In recent decades, the incidence of cutaneous malignant melanoma (CMM) in white people has been increasing steadily (1, 2). Meanwhile, a significant improvement in CMM patients’ 5-year overall survival has also been reported, and related mostly to the increasing prevalence of cancers detected in their earliest, “thinner” stage” (3, 4). Both the rising incidence of CMM (all stages), and changes in the treatment panorama (also including the advent of targeted therapies) prompt the collection of updated information which might re-orient both prevention efforts and diagnostic/therapeutic strategies.

Based on the natural history of CMM, a well-established set of clinicopathological variables has been significantly correlated with the clinical outcome of melanoma patients. Unfortunately, these data are often inconsistently recorded and/or scattered over different digital archives. This situation interferes with efforts to validate prognostic variables in the “real world” of large-scale population-based studies.

As for the stage-specific survival of CMM patients, most information comes from national cancer registries, and the USA American Surveillance, Epidemiology and End Results program (SEER) in particular (5). To the best of our knowledge, few registry-based studies on the stage-specific survival of CMM patients have been conducted in Italy or elsewhere in Europe in the last two decades (6–10).

The present study investigates the five-year melanoma-specific survival (MSS) for all cases of CMM recorded in 2015 in the resident population of a north-eastern Italian region (Veneto). Both demographic and clinical-pathological variables have been considered to measure their impact on patient survival in this cohort of CMM patients.

In 2015, the Veneto Cancer Registry 1,279 incident CMM-patient were registered at. Table 1 shows patients’ demographics (M/F: 1.13; median age: 58 years) and clinical-pathological profiles. Most of the invasive malignancies were diagnosed in the early stage (stage I: 71.8%). The mean follow-up was 1,670 ± 415 days.

Overall, the 5-year OS was 83.8% (95% CI: 81.8, 85.8) and it was higher for females (86.6%; 95% CI: 84.0, 89.4) than for males (81.2%; 95% CI: 78.4, 84.2). Five-year MSS was 92.5% (95% CI: 91.0, 94.0), with no significant survival advantage for females (93.6%; CI: 91.7, 95.6) over males (91.5%; CI: 89.4, 93.7).

Figure 1 shows Kaplan-Meier MSS curves by TNM clinical-pathological staging at initial diagnosis, which had a strong impact on survival; T, N and M values are also reported. The 5-year MSS was 99.4% (95% CI: 98.9-100.0) for stage I, 82.6% (95% CI: 76.6-89.0) for stage II, 69.3% (95% CI: 61.0-78.7) for stage III, and only 23.0% (95% CI: 10.3-51.4) for stage IV.

Figures 2 , 3 show the Kaplan-Meier MSS curves by each of the pathological variables considered at initial diagnosis (histological subtype, growth phase, mitotic index, ulceration, TILs). The 5-year MSS probability was 99.2% for the category 0-2 mitoses (95% CI: 98.6-99.8), and 76.2% (95% CI: 70.9-82.0) for more than 2 mitoses. Melanoma ulceration significantly affected the probability 5-year MSS (97.6%; 95%CI: 96.7-98.6 without ulceration versus 72.5%; 95% CI: 66.2-79.3). As for the tumor’s growth phase, survival was better for cases described as RGP (radial growth phase) at diagnosis than for those described as VGP (vertical growth phase): the 5-year MSS probability was 100.0% (95%CI: 100.0-100.0) for the former, and 91.6% (95%CI: 89.6- 93.8) for the latter. TIL status (presence versus absence) was associated with a small, but significant impact on 5-year MSS probability(94.4%, 95%CI: 92.9-95.9 versus 90.5%, 95%CI: 86.4-94.9, respectively). Finally, the survival analysis by histological subtype at diagnosis showed that nodular melanoma carried the worst 5-year MSS probability, at 70.3% (95%CI: 63.2-78.1). Superficial spreading melanoma had the highest 5-year MSS probability, at 96.9% (95% CI: 95.8-98.1). Intermediate survival probabilities were revealed for lentigo maligna melanoma (92.9%, 95% CI: 83.8-100.0).

Table 2 shows the results of Cox’s regression model for MSS, adjusting for sex, age, histological subtype, ulceration, mitoses, site of tumor, stage at diagnosis and TILs. Compared with patients with a melanoma in stage I, the risk of death was increased for stage II (HR=3.31, 95% CI: 0.94-11.76, p=0.064), it was almost ten times higher for stage III (HR=10.51, 95% CI: 3.16-35.02, p<0.001), and it was more than a hundred times higher for stage IV (HR=117.17, 95% CI: 25.30-542.62, p<0.001). Superficial spreading melanoma carried a more than eleven times greater risk of death than lentigo maligna (HR=12.61, 95% CI: 1.42-112.02, p=0.023), and nodular melanoma a fourteen times higher risk (HR=15.04, 95% CI: 1.69-133.30, p=0.015). Sites of tumor involving the lower limbs, upper limbs and trunk had a better prognosis than those involving the hands and feet, with the difference reaching borderline statistical significance (p=0.058, p=0.083, p=0.066). Among the other variables included the model, the presence of mitoses emerged as an independent risk factor for death (HR=6.85, 95%CI: 2.21-21.28, p<0.001). The sensitivity analysis, excluding stage IV, generated much the same results as the previous model (data not shown). The analysis of overall survival produced similar results too, except that male sex coincided with a significantly worse prognosis (HR=1.75, % CI: 1.18-2.60, p=0.005).

In a population-based cohort of 1,279 incident CMM patients, this study focuses on the prognostic impact of both demographics and clinical-pathological variables, as recorded in a high-resolution Italian cancer registry.

The results obtained prompt two main types of consideration: one refers to the validation of the CMM-associated prognostic variables in a large cohort of consecutive patients; the other relates to the value of population-based trials for the purpose of updating/improving patient management based on a critical analysis of real-world clinical practice.

As regards the first point, the present results support the prognostic impact of (mostly) well-established clinical-pathological variables (6, 14, 15). In particular, the Kaplan-Meier analysis showed that none of the RGP CMMs resulted in a melanoma-specific death within 5 years after the initial diagnosis (16). The present results also provide evidence to show that extra-nodal metastases from RGP CMMs are extremely rare (less than 3%), while almost all extra-nodal metastatic implants result from “vertically-growing” CMMs (17). Consistently with these findings, both the worst MSS rate and the highest risk of CMM-related death were associated with nodular CMMs. Based on the assumption that any greater risk associated with a nodular histology overlaps with the prognostic impact of a melanoma’s thickness and ulceration, the American Joint Committee on Cancer (AJCC)’s staging system does not include the CMM subtype among the “discriminating” prognostic variables (14, 15). A recent analysis of the SEER cohort (18) nonetheless identifies the histological subtype as an independent predictor of survival, even after adjusting for CMM stage, thickness, ulceration, and mitotic index.

Previous studies found that the mitotic rate (more than neoplastic ulceration) is an independent prognostic factors in primary CMMs (irrespective of their thickness) (19–26). The present results associate a number of mitoses with a worse survival, further supporting the inclusion of the mitotic rate in the staging of thin, non-ulcerated CMMs.

A high-resolution cancer registry primarily needs to contain comprehensive, reliable, and accessible clinical information. All these conditions are hard to achieve, and the present study is no exception. In fact, our study suffered from the difficulty of assembling the necessary clinicopathological data, largely because of inconsistencies in the data format and/or their location in different digital repositories. The present study also suffers from a lack of important information on patients’ socio-economic profiles and - even more important - data on the molecular biology profile of the malignancies considered (27). In this respect, the present study further supports the crucial importance of promoting standardized/synoptic formats in the recording of clinicopathological variables, as obtained by the main clinical actors involved in patient management (especially oncologists, radiologists, and clinical and surgical pathologists).

Inconsistencies in the recording of diagnostic procedures and the “scattering” of results in different datasets represent major limits to operative efforts to pursue the high-resolution cancer registration potentially capable of providing both clinicians and healthcare policy-makers with reliable information on the clinical management of CMM patients.

The data analyzed in this study is subject to the following licenses/restrictions: The dataset generated as part of the present study is not publicly available, but available from the corresponding author (alessandra.buja@unipd.it) on reasonable request. Requests to access these datasets should be directed to alessandra.buja@unipd.it.

The studies involving human participants were reviewed and approved by Veneto Oncological Institute Ethics Committee (n 695/20.10.2016). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

ABu and GD conceived the presented idea. MZ, RS, AV, PF, and SM collected the data, verified its accuracy, and developed the methods. CT verified the analyses. ABa, ABu, and RF wrote the draft. MR, VB, GD, and ABu. supervised the project and revised the draft. CR found the financial support for the project. All authors read and approved the final manuscript.

CARIPARO - Fondazione Cassa di Risparmio di Padova e Rovigo.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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