancers of the rectum and the prostate [7].
MCCs were recently found to frequently harbour a novel, clonally integrated virus named Merkel cell polyomavirus (MCPyV) [8]. MCPyV DNA is present in approximately 70–80% of the MCCs [8], [9], [10], [11], [12]. The importance of viral infection in the pathogenesis of MCC is not yet fully understood, but it may be associated with genesis and progression of many MCCs. Patients whose MCC contains MCPyV DNA have often a tumour arising in the limbs, and they have more favourable prognosis compared to patients whose MCC does not contain viral DNA, which findings lend support to a role of MCPyV infection in the molecular pathogenesis of MCC [13].
The purpose of the present study was to investigate whether individuals diagnosed with MCC have an increased risk for developing a second primary cancer after the diagnosis of MCC, some of which might be associated with viral infection. The study is based on the files of the Finnish Cancer Registry, where virtually all cancers diagnosed in Finland are registered. A great majority of cancers registered are diagnosed histologically, which creates a reliable basis for assessment of the risk of second cancers following the diagnosis of MCC.
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Patients and methods
Subjects diagnosed with MCC were identified from the files of the Finnish Cancer Registry, founded in 1952. The registry is a population-based registry that covers the entire Finnish population (5.3 million in 2009). Hospitals, practicing physicians, and pathology and haematology laboratories are requested to report to the Finnish Cancer Registry all cases of cancer that come to their attention. Data of all death certificates that mention cancer are transferred to the registry annually. Deaths
Results
A total of 172 individuals were diagnosed with MCC as a first cancer in Finland in 1979–2006. All MCC diagnoses were based on histological examination. Only fourteen (8.1%) cases were diagnosed before the year 1990. All patients were Caucasian. Only 4 (2.3%) patients were younger then 45 years at the time of the diagnosis, while 104 (60.5%) were 75 years of age or older. Most (n = 119, 69.2%) patients were female, resulting in a female-to-male ratio of 2.2:1. The mean follow-up time after the
Discussion
Patients diagnosed with MCC had a significantly increased risk for being diagnosed with a second primary cancer. Yet, approximately one third of the second tumours were basal cell carcinomas of the skin, which are usually cured by surgery. Patients diagnosed with MCC were also more likely than the general population to be diagnosed with CLL.
MCC disease is a relatively new entity. Although first described in 1972 with the designation of “trabecular carcinoma of the skin” [1] the term “Merkel
Conflict of interest statement
On behalf of myself and my co-authors, no financial or other conflict of interest exists regarding financial or other relationship. Funding of this article was from departmental sources only.
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Cited by (36)
Diagnosis and treatment of Merkel cell carcinoma: European consensus-based interdisciplinary guideline – Update 2022
2022, European Journal of CancerMerkel cell polyomavirus and associated Merkel cell carcinoma
2022, Tumour Virus ResearchCitation Excerpt :Several studies have established that patients with CLL are predisposed to MCC [110–112]. Though immune suppression caused by CLL has been suggested as the reason for this relationship, the reverse has also been established—namely, that MCC patients are also at a higher risk of subsequent development of CLL [113]. Several groups have also detected MCPyV DNA at low levels in CLL cells [31,114–116].
Multiple primary cancers associated with merkel cell carcinoma in Queensland, Australia, 1982-2011
2014, Journal of Investigative DermatologyCitation Excerpt :Again, the relative risk for subsequent MCCs in Queensland was much greater than that in the United States (Howard et al., 2006; SIR=1.4) but similar to Denmark (Kaae et al., 2010; SIR=2.6). It should be noted that the results from the United States probably provide the most valid benchmark for the Queensland data because the overall SIRs from other countries have included keratinocyte cancers (basal cell carcinomas and/or SCCs of the skin), which have been found to have very high SIRs (Kaae et al., 2010; Koljonen et al., 2010; Bzhalava et al., 2011) and would most likely elevate the total relative risk. Although MCC is known to occur with other cutaneous tumors and some solid tumors, the strongest associations have been found for hematological malignancies, particularly chronic lymphocytic leukemia (Howard et al., 2006; Kaae et al., 2010; Tadmor et al., 2012).
Detection of Merkel cell polyomavirus in chronic lymphocytic leukemia T-cells
2013, Experimental and Molecular PathologyCitation Excerpt :Viruses from the family polyomaviridae, specifically simian vacuolating virus 40 (SV40), have a proposed tumorogenic mechanism that involves integration into the host genome, mutations in the viral Large T Antigen, and subsequent inactivation of the host tumor suppression genes retinoblastoma and p53 (recently reviewed in (Chang and Moore, 2012)). Patients with MCC have an increased risk of developing chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), and vice versa (Kaae et al., 2010; Koljonen et al., 2009, 2010). With this epidemiologic link and a long-suspected viral association in CLL/SLL based upon immunoglobulin heavy locus stereotypy, there has been an interest in exploring possible relationships between MCPyV and CLL/SLL (Johnson et al., 1997; Rosen et al., 2010; Tsakou et al., 2012).
Cutaneous Merkel cell carcinoma
2012, American Journal of Otolaryngology - Head and Neck Medicine and SurgeryCitation Excerpt :Although the incidence is reportedly rising, it is unclear whether this represents a true increased incidence or an increased recognition of MCC. Risk factors for MCC are sun exposure and immune suppression, including chronic lymphocytic leukemia, solid organ transplant, and HIV [4-6]. Human polyoma virus appears to be etiologic in a significant proportion of patients with MCC; the presence of human polyoma virus DNA in the MCC cells may be associated with an improved prognosis [5].
Cancer of the skin
2018, DeVita, Hellman, and Rosenberg's Cancer: Principles & Practice of Oncology