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Gynecomastia as a complication of chemotherapy for testicular germ cell tumors
CASE REPORT CME ARTICLE ELSEVIER
CYNECOMASTIA AS A COMPLICATION OF CHEMOTHERAPY FOR TESTICULAR GERM CELL TUMORS FAZIL
TUNCAY
AKI, MEHMET
ALTER@ -r&N,
AND
HAWK
OVEN
ABSTRACT Among 190 patients with metastatic testicular cancer who were treated by platinum-based combination chemotherapy and achieved complete remission, 4 (2.1%) developed gynecomastia 2 to 5 months after the cessation of chemotherapy. All of these patients had normal serum levels of the beta subunit of human chorionic gonadotropin and testosterone levels at the lower range of normal, but they had elevated levels of follicle-stimulating hormone, luteinizing hormone, and estradiol. The cause of gynecomastia in our patients was probably these increased levels of gonadotropins that, in turn, stimulated increased secretion of testicular estrogen, thus altering the normal estradiol-testosterone ratio. Treatment-related gynecomastia, which may occur several months after the cessation of cytotoxic chemotherapy, does not necessarily mean the return of disease. It is important to recognize this fact so as to prevent unnecessary investigations that will cause psychological distress in a young patient with testicular cancer. Copyright 1996 by Elsevier Science inc. UROLOGY 48: 944-946, 1996.
ynecomastia, defined as a concentric increase of greater than 2 cm in diameter in glandular and stromal tissue in the male breast, is a common disorder, especially in adolescent boys and during the male climacteric years.1,2 Some endrocrinopathies, some tumors, many drugs, and chronic systemic and familial diseases may cause gynecomastia.lm4 Development of gynecomastia in a patient who has a known malignant disease may cause physicians to anticipate a relapse. We herein report 4 men who developed gynecomastia after cytotoxic chemotherapy for metastatic testicular germ cell tumor. The importance of gynecomastia as a complication of the chemotherapy is discussed.
G
CASE REPORTS CASE 1
A 31-year-old man underwent right inguinal orchiectomy for an embryonal cell carcinoma of the testis. While the patient was under surveillance for From the School of Medicine, Department of Urology, Hacettepe University, Ankara, Turkey Reprint requests: H&k &en, M.D., Department of Uro-oncology, Kuleli Sokak, 9/2, Gaziosmanpasa 06700, Ankara, Turkey
Submitted: March 6, 1996, accepted (with 20, 1996
944
COPYRIGHT ALLRIGHTS
1996 BY ELSEVIER SCIENCE RESERVED
revisions): June
INC.
Stage I disease, a retroperitoneal lymph node metastasis of 3 cm was detected on computed tomography (CT) 5 months after orchiectomy. Serum beta subunit of human chorionic gonadotropin (beta-hCG > and alpha-fetoprotein (alpha-FP) were normal. After administration of three courses of bleomycin, eteposide, and cis-platin (BEP) combination chemotherapy, complete remission was achieved. Right-sided, painful, diffuse gynecomastia without discharge developed 4 months after the cessation of chemotherapy. The patient was taking no medication at this time. His hormonal profile is shown in Table I. Gynecomastia was thought to be a complication of systemic cytotoxic chemotherapy. The patient was followed up for 12 months after the onset of gynecomastia; he remained in complete remission without any therapy, and the gynecomastia resolved completely. CASE 2
A 17-year boy was found to have a right testicular mass. Following a right inguinal orchiectomy, BEP combination chemotherapy was administered for clinical Stage IIA embryonal cell carcinoma of the testis. Five courses of chemotherapy resulted in complete remission after 4 months. Five months after cessation of the chemotherapy, the patient noted an enlargement and tenderness of both 0090-4295/96/$15.00 PII SOO90-4295(96)00303-Z
TABLE
1.
Serum hormone levels of patients who developed affer cytotoxic chemotherapy
Patient
Beta-hCG (mlU/mL)
FSH (mlU/mL)
(mlkl7ml)
1 2 3 4 Normal values
1.6 1.8 2.1 1.4 O-10.4
19.5 19.9 22.4 21.6 0.9-9.8
13.8 15.2 14.6 14.8 2.2-12
KEY: beta-hCG
= beta subunit
of human
chorionic
gonadotropin,
FSH = follicle-stimulating
breasts without any discharge. At that time, he was in clinical remission and serum beta-hCG was normal. Follicle-stimulating hormone (FSH) , luteinizing hormone (LH) , and estradiol were elevated, as in our first patient (Table I). Testosterone was at the lower limit of normal. The gynecomastia resolved over the next 4 months, and 15 months after the end of the chemotherapy, the patient is still disease free. CASE 3 A 28-year-old man with stage IV-CL3 embryonal cell carcinoma of the right testis according to the Royal Marsden classification5 had a complete remission of the pulmonary metastases and partial remission of the abdominal mass after five courses of cis-platin, vincristine (oncovin) , methotrexate, and bleomycin (POMB) and four courses of actinomycin D, cyclophosphamide, and eteposide (ACE) chemotherapy. Pathological examination of the mass removed during postchemotherapeutic abdominal surgery revealed necrosis. Two months after completion of the chemotherapy, bilateral, nontender breast enlargement was noted. The patient’s serum beta-hCG was normal (Table I ) . The gynecomastia disappeared completely over the next 4 months, and the patient remained in complete remission without any therapy for 12 months after the cessation of the chemotherapy. CASE 4 A 25-year-old man was found to have a left testicular mass with palpable abdominal mass. Following left inguinal orchiectomy, BEP combination chemotherapy was administered for clinical Stage IIC mixed germ cell carcinoma of the testis. After five courses of chemotherapy and retroperitoneal postchemotherapeutic surgery, complete remission was achieved. Left-sided tender gynecomastia developed 3 months after the end of chemotherapy, the patient’s serum beta-hCG was normal, and hormonal data were comparable to those of our other 3 patients (Table I). Ten months following the recognition of left-sided gynecomastia, the patient remains in complete remission, and UROLOGY
48 (61, 1996
gynecomastia
Testosterone (ng/mLl
Estradiol @g/W
Prolactin (ng/mL)
95 76 88 82 lo-60
7.3 7.8 8.5 6.8 0.2-9.4
4.9 4.2 4.3 5.1 3-10 hormone,
LH = luteinizing
hormone.
the gynecomastia disappeared spontaneously 3 months after its onset. However, the patient occasionally complains of mild breast tenderness. COMMENT Over the last 5 years, we have treated and followed 190 patients with testicular cancer with platinum-based chemotherapy; thus the 4 patients presented here represent 2.1% of our patient group. Gynecomastia can be associated with a number of disorders. In our patients, gynecomastia appeared several months after the cessation of the cytotoxic chemotherapy for testicular germ cell cancer. There was no clinical evidence of any endocrine and systemic disease and no history of drug abuse or medication in these patients. Gynecomastia has resolved in all of our patients within 4 months at most. Similarly, Tseng et a1.6 and Saeter et ~1.~ have also reported that chemotherapy-related gynecomastia subsided within a period of 12 months, in 100% and 75% of patients, respectively. In a patient with testicular cancer, breast enlargement may also be associated with ectopic production of beta-hCG by the neoplastic tissue,’ but this was not the case in the patients we discuss here. Gynecomastia may also develop as a side effect of the chemotherapy.6’7’9-12 Elevated serum FSH level secondary to testicular germ cell damage due to chemotherapeutic agents is well known. Increased concentration of LH may indicate damage of the Leydig cells. On the other hand, elevated serum LH values with normal serum testosterone levels indicate a slightly decreased but compensated Leydig cell function. Under the influence of high gonadotropin levels, the testis secretes relatively more estrogen than testosterone.g Sherins et a1.l’ have described gynecomastia in adolescent boys treated with combination chemotherapy for Hodgkin’s disease and have suggested that alterations in the testosterone/estrogen ratio may be responsible for the development of treatment-related gynecomastia. Glass and Berenberg” and Trumph et a1.9 have each described gynecomastia after cy945
totoxic chemotherapy in patients with testicular cancer and have suggested an elevated estrogen/ androgen ratio as the cause. It has also been suggested that, the latter ratio may be changed by alterations in the peripheral metabolism of testosterone and that the resulting elevation of estradiol may promote the development of gynecomastia. However, this hypothesis needs to be confirmed. The findings in our 4 patients of increased serum FSH, LH, and estradiol levels and normal levels of testosterone, with all serum testosterone values at the lower range of normal, suggest that this ratio is indeed important in the development of gynecomastia. Although many alterations occur in estrogen and testosterone production, hormonal status, and gonadal function in patients receiving chemotherapy for cancer, there are no convincing data available to explain the exact mechanism of postchemotherapy gynecomastia. The incidence of treatment-related gynecomastia is expected to be higher in patients with testicular cancer than in other cancer patients owing to the significant reduction of a testosterone-producing tissue. On the other hand, the observation of unilateral gynecomastia in 2 of 4 of our patients emphasizes that not only hormonal disturbances but also local phenomena such as the number of estrogen receptors in the breast tissue may be factors in the development of gynecomastia. Saeter et ~1.~ have speculated that gynecomastia was not a direct result of hormonal disturbances only, as a few of their patients who had high estradiol, LH, and FSH did not develop gynecomastia. The observation that the hormonal disturbances did not necessarily return to normal with the resolution of gynecomastia also casts doubt on a hormonal theory. Further studies are required to shed light on the pathogenic process. Gynecomastia at the time of diagnosis has been found to be an unfavorable prognostic sign for patients with testicular cancer.6 Trumph and Anderson i2 suggested that patients who developed treatment-related gynecomastia had a favorable prognosis, However, Tseng et ~1.~ and Saeter et a1.7 have not found a statistically significant difference
946
in the survival of patients who developed treatment-related gynecomastia. The small number of patients with gynecomastia whom we have treated does not support firm conclusions about the prognostic effect of treatment-related gynecomastia. Larger series and longer follow-up is required. Whatever the mechanism, in adults, gynecomastia may occur several months following the cessation of cytotoxic chemotherapy of testicular cancer and does not necessarily mean the return of disease. Recognition of this fact is important to prevent unnecessary investigations that will cause psychological distress in a young patient with testicular cancer. REFERENCES 1. Mahoney CP: Adolescent gynecomastia: differential diagnosis and management. Pediatr Clin North Am 37: 13891404, 1990. 2. Braunstein GD: Gynecomastia. N Engl J Med 328: 490-495,1993. 3. Carlson HE: Current concepts. Gynecomastia. N Engl J Med 303: 795-799, 1980. 4. Lemack GE, Poppas DP, and Vaughan ED: Urologic causes of gynecomastia: approach to diagnosis and management. Urology 45: 313-319, 1995. 5. Richie JP: Neoplasms of the testis, in Walsh PC, Retik AB, Stamey TA, and Vaughan ED Jr (Eds): Campbell’s LJrology. Philadelphia, WB Saunders, 1992, vol. 2, pp 1222-1262. 6. Tseng A Jr, Sandra JH, Freiha FS, Resser JK, Hannigan JF Jr, and Torti FM: Gynecomastia in testicular cancer patients: prognostic and therapeutic implications. Cancer 56: 2534-2538, 1985. 7. Saeter G, Fossa SD, and Norman N: Gynecomastia following cytotoxic therapy for testicular cancer. Br J Urol 59: 348-352, 1986. 8. Stepanas AV, Samaan NA, Schultz PN, and Holoye PY: Endocrine studies in testicular tumor patients with and without gynecomastia. Cancer 41: 369-376, 1978. 9. Trumph DL, Pavy MD, and Staal S: Gynecomastia in men following antineoplastic therapy. Arch Intern Med 142: 511-513, 1982. 10. Sherins RJ, Olweny CLM, and Ziegler JL: Gynecomastia and gonadal dysfunction in adolescent boys treated with combination chemotherapy for Hodgkin’s disease. N Engl J Med 299: 12- 16, 1978. 11. Glass MAR, and Berenberg LCJ: Gynecomastia after chemotherapy for lymphoma. Arch Intern Med 139: 10481049, 1979. 12. Trumph DI, and Anderson SA: Painful gynecomastia following cytotoxic therapy for testis cancer. A potentially favorable prognostic sign? J Clin Oncol 1: 416-420, 1983.
UROLOGY
48 (61, 1996
CYNECOMASTIA AS A COMPLICATION OF CHEMOTHERAPY FOR TESTICULAR GERM CELL TUMORS FAZIL
TUNCAY
AKI, MEHMET
ALTER@ -r&N,
AND
HAWK
OVEN
ABSTRACT Among 190 patients with metastatic testicular cancer who were treated by platinum-based combination chemotherapy and achieved complete remission, 4 (2.1%) developed gynecomastia 2 to 5 months after the cessation of chemotherapy. All of these patients had normal serum levels of the beta subunit of human chorionic gonadotropin and testosterone levels at the lower range of normal, but they had elevated levels of follicle-stimulating hormone, luteinizing hormone, and estradiol. The cause of gynecomastia in our patients was probably these increased levels of gonadotropins that, in turn, stimulated increased secretion of testicular estrogen, thus altering the normal estradiol-testosterone ratio. Treatment-related gynecomastia, which may occur several months after the cessation of cytotoxic chemotherapy, does not necessarily mean the return of disease. It is important to recognize this fact so as to prevent unnecessary investigations that will cause psychological distress in a young patient with testicular cancer. Copyright 1996 by Elsevier Science inc. UROLOGY 48: 944-946, 1996.
ynecomastia, defined as a concentric increase of greater than 2 cm in diameter in glandular and stromal tissue in the male breast, is a common disorder, especially in adolescent boys and during the male climacteric years.1,2 Some endrocrinopathies, some tumors, many drugs, and chronic systemic and familial diseases may cause gynecomastia.lm4 Development of gynecomastia in a patient who has a known malignant disease may cause physicians to anticipate a relapse. We herein report 4 men who developed gynecomastia after cytotoxic chemotherapy for metastatic testicular germ cell tumor. The importance of gynecomastia as a complication of the chemotherapy is discussed.
G
CASE REPORTS CASE 1
A 31-year-old man underwent right inguinal orchiectomy for an embryonal cell carcinoma of the testis. While the patient was under surveillance for From the School of Medicine, Department of Urology, Hacettepe University, Ankara, Turkey Reprint requests: H&k &en, M.D., Department of Uro-oncology, Kuleli Sokak, 9/2, Gaziosmanpasa 06700, Ankara, Turkey
Submitted: March 6, 1996, accepted (with 20, 1996
944
COPYRIGHT ALLRIGHTS
1996 BY ELSEVIER SCIENCE RESERVED
revisions): June
INC.
Stage I disease, a retroperitoneal lymph node metastasis of 3 cm was detected on computed tomography (CT) 5 months after orchiectomy. Serum beta subunit of human chorionic gonadotropin (beta-hCG > and alpha-fetoprotein (alpha-FP) were normal. After administration of three courses of bleomycin, eteposide, and cis-platin (BEP) combination chemotherapy, complete remission was achieved. Right-sided, painful, diffuse gynecomastia without discharge developed 4 months after the cessation of chemotherapy. The patient was taking no medication at this time. His hormonal profile is shown in Table I. Gynecomastia was thought to be a complication of systemic cytotoxic chemotherapy. The patient was followed up for 12 months after the onset of gynecomastia; he remained in complete remission without any therapy, and the gynecomastia resolved completely. CASE 2
A 17-year boy was found to have a right testicular mass. Following a right inguinal orchiectomy, BEP combination chemotherapy was administered for clinical Stage IIA embryonal cell carcinoma of the testis. Five courses of chemotherapy resulted in complete remission after 4 months. Five months after cessation of the chemotherapy, the patient noted an enlargement and tenderness of both 0090-4295/96/$15.00 PII SOO90-4295(96)00303-Z
TABLE
1.
Serum hormone levels of patients who developed affer cytotoxic chemotherapy
Patient
Beta-hCG (mlU/mL)
FSH (mlU/mL)
(mlkl7ml)
1 2 3 4 Normal values
1.6 1.8 2.1 1.4 O-10.4
19.5 19.9 22.4 21.6 0.9-9.8
13.8 15.2 14.6 14.8 2.2-12
KEY: beta-hCG
= beta subunit
of human
chorionic
gonadotropin,
FSH = follicle-stimulating
breasts without any discharge. At that time, he was in clinical remission and serum beta-hCG was normal. Follicle-stimulating hormone (FSH) , luteinizing hormone (LH) , and estradiol were elevated, as in our first patient (Table I). Testosterone was at the lower limit of normal. The gynecomastia resolved over the next 4 months, and 15 months after the end of the chemotherapy, the patient is still disease free. CASE 3 A 28-year-old man with stage IV-CL3 embryonal cell carcinoma of the right testis according to the Royal Marsden classification5 had a complete remission of the pulmonary metastases and partial remission of the abdominal mass after five courses of cis-platin, vincristine (oncovin) , methotrexate, and bleomycin (POMB) and four courses of actinomycin D, cyclophosphamide, and eteposide (ACE) chemotherapy. Pathological examination of the mass removed during postchemotherapeutic abdominal surgery revealed necrosis. Two months after completion of the chemotherapy, bilateral, nontender breast enlargement was noted. The patient’s serum beta-hCG was normal (Table I ) . The gynecomastia disappeared completely over the next 4 months, and the patient remained in complete remission without any therapy for 12 months after the cessation of the chemotherapy. CASE 4 A 25-year-old man was found to have a left testicular mass with palpable abdominal mass. Following left inguinal orchiectomy, BEP combination chemotherapy was administered for clinical Stage IIC mixed germ cell carcinoma of the testis. After five courses of chemotherapy and retroperitoneal postchemotherapeutic surgery, complete remission was achieved. Left-sided tender gynecomastia developed 3 months after the end of chemotherapy, the patient’s serum beta-hCG was normal, and hormonal data were comparable to those of our other 3 patients (Table I). Ten months following the recognition of left-sided gynecomastia, the patient remains in complete remission, and UROLOGY
48 (61, 1996
gynecomastia
Testosterone (ng/mLl
Estradiol @g/W
Prolactin (ng/mL)
95 76 88 82 lo-60
7.3 7.8 8.5 6.8 0.2-9.4
4.9 4.2 4.3 5.1 3-10 hormone,
LH = luteinizing
hormone.
the gynecomastia disappeared spontaneously 3 months after its onset. However, the patient occasionally complains of mild breast tenderness. COMMENT Over the last 5 years, we have treated and followed 190 patients with testicular cancer with platinum-based chemotherapy; thus the 4 patients presented here represent 2.1% of our patient group. Gynecomastia can be associated with a number of disorders. In our patients, gynecomastia appeared several months after the cessation of the cytotoxic chemotherapy for testicular germ cell cancer. There was no clinical evidence of any endocrine and systemic disease and no history of drug abuse or medication in these patients. Gynecomastia has resolved in all of our patients within 4 months at most. Similarly, Tseng et a1.6 and Saeter et ~1.~ have also reported that chemotherapy-related gynecomastia subsided within a period of 12 months, in 100% and 75% of patients, respectively. In a patient with testicular cancer, breast enlargement may also be associated with ectopic production of beta-hCG by the neoplastic tissue,’ but this was not the case in the patients we discuss here. Gynecomastia may also develop as a side effect of the chemotherapy.6’7’9-12 Elevated serum FSH level secondary to testicular germ cell damage due to chemotherapeutic agents is well known. Increased concentration of LH may indicate damage of the Leydig cells. On the other hand, elevated serum LH values with normal serum testosterone levels indicate a slightly decreased but compensated Leydig cell function. Under the influence of high gonadotropin levels, the testis secretes relatively more estrogen than testosterone.g Sherins et a1.l’ have described gynecomastia in adolescent boys treated with combination chemotherapy for Hodgkin’s disease and have suggested that alterations in the testosterone/estrogen ratio may be responsible for the development of treatment-related gynecomastia. Glass and Berenberg” and Trumph et a1.9 have each described gynecomastia after cy945
totoxic chemotherapy in patients with testicular cancer and have suggested an elevated estrogen/ androgen ratio as the cause. It has also been suggested that, the latter ratio may be changed by alterations in the peripheral metabolism of testosterone and that the resulting elevation of estradiol may promote the development of gynecomastia. However, this hypothesis needs to be confirmed. The findings in our 4 patients of increased serum FSH, LH, and estradiol levels and normal levels of testosterone, with all serum testosterone values at the lower range of normal, suggest that this ratio is indeed important in the development of gynecomastia. Although many alterations occur in estrogen and testosterone production, hormonal status, and gonadal function in patients receiving chemotherapy for cancer, there are no convincing data available to explain the exact mechanism of postchemotherapy gynecomastia. The incidence of treatment-related gynecomastia is expected to be higher in patients with testicular cancer than in other cancer patients owing to the significant reduction of a testosterone-producing tissue. On the other hand, the observation of unilateral gynecomastia in 2 of 4 of our patients emphasizes that not only hormonal disturbances but also local phenomena such as the number of estrogen receptors in the breast tissue may be factors in the development of gynecomastia. Saeter et ~1.~ have speculated that gynecomastia was not a direct result of hormonal disturbances only, as a few of their patients who had high estradiol, LH, and FSH did not develop gynecomastia. The observation that the hormonal disturbances did not necessarily return to normal with the resolution of gynecomastia also casts doubt on a hormonal theory. Further studies are required to shed light on the pathogenic process. Gynecomastia at the time of diagnosis has been found to be an unfavorable prognostic sign for patients with testicular cancer.6 Trumph and Anderson i2 suggested that patients who developed treatment-related gynecomastia had a favorable prognosis, However, Tseng et ~1.~ and Saeter et a1.7 have not found a statistically significant difference
946
in the survival of patients who developed treatment-related gynecomastia. The small number of patients with gynecomastia whom we have treated does not support firm conclusions about the prognostic effect of treatment-related gynecomastia. Larger series and longer follow-up is required. Whatever the mechanism, in adults, gynecomastia may occur several months following the cessation of cytotoxic chemotherapy of testicular cancer and does not necessarily mean the return of disease. Recognition of this fact is important to prevent unnecessary investigations that will cause psychological distress in a young patient with testicular cancer. REFERENCES 1. Mahoney CP: Adolescent gynecomastia: differential diagnosis and management. Pediatr Clin North Am 37: 13891404, 1990. 2. Braunstein GD: Gynecomastia. N Engl J Med 328: 490-495,1993. 3. Carlson HE: Current concepts. Gynecomastia. N Engl J Med 303: 795-799, 1980. 4. Lemack GE, Poppas DP, and Vaughan ED: Urologic causes of gynecomastia: approach to diagnosis and management. Urology 45: 313-319, 1995. 5. Richie JP: Neoplasms of the testis, in Walsh PC, Retik AB, Stamey TA, and Vaughan ED Jr (Eds): Campbell’s LJrology. Philadelphia, WB Saunders, 1992, vol. 2, pp 1222-1262. 6. Tseng A Jr, Sandra JH, Freiha FS, Resser JK, Hannigan JF Jr, and Torti FM: Gynecomastia in testicular cancer patients: prognostic and therapeutic implications. Cancer 56: 2534-2538, 1985. 7. Saeter G, Fossa SD, and Norman N: Gynecomastia following cytotoxic therapy for testicular cancer. Br J Urol 59: 348-352, 1986. 8. Stepanas AV, Samaan NA, Schultz PN, and Holoye PY: Endocrine studies in testicular tumor patients with and without gynecomastia. Cancer 41: 369-376, 1978. 9. Trumph DL, Pavy MD, and Staal S: Gynecomastia in men following antineoplastic therapy. Arch Intern Med 142: 511-513, 1982. 10. Sherins RJ, Olweny CLM, and Ziegler JL: Gynecomastia and gonadal dysfunction in adolescent boys treated with combination chemotherapy for Hodgkin’s disease. N Engl J Med 299: 12- 16, 1978. 11. Glass MAR, and Berenberg LCJ: Gynecomastia after chemotherapy for lymphoma. Arch Intern Med 139: 10481049, 1979. 12. Trumph DI, and Anderson SA: Painful gynecomastia following cytotoxic therapy for testis cancer. A potentially favorable prognostic sign? J Clin Oncol 1: 416-420, 1983.
UROLOGY
48 (61, 1996