|Ahead of print publication
Cutaneous melanoma survival rates of the elderly are not worse than those of the young, yet they have some specific differences
Ferhat Ferhatoglu1, Kayhan Erturk2, Tas Faruk1
1 Department of Medical Oncology, Istanbul University Institute of Oncology, Istanbul, Turkey
2 Department of Medical Oncology, Koc University, Istanbul, Turkey
|Date of Submission||20-May-2021|
|Date of Acceptance||09-Jul-2021|
|Date of Web Publication||14-Jan-2022|
Department of Medical Oncology, İstanbul University Institute of Oncology, Millet Street, 34093 Capa-Fatih-Istanbul
Source of Support: None, Conflict of Interest: None
Introduction: The incidence of cutaneous melanoma among the elderly has increased significantly. Unfavorable survival rates are associated with insufficient patient managements and poor prognostic features in the elderly. We aimed to compare elderly (≥75 years) and younger (<75 years) patients with cutaneous melanoma to determine the differences and the prognostic significance of age.
Materials and Methods: The retrospective data of 117 elderly and 232 younger patients with cutaneous melanoma were compared.
Results: The median age of the elderly patients was 78 years (75–104), and 51.3% of the patients were female. Of the patients, 14.5% were in the metastatic stages. Clinicopathologic factors such as extremity melanomas (P = 0.01), Clark levels IV–V (P = 0.04), ulceration (P = 0.009), and neurotropism (P = 0.03) were significantly more common in elderly patients. However, BRAF mutation was significantly more common in younger patients (P = 0.003). Overall survival (OS) and recurrence-free survival (RFS) rates of both the groups were similar. Lymph node involvement (P < 0.005), distant metastasis (P < 0.005), and relapse of disease (P = 0.02) were associated with poor OS in elderly patients. Tumor-infiltrating lymphocytes was associated with prolonged RFS (P = 0.05), while extremity melanomas (P = 0.01), lymphovascular invasion (P = 0.006), and lymph node involvement (P < 0.005) had negative impact on RFS.
Conclusions: Although elderly patients with cutaneous melanoma had different clinicopathologic features in our series, their survival rates are similar to those of younger patients, which shows that age alone is inadequate to determine the prognosis. Disease stage and a comprehensive geriatric assessment might assist to determine appropriate management.
Keywords: Elderly, melanoma, prognosis, prognostic factor, survival
|How to cite this URL:|
Ferhatoglu F, Erturk K, Faruk T. Cutaneous melanoma survival rates of the elderly are not worse than those of the young, yet they have some specific differences. J Can Res Ther [Epub ahead of print] [cited 2022 Dec 4]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=335491
| > Introduction|| |
Aging is a physiological process involving all organs and systems. Adaptation to environmental stressors gradually decreases with aging. With many accompanying comorbidities, elderly patients constitute a special population that needs more care in terms of treatment.
According to the World Health Organization, ≥65 years and ≥ 80 years are defined as elderly and oldest-old, respectively. The United States National Institute of Aging subdivided elderly patients into three groups: “young-old” (65–74 years), “older-old” (75–84 years), and “oldest-old” (≥85 years). National Comprehensive Cancer Network states that ≥65 years is generally accepted as a chronological limit for elderly patients, but the definition based on functional capacity is more appropriate. Due to different chronological definitions in the literature, it is difficult to determine certain categorical values to define the elderly.
Cutaneous melanoma is the fifth (7%) and the sixth (4%) most common types of cancer in men and women, respectively, in the US. The incidence of the disease has been increasing significantly in recent years. According to the SEER data, the median age at diagnosis is 65 years, and the annual incidence had increased approximately 60% in people ≥65 years between 2000 and 2017. Significant increase rates in cutaneous melanoma in patients ≥65 years are also observed in other developed and developing countries. These data prove that cutaneous melanoma will be seen more and more in the future in elderly patients. Furthermore, in a study investigating the economic burden of elderly cancer patients, it was observed that the cost of melanoma patients was quite high, especially in case of distant metastasis, the cost increased eight times compared to the early stage. Therefore, it is becoming increasingly important to investigate the clinicopathological features and treatment approaches of cutaneous melanoma in the elderly population.
Cutaneous melanomas in head-and-neck regions are more common in the elderly,, so are some of the pathologic subtypes, such as nodular melanomas, lentigo malign melanomas, and acral lentiginous melanomas,,, and some of the prognostic indicators, such as deeper Breslow thickness and ulceration.,, In addition to these, the elderly are diagnosed at more advanced stages. In retrospective cohort studies, elderly patients have been shown to have lower melanoma-specific survival than younger patients., So what could be the etiological factors that make up these different patterns?
First, as the cumulative effect of ultraviolet (UV) light manifests itself, especially in the head-and-neck region with advancing age, the frequency of cutaneous melanoma might be higher in these regions. Likewise, the association between lentigo maligna melanoma, which is more common in the elderly, and UV exposure is more pronounced than other histological types. ,, Second, attention deficit and visual defects that develop with aging make it difficult to detect skin changes and cause delays in diagnosis. Third, it has been reported that both surgical approaches and systemic treatments applied to elderly patients are more limited compared to younger ones.,,
It should be noted that most of these studies were conducted in northern Europe, North America, and Australia. However, as the angle of sunlight and climatic conditions vary at every latitude, the effect of UV exposure also varies. Another important risk factor for the development of cutaneous melanoma is racial differences, including skin color, hair, and eye color.
In our study, we aimed to compare the demographic and clinicopathological characteristics and survivals of the elderly cutaneous melanoma patients with the younger patients.
| > Materials And Methods|| |
The medical records of 117 cutaneous melanoma patients, aged ≥75 years and followed up at the Institute of Oncology Istanbul University – a tertiary referral center – from January 1993 to January 2021, were evaluated retrospectively. For comparison, 232 cutaneous melanoma patients aged <75 years and selected randomly from 1466 patients were included in the analysis as a control group. We defined the patients ≥75 years as “elderly” and the patients <75 years as “younger.” Demographic informations including age and gender, clinicopathologic features, and survival outcomes were retrieved from the medical records of the patients. Clinical staging was done according to the 8th edition of the American Joint Committee on Cancer melanoma staging system. Lymph node status was determined by either sentinel lymph node biopsy (SLNB) or lymph node dissection. Patients with confirmed pathologically positive sentinel lymph nodes underwent complete lymph node dissection. The study was reviewed and approved by the regional ethical committee.
IBM SPSS Statistics for Windows, Version 21.0 (SPSS Inc, Chicago, Ill), was used for statistical analysis. For descriptive statistics, categorical variables were represented as numbers and percentages. Proportions in younger and older groups were analyzed using the Chi-square test. Overall survival (OS) and recurrent free survival (RFS) were primarily targeted in the survival analysis. OS was described to be the time interval from the date of diagnosis of the disease to the date of death. RFS was considered to be the time interval from the completion of primary therapy to the time of the first relapse. Survival rates were calculated using the Kaplan–Meier analysis. To evaluate risk factors, univariate Cox regression analysis was used. The statistical significance was accepted as P ≤ 0.05.
| > Results|| |
Demographic and clinicopathologic features
The median age was 78 years (range: 75–104) in the elderly patients. The female-to-male ratio was 51.3% versus 48.7%. In elderly patients, extremity melanomas (54.0%) were more common than in other localizations. At the time of diagnosis, 57.3% of the elderly patients were in early stages (stage I-II) and 14.5% were in metastatic stages. Some other prognostic factors such as Clark level IV-V (83.9%), Breslow depth ≥ 2 mm (72.4%), ulceration (71.6%), vertical growth phase (93.0%), and BRAF wild-type (86.4%) were found to be more common in elderly patients.
Compared to younger patients, the ratio of extremity lesions (54.0% vs. 40.2%, P = 0.01) and the Clark levels IV–V (83.9% vs. 72.8%, P = 0.04) were significantly higher in elderly patients. In addition, elderly patients were associated more frequently with ulcerated lesions (71.6% vs. 54.1%, P = 0.009). While neurotropism was less common among younger patients (3.5% vs. 11.9%, P = 0.03), BRAF mutation was less common in the elderly patients (13.6% vs. 49.2%, P = 0.003). The comparative demographic and clinicopathological characteristics of both groups are listed in [Table 1].
|Table 1: Demographic and clinicopathological characteristics of the patients|
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Survival and risk factors
The median OS of the elderly patients was 22.0 months. In addition, 5-year OS and 5-year RFS were 49.6% and 61.7%, respectively. There was no statistically significant difference between the two groups regarding OS (P = 0.6) and RFS (P = 0.2) [Table 2]. The comparative OS and RFS curves of both the groups are shown in [Figure 1] and [Figure 2], respectively.
|Figure 1: Recurrence free survival curves of both elderly and younger patients (0.6)|
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|Figure 2: Overall survival curves of both elderly and younger patients (0.2)|
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Univariate Cox regression analyses of possible clinicopathological parameters in elderly melanoma patients showed that lymph node involvement (hazard rate (HR) = 3.30, 95% confidence interval [CI]: 1.78–6.13, P < 0.005), distant metastasis (HR = 6.39, 95% CI: 3.07–13.30, P < 0.005), and relapse of disease (HR = 2.30, 95% CI: 1.14–4.66, P = 0.02) were unfavorable on OS. In addition, extremity melanoma (HR = 2.53, 95% CI: 1.17–5.46, P = 0.01), lymphovascular invasion (LVI) (HR = 4.05, 95% CI: 1.49–10.96, P = 0.006), and lymph node involvement (HR = 4.30, 95% CI: 2.04–9.04, P < 0.005) have negative impact on RFS. Tumor-infiltrating lymphocytes (TIL) might also be accepted as a significant predictor on RFS (HR = 0.37, 95% CI: 0.14–1.00, P = 0.052) [Table 3].
| > Discussion|| |
We compared clinicopathologic features of 117 elderly cutaneous melanoma patients (≥75 years) with 232 younger melanoma patients to detect unique characteristics of the disease regarding advanced age.
Similar to our results, a study conducted in Brazil showed that the ratio of females in melanoma patients above 60 years of age was slightly higher (52.5%). However, the SEER database and other studies concluded that the number of males was higher in elderly patients.,,, This might be so because, in developed countries, women use sunscreen more frequently and consult a doctor more often for suspicious skin lesions. Contrary to current literature, the rates of metastatic stage were insignificant between elderly and younger patients in our results (14.5% vs. 12.9%, respectively; P = 0.6). In addition, the frequency of nodular melanoma, which is associated with advanced stage and mortality, was not significant between the two groups (P = 0.7).,, These differences might be attributed to different study designs and both regional and sociocultural factors.
In elderly patients, extremity melanomas were more common (54.0% vs. 40.2%, P = 0.01). A possible explanation might be that the damage caused by the cumulative effect of UV is more pronounced on the extremities. The head-and-neck region is another susceptible area exposed to UV, and it has been shown that the prevalence of melanoma in this region increases with age.,, With the increase of the elderly population following years, the frequency of cutaneous melanomas on body areas exposed to intense sun exposure is expected to increase as well.
In our cohort, the prognostic factors such as Clark level (III-IV) (P = 0.04), ulceration (P = 0.009), and neurotropism (P = 0.03) were significantly higher among elderly patients compared to younger patients. A study conducted by Rees et al. showed that in the oldest-old (≥85 years) cutaneous melanoma patients' group, most of the patients had ulcerated lesions with high mitotic activity and deep Breslow thickness. Higher rates of poor prognostic factors in elders were also observed in other studies.,, Gordon et al. showed that cumulative UV exposure in poor-visible areas of the body (scalp, retroauricular area, back, posterior upper arms and thighs, buttocks, pubic area) has poorer survival than well-visible areas (face, chest, abdomen, anterior upper arms and thighs, lower arms and legs, dorsum of hands and feet, palms). Such an anatomical classification might be more helpful in determining the prognostic features of elderly patients. In addition, elderly patients' accesses to health services are worse than young patients, and they less likely to participate in skin screening programs. And finally, comorbidities that increase with aging and difficulties in recognizing skin changes might contribute to poor prognostic features in elderly patients.
About 60% of cutaneous melanomas have oncogenic mutation in BRAF gene (V600E), an important therapeutic target., Besides, 80% of benign melanocytic nevi also have oncogenic BRAF mutation. Bauer et al. showed in patients from Europe, North America, and Australia that BRAF mutation was more common in patients under <60 years of age and less frequent in head-and-neck melanomas. Similarly, melanoma patients with a precursor lesion are less likely to be older. In accordance with the current literature, we found that the rates of precursor nevus (25.5%) and BRAF mutation (13.6%) were lower in elderly patients. Hence, it can be hypothetically argued that as age increases, chronic sun exposure and presence of a precursor lesion have an inverse relationship with BRAF mutation. The conclusion that the incidence of BRAF-mutant melanoma is higher on the trunk of people exposed to intermittent sunlight also supports this view. In addition, owing to various immune system deteriorations, immune escape mechanisms might help explain the carcinogenesis of de novo and BRAF-wild melanomas in elderly patients.
Axial melanomas, LVI, and nodal involvement increased the risk of recurrence; however, TIL was found to have a favorable effect on RFS. The detrimental factors on OS were lymph node involvement, metastasis, and recurrence of disease. There was no survival disadvantage in elderly patients compared to younger patients. In a study evaluating 399 early-stage melanoma patients, who underwent SLNB, the patients were divided into two groups at the age of 50 as a cutoff. There were no differences in metastasis rates between the two groups, but OS was better in the younger ones. The authors associated the difference in survival with more males in the elderly group. There are other studies demonstrating that advanced age is one of the most important factors that negatively affect survival., However, recent studies proved that the treatments applied at each stage in elderly patients were more limited than in younger patients., Hence, our study showed that the prognostic value of advanced age alone might be misleading. We believe that comprehensive geriatric assessment, life expectancy, and consideration of the disease stage in elderly patients might contribute more to more accurate treatment.
Due to the retrospective nature of our study, some medical information on the patients was absent. In addition, due to the changing treatment protocols over time, there might be differences in treatments applied to the patients. And since we are a tertiary reference center, the rate of advanced-stage patients is higher. These limitations make it difficult to interpret the results of our study. To eliminate the conflicting literature results, more comprehensive studies should be supported.
| > Conclusions|| |
Certain poor prognostic features are more common in elderly cutaneous melanoma patients. In our study, extremity melanomas, high Clark level, ulceration, and neurotropism were more common in patients ≥ 75 years of age; however, the BRAF mutation rate was significantly lower in elderly patients. The most important factors affecting survival in elderly patients were lymph node involvement, metastasis, and relapse of disease. There was no difference in RFS and OS between the two groups. Our results show that age alone is inadequate at determining the prognosis. When evaluating elderly patients, disease stage and comprehensive geriatric assessment will assist in decision-making for an appropriate treatment.
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]