Testicular Germ Cell Cancer Research Articles

Prognostic factors for relapse in patients with clinical stage I testicular cancer: protocol for a Danish nationwide cohort study

IntroductionApproximately one-fourth of patients with clinical stage I testicular germ cell cancer will relapse within 5 years of follow-up. Certain histopathological features in the primary tumour have been associated with...

984P - Prognosis of anaemia in disseminated testicular germ cell tumours. On behalf of the Spanish Germ Cell Cancer Group (SGCCG)

BackgroundDespite improvements in diagnosis and aggressive chemotherapy treatment, a proportion of young patients are still dying from germ cell cancer (GCC). We aim to identify additional prognostic factors that help to select patients that might benefit from new treatment strategies. Anaemia is prognostic in several tumours. Thus, our objective was to address the prognostic significance of anaemia in disseminated testicular GCC. MethodsA multicentre, observational, retrospective study of patients with disseminated testicular GCC receiving first-line platinum-containing chemotherapy between 2000-2014, pooled from the Spanish Germ-Cell Cancer Group registry and another 3 tertiary hospitals. All patients with haemoglobin level available at diagnosis were selected for the analysis. We used the Cox-proportional hazard model to identify prognostic factors. Results665 consecutive patients from 18 centres were included for analysis. The patient distribution according to the International Germ Cell Cancer Collaboration Group (IGCCCG) classification was: 427, 125 and 113 patients for good, intermediate and poor risk categories, respectively. Hb<10g/dL (anaemia) was observed in 22 (3%) patients and was associated with worse PFS (p<0.001) and OS (p<0.001). Anaemia was more frequently observed in the poor prognostic group (good risk: 1.4%, intermediate risk: 2.6% and poor risk: 13.1%, p<0.001), and in the multivariate analysis we observed an interaction between anaemia and the IGCCCG classification. We then analysed the prognostic significance of anaemia in each risk group. Anaemia remained as an independent prognostic factor in the poor risk group both for PFS (HR=2.18, 95%CI: 1.02-4.64; p=0.04) and for OS (HR=3.29, 95%CI: 1.42-7.65; p=0.006). No effect was observed in the good and intermediate risk group, although statistical power was limited in these subgroups due to the low number of patients with anaemia and events. ConclusionsIn our series, Hb<10g/dL at diagnosis was an independent prognostic factor in poor risk disseminated testicular GCC. Future collaborative studies in order to validate these finding in an independent cohort are needed. Legal entity responsible for the studyThe Spanish Germ Cell Cancer Group (SGCCG). FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Primary robotic RLPND for nonseminomatous germ cell testicular cancer: a two-center analysis of intermediate oncologic and safety outcomes.

To evaluate the intermediate-term oncologic outcomes and safety profile of the largest case series of primary robotic retroperitoneal lymphadenectomy for low-clinical-stage non-seminomatous germ cell testicular cancer. This was a two-center retrospective analysis of robotic RPLND cases for low-clinical-stage (stage I-IIB) non-seminomatous germ cell testicular cancer in the primary setting. Demographic, perioperative, operative and oncologic variables were collected between March 2008 and May 2019. Descriptive analyses were performed and presented as medians with interquartile ranges for continuous variables and frequency and proportions for categorical variables. A survival analysis of time to recurrence was performed using Cox proportional hazards model. Using logistic regression, risk factors for complications were analyzed. Both univariate and multivariate analyses were performed. A total of 58 patients (CS 1 = 56, CS IIA = 2, CS IIB = 0) were identified. The median follow-up was 47months and the 2-year recurrence-free survival rate was 91%. The five recurrences were all out of the performed dissection template (pelvis = 1 and lung = 4). Only five patients (29%) with occult metastasis underwent adjuvant chemotherapy. The median operative time was 319min [interquartile range (IQR) 276-355min], estimated blood loss was 100ml (IQR 75-200ml), node count was 26 (IQR 20-31), and length of stay 2 d (IQR 1-3days). There were 2 (3.3%) intraoperative complications, 19 (32.7%) 30-day postoperative complications to include 14 (24.1%) Clavien grade I, 4 (6.9%) Clavien grade II, 1 (1.7%) Clavien grade III and 0 Clavien grade IV complications. No statistical significance was found on multivariate or univariate analysis for survival analysis of time to recurrence and risk factors for complications. This study represents the largest case series of primary R-RPLND for the treatment of low-stage non-seminomatous germ cell tumors (NSGCT). With 47months of follow-up and a low rate of adjuvant chemotherapy, intermediate oncologic efficacy appears to be comparable to the gold standard open approach.

Robot-assisted laparoscopic retroperitoneal lymph node dissection with concomitant inferior vena cava thrombectomy for metastatic mixed testicular germ cell cancer: a case report

BackgroundThe robot-assisted laparoscopic management of post-chemotherapy retroperitoneal metastasis and inferior vena cava tumor thrombus secondary to testicular cancer is a challenging task for urologists.Case presentationA pathological examination of a 36-year-old Caucasian man who had undergone a right radical orchiectomy showed mixed testicular germ cell cancer (70% embryonal cancer and 30% seminoma); he had undergone four prior courses of cisplatin, etoposide, and bleomycin chemotherapy and was found to have residual retroperitoneal enlarged lymph nodes close to the right renal hilum and a 9.8 cm inferior vena cava tumor thrombus (pT1, N2, M1, S2). Pre-surgical three-dimensional image reconstruction was performed based on contrast computed tomography data. The inferior vena cava tumor thrombus was found in the vena cava at the level of the celiac trunk and the inferior mesenteric artery.Our patient accepted treatment with robot-assisted laparoscopic retroperitoneal lymph node dissection with concomitant inferior vena cava thrombectomy and cava reconstruction on September 12, 2018. During the procedure, a drop-in robotic ultrasound probe was used to define the thrombus. Vena cavoscopy using a flexible ureteroscope found that the tumor thrombus adhered to the cava wall in all directions. The tumor thrombus was dissected free from the inferior vena cava lumen, and vena cava reconstruction was achieved using the da Vinci™ Si HD surgical system.The operative time was 550 minutes. The intraoperative estimated blood loss was 2300 ml. Intraoperative blood transfusions consisted of 10 units of red blood cells (Clavien-Dindo grade II). No Clavien-Dindo grade III or above perioperative complications occurred. The length of hospital stay was 7 days. Pathology revealed no viable cancer cells in any of the residual lymph node tissues or in the vena cava tumor thrombus. ConclusionThis is the first case of robot-assisted laparoscopic retroperitoneal lymph node dissection with concomitant inferior vena cava thrombectomy and reconstruction for metastatic mixed testicular germ cell cancer published to date. This complicated surgical procedure was facilitated by the innovative usage of three-dimensional image reconstruction for defining the vena cava tumor thrombus, a robotic ultrasound probe for intraoperatively defining the vena cava tumor thrombus, and vena cavoscopy using a flexible ureteroscope.

A case report on stage IIB testicular seminoma with hydropnephrosis and hydro ureter

Testicular Germ Cell cancers are classified into seminiferous Germ cell Tumors (SGCTs) and Non Seminomatous Germ cell Tumors (NSGCTs). The differentiation of above two entities is an important factor in Therapeutic Strategy and prognostic Index. The retroperitoneal lymphnode (RPLN) is a common site of metastasis in advanced testicular tumors, and large metastases in RPLN lead to ureteral obstruction and resultant hydronephrosis. But it can occur in early stage as happened with our patient.

Testicular germ cell cancer: recent developments in biology and clinical management.

Testicular germ cell cancer: recent developments in biology and clinical management.

Testicular epidermoid cysts: a reevaluation

BackgroundTesticular epidermoid cysts (TECs) are rare benign testicular neoplasms. As TECs are rarely associated with germ cell tumours (GCTs), the understanding of biological behaviour and clinical management of TEC is unresolved.MethodsWe retrospectively searched the files of patients treated for testicular neoplasms and germ cell cancer in the time from 2000 to 2017. Those with TEC were subjected to closer review looking to clinical and histological features, and to results from imaging with ultrasonography (US), contrast enhanced sonography (CEUS) and magnetic resonance imaging (MRI).ResultsAmong 589 patients undergoing surgery for testicular tumour, nine simple TECs were identified (1.5, 95% confidence intervals 0.53–2.50%). Median age was 26 years. Imaging revealed sharply demarcated roundish lesions with avascular central areas. Eight patients underwent testis-sparing excision with no recurrence ensuing. One had orchiectomy because of large size of the mass. Histologically, TECs consisted of cornifying squamous cell epithelium and no accompanying germ cell neoplasia in situ. Two additional cases (0.3% of all) required orchiectomy because these TECs were associated with ipsilateral GCT.ConclusionsTEC is usually a benign lesion that can safely be diagnosed with US, CEUS and MRI due to its roundish shape and its avascular centre. Histologically, this TEC corresponds to the prepubertal-type teratoma unrelated to germ cell neoplasia in situ of the 2016 WHO classification. The other subtype of TEC that is associated with invasive GCT represents a teratoma of postpubertal-type. From a clinical point of view it could be easier to differentiate between a “simple TEC” which is benign (prepubertal type) and a “complex TEC” which is malignant because of its association with invasive GCT.

Cancer therapy and risk of congenital malformations in children fathered by men treated for testicular germ-cell cancer: A nationwide register study.

BackgroundBecause of the potential mutagenic effects of chemo- and radiotherapy, there is concern regarding increased risk of congenital malformations (CMs) among children of fathers with cancer. Previous register studies indicate increased CM risk among children conceived after paternal cancer but lack data on oncological treatment. Increased CM risk was recently reported in children born before paternal cancer. This study aims to investigate whether anti-neoplastic treatment for testicular germ-cell cancer (TGCC) implies additional CM risk.Methods and findingsIn this nationwide register study, all singletons born in Sweden 1994–2014 (n = 2,027,997) were included. Paternal TGCC diagnoses (n = 2,380), anti-neoplastic treatment, and offspring CMs were gathered from the Swedish Norwegian Testicular Cancer Group (SWENOTECA) and the Swedish Medical Birth Register. Children were grouped based on +/- paternal TGCC; treatment regimen: surveillance (n = 1,340), chemotherapy (n = 2,533), or radiotherapy (n = 360); and according to time of conception: pre- (n = 2,770) or post-treatment (n = 1,437). Odds ratios (ORs) for CMs were calculated using logistic regression with adjustment for parental ages, maternal body mass index (BMI), and maternal smoking. Children conceived before a specific treatment acted as reference for children conceived after the same treatment. Among children fathered by men with TGCC (n = 4,207), 184 had a CM. The risk of malformations was higher among children of fathers with TGCC compared with children fathered by men without TGCC (OR 1.28, 95% confidence interval [CI] 1.19–1.38, p = 0.001, 4.4% versus 3.5%). However, no additional risk increase was associated with oncological treatment when comparing post-treatment–to pretreatment-conceived children (chemotherapy, OR = 0.82, 95% CI 0.54–1.25, p = 0.37, 4.1% versus 4.6%; radiotherapy, OR = 1.01, 95% CI 0.25–4.12, p = 0.98, 3.2% versus 3.0%). Study limitations include lack of data on use of cryopreserved or donor sperm and on seminoma patients for the period 1995–2000—both tending to decrease the difference between the groups with TGCC and without TGCC. Furthermore, the power of analyses on chemotherapy intensity and radiotherapy was limited.ConclusionsNo additional increased risk of CMs was observed in children of men with TGCC treated with radio- or chemotherapy. However, paternal TGCC per se was associated with modestly increased risk for offspring malformations. Clinically, this information can reassure concerned patients.

MRI in the Follow-up of Testicular Cancer: Less is More.

This study aimed to report the location of abdominal relapse in patients with testicular cancer. This is a retrospective cross-sectional study including patients who underwent abdominal magnetic resonance imaging (MRI) after treatment of testicular germ cell cancer. MRI reports were classified as negative or positive, and positive results were cross-checked with follow-up imaging and biopsy results. Positive histology or cytology defined a true-positive finding. The location of relapse was registered according to the anatomical site. In a 2-year period, 2,315 MRI examinations were performed. Relapse was detected in 0.7% (95% CI=0.4-1.1) of the examinations. Among these, 75% were seminomas and 25% were non-seminomas. Retroperitoneal lymph nodes were affected in 88% of cases, and pelvic and inguinal lymph nodes affected in 12% of cases. No metastases were found in parenchymatous organs or bony structures. All cases of abdominal relapse occurred in retroperitoneal or pelvic lymph nodes. This suggests that MRI should be directed towards the retroperitoneum and pelvis only.

Phase II study of avelumab in multiple relapsed/refractory testicular germ cell cancer.

e16045 Background: Testicular germ cell tumors (TGCTs) represent a highly curable disease; however, a small proportion of patients develop disease recurrence. PD-L1 expression is significantly higher in germ cell tumors (GCTs) in comparison to normal testicular tissue and high PD-L1 expression is associated with inferior progression-free and overall survival compared to patients with low PD-L1 expression. This study aimed to determine the efficacy and toxicity of PD-L1 antagonist, Avelumab, in patients with refractory GCTs. Methods: From November 2017 to January 2018, 8 patients with refractory GCTs were enrolled in the phase II study. All patients were pretreated with at least 2 cisplatin-based therapies (median 5, range 2 – 6); 5 tumors (62.5%) were absolutely refractory to cisplatin and 5 patients (62.5%) had visceral non-pulmonary metastases. Avelumab was administered at a dose of 10mg/kg biweekly until progression or unacceptable toxicity. The primary end point was 12-weeks progression-free survival (PFS). If &lt; 8 responses to study therapy will be observed among the first 15 patients, the study will be terminated. Results: Median age was 29 years (range: 22 – 52 years). During a median follow-up period of 2.6 months (range: 0.3 - 14.4), 7 (87.5%) patients experienced disease progression and 6 patients (80.0%) died. Twelve-week PFS was 0%, median PFS was 1.4 months, 95%CI (0.9 – 1.4) and median OS was 2.7 months, 95% CI (1.0 – 3.3). No objective response was observed. Avelumab was well tolerated, no severe adverse event was observed. Conclusions: This study failed to achieve its primary end point and our data suggest lack of Avelumab efficacy in unselected multiple relapsed/refractory TGCTs. Clinical trial information: NCT03403777.

Is gynecomastia related to the disease characteristics and prognosis in testicular germ cell tumor patients?

We aimed to assess the relationship between gynecomastia and tumor markers, histologic subtypes, and prognosis in patients with testicular germ cell tumors. This study included 73 testicular germ cell cancer patients with pretreatment chest, abdomen and pelvis computed tomography (CT) scans and tumor markers (β-human chorionic gonadotropin [β-hCG], lactate dehydrogenase [LDH], α-fetoprotein [AFP]). The volumetric analysis of the breast glandular tissue, the presence of gynecomastia and metastatic disease were determined using CT scans. Patients were classified according to the International Germ Cell Cancer Collaborative Group (IGCCCG) prognostic classification. The association between gynecomastia, breast glandular tissue volume, tumor markers, metastatic disease, and disease prognosis were evaluated. Thirty-four of the patients (46.6%) had gynecomastia. A breast volume cutoff value of 0.78 cm3 to diagnose gynecomastia led to 85% sensitivity and 95% specificity. Serum β-hCG level correlated with the breast glandular tissue volume weakly (r=0.242, P = 0.039). Gynecomastia was more common in patients with elevated β-hCG levels (P = 0.047), and was not associated with pulmonary, nonpulmonary distant, or nodal metastases (P = 0.378, P = 0.884, P = 0.333, respectively). No significant association was found between the disease prognosis and gynecomastia (P = 0.556). Gynecomastia was common among testicular germ cell cancer patients with elevated β-hCG. However, it was not associated with metastatic disease and prognosis.

Outcome Definition Influences the Relationship Between Genetic Polymorphisms of ERCC1, ERCC2, SLC22A2 and Cisplatin Nephrotoxicity in Adult Testicular Cancer Patients.

Although previous research identified candidate genetic polymorphisms associated with cisplatin nephrotoxicity, varying outcome definitions potentially contributed to the variability in the effect size and direction of this relationship. We selected genetic variants that have been significantly associated with cisplatin-induced nephrotoxicity in more than one published study (SLC22A2 rs316019; ERCC1 rs11615 and rs3212986; ERCC2 rs1799793 and rs13181) and performed a replication analysis to confirm associations between these genetic polymorphisms and cisplatin nephrotoxicity using various outcome definitions. We included 282 germ cell testicular cancer patients treated with cisplatin from 2009–2014, aged >17 years recruited by the Canadian Pharmacogenomics Network for Drug Safety. Nephrotoxicity was defined using four grading tools: (1) Common Terminology Criteria for Adverse Events (CTCAE) v4.03 for acute kidney injury (AKI) or CTCAE-AKI; (2) adjusted cisplatin-induced AKI; (3) elevation of serum creatinine; and (4) reduction in the estimated glomerular filtration rate (eGFR). Significant associations were only found when using the CTCAE v4.03 definition: genotype CA of the ERCC1 rs3212986 was associated with decreased risk of cisplatin nephrotoxicity (ORadj = 0.24; 95% CI: 0.08–0.70; p = 0.009) compared to genotype CC. In contrast, addition of allele A at SLC22A2 rs316019 was associated with increased risk (ORadj = 4.41; 95% CI: 1.96–9.88; p < 0.001) while genotype AC was associated with a higher risk of cisplatin nephrotoxicity (ORadj = 5.06; 95% CI: 1.69–15.16; p = 0.004) compared to genotype CC. Our study showed that different case definitions led to variability in the genetic risk ascertainment of cisplatin nephrotoxicity. Therefore, consensus on a set of clinically relevant outcome definitions that all such studies should follow is needed.

Environmental endocrine disruptors and testicular germ cell cancer

Environmental endocrine disruptors and testicular germ cell cancer

Re: Risk of Solid Cancer after Treatment of Testicular Germ Cell Cancer in the Platinum Era.

Re: Risk of Solid Cancer after Treatment of Testicular Germ Cell Cancer in the Platinum Era.

Molecular heterogeneity and early metastatic clone selection in testicular germ cell cancer development

BackgroundTesticular germ cell cancer (TGCC), being the most frequent malignancy in young Caucasian males, is initiated from an embryonic germ cell. This study determines intratumour heterogeneity to unravel tumour progression from initiation until metastasis.MethodsIn total, 42 purified samples of four treatment-resistant nonseminomatous (NS) TGCC were investigated, including the precursor germ cell neoplasia in situ (GCNIS) and metastatic specimens, using whole-genome and targeted sequencing. Their evolution was reconstructed.ResultsIntratumour molecular heterogeneity did not correspond to the supposed primary tumour histological evolution. Metastases after systemic treatment could be derived from cancer stem cells not identified in the primary cancer. GCNIS mostly lacked the molecular marks of the primary NS and comprised dominant clones that failed to progress. A BRCA-like mutational signature was observed without evidence for direct involvement of BRCA1 and BRCA2 genes.ConclusionsOur data strongly support the hypothesis that NS is initiated by whole-genome duplication, followed by chromosome copy number alterations in the cancer stem cell population, and accumulation of low numbers of somatic mutations, even in therapy-resistant cases. These observations of heterogeneity at all stages of tumourigenesis should be considered when treating patients with GCNIS-only disease, or with clinically overt NS.

Re: MicroRNA-371a-3p as Informative Biomarker for the Follow-up of Testicular Germ Cell Cancer Patients.

Re: MicroRNA-371a-3p as Informative Biomarker for the Follow-up of Testicular Germ Cell Cancer Patients.

Evaluation of Serum Biomarkers (FGF-2, HGF, MIF and PTN) in Patients With Testicular Germ Cell Cancer.

FGF-2, HGF, MIF and PTN have been suggested as biomarkers for testicular germ cell cancer patients in earlier studies. Our study was designed to validate these potential novel tumor markers. Serum FGF-2, HGF, MIF and PTN levels were analysed using an ELISA technique in a screening cohort of 20 testicular germ cell cancer patients and 10 healthy men. MIF levels were measured in a validation cohort of 84 patients with testicular cancer, 24 with non-malignant testicular tumors and 64 healthy men. Serum FGF-2, HGF and PTN levels did not differ in cancer patients and healthy males within the screening cohort, whereas MIF was significantly increased among cancer patients. Within the validation cohort, a modest but insignificant increase of serum MIF was observed in TGCT patients compared to healthy men. MIF levels were not correlated with adverse clinical-pathological parameters. FGF-2, HGF, MIF and PTN are not suitable as non-invasive biomarkers for testicular germ cell cancer patients.

Paper-based immunocapture for targeted protein analysis

A novel sampling concept for mass spectrometric bottom-up targeted protein analysis is here demonstrated with polymeric sampling spots integrated with instant immunocapture for analysis of dried matrix spots. The polymers 2-hydroxyethyl methacrylate-co-2-vinyl-4,4-dimethyl azlactone (pHEMA-VDM) and pHEMA-Tosyl for covalent attachment of antibodies where investigated alongside with adsorption on non-treated filter paper. From performance characterization, the pHEMA-VDM had the best performance. The sampling spots demonstrated fast and easy sampling and preparation of human serum spiked with the biomarker human chorionic gonadotropin. The sampling spots enabled a detection limit of 1 ng/mL (26.4 pM) within a five point concentration curve from 1 ng/mL to 20 ng/mL (R2 = 0.97). The detection limit was demonstrated to be two times lower than previously demonstrated with standard DMPK-C sampling cards. A five point concentration curve from 100 ng/mL to 2000 ng/mL was also investigated (R2 = 0.998). Intra day precision was within 16% and 23% for concentration range 1 ng/mL to 20 ng/mL and 100 ng/mL to 2000 ng/mL, respectively. Inter day precision was within 20%. Accuracy was determined to 10% and 11% for 2.5 ng/mL and 20 ng/mL, respectively. The sampling spots were also demonstrated in a realistic setting where serum samples from two confirmed patients with testicular germ cell cancer were analyzed. These analyses confirmed an elevated hCG content in the sera of 418.5 ± 4.2 ng/mL and 21 ± 0.02 ng/mL hCG for patient one and two respectively.

Deep learning for detecting tumour-infiltrating lymphocytes in testicular germ cell tumours

AimsTo evaluate if a deep learning algorithm can be trained to identify tumour-infiltrating lymphocytes (TILs) in tissue samples of testicular germ cell tumours and to assess whether the TIL counts...

TargetClone: A multi-sample approach for reconstructing subclonal evolution of tumors.

Most tumors are composed of a heterogeneous population of subclones. A more detailed insight into the subclonal evolution of these tumors can be helpful to study progression and treatment response. Problematically, tumor samples are typically very heterogeneous, making deconvolving individual tumor subclones a major challenge. To overcome this limitation, reducing heterogeneity, such as by means of microdissections, coupled with targeted sequencing, is a viable approach. However, computational methods that enable reconstruction of the evolutionary relationships require unbiased read depth measurements, which are commonly challenging to obtain in this setting. We introduce TargetClone, a novel method to reconstruct the subclonal evolution tree of tumors from single-nucleotide polymorphism allele frequency and somatic single-nucleotide variant measurements. Furthermore, our method infers copy numbers, alleles and the fraction of the tumor component in each sample. TargetClone was specifically designed for targeted sequencing data obtained from microdissected samples. We demonstrate that our method obtains low error rates on simulated data. Additionally, we show that our method is able to reconstruct expected trees in a testicular germ cell cancer and ovarian cancer dataset. The TargetClone package including tree visualization is written in Python and is publicly available at https://github.com/UMCUGenetics/targetclone.