~
The Japanese Journal of Surgery (1992) 22:171-175
. SURGERYTOOAV
© Springer-Verlag 1992
Primary Anorectal Malignant Melanoma MASAKI MIYAHARA,TAKAO SAITO, KOICHI SATO, KAZUTOSHIKAKETANI,TAKANORIYOSHIDA, MASAFUMIINOMATA, MICHIO KOBAYASHI,1 and KENICHIRO YOSHIKAWA2 ~The First Department of Surgery, Medical College of Oita, Oita, Japan and 2Tomachidai Hospital, Oita, Japan
Abstract: A case of primary anorectal malignant melanoma seen in a 46 year old woman is presented herein. Her most marked symptoms were bloody stools and anal pain. Endoscopic examination indicated a tumor with ulceration but without pigmentation in the anorectal region. Hist01ogic examination of the biopsied specimens showed spindle-shaped cells with atypia proliferating in a bandlike arrangement, as in leiomyosarcoma. An abdominoperineal resection was done and detailed histological examination of the tumor comfirmed the nature of the tumor to be malignant melanoma. The postoperative immunochemotherapy consisted of Dimetyl-Triazeno-Imidasole-Carboxamide (DTIC), Amino-Methyl-Pyrimidinyl-Methyl-Chlorethyl-Nitrosourea-Hydrochloride (ACNU), Vincristine (VCR) and OK-432. The patient has been well without recurrence for fifteen months following her operation through the continuous administration of these agents. Key Words: malignant melanoma, anorectal tumor, immunochemotherapy
Introduction
Anorectal malignant melanoma is a rare disease, its frequency ranging between 0.4 and 5.6 per cent of all melanomas, 1-5 and between 0.2 and 1.6 per cent of all malignant tumors of the anorectum. 4'7 Cooper et al. reviewed 267 cases reported in the English literature in 19826 and to our knowledge, only 141 cases have been published to date in Japan. This disease is extremely aggressive in its biological behavior, but is sometimes misdiagnosed as a benign or a different type of malignant tumor even after histological examination. 3'6
Reprint requests to: Masaki Miyahara, MD, The First Department of Surgery, Medical College of Oita, 1-1 Idaigaoka Hasama-machi, Oita-gun, Oita 879-56, Japan (Received for publication on Sept. 10, 1990)
We recently experienced a case of primary anorectal malignant melanoma which was unable to be histologically differentiated from leiomyosarcoma in a preoperative biopsied specimen. The pathological features and detailed clinical course of this case are reported herein, followed by a review of the literature.
Case Report
A 46 year old Japanese woman was admitted to our department on March 28th, 1989, with a 7 day history of bloody stools. For four months prior to admission, she had experienced analpain on defecation. On physical examination, the abdomen was flat and soft with no palpable tumor and no lymphadenopathy was noted in the inguinal region. Digital examination indicated a well defined palpable elevated lesion with ulceration, involving the posterior half of the circumference of the lower rectum. All routine laboratory findings were within normal limits. The serum level of carcinoembryonic antigen (CEA) was 0.74ng/ml. Barium enema showed a filling defect in the posterior lower rectum (Fig. 1).. Colonofiberscopic examination indicated a tumor with a white coated shallow ulcer in the lower rectum immediately oral to the dentate line (Fig. 2). No blackish pigmentation could be seen in the lesion. The endoscopic findings were not different from those of usual ulcerated adenocarcinoma with a sharply defined border. However, biopsied specimens of the tumor on colonofiberscopic examination showed a bandlike arrangement of spindleshaped cells with atypia (Fig. 3), indicating possible leiomyosarcoma of the anorectum. No distant metastasis was found on a total body CT scan. An abdominoperineal resection with pelvic node dissection was conducted under the diagnosis of leiomyosarcoma of the anorectum. Macroscopically, the tumor appeared not to invade the adventitia, but
172
M, Miyahara et al.: Anorectal Malignant Melanoma
Fig. 3. Microphotography of the biopsied specimen. A bandlike arrangement of spindle-shaped cells with atypia resembling teiomyosarcoma is observed (HE, x 100)
Fig. 1. Barium enema showing a filling defect in the posterior lower.rectum (arrows)
Fig. 4. Gross findings of the resected specimen. In the lower rectum and anal canal, an ulcerated tumor with a sharply defined border is observed. There is no visible blackish pigmentation
Fig, 2, Endoscopic findings, An ulcerated tumor with a sharply defined border can be seen without any blackish pigmentation, These endoscopic findings show no difference from those of a usual adenocarcinoma of the rectum
the inferior rectal and obturamr lymph nodes showed swelling. No metastasis to the distant organs could be detected. The tumor in the resected specimen measured 5.3 x 4.2 cm and had an ulcer in its center but there was no visible blackish pigmentation (Fig. 4). For a detailed histological examination, the resected specimen was divided into 16 blocks as shown in Fig. 5. The bandlike arrangement of spindle-shaped cells appeared virtually throughout the tumor (Fig. 6.a), as in the preoperative biopsied specimen. However, the alveolar formation of pleomorphic cells could be seen in the deeper parts of three blocks (Fig. 6.b). Some pleomorphic cells contained massive pigment deposition (Fig. 6.c). These cells were stained positively by Fontana-Masson's
M. Miyahara et al.: Anorectal Malignant Melanoma
Dentate line
/
\ |
,
Fig. 5. Schematic illustrationof the resected specimen. Pleomorphic cells with melanin pigment deposition exist only in 2 of the 16 divided blocks. []: spindle-shaped cells; N: pleomorphic cells (melanin -), . : pleomorphic cells (melanin +)
173 staining, and Neuron Specific Enolase (NSE) and S-100 protein were detected by immunohistochemical staining. The histological diagnosis was thus confirmed to be primary anorectal malignant melanoma. Obvious adventitial invasion, as well as venous and lymphatic vessel invasion of the tumor cells and metastasis of the obturator lymph nodes were clearly indicated by microscopic examination. Bilateral inguinal lymph node dissection was subsequently conducted 34 days following the initial operation, but no lymph node metastasis in this region could be found grossly. Adjuvant immunochemotherapy composed of DTIC, ACNU, VCR (DAV) and OK-432 was given postoperatively. DTIC 100 mg/day was given intravenously for 5 days, while ACNU 50 mg and VCR i mg were given intravenously on the first day of the week for 4 weeks. This regime was able to be followed safely without producing any significant side effects for a total 13 administrations. OK-432 5.0 KE is still being given intracutaneously 3 days a week. There has been no evidence of tumor recurrence in the 15 months following her operation.
Fig. 6. Microphotography of the resected specimen showing a a bandlike arrangement of spindle-shaped cells throughout the tumor, b the alveolar formation of pleomorphic cells without and c with melanin pigment deposition in the deeper parts of the tumor (HE, ×200)
174 Discussion According to available literature, the average survival of patients with primary anorectal malignant melanoma ranges from 9 months to 2.8 years and the five year survival rate of treated patients is about 10 per cent. 2'8-1° These statistics are much poorer than those for adenocarcinoma or squamous cell carcinoma of the anorectal region. Several cases have indicated that the poorer prognoses of patients with this tumor are possibly attributed not only to the aggressive malignant potential of the tumor itself, but also to late recognition and diagnosis, thereby causing delayed treatment. 5'11 The main clinical symptoms are anal bleeding, an anal mass and anal pain. The lesions vary in gross form from a small sessile or pedunculated polyp to a bulky ulcerated tumor with marginal elevation. These clinical findings often lead to such misdiagnoses as benign thrombotic hemorrhoid, rectal polyp or ulcerated adenocarcinoma. 5'6'12 The most determinant diagnostic gross finding is the blackish brown or black appearance of melanotic melanoma, however, a melanoma with sparse melanin pigments, as in that of the present case, can rarely be differentiated from usual adenocarcinoma of the anorectum. Even if the lesion is biopsied, amelanotic melanoma, found in about 30 per cent of cases 2's or melanotic melanoma containing few melanin granules is frequently difficult to differentiate from undifferentiated carcinoma, poorly differentiated squamous cell carcinoma, lymphosarcoma and others. 13 In the present case, where few melanin containing cells were found, histological differentiation from leiomyosarcoma by hematoxylin and eosin staining was difficult, not only in the preoperative biopsied specimen but also in most of the resected specimen. However, NSE and S-100 protein were detected by immunohistological staining and, although Dopa-reaction in the fresh specimen was not done in the present case, it is known to be a useful diagnostic method for amelanotic melanoma. Our experience shows that emphasis should be placed on establishing an accurate diagnosis of this disease in its early stage and also how important it is to bear in mind that a rare malignant melanoma, frequently without macroscopic blackish pigmentation, may be encountered in the anorectal tumor. Thus, in the case of an anorectal tumor whose biopsied specimen shows neither apparent benign tissue or differentiated adenocarcinoma by hematoxylin and eosin staining, Dopa reaction, Fontana-Masson's staining and immunohistochemical stainings to detent S-100 protein and NSE should be done to determine a conclusive diagnosis. No single superior surgical procedure has been established for this disease. Pock et al. recommended
M. Miyahara et al.: Anorectal Malignant Melanoma abdominoperineal resection in conjunction with pelvic and bilateral inguinal lymph node dissections. 2 However, survival has been found to be related more to stage than treatment. 1'9 Wanebo et al. from a clinicopathological analysis of 36 patients, emphasized that the depth of invasion is the most important prognostic factor and concluded that abdominoperineal resection with pelvic node dissection but without elective inguinal dissection should be attempted only for lesions less than 3 mm thick. 5 In a review of 138 Japanese cases, Okabe et al. reported rectal amputation to have been conducted in 82 per cent and local resection in 10 per cent, and stated that the survival' of cases treated by rectal amputation with inguinal dissection was superior to that of those treated by local resection. 13 Chemotherapy is still being investigated. In the case presented here, OK-432 was given with the D A V (DTIC, A C N U , VCR) 14 regime as postoperative adjuvant immunochemotherapy. The patient has so far received 13 administrations of D A V since surgery without any significant side effects and shows no evidence of recurrence, despite the advanced disease at the time of surgery. We conclude, therefore, that improvement in the prognosis of anorectal malignant melanoma depends upon correct diagnosis at an early stage, rectal amputation with extended lymph node dissection and long-term adjuvant immunochemotherapy.
References 1. Mason JK, Helwig EB (1966) Anorectal melanoma. Cancer 19:39-50 2. Pack GT, Oropeza R (1967) A comparativestudy of melanoma and epidermoid carcinoma of the anal canal: A review of 20 melanomas and 29 epidermoid carcinomas. Dis Colon Rectum 10:161-176 3. RemigioPA, Der BK, FovsbergRT (1976)Anorectal melanoma. Dis Colon Rectum 19:350-365 4. Braasted FW, Dockert MB, Dixon CF (1949)Melanoepithelioma of the anus and rectum. Surgery 25:82-90. 5. Wanebo HJ, WoodruffJM, Farr GH, Quan SH (1981) Anorectal melanoma. Cancer 47:1891-1900 6. Cooper PH, Mills SE, Allen MS Jr (1982) Malignant melanoma of the anus. Report of 12 patients and analysis of 255 additional cases. Dis Colon Rectum 25:693-703 7. Morson BC, Volkstat H (1963) Malignant melanoma of the anal canal. J Clin Path 16:126-132 8. Balch CM, Soong SJ, Murad TM, Ingalls AL, Maddox WA (1979) A multifactorial analysis of melanoma. II. Prognostic factors in patients with Stage I (localized) melanoma. Surgery 86:343-350 9. Husa A, Hocherstedt AK (1974) Anorectal melanoma. A report of 14 cases. Acta Chir Scand 140:68-72 10. Quan SHQ, White JE, Deddish MR (1959) Malignant melanoma of the anorectum. Dis Colon Rectum 2:275-283 11. Smith LS Jr. (1977) Early detection and diagnosis of malignant melanoma pathology. Postgraduate course #10, 123-235, Comm. of Cancer, Am. College of Surgeons
M. Miyahara et al.: Anorectal Malignant Melanoma 12. Chiu YS, Unni KK, Beanst RW Jr. (1980) Malignant melanoma of the anorectum. Dis Colon Rectum 23:122-124 13. Okabe S, Nakajima K, Kaneko Y, Takemura K, Goseki N, Endo M, Oohashi K, Kamiyama R, Kasuga T (1987) Malignant melanoma of the anorectum-report of a case and review of 137 cases reported in Japan. Nippon Daicho-komonbyo Gakkai
175 Zasshi (In Japanese, with English Abst.) (J Jpn Soc Coloproctol) 40:401-407 14. DTIC Clinical Research Group (chairman: Ikeda S, Ishihara K) (1982) Clinical effect of Dacarbazine (DTIC) on malignant melanoma. (In Japanese, with English Abst.) Rinsho Hifuka 36:183-188
The Japanese Journal of Surgery (1992) 22:171-175
. SURGERYTOOAV
© Springer-Verlag 1992
Primary Anorectal Malignant Melanoma MASAKI MIYAHARA,TAKAO SAITO, KOICHI SATO, KAZUTOSHIKAKETANI,TAKANORIYOSHIDA, MASAFUMIINOMATA, MICHIO KOBAYASHI,1 and KENICHIRO YOSHIKAWA2 ~The First Department of Surgery, Medical College of Oita, Oita, Japan and 2Tomachidai Hospital, Oita, Japan
Abstract: A case of primary anorectal malignant melanoma seen in a 46 year old woman is presented herein. Her most marked symptoms were bloody stools and anal pain. Endoscopic examination indicated a tumor with ulceration but without pigmentation in the anorectal region. Hist01ogic examination of the biopsied specimens showed spindle-shaped cells with atypia proliferating in a bandlike arrangement, as in leiomyosarcoma. An abdominoperineal resection was done and detailed histological examination of the tumor comfirmed the nature of the tumor to be malignant melanoma. The postoperative immunochemotherapy consisted of Dimetyl-Triazeno-Imidasole-Carboxamide (DTIC), Amino-Methyl-Pyrimidinyl-Methyl-Chlorethyl-Nitrosourea-Hydrochloride (ACNU), Vincristine (VCR) and OK-432. The patient has been well without recurrence for fifteen months following her operation through the continuous administration of these agents. Key Words: malignant melanoma, anorectal tumor, immunochemotherapy
Introduction
Anorectal malignant melanoma is a rare disease, its frequency ranging between 0.4 and 5.6 per cent of all melanomas, 1-5 and between 0.2 and 1.6 per cent of all malignant tumors of the anorectum. 4'7 Cooper et al. reviewed 267 cases reported in the English literature in 19826 and to our knowledge, only 141 cases have been published to date in Japan. This disease is extremely aggressive in its biological behavior, but is sometimes misdiagnosed as a benign or a different type of malignant tumor even after histological examination. 3'6
Reprint requests to: Masaki Miyahara, MD, The First Department of Surgery, Medical College of Oita, 1-1 Idaigaoka Hasama-machi, Oita-gun, Oita 879-56, Japan (Received for publication on Sept. 10, 1990)
We recently experienced a case of primary anorectal malignant melanoma which was unable to be histologically differentiated from leiomyosarcoma in a preoperative biopsied specimen. The pathological features and detailed clinical course of this case are reported herein, followed by a review of the literature.
Case Report
A 46 year old Japanese woman was admitted to our department on March 28th, 1989, with a 7 day history of bloody stools. For four months prior to admission, she had experienced analpain on defecation. On physical examination, the abdomen was flat and soft with no palpable tumor and no lymphadenopathy was noted in the inguinal region. Digital examination indicated a well defined palpable elevated lesion with ulceration, involving the posterior half of the circumference of the lower rectum. All routine laboratory findings were within normal limits. The serum level of carcinoembryonic antigen (CEA) was 0.74ng/ml. Barium enema showed a filling defect in the posterior lower rectum (Fig. 1).. Colonofiberscopic examination indicated a tumor with a white coated shallow ulcer in the lower rectum immediately oral to the dentate line (Fig. 2). No blackish pigmentation could be seen in the lesion. The endoscopic findings were not different from those of usual ulcerated adenocarcinoma with a sharply defined border. However, biopsied specimens of the tumor on colonofiberscopic examination showed a bandlike arrangement of spindleshaped cells with atypia (Fig. 3), indicating possible leiomyosarcoma of the anorectum. No distant metastasis was found on a total body CT scan. An abdominoperineal resection with pelvic node dissection was conducted under the diagnosis of leiomyosarcoma of the anorectum. Macroscopically, the tumor appeared not to invade the adventitia, but
172
M, Miyahara et al.: Anorectal Malignant Melanoma
Fig. 3. Microphotography of the biopsied specimen. A bandlike arrangement of spindle-shaped cells with atypia resembling teiomyosarcoma is observed (HE, x 100)
Fig. 1. Barium enema showing a filling defect in the posterior lower.rectum (arrows)
Fig. 4. Gross findings of the resected specimen. In the lower rectum and anal canal, an ulcerated tumor with a sharply defined border is observed. There is no visible blackish pigmentation
Fig, 2, Endoscopic findings, An ulcerated tumor with a sharply defined border can be seen without any blackish pigmentation, These endoscopic findings show no difference from those of a usual adenocarcinoma of the rectum
the inferior rectal and obturamr lymph nodes showed swelling. No metastasis to the distant organs could be detected. The tumor in the resected specimen measured 5.3 x 4.2 cm and had an ulcer in its center but there was no visible blackish pigmentation (Fig. 4). For a detailed histological examination, the resected specimen was divided into 16 blocks as shown in Fig. 5. The bandlike arrangement of spindle-shaped cells appeared virtually throughout the tumor (Fig. 6.a), as in the preoperative biopsied specimen. However, the alveolar formation of pleomorphic cells could be seen in the deeper parts of three blocks (Fig. 6.b). Some pleomorphic cells contained massive pigment deposition (Fig. 6.c). These cells were stained positively by Fontana-Masson's
M. Miyahara et al.: Anorectal Malignant Melanoma
Dentate line
/
\ |
,
Fig. 5. Schematic illustrationof the resected specimen. Pleomorphic cells with melanin pigment deposition exist only in 2 of the 16 divided blocks. []: spindle-shaped cells; N: pleomorphic cells (melanin -), . : pleomorphic cells (melanin +)
173 staining, and Neuron Specific Enolase (NSE) and S-100 protein were detected by immunohistochemical staining. The histological diagnosis was thus confirmed to be primary anorectal malignant melanoma. Obvious adventitial invasion, as well as venous and lymphatic vessel invasion of the tumor cells and metastasis of the obturator lymph nodes were clearly indicated by microscopic examination. Bilateral inguinal lymph node dissection was subsequently conducted 34 days following the initial operation, but no lymph node metastasis in this region could be found grossly. Adjuvant immunochemotherapy composed of DTIC, ACNU, VCR (DAV) and OK-432 was given postoperatively. DTIC 100 mg/day was given intravenously for 5 days, while ACNU 50 mg and VCR i mg were given intravenously on the first day of the week for 4 weeks. This regime was able to be followed safely without producing any significant side effects for a total 13 administrations. OK-432 5.0 KE is still being given intracutaneously 3 days a week. There has been no evidence of tumor recurrence in the 15 months following her operation.
Fig. 6. Microphotography of the resected specimen showing a a bandlike arrangement of spindle-shaped cells throughout the tumor, b the alveolar formation of pleomorphic cells without and c with melanin pigment deposition in the deeper parts of the tumor (HE, ×200)
174 Discussion According to available literature, the average survival of patients with primary anorectal malignant melanoma ranges from 9 months to 2.8 years and the five year survival rate of treated patients is about 10 per cent. 2'8-1° These statistics are much poorer than those for adenocarcinoma or squamous cell carcinoma of the anorectal region. Several cases have indicated that the poorer prognoses of patients with this tumor are possibly attributed not only to the aggressive malignant potential of the tumor itself, but also to late recognition and diagnosis, thereby causing delayed treatment. 5'11 The main clinical symptoms are anal bleeding, an anal mass and anal pain. The lesions vary in gross form from a small sessile or pedunculated polyp to a bulky ulcerated tumor with marginal elevation. These clinical findings often lead to such misdiagnoses as benign thrombotic hemorrhoid, rectal polyp or ulcerated adenocarcinoma. 5'6'12 The most determinant diagnostic gross finding is the blackish brown or black appearance of melanotic melanoma, however, a melanoma with sparse melanin pigments, as in that of the present case, can rarely be differentiated from usual adenocarcinoma of the anorectum. Even if the lesion is biopsied, amelanotic melanoma, found in about 30 per cent of cases 2's or melanotic melanoma containing few melanin granules is frequently difficult to differentiate from undifferentiated carcinoma, poorly differentiated squamous cell carcinoma, lymphosarcoma and others. 13 In the present case, where few melanin containing cells were found, histological differentiation from leiomyosarcoma by hematoxylin and eosin staining was difficult, not only in the preoperative biopsied specimen but also in most of the resected specimen. However, NSE and S-100 protein were detected by immunohistological staining and, although Dopa-reaction in the fresh specimen was not done in the present case, it is known to be a useful diagnostic method for amelanotic melanoma. Our experience shows that emphasis should be placed on establishing an accurate diagnosis of this disease in its early stage and also how important it is to bear in mind that a rare malignant melanoma, frequently without macroscopic blackish pigmentation, may be encountered in the anorectal tumor. Thus, in the case of an anorectal tumor whose biopsied specimen shows neither apparent benign tissue or differentiated adenocarcinoma by hematoxylin and eosin staining, Dopa reaction, Fontana-Masson's staining and immunohistochemical stainings to detent S-100 protein and NSE should be done to determine a conclusive diagnosis. No single superior surgical procedure has been established for this disease. Pock et al. recommended
M. Miyahara et al.: Anorectal Malignant Melanoma abdominoperineal resection in conjunction with pelvic and bilateral inguinal lymph node dissections. 2 However, survival has been found to be related more to stage than treatment. 1'9 Wanebo et al. from a clinicopathological analysis of 36 patients, emphasized that the depth of invasion is the most important prognostic factor and concluded that abdominoperineal resection with pelvic node dissection but without elective inguinal dissection should be attempted only for lesions less than 3 mm thick. 5 In a review of 138 Japanese cases, Okabe et al. reported rectal amputation to have been conducted in 82 per cent and local resection in 10 per cent, and stated that the survival' of cases treated by rectal amputation with inguinal dissection was superior to that of those treated by local resection. 13 Chemotherapy is still being investigated. In the case presented here, OK-432 was given with the D A V (DTIC, A C N U , VCR) 14 regime as postoperative adjuvant immunochemotherapy. The patient has so far received 13 administrations of D A V since surgery without any significant side effects and shows no evidence of recurrence, despite the advanced disease at the time of surgery. We conclude, therefore, that improvement in the prognosis of anorectal malignant melanoma depends upon correct diagnosis at an early stage, rectal amputation with extended lymph node dissection and long-term adjuvant immunochemotherapy.
References 1. Mason JK, Helwig EB (1966) Anorectal melanoma. Cancer 19:39-50 2. Pack GT, Oropeza R (1967) A comparativestudy of melanoma and epidermoid carcinoma of the anal canal: A review of 20 melanomas and 29 epidermoid carcinomas. Dis Colon Rectum 10:161-176 3. RemigioPA, Der BK, FovsbergRT (1976)Anorectal melanoma. Dis Colon Rectum 19:350-365 4. Braasted FW, Dockert MB, Dixon CF (1949)Melanoepithelioma of the anus and rectum. Surgery 25:82-90. 5. Wanebo HJ, WoodruffJM, Farr GH, Quan SH (1981) Anorectal melanoma. Cancer 47:1891-1900 6. Cooper PH, Mills SE, Allen MS Jr (1982) Malignant melanoma of the anus. Report of 12 patients and analysis of 255 additional cases. Dis Colon Rectum 25:693-703 7. Morson BC, Volkstat H (1963) Malignant melanoma of the anal canal. J Clin Path 16:126-132 8. Balch CM, Soong SJ, Murad TM, Ingalls AL, Maddox WA (1979) A multifactorial analysis of melanoma. II. Prognostic factors in patients with Stage I (localized) melanoma. Surgery 86:343-350 9. Husa A, Hocherstedt AK (1974) Anorectal melanoma. A report of 14 cases. Acta Chir Scand 140:68-72 10. Quan SHQ, White JE, Deddish MR (1959) Malignant melanoma of the anorectum. Dis Colon Rectum 2:275-283 11. Smith LS Jr. (1977) Early detection and diagnosis of malignant melanoma pathology. Postgraduate course #10, 123-235, Comm. of Cancer, Am. College of Surgeons
M. Miyahara et al.: Anorectal Malignant Melanoma 12. Chiu YS, Unni KK, Beanst RW Jr. (1980) Malignant melanoma of the anorectum. Dis Colon Rectum 23:122-124 13. Okabe S, Nakajima K, Kaneko Y, Takemura K, Goseki N, Endo M, Oohashi K, Kamiyama R, Kasuga T (1987) Malignant melanoma of the anorectum-report of a case and review of 137 cases reported in Japan. Nippon Daicho-komonbyo Gakkai
175 Zasshi (In Japanese, with English Abst.) (J Jpn Soc Coloproctol) 40:401-407 14. DTIC Clinical Research Group (chairman: Ikeda S, Ishihara K) (1982) Clinical effect of Dacarbazine (DTIC) on malignant melanoma. (In Japanese, with English Abst.) Rinsho Hifuka 36:183-188
