Chemical Exposures: Prostate Cancer and Early BPA Exposure

In animal models, estrogens can drive carcinogenesis of the prostate and have long been suspected of playing a role in human prostate cancer. Scientists have hypothesized that prenatal exposure to estrogen-like compounds, including monomeric bisphenol A (BPA), may account for recent increases in rates of prostate cancer. Now a rat study by Gail Prins of the University of Illinois at Chicago Department of Urology, Shuk-Mei Ho of the University of Cincinnati Department of Environmental Health, and their colleagues provides the first evidence of a direct link between low-dose BPA exposure during development and later prostate cancer. 
 
BPA initially was synthesized for use in also is used as a cross-linking compound in the manufacture of polycarbonate plastics and epoxy resins. It leaches from food and beverage containers and from dental sealants, although the latter currently are not thought to be a major source of exposure. Today, this hormonally active chemical is widespread in the environment, with detectable serum levels present in approximately 90% of humans in the United States and other industrialized countries, by Prins’s estimate. BPA concentrations measured in placental and fetal tissues may be fivefold higher than maternal serum levels, with higher levels found in male fetuses compared to females, according to Prins. 
 
BPA has been in use for about 50 years in the industrialized world. Some investigators have proposed that widespread ingestion of monomeric BPA from polycarbonate food and drink containers might partially explain recent increases in prostate cancer rates. According to the American Cancer Society, rates have been on the rise since 1975. With the 1987 introduction of prostate-specific antigen testing, the newly enhanced ability to diagnose the disease caused incidence to spike to 240 age-adjusted cases per 100,000 men by 1992. After this “catch-up” period, rates dropped for three years, but are now back on the rise. 
 
In the study, described in the 1 June 2006 issue of Cancer Research, groups of newborn rats were given high or low doses of estradiol or an environmentally relevant dose of BPA. The findings provide a molecular underpinning for potential long-term effects by showing changes in methyl groups on DNA that are responsible for turning genes on or off. For example, one key prostate gene that normally fuels cell growth during development stayed turned on in the prostates of male rats exposed to BPA or elevated estradiol from birth, says Prins. Such epigenetic alterations may leave a permanent impression on genes, possibly sensitizing the animal to developing diseases later in life. 
 
One must exercise caution, however, in extrapolating the current rat findings to humans. How might one conduct an analogous program of research on men? The researchers consider such a program virtually impossible because 50 years or more typically would be required for results of early exposure to BPA to show up as prostate cancer. 
 
Indeed, Rebecca Sokol, a professor of medicine at the University of Southern California, cautions against extrapolating human effects from rat studies. She does, however, note that unlike strong carcinogens that damage DNA profoundly, BPA appears to cause subtle changes that may pass from one generation to the next. She asks whether something is happening to alter genes seemingly without changing the genetic code itself. 
 
Says Prins, “Our evidence shows that in an animal model, some genes are altered by the addition or removal of methyl groups on the DNA, which changes the ability of those genes to be transcribed and translated to proteins. It is possible that these effects may pass through generations as has been shown recently for sperm cells.” However, she adds, that analysis awaits future studies.

Cryptorchidism occurs in approximately 1 in 500 live births. A history of cryptorchidism is obtainable in 2.9-16.1% of testicular tumours. Cryptorchid testis is 30-50 times more susceptible to malignant change (Batata et al.. 1982). According to some. the practice of elective orchiopexy in early childhood reduces the risk of this cancer, but there is no universal agreement on this (Pinczowski et al.. 1981). In some parts of India we continue to see patients in whom cryptorchidism is not corrected early and who go on to develop malignancy. Tumours of the uncorrected cryptorchid testis are now extremely rarely seen in the West. There are therefore very few reports on the management of such cases in the post-cisplatin era. The aim of this presentation is to put on record our experience with such tumours, to assess the impact of modern management. including cisplatin-based chemotherapy. on such tumours and briefly to compare their presentation with tumours of normally descended testis.

Methods and Results
Case records of 164 consecutive patients with primary germ cell tumours of testis seen over a 6 year period from June 1987 to June 1993 at IRCH, a regional cancer centre located at AIIMS New Delhi, were analysed. In addition to routine investigations, serum a-fetoprotein (AFP) and frhuman chorionic gonadotrophin (P-HCG) were estimated in all patients and computerised tomography (CT) of abdomen, pelvis and chest was performed. Staging was done according to the Royal Marsden Hospital (RMH) classification system (Peckham et al., 1979). Histology was obtained on laparotomy or on CT or ultrasound-guided Trucut biopsy and reporting was done according to the WHO classification (Mostofi and Sobin, 1977). The probability of survival was calculated using the Kaplan-Meier method. at 20 years. Twenty-two patients presented with abdominal pain or masses and one with an inguinal mass. Two patients had significant ascites with abdominal masses. The duration of symptoms ranged from 3 to 30 months with an average of 7 months. Site, staging and histological distribution are given in Tables I and II. In only nine patients had a correct diagnosis of a tumour been made pnror to referral. The management in earlier cases was complete resection and if this was not possible. debulking or biopsy. Subsequent treatment depended on histology. Patients with seminoma were subjected to radiotherapy, and those who could not undergo complete resection and those with bulky tumours (i.e. stage lIc) were subjected to chemotherapy. Patients with a composite tumour or NSGCT were subjected to chemotherapy. In January 1991 this policy was changed because of the excellent results being reported for cisplatin in germ cell   I  29  16  3  36  2  1  1  16   II  11  20  2  24  8  3  4   62  III  3  5  6  0  0  0  IV  8  27  6  30  2  3  21  Total  51  66  11  12  7  tumours. In our previous experience s were not completely resectable. Patic chemotherapy post-operatively. Therefo absent scrotal testis and abdominal mas investigated for germ cell tumour. Histoli Trucut biopsy under CT or ultrasounc therapy was given followed by resection and orchidectomy.

Management
Of 16 patients seen before 1991, com carried out in eight and partial resecti seven. This was followed by radiotheral source to regional and retroperitoneal i Eight patients with seminoma received three received radiotherapy and chemoth had bulky seminoma and four others composite tumour or NSGCT received seven patients who received chemothera PVB (platinum, vinblastine, bleomycin, (vinblastine, dactinomycin, bleomycin, (Einhorn et al., 1977;Vugrin et al., 1981 scrotal testis and mature teratoma and treatment. This patient is alive at 30 mon lost to follow-up after staging. Seven pat chemotherapy. Six patients had NSG4 seminoma (stage IIC). These patients fell nostic groups according to the EORTC given different chemotherapy protocols Kaye, 1992). Four patients who were in group' received BOP-VIP (bleomycin, VP-1 6, ifosfamide, platinum). Although four patients achieved complete radiological remission, all were subjected to laparotomy. The reasons for operating were: (i) to remove testis affected by tumour; or (ii) to perform orchipexy of the contralateral testis in those with bilateral cryptorchidism. Since post-chemotherapy CT scans 3"-; C ; of all these patients were abnormal because of intraabdominal and intrapelvic testis, and since a residual small tumour in or around the testis could not be excluded on CT scan, it was essential to obtain histology in all. At surgery, 1 . which included resection of residual tumour and retroperitoneal lymph node dissection, three patients were found to have no tumour and received no further treatment and one patient had a 2 cm residual lesion in the pelvis and was given three courses of VIP chemotherapy (Loehrer et al., 1986). This patient is alive at 30 months. Three patients with 78 6 2 bilateral cryptorchidism underwent bilateral orchidectomy either because orchiopexy in the other testis was not possible or because the testes were markedly atrophic and there was a umours at IRCH. 0, risk of development of tumour subsequently. Younger patients in this group were put on maintenance testosterone injections. Five patients are alive at 4-30 months (median follow-up 20 months). Overall, 18 patients achieved a comsome large tumours plete response. Five patients have died. Death in three of .nts often required these was partly related to poor compliance. Three patients Ire any patient with with NSGCT died of progressive disease, all had stage IV as and or ascites was disease with pulmonary or hepatic metastases and had ogy was obtained by received BOP-VIP chemotherapy from the beginning. The J guidance. Chemoother patient had a good partial remission but refused to of residual tumour undergo resection of the residual mass and experienced disease progression. Three patients were lost to follow-up. The probability of overall survival was 0.65, with 14 patients at risk at 36 months ( Figure 1). There was no significant difference in the overall survival of this group as compared iplete resection was with the 114/140 patients with tumours of normally ton or debulking in descended testis (P = 0.952) (excluding 26 patients in whom py: 25 Gy by cobalt information on survival was not available). The number of nodes in seminoma. patients in each histological and stage subgroup was small radiotherapy alone, and management was variable. Hence, stage and histological erapy, of whom two subgroups were not compared. who had either a I chemotherapy. Of py, four were given ) and three VAB-6 platinum, endoxan) ). One patient had a received no further ths. One patient was tLients received initial CT and one bulky I into different progcriterion and were (Stoter et al., 1990; the 'poor prognosis oncovin, platinumithers were in the these two received nd one received VIP Lewis et al., 1991).
One of the most noticeable findings was that 21 of these 24 patients came from very backward areas of the country and had never gone to school and never had a complete medical examination. The other three patients came from urban areas and had received education up to university level. Some patients had been aware of the missing scrotal testis before tumours developed but felt too shy to report it. In a series from South Africa the incidence of cryptorchid testis among germ cell tumours of testis was 11%. Interestingly none of the black patients had undergone orchipexy, whereas 71% of those of mixed race and 87% of white patients had undergone orchipexy (Abratt et al., 1992). The mean age of our patients was 24 years compared with 32 years in the series reported by Batata (1982). In a series from Bombay the age range was 24-38 years (Kulkarni et al., 1991). The right side v t * .
was common in our series, as in the senres of Batata (1982).
Degenerative changes in cryptorchid testis begin as early as 2-3 years. suggesting that it is gonadal dysgenesis rather than ectopy per se which increases the risk of tumours (Batata et al.. 1982). It is not established whether orchidopexy abolishes the higher risk of cancer in these patients. In a large epidemiological study it was suggested that a low absolute risk of testicular cancer in corrected patients did not justify surveillance after operation (Pinczowski et al.. 1981). The age distribution of patients with cancer of undescended testis is generally similar to those who develop germ cell tumours on scrotal testis (Batata et al., 1982). This finding also favours the view that failure of complete descent is not the sole factor for the development of cancer (Kulkarni et al.. 1991). There is a suggestion from some studies that patients who undergo orchipexy before the age of 10 years have a relatively low risk of developing tumours compared with those who undergo correction later (Martin et al., 1979;Strader et al., 1988). It is for these reasons that some authors have recommended orchidectomy for unilateral undescended testis when diagnosed after puberty (Ford et al., 1985).
In contrast to the West, where the majority of the patients present early. only six patients had stage I disease and no patient had stage Ila disease. All others had stage IIB-IV disease. Many studies have revealed that chemotherapy has as good an impact on tumours of uncorrected cryptorchid testis as in normally descended testis. In the series by Batata et al. (1982). 5 year survival was 61% in corrected and 63% in uncorrected cases and 79% in seminoma and 50% in NSGCT. Kulkarni et al. (1991) demonstrated 100% 5 year survival in stage I and II and 33% in stage IV disease. indicating that tumours in undescended testis respond in a way similar to those in normally descended testis. Our results also do not indicate any significant difference in the overall survival of patients with tumours of cryptorchid testis as compared with those with tumours arising from normally descended testis in both the updated analysis as well as a previous analysis of testicular tumours in general (Raina et al., 1993).
Of 38 uncorrected cases in the series by Batata et al. (1982) 14 had an abdominal and 24 an inguinal testis. In the series by Kulkami and Kamat (1991) 15 21 patients had an inguinal testis. and Redman (1980) also found the inguen to be the most common site. In our study 22 24 patients had a testis located in the abdomen and pelvis.
The histology of testicular tumours in relation to the degree of descent is also interesting. Batata et al. (1982) encountered seminoma as the commonest category: with descent of the cryptorchid testis, malignant germinomas other than pure seminoma increased in frequency: 7% of patients with abdominal, 37% of patients with inguinal and 72% of patients with scrotal testis had NSGCT. A review of 724 patients treated at Royal Marsden Hospital between 1975 and 1984 showed no statistically significant difference in histology between those with and without a history of undescended testis (Pike et al.. 1986). In a more recent study of 319 patients from the Royal London Hospital. London, three-quarters of tumours in patients with uncorrected cryptorchidism were seminomas, whereas 80% of tumours in patients with corrected cryptorchidism were malignant teratomas. suggesting that operative correction may have something to do with histology of these tumours (Raja et al., 1992). In our series seminoma and NSGCT occurred almost equally frequently. We cannot comment on the predilection for other histological sites as very few of our patients had an inguinal or scrotal testis. Cryptorchidism may also increase the risk of bilateral disease, as observed by Welvaart and Tijssen (1981). Three of our 24 patients i.e. 12%. had bilateral tumours.
In conclusion. (i) 14% of our patients with germ cell tumours had a cryptorchid testis, of whom 23 24 had never undergone correction: (ii) the commonest location was intraabdominal, resulting in delayed diagnosis and poor risk factors: (iii) seminoma and NSGCT occurred almost in equal proportion: (iv) there is a need for improved screening and correction at a younger age. which will enable early diagnosis, thereby downstaging the tumour; (v) our data do not indicate a significant difference in the overall survival of patients with tumours of uncorrected cryptorchid testes as compared with those with tumours of normally descended testes; (vi) chemotherapy before surgery seems to be an effective option, with surgery being reserved for residual or refractory tumours or for orchidopexy or orchidectomy.