Klaus-Peter Dieckmann

Prevalence of contralateral testicular intraepithelial neoplasia in patients with testicular germ cell neoplasms.

PURPOSE Testicular intraepithelial neoplasia ([TIN], so-called carcinoma in situ of the testis) is hypothesized to be the precursor of testicular germ cell neoplasms. According to previous studies, it can be detected by testicular biopsy. Since patients with a unilateral testicular tumor are at high risk of a second testicular tumor, it seemed feasible to examine the prevalence of contralateral TIN in patients with testicular germ cell cancer and correlate it with the known prevalence of bilateral testicular tumors. The aim was to provide more evidence for the role of TIN as the preinvasive stage of testicular cancer. PATIENTS AND METHODS Nineteen hundred fifty-four consecutive patients with a unilateral testicular germ cell tumor underwent contralateral biopsy. All specimens were examined immunohistologically. RESULTS TIN was observed in 4.9% (95% confidence interval [CI], 3.95% to 5.91%). Testicular atrophy and a history of undescended testis were more frequently observed in patients with contralateral TIN, but only atrophy was shown to be independently associated by multivariate analysis. Patients with testicular atrophy have a 4.3-fold increased risk of having contralateral TIN. Sixty-four percent of TIN cases were found in normal testes. Patients with TIN were significantly younger than those without (P < .0017). Three patients developed a second testicular tumor despite a negative biopsy for TIN. CONCLUSION The prevalence of contralateral TIN corresponds well to the known prevalence of bilateral testicular tumors. Testicular atrophy is a strong indicator for the presence of TIN, but approximately 60% of TIN cases occur without atrophy. The present data are in accordance with the theory that TIN is an early step in the histogenesis of testicular germ cell neoplasms.

Adjuvant treatment of clinical stage I seminoma: is a single course of carboplatin sufficient?

OBJECTIVES Adjuvant radiotherapy produces excellent disease-free rates in clinical Stage I seminoma. However, concern is growing about side effects and late hazards of this treatment. Carboplatin has been suggested to supplant radiotherapy. To date, there is little experience with this drug in the adjuvant treatment of seminoma. In particular, it is unclear whether one or two courses should be administered. METHODS In a nonrandomized study, 125 patients with pure clinical Stage I seminoma were given adjuvant carboplatin treatment (400 mg/m2). Ninety-three patients received one course and 32 two courses. The median follow-up time was 48 months. To assess gonadal toxicity, serial measurements of follicle-stimulating hormone (FSH) levels were done. To assess myelotoxicity, platelet counts at 3 and 4 weeks after treatment were monitored. RESULTS There were no relapses after two courses of carboplatin. After one course of carboplatin, eight relapses occurred (8.6%; 95% confidence interval [CI] 3.79% to 16.2%). All the relapses were located in the para-aortic region, and all the patients were rescued with cisplatin-based chemotherapy. The median time to recurrence was 16 months. The 5-year actuarial progression-free survival rate after one course was 91.1% (95% CI 85.25% to 97.01%). Younger patients (age groups: less than 30 years and 31 to 38 years) had relapses more frequently (P = 0.038) than those in the older age group (greater than 38 years). After 3 weeks, 32% of the patients had platelet counts below 150/nL. The median FSH level increased immediately after treatment, reaching a peak of 13.6 U/L. After 20 months, the median FSH level had returned to the normal range. CONCLUSIONS One adjuvant course of carboplatin was associated with low myelotoxicity and low gonadal toxicity; however, the recurrence rate was almost 9% and thus unsatisfactory. After two courses of carboplatin, no relapse was observed. Thus, the two-course regimen of carboplatin appears to be equivalent to radiotherapy, and because of its favorable toxicity profile, this regimen should be investigated in randomized trials.

Organ-Sparing Surgery for Adult Testicular Tumours: A Systematic Review of the Literature

CONTEXT According to current guidelines, radical orchidectomy is the standard treatment for testis tumours of malignant and unknown origin. Testis-sparing surgery (TSS) has recently been proposed as an alternative option in selected cases. OBJECTIVE Our aim was to analyse the cumulative evidence for TSS in the treatment of adult malignant tumours of different histology, including notes on operative technique, indications, complications, and oncologic and functional outcome. EVIDENCE ACQUISITION A systematic literature search of the Medline/PubMed database for full-length papers reporting on TSS for adult malignant tumours was performed up to September 2009. Bibliographies of retrieved articles and review articles were also examined. Only those articles with complete data on operative technique, complications, and oncologic or functional outcome were selected. Furthermore, published abstracts at major urologic meetings in the last decade (1999-2009) and guidelines on testis cancer from major oncologic and urologic medical associations were searched and evaluated. EVIDENCE SYNTHESIS No randomised controlled trials have compared TSS and radical orchidectomy; only retrospective outcome studies and case reports on TSS are available. In patients with small malignant germ cell tumours arising in both or in solitary testes, TSS coupled with local adjuvant radiotherapy ensures good oncologic control and is associated with a preserved endocrine function in most cases. In patients with small Leydig cell tumours, TSS can also be performed with elective indications (healthy contralateral testes), provided that pathology fails to reveal aggressive features. Finally, TSS is an option for patients with small ultrasound-detected, nonpalpable tumours even with elective indications because the incidence of benign definitive histology is high at approximately 80%. The overall complication rate is low (<6%). Data on exocrine and endocrine gonadal function, male body image, and health-related quality of life after TSS are still immature. CONCLUSIONS TSS can be safely adopted for the treatment of carefully selected cases of tumours of different histology. Prospective multicentre studies are warranted to further qualify TSS as a treatment option to be recommended as an alternative to radical orchidectomy and to explore the perceived functional advantages of testis preservation.

Bilateral testicular germ cell tumors. Report of nine cases and review of the literature

In a series of 181 patients with testicular germ cell tumors, the phenomenon of bilateral involvement of the testicles was observed nine times (5%). Two patients evidenced a simultaneous bilateral tumor, and, in seven others, a second tumor occurred after an interval ranging between 8 months and 6 years and 11 months. The incidence, histologic findings, therapy, and prognosis of bilateral testicular tumors are discussed on the basis of a survey of the literature. Emphasis is placed on the significance of a long‐term follow‐up period as well as on the important role of sonography in the early detection of a contralateral tumor.

Adrenal myelolipoma: Clinical, radiologic, and histologic features

The adrenal myelolipoma is a benign, endocrinologically inactive tumor whose histologic structure consists of mature adipose tissue with foci of hematopoietic cells. A case is presented of a seventy-one-year-old woman in whom the diagnosis was established preoperatively by means of sonography, computerized tomography, and magnetic resonance tomography. In a review of the literature, the radiologic profile is discussed, and based on the analysis of 59 surgically treated cases a therapy recommendation is given.

How Valid Is the Prenatal Estrogen Excess Hypothesis of Testicular Germ Cell Cancer

Purpose/Aims: The prenatal estrogen excess hypothesis postulates abnormally high estrogen levels during pregnancy which predispose the developing gonad to testicular germ cell cancer (GCT) in adulthood. As no direct measurements are possible to support this hypothesis, evidence must come from clinical and epidemiological observations. The present study looked to surrogate parameters that purportedly point to high estrogenic influence in utero. Methods/Patients: In a case–control study design, 418 cases with GCT were compared to 636 controls having fractures, injuries or nephrolithiasis. A second comparison was done with 120 men suffering from malignant melanoma. The following factors were investigated: maternal and paternal age at birth of proband, birth–order, distribution of brothers and sisters in sibs of patients, sibship size, status of being a twin, status of being a singleton child, handedness, and frequency of breast cancer in mothers and sisters. Results: Status of being a twin was significantly associated with GCT risk (OR 2.41; 95% CI 1.04– 5.63) if compared to men with fractures or stones. Comparison with melanoma controls showed only a nonsignificant trend. Frequency of breast cancer was insignificantly higher in mothers of GCT patients. Maternal age above 30 years was associated with decreased risk of GCT, which is contradictory to the hypothesis. No other parameter was significantly different in cases and controls. Conclusion: The present investigation failed to produce evidence for the estrogen excess hypothesis. Obviously, the parameters tested are only weak indicators of estrogenic influence during embryogenesis. Thus, the sample size and statistical power of the trial might have been too low to show any significant association. But, assessing the negative results of this study in light of equally negative results in previous investigations, the estrogen excess hypothesis still remains to be hypothetic.

The value of the biopsy of the contralateral testis in patients with testicular germ cell cancer: The recent German experience

Purpose: Testicular intraepithelial neoplasia (TIN; so‐called carcinoma in situ of the testis), the precursor of testicular germ cell neoplasms can be detected by testicular biopsy many years before the clinical manifestation of the tumour. This study looked at the prevalence of contralateral TIN in patients with testicular germ cell cancer. The purpose was to evaluate this new approach of early detection of testicular cancer and to evaluate the current management strategies. Patients, methods: 1954 consecutive patients with unilateral testicular germ cell tumour underwent contralateral biopsy. All specimens were examined immunohistologically with staining for placental alkaline phosphatase. Patients with TIN were usually submitted to low‐dose radiotherapy of the testis. A rebiopsy was performed after 3 months. Endocrinological evaluations were done before, during and after treatment. Results: TIN was observed in 4.9% (95% confidence intervals 3.95%– 5.91%). Testicular atrophy constitutes a 4.3 fold increased risk of having contralateral TIN. 64% of the cases with TIN were found in clinically normal testes. Patients with TIN were significantly younger than those without (p<0.017). No case with TIN was found in patients older than 50 years. Three patients developed a second testicular tumour during follow‐up despite a negative biopsy. After radiotherapy, all of 23 patients had complete disappearance of TIN in the rebiopsy. After chemotherapy, 3 of 10 patients had persistent TIN histologically. After radiotherapy, 12 of 41 patients required testosterone replacement. Conclusion: The prevalence of contralateral TIN accords well with the known prevalence of bilateral testicular tumours. Testicular atrophy is a strong indicator for the presence of TIN but about 60% of TIN‐cases occur without atrophy. Local radiotherapy to the testis with 18 – 20 Gy is efficaceous in eradicating TIN, but it causes significant damage to almost one quarter of these patients. Chemotherapy is an unsafe treatment for TIN. This study shows the feasibility of early detection of testicular cancer in a high‐risk population by means of searching for TIN. Although the management of the condition still needs refinement, the TIN‐concept offers an avenue for the early detection of testicular cancer and early conservative management.

Changes in epidemiologic features of testicular germ cell cancer: Age at diagnosis and relative frequency of seminoma are constantly and significantly increasing

OBJECTIVES Testicular germ cell tumors (GCTs) have their incidence peak in the third and fourth decades of life. Histologically, GCTs comprise of seminoma and nonseminoma at almost equal proportions with a slight preponderance of nonseminoma in most of the major series. Since decades, there is a shift toward decreasing age at presentation. Recently, there are suggestions of a reversal of the age trend, and also, the histologic subtype ratio appears to shift toward seminoma. We retrospectively looked to our patient populations to verify these recent trends. METHODS A total of 2,482 patients with histologically proven GCT diagnosed between 1976 and 2010 were retrospectively evaluated regarding the year of diagnosis, histology of primary tumor, and age at presentation. Patients were categorized according to the following time periods of treatment: before 1990, 1990 to 1994, 1995 to 1999, 2000 to 2004, and 2005 to 2010. Mean age and relative proportion of seminoma were compared among patient categories by employing the chi-square test and analysis of variance, respectively. RESULTS The mean age significantly increased from 28 to 36 years. The age difference between the 2 histologic subtypes remained constant between 6 and 8 years during the entire observation period. The relative proportion of seminoma continuously increased from 30.9% to 56% (P <0.001). CONCLUSION There is evidence of a significant shift toward older age at diagnosis of GCT. In addition, the proportion of seminoma is constantly increasing at the expense of nonseminoma. The reasons for these developments are obscure. However, 2 old theories regarding the pathogenesis of GCT may receive support from our results: first, the theory of divergent pathogenetic pathways of seminoma and nonseminoma and second, the involvement of postnatal environmental factors in the pathogenesis of GCTs.

Association of Down's Syndrome and Testicular Cancer

PURPOSE We present additional clinical evidence for the suspected association of Downs syndrome and testicular germ cell tumors. MATERIALS AND METHODS Four cases of Downs syndrome and testicular cancer are reported. The literature was reviewed for previous cases and analysis regarding common features. RESULTS The 4 patients were 29 to 35 years old and had clinical stage I seminoma of the testis. Two patients received prophylactic abdominal radiotherapy, 1 is being followed and 1 received adjuvant carboplatin treatment. There was no relapse at followup of 1 to 8 years. One patient also had contralateral cryptorchidism. A total of 16 cases with the association of Downs syndrome and testicular germ cell cancer was documented previously. CONCLUSIONS Evidence for the suspected association of Downs syndrome and testicular cancer is now accumulating. Etiologically it is suspected that, along with genetically determined malformations in many other organs in trisomy 21, the gonads also undergo maldevelopment, thus creating the conditions for step 1 of germ cell tumor oncogenesis in utero. Physicians caring for patients with Downs syndrome should be aware of the possible association with testicular neoplasms.

Serum Levels of MicroRNAs miR-371-3: A Novel Class of Serum Biomarkers for Testicular Germ Cell Tumors?

Clinical management of testicular germ cell tumors (GCTs) is greatly based on serum biomarker monitoring [1]. However, as only 60% of all GCT patients have elevations of the markers a-fetoprotein, human chorionic gonadotropin, and lactate dehydrogenase, there is an ongoing need for new biomarkers. MicroRNAs (miRNAs) are small RNA molecules involved in several essential biological processes. MiRNAs have the potential to qualify as biomarkers in various malignancies because some of them are abundantly expressed in cancer tissues [2] and most of them reveal high stability in body fluids. MiRNA 302 and the cluster miR-371-3 are overexpressed in GCTs [3]. Accordingly, their high expression in serum was demonstrated in one pediatric GCT case [4]. We looked to serum levels of miRNAs miR-371-3 in GCT patients and in controls with the aim of exploring the feasibility of this miRNA as a biomarker of GCT. Serum levels of miRNAs miR371-3 were measured by quantitative real time polymerase