Volker Loy

Risk Factors for Relapse in Clinical Stage I Nonseminomatous Testicular Germ Cell Tumors: Results of the German Testicular Cancer Study Group Trial

PURPOSE To prospectively assess potential risk factors for relapse in clinical stage I nonseminomatous germ cell tumors of the testis (CS I NSGCT). PATIENTS AND METHODS From September 1996 to May 2002, 200 patients with CS I NSGCT were prospectively assigned to retroperitoneal lymph node dissection (RPLND), and risk factor assessment was performed within a multicenter protocol. One hundred sixty-five patients had an adequate minimum follow-up of 12 months (mean, 34.5 months) or had pathologic stage II. RESULTS Pathologic stage II disease was found in 27.9% of patients. Only 0.6% of patients relapsed in the retroperitoneum after confirmation of pathologic stage I disease. With reference pathology, vascular invasion (VI) was most predictive of stage in multifactorial analysis (accuracy, 65.1%). However, the positive predictive value (PPV) of VI to predict patients who have metastatic disease or relapse during follow-up was only 52.7%. With absent VI, low-risk patients had a negative predictive value (NPV) of 76.9%. With a combination of several risk factors, the PPV increased to 63.6% and the negative predictive value increased to 86.5%. CONCLUSION Even with an optimal combination of prognostic factors and reference pathology, more than one third of patients predicted to have pathologic stage II or relapse during follow-up will not harbor metastatic disease and, therefore, would be overtreated with adjuvant therapy. However, patients at low risk may be predicted at an 86.5% level, and thus, surveillance in highly compliant patients would be a valuable option. For high-risk patients, further reduction of adjuvant treatment is necessary.

Residual tumor discovered in routine second transurethral resection in patients with stage T1 transitional cell carcinoma of the bladder.

When a second transurethral resection was routinely performed 8 to 14 days after the initial transurethral resection in 46 patients for stage T1 bladder tumors residual disease was found in 20 despite the surgical report of complete resection in 40. In only 13 patients was residual tumor noted at repeat resection by the senior urologist performing the operation and residual tumor was confirmed histologically in 10 of them. The extent of the lesion is easily misjudged even by experienced surgeons. Early cystoscopy cannot exclude residual tumor. Residual tumor is an important cause of early recurrence and repeat resection of stage T1 lesions is recommended.

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.

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.

Prognostic impact of lymphovascular invasion in radical prostatectomy specimens

To estimate the prognostic value of lymphovascular invasion (LVI) in patients with node‐negative prostate cancer treated by radical prostatectomy (RP).

Spermatogenesis in the contralateral testis of patients with testicular germ cell cancer: histological evaluation of testicular biopsies and a comparison with healthy males

Associate Editor

FALSE-NEGATIVE BIOPSIES FOR TESTICULAR INTRAEPITHELIAL NEOPLASIA

PURPOSE Testicular intraepithelial neoplasia, also called carcinoma in situ of the testis, is diagnosed by conventional surgical biopsy based on the assumption that testicular intraepithelial neoplasia is randomly distributed throughout the testis. We evaluate the frequency of and possible reasons for false-negative biopsies. MATERIALS AND METHODS Contralateral testicular biopsy was performed in 1,954 consecutive patients with testicular germ cell tumor. Of the patients 1,859 with a negative biopsy for testicular intraepithelial neoplasia were followed for a median of 6 years. Patients with a second testicular tumor despite previous negative biopsy were evaluated clinically and biopsy specimens were reexamined immunohistologically. RESULTS Despite negative biopsy 5 patients had a second testis tumor. Testicular intraepithelial neoplasia was detected on reexamination in 2 of the specimens, and mechanical damage to the specimen and technical problems with immunohistochemical staining accounted for the diagnostic failures. The proportion of false-negative biopsies was 0.3% (95% confidence intervals [CI] 0.087 to 0.627). The sensitivity of testicular biopsies to detect testicular intraepithelial neoplasia was 0.95 (95% CI 0.887 to 0.984) and the overall accuracy of the biopsy was 0.997 (95% CI 0.994 to 0.999). To our knowledge 14 cases have been previously reported in the literature, including 2 treated with chemotherapy before testicular biopsy. CONCLUSIONS The overall proportion of false-negative biopsies for testicular intraepithelial neoplasia is as low as 0.3%. The main reason for diagnostic failure is probably the nonrandom distribution of testicular intraepithelial neoplasia within the testis. Previous chemotherapy and rare technical failures, in particular mechanical damage to the biopsy specimen, may also account for diagnostic failures. Surgical biopsy remains the gold standard for the diagnosis of testicular intraepithelial neoplasia.

Prognostic significance of proliferation activity and neuroendocrine differentiation to predict treatment failure after radical prostatectomy.

Objectives. Neuroendocrine (NE) cells in prostate cancer may influence tumor cell proliferation in a paracrine fashion. The aims of this study were to clarify the prognostic value of tumor cell proliferation and NE tumor cell differentiation in prostate cancer after radical prostatectomy, and to compare these parameters with each other. Material and methods. Specimens were pooled from a total of 528 patients treated with radical prostatectomy without neoadjuvant hormonal therapy between 1996 and 2003. NE differentiation (NED) was determined by immunohistochemistry using antibodies directed against chromogranin A (CgA), and was scored as either NE-negative (0–1+) or -positive (2–3+). Tumor cell proliferation was assessed by means of the Ki-67 labeling index (Ki-67 LI). The mean post-surgical follow-up period was 49 months (range 10–116 months). Any subsequent rise in prostate-specific antigen (PSA) level was regarded as reflecting disease progression. The prognostic values of Ki-67 and CgA were comparatively analyzed using multivariate Cox regression. Results. NED was present in 6.1% of tumors. The mean Ki-67 LI was significantly higher in the CgA-positive group in comparison with CgA-negative specimens (6.6% vs 5.0%; p=0.029). The Ki-67 LI showed the highest correlations with Gleason score and pathological tumor stage (r=0.31 and r=0.3, respectively). NED was found to have the strongest association with pathological tumor stage (r=0.2). Multivariate analysis determined Gleason score ≥7 (4+3) [hazard ratio (HR) 3.04], NED (HR 1.89), lymph node metastases (HR 1.84), preoperative PSA level>20 ng/ml (HR 1.66), and Ki-67 LI≥5% (HR 1.62) to be significant predictors of biochemical progression. Conclusion. Our results identify Ki-67 LI and NED as additional prognostic markers after radical prostatectomy.

Testicular Germ Cell Cancer despite Previous Local Radiotherapy to the Testis

BACKGROUND Testicular intraepithelial neoplasia (TIN, also carcinoma in situ of the testis) is the uniform precursor of testicular germ cell cancer. Local radiotherapy to the testis with dosages of 18-20 Gy has been found to safely eradicate TIN and germ cells, too. Thus, the general assumption is that the development of invasive germ cell tumours can be prevented by this radiotherapy. PATIENTS AND METHODS Herein, we report two patients with one-sided testicular tumour and biopsy-proven contralateral TIN. Both of them developed germ cell neoplasms in the remaining testis although local radiotherapy with 20 Gy had been applied to the testis. RESULTS One patient developed pure seminoma 7 years after completion of radiotherapy, the other developed a combined tumour consisting of embryonal carcinoma and seminoma after 5 years. Treatment consisted of orchiectomy in each of the cases. Histologically, both had TIN in the testicular tissue surrounding the new growths. CONCLUSIONS Pathogenetically, a small fraction of radioresistent TIN cells overcoming irradiation and progressing to full-blown germ cell cancer in the later course may be the histogenetic clue to explain these unexpected events. Other explanations, though less probable, could be technical radiotherapeutic failure due to targeting problems and a pre-existing radioresistent germ cell tumour in the irradiated testicle.

Low-dose radiation therapy for testicular intraepithelial neoplasia

Four patients with unilateral testicular germ-cell tumor and biopsy-proven contralateral testicular intraepithelial neoplasia (TIN; so-called carcinoma in situ) received localized low-dose radiation therapy (18–20 Gy) of the testis with TIN. Repeated biopsies disclosed the disappearance of TIN and germ cells. No recurrence of TIN or germ cells was observed after a follow-up of 18–42 months. All patients reported a normal sex life without need of androgen supplementation. Serum follicle-stimulating hormone increased significantly immediately after radiation treatment and started to decline after 24 months. Serum luteinizing hormone increased slightly but not significantly. A decline after 24 months was observed in only one of three patients. Serum testosterone decreased significantly in all patients after 1 year but never became subnormal. Low-dose radiation treatment is efficacious in eradicating testicular intraepithelial neoplasia without destroying Leydig cells or stromal cells of the testis. Thus, a patient otherwise destined to develop a second testicular tumor can be spared orchiectomy and life-long hormonal replacement.