Peter Meidahl Petersen

Germ cell cancer and disorders of spermatogenesis: An environmental connection?

Why is there a small peak of germ cell tumours in the postnatal period and a major peak in young age, starting at puberty? And, paradoxically, small risk in old age, although spermatogenesis is a lifelong process? Why is this type of cancer more common in individuals with maldeveloped gonads, including undescended testis, gonadal dysgenesis and androgen insensitivity syndrome? Why has there, during the past 50 years, been a quite dramatic increase in testicular cancer in many developed countries? These are just a few of many questions concerning testicular cancer. However, the recent progress in research in the early stages of testicular cancer (carcinoma in situ testis (CIS)) allows us to begin to answer some of these questions. There is more and more evidence that the CIS cell is a gonocyte with stem cell potential, which explains why an adult man can develop a non‐seminoma, which is a neoplastic caricature of embryonic growth. We consider the possibility that CIS cells may loose their stem cell potential with ageing. Along these lines, a seminoma is regarded a gonocytoma where the single gonocytes have little or no stem cell potential. The Sertoli and Leydig cells, which are activated postnatally and during and after puberty, may play a crucial role for both the development of the CIS gonocyte and progression of the neoplasm to invasiveness. The reported increase in testicular cancer is not the only sign that male reproductive health is at risk. There are reports that undescended testis and hypospadias have become more common. Also semen quality has deteriorated, at least in some countries. The epidemiological evidence suggests that environmental factors may play a role. Are the environmental hormone disrupters (e.g. DDT, PCB, nonylphenol, bisphenol A) to be blamed for the apparently synchronised deterioration in these aspects of male reproductive health?

Semen Quality and Reproductive Hormones Before Orchiectomy in Men With Testicular Cancer

PURPOSE To obtain information about preorchiectomy gonadal function in patients with testicular germ cell cancer to improve the clinical management of fertility and other andrologic aspects in these men. PATIENTS AND METHODS In group 1, a group of 83 consecutive patients with testicular germ cell cancer (TGCC) investigated before orchiectomy, semen analysis was carried out in 63 patients and hormonal investigations, including measurement of follicle-stimulating hormone, luteinizing hormone (LH), testosterone, estradiol, sex hormone-binding globulin (SHBG), inhibin B, and human chorionic gonadotropin (hCG), in 71 patients. Hormone levels in patients with elevated hCG (n = 41) were analyzed separately. To discriminate between general cancer effects and specific effects associated with TGCC, the same analyses were carried out in a group of 45 consecutive male patients with malignant lymphoma (group 2). Group 3 comprised 141 men employed in a Danish company who served as controls in the comparison of semen parameters. As a control group in hormone investigations, 193 men were selected randomly from the Danish National Personal Register to make up group 4. RESULTS We found significantly lower sperm concentration (median, 15 x 10(6)/mL; range, 0 to 128 x 10(6)/mL) and total sperm count (median, 29 x 10(6)/mL; range, 0 to 589 x 10(6)) in patients with testicular cancer than in patients with malignant lymphomas (sperm concentration: median, 48 x 10(6)/mL; range, 0.04 to 250 x 10(6)/mL; sperm count: median, 146 x 10(6); range, 0.05 to 418 x 10(6)) (P < .001 and P < .001) and healthy men (sperm concentration: median, 48 x 10(6)/mL; range, 0 to 402 x 10(6)/mL; sperm count: median, 162 x 10(6); range, 0 to 1253 x 10(6)) (P < .001 and P < .001). FSH levels were increased in men with testicular cancer (median, 5.7 IU/L; range, 2.0 to 27 IU/L) compared with both men with malignant lymphomas (median, 3.3 IU/L; range, 1.01 to 12.0 IU/L) and healthy controls (median, 4.1 IU/L; range, 1.04 to 21 IU/L)(P = .001 and P = .007, respectively). Surprisingly, we found significantly lower LH in the group of men with TGCC (median, 3.6 IU/L; range, 1.12 to 11.9 IU/L) than in healthy men (median, 4.7 IU/L; range, 1.3 to 11.9 IU/L) (P = .01). We could not detect any differences between men with testicular cancer and men with malignant lymphomas and healthy men with regard to serum levels of testosterone, SHBG, and estradiol. Men with testicular cancer who had increased hCG levels had significantly lower LH and significantly higher testosterone and estradiol than those without detectable hCG levels. CONCLUSION Spermatogenesis is already impaired in men with testicular cancer before orchiectomy. Neither local suppression of spermatogenesis by tumor pressure nor a general cancer effect seems to fully explain this impairment. The most likely explanation is preexisting impairment of spermatogenesis in the contralateral testis in men with testicular cancer. The question of whether also a pre-existing Leydig cell dysfunction is present in men with testicular cancer could not be answered in this study because the tumor seems to have a direct effect on the Leydig cells. Men with testicular cancer had low LH values as compared with controls. We speculate that increased intratesticular level of hCG also in men without measurable serum hCG may play a role by exerting LH-like effects on the Leydig cells, causing increased testosterone and estrogen levels and low LH values in the blood.

Effect of graded testicular doses of radiotherapy in patients treated for carcinoma-in-situ in the testis

PURPOSE To determine the effect of radiotherapy in doses 14 to 20 Gy on eradication of carcinoma-in-situ (CIS) testis and on the Leydig cell function. PATIENTS AND METHODS Forty-eight patients presented with unilateral testicular germ cell cancer and CIS of the contralateral testis. The CIS-bearing testis was treated with daily irradiation doses of 2 Gy, 5 days a week, to a cumulative dose of 20 Gy (21 patients), 18 Gy (three patients), 16 Gy (10 patients), and 14 Gy (14 patients). RESULTS All patients treated at dose levels 20 Gy to 16 Gy achieved histologically verified complete remission without signs of recurrence of CIS after an observation period of more than 5 years. One of 14 patients treated at dose level 14 Gy had a relapse of CIS 20 months after irradiation. Leydig cell function was examined before and regularly after radiotherapy in 44 of 48 patients. The levels of testosterone were lower after radiotherapy than before. Testosterone showed a stable decrease for more than 5 years after treatment (3.6% per year) without dose dependency. The levels of luteinizing hormone and follicle-stimulating hormone were increased after radiotherapy. The need of androgen substitution therapy was similar at all dose levels. CONCLUSION Testicular irradiation is a safe treatment at dose level 20 Gy (10 x 2 Gy). Decrease of dose to 14 Gy (7 x 2 Gy) might lead to risk of relapse of CIS. Impairment of hormone production without clinically significant dose dependency is seen in the dose range 14 to 20 Gy.

Surveillance in stage I testicular cancer

Treatment results on 695 stage I testicular cancer patients followed with surveillance are described. Seminoma (SGCT) was present in 394 patients and nonseminoma (NSGCT) in 301 patients. Relapses were detected in 155 patients (22%), in 69 patients with SGCT (17%) and 86 with NSGCT (29%). In patients with vascular invasion, relapse was detected in 54% of patients with NSGCT and 38% of patients with SGCT. Time to relapse was median 13 months (range 1 to 84 months) for SGCT and 5 months (range 1 to 171 months) for NSGCT. Forty‐nine percent of relapses in SGCT patients were seen within the first year, 87% of the relapses were diagnosed within the first two years, and 98% of the relapses were detected within 5 years. The figures for NSGCT were 80%, 89% and 95%, respectively. Forty‐five patients had carcinoma in situ in the contralateral testis, 62% had this together with a seminoma in the other testis. Ten patients died during the follow‐up period. None of these deaths were caused by the germ cell tumour or the treatment. The overall survival for patients with stage I disease is 98.6%, and the cause specific survival 100%.

Impaired Testicular Function in Patients With Carcinoma-In-Situ of the Testis

PURPOSE To elucidate the biologic association between germ cell neoplasia and testicular dysfunction, through investigation of Leydig cell function and semen quality in men with carcinoma-in-situ (CIS) of the testis. PATIENTS AND METHODS We examined two groups of men, unilaterally orchidectomized for testicular cancer. Biopsy of the contralateral testis had showed CIS in a group of 24 patients and no evidence of CIS in the other group of 30 patients. Semen quality and serum levels of testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were compared in these two groups of men after orchidectomy but before further treatment for testicular cancer. RESULTS Significantly higher LH levels (median, 8.1 IU/L v 4.8 IU/L; P < .001) and generally lower testosterone levels (median, 12.5 nmol/L v 15.5 nmol/L; P = .13) were found in the CIS group. The proportion of patients with Leydig cell dysfunction was higher in the group of patients with CIS (11 of 24) than in the group of patients without (two of 30) (P = .01). Sperm concentration and total sperm count were significantly lower (P < .001) in patients with CIS (median, 0.03 x 10(6)/mL and 0.10 x 10(6), respectively) than in patients without (median, 9.1 x 10(6)/mL and 32 x 10(6), respectively), whereas the levels of FSH were significantly higher (P < .001) in the former group of men (median, 19.6 IU/L v 9.0 IU/L). CONCLUSION Not only spermatogenesis but also Leydig cell function is impaired in testes with CIS. This impairment could be due to common factors in the pathogenesis of germ cell neoplasm and testicular dysfunction. Alternatively, CIS cells may have a negative impact on Leydig cell function.

Estimated risk of cardiovascular disease and secondary cancers with modern highly conformal radiotherapy for early-stage mediastinal Hodgkin lymphoma

BACKGROUND Hodgkin lymphoma (HL) survivors have an increased morbidity and mortality from secondary cancers and cardiovascular disease (CD). We evaluate doses with involved node radiotherapy (INRT) delivered as 3D conformal radiotherapy (3D CRT), volumetric modulated arc therapy (VMAT), or proton therapy (PT), compared with the extensive Mantle Field (MF). PATIENTS AND METHODS For 27 patients with early-stage, mediastinal HL, treated with chemotherapy and INRT delivered as 3D CRT (30 Gy), we simulated an MF (36 Gy), INRT-VMAT and INRT-PT (30 Gy). Dose to the heart, lungs, and breasts, estimated risks of CD, lung (LC) and breast cancer (BC), and corresponding life years lost (LYL) were compared. RESULTS 3D CRT, VMAT or PT significantly lower the dose to the heart, lungs and breasts and provide lower risk estimates compared with MF, but with substantial patient variability. The risk of CD is not significantly different for 3D CRT versus VMAT. The risk of LC and BC is highest with VMAT. For LYL, PT is the superior modern technique. CONCLUSIONS In early-stage, mediastinal HL modern radiotherapy provides superior results compared with MF. However, there is no single best radiotherapy technique for HL-the decision should be made at the individual patient level.

Cryopreservation of semen from pubertal boys with cancer

BACKGROUND The possibility of cryopreservation of semen from adolescents has until now received only little attention. Therefore, we have investigated the possibility of cryopreservation of semen in adolescent boys with cancer. PROCEDURE Forty-five boys, aged 13-18 years, admitted because of cancer during the period January 1, 1995 to July 31, 1998 were eligible. Semen was obtained after masturbation in the majority of the cases. In three boys, semen was preserved after penile vibration or electroejaculation in general anaesthesia. The semen samples were analysed for concentration, motility, and morphology according to the WHO guidelines. The sample was transferred into straws prior to cryopreservation at 196 degrees C in liquid nitrogen. RESULTS Twenty-one boys delivered a semen sample for cryopreservation. Four boys were offered and accepted sperm banking but were not able to produce a sample. In 20 cases time did not allow an attempt of sperm banking, the boy was not assessed to be mature enough to deliver a semen sample, or the procedure was not accepted. The boys delivered 1-3 samples, and the total number of spermatozoa ranged from 0-210 millions. Median percentage of motile sperm was 50% (range 9-86%). Semen quality improved with age; however, a 13- year- old boy produced 75 million spermatozoa with 38% motile cells. CONCLUSIONS Pubertal maturation should be assessed in all boys admitted for cancer, and the possibility of sperm banking should be discussed with the patient and his parents.

Risk of Developing Cardiovascular Disease After Involved Node Radiotherapy Versus Mantle Field for Hodgkin Lymphoma

PURPOSE Hodgkin lymphoma (HL) survivors are known to have increased cardiac mortality and morbidity. The risk of developing cardiovascular disease after involved node radiotherapy (INRT) is currently unresolved, inasmuch as present clinical data are derived from patients treated with the outdated mantle field (MF) technique. METHODS AND MATERIALS We included all adolescents and young adults with supradiaphragmatic, clinical Stage I-II HL treated at our institution from 2006 to 2010 (29 patients). All patients were treated with chemotherapy and INRT to 30 to 36 Gy. We then simulated a MF plan for each patient with a prescribed dose of 36 Gy. A logistic dose-response curve for the 25-year absolute excess risk of cardiovascular disease was derived and applied to each patient using the individual dose-volume histograms. RESULTS The mean doses to the heart, four heart valves, and coronary arteries were significantly lower for INRT than for MF treatment. However, the range in doses with INRT treatment was substantial, and for a subgroup of patients, with lymphoma below the fourth thoracic vertebrae, we estimated a 25-year absolute excess risk of any cardiac event of as much as 5.1%. CONCLUSIONS Our study demonstrates a potential for individualizing treatment by selecting the patients for whom INRT provides sufficient cardiac protection for current technology; and a subgroup of patients, who still receive high cardiac doses, who would benefit from more advanced radiation technique.

Detection of chromosomal aberrations in seminomatous germ cell tumours using comparative genomic hybridization

Comparative genomic hybridization (CGH) was used to evaluate tissue specimens from 16 seminomas in order to elucidate the pathogenesis of germ cell tumours in males. A characteristic pattern of losses and gains within the entire genomes was detected in 94% of the seminomas by comparing the ratio profiles of the tumours with a standard of cytogenetically normal genomic DNA. Losses represented 43% of the total number of alterations often affecting chromosomes and chromosome arms 4, 5, 11, 13q, and 18q. Gains amounted to 57% and were often observed on 1q, 7, 8, 12, 14q, 15q, 21q, and 22q. Aberrations of 12p and 21q appeared most consistently. Results from CGH analysis displayed no relationship to the clinical stages of the malignancy. Some rare aberrations appeared, however, only in clinical stage II and in tumours showing relapse in the contralateral testis following orchiectomy, although the alterations were not present in all of the tumours in question. Losses of 16q13‐21 and gains of 9q22.1‐22.2 were demonstrated in both groups, while loss of 16p12 and gains of 6p21 and 6q23.3‐24 were detected in the latter group as well. In conclusion, a specific pattern of chromosomal alterations was demonstrated in the seminomas by improved detection criteria, which increased specificity and sensitivity. The rare aberrations, which appeared only in tumours in clinical stage II and relapsed tumours, may be linked to tumour progression, invasiveness, and bilateral disease. Genes Chromosomes Cancer 20:412–418, 1997.

Risk factors for radiation-induced hypothyroidism: a literature-based meta-analysis.

A systematic overview and meta‐analysis of studies reporting data on hypothyroidism (HT) after radiation therapy was conducted to identify risk factors for development of HT.