Primary Testicular Germ Cell Tumors Research Articles

Editorial Comment on “Long-term Outcomes of Regressed or ‘Burnt Out’ Primary Testicular Germ Cell Tumors”

Editorial Comment on “Long-term Outcomes of Regressed or ‘Burnt Out’ Primary Testicular Germ Cell Tumors”

Long-term Outcomes of Regressed or “Burnt Out” Primary Testicular Germ Cell Tumors

ObjectiveTo review the presentation and long-term oncologic outcomes of patients with regressed (“burnt out”) primary testicular germ cell tumors (GCT). Certain testicular GCT can present with complete regression of the primary tumor. It is not well established if this is associated with more aggressive disease or worse oncologic outcomes. MethodsWe queried our prospectively maintained testicular cancer clinical database at a tertiary cancer center and identified patients without prior chemotherapy who had regressed primary GCT at radical orchiectomy from 1990–2023. All specimens were reviewed by a genitourinary pathologist at diagnosis. Long-term clinical outcomes were reported by Kaplan-Meier method. ResultsFifty-six patients met inclusion criteria; at diagnosis, 17 had no evidence of extra-testicular disease and 39 had advanced (clinical stage [CS] II+) GCT. All CSx (no viable disease or germ cell neoplasia in situ at orchiectomy, and no evidence of advanced disease) and CS0 patients were managed with surveillance and had 5-year recurrence-free survival (RFS) of 88% (95% CI: 39%, 98%). All patients with CS II+ disease underwent primary treatment with surgery (n=5) or first-line chemotherapy (n=34). Two- and 5-year RFS for patients with CSII+ disease was 94% (95% CI: 78%, 98%) and 90% (95% CI: 72%, 97%), respectively. ConclusionPatients with regressed primary testicular GCT often present with advanced disease, possibly due to lack of early clinical signs from the primary tumor. Our analysis shows excellent long-term oncologic outcomes similar to those reported in the literature for patients with viable primary testicular GCT.

Testicular germ cell tumor survival among children, adolescents, and young adults: A population-based retrospective cohort study.

10035 Background: While testicular germ cell tumor (TGCT) overall survival (OS) exceeds 90%, some patient groups, such as adolescents, have inferior event free survival (EFS) outcomes. There is a paucity of granular, population-derived data about outcomes in children, adolescents, and young adults (CAYA) with TGCT, limiting a deeper understanding of the factors that impact their survival. Methods: All male CAYA (ages 11-21 years) in Ontario, Canada diagnosed with TGCT between 1992-2021 were identified using provincial cancer registries. Detailed disease and treatment characteristics were chart abstracted for ~2/3 of the cohort and determined through health administrative databases for the remainder. We assessed 5-year OS and EFS (first of death, recurrence/progression, or subsequent malignant neoplasm [SMN]) using Kaplan-Meier analysis and the log rank test. Follow-up started at TGCT diagnosis, except for survival after SMN or recurrence, where follow-up started at event date. Results: 748 TGCT patients were identified; 521 were chart abstracted and thus had EFS data available. Median age at diagnosis was 19 years (interquartile range:18-21) and 83.6% had non-seminoma histology. OS and EFS ± standard error (SE) were (94.7 ± 0.8 %, n=748) and (76.4 ± 1.9%, n=521), respectively. Among patients with chart abstracted data, OS and EFS differed by cancer extent at diagnosis and were lowest among CAYA with non-lung organ metastases (Table). Patients who underwent retroperitoneal lymph node dissection (RPLND) for initial treatment (91/521) had higher survival than those who did not (OS 96.6 ± 1.9% vs 93.7 ± 1.2%, p=0.04; EFS 87.6 ± 3.5 % vs 74.1 ± 2.1 %, p=0.0008), particularly CAYA with lung-only organ metastases. OS post SMN (n=28) was 77.3 ± 8.2%, with lower OS after non-TGCT SMN (50.8 ± 14.4%, n=13) than second primary TGCT (100 ± 0%, n=15), p=0.002. OS after recurrence/progression (n=116) was superior in the 59 who did not receive chemotherapy at initial diagnosis (89.7 ± 4%) compared to the 57 who had initial chemotherapy (65.9 ± 6.4%; p=0.0001). Conclusions: CAYA with TGCT have low EFS, consistent with previous studies. The extent of metastasis is a significant predictor. Efforts are needed to improve the survival outcomes of young TGCT patients with organ metastasis at diagnosis, and those who recur or develop a non-TGCT SMN. [Table: see text]

EHMT2/G9a and EZH2: Epimarkers in testicular germ cell tumors.

Testicular germ cell tumors remain the most frequent solid malignancies in young males. Despite excellent prognosis, the fact that only 60% of patients at diagnosis have elevated serum tumor markers (dependent on stage and histology) and the poor quality of life of patients who develop resistance to chemotherapy cannot be neglected. Consequently, it is mandatory to bring out novel biomarkers. The main goal was to evaluate EZH2 and EHMT2/G9a immunoexpression in a well-characterized patients' cohort of primary and metastatic testicular germ cell tumors, seeking associations with clinicopathological features and discovering differential immunoexpression patterns among specific subtypes. First, an in silico analysis of the Cancer Genome Atlas database was performed regarding EZH2 and EHMT2/G9a. Then, immunohistochemistry for EZH2 and EHMT2/G9a was carried out in a cohort of testicular germ cell tumor patients, comprising 155 chemo-naïve primary tumors and 11 chemo-treated metastases. Immunoexpression was evaluated using a digital pathology analysis software. Higher EZH2 and EHMT2/G9a expression levels were found in non-seminoma in the in silico analysis, particularly in embryonal carcinoma. Through digital pathology analysis, non-seminomas showed significantly higher EZH2 and EHMT2/G9a immunoexpression, with embryonal carcinoma showing higher expression. Moreover, mixed tumors with 50% or more of embryonal carcinoma component revealed the highest nuclei positivity for both biomarkers. Cisplatin-exposed metastases demonstrated a higher EZH2-positive nuclei and H-score, as well as higher EHMT2/G9a-positive nuclei. Overall, our data suggest that EZH2 and EHMT2/G9a might be associated with greater aggressiveness and, eventually, involved in the metastatic setting, paving the way for testing targeted therapies.

Identification of a panel of microRNA biomarkers for the management of patients with refractory germ cell tumor of the testis.

521 Background: In 1946, nearly 90% of patients diagnosed with metastatic Testicular Germ Cell Tumor (TGCT) succumbed to the disease within a year. In the present day, over 90% of such patients are successfully cured. However, there is a remaining 10% of patients have tumors that consist of chemotherapy-resistant forms of TGCT, such as yolk sac tumors and teratomas. This underlines the need for developing biomarkers that can guide the choice between additional chemotherapy and surgical intervention. MicroRNAs (miRNAs), non-coding RNA molecules that control post-transcriptional modifications, have shown promise in identifying TGCTs. Research has particularly highlighted the overexpression of miR-371a-3p and miR-375-3p in TGCTs. Nevertheless, these miRNAs are not effective in distinguishing between teratomas and other TGCT types. The Cancer Genome Atlas (TCGA), a publicly accessible database, offers clinical and miRNA data on various tumors, including TGCTs. Our objective is to leverage TCGA to identify miRNAs that can be used to classify TGCTs containing teratomas from those that do not. Methods: Between 2001 and 2013, TCGA gathered a total of 135 primary TGCT samples. We group these tumors into those without teratomas and those with any teratomatous components. We used EdgeR, a Bioconductor package designed for differential expression analysis of RNA that accounts for both biological and technical variation. A false discovery rate of less than 1e-8 was applied. A heatmap was generated to display the hierarchical clustering of differentially expressed miRNAs. Results: Based on the above cut-off, a panel of 50 miRNAs of differentially expressed miRNA were used to generate a hierarchical clustering that showed clear clustering between the two groups. Notably, tumor suppressor miRNAs such as hsa-mir-203a, hsa-mir-199, and hsa-mir-152, which are usually downregulated in non-teratoma TCGT, are overexpressed in teratomas. Other miRNA including hsa-mir-146a and hsa-mir-3607, which are downregulated tumor suppressors for non-TCGT are also downregulated in teratomas but not in teratoma-free TGCT. Conclusions: Despite the high cure rate for TGCTs, tumors containing chemotherapy-resistant teratomas still contribute to elevated mortality rates. Utilizing TCGA data, we identified a set of miRNAs that are effective in distinguishing between teratoma-containing and teratoma-free TGCTs. This miRNA panel has the potential to inform decisions related to surgical treatment plans and provide further insight into the biology of the disease.

SMARCB1-Deficient Skull Base Chondrosarcoma with 12p Duplication Presenting as Somatic-Type Malignancy Arising from Metastatic Seminoma

Somatic-type malignancy (STM) can occur infrequently within a primary or metastatic testicular germ cell tumor (TGCT) and is associated with dismal prognosis and survival. STM with chondrosarcomatous features is exceedingly rare and head and neck involvement has not been previously documented. A 39-year-old white man presented with nasal obstruction and epistaxis. Imaging disclosed a 6.9-cm expansile tumor involving the nasal cavity and skull base with intraorbital and intracranial extension. The histopathologic properties of the tumor were compatible with chondrosarcoma, grade II-III. Immunohistochemically, malignant cells were strongly and diffusely positive for S100 and epithelial markers, and showed loss of SMARCB1 expression. IDH1/2 mutations were not detected. Following whole-body PET scan, a 7.0-cm left testicular mass was discovered and diagnosed as seminoma with syncytiotrophoblastic cells, stage pT3NXM1b. Extensive retroperitoneal, mediastinal, and supraclavicular lymphadenopathy was also noticed. Histopathologic examination of the left supraclavicular lymph node revealed metastatic seminoma. By FISH, most metastatic nodal seminoma cells harbored 1 to 4 copies of isochromosome 12p, while the chondrosarcoma featured duplication of 12p. Presence of a malignant TGCT with disseminated supradiaphragmatic lymphadenopathy, the unique immunophenotypic properties of the skull-based chondrosarcoma and lack of IDH1/2 aberrations with gain of 12p strongly support the diagnosis of STM chondrosarcoma arising from metastatic TGCT. The patient did not respond to chemotherapy and succumbed three months after diagnosis. Although exceedingly uncommon, metastasis to the head and neck may occur in patients with TGCT. This case of STM chondrosarcoma demonstrated divergent immunophenotypic and molecular characteristics compared to “typical” examples of head and neck chondrosarcoma. High index of suspicion is advised regarding the diagnosis of lesions that present with otherwise typical histomorphology but unexpected immunohistochemical or molecular features.

Abnormal methylation of HOXA11 promoter promotes tumor progression in testicular germ cell tumor.

To investigate the methylation of HOXA11 gene promoter in testicular germ cell tumor (GCT). The clinicopathological data of 63 patients with primary testicular GCT who underwent surgery during Apr. 2019 to Mar. 2021, were retrospectively analyzed. Their GCT tissue and paraneoplastic testicular tissue were obtained, and genomic DNA was extracted from both. The methylation of HOXA11 gene promoter region was detected by methylation-specific PCR (MSP). The incidence of HOXA11 methylation in testicular GCT and adjacent tissues was compared, and the connection between methylation level in testicular GCT and clinicopathologic features of patients was statistically analyzed. Testicular GCT cells were treated with methylated transferase inhibitor 5-Aza-dC in vitro, and HOXA11 mRNA expression was detected by real-time PCR. The positive rate of HOXA11 promoter methylation in testicular GCT tissues was notably higher than that of paired adjacent tissues (P<0.05). The abnormal methylation of HOXA11 gene promoter was correlated with lymph node metastasis and TNM stage in patients (P<0.05). HOXA11 mRNA expression in testicular GCT cells treated with 5-Aza-dC was increased (P<0.05). Abnormal methylation of HOXA11 gene promoter in testicular germ cell tumor tissue inhibits transcription and expression of HOXA11 gene. The abnormal methylation of HOXA11 promoter region is tightly associated with lymph node metastasis and TNM staging in testicular germ cell tumors.

Predictors of Relapse and Survival in Testicular Germ cell Tumors in Children

Background: Testicular germ cell tumors are common solid organ malignancies in children with a survival rate of more than 90 %. This study aims to assess the predictors of relapse and survival in testicular germ cell tumors in children.&#x0D; Methodology: A retrospective review was conducted on children up to the age of 18-years from January 2010 to December 2020 with a diagnosis of primary testicular germ cell tumors. Factors related to relapse and survival like age, baseline levels of tumor markers in serum and on relapse, stage at diagnosis, histological type, tumor laterality &amp; size of the tumor in testicular germ cell tumors were analyzed. The data was entered into SPSS version 20. Statistical significance was set at a p-value ≤0.05.&#x0D; Results: A total of 115 patients with a mean age of 5.42+ 1.54 years having testicular germ cell tumor were treated. Seventeen patients (14.7 %) had relapse of disease. Relapse was highest in patients with stage I disease (64.7 %). Yolk sac tumor was the most common pathology that was noted in twelve (70 %) patients. The most common site of relapse was the retroperitoneum (70 %). Age of patient, stage of disease, and lymphovascular invasion were significant predictors of relapse and survival in testicular germ cell tumors.&#x0D; Conclusion: Management of patients with testicular germ cell tumors requires standardized follow-up protocol for early detection and treatment of disease relapse. Complete surgical excision with meticulous control of the residual disease is critical to prevent disease relapse.&#x0D; Keywords: Chemotherapy, Children, Outcome, Relapse, Testicular Tumor&#x0D; &#x0D;

Retroperitoneal germ cell tumor, primary or secondary: A diagnostic conundrum

Abstract Germ cell tumor, seminoma, is the most common cancer in young men’s testis. However, a small subset of tumors (1%–2%) originate in other locations and are referred to as primary extragonadal germ cell tumors. But such type of tumors’ origin is thought to be controversial as a significant bulk may represent metastases from primary occult/regressed testicular germ cell tumors. The entire primary extragonadal germ cell tumor is mostly non-seminomatous and present in higher ages than primary testicular germ cell tumors, most of which are seminoma. A 50-year-old male presented with a brief history of abdominal pain for 10 days. Ultrasonography of his abdomen revealed multiple enlarged retroperitoneal lymph nodes. Biopsy and immunohistochemistry of the left iliac node showed features consistent with metastatic seminoma. Ultrasound of the left testis showed a hypoechoic lesion. Positron emission tomography scan showed increased tracer uptake in both the testes without any abnormal enhancing mass lesion and increased fluorodeoxyglucose uptake in the retroperitoneal lymph nodes. A high left inguinal orchidectomy revealed no tumor but a fibrotic scar tissue showing atrophic and ghost tubules, dense lymphoplasmacytic cells, and increased vascularity, implying regressed (burnt-out) seminoma. Regression of testicular seminoma shows a distinct constellation of findings permitting its diagnosis as a primary testicular tumor, which is imminent from a prognostic and therapeutic perspective.

MP50-13 OPEN VERSUS MINIMAL INVASIVE RETROPERITONEAL LYMPH NODE DISSECTION: A NATIONAL CANCER DATABASE ANALYSIS

You have accessJournal of UrologyCME1 Apr 2023MP50-13 OPEN VERSUS MINIMAL INVASIVE RETROPERITONEAL LYMPH NODE DISSECTION: A NATIONAL CANCER DATABASE ANALYSIS Harshit Garg, Mukund Bhandari, Gilda Digman, Onika Noel, Furkan Dursun, Dharam Kaushik, Deepak Pruthi, Michael Liss, Chethan Ramamurthy, and Ahmed Mansour Harshit GargHarshit Garg More articles by this author , Mukund BhandariMukund Bhandari More articles by this author , Gilda DigmanGilda Digman More articles by this author , Onika NoelOnika Noel More articles by this author , Furkan DursunFurkan Dursun More articles by this author , Dharam KaushikDharam Kaushik More articles by this author , Deepak PruthiDeepak Pruthi More articles by this author , Michael LissMichael Liss More articles by this author , Chethan RamamurthyChethan Ramamurthy More articles by this author , and Ahmed MansourAhmed Mansour More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003298.13AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Minimal invasive retroperitoneal lymph node dissection (RPLND), either by laparoscopic or robotic approach, has increasingly become popular. However, data comparative data on perioperative outcomes and survival outcomes is limited. In this study, we aim to compare minimal invasive -RPLND (MI-RPLND) with open (O-RPLND) using National Cancer Database. METHODS: Using the 2010-2019 National Cancer Database, patients with primary testicular germ cell tumors undergoing RPLND were identified and classified as Group A: O-RPLND and Group B: MI-RPLND. The primary outcome was overall survival (OS). Secondary outcomes included lymph nodal yield, death within 30 and 90 days of surgery, length of stay after surgery, and frequency of unplanned readmission within 30 days of surgical discharge. Inverse probability weighting (IPW) was utilized to balance the two groups. RESULTS: Overall, 3,184 patients were identified; 2971 (93.3%) patients were included in Group A and 213(6.7%) patients were included in Group B. Amongst them, 2419 (76%) had NSGCT. Factors associated with increased likelihood of MI-RPLND were treatment at academic research programs (p=0.003) and the treatment period between 2015-2019 (p<0.001). The median lymph nodal yield in O-RPLND and MI-RPLND group were similar [19 vs 22, p=0.623]. The 5-year OS was similar between the two groups [94.3% in O-RPLND vs 94.7%, in MI-RPLND p=0.77) (Figure 1a). The length of stay after surgery (p=0.623), frequency of unplanned readmission within 30 days of discharge (p=0.728), death within 30-days of surgery (p=0.74) and death within 90-days of surgery (p=0.06) were similar between the two groups. After IPW matched cohort analysis, the 5y-OS remained similar between the open and minimally invasive approach. [93.9% in O-RPLND vs 93.7% in MI-RPLND, p=0.94] (Figure 1b). CONCLUSIONS: Both O-RPLND and MI-RPLND are associated with similar OS. In terms of perioperative outcomes, both surgical approaches have similar length of hospital stay, similar rates of mortality within 30-day and 90-day of surgery, and similar rates of unplanned readmission rate within 30 days of surgical discharge. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e689 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Harshit Garg More articles by this author Mukund Bhandari More articles by this author Gilda Digman More articles by this author Onika Noel More articles by this author Furkan Dursun More articles by this author Dharam Kaushik More articles by this author Deepak Pruthi More articles by this author Michael Liss More articles by this author Chethan Ramamurthy More articles by this author Ahmed Mansour More articles by this author Expand All Advertisement PDF downloadLoading ...

The value of contrast-enhanced ultrasonography in differential diagnosis of primary testicular germ cell tumors and non-germ cell tumors over 50 years old.

Unlike young and middle-aged patients, seminoma is not common in patients with primary testicular tumors over the age of 50, so it cannot follow the general ideas and norms for diagnosing and treating testicular tumors, and its characteristics need to be considered separately. The conventional ultrasonography and contrast-enhanced ultrasonography (CEUS) findings of primary testicular tumors in patients over 50 years old were retrospectively analyzed and compared with the pathological results to compare the diagnostic value of these two methods. Of the 13 primary testicular tumors, 8 were primary lymphomas. Conventional ultrasound of 13 cases of testicular tumors showed hypoechoic with rich blood flow, and it was difficult to identify the type accurately. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of conventional ultrasonography in diagnosing non-germ cell tumors (lymphoma and Leydig cell tumor) were 40.0%, 33.3%, 66.7%, 14.3%, and 38.5%, respectively. CEUS findings: 7 of 8 lymphomas showed uniform hyperenhancement. 2 cases of Leydig cell tumors showed uniform high enhancement. 2 cases of seminoma and 1 case of spermatocytic tumor showed heterogeneous enhancement, with necrosis in the interior. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy rate of non-germ cell tumor diagnosis according to the non-necrotic area of CEUS were 90.0%, 100.0%, 100.0%, 75.0% and 92.3%, respectively. Compared with conventional ultrasound, the difference was statistically significant (P=0.039). Primary testicular tumors in patients over 50 years old are mainly lymphoma, and CEUS is significantly different between germ cell tumors and non-germ cell tumors. Compared with conventional ultrasound, CEUS can distinguish testicular germ cell tumors from non-germ cell tumors more accurately. Preoperative ultrasonography is significant for accurate diagnosis and can guide clinical treatment.

EDEN (Etude Désescalade sEmiNome): Prospective therapeutic de-escalation and miRNA-M371 biomarker evaluation phase II study for stage IIa/IIb &lt; 3 cm seminomas.

TPS434 Background: At diagnosis, 10 to 15% of testicular pure seminomas have a stage II defined by the presence of retroperitoneal lymph node metastases. The optimal choice of treatment modalities are associated with excellent efficacy but also acute and late toxicities. De-escalating treatment for seminoma patients with stage IIb, IIc and III and good prognosis according to IGCCCG (International Germ Cell Cancer Collaborative Group) based on negative FDG-PET (Fluorodeoxyglucose Positron Emission Tomography) after 2 cycles of EP (etoposide, cisplatine) chemotherapy seems feasible and safe according to SEMITEP cohort 2 results (Loriot Y, and al GETUG SEMITEP Trial: Eur Urol. 2022 Aug;82(2):172-179). Serum levels of microRNA (miR)-371a-3p (miRNA-M371) have been significantly associated with clinical stage and response to treatment in testicular germ cell tumors, with sensitivity and specificity higher than those of classic markers. The aim of the study NCT05529251 is to propose a new therapeutic approach for the stages IIa/IIb. Methods: This phase II, multicenter, prospective, randomized, non-comparative, de-escalation study will include patient with primary testicular seminomatous germ cell tumor with stage IIa/IIb &lt; 3 cm in largest diameter seminoma, histologically proved after orchiectomy and good prognosis according to IGCCCG and LDH (Lactate DesHydogenase) &lt; 2.5 x Upper Limit of Normal (ULN). They must have progressive disease and no prior treatment with radiotherapy or chemotherapy. In case of negative week-3 (after 1 EP cycle) PET-scan, patients will be randomized according to 2 arms ARM A: Boost of radiotherapy 20 to 30 Gray (Gy); ARM B Carboplatin AUC7 chemotherapy. In case of positive week-3 PET-scan: 3 courses of EP chemotherapy (ARM C). Primary outcome will include progression-free rate at 36 months. Secondary Outcome Measures will be serum level of miRNA M371, correlation with response to treatments and PET scan results, overall survival (OS), quality of life and tolerance to treatment. Blood samples (miRNA-M371) will be collected at screening, at the time of randomization before second cycle of chemotherapy or radiotherapy, at the end of treatment and at relapse. Enrollment has started in October 2022. A total of 90 patients will be included in the interventional study, leading to approximately 60 patients with negative FDG-PET randomized. Clinical trial information: NCT05529251 .

PSAT048 Management of a Unilateral Testicular Tumor in a Patient with Congenital Adrenal Hyperplasia – Malignancy or Testicular Adrenal Rest Tumor?

Abstract Male patients with Congenital Adrenal Hyperplasia (CAH) are at risk of developing testicular adrenal rest tumors (TART). Late presentations are rare and often misdiagnosed as primary testicular germ cell tumors or other more common benign testicular lesions. We describe the case of a patient with CAH and a unilateral testicular tumor with regression in size after initiation of dexamethasone. A 24-year-old male with salt-wasting form of 21-hydroxylase deficiency underwent testicular U/S for evaluation of TART. While aware of a painless firm nodule on the latero-posterior aspect of his left testicle, his main concern was new onset infertility as he had conceived previously. He denied personal or family history of malignancy. Testicular U/S showed a 1.1×0.7×0.8 cm ill-defined, heterogeneously hypoechoic lesion with scattered calcifications and internal vascularity. He was referred to urology to undergo evaluation for possible for testicular cancer. CT abdomen/pelvis showed no evidence of metastatic disease. AFP was less than 2.5 ng/mL (reference range &amp;lt; 9.0 ng/mL), hCG was less than 1.0 mIU/mL (reference range&amp;lt;5.0 mIU/mL), and LDH was 221 U/L (reference range 140-271 U/L). The patient declined surgical intervention at this point and requested medical management. After discussion with the patient, we opted to trial dexamethasone to help suppress the nocturnal surge of ACTH in addition to his physiological dose of prednisone and fludrocortisone for CAH. He was started on 0.25 mg of dexamethasone followed closely with serial imaging and labs. Prior to initiation of dexamethasone, ACTH was 90.3 pg/mL (reference range 7.2–63.3 pg/mL). Two months after initiation of dexamethasone, ACTH decreased to 10.0 pg/mL. LH after initiation of dexamethasone was 8.58 mIU/mL (reference range 1.24–8.62 mIU/mL), FSH was 11.90 (reference range 1.27–19.26 mIU/mL), and testosterone level was 177 ng/dL (reference range 259-818 ng/dL). Testicular U/S six months after starting dexamethasone showed a 50% reduction in size of the heterogeneous hypoechoic left testicular lesion measuring 0.5×0.5×0.4 cm consistent with TART. However, he continued to have concerns regarding infertility, with work-up currently underway. TARTs are thought to arise from aberrant adrenal cells that may descend with the testes during embryogenesis. High ACTH levels in CAH due to lack of negative feedback can cause proliferation of these undifferentiated adrenal cells. Infertility is a predominant symptom due to local mass effect on the testes. Treatment of TART to prevent infertility requires elucidating an optimal steroid regimen that suppresses ACTH production, without suppression of LH and FSH. Moreover, most of the TARTs (around 80%) are bilateral and never malignant. Our patient's testicular tumor poses a diagnostic challenge given the late and atypical presentation of a unilateral tumor. The response to dexamethasone is very reassuring but continued surveillance is warranted. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Burned-Out Testicular Germ Cell Tumor Presenting as Retroperitoneal Lymphadenopathy in a Patient With Cryptorchidism: A Case Report &amp; Review of Literature

Testicular germ cell tumors are the most common malignancy in young and middle-aged men. Spontaneous primary testicular tumor regression, or testicular tumor burn-out, is a rare clinical phenomenon where extragonadal metastatic lesions are observed concurrently with the spontaneous regression of the primary testicular germ cell tumors. Here, we describe the case of a 36-year-old male who presented to our hospital with left-sided abdominal pain and testicular swelling and was found to have significant retroperitoneal lymphadenopathy on his abdominopelvic CT scan. His testicular ultrasound showed multiple echogenic calcifications through the right testicle consistent with microlithiasis. Biopsy of the retroperitoneal lesion revealed a mixed germ cell tumor of testicular origin composed of embryonal carcinoma and teratoma. The patient received four cycles of bleomycin, etoposide, and cisplatin, followed by retroperitoneal lymph node dissection (RPLND) and radical right testicular orchiectomy. Here, we report the second case of burned-out testicular tumor in a patient with ipsilateral cryptorchidism. Furthermore, we elucidate the etiology, clinical presentation, and diagnostic modalities in burned-out testicular germ cell tumors.

Molecular analysis of primary testicular germ cell tumor and matched metastatic teratomas.

425 Background: Metastastic teratoma (MT) is a unique germ cell tumor (GCT) subhistology characterized by resistance to platinum-based chemotherapy. Metastatic teratoma requires complete surgical excision, usually via retroperitoneal lymph node dissection (RPLND), following chemotherapy as a part of multidisciplinary GCT care. Molecular characterization of post-chemotherapy metastatic teratoma along with companion pre-chemotherapy testicular primary tumors could inform 1) the origin and differentiation site of metastatic teratomas, 2) mechanisms of platinum-resistance, 3) novel therapeutic options for patients with unresectable teratomas. Methods: We performed integrated molecular analysis for 16 primary germ cell tumors and 18 metastatic teratomas, 11 were matched tumor/metastasis pairs. All teratomas in our cohort were collected after induction platinum-based chemotherapy. In addition to SNV analysis, we conducted a chromosomal copy number gain and loss analysis for selected teratomas, matched primary tumors and primary teratomas from the TCGA. Results: Metastatic teratomas as well as their tumors of origin had low tumor mutation burden (0.65 and 0.47 accordingly). Amongst 583 SNVs detected in the study cohort, only two (KRAS p.Gly12Asp and KRAS p.Gly12Val) were previously described as oncogenic. Analysis of SNVs in proteins playing key roles in oncogenic signaling [1] showed that TP53 and Ras pathways were the most affected in metastatic teratomas. The majority of metastatic teratomas possess gain of 3p11.1 and loss of 10q26.3, 16p11.2, 19p13.2, 19q12 and 22q12.3 loci. Within 3p11.1 we did not identify any previously described oncodrivers. However, 5 chromosomal loci with lost heterozygosity contained 16 previously annotated tumor suppressor genes (15 protein coding and 1 microRNA, MIR199A1). Amongst those, GADD45GIP1 inhibition (growth arrest and DNA-damage-inducible, gamma interacting protein 1) is known for playing a role in cisplatin resistance through mechanism of cellular senescence [2]. Conclusions: Metastatic teratoma in our cohort is characterized by low tumor mutational burden, recurring copy number changes, and lack of recurring SNVs. Molecular insight of teratoma may inform disease biology and treatment.

Iso-chromosome 12p Analysis by Fluorescent In-Situ Hybridization: An Academic Institutional Experience

Abstract Introduction/Objective Chromosome 12 abnormalities like iso-chromosome 12p (i12p) and amplification of 12p are seen in majority (89%) of the primary and metastatic testicular germ cell tumors (TGCTs). i12p can be detected by karyotyping, fluorescent in-situ hybridization (FISH) or reverse transcriptase polymerase chain reaction. The aim of this study was to review i12p FISH data at our institution and assess the clinical utility. Methods/Case Report Laboratory information system was queried over a period of 15 years to search for cases where i12p FISH test was requested. FISH test was performed using TelVysion 12p telomeric probe and CEP 12 centromere probe on paraffin-embedded tissue or cell blocks. A ratio of 12ptel/CEP12 signal of 1.4 or greater was considered as positive. Patient demographics, clinical presentation, pathologic findings, and follow-up data were documented and correlated. Results (if a Case Study enter NA) Total 58 cases were identified with an age range of 14 to 76 years. Majority were male (M=52, F=6). Of these cases, 15 were testicular and 43 extra-testicular cases that included resection (n=35), biopsy (n=20) and cell-blocks (n=3). i12p was detected in 8 out of 15 testicular cases while i12p was detected in 16 out of the 43 extra-testicular cases. The extra- testicular cases included 17 retroperitoneal lesions, 8 lesions from the mediastinum, 6 lymph nodes from other sites and 12 miscellaneous lesions. Using pathology diagnosis with immunohistochemistry as gold standard, overall sensitivity was 60% and specificity was 86%. There were 3 false positive cases [Benign testicular parenchyma (n=1), suspicious for germ cell neoplasia in-situ (n=1) and undifferentiated epithelioid neoplasm (n=1)]. Conclusion Our results show that although the sensitivity was limited, FISH test for i12p demonstrated high specificity(86%) for diagnosis of primary or metastatic TGCTs. As an adjunct test, i12p FISH can help identify and further characterize a significant number of GCTs with unusual morphology or clinical presentation.

Primary Mediastinal and Testicular Germ Cell Tumors in Adolescents and Adults: A Comparison of Genomic Alterations and Clinical Implications.

Simple SummaryThe germ cell tumors (GCTs) family is a heterogeneous group of neoplasms that includes tumors affecting testis (TGCTs) and rarer cases occurring in extragonadal sites. Mediastinal germ cell tumors (MGCTs) are more aggressive and have poorer prognosis. Due to their rarity of MGCTs, few molecular and clinical studies are reported. MGCTs share biological similarities with TGCT, and international guidelines recommend use of the same therapies validated for TGCT. However, while high response rate is achieved in TGCT, MGCT tend to be resistant to therapy. This review resumes all molecular findings reported in MGCTs, summarizing molecular characteristics common with TGCT and highlighting the different molecular alterations that characterize mediastinal tumors. A deeper understanding of the MGCT biology will help in clinical management of these patients.Mediastinal germ cell tumors (MGCTs) share histologic, molecular and biomarkers features with testicular GCTs; however, nonseminomatous MGCTs are usually more aggressive and have poorer prognosis than nonseminomatous TGCTs. Most nonseminomatous MGCT cases show early resistance to platinum-based therapies and seldom have been associated with the onset of one or more concomitant somatic malignancies, in particular myeloid neoplasms with recent findings supporting a common, shared genetic precursor with the primary MGCT. Genomic, transcriptomic and epigenetic features of testicular GCTs have been extensively studied, allowing for the understanding of GCT development and transformation of seminomatous and nonseminomatous histologies. However, MGCTs are still lacking proper multi-omics analysis and only few data are reported in the literature. Understanding of the mechanism involved in the development, in the progression and in their higher resistance to common therapies is still poorly understood. With this review, we aim to collect all molecular findings reported in this rare disease, resuming the similarities and disparities with the gonadal counterparts.

Impact of Testicular Germ Cell Tumor Laterality on Recurrence-Free Survival in the Mexican Population.

BackgroundTo date, the prognostic value of laterality for testicular germ cell tumors remains unknown. Herein, we describe this prognostic factor in the Mexican population.MethodsA retrospective single-center study that included 37 patients with primary testicular germ cell tumors was conducted. Primary outcome was recurrence-free survival (RFS) at 2 years. Secondary outcomes were RFS by histology, progression-free survival by laterality, and 2-year overall survival.ResultsThirty-seven patients were included, of which five showed relapses. By laterality, the 2-year RFS rate was 100% for left tumors and 77.3% for right tumors, with a trend toward statistical significance (P = 0.058). By histology, the RFS rate was higher for seminomas than non-seminomas (89% vs. 83%, respectively) without this difference being statistically significant. Progression-free survival was higher for right tumors than left tumors (91% vs. 80%, respectively) but without reaching statistical significance. The overall survival rate for the entire cohort was 94.5%.ConclusionsOur study shows that patients with primary germ cell tumors of the right testicle have a higher risk of recurrence than those with primary germ cell tumors of the left testicle, with a trend toward statistical significance.

Differential methylation EPIC analysis discloses cisplatin-resistance related hypermethylation and tumor-specific heterogeneity within matched primary and metastatic testicular germ cell tumor patient tissue samples

Testicular germ cell tumors (TGCTs) are among the most common solid malignancies in young-adult men, and currently most mortality is due to metastatic disease and emergence of resistance to cisplatin. There is some evidence that increased methylation is one mechanism behind this resistance, stemming from individual studies, but approaches based on matched primary and metastatic patient samples are lacking. Herein, we provide an EPIC array-based study of matched primary and metastatic TGCT samples. Histology was the major determinant of overall methylation pattern, but some clustering of samples related to response to cisplatin was observed. Further differential analysis of patients with the same histological subtype (embryonal carcinoma) disclosed a remarkable increase in net methylation levels (at both promoter and CpG site level) in the patient with cisplatin-resistant disease and poor outcome compared to the patient with complete response to chemotherapy. This further confirms the recent results of another study performed on isogenic clones of sensitive and resistant TGCT cell lines. Differentially methylated promoters among groups of samples were mostly not shared, disclosing heterogeneity in patient tissue samples. Finally, gene ontology analysis of cisplatin-resistant samples indicated enrichment of differentially hypermethylated promoters on pathways related to regulation of immune microenvironment, and enrichment of differentially hypomethylated promoters on pathways related to DNA/chromatin binding and regulation. This data supports not only the use of hypomethylating agents for targeting cisplatin-resistant disease, but also their use in combination with immunotherapies and chromatin remodelers.

Dose-Dependent Effect of Platinum-Based Chemotherapy on the Risk of Metachronous Contralateral Testicular Cancer.

Patients with testicular germ cell tumor (TGCT) are at increased risk of developing a contralateral TGCT (CTGCT). Although some studies suggest that prior treatment with platinum-based chemotherapy affects CTGCT risk, a relationship between CTGCT risk and platinum dose has not previously been assessed. We analyzed the association between the number of platinum-based chemotherapy cycles and CTGCT risk. The risk of developing a metachronous CTGCT was evaluated in a nationwide cohort of 4,755 patients diagnosed with primary TGCT in the Netherlands between 1989 and 2007. Standardized incidence ratios were computed to compare CTGCT incidence with expected TGCT on the basis of TGCT incidence in the general population. The cumulative incidence of CTGCT was estimated in the presence of death as competing risk. The effect of treatment with platinum-based chemotherapy on CTGCT risk was assessed using multivariable Cox proportional hazards regression models. CTGCT was diagnosed in 136 patients (standardized incidence ratio, 14.6; 95% CI, 12.2 to 17.2). The cumulative incidence increased up to 20 years after primary diagnosis, reaching 3.4% (95% CI, 2.8% to 4.0%) after 20 years of follow up. The risk of developing a CTGCT decreased with age (hazard ratio [HR], 0.93; 95% CI, 0.90 to 0.96), was lower after nonseminomatous germ cell tumor (HR, 0.58; 95% CI, 0.35 to 0.96) and decreased with every additional cycle of chemotherapy (HRper cycle, 0.74; 95% CI, 0.64 to 0.85). Approximately one in every 30 survivors of TGCT will develop a CTGCT, with CTGCT incidence increasing up to 20 years after a primary TGCT. Treatment with platinum-based chemotherapy shows a dose-dependent inverse association with CTGCT risk.