Genetically Enriched Melanoma: Predictive Value of Clinicopathological Characteristics in a Single-Center Cohort

1. Introduction

Cutaneous melanoma represents the most aggressive form of skin cancer, with a rising incidence globally despite notable advances in prevention and early diagnosis [1]. Despite the fact that ultraviolet (UV) radiation is established as the main risk factor, melanoma development is considered as the result of complex interactions between environmental exposures and genetic susceptibility [2,3,4]. While most melanomas arise sporadically, approximately a 7%–15% of them occur in individuals with clinical features suggestive of genetic predisposition [5,6,7]. Early identification of these patients is important, as they may benefit from genetic counseling, germline testing, tailored surveillance programs, and individualized management [8,9].

Over the past two decades, our knowledge on melanoma genetics has broadened our understanding of hereditary melanoma. Germline pathogenic variants in high- and intermediate-penetrance genes, including CDKN2A, CDK4, BAP1, MITF, POT1, and TERT, have been associated with an increased risk of melanoma development [5,10,11,12]. Patients with melanoma harboring these germline variants, usually present at a younger age, develop multiple primary melanomas, and report a positive family history of melanoma. However, currently recognized susceptibility genes account for only a proportion of melanoma cases with positive personal or family history, suggestive of genetic susceptibility. Indeed, hereditary melanoma, linked to high penetrance susceptibility genes, accounts for 2% of melanoma cases, while familial melanoma defined as melanoma diagnosis in two first-degree relatives or three or more relatives of any degree from the same side of the family with a melanoma diagnosis, accounts for 5% - 12% of melanoma cases [7]. This observation indicates that additional genetic variations, biological–environment interactions, and yet unidentified factors contribute to melanoma predisposition [13,14,15,16].

Several clinical characteristics have been associated with an increased likelihood of inherited genetic susceptibility to melanoma, most notably early-onset melanoma, familial melanoma, and multiple primary melanomas. To our knowledge, these patient groups have predominantly been investigated as distinct clinical entities [5,17,18,19,20,21]. Despite their phenotypic heterogeneity, they share a common biological and clinical rationale: each identifies patients with a substantially higher probability of harboring inherited genetic susceptibility than unselected melanoma populations. Although not all individuals meeting these clinical criteria carry identifiable pathogenic germline variants, they remain enriched for genetic predisposition and therefore constitute a clinically relevant population for genetic investigation. Current international guidelines for genetic counseling rely largely on combinations of clinical characteristics rather than on molecular testing alone [22,23,24]. However, little is known about clinicopathological characteristics and prognosis of patients belonging to these groups compared with patients with sporadic melanoma. Most published studies have focused on certain hereditary melanoma syndromes, specific germline gene mutations, or limited high-risk populations, providing only a fragmented understanding of the broader phenotype associated with increased genetic susceptibility [10,18,25,26,27]. A broader evaluation of this population may improve patient selection for genetic assessment and contribute to more personalized surveillance and management strategies.

In the present study, we use the pragmatic term of genetically enriched (GE) melanoma, defined as melanoma occurring in patients presenting with at least one of the following characteristics: early-onset melanoma, familial melanoma, or multiple primary melanomas. We highlight that this concept does not represent a distinct biological subtype but rather describes a clinically defined cohort consisting of subjects with an increased probability of inherited genetic susceptibility. By combining these overlapping high-risk clinical phenotypes into a single study population, we aimed to investigate whether they represent a subgroup with unique phenotypic and prognostic characteristics.

Therefore, we aimed to compare patients with sporadic melanoma and GE melanoma from a demographic, clinicopathological, and prognostic perspective. Specifically, we evaluated differences in tumor features, recurrence patterns, and survival outcomes between the two cohorts. We aimed to investigate whether patients fulfilling established clinical criteria suggestive of genetically predisposed melanoma represent a distinct subgroup characterized by unique clinicopathological features and different disease behavior compared with sporadic melanoma, reflecting the contribution of inherited genetic susceptibility to melanoma development and progression.

2. Materials and Methods

Patients with histologically confirmed primary cutaneous melanoma diagnosed and followed at ‘Andreas Sygros’ Hospital Melanoma Center between January 1980 and December 2024 were eligible for inclusion. Individuals with incomplete information regarding age at diagnosis, family history, or number of primary melanomas were excluded. Subjects were divided into two distinct cohorts as follows —GE melanomas (Cohort A) and sporadic melanomas (Cohort B). Patients were included in the GE cohort if they fulfilled at least one of the following criteria: a. Early onset (EO) melanoma, defined as first melanoma diagnosis at < 40 years; b. familial melanoma (FM), defined as melanoma in patients with at least one first-degree relative diagnosed with melanoma, or with at least two relatives of any degree from the same side of the family diagnosed with melanoma; or c. Multiple primary melanoma (MPM) defined as diagnosis of two or more primary melanomas in the same patient, either synchronous or metachronous [7,28,29]. Patients fulfilling more than one criterion remained classified within the GE cohort; therefore, the EO, FM, and MPM categories were not mutually exclusive. Cases with none of the aforementioned criteria were categorized as sporadic.

Demographic and histopathological data, including age, sex, history of malignancy, Breslow thickness, ulceration, histological subtype, and lymph node involvement was retrospectively collected from patients’ records. Lymph node involvement was defined as the presence of regional lymph node metastasis, either detected clinically (palpable and/or radiologically suspicious lymph nodes) or confirmed pathologically following sentinel lymph node biopsy or lymph node dissection. Subjects were routinely followed according to institutional protocols, including regular clinical examination and imaging when clinically indicated. Disease recurrence was defined as the first documented local, regional, or distant melanoma recurrence occurring after primary melanoma diagnosis. Disease-free survival (DFS) was calculated from the date of primary melanoma diagnosis to the date of first recurrence.

Variables with missing values were analyzed using available case analysis. The number of patients included in each analysis is reported where appropriate.

Continuous variables were summarized as median and interquartile range (IQR), whereas categorical variables were presented as frequencies and percentages. Comparisons between Cohort A and Cohort B were performed using the chi-square test or Fisher’s exact test, as appropriate, for categorical variables, with odds ratios (ORs) and corresponding 95% confidence intervals (CIs) calculated where applicable. Continuous variables were compared using the Mann–Whitney U test. Comparisons of age at diagnosis among the four melanoma subgroups (EO, FM, MPM and sporadic melanoma) were performed using the Kruskal–Wallis test, followed by Dunn’s post hoc test with Holm correction for multiple comparisons. To determine whether the association between melanoma cohort and previous malignancy was independent of age, a multivariable binary logistic regression model was constructed, including cohorts and age at melanoma diagnosis as independent variables. Adjusted odds ratios (aORs) with 95% confidence intervals (CIs) were calculated. Disease-free survival (DFS) was estimated using the Kaplan–Meier method and compared using the log-rank test. Univariate Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for variables associated with recurrence. Statistical significance was defined as a two-sided p-value < 0.05. Statistical analyses were performed using R version 4.5.1.

The study was approved by the Institutional Ethics Committee of ‘Andreas Sygros’ University Hospital. Owing to the retrospective nature of the study, the requirement for informed consent was waived.

3. Results

A total of 1,874 patients with cutaneous melanoma were included in the study. Of these, 796 (42.5%) fulfilled at least one criterion for GE melanoma and were assigned to Cohort A, whereas 1,078 (57.5%) were classified as sporadic melanoma (Cohort B). Within the GE cohort, 506 patients (27.0%) had EO melanoma, 184 (9.8%) had FM, and 106 (5.7%) had MPM.

The clinicopathological characteristics of the study cohorts are summarized in Table 1. Age at diagnosis differed significantly across the four melanoma subgroups (Kruskal–Wallis test, p < 0.001). Median age at diagnosis was 35 years (IQR, 31–38) in patients with EO melanoma, 47.5 years (IQR, 38–60.25) in those with FM, 54.5 years (IQR, 43–62) in patients with MPM, and 57 years (IQR, 50–66) in patients with sporadic melanoma (Table 2a). Patients with GE melanoma were diagnosed at a significantly younger age than those with sporadic melanoma (median age, 37 years [IQR 32–43] vs 57 years [IQR 50–66], Mann–Whitney U test, p < 0.001). Post hoc Dunn analyses with Holm correction showed significant differences in age at diagnosis across all pairwise subgroup comparisons (Table 2b). Female patients were more frequently represented in Cohort A than in Cohort B (56.8% vs. 51.4%, p = 0.024).

A history of previous malignancy was reported in 56/774 (7.2%) patients in Cohort A compared with 144/1,057 (13.6%) patients in Cohort B. This difference was statistically significant in the unadjusted analysis (χ² = 18.6, p < 0.001), with GE status associated with lower odds of a previous malignancy (OR, 0.49; 95% CI, 0.36–0.68). However, after adjustment for age using multivariable logistic regression, cohort status was no longer associated with previous malignancy (adjusted OR 0.93, 95% CI 0.64–1.34; p = 0.687). In contrast, increasing age remained an independent predictor of previous malignancy (adjusted OR 1.039 per year, 95% CI 1.027–1.051; p < 0.001). The distribution of previous malignancies according to primary tumor site is presented in Table 3.

Among patients with available data, superficial spreading melanoma was the predominant histological subtype in both cohorts, accounting for 63.6% and 64.4% of Cohort A and Cohort B respectively. However, the distribution of histological subtype differed significantly between the two cohorts (p<0.001). Compared with GE melanomas, sporadic melanomas demonstrated a higher proportion of acral lentiginous melanoma (3.5% vs. 1.1%) and lentigo maligna melanoma (5.2% vs. 1.4%). Melanoma in situ was more frequently observed in the GE cohort (20.2% vs. 15.2%). The majority of tumors in both cohorts had a Breslow thickness <1 mm (52.5% and 51.8%, respectively). Median Breslow thickness was 0.90 mm (IQR, 0.55–1.98) in the GE melanoma cohort and 0.96 mm (IQR, 0.53–1.81) in the sporadic melanoma cohort. There was no statistically significant difference between the two cohorts (Mann–Whitney U test, p = 0.826). Ulceration was present in 143/584 (24.5%) patients in the GE cohort and 214/860 (24.9%) patients in the sporadic cohort, with no significant difference (χ² = 0.03, p = 0.864; OR, 1.02; 95% CI, 0.80–1.30). Similarly, lymph node involvement was observed in 94/796 (11.8%) patients in the GE cohort and 120/1,078 (11.1%) patients in the sporadic cohort, with no significant difference (χ² = 0.20, p = 0.65; OR, 1.07; 95% CI, 0.80–1.42).

Follow-up information was available for 1,680 patients, including 706 (88.7%) in the GE cohort and 974 (90.4%) in the sporadic cohort. The median follow-up duration was 8 years (0.5 – 41).

During follow-up, melanoma recurrence occurred in 183 patients, including 77 (10.9%) in the GE cohort and 106 (10.9%) in the sporadic cohort. The median disease-free survival (DFS) was not reached in either cohort during the study period. Kaplan–Meier analysis demonstrated no statistically significant difference in DFS between patients in the two cohorts (log-rank p=0.23) (Figure 1).

The estimated 5-year DFS rate was 90.0% (95% CI, 87.5–92.5) in the GE cohort and 94.5% (95% CI, 93.0–95.9) in the sporadic cohort. Likewise, the 10-year and 15-year DFS rates were comparable between the two groups (Table 4).

Univariate Cox regression analyses were performed separately for each study cohort (Table 5 and Table 6).

Within the GE cohort, both age and sex were significantly associated with DFS. Increasing age was associated with a higher risk of melanoma recurrence, with each additional year of age increasing recurrence risk by approximately 2% (p=0.003, HR 1.02, 95% CI, 1.01–1.04). Male patients had approximately two-fold higher risk of recurrence compared with female patients (p=0.003, HR 2.01, 95% CI, 1.27–3.16) (Table 5, Figure 2).

Similarly, in the sporadic melanoma cohort, increasing age was significantly associated with recurrence risk, with each additional year increasing the risk of recurrence by approximately 3% (p=0.004, HR 1.03, 95% CI, 1.01–1.05) (Table 6). No other evaluated variables demonstrated a statistically significant association with disease-free survival in the univariate analyses.

4. Discussion

The present study adopts the pragmatic concept of GE melanoma, a clinically defined population comprising patients with EO melanoma, FM, or MPM [5,30,31]. Rather than representing a distinct biological subtype, this cohort encompasses patients with an increased likelihood of genetic susceptibility based on clinical criteria, traditionally used for referral to genetic counseling. By evaluating this broader high-risk population as a single entity, our study provides more comprehensive insights of the clinicopathological characteristics and prognosis associated with suspected hereditary melanoma in routine clinical practice.

The main finding of our study is that, despite clear demographic and clinicopathological differences, GE melanoma was not associated with inferior DFS compared with sporadic melanoma. Although patients in the GE cohort were diagnosed at a substantially younger age, recurrence rates and long-term DFS were comparable between the two groups. These findings suggest that clinical features associated with inherited melanoma susceptibility primarily influence melanoma development rather than subsequent tumor aggressiveness and disease progression.

Our findings are broadly consistent with previous observations indicating that hereditary melanoma often presents earlier in life and is characterized by the occurrence of multiple primary tumors rather than an intrinsically more aggressive biological behavior [27,28,32,33]. Germline pathogenic variants in melanoma susceptibility genes, particularly CDKN2A, have been consistently associated with increased melanoma risk; however, evidence regarding their impact on survival has remained inconsistent. Several studies have suggested no significant differences in melanoma-specific survival between carriers and non-carriers after adjustment for established prognostic factors, whereas others have reported conflicting results [34,35,36,37]. Importantly, our study extends prognostic observations beyond genetically confirmed carriers by examining a clinically defined population enriched for genetic predisposition, thereby reflecting real-world clinical decision-making.

An interesting finding of our study was the clear gradient in age at melanoma diagnosis across the four clinical subgroups. Patients with EO melanoma were diagnosed at a markedly younger age than all other groups, which was anticipated. Patients with FM were diagnosed significantly earlier than those with MPM and sporadic melanoma. Furthermore, individuals with MPM were also diagnosed at a younger age than patients with sporadic melanomas. These findings support a biological rationale underlying the concept of GE melanoma, as each of its subgroups demonstrates an earlier age of onset than sporadic melanoma to a different extent. The observed age gradient likely reflects varying contributions of inherited genetic susceptibility, environmental exposure, and cumulative lifetime risk. The remarkably young age of patients with EO melanoma may indicate an underlying genetic susceptibility, even in the absence of a positive family history or multiple primary tumors. Collectively, these results suggest that age at diagnosis is not a simple demographic characteristic but may serve as a clinical marker for identifying patients who may benefit from genetic counseling and intensified surveillance.

An additional noteworthy finding was the higher proportion of female patients within the GE cohort. Similar sex differences have occasionally been reported in some genetically predisposed melanoma cohorts [38,39], although the underlying mechanisms remain uncertain. Increased healthcare utilization, greater participation in skin cancer surveillance programs or differences in sun-exposure behavior may all contribute to this observation [38,40]. Likewise, the higher proportion of melanoma in situ and the lower frequency of acral lentiginous and lentigo maligna melanoma likely reflect differences in melanoma pathogenesis and surveillance practices. Individuals with familial risk or previous melanoma diagnoses frequently undergo intensive dermatological follow-up, facilitating earlier detection of thinner and in situ lesions before progression to invasive disease [32,41].

Interestingly, patients in the GE cohort had a significantly lower prevalence of previous malignancies compared with those with sporadic melanoma. This difference could be explained, at least in part, by the substantially younger age of the GE population, which provides less cumulative time for the development of additional primary cancers. In fact, this association was no longer observed after adjustment for age. This finding indicates that the lower prevalence of previous malignancies among GE patients is largely attributable to their substantially younger age at melanoma diagnosis rather than to GE melanoma status itself. Given that cancer incidence increases with age, this result is biologically plausible and highlights the importance of accounting for age as a major confounder when comparing cancer histories between melanoma populations. These findings further emphasize that crude differences between cohorts should be interpreted cautiously and reinforce the value of multivariable analyses in characterizing the clinical phenotype of GE melanoma. The distribution of sites of previous malignancies, as shown in Table 3, are in line with literature [42].

The most clinically relevant finding is the absence of a worse oncological outcome among GE patients despite their increased inherited susceptibility. This observation supports the concept that inherited predisposition primarily increases the probability of developing melanoma rather than conferring an aggressive tumor phenotype [20,43]. Consequently, the rationale for intensified surveillance in these patients may lie principally in facilitating earlier diagnosis of subsequent primary melanomas rather than anticipating more aggressive disease behavior following melanoma diagnosis.

Within the genetically enriched cohort, increasing age and male sex emerged as significant predictors of disease recurrence, findings that mirror those observed in the general melanoma population [44]. Male sex has consistently been associated with poorer melanoma outcomes across numerous studies, potentially reflecting biological differences, delayed diagnosis, or behavioral factors [45,46]. Similarly, increasing age remained independently associated with recurrence risk, reinforcing the notion that conventional prognostic determinants continue to influence outcomes even among patients with increased inherited susceptibility [47,48].

The present study possesses several important strengths. It represents one of the largest single-center analyses evaluating patients selected according to clinical criteria suggestive of genetic predisposition. Especially, in the context of global disparities in genetic testing availability. Furthermore, by combining EO melanoma, FM, and MPM into a unified clinically defined cohort, our study more closely reflects the way patients are currently identified for genetic counseling in everyday practice. The long follow-up period further enhances the robustness of survival analyses.

Several limitations should also be acknowledged. First, the retrospective single-center design introduces the possibility of selection and information bias. Second, GE melanoma represents a clinically defined rather than molecularly confirmed population. Although this approach reflects current clinical practice, some patients classified as GE may not harbor identifiable pathogenic germline variants. In contrast, a proportion of patients categorized as sporadic may possess unrecognized hereditary susceptibility. AJCC stage was not included in the analysis because the study covered a period during which several revisions of the AJCC staging system were implemented, potentially introducing stage migration and limiting the comparability of staging data across the cohort. Instead, individual pathological characteristics were analyzed.

5. Conclusions

In conclusion, our findings suggest that patients fulfilling established clinical criteria suggestive of genetically predisposed melanoma constitute a distinct demographic and clinicopathological subgroup with no inferior DFS compared with patients with sporadic melanoma. The concept of GE melanoma provides a pragmatic clinical foundation for investigating inherited melanoma susceptibility beyond molecularly confirmed hereditary syndromes and may provide a practical framework for identifying patients who could benefit from genetic counseling, intensified surveillance, and future translational research.