Cutaneous melanoma is now regarded as the fifth most common cancer in the United States. It was estimated that there were approximately 96,480 new cases, and 7,230 deaths due to melanoma of the skin will be newly diagnosed in 2019 (1). Despite being the deadliest form of skin cancer with a high mortality rate, many melanoma patients are cured after surgical excision of their primary tumor at an early stage; however, some still relapse after surgical excision. It is locally invasive and frequently spread out to regional lymph nodes and remote organs, including lung, liver, bone, and brain (2). The most common risk factors for malignant melanoma include family history, multiple moles, ultraviolet radiation, fair skin, and immunosuppression (3, 4). The incidence rate of melanoma has been increasing by between 3% and 7% per year globally for Caucasians (5). The incidence rate (less than 1/100,000) was lower in residents of Asia, including China, India, Singapore, and Japan (6). In Taiwan, the age-adjusted rate in 2006 for aggressive melanoma was 0.65/100,000 (0.71/100,000 for men, and 0.58/100,000 for women). The age distribution plot showed a peak among melanoma patients aged 70–79 years. According to the investigation of the incidence of melanoma from 1997 to 2008 by year and sex, the yearly incidence ranged from 0.66 to 1.24 (mean: 0.9) cases per 100,000 people in Taiwan (7). Excessive exposure to ultraviolet radiation is not the risk factor for most Taiwanese melanoma cases. In addition, 58% of cutaneous melanoma belongs to acral lentiginous melanoma. Advanced disease is found in 50% of cases (8).

Studies on various prognostic factors affecting melanoma survival have been reported frequently. Age has been proven to be a very strong and independent predictor of survival outcome after accounting for all the dominant prognostic factors (9). Sentinel node biopsy is an important prognostic factor in melanoma (10). Lower socioeconomic status (SES) was associated with a decreased median survival time in a statistically significant amount for all stages of melanoma (11). Men have a greater risk of having advanced disease with a poorer outcome (12). Studies have shown that the presence of a melanoma on an axial site conferred a worse prognosis than an extremity site (9). Older age and advanced stage have significant negative effects on the survival of mucosal melanoma (13). The mitotic rate is a continuous prognostic variable. It is a strong independent predictor of outcome and should be assessed and recorded in all primary melanomas including in both initial and excision biopsies (14). Level of invasion has prognostic significance in univariate analysis and remains an independent predictor of outcome in more contemporary analyses. Clinical parameters such as age, sex, skin color, pigmentation status of the tumor, and site of the primary tumor play an important role for the outcome of patients. Ulceration is an adverse prognostic factor of melanoma (15). Stage and anatomic site, but not thickness (i.e., Breslow depth), race, or ethnicity, determine prognosis of mucosal melanomas (16). Stage, male gender, and age are associated with overall survival, along with SES and the presence of multiple comorbidities (17–19). Taken together, various prognostic factors affecting melanoma survival interact mostly synergistically. The prognostic influence of comorbidity and stage on melanoma has also caused many scientists to make many valuable reports. The prevalence of chronic disease in patients with melanoma varies from 19% to 80% (20). The presence of chronic conditions prevents physicians from aggressive treatment for melanoma patients, thereby increasing the mortality rate (20). The prevalence of multiple chronic conditions increased with age (21). The majority of studies from a systematic review reported decreased chemotherapy use (75%) and inferior survival (69%) for patients with comorbidities compared to those without comorbidities (22). Patient comorbidity has a substantial effect on the cancer stage at diagnosis (23). In a cohort study conducted using Danish registry data of 23,476 melanoma patients, Grann et al. (20) reported a higher prevalence of comorbidity associated with more advanced cancer stages. Similar results were acquired by Gonzalez et al. (24) using data from the Florida State Tumor Registry (N = 32,074) in 1994 on colorectal, melanoma, breast, and prostate cancers. Comorbidity was associated with late-stage diagnosis in all four cancers, with the odds of 62% for late-stage melanoma (24). In Taiwan, just a few reports paid attention to malignant melanoma (25–27). Our current study aims at clarifying how comorbidity and stage may affect the prognosis of Taiwan melanoma patients from 2009 to 2017.

In this nationwide registry-based cohort study, we included 476 men and women diagnosed with melanoma. According to tumor stage, 52 (10.9%) in situ, 398 (83.6%) had a localized tumor, 8 (1.7%) had regional metastases, 18 (3.8%) had distant metastases, and 364 (55.5%) suffered from one or more comorbidities ( Table 1 ). Our study unraveled an association between a higher prevalence of comorbidities and a higher risk of death. The more comorbidity, the higher the risk of mortality. Comorbidity commonly is associated with poorer survival. Old age was associated with a significantly increased risk of death. In our study, patients greater than and equal to 70 years of age (HR = 18.64, 95% CI: 10.96–31.72) had a worse risk of death than patients 55–69 years of age ( Table 2 ). There was an association between older age and more advanced tumors at diagnosis, leading to higher mortality among elderly people (34, 35). In Taiwan, malignant melanoma is an uncommon but fatal disease. One possible reason for low survival was that farmers delayed the diagnosis to old age. The comorbidities, or neglecting consciousness of melanoma, adverse effects of their treatment, or disguising the symptoms of the disease by the patient or doctor could be another possibility for late detection in people with comorbid conditions (36).

Gonzalez et al. (24) demonstrated that having comorbidity and cancer (colorectal, melanoma, breast, prostate) has resulted in late diagnosis of cancer. A previous study from Grann et al. (20) showed that comorbidity initiated a higher risk of complications and worse functional status, decreased quality of life, and poorer survival—especially in older patients. Houterman et al. (37) reported that increased levels of severe comorbidity led to less aggressive treatment that negatively influenced the survival of elderly patients aged 60–79 years. Comorbidities could worsen comorbid diseases and lower the functional status of metastatic melanoma patients receiving curative treatment (20). Research from Taiwan reported that a worse prognosis with great differences was mostly found in histologic subtypes, advanced stages, and acral lentiginous melanoma. Melanoma patients had a poorer prognosis when they were diagnosed with more advanced stage (26). Some studies suggested that coexistent disease was associated with worse survival and increased the possibility of being diagnosed with distant metastasis (8, 23, 38–43). Our study revealed the association between comorbidity and stage that may influence the prognosis of melanoma patients in Taiwan. Table 4 showed that for people with comorbidity scores 3 and ≥4, HR of the risk of mortality was relatively higher than scores 1 and 2. The risk of mortality for patients with comorbidity score ≥2 at stages 0, I was a little higher than those with comorbidity score 1. The risk of mortality for patients with comorbidity score ≥2 at stage II was significantly higher than those with comorbidity score 1. Though the risk of mortality for patients with comorbidity score ≥2 at stages III, IV was lower than those with comorbidity score 1, no major differences were found because of too small a patient population.

Comorbidity might reduce survival because curative treatment is used less frequently in older patients. Consequently, survival of patients older than 70 years was not significantly influenced by comorbidity (44). Bradley et al. (45) reported that men with more comorbid conditions were less likely to receive treatment than those without comorbidities. The decision to receive treatment was determined mainly by the patient’s age, disease stage, tumor characteristics, and experience of the urologist (44, 46). Fowler et al. (47) revealed that associations between age and comorbidity were highly significant (p < 0.0001), as the age-adjusted risk of comorbid death was 5.7 times greater in men with severe compared to those without comorbidities. Two previous studies showed that less aggressive treatment for melanoma among patients with comorbidity may affect the mortality rate because of some of the interactions between melanoma and comorbidity. Decreased function of the immune system in older patients with more comorbidities may result in higher mortality because of the interaction between comorbidity and melanoma (48, 49). Koppie et al. (50) also reported that the conditions required for treatment, such as a history of comorbidities, age, performance status, and other related factors, are important for melanoma patients when they plan to receive necessary treatment. Generally, elderly patients with more comorbidities are less likely to receive the most aggressive chemotherapy combinations for avoiding a high risk of significant morbidity (50).

The minority of melanoma patients (44.5%) had none of the selected comorbidities since their melanoma was diagnosed. In the remaining 55.5% of the melanoma cohort with some prevalent comorbidity, the most common comorbid diseases were diabetes without chronic complication, chronic pulmonary disease, peptic ulcer disease, and cerebrovascular ( Table 1 ). Among melanoma and non-melanoma groups, the proportion diagnosed with severe comorbidity increased with an increasing mortality rate, and the level of comorbidity was strongly associated with mortality ( Figure 3 ).

However, the weight of the association differs by specific comorbid disease, patient age, cancer characteristics, and overall comorbidity burden (23, 34, 35). Comorbidity can be measured by counting the number of coexisting illnesses diagnosed in a cancer patient or by using a comorbidity index that integrates the number and severity of the comorbidity (51). Nowadays, the CCI is the most commonly applied index for comorbidities in cancer patients. The CCI score is the sum of weights of a patient’s coexisting conditions based on 19 disease categories. The weights originated from relative risk assessment acquired from a regression model. They are usually assigned from 1 to 6 points and then collapsed into categories of 0 point, 1 to 2 points, 3 to 4 points, and 5 or more points, respectively. The CCI has been previously verified as a prognostic method of comorbidity for some index cancers (31).

A study previously showed that both the survival and treatment of patients were affected by age and the extent of comorbidity. Racial differences in survival were greatest for patients without comorbidities and less pronounced at higher levels of comorbidity. Comorbidity elicited differential impact for prognosis, treatment, and survival (52). However, the outcomes of this study by using the CCI score were similar with many reports in Western countries (24, 39). Comorbidities that influence prognosis seriously may differ between Eastern and Western countries. We expect that future research can focus on which of these comorbidities may most seriously affect the prognosis of melanoma patients.

There is a limitation in this study. From Taiwan’s NHIRD, we selected random samples of 2 million from 23 million beneficiaries. Because melanoma is an unusual illness in Taiwan, the sample size of melanoma patients was relatively small in our research. However, NHIRD is a randomly selected representative sample of Taiwan’s general population. This may avoid sampling deviation or selection bias and provide more nationwide information in this study.

In conclusion, melanoma patients in Taiwan with comorbidity were associated with poorer survival. The level of comorbidity was robustly associated with the mortality rate. The presence of severe comorbidity was associated with an advanced stage of melanoma. The mortality rate was higher among patients with more comorbidities, and the influence of comorbidity varied by stage. Old age was associated with a significantly increased risk of death. A higher risk of mortality was found in patients who had localized tumors, regional metastases, or distant metastases with more comorbidity scores. Our study demonstrated that comorbidity and stage had an impact on the prognosis of Taiwan melanoma patients.

The data in this study we used were from the National Health Insurance Research Database and Taiwan Cancer Registry.

All authors listed have contributed to the work and approved its publication. Contributors: All other authors (YSH, PNC, SCC, JYH, YHW and JCCW) provided their input by contributing to the conceptualization. CKC contributed to the editing of the article.

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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