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Primary choriocarcinoma of the urinary bladder: A case report
Clinical Oncology (1996) 8:59-61 © 1996 The Royal College of Radiologists
Clinical Oncology
Case Report P r i m a r y C h o r i o c a r c i n o m a of the U r i n a r y Bladder: A Case R e p o r t S. D. Tinkler 1, J. T. Roberts 1, M. C. Robinson a and P.D. Ramsden 2 aNewcastle General Hospital and Freeman Hospital, Newcastle upon Tyne, UK
Abstract. We present a 37-year-old patient with primary choriocarcinoma arising in the urinary bladder, who received 5 months of intensive chemotherapy with a very good response. He died of a pulmonary embolus before his treatment could be completed. A post-mortem examination revealed extensive necrotic nodules in the lungs and brain. There was only one small focus of viable tumour in the brain. There was no residual tumour in the bladder, and no testicular tumours or scars fulfilling the criteria for a true extragonadal teratoma. It is likely that the origin of the bladder choriocarcinomas is from metaplasia/de-differentiation of a transitional cell carcinoma to the level of trophoblast. Lesser degrees of differentiation producing functional changes in the carcinoma cells with secretion of flhCG without structural changes are much more common.
Keywords: Bladder; Choriocarcinoma
INTRODUCTION There have been 11 well documented case reports of extragonadal choriocarcinoma arising in the urinary bladder published in the English literature, the first in 1939 by Weinberg [1] (Djewitzki, however, reported the first patient in 1904 [2]). Three tumours were pure choriocarcinoma [1,3,4], eight were associated with either transitional cell carcinoma [5-10] or 'undifferentiated carcinoma' [11,12]. Most patients were elderly and all presented with a short history of haematuria and developed pulmonary metastases. There have been no reported long term survivors. All the patients reported in the literature were dead at the time of publication except for one, whose follow-up time was very short [11]. There have been other reported choriocarcinomas arising in the urinary bladder, but there is some doubt about the sites of origin, as thorough examinations of the testes were not performed. It is generally accepted that the testes must be free of cysts, tumour, scars etc. on serial histological sections before a choriocarcinoma can be classed as extragonadal [6,12,13].
Correspondence and offprint requests to: Dr S. D. Tinkler, Wessex Radiotherapy Centre, Royal South Hants Hospital, Off Brinton Terrace, St Mary's Road, Southampton SO14 0YG, UK.
We present a case report of choriocarcinoma of the urinary bladder, which occurred in a 37-year-old man.
CASE REPORT A 37-year-old heavy goods vehicle driver presented with a 3-year history of intermittent painless haematuria. This had become much worse prior to referral, with the passage of bright red blood two or three times per day. He had also been passing small stones in the urine every few months. His haematuria had been investigated 26 months before presentation, with urine cytology, intravenous urography and cystoscopy. Apart from the presence of a 3 mm renal calculus and a small localized area of biopsy-proven chronic cystitis above the lateral to the right ureteric orifice, no abnormalities were found. On admission he was clinically anaemic but otherwise well with no abdominal, genital or rectal abnormality. Anaemia was confirmed at a haemoglobin of 8.3 g/dl, with the hypochromic, microcytic picture of iron deficiency. He was admitted to hospital 4 days later with increasing weakness, breathlessness on minimal exertion, and nocturia. He was very pale and unwell. The haemoglobin had fallen to 7.2 g/dl. He was transfused while further investigations were instituted. Urine cytology was normal. A chest radiograph (CXR) showed extensive bilateral intrapulmonary opacities consistent with metastases. A C T scan confirmed extensive pulmonary metastases and demonstrated a large mass, containing some calcification, arising from the fundus and extending into the right lateral wall of the bladder. There was also evidence of extension into the perivescial fat and sigmoid colon. Bimanual examination under anaesthesia revealed a 15 cm firm mobile mass at the apex of the bladder. At cystoscopy the lumen of the bladder was entirely filled by a massive solid tumour. Deep resection biopsies were taken, but complete resection of the mass was not attempted and bimanual examination following this procedure was unchanged. Initial histological examination of the bladder biopsies suggested an anaplastic bladder carcinoma. The patient was immediately commenced on chemotherapy with epirubicin 50 mg/m 2 and cisplatin 70 mg/m a on day 1 (with hydration and antiemetics), followed by methotrexate 40 mg/m 2 on days 8 and 15 (EPI C-M). Following the first day of chemotherapy he became confused and developed hiccoughs; these symptoms rapidly settled. A cerebral CT scan was normal. Prior to the second course of chemotherapy, the results of the initial serum flhCG became available. This was grossly elevated at 64 600 iu/1. Serum levels of alpha-foetoprotein (AFP) and lactic dehydrogenase (LDH) were normal. As he was tolerating the chemotherapy very well, his symptoms had improved,
60 and the serum flhCG had fallen to 21800 iu/1, he received a second course without event. Unfortunately, the serum flhCG began to rise again (to 47100 iu/1) before the third course. The turnout pathology was reviewed at this time. Histological examinations of the biopsies showed an extensively haemorrhagic and necrotic tumour composed of two cell types (Fig. 1). There were large numbers of multinucleated synctiotrophoblastic giant cells, which stained positively for flhCG, admixed with sheets of cytotrophoblastic cells having clear or basophilic cytoplasm and sharp cellular borders. In other areas, undifferentiated tumour was seen. No papillary transitional cell carcinoma was identified and there was no urothelial dysplasia. There were large vascular spaces within the tumour, which invaded the detrusor muscle. The diagnosis of choriocarcinoma was made. It was not clear whether the undifferentiated elements represented solid urothelial carcinoma or pure cytotrophoblast. It was considered that, in the absence of definitive transitional cell elements within the tumour, it was more correctly regarded as a primary choriocarcinoma of the bladder. In view of this, and a rising serum flhCG, a decision was made to change to a chemotherapy regimen more appropriate for the treatment of a germ cell tumour. The patient Was started on POMB/ACE chemotherapy initially, with two courses of POMB followed by ACE, then alternating POMB with ACE. POMB consisted of day 1: vincristine 1 mg/m2 i.v. bolus and methotrexate 300 mg/m2 i.v. over 12 hours; day 2: bleomycin 15 mg as a 24hour i.v. infusion and folinic acid rescue; day 3: bleomycin 15 mg infused i.v. over 24 hours; day 4: cisplatin 120 mg/m2 infused i.v. over 12 hours with hydration and antiemetics. A C E consisted of etoposide 100 mg/m 2 on days 1-5 inclusive, actinomycin-D 0.5 mg on days 3-5, and cyclophosphamide 500 mg/m 2 on day 5. The interval between each course was 9-11 days. He received a total of four courses of POMB and two courses of ACE. He tolerated the chemotherapy well. During the admission for his first course of POMB he complained of persistent headaches. A CT scan showed the presence of multiple small brain metastases. Dexamethasone was started with good resolution of the headaches. Throughout the chemotherapy, the serum flhCG continued to fall, to reach its lowest level of 12 iu/1, 5 months after presentation (Fig. 2). The serum AFP remained normal throughout, although the serum LDH rose steadily from 346 iu/1 (normal) in August, at the start of the intensive chemotherapy, to 1775 iu/1 in November. The CXR appearance steadily improved with the chemotherapy, although the metastases were still visible. The clinical course was further complicated by the
Fig. 1. Choriocarcinoma showing positive staining reaction for the beta subunit of hCG in the synctiotrophoblast (broad arrow). The cytotrophoblast (narrow arrow) in unstained (× 300).
S. D. Tinkler et al. b
c
d
e
f
g
h
100000
10000 .E
1000
=o E
100
(/3
10
0
I
I
I
I
50
I00
150
200
Time (days from diagnosis)
Fig. 2. Serum flhCG levels throughout treatment. The arrows indicate day 1 of each cycle of chemotherapy (see text for details). a: first EPIC-M; b: second EPIC-M; c: first POMB; d: second POMB; e: first ACE; f: third POMB; g: second ACE; h: fourth pOMB.
development of a left deep vein thrombosis just prior to the second and last course of ACE. The patient was prescribed ibuprofen and given elasticated leg stockings. He was not anticoagulated because of the risk of haemorrhage into the brain metastases. The day after completion of the second A C E chemotherapy he became acutely breathless and was found to be in fast atrial fibrillation. He was digitalized, with resolution of the symptoms and normalization of the heart rate. When he was admitted for the next course of chemotherapy he was found to be unwell with anorexia, nausea, vomiting and increasing lethargy. Acute renal failure was diagnosed; the serum urea was 101.5 mmol/1 and the creatinine 2245/~mol/l. A n ultrasound examination showed abnormal echoity of the renal pyramids but no hydronephrosis. Haemodialysis produced rapid normalization of the serum urea and creatinine although he had episodes of hypotension. A repeat cerebral CT scan showed improvement, with no metastases visible. Unfortunately, the patient had a respiratory arrest 5 days after commencing haemodialysis and, although he was successfully resuscitated, he required ventilation in the intensive care unit. There he continued to have problems with hypotension despite inotropic support. He also developed a right-sided pneumothorax and a bronchopleural fistula. A CXR still showed the presence of pulmonary metastases and a decision was taken to withdraw further active therapy when his clinical condition continued to deteriorate. He died soon after this, almost 6 months after the initial diagnosis. A post-mortem examination was performed, which showed the cause of death to be a massive pulmonary embolism. There were pulmonary infarcts in both lungs and a bronchopleural fistula had developed within a ruptured pulmonary infarct. Multiple metastatic deposits of necrotic yellow tumour were present in both lungs, ranging from 0.5 cm to 1.5 cm in diameter and there were multiple metastatic nodules of tumour in the brain measuring up to 1.2 cm. Histological examination of the lung nodules showed complete tumour necrosis, with no viable tumour. The cerebral nodules were also necrotic but one nodule showed a residual focus of viable choriocarcinoma. The bladder was filled with spiky calculus material. The wall at the dome was fibrotic and thickened and showed a yellow-brown appearance. Histological examination showed fibrosis and dystrophic calcification only, with no evidence of residual bladder tumour. The testes showed no evidence of tumour or of a fibrous scar.
Primary Choriocarcinoma of the Urinary Bladder
61
DISCUSSION
CONCLUSION
Our patient was much younger than the previously reported patients with choriocarcinoma of the urinary blad~i~r. This disease appears to pursue a very aggressive clinical course, as all the other reported patients had a very short history of symptoms prior to presentation and a rapid decline thereafter. Our patient gave a 3-year history of haematuria, which became much more severe prior to his presentation. It was associated with a short history of breathlessness. The rapid worsening of the symptoms would be in keeping with the aggressive behaviour seen with this type of tumour. It seems likely that the initial intermittent haematuria was due to bladder calculi and that the choriocarcinoma had only been present for a few months. Our patient also differed from most of those reported in the literature in that the diagnosis was made when his clinical condition was relatively good. This, in addition to his relatively young age, allowed us to prescribe aggressive chemotherapy. He received 5 months of intensive chemotherapy before he died of the sequelae of a pulmonary embolus. He was also unique in that his death was not due directly to the tumour, but to a complication of the disease and its treatment. The very good response of this tumour to chemotherapy may offer some hope for treatment of this aggressive disease, which apears to be uniformly fatal. Most of the other reported patients who were given chemotherapy received only a small amount before turnout progression and clinical deterioration prevented further active management [5-7]. Germ cell tumours with adverse prognostic features, for example high levels of turnout markers (AFP >1000 iu/l; ¢flaCG >10000 iu/1) have a relatively poor prognosis with conventional BEP chemotherapy (Neomycin, etoposide and cisplatin). There are four main methods of modifying standard chemotherapy schedules: the introduction of new chemotherapeutic agents; the use of alternating drug combinations; high dose chemotherapy schedules; and chemotherapy using drugs at increased frequency. The POMB/ ACE chemotherapy used in the treatment of our patient has several advantages over BEP in the management of patients with a poor prognosis. The limited myelosuppression of POMB enables the interval between courses to be reduced, and, together with the inclusion of a total of seven drugs in the regimen, the possibility of tumour recovery between courses and the chance of drug resistance developing is reduced. A number of theories of the origin of choriocarcinoma o f the urinary bladder have been proposed. The most feasible is the occurrence of neoplastic transformation, or retrodifferentiation, of a transitional cell carcinoma to the level o f embyronal trophoblast [9,14]. Transitional cell carcinomas of the bladder have been shown to secrete/3hCG into the urine and serum [15-16]. This appears to be relatively common and implies functional, but not structural, differentiation of the carcinomas. It is often associated with a poor prognosis. Full trophoblastic differentiation to produce a choriocarcinoma, however, remains rare. Further support for this theory i s the great ability of transitional cell carcinomas to de-differentiation along several cell lines, as shown by the frequent occurrence of squamous, glandular and, less commonly, small cell elements in these tumours.
Choriocarcinoma of the urinary bladder remains a rare and aggressive disease, which is fatal, often rapidly so. This c~+se report indicates that it can be a very chemosensitive tumour and may offer some hope for future patients in whom it develops. The origin of the tumour is likely to be from metaplasia/de-differentiation of a carcinoma. Lesser degrees of this differentiation appear to be relatively common in transitional cell carcinomas, which can secrete /3hCG without the structural changes necessary for the diagnosis of choriocarcinoma.
References 1. Weinberg T. Primary chorionepithelioma of the urinary bladder in a male patient: A report of a case. Am J Pathol 1939;15:783-95. 2. Djewitzki W. Uber einen fall von chorionepithelioma der harnblase. Virchows Arch 1904;178:451-64. 3. Pollack AD. Malignant teratoma of the urinary bladder: Report of a case. Am J Pathol 1936;12:561-8. 4. Ainsworth RW, Cresham GA. Primary choriocarcinoma of the urinary bladder in a male. J Pathol Bacteriol 1960;79:18592. 5. Fowler AL, Hall E, Rees G. Choriocarcinoma arising in transitional cell carcinoma of the bladder. Br J Urol 1992;70:333-4. 6. Dennis PM, Turner AG. Primary choriocareinoma of the bladder evolving from a transitional cell carcinoma. J Clin Pathol 1984;37:503-5. 7. Obe JA, Rosen N, Koss LG. Primary choriocarcinoma of the urinary bladder: Report of a case with probable epithelial origin. Cancer 1983;52:1405-9. 8. Civantos F, Rywlin AM. Carcinomas with trophoblastic differentiation and secretion of chorionic gonadotrophins. Cancer 1972;29: 789-98. 9. Abrass RP, Temple-Camp CRE, Pontin AR. Choriocarcinoma and transitional cell carcinoma of the bladder: A case report and review of the clinical evolution of disease in reported cases. Eur J Surg Oncol 1989; 15:149-53. 10. Norton KD, Burnett RA. Choriocarcinoma arising in transitional cell carcinoma of the bladder: A case report. Histopathology 1988;12:325-8. 11. Gallagher L, Lind R, Oyasu R. Primary chorioeareinoma of the urinary bladder in association with undifferentiated carcinoma. Hum Pathol 1984;15:793-5 12. Kawamura J, Rhinsho K, Taki Y, et al. Choriocarcinoma and undifferentiated cell carcinoma of the bladder with gonadotrophin secretion. J Urol 1979;121:684-6 13. Grammatico D, Grignon DJ, Eberwein P, et al. Transitional cell carcinoma of the renal pelvis with choriocarcinomatous differentiation. Cancer 1993;71:1835-41. 14. Burry AF, Munn SR, Arnold EP, et al. Trophoblastic metaplasia in urothelial carcinoma of the bladder. Br J Urol 1986;58:143-6. 15. Dexeus F, Logothetis C, Hossan E, et al. Carcinoembryonic antigen and beta human chorionic gonadotrophin as serum markers for advanced urothelial malignancies. J Urol 1986;136:403-7. 16. Crawford SM, Ledermann JA, Turkie W, et al. Is ectopic production of human chorionic gonadotrophin (HCG) or alpha fetoprotein (AFP) by tumours a marker of chemosensitivity? Eur J Cancer Clin Oncol: 1986;22:1483-7.
Received for publication March 1995 Accepted August 1995
Clinical Oncology
Case Report P r i m a r y C h o r i o c a r c i n o m a of the U r i n a r y Bladder: A Case R e p o r t S. D. Tinkler 1, J. T. Roberts 1, M. C. Robinson a and P.D. Ramsden 2 aNewcastle General Hospital and Freeman Hospital, Newcastle upon Tyne, UK
Abstract. We present a 37-year-old patient with primary choriocarcinoma arising in the urinary bladder, who received 5 months of intensive chemotherapy with a very good response. He died of a pulmonary embolus before his treatment could be completed. A post-mortem examination revealed extensive necrotic nodules in the lungs and brain. There was only one small focus of viable tumour in the brain. There was no residual tumour in the bladder, and no testicular tumours or scars fulfilling the criteria for a true extragonadal teratoma. It is likely that the origin of the bladder choriocarcinomas is from metaplasia/de-differentiation of a transitional cell carcinoma to the level of trophoblast. Lesser degrees of differentiation producing functional changes in the carcinoma cells with secretion of flhCG without structural changes are much more common.
Keywords: Bladder; Choriocarcinoma
INTRODUCTION There have been 11 well documented case reports of extragonadal choriocarcinoma arising in the urinary bladder published in the English literature, the first in 1939 by Weinberg [1] (Djewitzki, however, reported the first patient in 1904 [2]). Three tumours were pure choriocarcinoma [1,3,4], eight were associated with either transitional cell carcinoma [5-10] or 'undifferentiated carcinoma' [11,12]. Most patients were elderly and all presented with a short history of haematuria and developed pulmonary metastases. There have been no reported long term survivors. All the patients reported in the literature were dead at the time of publication except for one, whose follow-up time was very short [11]. There have been other reported choriocarcinomas arising in the urinary bladder, but there is some doubt about the sites of origin, as thorough examinations of the testes were not performed. It is generally accepted that the testes must be free of cysts, tumour, scars etc. on serial histological sections before a choriocarcinoma can be classed as extragonadal [6,12,13].
Correspondence and offprint requests to: Dr S. D. Tinkler, Wessex Radiotherapy Centre, Royal South Hants Hospital, Off Brinton Terrace, St Mary's Road, Southampton SO14 0YG, UK.
We present a case report of choriocarcinoma of the urinary bladder, which occurred in a 37-year-old man.
CASE REPORT A 37-year-old heavy goods vehicle driver presented with a 3-year history of intermittent painless haematuria. This had become much worse prior to referral, with the passage of bright red blood two or three times per day. He had also been passing small stones in the urine every few months. His haematuria had been investigated 26 months before presentation, with urine cytology, intravenous urography and cystoscopy. Apart from the presence of a 3 mm renal calculus and a small localized area of biopsy-proven chronic cystitis above the lateral to the right ureteric orifice, no abnormalities were found. On admission he was clinically anaemic but otherwise well with no abdominal, genital or rectal abnormality. Anaemia was confirmed at a haemoglobin of 8.3 g/dl, with the hypochromic, microcytic picture of iron deficiency. He was admitted to hospital 4 days later with increasing weakness, breathlessness on minimal exertion, and nocturia. He was very pale and unwell. The haemoglobin had fallen to 7.2 g/dl. He was transfused while further investigations were instituted. Urine cytology was normal. A chest radiograph (CXR) showed extensive bilateral intrapulmonary opacities consistent with metastases. A C T scan confirmed extensive pulmonary metastases and demonstrated a large mass, containing some calcification, arising from the fundus and extending into the right lateral wall of the bladder. There was also evidence of extension into the perivescial fat and sigmoid colon. Bimanual examination under anaesthesia revealed a 15 cm firm mobile mass at the apex of the bladder. At cystoscopy the lumen of the bladder was entirely filled by a massive solid tumour. Deep resection biopsies were taken, but complete resection of the mass was not attempted and bimanual examination following this procedure was unchanged. Initial histological examination of the bladder biopsies suggested an anaplastic bladder carcinoma. The patient was immediately commenced on chemotherapy with epirubicin 50 mg/m 2 and cisplatin 70 mg/m a on day 1 (with hydration and antiemetics), followed by methotrexate 40 mg/m 2 on days 8 and 15 (EPI C-M). Following the first day of chemotherapy he became confused and developed hiccoughs; these symptoms rapidly settled. A cerebral CT scan was normal. Prior to the second course of chemotherapy, the results of the initial serum flhCG became available. This was grossly elevated at 64 600 iu/1. Serum levels of alpha-foetoprotein (AFP) and lactic dehydrogenase (LDH) were normal. As he was tolerating the chemotherapy very well, his symptoms had improved,
60 and the serum flhCG had fallen to 21800 iu/1, he received a second course without event. Unfortunately, the serum flhCG began to rise again (to 47100 iu/1) before the third course. The turnout pathology was reviewed at this time. Histological examinations of the biopsies showed an extensively haemorrhagic and necrotic tumour composed of two cell types (Fig. 1). There were large numbers of multinucleated synctiotrophoblastic giant cells, which stained positively for flhCG, admixed with sheets of cytotrophoblastic cells having clear or basophilic cytoplasm and sharp cellular borders. In other areas, undifferentiated tumour was seen. No papillary transitional cell carcinoma was identified and there was no urothelial dysplasia. There were large vascular spaces within the tumour, which invaded the detrusor muscle. The diagnosis of choriocarcinoma was made. It was not clear whether the undifferentiated elements represented solid urothelial carcinoma or pure cytotrophoblast. It was considered that, in the absence of definitive transitional cell elements within the tumour, it was more correctly regarded as a primary choriocarcinoma of the bladder. In view of this, and a rising serum flhCG, a decision was made to change to a chemotherapy regimen more appropriate for the treatment of a germ cell tumour. The patient Was started on POMB/ACE chemotherapy initially, with two courses of POMB followed by ACE, then alternating POMB with ACE. POMB consisted of day 1: vincristine 1 mg/m2 i.v. bolus and methotrexate 300 mg/m2 i.v. over 12 hours; day 2: bleomycin 15 mg as a 24hour i.v. infusion and folinic acid rescue; day 3: bleomycin 15 mg infused i.v. over 24 hours; day 4: cisplatin 120 mg/m2 infused i.v. over 12 hours with hydration and antiemetics. A C E consisted of etoposide 100 mg/m 2 on days 1-5 inclusive, actinomycin-D 0.5 mg on days 3-5, and cyclophosphamide 500 mg/m 2 on day 5. The interval between each course was 9-11 days. He received a total of four courses of POMB and two courses of ACE. He tolerated the chemotherapy well. During the admission for his first course of POMB he complained of persistent headaches. A CT scan showed the presence of multiple small brain metastases. Dexamethasone was started with good resolution of the headaches. Throughout the chemotherapy, the serum flhCG continued to fall, to reach its lowest level of 12 iu/1, 5 months after presentation (Fig. 2). The serum AFP remained normal throughout, although the serum LDH rose steadily from 346 iu/1 (normal) in August, at the start of the intensive chemotherapy, to 1775 iu/1 in November. The CXR appearance steadily improved with the chemotherapy, although the metastases were still visible. The clinical course was further complicated by the
Fig. 1. Choriocarcinoma showing positive staining reaction for the beta subunit of hCG in the synctiotrophoblast (broad arrow). The cytotrophoblast (narrow arrow) in unstained (× 300).
S. D. Tinkler et al. b
c
d
e
f
g
h
100000
10000 .E
1000
=o E
100
(/3
10
0
I
I
I
I
50
I00
150
200
Time (days from diagnosis)
Fig. 2. Serum flhCG levels throughout treatment. The arrows indicate day 1 of each cycle of chemotherapy (see text for details). a: first EPIC-M; b: second EPIC-M; c: first POMB; d: second POMB; e: first ACE; f: third POMB; g: second ACE; h: fourth pOMB.
development of a left deep vein thrombosis just prior to the second and last course of ACE. The patient was prescribed ibuprofen and given elasticated leg stockings. He was not anticoagulated because of the risk of haemorrhage into the brain metastases. The day after completion of the second A C E chemotherapy he became acutely breathless and was found to be in fast atrial fibrillation. He was digitalized, with resolution of the symptoms and normalization of the heart rate. When he was admitted for the next course of chemotherapy he was found to be unwell with anorexia, nausea, vomiting and increasing lethargy. Acute renal failure was diagnosed; the serum urea was 101.5 mmol/1 and the creatinine 2245/~mol/l. A n ultrasound examination showed abnormal echoity of the renal pyramids but no hydronephrosis. Haemodialysis produced rapid normalization of the serum urea and creatinine although he had episodes of hypotension. A repeat cerebral CT scan showed improvement, with no metastases visible. Unfortunately, the patient had a respiratory arrest 5 days after commencing haemodialysis and, although he was successfully resuscitated, he required ventilation in the intensive care unit. There he continued to have problems with hypotension despite inotropic support. He also developed a right-sided pneumothorax and a bronchopleural fistula. A CXR still showed the presence of pulmonary metastases and a decision was taken to withdraw further active therapy when his clinical condition continued to deteriorate. He died soon after this, almost 6 months after the initial diagnosis. A post-mortem examination was performed, which showed the cause of death to be a massive pulmonary embolism. There were pulmonary infarcts in both lungs and a bronchopleural fistula had developed within a ruptured pulmonary infarct. Multiple metastatic deposits of necrotic yellow tumour were present in both lungs, ranging from 0.5 cm to 1.5 cm in diameter and there were multiple metastatic nodules of tumour in the brain measuring up to 1.2 cm. Histological examination of the lung nodules showed complete tumour necrosis, with no viable tumour. The cerebral nodules were also necrotic but one nodule showed a residual focus of viable choriocarcinoma. The bladder was filled with spiky calculus material. The wall at the dome was fibrotic and thickened and showed a yellow-brown appearance. Histological examination showed fibrosis and dystrophic calcification only, with no evidence of residual bladder tumour. The testes showed no evidence of tumour or of a fibrous scar.
Primary Choriocarcinoma of the Urinary Bladder
61
DISCUSSION
CONCLUSION
Our patient was much younger than the previously reported patients with choriocarcinoma of the urinary blad~i~r. This disease appears to pursue a very aggressive clinical course, as all the other reported patients had a very short history of symptoms prior to presentation and a rapid decline thereafter. Our patient gave a 3-year history of haematuria, which became much more severe prior to his presentation. It was associated with a short history of breathlessness. The rapid worsening of the symptoms would be in keeping with the aggressive behaviour seen with this type of tumour. It seems likely that the initial intermittent haematuria was due to bladder calculi and that the choriocarcinoma had only been present for a few months. Our patient also differed from most of those reported in the literature in that the diagnosis was made when his clinical condition was relatively good. This, in addition to his relatively young age, allowed us to prescribe aggressive chemotherapy. He received 5 months of intensive chemotherapy before he died of the sequelae of a pulmonary embolus. He was also unique in that his death was not due directly to the tumour, but to a complication of the disease and its treatment. The very good response of this tumour to chemotherapy may offer some hope for treatment of this aggressive disease, which apears to be uniformly fatal. Most of the other reported patients who were given chemotherapy received only a small amount before turnout progression and clinical deterioration prevented further active management [5-7]. Germ cell tumours with adverse prognostic features, for example high levels of turnout markers (AFP >1000 iu/l; ¢flaCG >10000 iu/1) have a relatively poor prognosis with conventional BEP chemotherapy (Neomycin, etoposide and cisplatin). There are four main methods of modifying standard chemotherapy schedules: the introduction of new chemotherapeutic agents; the use of alternating drug combinations; high dose chemotherapy schedules; and chemotherapy using drugs at increased frequency. The POMB/ ACE chemotherapy used in the treatment of our patient has several advantages over BEP in the management of patients with a poor prognosis. The limited myelosuppression of POMB enables the interval between courses to be reduced, and, together with the inclusion of a total of seven drugs in the regimen, the possibility of tumour recovery between courses and the chance of drug resistance developing is reduced. A number of theories of the origin of choriocarcinoma o f the urinary bladder have been proposed. The most feasible is the occurrence of neoplastic transformation, or retrodifferentiation, of a transitional cell carcinoma to the level o f embyronal trophoblast [9,14]. Transitional cell carcinomas of the bladder have been shown to secrete/3hCG into the urine and serum [15-16]. This appears to be relatively common and implies functional, but not structural, differentiation of the carcinomas. It is often associated with a poor prognosis. Full trophoblastic differentiation to produce a choriocarcinoma, however, remains rare. Further support for this theory i s the great ability of transitional cell carcinomas to de-differentiation along several cell lines, as shown by the frequent occurrence of squamous, glandular and, less commonly, small cell elements in these tumours.
Choriocarcinoma of the urinary bladder remains a rare and aggressive disease, which is fatal, often rapidly so. This c~+se report indicates that it can be a very chemosensitive tumour and may offer some hope for future patients in whom it develops. The origin of the tumour is likely to be from metaplasia/de-differentiation of a carcinoma. Lesser degrees of this differentiation appear to be relatively common in transitional cell carcinomas, which can secrete /3hCG without the structural changes necessary for the diagnosis of choriocarcinoma.
References 1. Weinberg T. Primary chorionepithelioma of the urinary bladder in a male patient: A report of a case. Am J Pathol 1939;15:783-95. 2. Djewitzki W. Uber einen fall von chorionepithelioma der harnblase. Virchows Arch 1904;178:451-64. 3. Pollack AD. Malignant teratoma of the urinary bladder: Report of a case. Am J Pathol 1936;12:561-8. 4. Ainsworth RW, Cresham GA. Primary choriocarcinoma of the urinary bladder in a male. J Pathol Bacteriol 1960;79:18592. 5. Fowler AL, Hall E, Rees G. Choriocarcinoma arising in transitional cell carcinoma of the bladder. Br J Urol 1992;70:333-4. 6. Dennis PM, Turner AG. Primary choriocareinoma of the bladder evolving from a transitional cell carcinoma. J Clin Pathol 1984;37:503-5. 7. Obe JA, Rosen N, Koss LG. Primary choriocarcinoma of the urinary bladder: Report of a case with probable epithelial origin. Cancer 1983;52:1405-9. 8. Civantos F, Rywlin AM. Carcinomas with trophoblastic differentiation and secretion of chorionic gonadotrophins. Cancer 1972;29: 789-98. 9. Abrass RP, Temple-Camp CRE, Pontin AR. Choriocarcinoma and transitional cell carcinoma of the bladder: A case report and review of the clinical evolution of disease in reported cases. Eur J Surg Oncol 1989; 15:149-53. 10. Norton KD, Burnett RA. Choriocarcinoma arising in transitional cell carcinoma of the bladder: A case report. Histopathology 1988;12:325-8. 11. Gallagher L, Lind R, Oyasu R. Primary chorioeareinoma of the urinary bladder in association with undifferentiated carcinoma. Hum Pathol 1984;15:793-5 12. Kawamura J, Rhinsho K, Taki Y, et al. Choriocarcinoma and undifferentiated cell carcinoma of the bladder with gonadotrophin secretion. J Urol 1979;121:684-6 13. Grammatico D, Grignon DJ, Eberwein P, et al. Transitional cell carcinoma of the renal pelvis with choriocarcinomatous differentiation. Cancer 1993;71:1835-41. 14. Burry AF, Munn SR, Arnold EP, et al. Trophoblastic metaplasia in urothelial carcinoma of the bladder. Br J Urol 1986;58:143-6. 15. Dexeus F, Logothetis C, Hossan E, et al. Carcinoembryonic antigen and beta human chorionic gonadotrophin as serum markers for advanced urothelial malignancies. J Urol 1986;136:403-7. 16. Crawford SM, Ledermann JA, Turkie W, et al. Is ectopic production of human chorionic gonadotrophin (HCG) or alpha fetoprotein (AFP) by tumours a marker of chemosensitivity? Eur J Cancer Clin Oncol: 1986;22:1483-7.
Received for publication March 1995 Accepted August 1995