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Cystic Fibrosis and Embryonal Carcinoma of the Testis
Case Report: Cystic Fibrosis and Embryonal Carcinoma of the Testis JEFFREY M. MILUNSKY, MD,
AUBREY MILUNSKY, MBBCh, DSc, FRCP, FACMG, DCH
ABSTRACT: The authors describe a patient with cystic fibrosis and a stage III testicular embryonal cell cancer. Because cystic fibrosis occurs in approximately 1 of 2,500 births and embryonal carcinoma in 3 of 100,000, the likelihood of concurrence for both disorders in the same patient is approximately 1 in 80 million. Involvement of the vas deferens in cystic fibrosis raises the possibility of a fundamental embryologic basis that explains the pathogenesis of this association. KEY INDEXING TERMS: Cystic fibrosis; Embryonal carcinoma. [Am J Med Sci 1996;311(4):191-192.]
A
n increased risk of gastrointestinal tract cancers in patients with cystic fibrosis (CF) was reported.1 The proposed etiologic mechanism for this association is a disruption in an organ system affected by the cystic fibrosis disease process. Certain urogenital findings described in CF include bilateral absence of the vas deferens,Z· 3 rudimentary development of the entire mesonephric ductal system, and an increased incidence of inguinal hernias, hydrocele, and undescended testes. 4 In this context, we describe a patient with CF with stage III testicular embryonal cancer. Case Report The patient was a 25-year-old white man homozygous for the common CF mutation with significant pulmonary disease (with Pseudomonas infection) and moderate pancreatic insufficiency. His family history was notable for colon cancer in a paternal grandmother and a maternal grandfather. His mother had diverticulitis and polyps. Two weeks before admission, the patient experienced scrotal discomfort and noticed an enlargement in his right testicle, with increased firmness and irregularity. On physical examination, his right testis was approximately twice the size of the left. The anterior inferior pole was irregular and hard to palpation. The epididymis was felt posteriorly and the spermatic cord was palpated. The left testis appeared to be normal, as was the remainder of the urogenital ex-
From the Center for Human Genetics, Boston University School of Medicine, Boston, Massachusetts. Submitted December 19, 1995, and accepted December 29, 1995. Correspondence: Aubrey Milunsky, MD, Center for Human Genetics, Boston University School of Medicine, 80 E. Concord St., W-409B, Boston, MA 02118. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
amination. On ultrasound, an intratesticular tumor with hypoechoic areas on the mid and inferior pole of the right testicle was observed. The beta-hCG level was increased to 156 units/L (reference range < 2.5 units/L). The alpha-fetoprotein level was within the normal range. The patient underwent a right radical orchiectomy. During the operation, it was noted that after the spermatic cord was mobilized, the vas deferens could not be visualized or palpated. On gross examination of the specimen, the testis itself measured 4.3 X 3.5 X 3.0 em. The testicle was bivalved to reveal an irregular, necrotic, hemorrhagic, tan-to-red tumor measuring 3.0 em in diameter. On microscopic examination, numerous sections through the testicle revealed a malignant proliferation of papillary, solid, and gland-like clusters of highly anaplastic-appearing cells. This finding was consistent with embryonal carcinoma. There was no evidence of choriocarcinoma or seminoma microscopically. The tumor did not invade through the capsule or into any adjacent structures. Metastatic workup was negative at that time. His beta-hCG level returned to normal. Three months after his right radical orchiectomy, his beta-hCG level increased to 19 units/L and he underwent a modified retroperitoneal lymph node dissection. This revealed one lymph node, 2 em in size, that was positive for embryonal cancer. The patient underwent restaging 4 months later when his beta hCG level increased from <2.5 units/L to 31 units/L and then to 97.8 units/L, and his alpha-fetoprotein level was elevated for the first time at 11.7 mg/ mL (normal 0-6.6 mg/mL). Physical examination at this time was unremarkable. Chest computed tomography was notable for multiple pulmonary nodules several millimeters to 1 em in diameter, 5-10 per lung field, superimposed on the chronic changes associated with his CF. No mediastinal adenopathy was appreciated. Abdominal/pelvic computed tomography showed new minimal retroperitoneal adenopathy. The liver was normal and was described as free of tumor. The tumor was then classified as stage III. Four cycle chemotherapy with etoposide and platinum was started. Bleomycin was omitted from the regimen to avoid further pulmonary toxicity. After the first cycle, the pulmonary nodules were no longer evident on chest x-ray, demonstrating rapid good response to the chemotherapy. Subsequently, he experienced a relapse in the left lower lobe of the lung, confirmed by computed tomography-guided biopsy and treated with two cycles of salvage chemotherapy, with no response. He underwent radiation therapy to the left lung, with resolution of all pulmonary nodules. To date, more than 2 years after radiation treatment, there is no evidence of testicular cancer by physical examination, computed tomography scan, or tumor markers.
Discussion
The frequency of embryonal carcinoma is approximately 3 in 100,000, and occurs as the most common neoplasm in men between the ages of 25 and 35. 5 To our knowledge, this is the first case documenting the occurrence of embryonal carcinoma in a patient with CF. Neglia et al 6 describe a patient with CF and seminoma, and more recently, on four patients with CF 191
Cystic Fibrosis Testicular Cancer
with testicular cancers. 1 Two of these four patients had histologically proven embryonal carcinoma of the testis (JP Neglia, personal communication). These authors reported no significant increase in nondigestive tract cancers in patients with CF. The likelihood of concurrent CF and embryonal testicular cancer is so remote (1 in 80 million) that a less fortuitous association need be considered. This consideration may be especially important given the increasing numbers of surviving adults with CF. The previous apparent rarity of this association may be more reflective of earlier high mortality rates. Median survival age doubled between 1969 and 1990, from 14 to 28 years.7 A literature review revealed no other cases with this association. A fundamental embryologic basis may explain the pathogenesis of this association. During the fifth week of embryonal development, the gonadal ridge is formed on the medial side of the mesonephros. Cells from this area eventually differentiate into the testis. The efferent ductules of the head of the epididymis arise from remnants of the caudal tubules of the mesonephros. The W olffian or mesonephric duct gives rise to the ductus epididymis, vas deferens, and seminal vesicle. Arrest of development before a critical stage can result in incomplete formation of the epididymis, vas deferens, ejaculatory duct, and seminal vesicle in the presence of a fully developed testis. Embryonal carcinoma may have its root
192
in the arrest or disruption of embryonic cells that migrate to form the ductal system, which results in abnormal embryonic rests of cells that may later become neoplastic. Whether the association between CF and embryonal testicular cancer is significant remains to be established in surviving aging men. Given the increasing survival rates for CF, physicians could be encouraged not to omit annual testicular examinations in these adult men. References 1. Neglia JP, Fitzsimmons SC, Maisonneuve P, Schoni MH,
2.
3.
4.
5.
6. 7.
Schoni-Affolter F, Corey M, et al. The risk of cancer among patients wth cystic fibrosis. N Eng! J Med. 1995;332:494- 9. Anguiano A, Oates RD, Amos JA, Dean M, Gerrard B, Stewart C, et al. Congenital bilateral absence of the vas deferens. JAMA. 1992;267:1794-7. Mickle J, Milunsky A, Amos JA, Oates RD. Congenital unilateral absence of the vas deferens: A heterogeneous disorder with two distinct subpopulations based upon aetiology and mutational status of the cystic fibrosis gene. Hum Reprod. 1995;10: 1728- 35. Holsclaw DS, Perlmutter AD, Jockin H, Shwachman H. Genital abnormalities in male patients with cystic fibrosis. J Urol. 1971;106:568- 74. Schofield PN. Developmental tumours. Br Med Bull. 1991;47: 227- 43. Neglia JP, Wielinski CL, Warwick WJ. Cancer risk among patients with cystic fibrosis. J Pediatr. 1991;119:764-6. Fitzsimmons SC. The changing epidemiology of cystic fibrosis. J Pediatr. 1993;122:1-9.
April 1996 Volume 311 Number 4
AUBREY MILUNSKY, MBBCh, DSc, FRCP, FACMG, DCH
ABSTRACT: The authors describe a patient with cystic fibrosis and a stage III testicular embryonal cell cancer. Because cystic fibrosis occurs in approximately 1 of 2,500 births and embryonal carcinoma in 3 of 100,000, the likelihood of concurrence for both disorders in the same patient is approximately 1 in 80 million. Involvement of the vas deferens in cystic fibrosis raises the possibility of a fundamental embryologic basis that explains the pathogenesis of this association. KEY INDEXING TERMS: Cystic fibrosis; Embryonal carcinoma. [Am J Med Sci 1996;311(4):191-192.]
A
n increased risk of gastrointestinal tract cancers in patients with cystic fibrosis (CF) was reported.1 The proposed etiologic mechanism for this association is a disruption in an organ system affected by the cystic fibrosis disease process. Certain urogenital findings described in CF include bilateral absence of the vas deferens,Z· 3 rudimentary development of the entire mesonephric ductal system, and an increased incidence of inguinal hernias, hydrocele, and undescended testes. 4 In this context, we describe a patient with CF with stage III testicular embryonal cancer. Case Report The patient was a 25-year-old white man homozygous for the common CF mutation with significant pulmonary disease (with Pseudomonas infection) and moderate pancreatic insufficiency. His family history was notable for colon cancer in a paternal grandmother and a maternal grandfather. His mother had diverticulitis and polyps. Two weeks before admission, the patient experienced scrotal discomfort and noticed an enlargement in his right testicle, with increased firmness and irregularity. On physical examination, his right testis was approximately twice the size of the left. The anterior inferior pole was irregular and hard to palpation. The epididymis was felt posteriorly and the spermatic cord was palpated. The left testis appeared to be normal, as was the remainder of the urogenital ex-
From the Center for Human Genetics, Boston University School of Medicine, Boston, Massachusetts. Submitted December 19, 1995, and accepted December 29, 1995. Correspondence: Aubrey Milunsky, MD, Center for Human Genetics, Boston University School of Medicine, 80 E. Concord St., W-409B, Boston, MA 02118. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
amination. On ultrasound, an intratesticular tumor with hypoechoic areas on the mid and inferior pole of the right testicle was observed. The beta-hCG level was increased to 156 units/L (reference range < 2.5 units/L). The alpha-fetoprotein level was within the normal range. The patient underwent a right radical orchiectomy. During the operation, it was noted that after the spermatic cord was mobilized, the vas deferens could not be visualized or palpated. On gross examination of the specimen, the testis itself measured 4.3 X 3.5 X 3.0 em. The testicle was bivalved to reveal an irregular, necrotic, hemorrhagic, tan-to-red tumor measuring 3.0 em in diameter. On microscopic examination, numerous sections through the testicle revealed a malignant proliferation of papillary, solid, and gland-like clusters of highly anaplastic-appearing cells. This finding was consistent with embryonal carcinoma. There was no evidence of choriocarcinoma or seminoma microscopically. The tumor did not invade through the capsule or into any adjacent structures. Metastatic workup was negative at that time. His beta-hCG level returned to normal. Three months after his right radical orchiectomy, his beta-hCG level increased to 19 units/L and he underwent a modified retroperitoneal lymph node dissection. This revealed one lymph node, 2 em in size, that was positive for embryonal cancer. The patient underwent restaging 4 months later when his beta hCG level increased from <2.5 units/L to 31 units/L and then to 97.8 units/L, and his alpha-fetoprotein level was elevated for the first time at 11.7 mg/ mL (normal 0-6.6 mg/mL). Physical examination at this time was unremarkable. Chest computed tomography was notable for multiple pulmonary nodules several millimeters to 1 em in diameter, 5-10 per lung field, superimposed on the chronic changes associated with his CF. No mediastinal adenopathy was appreciated. Abdominal/pelvic computed tomography showed new minimal retroperitoneal adenopathy. The liver was normal and was described as free of tumor. The tumor was then classified as stage III. Four cycle chemotherapy with etoposide and platinum was started. Bleomycin was omitted from the regimen to avoid further pulmonary toxicity. After the first cycle, the pulmonary nodules were no longer evident on chest x-ray, demonstrating rapid good response to the chemotherapy. Subsequently, he experienced a relapse in the left lower lobe of the lung, confirmed by computed tomography-guided biopsy and treated with two cycles of salvage chemotherapy, with no response. He underwent radiation therapy to the left lung, with resolution of all pulmonary nodules. To date, more than 2 years after radiation treatment, there is no evidence of testicular cancer by physical examination, computed tomography scan, or tumor markers.
Discussion
The frequency of embryonal carcinoma is approximately 3 in 100,000, and occurs as the most common neoplasm in men between the ages of 25 and 35. 5 To our knowledge, this is the first case documenting the occurrence of embryonal carcinoma in a patient with CF. Neglia et al 6 describe a patient with CF and seminoma, and more recently, on four patients with CF 191
Cystic Fibrosis Testicular Cancer
with testicular cancers. 1 Two of these four patients had histologically proven embryonal carcinoma of the testis (JP Neglia, personal communication). These authors reported no significant increase in nondigestive tract cancers in patients with CF. The likelihood of concurrent CF and embryonal testicular cancer is so remote (1 in 80 million) that a less fortuitous association need be considered. This consideration may be especially important given the increasing numbers of surviving adults with CF. The previous apparent rarity of this association may be more reflective of earlier high mortality rates. Median survival age doubled between 1969 and 1990, from 14 to 28 years.7 A literature review revealed no other cases with this association. A fundamental embryologic basis may explain the pathogenesis of this association. During the fifth week of embryonal development, the gonadal ridge is formed on the medial side of the mesonephros. Cells from this area eventually differentiate into the testis. The efferent ductules of the head of the epididymis arise from remnants of the caudal tubules of the mesonephros. The W olffian or mesonephric duct gives rise to the ductus epididymis, vas deferens, and seminal vesicle. Arrest of development before a critical stage can result in incomplete formation of the epididymis, vas deferens, ejaculatory duct, and seminal vesicle in the presence of a fully developed testis. Embryonal carcinoma may have its root
192
in the arrest or disruption of embryonic cells that migrate to form the ductal system, which results in abnormal embryonic rests of cells that may later become neoplastic. Whether the association between CF and embryonal testicular cancer is significant remains to be established in surviving aging men. Given the increasing survival rates for CF, physicians could be encouraged not to omit annual testicular examinations in these adult men. References 1. Neglia JP, Fitzsimmons SC, Maisonneuve P, Schoni MH,
2.
3.
4.
5.
6. 7.
Schoni-Affolter F, Corey M, et al. The risk of cancer among patients wth cystic fibrosis. N Eng! J Med. 1995;332:494- 9. Anguiano A, Oates RD, Amos JA, Dean M, Gerrard B, Stewart C, et al. Congenital bilateral absence of the vas deferens. JAMA. 1992;267:1794-7. Mickle J, Milunsky A, Amos JA, Oates RD. Congenital unilateral absence of the vas deferens: A heterogeneous disorder with two distinct subpopulations based upon aetiology and mutational status of the cystic fibrosis gene. Hum Reprod. 1995;10: 1728- 35. Holsclaw DS, Perlmutter AD, Jockin H, Shwachman H. Genital abnormalities in male patients with cystic fibrosis. J Urol. 1971;106:568- 74. Schofield PN. Developmental tumours. Br Med Bull. 1991;47: 227- 43. Neglia JP, Wielinski CL, Warwick WJ. Cancer risk among patients with cystic fibrosis. J Pediatr. 1991;119:764-6. Fitzsimmons SC. The changing epidemiology of cystic fibrosis. J Pediatr. 1993;122:1-9.
April 1996 Volume 311 Number 4