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Late metastases of cutaneous melanoma: Case report and literature review
Late metastases of cutaneous melanoma: Case report and literature review Sebastiana Boi, MD, a and Maurizio Amichetti, M D b Trento,
Italy
The development of delayed metastases, although rare, is well documented in patients with invasive cutaneous melanoma. Only 24 cases, including ours, are clearly documented in the literature. We describe a 56-year-old woman who had an acral lentiginous melanoma of the right hand (thickness 1.2 mm). Thirteen years after excision and postoperative irradiation, a subcutaneous metastasis developed in the right arm. One year later the patient died with disseminated bone metastases. This case, as with most of those with delayed metastases, has typical features: female sex; location at a site other than the back, arm, neck, or scalp; and primary tumor thickness between 1.2 and 2.5 ram. (J AM Ac~J~DF.RMhTOL1991;24:335-8.) The delayed development of metastases is rare but well known. 1, 2 Freedom from recurrence for 10 years is generally accepted as a presumed cure, but late metastases (beyond 10 years) after initial treatment have been reported. The delayed development of metastases in cutaneous malignant melanoma ( C M M ) is a well-known phenomenon, but few cases are clearly documented. 313 W e report a case of C M M with metastases that developed 13 years after radical excision of the primary lesion. CASE REPORT
A 56-year-old woman was admitted to the hospital on Sept. 10, 1969, because of a nodule on the skin of the right hand. Excision revealed an acral lentiginous melanoma, level III, 1.2 mm thick (Figs. 1 and 2). Clinical examination, chest x-ray film, and routine blood tests, including liver and renal function tests, yielded no evidence of distant metastases. In October 1969 the patient received postoperative radiotherapy to the tumor bed. A total dose of 6000 cGy (250 cGy dose per fraction, five times a week, in 48 days, with a rest period of 10 days), administered with a "y-photon beam (6~ with an appositional field, was employed. The patient was examined regularly and remained free of disease until July 1982, when, 13 years after the initial diagnosis, she noticed a subcutaneous nodule on the right arm. A deeply infiltrating, 4 • 4 cm nodule was resected, but the borders of the excision were microscopically positive for neoplastic cells. Histologic examination revealed melanoma metastasis (Fig. 3). From the Department of Pathologya and the OncologyCenter? lstituti Ospedalieri di Trento. Reprint requests: Sebastiana Boi, MD, Department of Pathology, Istituff Ospedalieri, USL C5, 38100 Trento, Italy. 16/4/17602
Chest x-ray film, total body computerized tomogram, and results of clinical examination, ophthalmologic examination, and hematologic tests did not reveal a second primary melanoma or other distant metastases. Peripheral blood lymphocyte subpopulations and results of skin tests were normal. A course of radiation therapy (total dose 3000 cGy; 600 cGy dose per fraction, five times a week), together with local microwave hyperthermia to the metastatic site, was administered and resulted in resolution of the lesion. In September 1983 multiple bone metastases appeared, and the patient died on Jan. 15, 1984. DISCUSSION The biologic behavior of stage I C M M is extremely variable. Many factors, mainly stage and thickness, appear to influence the prognosis. 14"16 Nevertheless, some cases have an unpredictable outcome. Because almost all recurrences and deaths appear within 10 years, if after this time the patient is free of disease, he or she is generally presumed cured and follow-up examinations are discontinued. However, in some patients metastases can develop after this period. 12,16-18 Twenty-four cases of late recurrence (beyond 10 years) of CMM, including ours, have been reported, but a complete patient history is available in only 18 cases; six cases are incomplete because of lack of essential data, including information on clinical and histologic findings of both the primary and metastatic cutaneous melanoma, 3,5 age, and sex.11 Case reports of late metastases of CMM available in the English-language literature are reported in Table I. The primary tumor site was frequently the extremities (16 cases); the site of recurrence was 335
336
Journal of the American Academy of Dermatology
Boi and Amichetti
Fig. 1. Acral lentiginous melanoma: Clark level III, Breslow thickness 1.2 mm. (Hematoxylin-eosin stain; X25.)
!'
,
~ i
~'
Fig. 2. Higher magnification of specimen in Fig. 1. (Hematoxylin-eosin stain; • nodal in 10 cases, local and nodal in 3, local in 3, distant in 4, nodal and distant in 2, and unknown in the remaining 2 cases. Of the 24 patients, 19 were females between 15 and 54 years of age at the time of diagnosis of their primary lesion. Hormonal status is described in 12 cases ( 11 were premenopausal and 1 was postmenopausal); the other 7 were less than 50 years old and presumably were premenopausal when their first tumor was diagnosed. A clear relationship between the thickness of the tumor and late recurrence is reported. Patients with deep tumors ( > 3 m m ) have early relapseslg; pa-
tients with thinner tumors (<3 m m ) have later relapses. 2~ Thus lesion thickness in 10 patients with recurrence after 10 years ranged from 1.2 to 2.5 mm. All but one (20/21 ) of the tumors with a known primary site were in locations other than the back, arm, neck, and scalp (BANS). Day et al. a2 reported a relatively higher risk at 5 years of death from melanoma 0.76 to 1.69 in thickness in patients with BANS locations. This high mortality risk was confirmed in a recently reported meta-analysis by Weinstock et al. 23 More than 5 years after excision of the primary tumor, the opposite is true, and non-
Volume 24 Number 2, Part 2 February 1991
Late metastases o f m e l a n o m a
F i g . 3. Subcutaneous metastasis of melanoma, (Hemato•
337
stain; X 100.)
Table I. Late recurrence (beyond 10 years) in patients with cutaneous melanoma reported in the literature Author
No.
Sex
status
(ram)
site
period (yr)
NS NS Pre Pre NS
NS NS NS NS NS
Cheek Abdomen NS NS Leg
13 14 14 18 15
Hand Leg
11 26
Wilburg and Harman Hersperber and Neill White
3 4 5
Jackson
6
48/F 50/M F F 40/F
Olsen Miller and Pack
7 8
49/F 15/F
NS Pre
NS NS
Briele et al.
9
38/F 39/F 24/F 22/F 44/M
Pre Pre Pre Pre NS
NS Leg 2.5 Leg 1.77 Leg NS Forearm 1.45 Thigh
16 23 21 20 11
24/F 38/F 22/F 24/F 41/F NS NS NS 39/F 45/F 42/F
Pre Pre Pre NS NS NS NS NS Pre NS NS
NS NS 2.4 1.2 1.65 NS NS NS 1.6 2.2 1.75
Scapula Leg Chest Arm Leg Leg Skin (NS) Arm Foot Leg Sacral
14 11 10 18 14 20 11 13 13 18 18
54/F
Post
1.2
Hand
13
Koh et al.
10
Hendrix
11
Raderman et al. Steiner et al.
12 13
Our ease
Metastalic site
Local Liver
Outcome Outco~
Dead Dead NS NS NS NS Local, regional Dead nodes Local Dead Local, regional Dead nodes, brain Regional nodes Dead Regional nodes Dead Regional nodes NED Regional nodes NED Local, regional Dead nodes Regional nodes NED Local AWD Regional nodes NED Regional nodes Alive Regional nodes Alive Regional nodes NED Regional nodes NED Widespread Dead Regional nodes NED Subcutaneous NED Regional nodes, AWD subcutaneous Subcutaneous Dead
A HID,Alivewith disease;NED, no evidenceof disease;NS. not specified;Post, postmenopausal;Pre,premenopausal.
Survival (too)
NS NS NS NS NS NS 39 31 52 42 57 68 48 12 Few Few 96 180 Few 12 Few Few 18
338
Bet and Amichetti
B A N S lesions appear to be at higher risk. 24 Our findings seem to confirm this trend. AI1 primary tumors were surgically treated. For two primary tumors postoperative irradiation was administered. Among the 24 patients, l 0 died. Localization of the late recurrence in visceral or distant sites seems to be associated with a poor prognosis. 4' l l, t3 The cause of delayed metastasis is uncertain, although many factors have been considered. These include sex2s, 26 (with a better prognosis in women), endocrinologic factors linked with gonadal activity, 9 therapies with androgenic hormones, 27 and biologic properties of some "dormant" cellular subpopulations. 10 Our patient's history, including her age, sex, primary tumor, site, and primary tumor thickness, were similar to that of other described cases except that she was postmenopausal. Patients with C M M need long-term follow-up care (beyond 10 years), especially if they are women who are premenopausal at the time of the initial diagnosis. REFERENCES
1. Hoerr SO. Long-term results in patients who survived five or more years a fter gastric resection for primary carcinoma. Surg Gynecol Obstet 1981;153:820-2. 2. Bloom DA, Kaufman J J, Smith RB. Late recurrence of rehal tubular carcinoma. J Urol 1980;126:546-8. 3. Wilburg DL, Harman HR. Malignant melanoma with delayed metastatic growths. Ann Intern Med 1931 ;5:201-11. 4. Hersperber WB, Neill W Jr. Malignant melanoma: report of a case recurring after 14 years. Am J Surg 1941;52: 1li-4. 5. White LP. The role &natural resistance in the prognosis of human melanoma. Ann N Y Acad Sci 1963;100:115-22. 6. Jackson R. Observations on the natural course of skin cancer. Can Med Assoc J 1965;92:564-70. 7. Olsen G. The malignant melanoma of the skin: new theories based on a study of 500 cases. Acta Chir Scand [Suppl] 1966;365:1-222. 8. Miller TR, Pack GT. The familial aspect of malignant melanoma. Arch Dermatol 1962,86:35-9. 9. Bride HA, Beattie CW, Ronan SG, et al. Late recurrence of cutaneous melanoma. Arch Surg 1983;118:800-3. 10. Koh HK, Sober A J, Fitzpatrick TB. Late recurrence (beyond ten years) of cutaneous malignant melanoma. JAMA 1984;251:1859-62.
Journal of thc American Academy of Dermatology
I l. Hendrix RC. Unusual survival patterns of patients with metastatic melanoma. Cancer 1969;24:574-7. 12. Raderman D, Giler S, Rothem A, et al. Late metastases (beyond ten years) of cutaneous malignant melanoma, literature review and case report. J AM ACAD DERMATOL 1986;15:374-8. 13. Steiner A, Wolf C, Pehamberger H, et al. Late metastases of cutaneous malignant melanoma. Br J Dermatol 1986; 114:737-40. 14. Maize JC. Primary cutaneous malignant melanoma: an analysis of the prognostic value of histologic characteristics. J AM ACAD DERMATOL 1983;8:857-63. 15. Balch CM, Soong S J, Murad TM, et al. A multifactorial analysis of melanoma. II. Prognostic factors in patients with stage 1 (localized) melanoma. Surgery 1979;86:343-51. 16. Eldh J, Boeryd B, Peterson LE. Prognostic factors in cutaneous malignant melanoma in stage I. Seam J Hast Reconstr Surg 1978;12:243-55. 17. Epstein E. Curability of melanoma: a 25-year retrospective study. Cancer 1980;46:818-21. 18. Day CL, Mihm MC, Lew RA. Cutaneous malignant melanoma: prognostic guidelines for physician and patients. Cancer 1982;32:13-122. 19. Sober A J, Day CL, Fitzpatrick TB. Early death from clinical stage I melanoma. J Invest Dermatol 1983;80:50-2. 20. Day CL, Mihm MC, Sober A J, et al. Predictors of late deaths among patients with clinical stage I melanoma who have not had bony or visceral metastases within the first 5 years after diagnosis. J AM ACAD DERIvlATOL 1983;8: 864-8. 21. Khanna AK, Laidler P, Hughes LE. Can late recurrence be predicted at the time of primary treatment? Eur J Surg Oncol 1986; 12:9-12. 22. Day e L , Mihm MC, Sober A J, et al. Prognostic factors for melanoma patients with lesions 0.76-1.69 mm in thickness: an appraisal of "thin" level IV lesions. Ann Surg 1982; 195:30-4. 23. Weinstock MA, Morris BT, Lederman JS, ctal. Effect of BANS location on the prognosis of clinical stage I melanoma: new data and meta-analysis. Br J Dermatol 1988; 119:559-65, 24. Cascinelli N, Vaglini M, Bufalino R, et al. BANS: a cutaneous region with no prognostic significance in patients with melanoma. Cancer 1986;57;441-4. 25. Franklin JD, Reynolds VH, Page DL. Cutaneous melanoma: a twenty-year retrospective study with clinicopathologic correlation. Hast Reconstr Surg 1975;56:277-85. 26. MacKie RM, Carfrae DC, Cochran AJ. Assessment of prognosis in patients with malignant melanoma. Lancet 1972;2:455-6. 27. Rampen FHJ, Mulder JH. Malignant melanoma: an androgen-dependent tumour? Lancet 1980;I:563-5.
Italy
The development of delayed metastases, although rare, is well documented in patients with invasive cutaneous melanoma. Only 24 cases, including ours, are clearly documented in the literature. We describe a 56-year-old woman who had an acral lentiginous melanoma of the right hand (thickness 1.2 mm). Thirteen years after excision and postoperative irradiation, a subcutaneous metastasis developed in the right arm. One year later the patient died with disseminated bone metastases. This case, as with most of those with delayed metastases, has typical features: female sex; location at a site other than the back, arm, neck, or scalp; and primary tumor thickness between 1.2 and 2.5 ram. (J AM Ac~J~DF.RMhTOL1991;24:335-8.) The delayed development of metastases is rare but well known. 1, 2 Freedom from recurrence for 10 years is generally accepted as a presumed cure, but late metastases (beyond 10 years) after initial treatment have been reported. The delayed development of metastases in cutaneous malignant melanoma ( C M M ) is a well-known phenomenon, but few cases are clearly documented. 313 W e report a case of C M M with metastases that developed 13 years after radical excision of the primary lesion. CASE REPORT
A 56-year-old woman was admitted to the hospital on Sept. 10, 1969, because of a nodule on the skin of the right hand. Excision revealed an acral lentiginous melanoma, level III, 1.2 mm thick (Figs. 1 and 2). Clinical examination, chest x-ray film, and routine blood tests, including liver and renal function tests, yielded no evidence of distant metastases. In October 1969 the patient received postoperative radiotherapy to the tumor bed. A total dose of 6000 cGy (250 cGy dose per fraction, five times a week, in 48 days, with a rest period of 10 days), administered with a "y-photon beam (6~ with an appositional field, was employed. The patient was examined regularly and remained free of disease until July 1982, when, 13 years after the initial diagnosis, she noticed a subcutaneous nodule on the right arm. A deeply infiltrating, 4 • 4 cm nodule was resected, but the borders of the excision were microscopically positive for neoplastic cells. Histologic examination revealed melanoma metastasis (Fig. 3). From the Department of Pathologya and the OncologyCenter? lstituti Ospedalieri di Trento. Reprint requests: Sebastiana Boi, MD, Department of Pathology, Istituff Ospedalieri, USL C5, 38100 Trento, Italy. 16/4/17602
Chest x-ray film, total body computerized tomogram, and results of clinical examination, ophthalmologic examination, and hematologic tests did not reveal a second primary melanoma or other distant metastases. Peripheral blood lymphocyte subpopulations and results of skin tests were normal. A course of radiation therapy (total dose 3000 cGy; 600 cGy dose per fraction, five times a week), together with local microwave hyperthermia to the metastatic site, was administered and resulted in resolution of the lesion. In September 1983 multiple bone metastases appeared, and the patient died on Jan. 15, 1984. DISCUSSION The biologic behavior of stage I C M M is extremely variable. Many factors, mainly stage and thickness, appear to influence the prognosis. 14"16 Nevertheless, some cases have an unpredictable outcome. Because almost all recurrences and deaths appear within 10 years, if after this time the patient is free of disease, he or she is generally presumed cured and follow-up examinations are discontinued. However, in some patients metastases can develop after this period. 12,16-18 Twenty-four cases of late recurrence (beyond 10 years) of CMM, including ours, have been reported, but a complete patient history is available in only 18 cases; six cases are incomplete because of lack of essential data, including information on clinical and histologic findings of both the primary and metastatic cutaneous melanoma, 3,5 age, and sex.11 Case reports of late metastases of CMM available in the English-language literature are reported in Table I. The primary tumor site was frequently the extremities (16 cases); the site of recurrence was 335
336
Journal of the American Academy of Dermatology
Boi and Amichetti
Fig. 1. Acral lentiginous melanoma: Clark level III, Breslow thickness 1.2 mm. (Hematoxylin-eosin stain; X25.)
!'
,
~ i
~'
Fig. 2. Higher magnification of specimen in Fig. 1. (Hematoxylin-eosin stain; • nodal in 10 cases, local and nodal in 3, local in 3, distant in 4, nodal and distant in 2, and unknown in the remaining 2 cases. Of the 24 patients, 19 were females between 15 and 54 years of age at the time of diagnosis of their primary lesion. Hormonal status is described in 12 cases ( 11 were premenopausal and 1 was postmenopausal); the other 7 were less than 50 years old and presumably were premenopausal when their first tumor was diagnosed. A clear relationship between the thickness of the tumor and late recurrence is reported. Patients with deep tumors ( > 3 m m ) have early relapseslg; pa-
tients with thinner tumors (<3 m m ) have later relapses. 2~ Thus lesion thickness in 10 patients with recurrence after 10 years ranged from 1.2 to 2.5 mm. All but one (20/21 ) of the tumors with a known primary site were in locations other than the back, arm, neck, and scalp (BANS). Day et al. a2 reported a relatively higher risk at 5 years of death from melanoma 0.76 to 1.69 in thickness in patients with BANS locations. This high mortality risk was confirmed in a recently reported meta-analysis by Weinstock et al. 23 More than 5 years after excision of the primary tumor, the opposite is true, and non-
Volume 24 Number 2, Part 2 February 1991
Late metastases o f m e l a n o m a
F i g . 3. Subcutaneous metastasis of melanoma, (Hemato•
337
stain; X 100.)
Table I. Late recurrence (beyond 10 years) in patients with cutaneous melanoma reported in the literature Author
No.
Sex
status
(ram)
site
period (yr)
NS NS Pre Pre NS
NS NS NS NS NS
Cheek Abdomen NS NS Leg
13 14 14 18 15
Hand Leg
11 26
Wilburg and Harman Hersperber and Neill White
3 4 5
Jackson
6
48/F 50/M F F 40/F
Olsen Miller and Pack
7 8
49/F 15/F
NS Pre
NS NS
Briele et al.
9
38/F 39/F 24/F 22/F 44/M
Pre Pre Pre Pre NS
NS Leg 2.5 Leg 1.77 Leg NS Forearm 1.45 Thigh
16 23 21 20 11
24/F 38/F 22/F 24/F 41/F NS NS NS 39/F 45/F 42/F
Pre Pre Pre NS NS NS NS NS Pre NS NS
NS NS 2.4 1.2 1.65 NS NS NS 1.6 2.2 1.75
Scapula Leg Chest Arm Leg Leg Skin (NS) Arm Foot Leg Sacral
14 11 10 18 14 20 11 13 13 18 18
54/F
Post
1.2
Hand
13
Koh et al.
10
Hendrix
11
Raderman et al. Steiner et al.
12 13
Our ease
Metastalic site
Local Liver
Outcome Outco~
Dead Dead NS NS NS NS Local, regional Dead nodes Local Dead Local, regional Dead nodes, brain Regional nodes Dead Regional nodes Dead Regional nodes NED Regional nodes NED Local, regional Dead nodes Regional nodes NED Local AWD Regional nodes NED Regional nodes Alive Regional nodes Alive Regional nodes NED Regional nodes NED Widespread Dead Regional nodes NED Subcutaneous NED Regional nodes, AWD subcutaneous Subcutaneous Dead
A HID,Alivewith disease;NED, no evidenceof disease;NS. not specified;Post, postmenopausal;Pre,premenopausal.
Survival (too)
NS NS NS NS NS NS 39 31 52 42 57 68 48 12 Few Few 96 180 Few 12 Few Few 18
338
Bet and Amichetti
B A N S lesions appear to be at higher risk. 24 Our findings seem to confirm this trend. AI1 primary tumors were surgically treated. For two primary tumors postoperative irradiation was administered. Among the 24 patients, l 0 died. Localization of the late recurrence in visceral or distant sites seems to be associated with a poor prognosis. 4' l l, t3 The cause of delayed metastasis is uncertain, although many factors have been considered. These include sex2s, 26 (with a better prognosis in women), endocrinologic factors linked with gonadal activity, 9 therapies with androgenic hormones, 27 and biologic properties of some "dormant" cellular subpopulations. 10 Our patient's history, including her age, sex, primary tumor, site, and primary tumor thickness, were similar to that of other described cases except that she was postmenopausal. Patients with C M M need long-term follow-up care (beyond 10 years), especially if they are women who are premenopausal at the time of the initial diagnosis. REFERENCES
1. Hoerr SO. Long-term results in patients who survived five or more years a fter gastric resection for primary carcinoma. Surg Gynecol Obstet 1981;153:820-2. 2. Bloom DA, Kaufman J J, Smith RB. Late recurrence of rehal tubular carcinoma. J Urol 1980;126:546-8. 3. Wilburg DL, Harman HR. Malignant melanoma with delayed metastatic growths. Ann Intern Med 1931 ;5:201-11. 4. Hersperber WB, Neill W Jr. Malignant melanoma: report of a case recurring after 14 years. Am J Surg 1941;52: 1li-4. 5. White LP. The role &natural resistance in the prognosis of human melanoma. Ann N Y Acad Sci 1963;100:115-22. 6. Jackson R. Observations on the natural course of skin cancer. Can Med Assoc J 1965;92:564-70. 7. Olsen G. The malignant melanoma of the skin: new theories based on a study of 500 cases. Acta Chir Scand [Suppl] 1966;365:1-222. 8. Miller TR, Pack GT. The familial aspect of malignant melanoma. Arch Dermatol 1962,86:35-9. 9. Bride HA, Beattie CW, Ronan SG, et al. Late recurrence of cutaneous melanoma. Arch Surg 1983;118:800-3. 10. Koh HK, Sober A J, Fitzpatrick TB. Late recurrence (beyond ten years) of cutaneous malignant melanoma. JAMA 1984;251:1859-62.
Journal of thc American Academy of Dermatology
I l. Hendrix RC. Unusual survival patterns of patients with metastatic melanoma. Cancer 1969;24:574-7. 12. Raderman D, Giler S, Rothem A, et al. Late metastases (beyond ten years) of cutaneous malignant melanoma, literature review and case report. J AM ACAD DERMATOL 1986;15:374-8. 13. Steiner A, Wolf C, Pehamberger H, et al. Late metastases of cutaneous malignant melanoma. Br J Dermatol 1986; 114:737-40. 14. Maize JC. Primary cutaneous malignant melanoma: an analysis of the prognostic value of histologic characteristics. J AM ACAD DERMATOL 1983;8:857-63. 15. Balch CM, Soong S J, Murad TM, et al. A multifactorial analysis of melanoma. II. Prognostic factors in patients with stage 1 (localized) melanoma. Surgery 1979;86:343-51. 16. Eldh J, Boeryd B, Peterson LE. Prognostic factors in cutaneous malignant melanoma in stage I. Seam J Hast Reconstr Surg 1978;12:243-55. 17. Epstein E. Curability of melanoma: a 25-year retrospective study. Cancer 1980;46:818-21. 18. Day CL, Mihm MC, Lew RA. Cutaneous malignant melanoma: prognostic guidelines for physician and patients. Cancer 1982;32:13-122. 19. Sober A J, Day CL, Fitzpatrick TB. Early death from clinical stage I melanoma. J Invest Dermatol 1983;80:50-2. 20. Day CL, Mihm MC, Sober A J, et al. Predictors of late deaths among patients with clinical stage I melanoma who have not had bony or visceral metastases within the first 5 years after diagnosis. J AM ACAD DERIvlATOL 1983;8: 864-8. 21. Khanna AK, Laidler P, Hughes LE. Can late recurrence be predicted at the time of primary treatment? Eur J Surg Oncol 1986; 12:9-12. 22. Day e L , Mihm MC, Sober A J, et al. Prognostic factors for melanoma patients with lesions 0.76-1.69 mm in thickness: an appraisal of "thin" level IV lesions. Ann Surg 1982; 195:30-4. 23. Weinstock MA, Morris BT, Lederman JS, ctal. Effect of BANS location on the prognosis of clinical stage I melanoma: new data and meta-analysis. Br J Dermatol 1988; 119:559-65, 24. Cascinelli N, Vaglini M, Bufalino R, et al. BANS: a cutaneous region with no prognostic significance in patients with melanoma. Cancer 1986;57;441-4. 25. Franklin JD, Reynolds VH, Page DL. Cutaneous melanoma: a twenty-year retrospective study with clinicopathologic correlation. Hast Reconstr Surg 1975;56:277-85. 26. MacKie RM, Carfrae DC, Cochran AJ. Assessment of prognosis in patients with malignant melanoma. Lancet 1972;2:455-6. 27. Rampen FHJ, Mulder JH. Malignant melanoma: an androgen-dependent tumour? Lancet 1980;I:563-5.