Katsuhiro Yamada, Natsuko Noguti, Masaaki Tsuda, Hazime Nagato, Naoko Hasunuma, Yoshihiro Umebayashi and Motomu Manabe

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1 Akita J Med 36 : 45-52, Katsuhiro Yamada, Natsuko Noguti, Masaaki Tsuda, Hazime Nagato, Naoko Hasunuma, Yoshihiro Umebayashi and Motomu Manabe (Received 22 December 2008, Accepted 15 January 2009) Department of Dermatology and Plastic Surgery, Akita University School of Medicine, Akita, Japan Abstract A statistical investigation was conducted of melanoma patients who had been registered by Department of Dermatology and Plastic Surgery, Akita University School of Medicine, Akita, Japan. The subjects were 154 patients with malignant melanoma encountered at Akita University during the 35 - year period from 1973 to The data analyzed included sex, age, location, tumor thickness, tumor ulceration, Clark s subtype, UICC staging and chemotherapy. The survival rate was assessed by the Kaplan - Meier method, and the significance of differences was determined with the log - rank test. The number of patients with malignant melanoma was compared every 5 years from 1973 to 2007, and the number tended to increase. Factors associated with decreased survival rate included male, location in BANS region, increased tumor thickness, presence of ulcer, advanced stage at diagnosis and absence of chemotherapy. Key words : malignant melanoma, statistics, survival rate Introduction In Japan, malignant melanoma is relatively rare. Its incidence, however, is rising, as in many other countries of the world 1-5). The annual incidence rate for 1973 through 1977 was reported to be 0.2 to 0.4 per 100,000 individuals and had increased to 0.3 to 0.6 per 100,000 for 1978 through ). Melanoma carries a poor prognosis and resistance to most types of chemotherapy. Only a few English papers have reported statistical survey of Japanese melanoma so far 6,7). Sex, age, stage and subtype of melanoma had been reported to be important prognostic factors in a study of United States 1-3). A epidemiological Correspondence : Katsuhiro Yamada Department of Dermatology and Plastic Surgery, Akita University School of Medicine, Hondo, Akita, , Japan Tel : Fax : E - mail : katu@med.akita - u.ac.jp study in Japan showed that sex, stage, subtype, level of invasion and tumor thickness were related to prognosis 6,7). In this study, various factors in prognosis including sex, age, location, tumor thickness, tumor ulceration, Clark s subtype, UICC 8) staging and adjuvant chemotherapy were statistically analyzed in 154 patients registered at the Department of Dermatology and Plastic Surgery, Akita University School of Medicine, Akita, Japan. Patients and Methods Patients The subjects were 154 patients with malignant melanoma encountered at Akita University during the 35 - year period from 1973 to There were 74 male and 80 female patients. The patient age ranged from 23 to 88 years, with a mean age of 61.0 ± 1.23 years, and the patients in their 70s accounted for the highest ratio (28.6%) 45

2 46 statistical study of malignant melanoma Table 2. Number of melanoma patients by Clark s subtype. Clark s subtype Cases (%) ALM NM SSM LMM Unknown 33 Fig. 1. Number of melanoma patients stratified by sex and age of diagnosis. Table 1. Anatomical distribution of melanoma. Development site Cases (%) Scalp, face, neck Trunk Upper limbs Hand, finger Finger : subungual 12 8 Lower limbs Foot and toe dorsum Toe : subungual 6 4 Foot : Sole Mucosa 6 4 Unknown 4 ALM : acral lentiginous melanoma, NM : nodular melanoma, SSM : superficial spreading melanoma, LMM : lentigo maligna melanoma. Percentages exclude patients with unknown Clark s subtype. Table 3. Number of melanoma patients by disease stage. Disease stage Cases (%) IA IB IIA IIB IIC IIIA IIIB IIIC IV Unclear 6 Percentages exclude patients with unknown disease stage. (Fig. 1). The most frequent location of the tumor was sole in 39 cases (26%), followed by the scalp - face - neck in 19 (12.7%), trunk in 17 (11.3%), and hand - finger in 16 (10.7%) (Table 1). Eleven cases were included in BANS (upper back, posterolateral upper arm, posterior - lateral neck, posterior scalp) area. The primary tumor were 50 acral lentiginous melanomas (ALMs), accounting for the highest ratio (41.3%), followed by nodular melanomas (NMs) in 33 (27.3%), superficial spreading melanomas (SSMs) in 23 (19.0%), lentigo maligna melanomas (LMMs) in 15 (12.4%) and 33 unknown cases (Table 2). The pathological staging was determined using the new UICC 8) TNM classification established in Stage IA was most frequent, accounting for 18.2%, followed by Stage IIIC in 16.2%, Stage0 in 12.2%, and Stage IIB in 11.5%. A total of 51 cases were staged III or more progressed stage, accounting for 34.5% (Table 3). Statistical Analysis The 35 - year period was divided every 5 years into 7 phases, and changes in the number of the patients were investigated. Using the Kaplan - Meier method coupled with the log - rank test, survival analyses were performed for eight factors (sex, age, location, tumor thickness, presence or absence of ulcer, Clark s subtype, stage, and

3 47 presence or absence of adjuvant chemotherapy). Regarding adjuvant chemotherapy, of 41 stage - III patients, those who underwent 3 or more courses of post - operative chemotherapy with any regimens were regarded as chemotherapy 3, and those who underwent 2 or fewer courses and no chemotherapy were regarded as chemotherapy <3. Results The number of patients with malignant melanoma was compared every 5 years from 1973 to 2007, and the number tended to increase (Fig. 2). The 5 - year survival rate was 54.0% in male and 81.7% in female, showing that the prognosis was more favorable in female ( p=0.006) (Fig. 3). Many patients were staged II and III, in whom the survival rate was also higher in female, showing a favorable prognosis (stage II : p=0.007, stage III : p=0.027) (Figs. 4 and 5). The 5 - year survival rate of patients aged younger than the mean age, 61 years, was 73.6%, and 66.6% in those aged 61 years or older, showing that the prognosis was slightly favorable under 60 years of age, Fig. 2. Change in the number of melanoma patients. Fig. 4. The 5 - year survival rate of 42 stage II melanoma patients by sex was 35.5% in male and 88.0% in female ( p=0.007). Fig. 3. The 5 - year survival rate of 154 melanoma patients by sex was 54.0% in male and 81.7% in female (p=0.006). Fig. 5. The 5 - year survival rate of 41 stage III melanoma patients by sex was 26.8% in male and 74.0% in female ( p=0.027). 47

4 48 statistical study of malignant melanoma Fig. 6. The 5 - year survival rate of 154 melanoma patients by age of diagnosis was 73.6% in younger than mean age, 61 years, and 66.6% in those aged 61 years or older (p=0.400). Fig. 8. The 5 - year survival rate of 150 melanoma patients by location divided into BANS and non - BANS was 75.7% in non - BANS and 15.2% in BANS ( p< 0.001). BANS : upper back, posterolateral upper arm, posterior - lateral neck, posterior scalp Fig. 7. The 5 - year survival rate of 150 melanoma patients by location was 100% in mucosa, 74.8% in the lower limbs, 71.2% in the scalp - face - neck, 71.1% in the upper limbs, and 42.1% in trunk ( p=0.240). but the different was not significant ( p=0.400) (Fig. 6). The 5 - year survival rate was 100% in cases of tumors arising in mucosa, followed by 74.8% in the lower limbs, 71.2% in the scalp - face - neck, 71.1% in the upper limbs, and 42.1% in the trunk, showing that the 5 - year survival rate was lower in cases in which tumors developed in the trunk, but the difference was not significant ( p=0.240) (Fig. 7). The 5 - year survival rate was 75.7% in non - Fig. 9. The 5 - year survival rate of 131 melanoma patients by tumor thickness was 100% in Tis, 95.5% in T1, 76.2% in T2, 66.8% in T3, and 51.7% in T4 (p<0.001). Tis : melanoma in situ. T1 : < or =1.0 mm. T2 : mm. T3 : mm. T4 : >4.0 mm. BANS region and 15.2% in BANS region, showing that the survival rate was significantly lower when the tumor developed in BANS (p<0.001) (Fig. 8). The 5 - year survival rate was 100% in Tis cases, 95.5% in T1, 76.2% in T2, 66.8% in T3, and 51.7% in T4, show

5 49 Fig. 10. The 5 - year survival rates of 132 melanoma patients were 62.9% and 81.4% in with and without ulceration ( p=0.036). Fig. 12. The 5 - year survival rate of 121 melanoma patients by Clark s subtype was 87.7% in SSM, 80.5% in ALM, 77.9% in LMM, and 52.1% in NM (p=0.003). SSM : superficial spreading melanoma, ALM : acral lentiginous melanoma, LMM : lentigo maligna melanoma, NM : nodular melanoma. Fig. 11. The 5 - year survival rate of 148 melanoma patients by disease stage was 100% in Stage 0, 96.4% in Stage I, 66.1% in Stage II, 51.9% in Stage III, and 14.0% in Stage IV ( p<0.001). ing that the prognosis worsened as the tumor thickness increased ( p<0.001) (Fig. 9). The 5 - year survival rates were 62.9% and 81.4% in cases with and without ulcer, showing that the prognosis was more favorable in the absence of ulcer ( p=0.036) (Fig. 10). The 5 - year survival rate was 100% in Stage 0 cases, 96.4% in Stage I, 66.1% in Stage II, 51.9% in Stage III, and 14.0% in Stage IV, showing that the prognosis worsened as the disease stage progressed ( p<0.001) (Fig. 11). Fig. 13. The 5 - year survival rate of 78 melanoma patients (T1 - T3) by Clark s subtype was 84.8% in SSM, 80.2% in ALM, 75% in LMM, and 80% in NM (p=0.851). The 5 - year survival rate was the highest (87.7%) in SSM, followed by 80.5% in ALM, 77.9% in LMM, and 52.1% in NM, showing differences among the disease types ( p=0.003) (Fig. 12). When the survival rate was compared in T1 - T3 cases, limiting the tumor thickness, the survival rate was 75-85% in all disease types, show- 49

6 50 statistical study of malignant melanoma Fig. 14. The 5 - year survival rates of 41 stage III melanoma patients were 61.9% and 27.2% in cases chemotherapy 3 and chemotherapy <3 (p=0.041). ing no significant difference ( p=0.851) (Fig. 13). The 5 - year survival rates were 61.9% and 27.2% in cases chemotherapy 3 and chemotherapy <3, respectively, showing that adjuvant chemotherapy led to more favorable prognosis ( p=0.041) (Fig. 14). Discussion The recent rise of the incidence of cutaneous melanoma in many countries should be recognized as a serious problem 1-5). Several statistical and epidemiological investigations of malignant melanoma have been reported by various facilities 1-7, 9-16). One of the largest databases was represented by Chang et al. 3) who analyzed 84,836 cases of melanoma in United States. They reported the factors associated with decreased survival included male, increased age, advanced stage, subtype of NM or ALM. On the other hand, the incidence of melanoma in Japan was reported to be lower than that among European or North American Caucasians. The best nationwide survey was reported by Ishihara et al. 6,14) who investigated 3,708 melanoma patients registered during by the Progress and Statistical Investigation Committee of the Japanese Skin Cancer Society. They reported that the important prognostic factors that worsened the survival rate of Japanese melanoma patients were male, NM, stage IIIB and IV, advanced Clark s level of invasion, increase in Breslow s tumor thickness of the primary lesions. To compare the results of our facility with that of these papers, we sum up the results of our analyses as follows. Namely, the Kaplan - Meier life table method demonstrated the following 7 factors that worsened patient survival significantly : male, primary tumors in BANS region, increase in tumor thickness, tumor with ulceration, advancement of pathological stage, NM, chemotherapy <3 in stage III. Poorer prognosis in male patients, NM, and advanced stage, including increased thickness and presence of ulcer, were common results among these survival analyses. UICC stage, thickness and ulceration, these two were concerned with staging, were naturally significant prognostic factors. Numerous studies have shown that female patients with melanoma have better survival rates than male patients. Balch et al. 1, 2) suggested that this sex difference in prognosis could be partly accounted for by the higher proportion of men with ulceration. Several centers identified the type of growth pattern as an important prognostic factor. NM was associated with a much poorer prognosis than those of other type of growth pattern. Nonetheless, it was revealed that the survival rate was not significantly different among all subtypes when the tumor thickness was limited to T1-3. It suggested that poorer prognosis in NM was probably due to thicker lesions in these subtype. Controversy exists whether the tumor location is a prognositic factor or not. In a large study of 5,093, melanomas on the BANS regions were associated with significantly lower survival rates than melanomas on the other anatomic sites 1). Although our result was consistent with this study, many reports had not analyzed relationship between anatomical site of primary tumor and survival rate, or did not confirm BANS as a prognostic factor 7, 15). We consider it is important that our study revealed location of the primary tumor is a significant prognostic factor in Japanese melanoma. Yamamoto et al. 17) showed that prognosis for stage III melanoma with DAV (DTIC, ACNU, VCR)+IFN - β was significantly better than with DAV alone. Although this study was not randomized analysis in itself, the Japanese guideline for cutaneous malignant tumor 18) recommended DAV+IFN - β as post - operative adjuvant chemotherapy for stage III melanoma. The result of our study suggest

7 51 ed that adjuvant chemotherapy more than 3 courses significantly improve prognosis. Since repeated chemotherapy may be desirable, we usually perform 6 courses of DAV+IFN - β therapy after surgical operation. As for the stage IV melanoma, no regimen of chemotherapy has been established to be effective against the advanced tumors so far 19, 20). To improve the prognosis of melanoma patients, early primary tumor and micro - metastasis of regional lymph nodes should be detected. Recently, new diagnostic methods such as dermoscopy and sentinel node biopsy 21) had appeared and should contribute to early detection of the primary and metastatic tumor. References 1) Balch, C.M., Soong, S.J., Shaw, H.M., Urist, M.M. and McCarthy, W.H. (1992) An analysis of prognostic factors in 8500 patients with cutaneous melanoma. In Balch, C.M., Houghton, A.N., Milton, G.W., Sober, A.J., Soong, S. (ed.) Cutaneous melanoma. Lippincott, Philadelphia, pp ) Balch, C.M., Cascinelli, N., Drzewiecki, K.T. et al. (1992) A comparison of prognostic factors worldwide. In Balch, C.M., Houghton, A.N., Milton, G.W., Sober, A.J., Soong, S. (ed.) Cutaneous melanoma. Lippincott, Philadelphia, pp ) Chang, A.E., Karnell, L.H. and Menck, H.R. (1998) The national cancer data base report on cutaneous and noncutaneous melanoma. Cancer, 83, ) Jelfs, P.L., Giles, G., Shugg, D., Coates, M., Durling, G., Fitzgerald, P. and Ring, L. (1994) Cutaneous malignant melanoma in Australia, Med. J. Australia, 161, ) Martin, R.C.W. and Robinson, E. (2004) Cutaneous melanoma in caucasian New Zealanders : ANZ J. Surg., 74, ) Ishihara, K., Saida, T. and Yamamoto, A. (2001) Updated statistical data for malignant melanoma in Japan. Int. J. Clin. Oncol., 6, ) Ueda, E., Kishimoto, S. and Yasuno, H. (1995) Statistical survey from 1982 to 1991 of 49 patients with malignant melanocytic tumors. J. Dermatol., 22, ) Sobin, L.H. and Wittekind, C.H. (2002) UICC TNM classification of malignant tumors, 6 th ed. John Wiler, Splinger, Berlin - Heidelberg, Tokyo. 9) Florell, S.R., Boucher, K.M., Gariboti, G. et al. (2005) Population - based analysis of prognostic factors and survival in familial melanoma. J. Clin. Oncol., 23, ) Balch, C.M., Soong, S.J., Gershenwald, J.E. et al. (2001) Prognostic factors analysis of melanoma patients : Validation of the American Joint Committee on Cancer melanoma staging system. J. Clin. Oncol., 19, ) Balch, C.M., Buzaid, A.C., Soong, S.J. et al. (2003) New TNM melanoma staging system : Linking biology and natural history to clinical outcomes. Seminars in Surgical Oncology, 21, ) Balch, C.M., Soong, S.J., Atkins, M.B. et al. (2004) An evidence - based staging system for cutaneous melanoma. CA. Cancer J. Clin., 54, ) Kirsner, R.S., Willkinson, J.D., Fangchao Ma, Pacheco, H. and Federman, D.G. (2005) The association of medicare health care delivery systems with stage at diagnosis and survival for patients with melanoma. Arch. Dermatol., 141, ) Ishihara, K. (2007) Past statistics and prognostic factors for malignant skin tumors. Skin Cancer (Japan), 22, ) Ohshima, A., Horibe, T., Yoshinari, Y., Ito, T., Yagi, H., Hashizume, H. and Takigawa, M. (2005) Statistical analysis of malignant melanoma at Hamamatsu University School of Medicine. Skin Cancer (Japan), 20, ) Saito, M., Ito, T., Kato, Y., Ooi, T. and Tsuboi, R. (2004) A statistical survey of 57 case of malignant melanoma at the Department of Dermatology, Tokyo Medical University. Skin Cancer (Japan), 19, ) Yamamoto, A. and Isihara, K. (1996) Clinical study of DAV+IFNβ therapy (combination adjuvant therapy with intravenous DTIC, ACNU and VCR, and local injection of IFNβ) for malignant melanoma. Int. J. Immunotherapy, 12, ) The Japanese skin cancer society (2007) Evidence - based clinical guidelines for malignant neoplasms of the skin. Kanehara Shuppan, Tokyo, pp ) Khayat, D. and Coeffic, D. (2000) Chemotherapy and 51

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