Primary Mediastinal Germ Cell Tumors—The University of Western Ontario Experience

Extragonadal germ cell tumors account for 2–5.7% of germ cell tumors (GCTs). Of these, primary mediastinal GCTs (PMGCTs) are responsible for 16–36% of cases. Given the rarity of these tumors, specific treatment strategies have not been well defined. We report our experience in treating these complex patients. In total, 318 men treated at our institution with chemotherapy for GCTs between 1980 and 2016 were reviewed. PMGCT was defined as clinically diagnosed mediastinal GCT with no evidence of testicular GCT (physical exam/ultrasound). We identified nine patients diagnosed with PMGCT. All patients presented with an anterior mediastinal mass and no gonadal lesion; four patients also had metastatic disease. Median age at diagnosis was 30 years (range, 14–56) and median mass size at diagnosis was 9 cm (range, 3.4–19). Eight patients had non-seminoma and one had pure seminoma. All patients received cisplatin-based chemotherapy initially. Surgical resection was performed in four patients; three patients had a complete resection and one patient was found to have an unresectable tumor. At a median follow-up of 2 years (range, 3 months–28 years) six patients had progressed. Progression-free survival was short with a median of 4.1 months from diagnosis (range 1.5–122.2 months). Five patients died at a median of 4.4 months from diagnosis. One and 5-year overall survivals were 50% and 38%, respectively. PMGCT are rare and aggressive. Our real-life Canadian experience is consistent with current literature suggesting that non-seminoma PMGCT has a poor prognosis despite prompt cisplatin-based chemotherapy followed by aggressive thoracic surgery.     

Risk of metachronous contralateral testicular germ cell tumors: a population-based study of 7,102 Norwegian patients (1953-2007)

The purpose of the study was to identify overall incidence and risk of developing a metachronous contralateral testicular germ cell tumor (TGCT) and compare the risk for patients treated before and after 1980 (cisplatin became available for patients with metastatic TGCT). Our hypothesis was that the risk of metachronous TCGT would be reduced for patients with metastatic disease diagnosed after 1980. We included 7,102 men with unilateral TGCT, recorded in the Cancer Registry of Norway. Allowing for competing risk, cumulative incidence and adjusted hazard ratio (HR) were estimated for different subgroups, and the diagnostic periods 1953-1979 (I) and 1980-2007 (II). Relative risks were assessed by standardized incidence ratio (SIR). In Period I and Period II, 38 and 137 males, respectively, were diagnosed with metachronous contralateral TGCT. Corresponding 20-year cumulative incidences were 1.9% and 3.9%. In Period II, risk of a second TGCT was halved [HR = 0.5, 95% confidence interval (95% CI) = 0.33-0.77] for patients with metastatic compared to localized disease. For patients presenting with localized and metastatic disease, the SIRs for Period I were 14.6 (95% CI = 9.6-21.2) and 25.3 (95% CI = 12.1-46.5), respectively. In Period II, the corresponding numbers were 19.0 (95% CI = 15.6-22.9) and 9.8 (95% CI = 6.4-14.5). In conclusion, the risk of metachronous contralateral TGCT was halved for patients with metastatic compared to localized disease in Period II, whereas this protective effect of extent of disease lacked significance for Period I. These findings support our hypothesis that cisplatin-based chemotherapy reduced the risk of a second TGCT for patients with metastatic TGCT diagnosed after 1980.     

Efficacy of first-line bleomycin, etoposide, and cisplatin chemotherapy for peripheral blood stem cell mobilization in patients with germ cell cancer

Background We assessed the efficacy of first-line bleomycin, etoposide, and cisplatin (BEP) chemotherapy for the mobilization of peripheral blood stem cells (PBSC) in patients with testicular cancer, and analyzed the predictive factors indicating the optimal time of PBSC harvest. Patients and Methods A total of 29 aphereses, performed during first-line BEP chemotherapy between 1994 and 1996 for 10 patients with metastatic germ cell cancer were analyzed. The predictive value for the optimal time of PBSC harvest was determined by analysis of the correlation between the rate of each cellular component in peripheral blood, and the number of CD34-positive cells harvested. Results The median number of CD34-positive cells obtained at a single apheresis was 11.2×10⁶/kg (range, 0.14 to 47.9×10⁶/kg), and the median cumulative number of CD34-positive cells collected during first-line BEP chemotherapy per patient was 31.9×10⁶/kg (range, 9.7 to 75.5×10⁶/kg). The percentage of immature leukocytes (myelocytes plus metamyelocytes) was significantly correlated with the number of harvested CD34-positive cells. Conclusion Adequate amounts of CD34-positive cells can be harvested during first-line BEP chemotherapy for patients with germ cell cancer. The monitoring of the percentage of immature leukocytes might be useful in ascertaining the optimal time of apheresis.     

Metachronous testicular teratoma,testicular seminoma and papillary thyroid carcinoma occurring in a single individual: a report of two unrelated cases

SYED A.A., JONES N.A.G., BLISS R.D., ROBERTS J.T., MALLICK U.K., JOHNSON S.J., DOUGLAS S.F., PERROS P. & QUINTON R. (2010) European Journal of Cancer Care 19 , 701–702 Metachronous testicular teratoma, testicular seminoma and papillary thyroid carcinoma occurring in a single individual: a report of two unrelated cases We describe two unrelated men who both developed teratomas in one testis followed by seminomas in the contralateral testis followed by papillary thyroid carcinomas. Neither man had a family history of cancers. Although random occurrence is possible, genetic predisposition and/or environmental influence would seem a likely explanation for this previously unreported combination of tumours.     

Increased mortality rates in young and middle-aged patients with malignant germ cell tumours

Cisplatin-based chemotherapy of malignant germ cell tumours (MGCT) has been reported to increase the risk of cardiovascular morbidity. A high incidence of second nongerm cell malignancies is well documented in MGCT survivors. The death risk due to these conditions is, however, more unknown in MGCT patients. Standard mortality rates (SMRs) were established in 3378 Norwegian MGCT patients treated from 1962 to 1997 aged 相似文献   

Associations between birth defects and childhood and adolescent germ cell tumors according to sex,histologic subtype,and site

Background

Studies have reported increased rates of birth defects among children with germ cell tumors (GCTs). However, few studies have evaluated associations by sex, type of defect, or tumor characteristics.

Methods

Birth defect–GCT associations were evaluated among pediatric patients (N = 552) with GCTs enrolled in the Germ Cell Tumor Epidemiology Study and population-based controls (N = 6380) without cancer from the Genetic Overlap Between Anomalies and Cancer in Kids Study. The odds ratio (OR) and 95% confidence interval (CI) of GCTs according to birth defects status were estimated by using unconditional logistic regression. All defects were considered collectively and by genetic and chromosomal syndromes and nonsyndromic defects. Stratification was by sex, tumor histology (yolk sac tumor, teratoma, germinoma, and mixed/other), and location (gonadal, extragonadal, and intracranial).

Results

Birth defects and syndromic defects were more common among GCT cases than controls (6.9% vs. 4.0% and 2.7% vs. 0.2%, respectively; both p < .001). In multivariable models, GCT risk was increased among children with birth defects (OR, 1.7; 95% CI, 1.3–2.4) and syndromic defects (OR, 10.4; 95% CI, 4.9–22.1). When stratified by tumor characteristics, birth defects were associated with yolk sac tumors (OR, 2.7; 95% CI, 1.3–5.0) and mixed/other histologies (OR, 2.1; 95% CI, 1.2–3.5) and both gonadal tumors (OR, 1.7; 95% CI, 1.0–2.7) and extragonadal tumors (OR, 3.8; 95% CI, 2.1–6.5). Nonsyndromic defects specifically were not associated with GCTs. In sex-stratified analyses, associations were observed among males but not females.

Conclusions

These data suggest that males with syndromic birth defects are at an increased risk of pediatric GCTs, whereas males with nonsyndromic defects and females are not at an increased risk.

Plain Language Summary

• We investigated whether birth defects (such as congenital heart disease or Down syndrome) are linked to childhood germ cell tumors (GCTs), cancers that mainly develop in the ovaries or testes.
• We studied different types of birth defects (defects that were caused by chromosome changes such as Down syndrome or Klinefelter syndrome and defects that were not) and different types of GCTs.
• Only chromosome changes such as Down syndrome or Klinefelter syndrome were linked to GCTs.
• Our study suggests that most children with birth defects are not at an increased risk of GCTs because most birth defects are not caused by chromosome changes.

     

Case-Control Comparison of Quality of Life in Long-Term Ovarian Germ Cell Tumor Survivors: A Gynecologic Oncology Group Study

ABSTRACT

Ovarian germ cell cancer is a rare tumor. Approximately 1000 to 2000 women in the United States will be diagnosed with ovarian germ cell cancer in 2007. When it occurs, it is usually diagnosed before age 20 and is highly responsive to therapy. Most patients live a full life span. The 5-year relative survival rate is 95%. This article describes differences in quality of life issues between ovarian germ cell cancer survivors and young women who have not experienced cancer and were matched to survivors on age, education, and race (by the acquaintance control method). Survivors and controls completed mail and phone surveys. A multivariable logistic regression model was adjusted for age, education, household income, marital status, and perception of fertility. Compared to controls, germ cell cancer survivors expressed more reproductive concerns and reported worse sexual functioning, but they also experienced greater appreciation of life and more affective (i.e., emotional) social support. Future research is suggested to test interventions to enhance quality of life for ovarian germ cell cancer survivors in the areas of sexual functioning and reproductive concerns, but only for survivors who are in distress or in need of the support. Potential screening questions are offered for clinicians, but further research is needed to assess their validity as screening tools.     

Hospitalizations among children of survivors of childhood and adolescent cancer: a population-based cohort study

Curative but potentially mutagenic cancer therapy might lead to untoward disorders and increased hospitalization among the offspring of childhood cancer survivors. Hospitalizations in childhood were evaluated in a population-based cohort of 1,920 offspring of 3,963 childhood cancer survivors, 6,394 offspring of 5,657 siblings and 9,594 population-based comparisons. The Danish Cancer Registry, Central Population Register and National Hospital Register were used to identify study subjects and hospitalizations. The probability for children in the offspring cohorts of being hospitalized before a given age was estimated using the Kaplan-Meier method. Hospitalization rate ratios (HRRs) were calculated using a Cox proportional hazards model with population comparisons as referent. Little differences in hospitalization histories were seen among offspring in the 3 cohorts. HRRs of overall hospitalization was 1.05 (95% CI, 0.98-1.12) for offspring of survivors and 1.01 (95% CI, 0.97-1.05) for offspring of siblings, neither of which was significantly different from that of population comparisons. No significant associations were seen for most of the main diagnostic groups of diseases including infections and perinatal disorders. A 6-fold excess risk of hospitalization for malignant tumors in survivors' offspring, however, could largely be explained by hereditary cancer syndromes, and part of the 2-fold excess hospitalization for benign tumors might similarly be explained by an underlying genetic susceptibility or by increased surveillance of children born to survivors. Assuming that hospitalization is an indicator of multifactorial genetic disease, the findings provide further reassurance that cancer therapies do not confer a high risk of such conditions in offspring born after treatments.     

Safety and efficacy of resistance training in germ cell cancer patients undergoing chemotherapy: a randomized controlled trial

Background:

Bleomycin–etoposid–cisplatin (BEP) chemotherapy is curative in most patients with disseminated germ cell cancer (GCC) but also associated with toxic actions and dysfunction in non-targeted tissues. We investigated changes in muscle function during BEP and the safety and efficacy of resistance training to modulate these changes.

Methods:

Thirty GCC patients were randomly assigned to resistance training (resistance training group (INT), n=15) or usual care (CON, n=15) during 9 weeks of BEP therapy. Resistance training consisted of thrice weekly sessions of four exercises, 3–4 sets/exercise of 10–15 repetitions at 12–15 repetition maximum load. The primary endpoint was muscle fibre size, assessed in muscle biopsies from musculus vastus lateralis. Secondary endpoints were fibre phenotype composition, body composition, strength, blood biochemistry and patient-reported endpoints. Healthy age-matched subjects (REF, n=19) performed the same RT-programme for comparison purposes.

Results:

Muscle fibre size decreased by −322 μm² (95% confidence interval (CI): −899 to 255; P=0.473) in the CON-group and increased by +206 μm² (95% CI: −384 to 796; P=0.257) in the INT-group (adjusted mean difference (AMD), +625 μm², 95% CI: −253 to 1503, P=0.149). Mean differences in type II fibre size (AMD, +823 μm², P=0.09) and lean mass (AMD, +1.49 kg, P=0.07) in favour of the INT-group approached significance. The REF-group improved all muscular endpoints and had significantly superior changes compared with the INT-group (P<0.05).

Conclusions:

BEP was associated with significant reduction in lean mass and strength and trends toward unfavourable changes in muscle fibre size and phenotype composition. Resistance training was safe and attenuated dysfunction in selected endpoints, but BEP blunted several positive adaptations observed in healthy controls. Thus, our study does not support the general application of resistance training in this setting but larger-scaled trials are required to confirm this finding.     

Frequent PD-L1 expression in testicular germ cell tumors

Background:

Many testicular germ cell cancers are curable despite metastatic disease, but about 10–15% of patients fail cisplatin-based first-line treatment. Immunotherapy is considered as additional treatment approach for these patients. Inhibition of the interaction between Programmed Death Receptor 1 (PD-1) and Programmed Death Receptor Ligand 1 (PD-L1) enhances T-cell responses in vitro and mediates clinical antitumour activity. We analysed the expression of PD-L1 in testicular germ cell tumours to evaluate its potential as target for immunotherapeutic strategies.

Methods:

Immunohistochemistry was performed in 479 formalin-fixed paraffin-embedded specimens using a rabbit monoclonal antibody (E1L3N). The tissue microarray consisted of 208 pure seminomas, 121 non-seminomas, 20 intratubular germ cell neoplasia unclassified (IGCNU) and 20 specimens of non-neoplastic testicular tissue.

Results:

Programmed Death Receptor Ligand-1 expression was found in 73% of all seminomas and in 64% of all non-seminomas. None of 20 IGCNU and none of 20 normal tissue specimens exhibited PD-L1 expression. PD-L1 positive stromal cells were only detected in seminomas, but not in non-seminomas. The anti PD-L1 antibody showed a pre-dominantly membranous staining pattern in testicular tumour cells, as well as expression in stromal cells.

Conclusions:

This frequent expression of PD-L1 in human testicular germ cell tumours suggests that patients with testicular germ cell tumours could profit from immunotherapeutic strategies using anti-PD1 and anti-PDL1 antibodies.     

High-dose chemotherapy and stem cell transplantation for advanced testicular cancer

High-dose chemotherapy (HDCT) with autologous stem cell support has been studied in both the salvage and first-line setting in advanced germ cell tumor (GCT) patients with poor-risk features. While early studies reported significant treatment-related mortality, introduction of peripheral blood stem cell transplantation, recombinant growth factors and better supportive care have decreased toxicity; and in more recent reports treatment-related deaths are observed in <3% of patients. Two to three cycles of high-dose carboplatin and etoposide is the standard backbone for HDCT, given with or without additional agents including ifosfamide, cyclophosphamide and paclitaxel. Three large randomized Phase III trials have failed to show a benefit of HDCT over conventional-dose chemotherapy (CDCT) in the first-line treatment of patients with intermediate- or poor-risk advanced GCT, and to date the routine use of HDCT has been reserved for the salvage setting. Several prognostic models have been developed to help predict outcome of salvage HDCT, the most recent of which applies to both CDCT and HDCT in the initial salvage setting. Patients that relapse after HDCT are usually considered incurable, and additional therapy is provided with palliative intent.     

Venous Thromboembolism During Chemotherapy for Testicular Cancer: A Population-Based Study

AimsVenous thromboembolism (VTE) is a potential complication among germ cell tumour patients. We evaluated the incidence rate, timing and factors associated with VTE among patients with germ cell cancer in routine practice.Materials and methodsThe Ontario Cancer Registry was linked to electronic records of treatment to identify all cases of testicular cancer treated in Ontario during 2000–2010. Administrative databases were used to identify VTE in the 3 months before and 5 years after orchiectomy. We explored patient-, disease- and treatment-related factors associated with VTE among all patients as well as those with detailed chemotherapy records available.ResultsDuring 2000–2010, 2650 patients underwent orchiectomy for testicular cancer; among this cohort, 920 (33%) received chemotherapy. The VTE rate was 8% (69/920) among patients treated with chemotherapy and 0.6% (11/1730) among those without chemotherapy. Among the patients treated with chemotherapy who had VTE, 13% (9/69) occurred in the month before starting chemotherapy, 62% (42/69) in the first 3 months after starting and 25% thereafter. For patients who received three and four cycles, VTE rates were 8% (21/258) and 16% (19/121), respectively. In adjusted analyses, the only factor independently associated with VTE was increasing number of cycles (odds ratio 3.91 for four cycles, odds ratio 1.63 for three cycles (P = 0.022) compared with one to two cycles).ConclusionThis population-based study confirms findings from institutional case series regarding the high rate of VTE among patients with germ cell tumours treated with chemotherapy. Future studies should evaluate the extent to which VTE prophylactic strategies might mitigate this risk.     

Outcome of patients with HIV-related germ cell tumours: a case-control study

Testicular germ cell tumour (GCT) is not an AIDS-defining illness despite an increased incidence in men with HIV infection. We performed a matched case-control study comparing outcomes in HIV-positive men and the general population with GCT, using three age and stage matched controls for each case. There was no difference in the 5-year GCT-free survival between cases and controls. However, overall survival was significantly decreased in the cases (log rank P=0.03). HIV was responsible for 70% of this mortality. The relapse-free survival for stage I patients treated with orchidectomy and surveillance was not affected by HIV status (log rank P=0.68). There was no difference in disease free survival in patients with metastatic disease (log rank P=0.78). The overall survival has not improved since the introduction of highly active antiretroviral therapy (log rank P=0.4). Thus, HIV-related GCT is not more aggressive than GCT in the general population.     

Comparative Effectiveness of Risk-adapted Surveillance vs Retroperitoneal Lymph Node Dissection in Clinical Stage I Nonseminomatous Germ Cell Testicular Cancer: A Retrospective Follow-up Study of 81 Patients

Purpose: To retrospective assess the potential predictors for relapse and create an effective clinical mode forsurveillance after orchidectomy in clinical stage I non-seminomatous germ cell testicular tumors (CSI-NSGCTs).Materials and Methods: We analyzed data for CSI-NSGCTs patients with non-lymphatic vascular invasion, %ECa< 50% (percentage of embryonal carcinoma < 50%), and negative or declining tumor markers to their half-lifefollowing orchidectomy (defined as low-risk patients); these patients were recruited from four Chinese centersbetween January 1999 and October 2013. Patients were divided into active surveillance group and retroperitoneallymph node dissection (RPLND) group according to different therapeutic methods after radical orchidectomywas performed. The disease-free survival rates (DFSR) and overall survival rates (OSR) of the two groups werecompared by Kaplan-Meier analysis. Results: A total of 121 patients with CSI-NSGCT were collected from fourcenters, and 81 low-risk patients, including 54 with active surveillance and 27 with RPLND, were enrolled atlast. The median follow-up duration was 66.2 (range 6-164) months in the RPLND group and 65.9 (range 8-179)months in the surveillance group. OSR was 100% in active surveillance and RPLND groups, and DFSR was 89.8%and 87.0%, respectively. No significant difference was observed between these two groups (X2=0.108, P=0.743).No significant difference was observed between the patients with a low percentage of embryonal carcinoma(<50%) and those without embryonal carcinoma (87.0% and 91.9%, X2=0.154, P=0.645). No treatment-relatedcomplications were observed in the active surveillance group whereas minor and major complications wereobserved in 13.0% and 26.1% of the RPLND group, respectively. Conclusions: Active surveillance resulted insimilar DFSR and OSR compared with RPLND in our trial. Patients with low-risk CSI-NSGCTs could benefitfrom risk-adapted surveillance after these patients were subjected to radical orchidectomy.     

Survival of patients with nonseminomatous germ cell cancer: a review of the IGCC classification by Cox regression and recursive partitioning

The International Germ Cell Consensus (IGCC) classification identifies good, intermediate and poor prognosis groups among patients with metastatic nonseminomatous germ cell tumours (NSGCT). It uses the risk factors primary site, presence of nonpulmonary visceral metastases and tumour markers alpha-fetoprotein (AFP), human chorionic gonadotrophin (HCG) and lactic dehydrogenase (LDH). The IGCC classification is easy to use and remember, but lacks flexibility. We aimed to examine the extent of any loss in discrimination within the IGCC classification in comparison with alternative modelling by formal weighing of the risk factors. We analysed survival of 3048 NSGCT patients with Cox regression and recursive partitioning for alternative classifications. Good, intermediate and poor prognosis groups were based on predicted 5-year survival. Classifications were further refined by subgrouping within the poor prognosis group. Performance was measured primarily by a bootstrap corrected c-statistic to indicate discriminative ability for future patients. The weights of the risk factors in the alternative classifications differed slightly from the implicit weights in the IGCC classification. Discriminative ability, however, did not increase clearly (IGCC classification, c=0.732; Cox classification, c=0.730; Recursive partitioning classification, c=0.709). Three subgroups could be identified within the poor prognosis groups, resulting in classifications with five prognostic groups and slightly better discriminative ability (c=0.740). In conclusion, the IGCC classification in three prognostic groups is largely supported by Cox regression and recursive partitioning. Cox regression was the most promising tool to define a more refined classification.British Journal of Cancer (2004) 90, 1176-1183. doi:10.1038/sj.bjc.6601665 www.bjcancer.com Published online 24 February 2004