Advanced Testicular Germ Cell Tumors Research Articles

Paraneoplastic Hyperthyroidism in advanced testicular non-seminomatous germ cell tumors: Prevalence and clinical Management.

Introduction Paraneoplastic hyperthyroidism (PH) has been reported in patients with testicular germ cell tumors (GCTs), sporadically. This disorder is caused by extremely elevated serum levels of beta-human chorionic gonadotropin (bHCG). To date, little is known about the prevalence of PH, and its clinical features are poorly understood. The aim of the present study was to analyze the relative frequency and clinical features of PH in GCTs and evaluate their effects on therapeutic outcomes. Methods A cohort of 438 patients treated for testicular GCT from to 2017-2023 was retrospectively analyzed for histology, age, clinical stage, and presence of PH. The clinical features of the patients with PH were evaluated descriptively. The relative frequency of PH was compared among the subgroups using descriptive statistical methods. Results Three patients with PH were identified; all had clinical symptoms of hyperthyroidism, suppressed serum levels of thyroid-stimulating hormone (TSH), and increased levels of triiodothyronin (fT3). All the patients had advanced, metastasized, and non-seminomatous (GCTs). Serum bHCG levels ranged from 225,00 U/l to 1,520,000 U/l. The prevalence of PH was 0.7% in the entire GCT population and 60% in those with very high bHCG serum levels. All the patients received standard cisplatin-based chemotherapy along with thyrostatic treatment. The clinical symptoms of the hyperthyroidism rapidly disappeared. Thyroid-stimulating hormone (TSH) levels normalized with decreasing bHCG levels. The PH treatment did not affect the therapeutic outcomes of the patients. Conclusion PH may occur in 0,7% of all patients with GCT, but may be present in up to 60% of patients with very high levels of bHCG. Measuring serum levels of TSH and fT3 should be performed in addition to routine diagnostic measures in all patients with poor prognosis GCTs. Thyrostatic medication is recommended for patients with the clinical symptoms of hyperthyroidism. Early recognition of hyperthyroidism and prompt intervention will reduce comorbidity and help optimize therapeutic outcomes.

Testicular GERM cell tumors treatment outcome in a national cancer institution in Peru.

e17031 Background: Testicular germ cell tumor (TGCT) is the most common neoplasm in young men and the incidence has been increasing over the last few decades, especially among Hispanic men. Multidisciplinary management is associated with excellent oncological outcomes. Here, we describe the treatment outcome of TGCT patients treated in single institution in Peru. Methods: We conducted a retrospective study of TGCT treated at Instituto Nacional de Enfermedades Neoplasicas from 2016 to 2019. Clinical and pathological data were collected from medical records. Progression-free survival (PFS) and overall survival (OS) were analyzed by the Kaplan-Meier method and compared with long-rank test. A level of p < 0.05 was considered significant. The statistical package SPSS v19 was used for the data analysis. Results: 221 patients were identified, 56% were non-seminomatous (NS) and 44% were seminomatous (S). Orchiectomy was performed in 94% of patients, only 6% underwent orchiectomy after chemotherapy. In both groups, the treatment regimens were: BEP (Bleomycin/Etoposide/cisplatin) 90%, Carboplatin 8.1% and EP (Etoposide/Cisplatin) 1.8%. 42 (21%) of patients receive rescue therapy, being the most frequent TIP (paclitaxel/ifosfamide/cisplatin). In NS patients, 5-year PFS was superior in good risk compared with poor risk (100% vs. 86%, p = 0.028) and for tumor markers level, S0 was superior to S3 (100% vs. 82%, p = 0.008). In S, 5-year PFS was no significant in any of groups of analysis. With a median follow-up of 57 months, OS in NS was 91%, 83% and 81% in 12, 36 and 60 months, respectively and OS in S was 96%, 87% and 87% in 12, 36 and 60 months, respectively. The analysis of 5-year OS according to clinical stage and risk stratification are shown in the Table 1. Only 2 patients received high-dose chemotherapy and still in complete response. Conclusions: Despite the high incidence of advanced TGCT, our patients had excellent survival results; being lower in those with CS III (both NS and S groups), poor risk and S3 for NS, and intermediate risk for S. Multidisciplinary management in a high volume institution is important for better outcomes in our patients. [Table: see text]

First cytogenomic characterization of murine testis tumor cell line MLTC-1

The cell line MLTC-1 was established in 1982 as a transplantable Leydig cell tumor from a C57BL/6 mouse. The cell line has already been applied in >100 studies: still, the only information about its genetic content is given in the first description: MLTC-1 initially had a polyploid karyotype. Here, a molecular karyotyping and multicolor banding-based molecular cytogenetic study was done to provide the first chromosomal/ (molecular) cytogenetic characterization of MLTC-1. A hexaploid karyotype with 72 to 105 chromosomes was hereby characterized. Besides polyploidy, unbalanced two- and three-way translocations, dicentrics and one neocentric derivative were identified. Also, no Y-chromosome could be detected in this clearly male derived cell line. Overall, a completely unbalanced genome is present in MLTC-1 with ~20 regions being subject to copy number losses or gains. After translating these imbalances into the human genome in a standardized way, a 40% match of imbalances with human Leydig cell tumors was evident; however, about the same rate of concordance was detectable for human spermatocytic seminomas and non-seminomas as well as testicular germ cell tumor. Accordingly, MLTC-1 is better suited as an advanced testicular germ cell tumor model in general, rather than specifically for human Leydig cell tumors.

Testis-expressed gene 11 inhibits cisplatin-induced DNA damage and contributes to chemoresistance in testicular germ cell tumor

Testicular germ cell tumor (TGCT) is a rare cancer but the most common tumor among adolescent and young adult males. Patients with advanced TGCT often exhibit a worse prognosis due to the acquisition of therapeutic resistance. Cisplatin-based chemotherapy is a standard treatment for advanced TGCTs initially sensitive to cisplatin, as exemplified by embryonal carcinoma. The acquisition of cisplatin resistance, however, could be a fatal obstacle for TGCT management. To identify cisplatin resistance-related genes, we performed transcriptome analysis for cisplatin-resistant TGCT cells compared to parental cells. In two types of cisplatin-resistant TGCT cell models that we established from patient-derived TGCT cells, and from the NEC8 cell line, we found that mRNA levels of the high-mobility-group nucleosome-binding gene HMGN5 and meiosis-related gene TEX11 were remarkably upregulated compared to those in the corresponding parental cells. We showed that either HMGN5 or TEX11 knockdown substantially reduced the viability of cisplatin-resistant TGCT cells in the presence of cisplatin. Notably, TEX11 silencing in cisplatin-resistant TGCT cells increased the level of cleaved PARP1 protein, and the percentage of double-strand break marker γH2AX-positive cells. We further demonstrated the therapeutic efficiency of TEX11-specific siRNA on in vivo xenograft models derived from cisplatin-resistant patient-derived TGCT cells. Taken together, the present study provides a potential insight into a mechanism of cisplatin resistance via TEX11-dependent pathways that inhibit apoptosis and DNA damage. We expect that our findings can be applied to the improvement of cisplatin-based chemotherapy for TGCT, particularly for TEX11-overexpressing tumor.

Structure of residual metastases in patients with advanced testicular non-seminomatous germ cell tumors and incomplete serological and radiological response to chemotherapy

Objective: to analyze histological structure and identify predictors of detecting malignant non-seminoma in residual tumor masses obtained from patients with testicular non-seminomatous germ cell tumors (TNSGCTs) who had not achieved complete serological and radiological response to chemotherapy (CT).Materials and methods. This study included 96 out of 703 patients with TNSGCTs (13.7 %) operated on in N.N. Blokhin National Medical Research Center of Oncology. The inclusion criteria were as follows: verified advanced TNSGCT, elevated levels of alpha-fetoprotein and/or chorionic gonadotropin at the moment of CT initiation, at least 3 completed courses of first-line or second-line platinum-based CT, residual tumor foci after CT visualized with radiological methods, alpha-fetoprotein >7.29 IU/mL or chorionic gonadotropin >5 mIU/mL 3 weeks after the initiation of the last CT course, and surgery after CT. Histological examination of the primary tumors demonstrated that they contained elements of seminoma (n = 14; 14.6 %), teratoma (n = 29; 30.2 %), choriocarcinoma in (n = 23; 23.9 %), embryonal carcinoma (n = 45; 46.9 %), and yolk sac (n = 18; 18.8 %). All study participants received first-line CT; 58 of them (60.4 %) also received second-line CT. All patients underwent surgery after CT, including retroperitoneal lymph node dissection (RPLND) (n = 96; 100 %) and excision of extra-retroperitoneal lesions (n = 8; 8.3 %).Results. Histological examination of excised retroperitoneal masses showed that they contained areas of necrosis and fibrosis (n = 25; 26.0 %), teratoma (n = 29; 30.2 %), and viable malignant non-seminoma (n = 42; 43.8 %). There was a strong positive correlation between the existence of residual malignant non-seminomatous components in retroperitoneal masses and presence of choriocarcinoma (r = 0.300; р = 0.004), as well as the absence of embryonal carcinoma in the primary tumor (r = –0.300; р = 0.004), invasion of retroperitoneal metastases into major vessels and/or adjacent organs (r = 0.243; р = 0.017), and second-line CT prior to RPLND (r = 0.413; р <0.0001). Patients having ≥3 risk factors were significantly more likely to have residual malignant non-seminoma in retroperitoneal masses than patients who had 0–2 risk factors (73.5 % vs 27.3 %; р <0.0001). Excised residual extra-retroperitoneal masses contained areas of necrosis and fibrosis (n = 3; 37.5 %), teratoma (n = 1; 12.5 %), and malignant non-seminoma (n = 4; 62.5 %). Concordant structure of retroperitoneal and extra-retroperitoneal lesions was observed in 4 patients (50.0 %).Conclusion. Malignant non-seminomas were detected in 43.8 % of retroperitoneal and 62.5 % of extra-retroperitoneal residual tumorsremoved after CT in patients with advanced TNSGCTs and incomplete serological and radiological response. Discordant structure of metastases at different locations was observed in 50 % of patients. Our finding can be used to select candidates for surgical excision of residual tumors among these patients.

Left Neck Mass: An Unusual Presentation of Testicular Cancer in a 50-Year-Old Man Case Report Seminoma - Havard'

Advanced testicular germ cell tumors commonly involve cervical lymph nodes. In most circumstances, the diagnosis of germ cell tumor is established before the neck disease is noted. In rare cases, these tumors have been found along with cervical lymphadenopathy in patients with a previously undiagnosed primary tumor. In this article, we report the unusual case of a 50-year-old man whose metastatic seminoma initially manifested as an asymptomatic neck mass. This finding reinforces the need to include metastatic disease in the differential diagnosis of neck masses. Our discussion of this case focuses on the appropriate management of cervical metastases of germ cell tumors.

Detection of Circulating Tumor Cells (CTCs) in Patients with Testicular Germ Cell Tumors.

While the majority of patients with advanced testicular germ cell tumors (GCT) achieve complete responses after chemotherapy and if indicated after postchemotherapy resection of residual lesions, about 20% of patients have incomplete responses or show relapses. Moreover, toxicity of chemotherapy is high, and severe adverse chronic effects have been described. Therefore, there is an urgent need for biomarkers that could help to improve tumor staging, and support decision-making, ideally including monitoring of therapy response and prediction of relapse. Besides the well-established serum markers lactate dehydrogenase, α-fetoprotein, and β-subunit of human chorionic gonadotropin, during recent years new noninvasive liquid biopsy markers have been investigated in GCT, including cell-free nucleic acids like microRNAs, and circulating tumor cells (CTCs).Prognostic relevance has been demonstrated for circulating tumor cells (CTCs) in patients with different cancers. However, little is known in GCT patients. Histologically, GCT are a very heterogeneous group of tumors comprising pure seminomas (consisting of cells that remember primordial germ cells) and nonseminomas, which are either undifferentiated (embryonal carcinoma) or differentiated, exhibiting different degrees of embryonic (teratoma) or extraembryonic (yolk sac tumor and choriocarcinoma) differentiation. This heterogeneity hampers capture and detection of CTCs deriving from those tumors using a single method or a single antibody. To date, label-independent capture methods that enrich tumor cells according to the density of GCT cells, which is similar to that of mononuclear cells, have been successfully applied. Since testicular GCT might also express epithelial proteins, methods based on enrichment of CTCs using epithelial markers are promising to detect CTCs in certain subgroups of patients with GCTs as well.Here, we describe and discuss a combination of methods to capture and detect GCT cells with epithelial and germ cell characteristics in blood.

Circulating tumor (ct)-DNA alterations in patients with testicular germ cell tumors.

415 Background: Testicular germ cell tumors (GCT) infrequently harbor somatic mutations. ctDNA assessment allows the noninvasive genomic profiling of malignancies and may assist with understanding molecular evolution of resistance. We report ctDNA profiling of patients (pts) with testicular GCTs. Methods: 40 patients (pts) with advanced testicular GCTs from multiple institutions in the USA that underwent ctDNA analysis using the Guardant (G)-360 platform were eligible and a total of 48 samples were collected. 36 pts had one sample, 3 pts had 2 samples, 1 pt had 6 samples. De-identified demographic data were collected in addition to data for ctDNA alterations. G360 employed a CLIA-certified ctDNA panel that assessed single nucleotide variant and copy number alterations in 68 to 73 genes for potentially actionable genomic alterations. Variants reported at least 3 times in the Catalogue of Somatic Mutations in Cancer (COSMIC) database or found in OncoKB were considered pathogenic. Results: Of 40 patients with testicular GCTs, 13pts (33%) were post systemic therapy. The median age was 36 years (range 20-61). 199 ctDNA alterations were detected in 35 patients (87.5%) across 41 genes. Among the 199 alterations, 102 were believed to be pathogenic and detectable in 26 samples from 25 pts (62.5) (%). The most common pathogenic somatic alterations were KRAS (n = 16/102, 16%), TP53 (n = 16/102, 16%), CCND2 (n = 9/102, 9%), CDK6 (n = 9/102, 9%), MET (n = 9/102, 9%), and RAF1 (n = 6/102, 6%). Conclusions: ctDNA alterations were frequently detected in resistant testicular GCTs and appear similar to alterations previously described in tumor tissue analyses of testicular GCTs. Given that ctDNA offers a non-invasive means of profiling tumor DNA, further development of this promising modality is warranted to study the evolution of resistance to cisplatin-based chemotherapy and new potentially actionable alterations.

Primary and Postchemotherapy Retroperitoneal Lymphadenectomy for Testicular Cancer

Clinical stage I (CS I) testicular non-seminomatous germ cell tumours (NSGCT) are highly curable. Following orchidectomy, a risk-adapted approach using active surveillance, nerve-sparing retroperitoneal lymph node dissection (RPLND) and primary chemotherapy is recommended by the current guidelines. CS I is defined as showing negative values for tumour markers (or values declining to their half-life following orchidectomy) and negative imaging studies of the chest, abdomen and retroperitoneum. Active surveillance can be performed in low- and high-risk NSGCT with an anticipated relapse rate of about 15% and 50%, respectively. The majority of patients will relapse with good and intermediate prognosis tumours, which have to be treated with 3 to 4 cycles of chemotherapy. About 25-30% of these patients will have to undergo postchemotherapy (PC) RPLND for residual masses. Primary chemotherapy with 1-2 cycles of cisplatin, etoposide, bleomycin (PEB) is a therapeutic option for high-risk CS I NSGCT associated with a recurrence rate of only 2-3% and a minimal acute and long-term toxicity rate. Nerve-sparing RPLND, if performed properly, will cure about 85% of all high-risk patients with CS I NSGCT without the need for chemotherapy. PC-RPLND plays an integral part of the multimodality treatment in patients with advanced testicular germ cell tumours (TGCT). According to current guidelines and recommendations, PC-RPLND in advanced seminomas with residual tumours is only indicated if a positron emission tomography scan performed 6-8 weeks after chemotherapy is positive. In non-seminomatous TGCT, PC-RPLND is indicated for all residual radiographical lesions with negative or plateauing markers. Loss of antegrade ejaculation represents the most common long-term complication, which can be prevented by a nerve-sparing or modified template resection. The relapse rate after PC-RPLND is around 12%; however, it increases significantly to about 45% in cases with redo RPLND and late relapses. Patients with increasing markers should undergo salvage chemotherapy. Only select patients with elevated markers who are thought to be chemo-refractory might undergo desperation PC-RPLND if all radiographically visible lesions are completely resectable. PC-RPLND requires a complex surgical approach and should only be performed in experienced, tertiary referral centres.

Deep exploration of the immune infiltrate and outcome prediction in testicular cancer by quantitative multiplexed immunohistochemistry and gene expression profiling

ABSTRACTPlatinum-based chemotherapy is usually curative for patients with testicular germ cell tumors (TGCT), but a subset of patients experience disease progression and poor clinical outcomes. Here, we tested whether immune profiling of TGCT could identify novel prognostic markers and therapeutic targets for this patient cohort. We obtained primary and metastatic TGCT samples from one center. We performed immune profiling using multiplexed fluorescence immunohistochemistry (FIHC) for T-cell subsets and immune checkpoints, and targeted gene expression profiling (Nanostring nCounter Immune panel). Publically available data sets were used to validate primary sample analyses. Nearly all samples had some degree of T-cell infiltration and immune checkpoint expression. Seminomas were associated with increased CD3+ T-cell infiltration, decreased Regulatory T-cells, increased PD-L1, and increased PD-1/PD-L1 spatial interaction compared with non-seminomas using FIHC. Gene expression profiling confirmed these findings and also demonstrated increased expression of T-cell markers (e.g., IFNγ, and LAG3) and cancer/testis antigens (e.g., PRAME) in seminomas, whereas non-seminomas demonstrated high neutrophil and macrophage gene signatures. Irrespective of histology, advanced TGCT stage was associated with decreased T-cell and NK-cell signatures, while Treg, neutrophil, mast cell and macrophage signatures increased with advanced stage. Importantly, cancer/testis antigen, neutrophil, and CD8+/regulatory T-cell signatures correlated with recurrence free survival. Thus, deep immune characterization of TGCT using IHC and gene expression profiling identified activated T-cell infiltration which correlated with seminoma histology and good prognosis. These results may provide a rationale for testing of anti-PD-1/PD-L1 agents and suggest prognostic markers.

Rare Cause of Cardiotoxicity

Etoposide based combination chemotherapy is used with curative intent in patients with advanced testicular germ cell tumors. Common side effects involve nausea and vomiting (up to 43%), alopecia (up to 66%), leukopenia (up to 91%). Cardiovascular side effects are rare, and hypotension only occurs in 1%-2% of patients. Etoposide is not known to cause thyroid dysfunction. We observed a case of bradycardia and QTc interval shortening after introduction of etoposide based chemotherapy.

Postchemotherapy residual tumour resection in complex metastatic sites of advanced testicular germ cell tumours

Postchemotherapy residual tumour resection (PC-RTR) is an integral part of the multimodal therapy for advanced testicular germ cell tumours. Depending on the extent and localisation of the residual mass, PC-RTR may necessitate a multidisciplinary procedure (which should be planned preoperatively), to resolve even complex situations in an oncologically sound manner, with lower treatment-related morbidity The aim of article is to report on the interdisciplinary management of complex residual masses. Of atotal of 162patients who underwent PC-RTR, 24 (17.8 %) patients underwent, in addition to abilateral postchemotherapy retroperitoneal lymphadenectomy (PC-RPLND), complex adjunctive resections including the abdominal aorta, the inferior vena cava, or the thoracic/lumbar spine, and the neighbouring vessels (n= 15). We performed aretrospective analysis of treatment-associated complications according to the Clavien-Dindo classification and of progression-free, cancer-specific and overall survival. Median patient age was 24.5 (18-52) years. All patients had an intermediate or poor prognosis according to the International Germ Cell Cancer Collaboration Group (IGCCCG). Median tumour diameter at the time of surgery was 18.6 (9.0-35) cm. In 5patients 1-2metastatic lumbar vertebral bodies were completely resected, stabilised and replaced by means of a cage. In 6 patients resection of the abdominal aorta/inferior vena cava with vascular prosthesis replacement was required owing to infiltration. In 2 patients the common iliac artery or vein was resected and replaced. In addition, retrocrural lymph nodes had to be resected in 5patients and 3patients required adjunctive nephrectomy. In another 4 patients the Whipple procedure was required owing to infiltration into the pancreas and/or duodenum. The median operating time was 7.8 (6-15) h, the median blood loss was around 1,450 (900-3,400) ml, and 2 Clavien-Dindo grade IVa complications occurred. Pathohistology revealed teratoma/vital cancer in 16/24patients and scarring/necrosis in 8 patients. After amedian follow-up of 2.5years, 1patient developed recurrent disease and 1 patient died of the disease. Postchemotherapy, a few patients with advanced nonseminomas (NS) need complex residual tumour resection in an interdisciplinary setting, with a good functional and oncological outcome. Even the involvement of vascular vertebral structures does not constitute a contraindication for complete resection.

Comprehensive genomic profiling (CGP) of advanced nonseminomatous testicular germ cell tumors (NSGCT) to reveal clinically relevant genomic alterations (CRGA) to guide targeted therapy.

477 Background: NSGCT, the most common solid malignancy in U.S. men ages 18-35, has a > 95% 5-year survival due to exquisite chemosensitivity; however, chemoresistant recurrences still contribute to 400 NSGCT deaths/year. We queried CGP results of the largest collection to date of recurrent NSGCT (n = 28) to identify targeted therapy options for this subset of high risk patients. Methods: DNA was extracted from 28 FFPE NSGCT clinical specimens. Hybridization captured libraries of 236 (FoundationOne, n = 20) or 305 (FoundationOne, n = 8) genes, plus select introns frequently rearranged in cancer were sequenced to high ( > 605x), uniform coverage. All classes of genomic alterations (GA; base subs, in/dels, rearrangements, and copy number alterations) were evaluated. CRGA were defined as GA associated with on-label targeted therapies and targeted therapies in mechanism-driven clinical trials. CGP coverage data was used to assess for chromosome 12p arm amplifications. Results: 28 samples (29% primary, 71% metastasis) from patients (avg 33.7 y) with recurrent NSGCT of predominant pattern of yolk sac tumor (43%), embryonal carcinoma (18%), choriocarcinoma (18%), or unspecified/mixed (21%) were profiled. 57% of NSGCT had chromosome 12p amplification ( > 6 copies). 89% had at least one GA not localized to chromosome 12p, including CRGA of CRKL (11%), MCL1 (11%), MDM2 (11%), GNAS (11%), KRAS (SV 7%), AURKA (7%), KIT (7%). CRGA in each of: AKT1, AKT2, BRAF, ERBB2, NF1, PIK3R2, PDGFRA, STK11 were identified in a single case. To date, we are aware of one patient in whom treatment with everolimus was initiated on the basis of the CGP results (inactivating point mutations in STK11 and PIK3R2) and who experienced marker stabilization lasting 5 months suggesting a biologic effect of this therapy. Conclusions: GA not accounted for by 12p amplification are present at a higher frequency than previously reported in recurrent or treatment-resistant NSGCT. The prevalence of CRGA and clinical response to targeted therapy in one such patient support the utility of CGP to identify additional therapeutic options for high risk NSGCT and warrants additional study.

Outcomes following retroperitoneal lymph node dissection in postchemotherapy residual masses in advanced testicular germ cell tumors.

Introduction:We aimed to study the outcomes of retroperitoneal lymph node dissection (RPLND) in postchemotherapy residual masses in advanced testicular germ cell tumor (GCT) in the Indian population.Patients and Methods:We retrospectively analyzed 35 patients who underwent postchemotherapy RPLND at our institute after primary (29 patients) or salvage (6 patients) chemotherapy over a period of 9 years (June 2003 to July 2012).Results:The mean age of our patients was 26.8 years. 18 (51.42%) presented with primary tumor in the right testis and 3 (8.51%) had bilateral tumors. Mixed GCT was the most common histology among 19 (54.3%) patients. 14 (40%) patients had the residual mass in para-aortic location, which was the most common site. 14 (40%) patients required an adjunctive procedure, most commonly nephrectomy which was required in 9 out of 14 (25.7%). We recorded 25 complications, mostly Clavien-Dindo grade II. Histopathology of residual mass was necrosis in 17 (48.57%), teratoma in 12 (34.28%), and viable tumor in 6 (17.14%) patients.Conclusion:Nearly half of the patients had either teratoma or viable tumor, thus justifying the surgical resection of postchemotherapy residual mass. Although nearly half of the patients had complications, they were adequately managed and there was no mortality. Thus, postchemotherapy RPLND can be a useful procedure in multimodality approach to GCT in carefully selected patients.

601 Complicated postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) in advanced testicular germ cell tumours – is it worth the efforts?

601 Complicated postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) in advanced testicular germ cell tumours – is it worth the efforts?

Complicated postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) in advanced testicular germ cell tumours: Is it worth the efforts?

382 Background: PC-RPLND is performed in patients with residual masses following chemotherapy for advanced testicular cancer. Complicated PC-RPLND is defined by redo, salvage or desperation procedures including the necessity to resect major adjacent vascular, skeletal or intestinal structures. We report on our single centre experience of complicated (group A) versus uncomplicated PC-RPLND (group B). Methods: A total of 138 patients underwent PC-RPLND and 24 (14.8%) patients underwent complicated RPLND: resection of major retroperitoneal vessels n=15 (9.3%), skeletal and pancreaticoduodenal structures in 5 (3.1%) and 4 (2.5%) patients, respectively. We performed a retrospective analysis of treatment-associated complications (Clavien-Dindo classification). Progression-free, cancer-specific and overall survival was calculated. Results: There were significant differences between group A and B concerning tumour diameter (5.9 vs 18.6cm, p = 0.03), intermediate/poor IGCCCG risk (39.9% vs 83.4%, p=0.02), seminomatous primary (7.9% vs 20.8%, p=0.03). Pathohistology of the residual masses was significantly different between group A and B: vital cancer was identified in 6 (4.3%) and 8/24 (33.3%, p=0.02) pts, resp., whereas teratoma was identified in 37 (26.8%) and 14/24 (58.3%, p=0.01), resp. In addition 3 pts in group B demonstrated malignant somatic transformation. After a median follow-up of 32 months for group B, 3 patients with MTS experienced recurrences, 1 patient died of the disease. The remainder survived event-free. In group A, median follow-up was 37 months and DOD was observed in 2 pts, 8 pts (5.8%) experienced recurrences. Frequency of complications grade I-IIIb did not differ significantly between group A and B with vascular or skeletal surgery (6.2 vs 13.3%), however, it increased significantly to 65% in pancreatic surgery (p < 0.001). Conclusions: Few patients with advanced NS need complex surgery in an interdisciplinary setting with good functional and oncological outcome. Despite an increased risk of short-term complications complicated PC-RPLND results in long-term survival > 90% and it is justified if performed at specialized centres.

Outcomes following retroperitoneal lymph node dissection in postchemotherapy residual masses in advanced testicular germ cell tumors

Outcomes following retroperitoneal lymph node dissection in postchemotherapy residual masses in advanced testicular germ cell tumors

Surgical management of testicular cancer patients with complex postchemotherapy residual masses: Aachen University experience.

387 Background: Post-chemotherapy retroperitoneal lymphadenectomy (PC-RPLND) represents the treatment of choice in patients with residual masses following chemotherapy for advanced non-seminomatous testicular germ cell tumors (NSGCT). Involvement of the abdominal aorta, the inferior vena cava or the thoracic/lumbar spine are rare but need complete resection for curative intent. We report on our single center experience in the management of such complex cases. Methods: Between January 2009 and September 2014 post-chemotherapeutic retroperitoneal lymph node dissection (PCRPLND) was performed in 162 patients (pts) with advanced NSGCT. Fourteen pts (4.9%) fulfilled the criteria of a GTS: enlarging metastatic mass in the retroperitoneum or visceral organs during systemic chemotherapy with normalized or regredient tumor markers. In all cases of GTS a complete radical bilateral PCRPLND including the resection of adjacent visceral and vascular structures was performed. Results: Median patient age was 24.5 (18 to 52). All patients exhibited NSGCT with a good or intermediate prognosis according to IGCCCG; 10 and 4 patients presented with clinical stage IIC and III, resp. Median tumor diameter at time of surgery was 6.5 (3,0-35)cm. Tumor markers were normalized in 12 out of 14 patients and markers plateauted in 2 out of 14 patients. Tumor masses were localized in the retroperitoneum in 12 pts; two pts had additional pulmonary metastases which were resected in a second approach. Median time from start of chemotherapy to surgery was 4.8 (1.5 to 26.5) months Median surgical time was 265 (165 to 585) minutes, median blood loss 650 (450 to 2,000) ml. Four pts required resection of the inferior vena cava or abdominal aorta with implantation of a prosthetic graft; adjunctive nephrectomy was performed in three pts. After a median follow-up of 4.2 years two pts developed recurrent disease; the remainder are alive without evidence of disease. Conclusions: Involvement of vascular structures and/or bone is a rare phenomenom among pts with advanced NSGCT and necessitates complete surgical resection of all masses with curative intention. Due to the complex surgery, treatment should be performed at specialized centers.

Complete Remission by Primary Chemotherapy of Advanced Non-Seminomatous Germ Cell Tumor in an Intra-Abdominal Testis

Ectopic testis predisposes to a high risk of germ cell tumor development. Treatment of advanced testicular germ cell tumor developing in an uncorrected abdominal testis is based on primary chemotherapy followed by removal of the testis along with residual masses. However, persistence of viable tumor particularly in the testis is always noted since testis penetration of chemotherapeutic agents is reduced. We report a case of complete pathological remission of a patient with advanced non-seminomatous germ cell tumor in intra-abdominal testis by primary chemotherapy alone, with a review of the literature.

Biological markers of cisplatin resistance in advanced testicular germ cell tumours

Germ cell tumours (GCTs) of the testis show exquisite sensitivity to treatment with cisplatin. Despite the high cure rates provided by platinum-based chemotherapy, 10-20% of patients die from progressive disease. Although various cellular pathways may influence cisplatin efficacy, their actual impact has not been comprehensively investigated in advanced GCTs. The objective of the present study was to clarify the role of the expression status of proteins involved in the Rb and p53 tumour suppressor pathways in sensitivity and resistance of GCTs to cisplatin-based chemotherapy. Paraffin-embedded tumour tissues from 84 patients with advanced GCT treated with cisplatin-based chemotherapy were analysed. Immunohistochemical expression of proteins p53 and mdm2, and the G1-phase cyclins D1 and D2 (CD1 and CD2) was assessed and correlated with the clinical course. The percentages of positive expression of p53, mdm2, CD1 and CD2 were 56, 57, 37.5 and 55%, respectively. From univariate analysis, there was no significant association between p53, mdm2 or CD1 expression and outcome. Instead, positive CD2 expression was found to be marginally associated with shorter median duration of progression-free survival (PFS) (p=0.06). In multivariate analysis, none of the molecular markers retained statistical significance with treatment response or survival. Tissular expression of p53, mdm2 and CD1 is not associated with prognosis or treatment response in patients with advanced GCT. Aberrant CD2 expression appears to further determine a shorter PFS. Larger and further studies are required to validate CD2 as a marker of cisplatin resistance.