Acral Melanoma in Japan

Acral Melanoma in Japan MAKOTO SEUI, M.D., HIDEAKI TAKEMATSU, M.D., MICHIKO HOSOKAWA, M.D., MASAAKI OBATA, M.D., YASUSHI TOMITA, M.D., TAIZO KATO, M.D., MASAAKI TAKAHASHI, M.D., AND MARTIN C. MIHM, JR., M.D. Clinical records and histologic materials from 81 patients with malignant melanoma at the Department of Dermatology at Tohoku University School of Medicine were reviewed. In addition, a statistical study on 1597 cases of malignant melanoma collected from the Japanese literature from 1961 to 1982 was performed. The annual mortality rate has been increasing almost linearly over the past 20 years. The mortality rate per year for 1980 was 0.21 per 100,000. Five-year survival rate at Tohoku University was 35 percent. The most common site of melanoma was acral, especially the plantar surfaces. The clinical and histologic study of acral melanomas showed that clinicopathologic features are the same as those reported for acral lentiginous melanoma in the United States. As a result of the dramatic increase in incidence and death rate of malignant melanoma over the past decade, malignant. melanoma is now being widely studied in Japan. Racial differences are quite pronounced in the incidence and predilection sites of melanomas [1]. Until recently, there were three recognized clinical and histologic types of malignant melanoma, i.e., lentigo maligna melanoma (LMM), superficial spreading melanoma (SSM), and nodular melanoma (NM) [2,3]. A fourth type has been designated as palmar-plantar-subungual-mucosal melanoma (P-S-M melanoma) [4], acral lentiginous melanoma [5], or acral melanoma [6]. Acral melanomas are the most common type of malignant melanoma in the Japanese people, but they also occur in other Orientals, blacks, and some Caucasians [4]. Through intensive studies of acral melanomas in Japan, clinical and histologic features of these tumors have been elucidated [7 13]. In the first, phase of this study, we reviewed 81 cases of malignant melanoma from the Department of Dermatology at Tohoku University School of Medicine and compared them with those reported in the Japanese literature. The cardinal clinical and histologic features of acral melanomas in Japan are presented. all medical journals in Japan. In order to carry out a more precise study, we tried as much as possible to eliminate overlapping cases by checking the individual journals in which the cases were reported. RESULTS Incidence Figure 1 shows the yearly incidence of malignant melanomas between 1961 and 1981. There was a peak in 1967. After 1909, there was an upward trend. Although the annual incidence of malignant melanomas in Japan has not been compiled statistically, the annual mortality rate can be calculated from the statistics collected by the Japanese government (Fig. 2). The mortality rate has been increasing almost linearly. It rose from 0.06 per 100,000 in 1960 to 0.21 per 100,000 in 1980. The incidence has increased three and half times from 1960 to 1980. Thus it can be estimated that at present there should be approximately 240 deaths from malignant melanoma annually in Japan. Age and Sex Distribution There was a peak in the sixth decade in both males and females. The male-to-female ratio was 1.2:1. MATERIALS AND METHODS The clinical records and histologic materials from 81 patients observed during a 10-year period (1972 1982) at the Department of Dermatology at Tohoku University School of Medicine were reviewed. The acral melanomas were treated by wide excision and immediate application of skin graft. Subungual melanomas located on the digits were treated by amputation at the metacarpophalangeal or metatarsophalangeal joint. In most cases, dissection of lymph nodes was performed. The statistical study was based on a review of these 81 cases and all cases of malignant melanoma reported in the Japana Centra Revuo Medicina from March of 1961 through January of 1982, between volumes 102 and 399 [13]. This is a journal in which abstracts appear from almost Department of Dermatology, Tohoku University School of Medicine, Sendai, Japan, and Departments of Pathology, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts, U.S.A. Dr. Makoto Seiji is deceased. Reprint requests to: Dr. Arthur J. Sober, Department of Dermatology, Massachusetts General Hospital, 32 Fruit Street, Boston, Mass. 02114. Abbreviations: LMM, lentigo maligna melanoma; NM, nodular melanoma; P-S-M melanoma, palmar-plantar-subungual-mucosal melanoma; SSM, superficial spreading melanoma FIG 1. Yearly incidence of malignant melanoma in Japan from 1961 to 1981. 56s

June 1983 ACRAL MELONOMA IN JAPAN TABLE II. Distribution of melanomas by body site and by sex in Japan Number of Primary lesion patients Male Female Unknown Skin: 564 (35.3%) 307 219 20 Scalp, face, and neck 85 (5.3%) 39 43 3 Trunk 117 (7.3%) 70 41 6 Upper extremity 84 (5.3%) 33 39 Lower extremity 268 (16.8%) 158 93 11 Unknown 10 (0.6%) 7 3 Mucosa: 427 (26.7%) 173 204 50 Nose 139 (8.7%) 68 55 16 Mouth 220 (13.8%) 89 89 33 Pharynx 7 (0.4%) 3 3 1 Genital organ 61 (3.8%) 13 48 FIG 2. Death rate from malignant melanoma per 100, 000 per year from I960 to 1980. (From the Ministry of Health and Welfare of Japan.) TABLE I. Distribution of melanomas by body site and by sex at tohoku university Primary lesion Number of patients Male Female Acral region: 48 (59%) 32 16 Palm 2 (2%) 2 0 Sole 25 (31%) 17 8 Finger 2 (2%) 0 2 Toe 3 (4%) 2 1 Back of foot 3 (4%) 1 2 Subungual 13 (16%) 10 3 Mucosa: 15 (18%) 3 12 Nose 2 (2%) 0 2 Mouth 3 (4%) 0 3 Eye 3 (4%) 2 1 External genitalia 6 (7%) 0 6 Esophagus 1(1%) 1 0 Others: 15 (18%) 5 10 Scalp, face, and neck 5 (6%) 2 3 Trunk 2 (2%) 1 1 Upper extremity (except acral regions) Lower extremity (except acral regions) 3 (4%) 1 2 3 (4%) 1 4 Unknown: 3 (4%) 2 1 TOTAL: 81 (100%) 42 39 The Sites of Involvement of Acral Melanomas Among the 81 cases of malignant melanoma seen at Tohoku University from 1972 to 1982, the proportion of acral tumors was Others: 518 (32.4%) 253 219 46 Brain and spinal cord 91 (5.7%) 51 27 13 Eye 318 (19.9%) 155 130 33 Gastrointestinal tract 102 (6.4%) 43 59 Lung 7 (0.4%) 4 3 Unknown: 85 (5.3%) 39 28 18 TOTAL: 1594 (100%) 783 677 134 59 percent (Table I). Among the acral melanomas, the sole and nail plate were especially frequent sites, with frequencies of 31 and 1(5 percent, respectively. While the sex ratio for all melanomas was 1.1:1, mucosal melanomas occurred more often in females than in males. Table II indicates the incidence of malignant melanoma in Japan by location and by sex. The most common site of cutaneous melanomas was the lower extremity, with relative sparing of the trunk. The incidence of the melanoma on the soles and toes was quite high among the Japanese people, and melanomas on the soles and toes were seen almost twice as often in men as in women (Fig. 3). Subungual Melanoma Figure 4,a shows the distribution of 13 cases of subungual melanoma at Tohoku University. The incidence of subungual melanoma on the hands was higher than that on the feet. The occurrences on both the thumbs and great toes were high; the most common site was the right thumb. There were 64 cases of subungual melanoma in the Japanese series, which constituted 4.6 percent of 1594 cases of malignant melanoma (Fig. 4,b). The number of subungual melanomas on the fingers was 46 (72 percent) and on the toes 18 (28 percent). The incidence of subungual melanoma on the thumbs and great toes was quite high; 82 percent of subungual melanomas occurred in these regions. Frequency of Associated Preexistent Pigmented Skin Lesions and Previous Trauma Seventeen percent of the patients noticed the preeexistence of some pigmented skin lesions, and 21 percent related a history of trauma. 57s

SEIJI ET AL. Vol. 80, No. 6 Supplement Classification Superficial spreading melanomas were not recognized in the 81 cases at Tohoku University (Fig. 5,a). Acral melanomas constituted 46 percent of the melanomas in this series. In Japan, lentigo maligna melanomas and superficial spreading melanomas showed low frequencies compared with Caucasians [11] (Fig. 5,b). Nodular melanomas revealed a similar frequency in both the Japanese and Caucasians. Acral melanomas constituted about, half the cases. FIG 3. Distribution of malignant melanomas on the lower extremities. Prognosis Among the 81 cases at Tohoku University, 41 cases were followed for 5 years. Overall 5-year survival rate was 35 percent. Overall 5-year survival rate for patients with plantar melanomas in Japan, collected by the Melanoma Research Group, was 29 percent, and that for other melanomas was 39 percent [11]. Clinical Features of Acral Melanoma Most acral melanomas exhibit a biphasic growth pattern clinically, i.e., the radial and vertical growth phases. In the radial growth phase, the macular lesions present highly irregular, notched borders and exhibit varying shades of tan to dark brown to black (Fig. 6). Most of these pigmented macules do not show an elevation. In the vertical growth phase, the central tumor nodules exhibit papules or nodules, sometimes with verrucose surfaces, which indicate the vertical growth of malignant melanocytes (Fig. 6). Subungual melanomas often begin as brown to black discolorations of the nail that frequently become bands or streaks of pigmentation. Thickening, splitting, or destruction of the nail plate may occur (Fig. 7). The irregular macular hyperpigmentation, colored tan to dark brown, is also recognized around the destructive nail plate. Histology of Acral Melanoma In the radial growth phase, the intraepidermal component of acral melanoma includes, when characteristic, large, atypical melanocytes with large, often bizarre nuclei and nucleoli, and cytoplasm filled with melanin granules (Fig. 8). These melanocytes in predominantly basilar disposition exhibit long, elaborate dendritic processes that may extend to the surface epithelium. The epidermis is usually hyperplastic. Single-cell invasion beneath these areas of proliferation is common. In some areas of the macular pigmented lesions of plantar melanoma, atypical melanocytes can be seen along the basal layer of the epithelium of the sweat ducts in the deep dermis. These atypical melanocytes have heavily pigmented granules (Fig. 9). FIG 4. Distribution of subungual melanomas at Tohoku University (a) and in Japan (b). 58s

June 1983 ACRAL MELONOMA IN JAPAN FIG 5. Incidence of various types of malignant melanoma at Tohoku University (a) and among Japanese and Caucasians [11] (b). FIG 6. Acral melanoma on the heel. The lesion shows a central nodule and adjacent pigmented macules. In the vertical growth phase, tumor nodules, the vertical growth component, may contain predominantly spindle-shaped cells and are often associated with a desmoplastic reaction. DISCUSSION Melanomas in the acral regions have been termed acral lentiginous melanomas based on certain histologic similarities to lentigo maligna melanomas [5]. The histology of melanoma in the acral regions, however, is strikingly different from that of lentigo maligna melanoma in its radial growth phase [4]. However, palmar-plantar-subungual-mucosal melanoma has been described on the basis of clinical and histologic similarities between the malignant melanomas on the palms, soles, subungual regions, and mucosas [4]. The clinical behavior of the lesions on the mucosas is different from that of lesions in other regions. Thus, for the time being, it was recommended that the acral melanomas and mucosal melanomas be treated separately until more information could be gathered to allow statistical evaluation of both their clinical and histologic features, as well as their courses [6]. The concept that subungual melanoma should be classified into the acral melanoma group is based on the histologic similarity to plantar melanoma. Statistical studies by us have shown that one of the characteristics of melanomas in Japan is a high frequency in the acral regions [13 15]. In African and North American Negroes, the highest incidence of cutaneous melanoma has been reported on relatively nonpigmented areas, such as the soles, nail plates, and mucous membranes [16 18]. In this regard, there appears to be some similarities between the Japanese and Negroes [13]. It is of interest to note that acral melanomas occurred twice as often in men as in women at Tohoku University and in Japan. Similar sex ratios have been reported for acral melanomas in the United States [18]. Subungual melanomas have been thought to be relatively rare in Japanese, as well as in Caucasians [19]. However, we found 13 subungual melanomas among 81 cases (16 percent) quite a high frequency. The high percentage of subungual melanomas on the fingernails and on the thumbs and great toes may suggest a role for trauma in the etiology of subungual melanoma. Only 35 percent of the patients survived at Tohoku University. A similar poor prognosis has been reported for melanomas in North 59s

SEIJI ET AL. Vol. 80, No. 6 Supplement FIG 9. Sweat duct epithelium in the deep dermis from the plantar melanoma. Several atypical melanocytes can be observed along the basal layer ( 257). FIG 7. Subungual melanoma on the righl thumb. The nail has been deformed traumaticially. There are darkly pigmented macules around the nail. FIG 8. A section through the dark brown macular portion. Almost the entire basal layer is replaced by large, pleomorphic, bizarre, and atypical melanocytes ( 257). American Negroes and for acral melanomas in the United States [17,18]. The reason for such a high rate of mortality for acral melanomas is still unknown. Intraepidermal proliferation of melanocytes may exist in the deep dermis along the epidermal appendages and the epithelium of the sweat ducts of the palms and soles. This means that even if only pigment macules exist clinically on the acral surfaces, it is possible that malignant melanocytes may already be present in the deep dermis along the epithelium of the sweat ducts [11]. REFERENCES 1. Blwood JM, Lee J AH: Recent data on the epidermiology of malignant melanoma. Semin Oncol 2:149 154, 1975 2. Clark WH Jr, From L, Bernardino EA, Mihm MC Jr: The histogenesis and biologic behavior of primary human malignant melanoma of the skin. Cancer Res 29:705 726, 1969 3. McGovern VJ: The classification of melanoma and its relationship with prognosis. Pathology 2:85 98, 1970 4. Seiji M, Mihm MC Jr, Sober AJ, Takahashi M, Kato T, Fitzpatrick TB: Malignant melanoma of the palmar-plantar-subungual-mu-cosal type. Clinical and histopathological features, Pigment Cell, Vol 5. Edited by SN Klaus. Basel, Karger, 1979, pp 95 104 5. Reed RJ; Acral lentiginous melanoma, New Concepts in Surgical Pathology of the Skin. New York, Wiley, 1976, pp 73 96 6. Mihm MC Jr, Lopansri S: A review of the classification of malignant melanoma. J Dermatol (Tokyo) 6:131 142, 1979 7. Seiji M, Takahashi M: Malignant melanoma with adjacent intraepidermal proliferation. Tohoku J Exp Med 114:93 107, 1974 8. Takahashi M, Seiji M: Malignant melanoma in Japan. Jpn J Clin Oncol 6:103 170, 1975 9. Seiji M, Takahashi M: Plantar malignant melanoma, J Dermatol (Tokyo) 2:103 170, 1975 10. Hosokawa M, Kato T, Seiji M, Abe R: Plantar malignant melanoma. Statistical and clinicopathological studies. J Dermatol (Tokyo) 7:137 142, 1980 11. Takahashi M, Seiji M, Tomita Y, Kato T: Acral melanoma in Japan, Pigment Cell 1981. Edited by M Seiji. Tokyo, University of Tokyo Press, 1981, pp 555 502 12. Seiji M, Takahashi M: Acral melanoma in Japan. Human Pathol 13:607 609, 1982 13. Takahashi M, Seiji M: Acral melanoma in Japan, Pigment Cell, Vol. 6. Edited by M Mackie. Basal, Karger, in press 14. Seiji M, Ohsumi T: Statistical study on malignant melanoma in Japan (1961 1970). Tohoku J Exp Med 107:115 125, 1972 15. Ohsumi T, Seiji M: Statistical study on malignant melanoma in Japan (1970 1976). Tohoku J Exp Med 121:355 364, 1972 16. Lewis MG, Kiryabwire, JWM: Aspects of behavior and natural history of malignant melanoma in Uganda. Cancer 21:876 887, 1968 17. Shah JP, Goldsmith HS: Malignant melanoma in the North American Negro. Surg Gynecol Obstet 133:437 439, 1971 18. Colemen WP III, Loria PR, Reed RJ, Krementz ET: Acral lentiginous melanoma. Arch Dermatol 110:773 770, 1980 19. Pack GT, Oropeza R: Subungual melanoma. Surg Gynecol Obstet 124:571 582, 1967 60s