On-line version ISSN 1806-4841
An. Bras. Dermatol. vol.84 no.4 Rio de Janeiro July/Aug. 2009
CLINICAL, EPIDEMIOLOGICAL, LABORATORY AND THERAPEUTIC INVESTIGATION
Rúbia BattistiI; Daniel Holthausen NunesII; Ariana Lebsa WeberIII; Louise Cardoso SchweitzerIV; Isadora SgrottV
of the sixth year of the undergraduate course of medicine of Universidade Federal
de Santa Catarina (UFSC) Santa Catarina (SC), Brazil IIMaster
and professor of the Department of Medical Clinic, subject of Dermatology of
Universidade Federal de Santa Catarina (UFSC). Preceptor of Medical Residency
in Dermatology of UFSC. Professor of Dermatology and Clinical Alergy of Universidade
do Sul de Santa Catarina (Unisul) Santa Catarina (SC), Brazil
IIIResident Physician of Infectology of Hospital Nereu Ramos Santa Catarina (SC), Brazil
IVStudent of the sixth year of the undergraduate course of medicine of Universidade Federal de Santa Catarina (UFSC) Santa Catarina (SC), Brazil
VStudent of the sixth year of the undergraduate course of medicine of Universidade Federal de Santa Catarina (UFSC) Santa Catarina (SC), Brazil
Melanoma is the cutaneous cancer which has the greatest lethality. Santa Catarina
is the Brazilian State that contributes the most to increase this rate.
OBJECTIVES: To estimate the mortality rate of melanoma in the fifth year of illness.
METHODS: The sample comprises 81 reports of primary cutaneous melanoma, in 75 patients, diagnosed in lorianopolis SC in 2002 and 2003. The protocol of research includes age, sex, patient's color, anatomical location, histological type, degree of invasion, Breslow index, inflammatory reaction, ulceration, regression, angiolymphatic invasion and tumor staging. The patients were contacted by telephone to verify their status (alive, killed by melanoma or dead for another reason). Fisher's exact test and Kaplan-Meier's survival curve were used for the statistical analysis.
RESULTS: The patients' profile was: female, white, 51.3 years of age, with invasive melanoma on the trunk and limbs, extensive spreading type, Breslow 2.63 mm. The mortality rate was 7.0%, greater among men (11.1%), Breslow above 4.0 mm (66.0%), with ulceration (33.3%) and stage IV (80.0%). The average survival period was 56.7 months. Conclusions: The mortality rate of primary cutaneous melanoma was 7.0%; ulceration and the final staging were the factors with statistic significance on the result.
Keywords: Melanoma; Mortality rate; Survival analysis
On recent decades, melanoma has become an issue of great interest, due to the significant increase in its incidence and its high lethality. Although it only accounts for 4% to 5% of skin cancer cases, melanoma causes most of the deaths due to cutaneous malignancy, because of its high potential of sending metastases to distant organs.1
In Brazil, there is little information on melanoma, both at country and regional levels. According to data the from National Cancer Institute-INCA. 1 In the year of 2008, 2,950 new cases of melanoma are expected in men, and 2,970 in women. The highest rates are in the south region, with its population formed mainly by Caucasians exposed to solar radiation many months a year, because of the weather conditions and leisure options. This can be one of the reasons for the high prevalence of melanoma in the Brazilian south.
Considering this scenario, this study has chosen as its research problem to analyze the epidemiological characteristics and to estimate mortality, up to the fifth year of disease, in patients with the diagnosis of primary cutaneous melanoma in the city of Florianópolis, Santa Catarina, Brazil; and to evaluate the survival of these patients. This study finds justification in the absence of follow-up data on melanoma patients from Santa Catarina, although this State accounts for a significant share of all national cases.
SAMPLE AND METHODS
This study selected patients with diagnosis of primary cutaneous melanoma histopathologically confirmed by the anatomical pathology laboratories of the University Hospital Polydoro Ernani de São Thiago (HU-UFSC) and Anatomical Pathology Diagnosis Institute (IDAP), both located in the city of Florianópolis-SC, from January 1st 2002 to December 31st 2003.
Patients whose primary tumor site was the skin were included regardless of sex, age, race, origin, or occupation. Patients with diagnosis of ocular or mucosal melanoma, recurrence of a tumor whose primary lesion was before 2002 and the patients who could not be found during the research were excluded.
A protocol including an ordered series of open or multiple choice questions was prepared for data collection with the following variables: age, sex, color, status of the patient (alive, dead due to melanoma or dead due to another cause) and anatomical site, histological type, degree of invasion, Breslow thickness, inflammatory infiltrate, ulceration, regression, angio-lymphatic invasion, and tumor staging.
Data were obtained from the review of the records of patients in the organizations where they received care. Additional information was collected from patients themselves or from a legal representative, through a phone call, in which we explained that the patient had the freedom to take part in the study and absolute data secrecy was assured. Patients received a Free and Informed Consent Form by mail.
Statistical analyses were performed with the software Stata, version 9.0. To test the association between results, exact Fisher's test was used, considering the statistical significance level of 5%. To evaluate patient survival Kaplan-Meier curve was used.
This study was submitted to and approved by the Ethics Committee of Universidade Federal de Santa Catarina, according to protocol number 327/07.
Reports of 133 patients with malignant melanoma were selected, totaling 126 people. Of those, 52 reports were excluded: 19 because they presented metastatic melanoma, 1 because of recurrence of a tumor whose first diagnosis had been before 2002, 3 because they presented mucosal melanoma, and 29 because the patient could not be found. The final sample had 81 reports of primary cutaneous melanoma, which corresponded to 75 patients.
Of those 75 patients, 42 (56%) were women and 33 (44%) men.
The age of patients, at the time of diagnosis, ranged from 17 to 83 years, with the average of 51.3. Among women, ages ranged from 17 to 83 years (average 50.42); among men, the variation was from 27 to 82 years (average 52.55).
Fifty-two patients had white skin; 23 patients did not remember their skin color.
The site of tumor varied among six anatomical regions: face (21 reports; 25.9%), neck (4 reports; 4.9%), torso (26 reports; 32. 1%), upper limb (15 reports; 18.5%), lower limb (14 reports; 17.3%), and buttocks (1 report; 1.2%). Among men, there was a higher prevalence of melanoma on the torso (21.0%) and face (12.3%); for women, there was a predominance in upper and lower limbs (25.9%) also followed by face (13.7%) (Table 1).
Of the 81 reports analyzed, 38 cases of in situ melanoma (46.9%) and 43 of invasive melanoma were diagnosed (53.1%).
Of the 43 cases of invasive melanoma, the superficial extensive histological subtype was the most prevalent, with 23 representatives (53.5%), followed by nodular, 15 cases (34.9%), lentigo maligna melanoma, 3 cases (7.0%), and acral lentiginous, 2 representatives (4.6%).
As to the thickness of invasive tumors measured according to Breslow's, this index was not presented in only 2 reports of invasive melanoma. Thickness ranged from 0.13 mm to 40.0 mm, with the average of 2.63 mm and median of 1.25 mm. Sixteen reports (37.0%) presented thickness smaller or equal to 1.00 mm; in 17 (39.0%) thickness was between 1.01 mm and 2.00 mm; 5 tumors (12.0%) were between 2.01 mm and 4.00 mm; and 3 (7.0%) had thickness above 4.00 mm (Table 2).
The presence of ulceration was described in 12 of the 81 reports (14.8%). In 5 reports (6.2%), there was presence of regression in lesion. Angio-lymphatic invasion was present in just one case(1.2%); in 59 tumors (72.8%) inflammatory infiltrate was found (Table 3).
Of the 43 reports with invasive tumors, 26 showed the presence of mitosis. Of those, 11 reports presented 5 or more mitosis through high power appearance (HPA) (Table 4).
As to tumor staging, there were 38 lesions at stage 0 (in situ melanoma, 46.9%), 24 lesions I A or B (29.6%), 13 tumors II A or B or C (16.0%), and 6 tumors at stage III A or B or C, or stage IV (7.4%). (Table 3).
As to mortality, 65 patients (86.0%) were alive in the fifth year after diagnosis and 10 of them (14.0%) had died in that period. Of those, the causa mortis of 5 patients (7.0%) had not been triggered by melanoma; in the other 5 patients (7.0%) the cause of death was directly related to the presence of tumor. These 5 patients corresponded to 6 reports, because in 1 patient who died due to melanoma, 2 lesions were detectedone in situ and another invasive. For the purpose of mortality analysis, the invasive tumor was considered for the patient with the two lesions.
Mortality due to melanoma among men was 11.1% and among women was 4.4%.
All 5 patients who died due to melanoma were part of the group of patients whose tumors presented inflammatory infiltrate; there were no deaths due to this cause among patients without inflammatory infiltrate (p: 0. 182). With regard to ulceration, 4 of the 5 patients who died due to melanoma presented ulcerated tumors; only one patient who died due to this cause did not present this factor (p: 0.004). Regression was present in the report of only 1 patient who died due to melanoma (p: 0.326). Also, just one patient whose report demonstrated angio-lymphatic invasion died due to melanoma; other 4 patients without invasion at the time of histopathology died from this cause (p: 0.074). (Table 3).
Among the patients with invasive tumors who died from melanoma, there was one patient did not present mitosis (5.9%), and 4 patients had mitosis, 2 of them had at least five mitosis/HPA (13.3%) and the other 2 had 5 or more mitosis/HPA (18.2%) (Table 4).
Mortality due to melanoma in patients with invasive lesions, according to Breslow thickness, was 1 patient (6.3%) in the group of lesions with thickness smaller or equal to 1.00 mm, 2 patients (12.0%) in the group from 1.01 mm to 2.00 mm and 2 (66.6%) among those with Breslow superior to 4.00 mm (Table 5).
When mortality is evaluated according to staging, it is possible to note that 1 patient (10.0%) in stage IB and 4 (80.0%) in stage IV died due to melanoma (p: 0.001). It should be noted that one patient from that last group also presented a second tumor, in stage 0 (in situ) (Table 3).
As to survival and considering the follow-up time of patients with primary cutaneous melanoma from the date of histopatological report to the contact with patients, average survival was 56.74 months. Chart 1 shows this.
The present study comprises a sample of 81 histopathological reports of cutaneous melanoma, corresponding to 75 patients. In this set of cases, there was predominance of lesions in women, which agrees with the national literature.2-4
The average age was 51.30 years, confirming literature data, which shows that young adults are the most susceptible to melanoma.4-6 Although these results are classically known, we do not yet know for sure the reason for which melanoma shows an increase trend of diagnosis rates among middle aged people, as a higher occurrence would be expected at older ages, as a result of the cumulative effect of solar radiation and deterioration of the immune system.7 We found a higher average age at diagnosis among men, 52.55 years, in contrast with 50.42 years for women; however, this difference is not statistically significant (p: 0.157).
All patients asked about their skin color were white, in agreement with the literature.8
In these cases, the highest percentage of patients with melanoma had as the primary site of lesion the torso, followed by face and limbs. Among women, there was predominance of melanoma on the limbs and face. In men, the most often affected sites were the torso and face (Table 1). These data corroborate current publications, in which melanomas originate more often in the upper and lower limbs in women and, with in the torso, head and neck more often in men.9,10. The differences in the way of dressing and lifestyles are factors that determine the differences in the topography of lesions depending on the sex.11
As to the histological classification of tumors, more than half of the cases were superficial extensive melanoma (53.3%), followed by nodular melanoma (34.9%), lentigo maligna melanoma (7.0%), and acral lentiginous melanoma (4.6%). The National Cancer Data Base Report, in a revision of 84.836 cases, presented similar data.12 Some studies mention nodular melanoma as the most prevalent.13
With relation to the degree of invasion, most of the tumors presented invasion beyond the basal layer, 53.1%, in contrast with 46. 9% cases of in situ melanoma. Sortino-Rachou et al.15 and Fernandes et al.3 found a smaller proportion of in situ tumors, only 2.8% and 21.5%, respectively. These data, disagreeing with the literature, may be a result of the unique features of each sample, but they suggest that physicians in the city of Florianópolis are highly suspicious of the diagnosis of melanoma, confirming it at early stages.
In 1970, Breslow16 described a system to measure the vertical thickness of tumors in millimeters, which permitted appropriate reproducibility among pathologists and which presented a perfect correlation with survival. Balch et al.17 collected data from 17.600 patients and confirmed that the measure of tumor thickness is the strongest predictor of the prognosis of patients with melanoma, because it is associated to an increasing risk of local recurrence, regional and distant metastases. Prognosis is worse as thickness increases as a continuous logarithmic function. Patients of this sample were divided in 4 groups, according to Breslow thickness (Table 2). Of the 43 patients with invasive melanoma, 41 had this measure in their reports. Of those, 76.0% presented thin melanomas at diagnosis (37.0% smaller or equal to 1.00 mm and 39.0% between 1.01 mm and 2.00 mm) and only 7.0% had tumors above 4.00 mm. Breslow average was 2.63 mm with a median of 1.25 mm. Gon et al.9 and Criado et al.10 found percentages of lesions with thickness smaller than 0.76 mm similar to this study (25.0% and 28.4% respectively) and the national average.
The proportion of deaths resulting from cutaneous melanoma in approximately five years was 7.0%, with a mortality incidence of 0.014 deaths due to melanoma per year. Among men, 11.1% died due to the tumor, in contrast with only 4.4% deaths due to melanoma among women. Several current studies present an increasing trend in mortality due to melanoma especially because of this index among men.18-20 Other publications, in contrast, presented data on the stabilization of mortality due to melanoma, and even a reduction when only the group of women is analyzed.21 This trend is possibly a result of greater concern with skin beauty and health among women and usually coincides with skin cancer prevention educational campaigns directed to the general public.
The infiltration of lymphocytes around melanoma cells is related to a better prognosis.22 This sample demonstrated, however, that all patients who died from melanoma presented inflammatory infiltrate on the lesion (Table 3), but this data was not statistically significant (p: 0.182). Ulceration, on the other hand, is a characteristic that is associated to greater aggressiveness. 22,23 In these cases, one third of the patients (33.3%) with ulcerations died due to melanoma, a number statistically greater than the proportion of deaths among patients without this manifestation (p: 0.004; Table 3). These rates corroborate the data from the literature. Of the patients with regression, only one died due to melanoma and among those without regression, there were 4 deaths due to the tumor (p: 0.326). Only one patient who presented angio-lymphatic invasion in his report died due to melanoma, and, although this attribute is considered a factor for poor prognosis, this association was not statistically significant (p: 0.074).
Mortality due to melanoma was equivalent among patients with less than five mitosis/HPA and those with five or more mitosis/HPA 2 cases in each group (Table 4). The percentage in the group of patients with high rates of mitosis, however, was slightly higher, confirming current studies, which consider a high number of mitosis a factor of poorer prognosis in patients with melanoma.
Mortality increased along with Breslow thickness. Although in absolute numbers, the deaths among patients with tumors of up to 2.00 mm was greater than the deaths in patients with lesions larger than 4.00 mm (three and two, respectively), the proportion of deaths per number of representatives of each group was superior in the latter, demonstrating its greater aggressivenes(Table 5)s. Garber et al.24 and Balch et al.17 report that the risk of dying due to melanoma increases linearly with tumor thickness, until is reaches a plateau, at approximately 6.0 to 8.0 mm.
All patients were staged according to the final version of AJCC.25 Only one patient with melanoma in stage 0 died due to the tumor; however, this patient presented a second lesion, with thickness of 40.0 mm, presence of ulceration and in stage IV, which, undoubtedly, was responsible for the death. Another patient with initial staging (IB) died due to melanoma (10.0%). The other four deaths (80.0%) occurred in patients with stage IV tumors (Table 3). The statistical analysis was significant when comparing mortality due to melanoma among different stages (p: 0.001), showing greater severity among patients with advanced lesions. Balch et al 25 demonstrated that mortality due to melanoma in five years varied from 4.7% to 11.0% for lesions IA and IB until 81.2 to 90.5% in metastatic tumors (IV).
With regard to survival, its frequency after five years of disease was 86.0%, with an average of 56.74 months, values close to those found in international publications.4.15.26 Among women, survival was 88.9%, exceeding that of men, 83.3%. Patients were assessed from the date of the histopathological report until the moment when they left the study, either due to death or at the time of contact with the researcher, considered the last accurate date when the participant was alive. The little mortality of this set of cases made the Kaplan-Meier curve stay at a high level (Chart 1). It is possible to see that a proportion close to 0.93 of the patients survived until the fifth year after diagnosis. The relationships between specific variables of the tumor and patient evolution would be very convenient for plotting survival curves; however, the small size of the sample would limit the statistical accuracy of results, and, therefore, they are not presented here.
Prevention is the most effective measure to reduce melanoma incidence rates, mortality due to this cancer, and to increase disease-free survival. Primary prevention involves avoiding exposure to the sun at times of greater irradiation of ultraviolet rays, encouraging the use of physical measures for sun protection, like hats and parasols, and also the use of sun screen lotions. Secondary prevention involves the population and healthcare workers after the early diagnosis of malignant skin lesions.
Sun exposure is a cultural habit in Brazil and is associated to several recreational activities. Protection against the harmful effects of the sun still is undervalued, a marking characteristic in Santa Catarina27, which makes it, along with Rio Grande do Sul, the Brazilian states with the highest prevalence of melanoma.1
It is necessary to make efforts with physicians, decision makers in the healthcare system and educational policy makers so that prevention to skin cancer becomes part of the routine of the population, starting still in childhood, thus reducing the cumulative exposure to the sun and is consequences.
Mortality due to primary cutaneous melanoma in patients diagnosed in the city of Florianópolis in the fifth year of disease was 7.0%. Mortality due to melanoma was higher among men, in patients with tumors with thickness greater than 4.00 mm (66.6%), with presence of ulceration (33.3%, p: 0.004) and in patients with stage IV tumors (80.0%, p: 0.001).
Average survival among patients with diagnosis of primary cutaneous melanoma in the city of Florianópolis was 56.74 months.
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Tel./Fax: 48 3263-1028 e 48 9907-7927
Conflict of interest:
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How to cite this article: Battisti R, Nunes DN, Lebsa-Weber A, Schweitzer LC, Sgrott I. Avaliação do perfil epidemiológico e da mortalidade dos pacientes com diagnóstico de melanoma cutâneo primário no município de Florianópolis, Santa Catarina, Brasil. An Bras Dermatol. 2009;84(4)