Using the largest series ever reported on, we have described some key epidemiologic features of cutaneous melanoma in situ (CMIS) that could shed some light on the clinical relevance of this nosologic entity. While presenting the results, we are aware of the fact that although the SEER database provides investigators with a unique opportunity of generating and testing medical hypotheses on an unprecedented large series of patients, under-reporting is a potential limit of this databank, especially when it comes to conditions like CMIS that are routinely and increasingly treated in the outpatient setting.
Although most investigators agree that the incidence of skin melanoma is rising worldwide [1
], some have questioned this statement, sustaining either that benign lesions are erroneously included in the calculations [46
] or that the increased incidence regards mainly invasive [47
] or in situ lesions [48
], or even that the incidence is declining [49
]. As shown in , according to the SEER data, the incidence of CMIS is remarkably increasing over the past 3 decades, which might be related to an actual “epidemic” of CMIS (as postulated for invasive melanoma [36
]) but also to the increased attention paid by physicians and the general population to the early diagnosis of skin melanoma (so called “skin awareness”) [50
]. As reported in the Results section, this rise of incidence is steeper than that of any other invasive and in situ malignancy. Importantly, the increase in CMIS incidence does not account for the whole increment in skin melanoma (in situ + invasive) incidence, as invasive melanoma rates are also growing, although at a slower pace ().
The parallel increase of both invasive and in situ melanoma supports the hypothesis that the former tumor passes through the phase of CMIS before becoming capable of infiltrating surrounding tissues and metastasizing. The small but consistent prevalence of left-sided lesions and male gender in both invasive and in situ melanoma might be seen as addition epidemiologic evidence of the relationship between the two diseases. On the other hand, the higher rate of CMIS in the head and neck region supports the hypothesis that lentigo maligna CMIS (the most frequent type of CMIS in this body area) has a lower tendency to progress to invasive melanoma.
Considering the last decade, the ratio between invasive and in situ melanoma is about 1.5:1 (); assuming that each invasive melanoma passes through the phase of CMIS (although no direct proof of this hypothesis exists), this ratio might imply that approximately 3 out of 5 cases of CMIS might progress to invasive melanoma. Lending support to this hypothesis, the risk of developing invasive melanoma is approximately eight times higher in people diagnosed with CMIS as compared with the general population (). The increased risk of invasive melanoma in patients with a previous diagnosis of CMIS was already known, although in smaller series its extent was probably overestimated: for instance, in a series of 3,766 Swedish patients diagnosed with CMIS from 1958 to 1992, Wassberg and colleagues reported a SIR of 22.2 [31
], which is almost three times higher than that observed in the SEER series. Moreover, the same investigators described a higher risk of cancer in general (SIR: 2.2, 95% CI: 2.0–2.4) and some tumors in particular, such as breast cancer (in females), gastrointestinal cancers, and hematologic malignancies [31
]. In this regard, the SEER data allowed us to confirm the higher risk of some hematologic tumors (), whereas no increased risk of breast carcinoma could be found (SIR: 1.01, 95% CI: 0.91–1.11). Surprisingly, we found that the risk of gastrointestinal tumors is even diminished in patients with CMIS (along with the risk of lung cancer; see ), which highlights the importance of having at disposal large databases to draw reliable conclusions, especially when the event rates are relatively low.
Despite the fact that CMIS is associated with a significantly increased risk of invasive tumors, it is interesting to note that the life expectancy overlaps with that of the general population (5-year relative survival rate = 100%; ). This might be linked (at least in part) by two factors: first, the melanoma-specific mortality rates are quite low (0.3% at 5 years), which suggests that invasive melanomas arising in people with CMIS are mainly represented by thin lesions with a high curability rate; this phenomenon might in turn be related to the enrollment of these patients into screening programs. Second—as mentioned above—persons with CMIS are at lower risk of cancers that are considered “big killers,” such as lung and colorectal carcinomas, an observation never reported before.
CMIS association with higher incidence of invasive melanoma could well be due to the similar genetic background and/or environmental risk factors characterizing the two nosologic entities; in contrast, it appears much more difficult to explain the finding that people with CMIS carry a lower risk of epithelial tumors generally featuring worse prognosis (in terms of mortality rates intended as ratio of disease-specific deaths to incidence) as compared with invasive melanoma. Considering that invasive melanoma shares this epidemiologic feature with CMIS, an intriguing hypothesis might be that the genetic background and/or the environmental risk factors underlying skin melanoma development can oppose the carcinogenesis of some epithelial tumors. Besides representing a scientific challenge, such findings could represent a hint (or a warning) while analyzing and/or comparing molecular profiles of different tumors, as they are (at least in past) conflicting with the theory of common cancer pathways [53
The extent of CMIS-free margins obtained with surgical excision does not appear to have a significant impact on melanoma-specific survival, as suggested by the similar rates of melanoma-related deaths in patients with <1 cm as compared with those with >1 cm excision margins. As a corollary, CMIS is likely best managed simply with a pathologically margin-free excision: wider margin excisions—which continue to represent a significant proportion of the surgical treatments (more than one third; see ) over the past 2 decades—should be discouraged.
Finally, the SEER data allowed us to verify whether the prognosis of invasive melanoma has been changing over the past 30 years independently of the impact of the increasing CMIS incidence. Interestingly, as shown in , the prognosis of patients diagnosed with cutaneous melanoma (invasive + CMIS) has been improving over the past 3 decades (the melanoma-specific survival rate increased from 85.0% to 93.9%); although slightly reduced, this favorable trend—which has been questioned by some investigators [56
]—is maintained also after removing the potentially “diluting” effect of CMIS advocated by some authors [57
]. Our data do not allow discernment on whether this positive finding is due to earlier diagnosis (which is notoriously accompanied by lower risk of melanoma-related death) or ameliorated therapeutic strategies (e.g., adjuvant interferon-alpha, sentinel node biopsy), which is a matter of continuous debate [57
]; however, within the fame of this debate, it appears important to have clarified—by means of such a large series—the separate impact of invasive and in situ melanoma in the epidemiology of the deadliest skin disease.
Taken together, the above analysis of the SEER data can be regarded both as the basis of a practical guideline for the management of CMIS and as a source of some hints regarding melanoma epidemiology and cancer predisposition. In particular, we conclude that CMIS is a condition more and more frequently diagnosed with no significant impact on life expectancy: accordingly, its relevance is mainly linked to the clinical [22
] and pathologic [21
] difficulty in making a differential diagnosis with invasive melanoma. Although their enrollment in screening programs for the early detection of skin melanoma is warranted because of the risk of developing invasive melanoma, patients diagnosed with CMIS should be reassured on the benign nature of their condition that is associated with a normal life expectancy. Finally, the fact that CMIS increasing incidence does not nullify the positive trend regarding the prognosis of invasive melanoma and the fact that an in situ tumor is associated with a lower risk of some invasive cancers deserves further attention and investigation.