We found that a history of cutaneous SCC was associated with a moderately increased mortality rate following a diagnosis of cancer of the lung, colon, rectum, breast, and NHL, but not in survivors of prostate cancer. The present study is the first to examine this association taking into account comorbidity and index cancer treatments. Adjustment for these factors had no substantial effect on our results, so it is unlikely that they have introduced major confounding in previous studies.
In agreement with the extant literature [4
], we find an overall increased mortality rate in cancer patients with a history of cutaneous SCC. When examining index cancer types individually, there are, however, some inconsistencies with previous studies. Askling et al
., Kahn et al
., and Nugent et al.
included prostate and breast cancer in their studies. All three studies found a 19 to 45% increased mortality rate among breast cancer patients with a history of cutaneous SCC. In comparison, we found a 9% increase. In contrast to Askling et al.
and Kahn et al
., we found no increased rate of death from prostate cancer. For the remaining index cancers, the finding of a poorer prognosis in patients with previous cutaneous SCC is consistent across studies [4
]. In both colon and rectal cancer, only Kahn et al.
found no increase in the mortality rate. This difference may be explained by the fact that they did not differentiate between NMSC subtypes, since Hjalgrim et al.
and Nugent et al.
showed that MRRs for these cancers were lower for BCC than SCC patients.
An association between a history of cutaneous SCC and a poor prognosis may be explained by an underlying immunodeficiency. Cumulative UVR exposure, the major risk factor of SCC of the skin [1
], is especially interesting since UVR induces cellular immune incompetence [6
]. This reduced immune function may be observed both locally and systemically and it is more pronounced in patients with previous skin cancer than in the general population [6
]. We therefore hypothesize that cutaneous SCC is a marker of underlying immunosuppression that compromises the patient's normal immune surveillance against nascent tumor cells resulting in poor prognosis of subsequent cancer. NHL is interesting from this immunologic perspective, given its strong association with immune function. Hence, we would have expected a greater increase compared with the other cancers that are not as strongly related to immune function. However, the imprecision of our estimates, especially for NHL, limit us from concluding on any substantial differences between cancers. Furthermore, alternative explanations such as field cancerization due to an unidentified carcinogen may also explain our findings.
The low number of observations limited the analysis of associations for subtypes of autoimmune diseases, and since the degree of immunosuppression varies with severity and type of autoimmune disease "a history of any autoimmune disease" may be an imperfect reflection of immunosuppression. Furthermore, information on a history of autoimmune disease may be underreported, especially in the mild cases. These limitations prevent us from ruling out a differential effect in people with autoimmune disease.
Our study has several limitations. Even though the Danish Cancer Registry is close to complete for most malignancies [15
], NMSC registration is probably underreported [5
] due to the high incidence of NMSCs burdening the systems and the high cure rate that may cause clinicians to consider it trivial, especially in patients with comorbidity [23
]. We do not, however, find it likely that mortality of a malignancy occurring later in time would affect misclassification of cutaneous SCC.
Misclassification of cause of death may be possible. The Danish Registry of Causes of Death has varying validity for different causes of death, although it is almost complete for cancer deaths [16
]. The major problem with the registry is that the sequence of events may not be accurate [25
]. To avoid this problem, we considered cause of death to be cancer if any cause on the death certificate was a malignancy. Moreover, we repeated all analyses for all-cause death by using the civil registration system, which is virtually complete [14
]. This change in outcome slightly attenuated the results, but they were not substantially different from the cancer-specific MRRs.
Surveillance bias might have affected our results if preceding SCC of the skin is associated with increased medical surveillance leading to earlier diagnosis, and hence, better prognosis. This bias would have worked against the direction of the observed association, so it cannot explain the results. In addition, a Danish study of NMSC and risk of subsequent cancer found no evidence of more intensive surveillance for internal malignancies [5
], which is in accordance with Danish guidelines on follow-up in patients with cutaneous SCC [26
]. Moreover, we found no substantial difference between mortality rates stratified on time between SCC and index cancer diagnoses.