Suitability of PSA-detected localised prostate cancers for focal therapy: experience from the ProtecT study.

BACKGROUND: Contemporary screening for prostate cancer frequently identifies small volume, low-grade lesions. Some clinicians have advocated focal prostatic ablation as an alternative to more aggressive interventions to manage these lesions. To identify which patients might benefit from focal ablative techniques, we analysed the surgical specimens of a large sample of population-detected men undergoing radical prostatectomy as part of a randomised clinical trial. METHODS: Surgical specimens from 525 men who underwent prostatectomy within the ProtecT study were analysed to determine tumour volume, location and grade. These findings were compared with information available in the biopsy specimen to examine whether focal therapy could be provided appropriately. RESULTS: Solitary cancers were found in prostatectomy specimens from 19% (100 out of 525) of men. In addition, 73 out of 425 (17%) men had multiple cancers with a solitary significant tumour focus. Thus, 173 out of 525 (33%) men had tumours potentially suitable for focal therapy. The majority of these were small, well-differentiated lesions that appeared to be pathologically insignificant (38-66%). Criteria used to select patients for focal prostatic ablation underestimated the cancer's significance in 26% (34 out of 130) of men and resulted in overtreatment in more than half. Only 18% (24 out of 130) of men presumed eligible for focal therapy, actually had significant solitary lesions. CONCLUSION: Focal therapy appears inappropriate for the majority of men presenting with prostate-specific antigen-detected localised prostate cancer. Unifocal prostate cancers suitable for focal ablation are difficult to identify pre-operatively using biopsy alone. Most lesions meeting criteria for focal ablation were either more aggressive than expected or posed little threat of progression.

A teratoid cyst containing nephrogenic tissue in a woman with a horseshoe kidney.

A 21 year old woman presenting with flank pain and vomiting was found to have a cystic lesion associated with a horseshoe kidney. The inner aspect of the cyst wall consisted of connective tissue intermingled with colonic-type epithelium. Within the cyst wall there were multiple foci of immature and incompletely differentiated renal elements, together with fragments of urothelium, smooth muscle, bone, and neuroendocrine tissue. No immature renal blastema were found. This lesion is unique and labelled as a teratoid cyst containing nephrogenic tissue.

Should we watch what we eat and drink? Report on the International Workshop on Hormones and Endocrine Disrupters in Food and Water: possible impact on human health, Copenhagen, Denmark, 27-30 May 2000.

The aim of this Workshop was to bring together scientists with different backgrounds, including clinical endocrinologists, basic researchers and epidemiologists, to discuss the complex and controversial topic of endocrine disrupters, and their impact on human health. Nearly 250 scientists attended the Workshop, and 50 lectures and 90 posters were presented and discussed. The most important scientific findings and reviews are to be published in Human Reproduction and Human Reproduction Update. Some of the highlights are presented here.

Testicular sex cord-stromal tumours: the Edinburgh experience 1988-2002, and a review of the literature.

AIMS: Sex cord-stromal tumours of the testis are uncommon tumours, accounting for around 5% of testicular neoplasms. Treatment is primarily surgical, with no adjuvant therapy of proven benefit. We present a single-centre experience over a period of 15 years. MATERIALS AND METHODS: From 1988 to 2002, 18 patients with a diagnosis of sex cord-stromal tumour were referred to our centre. A retrospective analysis of their case notes was made and a pathological review undertaken. RESULTS: Sixteen were Leydig-cell tumours and two were Sertoli cell. For the Leydig-cell tumours, the median age at presentation was 42 years, 50% presented with a testicular mass and 31% with gynaecomastia. Two patients followed a malignant course: one revealing disease dissemination at initial staging, and a second 12 months after potentially curative orchidectomy. Salvage retroperitoneal lymphadenectomy in the latter patient proved unsuccessful. Clinical outcome correlated strongly with the presence of adverse pathological features described previously in the literature. After a median follow-up of 46 months, two patients have developed progressive disease, and two patients have died, one of metastatic Leydig-cell tumour. No patient defined as being of low malignant potential on pathological examination has relapsed outside our review period of 2 years. CONCLUSION: We confirm the overall excellent prognosis for most of the patients with sex cord-stromal tumours of the testis. Compared with most previous reports, pathological features seem to predict with reasonable accuracy the risk of malignant behaviour, and can adequately inform the subsequent review policy.

Impact of the environment on reproductive health: executive summary.

The papers presented at the workshop on the "Impact of the Environment on Reproductive Health" are published in this issue of the EHP Supplements. After the formal presentation of the papers, the authors and scientists met to discuss the important aspects of environmental issues affecting human reproductive health. This Executive Summary was compiled by the organizers and editors of the workshop and the proceedings.

Regional and geographical variations in infertility: effects of environmental, cultural, and socioeconomic factors.

Fertility is affected by many different cultural, environmental, and socioeconomic factors, especially in developing countries where poverty and infections are commonplace. Environmental factors play a major role in infertility in Africa. One of the most important health problems in sub-Saharan Africa is the high rate of infertility and childlessness. The African society has a strong traditional heritage, and the study of the patterns of infertility in this part of the world would be incomplete without consideration of the sociocultural and environmental factors. The most cost-effective approach to solving the infertility problems in Africa is prevention and education. In Mexico, problems of reproductive health are associated with pregnancy in adolescents, sexually transmitted diseases and genitourinary neoplasms. Infertility affects 10% of couples, usually as a result of asymptomatic infection. Education, poverty, nutrition, and pollution are problems that must be tackled. The government has taken positive action in the State of São Paulo in Brazil, where gender discrimination is a major factor affecting women's health and reproductive outcomes. The implementation of new policies with adequate funding has resulted in marked improvements.

PIP: The impact of cultural, environmental, and socioeconomic factors on reproductive health and infertility are discussed in general terms. Conditions in sub-Saharan Africa, Kenya, Mexico, and Brazil are described. In Mexico, high levels of arsenic in drinking water pose a major environmental hazard affecting reproductive health. Chronic arsenic poisoning in Comarca Lagunera, Mexico, contributes to male infertility and birth defects. Additional problems are adolescent pregnancy, sexually transmitted diseases (STDs), congenital malformations, genitourinary neoplasms, malnourishment, and poverty. The example of Sao Paolo's investment in the well-being of women shows how effective government policy can accomplish rapid improvement in women's health. Infertility in Africa is around 30-40%. Infertility in the US is only 8%. The African cultural emphasis on women's status and childbearing makes infertility a major concern. African infertility is related to disease. In the Cameroon, over 50% of infertility is accounted for by pelvic inflammatory disease. Prevention programs should include improvement in diagnosis and treatment of sexually transmitted diseases (STDs), sex education for men and women, expanded family planning (FP) services, and better obstetric care. Infertility in Zaire, Cameroon, Gabon, and Uganda is high compared to other non-African countries. Infertility is geographically and ethnically variable within each country. Politics and government FP policy, traditional attitudes, polygamous relationships, and induced abortion all impact on infertility. Traditional practices, such as female genital mutilation, result in infections during the healing process; infections also occur during childbirth. Vesico-vaginal fistula and incontinence are problematic and can be corrected through surgical methods. Illegal abortions contribute to morbidity and mortality. STDs are a main cause of infertility in Kenya. Cultural beliefs place the blame on females. In both Africa and Mexico, men account for 30% of couple infertility.

The origin and biology of CIS cells: general discussion.

Participants at the 4th Copenhagen Workshop on Carcinoma in situ and Cancer of the Testis, representing cell biologists and tumour biologists, met together to discuss the similarities and differences between primordial germ cells (PGCs) of the embryo, and the carcinoma in situ (CIS) stem cell of human testicular germ cell tumours (GCTs). Much has been discovered about PGCs in the last 10 years and we still do not know the exact nature of CIS cells. Knowledge of PGCs comes mainly from mouse experiments and knowledge of CIS comes from the study of human tumours. A mouse model of human GCT would help to investigate the nature of CIS cells. Grafting mouse male genital ridges into mouse fetal testes results in the development of testicular tissue and the formation of teratomatous tumour components. Amplification of PGCs in culture is possible but this results in their transformation into embryonic germ (EG) cells. CIS cells die by apoptosis if they are isolated, and short-term culture is only possible if the CIS cells are cultured in their normal environment within seminiferous tubules. It may be possible for CIS cells to differentiate in culture although they cannot be maintained in culture as isolated cells. Human CIS cells are likely to be formed as a result of in utero factors rather than agents acting on normal adult testicular germ cells. EG cells stimulate feeder cells by paracrine factors but it is not known if these cells produce autocrine factors.

A radiofrequency method of thermal tissue ablation for benign prostatic hyperplasia.

OBJECTIVES: To evaluate the safety, feasibility, and efficacy of transurethral ablative prostatectomy (TURAPY), a radiofrequency method of thermal tissue ablation of benign prostatic hyperplasia (BPH). METHODS: Twenty men, ages 55 to 81 years (mean, 67), with symptomatic BPH and with peak flow rate 12 mL/s or less, were treated with the TURAPY device (Direx Medical Systems). A 2 cm long heating element and 2 thermoprobes (for simultaneous prostatic temperature monitoring) are mounted on a Foley-like catheter and used for TURAPY treatment administration. This TURAPY catheter was modified by placing an extra set of thermoprobes in the sphincter region to allow sphincteric temperature monitoring. The treatment was administered at a maximum temperature of 70 degrees to 75 degrees C for 1 hour under local anesthesia as a day case. RESULTS: All 20 patients completed the treatment. The maximum recorded rectal temperature was 39.5 degrees C. The maximum sphincter temperature was not allowed to exceed 42 degrees C. The post-treatment morbidity included dysuria and minor urethral bleeding in 12 patients. Three patients developed urinary infection requiring antibiotic treatment. All 20 patients were followed up 3 months after treatment. The mean International Prostate Symptom Score (IPSS) improved from 19.4 to 6.2 (68%), the mean peak flow rate increased from 7.9 to 12.9 mL/s (63%), and the mean postvoid residue decreased from 222 to 81 mL (64%). Overall, 80% of patients exhibited at least a 50% improvement in either the IPSS or the peak flow rate. There was a mean reduction in prostatic volume measured by transrectal ultrasound of 14 mL (29% reduction). The subjective and objective improvements, in 8 patients followed up 6 months after treatment, have been maintained. There was extensive coagulative heat necrosis of periurethral tissue with sparing of subcapsular tissue in prostate biopsy specimens taken from 1 patient 5 days after treatment. There was endoscopic and sonographic evidence of canalization of the obstructed prostatic urethra 3 months after treatment. CONCLUSIONS: Treatment with the TURAPY device was found to be safe, feasible, and effective in improving both subjective and objective measurements of benign prostatic obstruction in this pilot study on 20 patients.

Rhabdomyosarcoma of the adult urinary bladder after radiotherapy for carcinoma.

We report the case of an 83-year-old man who developed primary rhabdomyosarcoma of the urinary bladder 18 years after having a squamous carcinoma of the bladder treated with interstitial radiotherapy. The literature on adult urinary bladder rhabdomyosarcoma and radiation induced rhabdomyosarcoma is reviewed.

Carcinoma in situ in the testis.

Carcinoma in situ (CIS) of the testis is a common precursor of germ-cell tumours in adults and adolescents, with the exception of spermatocytic seminoma. This article reviews existing knowledge on the pathobiology, genetic aspects and epidemiology of CIS, discusses current hypotheses concerning pathogenesis and invasive progression of germ-cell neoplasms and provides guidelines for diagnosis and clinical management of CIS.

A new classification of germ cell tumours of the testis.

The partially conflicting British and WHO classifications of testicular tumours are confusing and fail to give due prominence to their histogenesis from carcinoma in situ (CIS). Spermatocytic seminoma does not originate from CIS and should be renamed 'spermatocytoma'. All other germ cell tumours are gonocytomas arising from CIS cells which have many of the characteristics of the gonocytes of the early embryo and fetus. Gonocytomas are subdivided into seminoma, if they retain their gonocyte characteristics, or teratogenic gonocytoma if the tumour stem cell has differentiation potential. A new category of anaplastic germ cell tumour is intermediate between seminoma and teratogenic gonocytoma. The teratogenic gonocytoma is an epiblastoma if no differentiation is manifest, but may differentiate along embryonic lines into teratoma or may show extraembryonic differentiation towards yolk sac tumour or choriocarcinoma. The new classification uses unambiguous terminology and is midway between the British and WHO classifications. Those familiar with either of these classifications should have no difficulty in adapting to the new proposals, and the new classification should help others to acquire a better understanding of the biology and pathology of testicular germ cell tumours.

Reproductive aspects of testicular germ cell cancer: general discussion.

Gonadal function is affected by both chemotherapy and radiotherapy in the treatment of testicular cancer. Leydig cells are more resistant than germ cells, but endocrine function is also affected. Sex life is affected by treatment for testicular cancer but major permanent sexual dysfunction is not common. Radiotherapy is more damaging to Leydig cells than chemotherapy and can also cause direct effects on Sertoli cells. Leydig cell dysfunction following chemotherapy is dose-dependent. Serum FSH levels may be elevated at the time of primary orchidectomy and this may be used to predict ultimate fertility in these patients. Fertility does not recover if FSH levels are greater than 24 IU/l which is twice the upper limit of normal. Retroperitoneal lymph node dissection does not cause erectile dysfunction, but may cause dry ejaculation unless a nerve sparing operation is performed by an experienced surgeon. LHRH analogues causes reduced testosterone secretion, impotence and loss of libido, and requires exogenous androgen therapy. CIS can be eradicated by 20 Gy fractionated radiotherapy. This dose has been shown to have some effect on Leydig cell function but this is not clinically significant in the first 5 years of follow-up. The effects of lower doses of irradiation, which may be less injurious to Leydig cells, are currently being investigated. The effects of chemotherapy on CIS is as yet unpredictable.

How should we identify high risk testicular tumour patients? Round table discussion.

Various prognostic models are used to predict the outcome of testicular tumour patients, and these are usually based on serum tumour marker levels (AFP and hCG), number and size of metastases to para aortic nodes, lungs and supraclavicular nodes. Greater predictive accuracy can be achieved if 'dynamic markers' are used in addition to these pretreatment variables. Dynamic markers are assessed during treatment by examining the rate of tumour marker decline. Prognostic models can subdivide patients into good risk, intermediate risk, and very poor risk groups. Cisplatin may be replaced by the less toxic carboplatin in good risk patients. High dose chemotherapy with autologous bone marrow transplantation should only be considered for very poor risk patients. Prognosis may be worse if the patient is a smoker, or if he has a first degree relative with testicular cancer. New markers such as chromosomal abnormalities or gene mutations should be examined.

Should high dose chemotherapy with, or without, autologous bone marrow transplant be included in the primary treatment of testicular cancer? Round table discussion.

Most patients with metastatic testicular cancer can be cured by standard chemotherapeutic regimes but the group of high risk patients fail to respond adequately. The results of salvage chemotherapy trials including high dose chemotherapy (HDCT) plus autologous bone marrow transplantation (ABMT) or peripheral stem cell reinfusion (PSCR) suggest a dose response relationship indicating that the inclusion of HDCT + ABMT/PSCR could also have the potential of increasing survival of high risk patients in first line treatment. Therefore, in a coordinated international clinical trial HDCT + ABMT should be compared with the standard chemotherapy. The standard drug treatment worldwide for testicular cancer is PEB (cisplatin, etoposide, bleomycin) x3 for good risk and x4 for high risk patients, but there is cumulating evidence that VIP (cisplatin, ifosfamide, etoposide) is more effective for poor risk patients. Therefore in the randomized trial standard dose VIP would be compared with high dose carboplatin, etoposide and ifosfamide or cyclophosphamide (CEI or CEC). Because of the toxicity and expense of HDCT + ABMT it must be discussed whether this treatment could be given upfront to all patients with high risk criteria, or only to patients with poor response under standard dose induction chemotherapy (intensification or consolidation). If HDCT is considered for first line chemotherapie the group of patients with very poor prognostic criteria have to be selected very carefully to avoid overtreatment.

Pathogenesis and cell biology of germ cell neoplasia: general discussion.

Malignant transformation of germ cells is an early event in the development of testicular cancer, occurring in the fetal gonad of the mouse and possibly also in humans. Germ cells with the characteristics of CIS have been identified in human fetal testes, however, immunocytochemical markers for CIS in the adult are detectable in normal fetal and infantile testicular germ cells. It is possible that CIS cells are protected from immunosurveillance. There are differences between infantile and adult germ cell tumours (GCT) suggesting that their pathogenesis may be different. Seminoma cell lines are described although these are difficult to establish in cell culture. Chemotherapy may selectively destroy malignant GCT components leaving residual mature teratoma. It is unlikely that drug therapy induces differentiation. Second tumours without germ cell components may develop in GCT patients, but these second tumours are probably of germ cell origin. It is not clear if progression of untreated CIS to invasive tumour is inevitable. The possibility of spontaneous regression of CIS may also be considered.

Hormones and growth factors in germ cell neoplasia: general discussion.

Fetal germ cells migrate along the dorsal mesentery to the genital ridge, and migration in the bloodstream occurs in some animals. Malignant transformation may occur before migration, and it is possible that testicular germ cell tumours have a monoclonal origin, even when bilateral. Different tumour foci have homogeneous chromosomal abnormalities. Migrating germ cells may lodge in extragonadal sites and give rise to tumours. Mouse fetuses exposed to oestrogen and testosterone in utero have an increased incidence of testicular maldescent and teratoma. Oestrogens and mullerian inhibitory substance in the fetus may influence human testicular tumour development. Testicular tumour patients may have elevated serum oestrogen levels which may be related to prognosis. Increased serum FSH may stimulate germ cell tumour growth. Ultrastructural studies indicate that malignant transformation of germ cells occurs early, but final tumour differentiation does not occur till after the malignant cells have invaded extratubular tissue.