Low level expression of human telomerase reverse transcriptase predicts cancer-related death and progression in embryonal carcinoma.

INTRODUCTION: hTERT (human telomerase reverse transcriptase) is a catalytic subunit of the enzyme telomerase and has a role in cell proliferation, cellular senescence, and human aging. MATERIALS AND METHODS: The purpose of this study was to evaluate the expression and significance of hTERT protein expression as a prognostic marker in different histological subtypes of testicular germ cell tumors (TGCTs), including 46 embryonal carcinomas, 46 yolk sac tumors, 38 teratomas, 84 seminomas as well as two main subtypes of seminomas and non-seminomas using tissue microarray (TMA) technique. RESULTS: The results showed that there is a statistically significance difference between the expression of hTERT and various histological subtypes of TGCTs (P < 0.001). In embryonal carcinoma, low level expression of hTERT protein was significantly associated with advanced pT stage (P = 0.023) as well as tunica vaginalis invasion (P = 0.043). Moreover, low level expression of hTERT protein was found to be a significant predictor of worse DSS (log rank: P = 0.011) and PFS (log rank: P = 0.011) in the univariate analysis. Additionally, significant differences were observed (P =0.021, P =0.018) with 5-year survival rates for DSS and PFS of 66% and 70% for moderate as compared to 97% and 97% for high hTERT protein expression, respectively. CONCLUSION: We showed that hTERT protein expression was associated with more aggressive tumor behavior in embryonal carcinoma patients. Also, hTERT may be a novel worse prognostic indicator of DSS or PFS, if the patients are followed up for more time periods.

Treatment and Outcome of Patients with Stage IS Testicular Cancer: A Retrospective Study from the Spanish Germ Cell Cancer Group.

PURPOSE: Stage IS testicular cancer is defined by the persistence of elevated serum tumor markers, including α-fetoprotein and/or ß-human chorionic gonadotropin, after orchiectomy without radiological evidence of metastatic disease. Current treatment recommendations include cisplatin based chemotherapy up front but the recommendations are based on limited single center series. MATERIALS AND METHODS: We retrospectively analyzed clinical and pathological characteristics, and long-term outcomes in 110 patients uniformly treated with primary chemotherapy between 1994 and 2016. The primary objective was to evaluate long-term disease-free survival. We also explored factors associated with the need for additional treatment. RESULTS: The elevated prechemotherapy tumor markers were α-fetoprotein in 48% of cases, ß-human chorionic gonadotropin in 14%, and α-fetoprotein and ß-human chorionic gonadotropin in 38%. Median α-fetoprotein and ß-human chorionic gonadotropin values were 71 ng/ml and 80 mIU/ml, respectively. The IGCCCG (International Germ Cell Cancer Collaborative Group) prognostic classification was good in 94% of cases. Mixed nonseminomatous germ cell tumor was found in 78% of cases. Of the patients 103 achieved a complete response to chemotherapy. In 6 patients radiological signs of progressive disease developed during chemotherapy, while 8 experienced relapse after an initial complete response. At a median followup of 108 months 108 patients were alive and disease-free. Five and 10-year disease-free survival rates were 87% and 85%, respectively. The predominance of embryonal carcinoma in the primary tumor was the only factor associated with the probability of needing additional therapy. CONCLUSIONS: Stage IS testicular cancer is more commonly associated with elevated α-fetoprotein, an IGCCCG good prognosis and mixed nonseminomatous germ cell tumor. Treatment with cisplatin based chemotherapy leads to cure in most cases. However, a proportion of patients require the integration of additional therapies, including more frequently when embryonal carcinoma is not predominant.

A refined risk stratification scheme for clinical stage 1 NSGCT based on evaluation of both embryonal predominance and lymphovascular invasion.

BACKGROUND: Active surveillance is an increasingly accepted approach for managing patients with germ-cell tumors (GCTs) after an orchiectomy. Here we investigate a time-to-relapse stratification scheme for clinical stage 1 (CS1) nonseminoma GCT (NSGCT) patients according to factors associated with relapse and identify a group of patients with a lower frequency and longer time-to-relapse who may require an alternative surveillance strategy. PATIENTS AND METHODS: We analyzed 266 CS1 GCT patients from the IRB-approved DFCI GCT database that exclusively underwent surveillance following orchiectomy from 1997 to 2013. We stratified NSGCT patients according to predominance of embryonal carcinoma (EmbP) and lymphovascular invasion (LVI), using a 0, 1, and 2 scoring system. Cox regression and conditional risk analysis were used to compare each NSGCT group to patients in the seminomatous germ-cell tumor (SGCT) category. Median time-to-relapse values were then calculated among those patients who underwent relapse. Relapse-free survival curves were generated using the Kaplan-Meier method. RESULTS: Fifty (37%) NSGCT and 20 (15%) SGCT patients relapsed. The median time-to-relapse was 11.5 versus 6.3 months for the SGCT and NSGCT groups, respectively. For NSGCT patients, relapse rates were higher and median time-to-relapse faster with increasing number of risk factors (RFs). Relapse rates (%) and median time-to-relapse (months) were 25%/8.5 months, 41%/6.8 months and 78%/3.8 months for RF0, RF1 and RF2, respectively. We found a statistically significant difference between SGCT and patients with one or two RFs (P < 0.001) but not between SGCT and NSGCT RF0 (P = 0.108). CONCLUSION: NSGCT patients grouped by a risk score system based on EmbP and LVI yielded three groups with distinct relapse patterns -and patients with neither EmbP nor LVI appear to behave similar to SGCT.

Relationship between primary and metastatic testicular germ cell tumors: a clinicopathologic analysis of 100 cases.

Testicular germ cell tumors (GCTs) commonly metastasize to the retroperitoneal lymph nodes (RPLNs). We evaluated 100 cases of RPLN dissection specimens with viable GCTs after chemotherapy and compared them with their corresponding orchiectomy specimens. The mean age of patients was 28 years (range, 15-58 years). The testicular tumors consisted of mixed GCT (n = 72), teratoma (n = 18), seminoma (n = 4), embryonal carcinoma (n = 3), yolk sac tumor (n = 1), and no viable tumor (n = 2). Somatic malignant components were found in 5 cases. The metastatic tumors in the RPLNs consisted of only teratoma (n = 77) and non-teratomatous GCT (n = 23). Twenty-one patients had only teratoma in the RPLNs but not in the testis, and 10 patients had metastatic non-teratomatous GCT components that were not observed in the testis. Six patients had somatic malignant components in the RPLNs, but only one of them had such a component in the testis. Overall, 13 patients died of disease in a mean of 42 months, and the patients with only teratoma in the RPLNs had a lower mortality rate (9%) than those with non-teratomatous components (26%) (P = .044). One patient with somatic components in the primary GCT and 3 patients with somatic components in the metastases died of disease. Our study demonstrates that there is frequent discordance of histologic composition between primary and metastatic testicular GCTs. Teratoma is the most common component in treated GCTs and is usually associated with a more favorable clinical outcome than non-teratomatous GCTs. The presence of somatic components in the RPLNs metastasis indicates a poor prognosis.

PARP expression in germ cell tumours.

BACKGROUND: Poly(ADP-ribose)polymerase (PARP) inhibitors represent a new class of promising drugs in anticancer therapy. AIMS: To evaluate PARP expression in testicular germ cell tumours (GCTs) and to correlate expression patterns with clinicopathological variables. METHODS: In this translational study, tumour specimens from 124 patients with GCTs (114 patients with testicular primary tumours and 10 with extragonadal GCTs) were identified. PARP expression was detected by immunohistochemistry using monoclonal antibodies, scored by the multiplicative quickscore (QS) method and compared to PARP expression in normal testicular tissue. RESULTS: We observed higher expression of PARP in testicular tumours compared to normal testicular tissue (mean QS=10.04 vs 3.31, p<0.0000001). Mean QS±SD for each histological subtype was as follows: intratubular germ cell neoplasia unclassified (IGCNU)=18.00±0.00, embryonal carcinoma=9.62±5.64, seminoma=9.74±6.51, yolk sac tumour=7.8±7.20, teratoma=5.87±5.34, and choriocarcinoma=4.50±8.33. The PARP overexpression (QS>9) was most often detected in IGCNU (100% of specimen with PARP overexpression), seminona (52.6%), embryonal carcinoma (47.0%), yolk sac tumour (33.3%), teratoma (26.7%) and choriocarcinoma (25.0%), compared to 1.9% of normal testicular tissue specimens. There was no association between PARP expression and clinical variables. CONCLUSIONS: In this pilot study, we showed for the first time, that PARP is overexpressed in testicular germ cell tumours compared to normal testis.

Expression of epidermal growth factor receptor and HER-2 in pediatric embryonal brain tumors.

BACKGROUND/AIMS: Medulloblastomas (MBs), atypical teratoid rhabdoid tumors (AT/RTs) and central nervous system primitive neuroectodermal tumors (PNETs) are aggressive embryonal brain neoplasms in children with overlapping histological features but with different pathogenetic pathways. We set out to evaluate the role of epidermal growth factor receptor (EGFR), HER-2, Ki-67 and p53 in embryonal tumors. MATERIAL AND METHODS: We retrospectively evaluated 36 children with embryonic tumors (27 MBs, 7 AT/RTs and 2 supratentorial PNETs). The immunohistochemical expression of EGFR and HER-2 was correlated to histology, expression of the Ki-67/MIB-1 proliferative index, p53 tumor suppressor oncoprotein and prognosis. RESULTS: High expression of Ki-67 was observed in all MBs being particularly increased (> 50%) in 8 cases, while p53 protein was detected in 25/27 MBs showing a high expression in 16 cases. EGFR and HER-2 expression was observed in 10/27 and 17/27 MBs, respectively. High Ki-67/MIB-1 and p53 expression was revealed in all AT/RTs and PNETs, while EGFR and HER-2 were detected in 3/7 and 6/7 AT/RTs, respectively. The 5-year progression-free survival and overall survival were 55.5 and 69.2%, respectively. In MBs, the univariate analysis revealed that the Ki-67 index and male gender were both at a significant level related to the survival of the patient. In multivariate analysis, the Ki-67 index was the only independent predictive variable. CONCLUSIONS: The Ki-67 index was identified as a factor with independent prognostic power. EGFR and HER-2 expression is variable in embryonal tumors. HER-2 expression, in a considerable number of MBs and AT/RTs, suggests that HER-2 may be implicated in their pathogenesis representing a potential target for novel therapies.

Retroperitoneal lymph node dissection in patients with high risk testicular cancer.

PURPOSE: In patients with testicular cancer the percent of embryonal carcinoma and lymphovascular invasion in the primary tumor have been identified as risk factors for occult metastatic disease. We reviewed differences between primary and post-chemotherapy retroperitoneal lymph node dissection in patients at high risk. MATERIALS AND METHODS: Patients who underwent retroperitoneal lymph node dissection at our institution from 1993 to 2006 were identified and the clinical charts were reviewed. A total of 247 patients with orchiectomy specimens containing greater than 30% embryonal carcinoma were identified and perioperative data were obtained. RESULTS: Of 247 patients 133 (53%) had greater than 30% embryonal carcinoma, including 76 (57%) with combined lymphovascular invasion. Median followup was 3.49 years. Of the patients 76 (57%) and 57 (43%) underwent primary and post-chemotherapy retroperitoneal lymph node dissection, respectively, of whom most received bleomycin, etoposide and cisplatin. Positive lymph nodes were identified at surgery in 37 (49%) and 35 patients (61%) with primary and post-chemotherapy retroperitoneal lymph node dissection, respectively. Of patients with negative pathological findings at surgery surveillance computerized tomography postoperatively identified retroperitoneal masses in 2 (5%) and 3 (14%) of those who underwent a primary and a post-chemotherapy procedure, respectively. Operative data on the primary vs post-chemotherapy groups showed an estimated blood loss of 166 vs 371 cc, an operative time of 2.7 vs 3.3 hours and a hospital stay of 4.4 vs 4.7 days. There were no deaths in either group. CONCLUSIONS: Patients with greater than 30% embryonal carcinoma with or without lymphovascular invasion are at significant risk for metastatic disease and they can be successfully treated with primary retroperitoneal lymph node dissection. Recurrence rates based on computerized tomography evaluation were low and similar between the chemotherapy and nonchemotherapy treated groups.

Primary germ cell tumors of the mediastinum: III. Yolk sac tumor, embryonal carcinoma, choriocarcinoma, and combined nonteratomatous germ cell tumors of the mediastinum--a clinicopathologic and immunohistochemical study of 64 cases.

BACKGROUND: Yolk sac tumor (YST), embryonal carcinoma (EC), choriocarcinoma (CC), and combined germ cell tumors (CGCTs) of the mediastinum are uncommon neoplasms. Only sporadic cases have been documented in the literature; therefore, the clinical behavior of these tumors when located in the mediastinum remains relatively unknown. METHODS: The clinical and pathologic features of 64 cases of primary YST, EC, CC, and CGCTs without teratomatous components were reviewed. The immunohistochemical findings in 29 cases were also analyzed using a panel of monoclonal and polyclonal antibodies in formalin fixed, paraffin embedded tissues. RESULTS: The patients were all men between the ages of 14 and 63 years (mean, 38.5 years). Their clinical symptoms included chest pain, shortness of breath, chills, fever, and superior vena cava syndrome. None of the patients had a previous history of testicular neoplasm or tumor elsewhere. Macroscopically, the lesions in 27 patients were described as large, soft, hemorrhagic, and in some cases necrotic, and varied in greatest dimension from 6 to 20 cm. Histologically, the tumors displayed morphologic features similar to those of their gonadal counterparts. Pure YSTs accounted for the majority of cases in this series (38 of 64, 60%), followed by pure CCs (8 of 64, 12%) and pure ECs (6 of 64, 9%). CGCTs accounted for only 18% of the total cases (12 of 64). YSTs showed a variety of growth patterns; however, the reticular pattern was the most commonly observed. ECs showed a more solid growth pattern with marked pleomorphism of the tumor cells and abundant areas of necrosis. CCs were characterized by the presence of cytotrophoblastic and syncytiotrophoblastic elements with frequent areas of necrosis and hemorrhage. The cases of nonteratomatous CGCT consisted of 5 cases of EC + YST, 2 cases of EC + seminoma, 4 cases of YST + seminoma, and 1 case of EC + CC. In clinical staging, 14 patients were Stage I, 6 were Stage II, and 19 were Stage III. Information on follow-up ranging from 1 month to 13 years was available for 40 patients. Seventeen patients with YST died of their tumors. Of these, 10 who presented with Stage III disease died within the first 2 years. Unfortunately, no clinical staging was obtained for the other 7 patients in this group, and they died within 6-36 months. It is noteworthy that 4 patients with YST have survived for more than 2 years; these patients presented in Stages I and II, and 2 of them received aggressive therapy with chemotherapeutic agents and radiation. Two patients with Stage III EC died within 2 years. The remaining 4 patients with EC were lost to follow-up. Eight patients with CC died within 6 months after initial diagnosis; 7 of them presented Stage III disease and only 1 presented with Stage I. In the nonteratomatous CGCT category, 2 patients with EC + YST died within 2 years after initial diagnosis, whereas 3 patients with YST + seminoma were alive after 4-9 years. CONCLUSIONS: The results of this study confirm the aggressive nature of primary nonseminomatous germ cell tumor of the mediastinum; 72% of the patients with adequate follow-up died of their tumors within 6-36 months after diagnosis, despite aggressive therapy. Clinical and pathologic staging of mediastinal YST, EC, and CGCT are important parameters that may be helpful in predicting the clinical outcomes of patients with these tumors. The authors' findings suggest that the majority of tumors that are not limited to the mediastinum at the time of diagnosis have more aggressive behavior. On the other hand, mediastinal choriocarcinomas appeared to follow a very aggressive clinical course, regardless of treatment modality or clinical tumor stage.

Familial testicular cancer and developmental anomalies.

Familial occurrence belongs to factors followed in etiology and pathogenesis of testicular germ-cell tumors. Association with abnormal testicular development, or with other risk factors is relatively frequent. In our material 650 patients had been treated for testicular cancer in the period of 1981-1995. Familial occurrence was observed 7-times (1.08%), most frequently in combination with cryptorchidism. Individual families were analyzed in details, including HLA typing. On basis of the observations the supplementation of initial examination of each patient with suspicious testicular cancer with detailed familial history aimed also at the occurrence of urogenital developmental anomalies and tumors has been recommended. The knowledge about familial tumor occurrence in the first-degree relatives in combination with thorough testicular self-examination is being considered of great importance in the secondary prevention.

Cisplatin, vinblastine and bleocin in the treatment of disseminated testicular cancer.

Fifty-nine stage IV disseminated testicular cancer patients underwent 5 or more courses of cisplatin, vinblastine and bleocin (PVB) chemotherapy from August 1981 to July 1989. Tumour histology included 15 seminomas, 13 embryonal carcinomas, 13 teratocarcinomas and 18 mixed tumours. Thirty-four patients (58%) achieved complete remission with an average duration of 56+ months (range 3 to 113+), and 12 patients (20%) achieved partial remission with an average duration of 8.5 months (range 2 to 33). The overall response rate was 78%. Four patients achieved complete remission after adjunctive surgery. The best response was obtained in seminoma patients (73% complete remission). The 5-year survival is 88% for complete responders, 10% for partial responders, and 53% overall. The PVB combination has considerably improved the survival of disseminated testicular cancer patients, but the low survival rate in poor-risk patients necessitates more aggressive chemotherapy regimens.