Malignant Melanoma in Turkey: A Single Institution s Experience on 475 Cases

Malignant Melanoma in Turkey: A Single Institution s Experience on 475 Cases Faruk Tas, Sidika Kurul, Hakan Camlica and Erkan Topuz Institute of Oncology, Istanbul University, Istanbul, Turkey Received June 5, 2006; accepted August 13, 2006; published online October 23, 2006 Background: This study was performed to determine the characteristics and the clinical outcomes of patients with cutaneous melanoma in Turkey. Methods: The medical records of patients between 1991 and 2003 at Institute of Oncology were retrieved from the cancer registry. Results: Of the 475 adult cases with complete staging procedure, the incidence of localized (stages I II) disease was 301 (63.4%), and followed by node involved (stage III) and metastatic (stage IV) disease with the incidence of 117 (24.6%) and 57 (12.0%), respectively. The median age of patients was 50 years (17 104 years) and male/female ratio was 1.1. Of 206 patients (43.4%) the diseases were located on extremities, 150 (31.6%) on the trunk, and 102 (21.5%) on the head and neck region. In cases with early/node negative stage, stage distribution was identical. The superficial spreading type was the commonest histology (52.2%). The Breslow thickness distributed equally, whereas tumor invasion aggregated mainly at Clark level III and IV. Half of the lesions were ulcerated and with low mitotic potential. In cases with the node involved stage, the majority of patients had only one lymph node involved. In metastatic patients, two thirds had distant metastases including lung metastases and half of them had single metastatic region. With the median follow-up of all patients of 5.2 years, the median overall survival of all patients was 62.2 months and the 5-year overall survival was 50.5%. Overall survival was significantly negatively correlated with male (P, 0.001), advanced stages (P, 0.001) and old ages (P ¼ 0.005). The five-year survival rates of patients with stages I II and III disease were 63.6% and 36.6%, respectively. Nodular histology subtype, deeper Breslow tumor depth, extensive invasion, presence of ulceration, advanced stage, presence of relapse, being male and elderly patient, presence of visceral recurrence, and high mitotic activity were found to be associated with poor prognosis for overall survival in localized disease. The median survival of metastatic patients was 9.9 months and 1-year overall survival rate was 32.7%. Unresponsiveness to chemotherapy, visceral metastasis, multiple metastases and not given chemotherapy were the poor prognostic factors for overall survival. Conclusion: The descriptive and prognostic factors in Turkey are similar to those in Western countries. Key words: melanoma prognostic factor Turkey Jpn J Clin Oncol 2006;36(12)794 799 doi:10.1093/jjco/hyl114 INTRODUCTION Recently, melanoma has become a major health problem in many countries. The incidence rate of melanoma is increasing worldwide much more rapidly than any other human malignancies. The life time risk of melanoma is 1:70 in For reprints and all correspondence: Faruk Tas, Istanbul Universitesi, Onkoloji Enstitusu, Capa 34390, Istanbul, Turkey. E-mail: faruktas2002@ yahoo.com the population of the USA and will probably be 1:50 in 2010 (1). Like any other malignancies, melanoma has the potential of metastasizing through lymph nodes to visceral organs. Survival of patients with melanoma is strongly associated with tumor stage at presentation. Therefore, the 5-year survival rates are 68 93% in stages I II, 45 49% in stage III, and 11 18% in stage IV disease (2 4). The strongest prognostic factors are the tumor thickness and ulceration in stages I II, number of lymph node # 2006 Foundation for Promotion of Cancer Research

Jpn J Clin Oncol 2006;36(12) 795 metastases in stage III and anatomic site of metastases in stage IV (3,4). Other crucial prognostic factors are the anatomic localization of lesion, age, gender and racial status. Additional negative prognostic factors include lesions located on the head and neck, and trunk, patient age more than 60 years, male gender and being nonwhite. Also, various histopathologic features including nodular and acral lentiginous subtypes, vertical growth phase, high mitotic activity and presence of microscopic satellites are associated with unfavorable prognosis. No report has been published in Pubmed literature that has examined the features of the Turkish melanoma patients. In order to understand the clinicopathological characteristics of malignant melanoma in Turkey, we studied a large series of cases collected between 1991 and 2003. PATIENTS AND METHODS The records of the cases of adult, cutaneous malignant melanoma which have been pathologically proven at the Institute of Oncology, Istanbul University between January 1991 and December 2003 were retrieved from the cancer registry for review of the clinicopathological features and outcome. Staging was determined according to the American Joint Committee on Cancer (AJCC) staging system. In situ melanoma patients were not included in the study. Overall survival was analyzed by the Kaplan Meier method. Overall survival time was calculated from the onset of primary melanoma diagnosis to the date of the last follow-up at which patients were still alive or to the date of death. Univariate analysis of the association between the prognostic factors and survival was performed using log rank. Values of P, 0.05 were considered to be significant. RESULTS DISTRIBUTION Four hundred and seventy-five adult cases of cutaneous malignant melanoma were recorded in the cancer registry. All of the patients were Caucasians. All characteristics concerning patients and the disease are shown in Table 1 on a stage basis. Of the 475 cases with complete staging procedure, the incidence of localized (stages I II) disease was 301 (63.4%), followed by node involved (stage III) and metastatic (stage IV) disease with the incidence of 117 (24.6%) and 57 (12.0%), respectively. The age of the 475 patients ranged from 17 to 104 years (median: 50 years). The male to female ratio was 1.1. The diseases were located on extremities (38 acral) in 206 (43.4%) patients, on the trunk in 150 (31.6%) and on the head and neck in 102 (21.5%). In 301 cases with early, node negative stage, stage distribution was equal. The superficial spreading was the Table 1. Patient and disease characteristics Patient group Parameter n % All patients No. of patients 475 100.0 Age (median, range) 50 (17 104) 249 233 49.1 50þ 242 50.9 Gender Male 248 52.2 Female 227 47.8 Localization Head neck 102 21.5 Trunk 150 31.6 Extremity 206 43.4 Primary unknown 13 2.7 Multiple 4 0.8 Stage I II 301 63.4 Stage IA 39 13.0 IB 40 13.3 IIA 45 15.0 IIB 41 13.6 IIC 36 12.0 Undetermined 100 33.1 Histology Superficial spreading 131 52.2 Nodular 69 27.5 Acral lentiginous 31 12.4 Lentigo maligna 15 6.0 Others and undifferentiated 5 2.0 Breslow thickness (mm),1 49 20.7 1 2 65 27.4 2 4 67 28.3.4 56 23.6 Clark invasion I 20 7.6 II 19 7.3 III 80 30.5 IV 116 44.3 V 27 10.3 Ulceration Yes 98 47.6 No 108 52.4 Mitosis 0 2 105 52.8 3 9 72 36.2 Continued

796 Melanoma in Turkey: analysis of 475 cases Table 1. Continued Patient group Parameter n %.10 22 11.1 Tumor infiltrating lymphocyte Absent 73 33.0 Present 148 67.0 Regression No 133 78.2 Yes 37 21.8 Interferon treatment (for stage IIb c) No 41 53.2 Yes 36 46.8 Relapse No 233 77.4 Yes 68 22.6 Site of recurrence Non-visceral 46 61.3 Visceral 29 38.7 Stage III 117 24.6 Nodal status N1 69 59.0 N2 26 22.2 N3 22 18.8 Application of sentinel node dissection Yes 33 45.8 No 39 54.2 Interferon treatment No 51 43.6 Yes 66 56.4 Relapse in patients treated with Interferon No 48 72.7 Yes 18 27.3 Stage IV 57 12.0 M1 stage M1a b 20 35.1 M1c 37 64.9 Number of metastases Single 31 54.4 Multiple 26 45.6 Application of chemotherapy Yes 40 70.2 No 17 29.8 Response to chemotherapy Yes 12 36.4 No 21 63.6 commonest histology (52.2%). The Breslow thickness of cases presented on equal distribution, whereas tumor invasion aggregated mainly at Clark level III and IV. Half of the lesions were ulcerated and with low mitotic potential. The majority of lesions were infiltrated by tumor lymphocytes and not regressed. The intermediate dose of adjuvant interferon treatment with either IFN alpha 2a, 9 MU or IFN alpha 2b, 10 MU per day, subcutaneously, for 1 year consisted of an induction period (5 days/week for 4 weeks) followed by 48 weeks of the same dose administered three times per week was given to nearly half of the patients with stages IIB and C. During follow-up of the patients, relapses occurred in 68 (22.6%) patients and most of them were non-visceral (61.3%). In 117 patients with node involvement, for the majority (59%), this was only in one lymph node. Sentinel lymph node biopsy was performed in almost half of the patients with clinically node negative lymph node to determine lymph node status (45.8%). The intermediate dose interferon treatment was preformed in 66 (56.4%) patients as adjuvant therapy. In patients (n ¼ 57) with metastatic lesions at presentation, two thirds were with distant metastases including lung metastases. Nearly half of them had single metastasis (54%). Chemotherapy consisting of various single and combination protocols was performed in majority of the patients, including good performance status and patients without brain metastasis (71%). Response to chemotherapy was determined in one-third of the patients (36%). SURVIVAL AND PROGNOSTIC FACTORS OVERALL STAGES The median follow-up of all patients was 62.2 months (range: 0 241.8 months). The median overall survival of all patients was 62.2 months (range: 0 241.8 months). A 5-year overall survival was 50.5 + 3.4% (Fig. 1). There were 146 (30.7%) deaths as a result of disease progression. Overall survival was significantly negatively correlated with male patients (P, 0.001), advanced stages (stages III IV) (P, 0.001) and elderly patients (P ¼ 0.005) (Table 2), but the site of disease did not effect survival (P ¼ 0.57). EARLY STAGES The median overall survival of 301 (63.4%) patients was 117.2 months (range: 0 241.8 months). The 5-year overall survival was 63.6 + 4.1% (Figs 2 and 3). There were 66 (21.9%) deaths resulting from disease progression. The nodular histology (P, 0.001), deeper tumor depth (P, 0.001), extensive invasion (P, 0.001), presence of ulceration (P, 0.001), advanced stage (P, 0.001), presence of relapse (P, 0.001), male patients (P ¼ 0.013), being advanced age (P ¼ 0.027), visceral recurrence (P ¼ 0.030) and high mitotic activity (P ¼ 0.038) were found to be poor prognostic factors for overall survival. However, regression status, treatment with interferon, tumor

Jpn J Clin Oncol 2006;36(12) 797 Table 2. Prognostic factors for overall survival in melanoma patients Stage status Prognostic factor Poor prognosis P value Figure 1. Overall survival of 475 patients with malignant melanoma. infiltrating lymphocytes and localization of tumor were not effective on survival (Table 2). NODE POSITIVE, STAGE III STAGES The median overall survival of 117 (24.6%) patients was 46.7 months (range: 0.6 25.6 months). The 5-year overall survival was 36.6 + 7.2% (Figs 2 and 4). There were 40 (34.2%) deaths resulting from disease progression. Overall survival was significantly negatively correlated with recurrence after interferon use (P, 0.001) and male gender (P ¼ 0.012). In contrast, the parameters such as, age of the patient, the use of adjuvant interferon, status (number) of involved lymph nodes and the site of primary tumor were not found to be significant predictors of prognosis on survival (Table 2). ADVANCED, METASTATIC STAGES The median overall survival of 57 (12.0%) patients was 9.9 months (range: 0 25.6 months). The 1-year overall survival was 32.7 + 7.0% (Figs 2 and 4). There were 40 (70.2%) deaths as a result of disease progression. The responses to chemotherapy (P ¼ 0.008), visceral metastasis (P ¼ 0.056), multiple metastases (P ¼ 0.057) and treatment with chemotherapy (P ¼ 0.059) were found to be prognostic factors for overall survival. However, age and gender of the patients and site of the primary tumor did not effect survival (Table 2). Early stage (Stage I II) Node (þ) stage (Stage III) Metastatic stage (Stage IV) Overall stages (Stage I IV) Histology Nodular,0.001 Breslow thickness.2mm,0.001 Clark level IV V,0.001 Ulceration Present,0.001 Stage IIB C,0.001 Relapse Present,0.001 Gender Male 0.013 Age.50 yrs 0.027 Site of recurrence Visceral 0.030 Mitosis.10/mm 2 0.038 Regression 0.059 Interferon therapy 0.410 Tumor infiltrating 0.450 lymphocyte Localization 0.520 Relapse after IFN use Present, 0.001 Gender Male 0.012 Age 0.29 Adjuvant IFN therapy 0.36 N status 0.67 Localization 0.71 Response to Yes 0.008 chemotherapy Stage M1c 0.056 Number of metastases Multiple 0.057 Chemotherapy usage Yes 0.059 Age 0.54 Localization 0.61 Gender 0.85 Stage Advanced (stage,0.001 III IV) Gender Male,0.001 Age.50 yrs 0.005 Localization 0.57 DISCUSSION In order to understand the clinicopathological characteristics of malignant melanoma in Turkey, we studied a large series of cases collected over 13 years. The results of the current analyses showed that histology, tumor thickness, level of invasion, ulceration, stage of the disease, recurrence, gender of the patients and mitotic rate in patients with localized

798 Melanoma in Turkey: analysis of 475 cases Figure 2. Survival estimates according to the stage of disease. Figure 3. Overall survivals of the early-stage (I II) melanoma patients. melanomas (stages I II) whereas gender of patients and relapse after interferon treatment in lymph node positive (stage III) patients were the most powerful predictors of overall survival. In metastatic patients (stage IV) these predictors were found to be stage, number of metastases, response to chemotherapy and chemotherapy usage. Considering the whole melanoma patient group (stages I IV), stage, gender and age of patients were the main predictors of overall survival. With the median follow-up of all patients of 5.2 years, the median overall survival of all patients was 62.2 months and 5-year overall survival was 50.5%. Five-year survival rates of patients with stages I II and III disease were 63.6 and 36.6%, respectively. The median survival of metastatic patients was 9.9 months and 1-year overall survival was 32.7%. These survival rates of our patients seem to be slightly worse compared to other Western originated studies. We supposed that these under normal results are explained by the presence of our slightly more advanced-stage diseases and have poorer prognostic factors in compared with other studies. The clinical and pathologic factors predicting the outcome of melanoma patients have been studied for several decades. After many analyses of prognostic factors from both single institutions and multi-institutional experience (5 9), the largest conducted study was published in 2001 (3). The evidencebased results were incorporated into the new and most up-to-date AJCC melanoma staging. In this trial, the AJCC Melanoma Database consisted of a total of 30 450 melanoma patients, of whom 17 600 patients (58%) had information available for all of the factors required for the proposed Tumor Node Metastasis (TNM) classification and stage grouping were used. Of the 17 600 patients included in this analysis, 12 837 (73%) had at least 5 years of follow-up information. Figure 4. Overall survivals of the advanced-stage (III IV) melanoma patients. In multivariate analysis of 13 581 patients with localized melanoma, the two most powerful independent characteristics of the melanoma among all the prognostic variables analyzed were tumor thickness and ulceration. Other statistically significant prognostic factors were patient age, localization of the primary melanoma, level of invasion and gender (3). The tumor thickness was the single most powerful prognostic factor in patients with localized melanoma

Jpn J Clin Oncol 2006;36(12) 799 (3 5,7,10). The invasion level does not reflect prognosis as accurately as tumor thickness, nevertheless, it does provide additional prognostic value in thin melanomas (3,4,11,12). Ulceration was identified as one of the most important features of melanoma (3 5,9,10,13,14). According to Balch et al. (3), the interpretation of melanoma ulceration is one of the most reproducible of all the major histopathologic features. The age of patient, especially those over 60 years of age, was demonstrated to be an independent prognostic factor possibly because of declining host defense mechanisms associated with advancing age (3,9,10,15). Data were available for 1201 patients with lymph node metastases, a multivariate analysis demonstrated that the number of metastatic nodes, the tumor burden at the time of staging and absence of ulceration of the primary melanoma were most significant (3). Overall, 49% of all patients with nodal metastases survived 5 years. The overall 5-year survival rate of our patients with node positive of 36.6% is poor and possibly does not reflect the number of involved node distribution because of similar ranges (rate of N1 in all stage III patients was 57 and 59% for Balch s and our patients, respectively). The number of metastatic nodes was the most significant prognostic variable of stage III patients (3,16 18). These findings are not consistent with data of our study. For stage IV, the survival rates were measured in months because only a minority of patients live beyond 1 year. The prognostic influence of different distant metastatic sites were analyzed in 1158 patients using various combinations of sites of metastases (3). With 1-year survival rates ranging from 41 to 59% when used to delineate the M categories into three groups such as M1a, M1b, and M1c, the only significant prognostic variable identified in this analysis was the site of distant metastasis, which was consistent with other studies (3,19 22). 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