We found that MCC patients were at increased risk of second primary cancers, in particular for non-melanoma and melanoma skin cancers. There was also a significantly increased risk for laryngeal cancers, but this was based on small numbers. Previously two registry-based studies have investigated the cancer risks among patients diagnosed with MCC (Howard et al, 2006
; Koljonen et al, 2010
). In the SEER program in the United States (Howard et al, 2006
), the risk of overall second malignancy after MCC diagnosis was 1.2 (95% CI: 1.0–1.5). There were also significantly elevated SIRs for salivary gland tumours, biliary tract cancer and non-Hodgkin lymphoma. In the Finnish Cancer Registry (Koljonen et al, 2010
), the SIRs for cancers at any site after MCC diagnosis was 2.3 (95% CI: 1.6–3.3). The SIRs of basal cell carcinoma and chronic lymphocytic leukaemia showed significantly increased risk among MCC patients (Koljonen et al, 2010
). Selection/surveillance biases, different qualities of different cancer registries, rare cancers and/or unstable findings are conceivable explanations for the fact that the three different studies have failed to identify the same cancer forms as the most frequently occurring secondary primaries following MCC diagnoses.
The small number of patients with other cancers occurring before or on the same date as MCC preclude a more detailed analysis of whether any cancer forms are linked also in the other direction, that is, whether MCC risks are increased after other cancer. However, it is interesting to note that not less than 26 out of the 40 other cancers occurring before or on the same date as MCC were non-melanoma skin cancers, suggesting that the link between MCC and non-melanoma skin cancer may be bidirectional.
Shared aetiological factors which may conceivably explain the increased risk of a second primary cancer after the diagnosis of MCC include exposure to ultraviolet-radiation, immunosuppression or MCV infection. Exposure to sunlight may be an explanation of concomitant associations of MCC, non-melanoma skin cancer and melanoma. Also, MCV DNA is reported to be frequently found in the skin, not only in MCC tissue (Feng et al, 2008
; Becker et al, 2009
), and involvement of MCV infection also in other skin diseases is, therefore, plausible.
Surveillance bias after diagnosis should always be considered as an explanation for excess risk of secondary cancers. Analysis of trends of excess risks over time after diagnosis is conventionally used to search for surveillance bias, as medical attention is intensified immediately after a cancer diagnosis. We excluded cases occurring less than 6 months after MCC diagnosis in our analysis and we also found limited changes in estimates by restricting the study to cancers occurring greater than 1 year after diagnosis. Thus, although we have no evidence for surveillance bias, it still should be considered as a likely explanation of our findings. Especially for skin cancers, there may be a prolonged increased vigilance, not only from physicians but also from the patients themselves. The fact that the excess risk of skin cancer was essentially restricted to females is difficult to explain, but it is conceivable that gender-related differences in skin surveillance may exist.
The assessment of the risk for second cancers requires a large study cohort and a long study time. MCC is a rare and aggressive cancer associated with a poor prognosis. As it occurs mostly in elderly patients, the numbers of person-years available for follow-up is limited. Although we combined data from three countries, a somewhat inadequate number of person-years of follow-up is still a limitation of our study.
The major strength of our study is that the data are from cancer registries of three Nordic countries. These population-based cancer registries provide long-term national data that are considered to be of comparably high quality, with the majority of diagnoses among cases histologically confirmed (Tulinius et al, 1992
We conclude that the incidence of second primary cancers is increased among patients diagnosed with MCC compared with the general population. Patients diagnosed with MCC are at an excess risk for malignant melanoma, larynx cancer and, in particular, for non-melanoma skin cancer.