Germ Cell Tumor Markers Research Articles

Potential next generation markers of testicular germ cell tumors: miRNA-371a-3p.

Testicular germ cell tumors (TGCTs) account for approximately 98% of all testicular cancers, predominantly affecting young to middle-aged men. Early diagnosis and treatment result in a cure rate of over 95%. However, conventional serum tumor markers (STMs) such as alpha-fetoprotein (AFP), β-human chorionic gonadotropin (β-hCG), and lactate dehydrogenase (LDH), which are recommended by NCCN and EAU guidelines, have limited sensitivity, often below 60%, which diminishes their clinical utility. Recently, miRNA-371a-3p, an embryonic stem cell-associated microRNA, has been identified as being specifically expressed in TGCTs. This microRNA can be reliably detected in peripheral blood and fulfills all seven Lange-Winfield criterias for tumor markers. Notably, miRNA-371a-3p has demonstrated superior diagnostic, therapeutic, and follow-up capabilities compared to conventional STMs in TGCTs. Its potential to replace conventional STMs in clinical practice is already recognized in several clinical guidelines. A PubMed search using subject headings and free-text terms related to MicroRNA-371a-3p in TGCT management was conducted. Relevant references were also tracked, and key studies were reviewed based on predefined exclusion criteria. Out of 368 identified studies, 67 met inclusion criteria. These studies focused on MicroRNA-371a-3p's discovery, detection methods, diagnostic utility in TGCTs, and cost-effectiveness. First identified over a decade ago, microRNA-371a-3p is now established as a highly specific blood-based marker for TGCTs, valuable for diagnosis, monitoring, and follow-up, and more cost-effective than conventional STMs. MicroRNA-371a-3p is a promising, highly sensitive marker for TGCTs, offering better performance and cost efficiency than conventional STMs, likely to become the next-generation diagnostic tool for TGCTs.

Epithelioid trophoblastic tumor in male patients with germ cell tumor: A clinicopathologic analysis of five cases

Epithelioid trophoblastic tumor (ETT) is an extremely rare chorionic-type neoplasm in the testis, with only seven cases reported in the literature. Here, we report five cases of testicular ETT from a single institution, constituting the largest series of this rare tumor to date. The patients had a mean age of 44 years (range, 20–68 years). Four patients had a previous history of testicular germ cell tumor (GCT) treated with chemotherapy, and they developed ETT in metastatic sites in a mean of 11 years (range, 3–15 years) after the initial diagnosis of testicular GCT. Only one patient had ETT in the testis. Three patients had a normal serum beta–human chorionic gonadotropin (β-hCG) level, and two patients had a level that was slightly elevated, but far below that typically seen in patients with choriocarcinoma. ETT was characterized by a proliferation of intermediate trophoblastic cells with abundant eosinophilic cytoplasm, and the tumors frequently had coagulative necrosis with eosinophilic debris, mimicking keratinizing squamous cell carcinoma. The trophoblastic phenotype of ETT was supported by its immunoreactivity for trophoblastic markers, including GATA-3 (3 of 3 cases tested), α-inhibin (3/4), p63 (3/5), and β-hCG (3/4). ETT was also positive for cytokeratin (4/4) and GCT marker SALL4 (3/3). Despite surgery and chemotherapy, two patients died of disease 17 months after ETT diagnosis, and three patients were alive with metastatic disease at a mean of 20 months (range, 15–28 months). Our results demonstrate that ETT may be an aggressive disease associated with distinct pathologic features and poor clinical outcome.

Pituitary stalk thickening in pediatric patients: an underrecognized diagnosis?

Pituitary stalk thickening (PST) is a rare condition in pediatric patients. Data on PST in Latin American pediatric populations are scarce. The aim of this study was to characterize a comprehensive cohort of pediatric patients diagnosed with PST in Chile between 2020 and 2022. Retrospective review of medical records from 2020 to 2022 of patients under 18 years old diagnosed with PST, defined as a pituitary stalk width ≥ 3 mm at the pituitary insertion and/or ≥ 4 mm at the optic chiasm. A literature review was also performed to compare the identified cases with previously published ones. Nine patients with PST were identified. Their mean age at diagnosis was 10.36 years (range 2.4-17 years). The patients' main manifestations were polydipsia and polyuria (100%) and poor growth (77.8%). Eight patients had germ cell tumors, while one patient had Langerhans cell histiocytosis. At the time of diagnosis, all patients had arginine vasopressin (AVP) deficiency, along with a deficiency in at least one anterior pituitary hormone. Germ cell tumor markers were negative in all patients. A biopsy-confirmed diagnosis was obtained in all cases. Four patients required a second biopsy. The frequency of PST due to germ cell tumors was four patients/year during the study period, which is twice the expected frequency in Chile. This study, characterizing the largest cohort of pediatric patients with PST in Latin America, found germ cell tumors to be the main etiology of this condition. It is important to focus diagnostic procedures on obtaining a correct diagnosis and promptly initiating appropriate treatment in patients with PST. Regional cooperation is essential for gathering data from larger cohorts to enhance our understanding of pediatric PST and improve patient outcomes.

Translationeel onderzoek naar testiculaire kiemceltumoren

AbstractTesticular germ cell tumors are the most common malignancy in men aged 14 to 44 years. Although exceptional cisplatin sensitivity results in cure rates of > 90%, resistance can occur for which there are currently no alternative treatment options. Translational research in recent years has led to various breakthroughs in detection and classification of these tumors. The identification of miRNA-371 expression as a marker of malignant testicular germ cell tumors (with the exception of teratomas) enables significantly more sensitive and specific detection of these cancers in various clinical contexts (primary tumor, residual disease, relapse etc.). Moreover, the identification of several genetic aberrations that are associated with treatment resistance and poor outcome, such as TP53 mutations or copy number gain on chromosome 3p, underlines the necessity of genetic screening for improved risk classification of testicular cancer patients.

AGCT1531: Evaluating the utility of circulating microRNA in the management of children, adolescents, and adults with malignant germ cell tumors.

TPS5104 Background: Conventional serum tumor markers for malignant germ cell tumors (MGCTs) have limited performance characteristics, especially in non-secreting histologies such as embryonal carcinoma or seminoma. Growing evidence has shown circulating microRNAs (miRNA), particularly miR-371a-3p, to be a more sensitive biomarker, elevated across all MGCT subtypes except teratoma. However, studies to date have been retrospective or non-randomized. If confirmed in prospective clinical trials, circulating miRNA may have the potential to become a universal MGCT biomarker, aiding in diagnosis, prognostication, relapse detection, and prediction of viable disease after chemotherapy. One of the key objectives of AGCT1531 is to test the performance characteristics of circulating miRNA in children, adolescents, and young adults (AYAs) with low-risk and standard-risk MGCTs. AGCT1531 is unique among MGCT trials for including patients across all ages, genders, sites, histologies, and treatments. Methods: AGCT1531 is a prospective clinical trial sponsored by the Children’s Oncology Group (COG), co-designed with United Kingdom, Japan, and India, and supported by all NCTN groups. It has three strata for low-risk tumors, defined as stage I tumors treated with surgery followed by active surveillance: non-seminomatous tumors of any site; testis seminomas; and ovarian immature teratomas. Patients of any age are eligible. Target accruals are 432, 277, and 212 patients, respectively. Key endpoints include overall and event-free survival and longitudinal measurements of circulating miRNA. Serum is collected at intervals aligned with NCCN follow-up guidelines to minimize testing burden. For patients over 11 years old with stage I non-seminomatous tumors, serum is collected at enrollment, months 4, 8, 12, 18, and 24; and (if applicable) at relapse. The trial also has two strata for standard-risk MGCTs: SR1 for children under age 11 years and SR2 for AYAs age 11-25 years. Target accruals are 518 and 595 patients, respectively. Both strata are randomized trials of cisplatin-based versus carboplatin-based regimens, with carboplatin used at doses higher than those previously tested in adult MGCTs. Serum collection is recommended at enrollment, months 6, 12, 18, 24, and (if applicable) at relapse. AGCT1531 was activated in August 2017. The low-risk seminoma stratum was added on November 2021. The trial is currently open at 466 sites across seven countries. For adults with testicular GCTs, data from AGCT1531 can contribute to joint analyses of parallel trials evaluating circulating miR-371a-3p in this population: SWOG1823, ANZUP1906 (CLIMATE), and ANZUP P3BEP. Together, this suite of trials will help validate the utility of circulating miRNA and set the stage for future investigations where miRNA is used to influence real-time management decisions for patients with MGCTs. Clinical trial information: NCT03067181 .

Two Cases of Burkitt Lymphoma Presenting as Solid Ovarian Masses

Background: Endemic Burkitt lymphoma has been associated with the Epstein Barr Virus (EBV), particularly in malaria-endemic regions. Primary ovarian Burkitt is an infrequent entity of this disease, and its diagnosis still poses a challenge. Summary: We present two cases. The first case is that of a 23-year-old female G1P1 who presented with a two-week history of abdominal pain and progressive distension. Her examination was remarkable for two pelvic masses and signs of ascites. An ultrasound scan showed bilateral solid adnexal masses, ascites, and mild splenomegaly. Tumor markers for ovarian and germ cell tumors were within the normal ranges. Cytology on ascitic fluid was negative for malignancy. Lactate dehydrogenase (LDH) level and further imaging were not done due to financial constraints. With the working diagnosis of an ovarian epithelial malignancy versus drop metastases, she underwent exploratory laparotomy, total abdominal hysterectomy, bilateral salpingo-oophorectomy, appendectomy, omentectomy, and debulking of peritoneal implants. Histopathology two weeks after surgery showed Burkitt lymphoma. The second case is that of a 12-year old female whose management averted surgery, following the recommendations made from our first case. Conclusion: Lymphomas are amongst the most common tumors in the pediatric age group. Clinicians should maintain a high index of suspicion in the face of fast-growing tumors. Burkitt lymphomas respond well to chemotherapy, and surgery is seldom necessary except for life-threatening presentations. Management of oncologic cases that are not straightforward should follow a multidisciplinary approach.

Evaluation of miR-371a-3p to predict viable germ cell tumor in patients with pure seminoma receiving retroperitoneal lymph node dissection.

Conventional serum tumor markers (STMs) for testicular germ cell tumors (GCTs) offer limited performance with particularly poor sensitivity in cases of minimal residual disease and pure seminoma. While growing evidence has indicated miR-371a-3p to be a superior biomarker, its utility in detecting pure seminoma at recurrence has not been extensively explored. This study's objective was to explore miR-371a-3p's utility in detecting metastatic pure seminoma at retroperitoneal lymph node dissection (RPLND). RNA was isolated from patient serum samples collected pre-RPLND. Fifteen patients were assigned to our 'benign' (n = 6) or 'seminoma' (n = 9) group based on pathological confirmation of viable seminoma. Five of the patients received chemotherapy before RPLND (PC-RPLND), and 10 were chemotherapy naïve. MiR-371a-3p expression was quantified via RT-quantitative polymerase chain reaction. The Cq values were statistically evaluated to obtain performance measurements. Median relative expression of miR-371a-3p was higher in the Seminoma group than the Benign, but this difference was not statistically significant (Rq = 3705 and 241, respectively, p = 0.2844). Of the 10 chemotherapy naïve patients, nine had viable seminoma at RPLND, and seven had elevated miR-371a-3p expression. Among the five postchemotherapy (PC) patients, zero had viable GCT at RPLND, and two had elevated miR-371a-3p expression. The primary RPLND group presented 78% sensitivity and 100% specificity. Specificity in the PC-RPLND group was 60%. An optimal Rq threshold of 28.62 was determined by Youden's J statistic, yielding 78% sensitivity and 67% specificity. Receiver operating characteristic analysis provided an AUC of 0.704 (95% CI: 0.43-0.98, p = 0.1949). Despite modest performance, miR-371a-3p exhibited improved sensitivity and specificity compared with conventional STMs. MiR-371a-3p outperformed STMs in the primary RPLND settings. However, miR-371a-3p was not a robust predictor of pathology in the PC setting. These results suggest that pure seminoma at RPLND is a clinical context, wherein the miRNA assay may require further refinement.

Detection of Specific Immune Cell Subpopulation Changes Associated with Systemic Immune Inflammation-Index Level in Germ Cell Tumors.

The tumor microenvironment (TME) and the host inflammatory response are closely interconnected. The interplay between systemic inflammation and the local immune response may influence tumor development and progression in various types of cancer. The systemic immune–inflammation index (SII) represents a prognostic marker for germ cell tumors (GCTs). The aim of the present study was to detect specific immune cell subpopulation changes which were associated with the SII level in chemotherapy-naïve GCT patients. In total, 51 GCT patients, prior to cisplatin-based chemotherapy, were included in the present study. Immunophenotyping of peripheral blood leukocyte subpopulations was performed using flow cytometry. The SII level was correlated with the percentage of various leukocyte subpopulations. The obtained results demonstrated that SII levels above the cut-off value of SII ≥ 1003 were associated with higher neutrophil percentages. An inverse correlation was found between the SII and the peripheral lymphocyte percentage that logically reflects the calculations of the SII index. Furthermore, the presented data also showed that in the lymphocyte subpopulation, the association with the SII was driven by T-cell subpopulations. In innate immunity–cell subpopulations, we observed a correlation between SII level and neutrophils as well as associations with eosinophil, basophil, natural killer cell and dendritic cell percentages. We suppose that the described interactions represent a manifestation of cancer-induced immune suppression. The results of the present study contribute to the elucidation of the interrelationship between tumor cells and the innate/adaptive immune system of the host.

Combining Hypermethylated RASSF1A Detection Using ddPCR with miR-371a-3p Testing: An Improved Panel of Liquid Biopsy Biomarkers for Testicular Germ Cell Tumor Patients.

Simple SummaryTesticular germ cell tumors are the most common solid cancers in men aged between 15–39 years. There is a need of non-invasive biomarkers for diagnosis and follow-up of these patients. miR-371a-3p has emerged as the most reliable biomarker of this disease, but fails to detect the teratoma subtype, which has clinical implications. In this work we describe a new method that combines miR-371a-3p quantification using RT-qPCR and hypermethylated RASSF1A quantification by droplet digital PCR in serum samples of these patients. The combination of both biomarkers detected disease (including teratoma) with a sensitivity of 100%, using cutoffs that made all healthy participants negative, being of interest for implementation in the clinical setting. The classical serum tumor markers used routinely in the management of testicular germ cell tumor (TGCT) patients—alpha fetoprotein (AFP) and human chorionic gonadotropin (HCG)—show important limitations. miR-371a-3p is the most recent promising biomarker for TGCTs, but it is not sufficiently informative for detection of teratoma, which is therapeutically relevant. We aimed to test the feasibility of hypermethylated RASSF1A (RASSF1AM) detected in circulating cell-free DNA as a non-invasive diagnostic marker of testicular germ cell tumors, combined with miR-371a-3p. A total of 109 serum samples of patients and 29 sera of healthy young adult males were included, along with representative cell lines and tumor tissue samples. We describe a novel droplet digital polymerase chain reaction (ddPCR) method for quantitatively assessing RASSF1AM in liquid biopsies. Both miR-371a-3p (sensitivity = 85.7%) and RASSF1AM (sensitivity = 86.7%) outperformed the combination of AFP and HCG (sensitivity = 65.5%) for TGCT diagnosis. RASSF1AM detected 88% of teratomas. In this representative cohort, 14 cases were negative for miR-371a-3p, all of which were detected by RASSF1AM, resulting in a combined sensitivity of 100%. We have described a highly sensitive and specific panel of biomarkers for TGCT patients, to be validated in the context of patient follow-up and detection of minimal residual disease.

Late relapsing germ cell tumors with elevated tumor markers

PurposeLate relapsing germ cell tumors (LR-GCT) are considered a rare distinct biologic entity as their clinical presentation and response to treatment is different to early recurrences. While serum tumor markers (AFP and ß-HCG) play an important role at the time of first diagnosis to correctly classify prognosis and treatment of germ cell tumors, they may not have the same significance in a late relapse situation.Patients and methodsThirty-seven patients with LR-GCT with elevated serum tumor markers were identified in our database. Twenty-six patients underwent primary surgical resection of the late relapsing tumor. Eleven patients received salvage chemotherapy and a post-chemotherapy residual tumor resection. Serum tumor markers, histological findings and oncological outcome were analyzed.ResultsIn the histopathological specimen, viable cancer was found in 20 cases (54%) and teratoma was found in 16 cases (43%). In nine cases (24%), a somatic-type malignant transformation was present. In 19 of 37 patients (51.4%), the late relapse specimen presented a histological type of GCT, which was not present in the primary histology. Twenty-two patients (59.5%) were included in follow-up analysis. Mean and median follow-up time was 62.2 and 53 months, respectively. Seventeen patients (77.3%) suffered a relapse or had progressive disease after LR therapy. Five patients (22.7%) have been relapse-free after LR therapy (mean FU 61.6 months). Ten patients died of disease during follow-up (45.5%) and had a mean time from LR to death of 66.4 months. Eleven patients were alive at last follow-up (mean FU 62.2 months). Relapse and survival rate were similar between patients who received primary resection of LR tumor and patients who received salvage chemotherapy followed by surgery.ConclusionPatients with a late relapsing germ cell tumor and elevated markers have a poor prognosis and a high risk for another relapse independent on primary treatment. The histological type and aggressiveness of a late relapsing tumor cannot be predicted with serum tumor marker levels at the time of diagnosis of LR. In up to 54% of cases, primary histology did not coincide with LR histology. Therefore, we propose primary surgical resection of a late relapsing tumor if a complete resection is feasible in order to gain exact histology and tailor further treatment.

SALL-4 and Beta-Catenin Expression in Sinonasal Teratocarcinosarcoma.

Sinonasal teratocarcinosarcoma (SNTCS) is a rare, aggressive malignancy that displays a heterogeneous combination of malignant blastema-like, epithelial and mesenchymal components. Its exact histogenesis is unknown with hypotheses ranging from true germ cell derivation to origin from pluripotent stem cells. However, despite this tumor's multiphenotypic histology, which includes frequent glandular, squamous, and neuroectodermal differentiation similar to adnexal germ cell tumors, SNTCS appears to have some differences from adnexal teratomas. For example, unlike adnexal teratomas, SNTCS has never been described as a component in a mixed germ cell tumor. Accurate recognition of SNTCS is difficult due to its rarity and histologic overlap with other sinonasal tumors. It is even more problematic on biopsy, since not all elements may be present in small samples. SNTCS can also share similar staining patterns with other neoplasms in the differential diagnosis. A recent study found nuclear β-catenin expression in a single TCS, but this has yet to be confirmed in additional cases. SALL-4, a marker of germ cell tumors, has not been examined. We performed β-catenin and SALL-4 immunohistochemistry on whole sections of 7 SNTCS and 19 other sinonasal neoplasms to assess whether β-catenin and SALL-4 are of utility in establishing a diagnosis of SNTCS. Intensity of expression and percentage of staining was noted for each tumor. For SNTCS, distribution of staining within each histologic component (immature neuroectodermal, epithelial, and mesenchymal) was also documented. Nuclear β-catenin expression was not identified in any SNTCS, with all cases demonstrating membranous expression (6 cases) or cytoplasmic and membranous expression (1 case). SALL-4 immunohistochemistry, however, was relatively sensitive (85.7%) and specific (89.5%) for SNTCS. SALL-4 expression was also identified in one poorly differentiated neuroendocrine carcinoma and one case of sinonasal undifferentiated carcinoma. SALL-4 appears to have utility in distinguishing SNTCS from other high grade sinonasal tumors.

Identification and validation of a five apoptosis-related genes signature for prediction of disease-free survival for testicular germ cell tumors.

BackgroundMore and more studies have paid attention to the role of apoptosis in tumorigenesis. A variety of apoptosis-related genes (ARGs) are related to tumor progression and resistance to chemotherapy drugs. Therefore, this study aims to establish a prognostic marker for ARG-based testicular germ cell tumors (TCGT).MethodsTCGT sequencing data and clinical information were downloaded from The Cancer Genome Atlas (TCGA) database and GEO database. The sequencing data of normal tissues came from the GTEx database. Through univariate COX, LASSO, and multiple COX regression analyses, we screened out key ARGs related to prognosis and constructed a risk signature and a prognostic nomogram. Finally, we performed internal and external verification to verify the signature we have established.ResultsFive ARGs, including CHGA, LPCAT1, PPP1CA, PSMB5, UBR2 were selected out and utilized to establish a novel signature. Based on this signature, TCGT patients were divided into high-risk groups and low-risk groups. The results showed that the disease-free survival (DFS) of patients in the high-risk group was lower than that in the low-risk group (P=0.02268). The subsequent univariate and multivariate Cox regression analysis further proved that the features we established are valuable independent prognostic factors (P<0.05). Also, a prognostic nomogram was created to visualize the relationship between various prognostic-related factors and the 1-, 3-, and 5-year DFS of TCGT in the TCGA cohort.ConclusionsWe constructed a new nomogram based on ARGs to predict the risk of testicular tumor recurrence. It can help clinicians better and more intuitively predict the survival of patients.

First person profile: George J. Bosl, MD: Former long-term chair of Memorial Sloan Kettering Cancer Center's Department of Medicine reflects on his multifaceted career.

First person profile: George J. Bosl, MD: Former long-term chair of Memorial Sloan Kettering Cancer Center's Department of Medicine reflects on his multifaceted career.

Terminal Deoxynucleotidyl Transferase Commonly Expresses in Germ Cell Tumors: Evaluation on a Large Series from Multiple Centers.

AimThe concrete features of expression of terminal deoxynucleotidyl transferase (TdT) are needed to be revealed in male and female germ cell tumors (GCTs).MethodsTdT immunostaining was performed in 195 GCTs, and the tumor and/or tumorous components included seminomas, germ cell neoplasias in situ (GCNISs), dysgerminomas, embryonal carcinomas (ECs), extragonadal germinomas, yolk sac tumors (YSTs), teratomas, and spermatocytic tumors. Twenty-one sex cord-stromal tumors were also added. Expression of the classical germ cell tumor markers (PLAP, OCT4, SALL4, CD117, and D2-40) was compared to that of TDT.ResultsNearly all (tumors or tumorous components) seminomas (99%, 107/108), GCNISs (98%, 51/52), dysgerminomas (94%, 17/18), ECs (100%, 15/15), and extragonadal germinomas (100%, 11/11) were positive for TdT. None of the cells in YSTs (0/38), teratomas (0/19), spermatocytic tumors (0/1), or sex cord-stromal tumors (0/21) were immunoreactive for TdT staining. The normal testicular and ovarian gonadal tissues were also negative for TdT. However, TdT presented with significant loss of antigen immunoreactivity in the paraffin-embedded tissues older than 3 years, giving rise to weak or moderate staining in a subset of cases. The expressions of TdT showed no significances with PLAP, OCT4, SALL4, CD117, and D2-40 during the diagnosis of the most GCTs (P>0.05), except for with PLAP, SALL4, or CD117 in YST (P=0.000 each), and D117 (P=0.000) or D2-40 (P=0.006) in ECs.ConclusionOur findings further verify that TdT can serve as a new GCT marker for seminomas, GCNISs, dysgerminomas, ECs, and extragonadal germinomas, with a highly positive rate. Awareness of TdT positivity in GCTs contributes to the prevention of erroneous diagnoses, particularly in the setting of core needle biopsies. To determine the properties where TdT staining may not be apparent in some old archived paraffin-embedded tissues, one could circumvent the potential misinterpretations of false-negative immunohistochemistry results.

Graded expression of microRNA-371a-3p in tumor tissues, contralateral testes, and in serum of patients with testicular germ cell tumor.

Background: Serum levels of microRNA-371a-3p represent a specific tumor marker of testicular germ cell tumors (GCTs) but the origin of circulating miR-371a-3p is not finally resolved. The correlation between miR-levels in tissue and serum is unclear. Results: MiR-levels in GCT tissue are 399-fold higher than in contralateral testicular tissue and 5843-fold higher than in non-testicular tissue. MiR tissue levels correlate with corresponding serum levels (r2 = 0.181). ISH detected miR-371a-3p intracellularly in GCT cells except teratoma. A low expression was also detected in normal testicular germ cells. Conclusions: Circulating miR-371a-3p is specifically derived from GCT tissue. The miR is present in GCT cells except teratoma. A low expression is also found in normal testicular tissue but not in non-testicular tissue. MiR-371a-3p levels in tissue and serum correlate significantly. This study underscores the usefulness of serum miR-371a-3p as tumor marker of GCT. Patients and methods: Expression levels of miR-371a-3p were concurrently measured in tissues of GCT, contralateral testes (n = 38), and in serum (n = 36) with real time PCR. For control, 5 healthy testicles and 4 non-testicular tissue samples were examined. MiR-levels were compared using descriptive statistical methods. We also performed in situ hybridization (ISH) of GCT tissue with a probe specific for miR-371a-3p.

Management of hydrocephalus in a pediatric bifocal germinoma

Germinomas represent the most frequent tumour type in the pineal region. However, the synchronous involvement of the suprasellar region, frequently termed bifocal intracranial germinoma (BFG) is quite rare. A literature search identified a further of 48 pediatric cases with a median age of 12.9 years. BFG is known to be highly radiosensitive. We presented a clinical case of pediatric bifocal germinoma. A 14-year-old boy presented with clinical features of progressive headaches since three months associated with vomits. MR showed two distinct lesions in the pineal and suprasellar regions. Neuroaxis spine MR was normal. Tumor markers for germ cell tumors from blood and cerebrospinal fluid were within the normal range. An endoscopic procedure was performed to treat the hydrocephalus (endoscopic third ventriculostomy) and, in the same procedure the suprasellar lesion was biopsied and the histology revealed a germinoma. She received chemotherapy and a focal radiotherapy covering the sites of primary disease and the ventricular system. Three months after the completion of treatment, the patient achieved a complete clinical and radiological response, which was maintained during the 5-years follow-up period. The optimum management of primary intracranial pineal and suprasellar (bifocal) germinomas still remains controversial. The definition as either localized or disseminated disease has major implications on required treatment and its associated late morbidity. Prospective studies with large cooperative groups worldwide and consensus meetings may reduce uncertainties regarding available management options.

Expression of miRNA-371a-3p in seminal plasma and ejaculate is associated with sperm concentration.

The microRNAs of the miR-371-3 cluster are novel serum markers for testicular germ cell tumors. Sporadic reports suggested the expression of this miRNA in semen. To verify the expression of miR-371a-3p in seminal plasma and unprocessed ejaculate; to compare seminal plasma miRNA levels in germ cell tumors patients with those of controls; to look for an association of miRNA levels with semen quality. The miR-371a-3p expression was analyzed with qPCR. The study population consisted of 100 participants: seminal plasma samples from 20 germ cell tumors patients and 30 controls, serum samples from 12 healthy men, ejaculate samples from 38 men undergoing fertility testing. The seminal plasma miR-371a-3p levels of germ cell tumors patients were not different from controls. The miRNA expression was very low in serum but much higher in seminal plasma. In ejaculate samples, the miRNA expression significantly correlated with sperm concentration and the total sperm count. miR-371-a-3p is present in sperm-containing fluids. Seminal plasma levels cannot be used to distinguish germ cell tumors from controls. The correlation with sperm concentration in ejaculate samples suggests the spermatozoa as possible source of miR-371a-3p production. The miR-371a-3p levels in ejaculate could represent a novel biomarker for the non-invasive evaluation of male infertility.

Exogenous estrogen therapy, testicular cancer, and the male to female transgender population: a case report

BackgroundOver the last 40 years, there has been a significant increase in the incidence of testicular cancer. The epidemiologic evidence to understand this phenomenon is unclear, however exogenous estrogen exposure is thought to be a driver in the development of testicular cancer. This is of particular importance in the transgender population because utilization of exogenous estrogen therapy is an essential aspect of the transition process.CaseWe present the case of a 38-year-old Caucasian male to female transgender patient who presented with metastatic testicular cancer 15 months after initiating estrogen therapy. She presented to our emergency department with worsening back pain and fatigue. A clinical examination revealed a right-sided testicular mass. A computed tomography scan of her abdomen/pelvis identified a right groin lesion measuring 6.4 cm, a retroperitoneal mass causing right-sided hydronephrosis, an extensive deep vein thrombosis, and pathologic abdominal lymphadenopathy. Germ cell tumor markers revealed an alpha-fetoprotein of < 2.5 μg/L and a beta-human chorionic gonadotrophin of 2526 IU/L. Her lactate dehydrogenase was 5294 U/L. Medical oncology advised the discontinuation of hormonal therapy at this time. On the basis of elevation in germ cell tumor markers and the burden of disease, she was treated with four cycles of bleomycin, etoposide, and cisplatin chemotherapy. A decision to defer upfront radical inguinal orchiectomy was made due to not wanting to have an early interruption in anticoagulation.Following the completion of the chemotherapy, a 6 cm retroperitoneal mass persisted. Due to the location of the mass and surgical morbidity associated with excision, she was followed with positron emission tomography-computed tomography by Uro-oncology, with no evidence of recurrent disease 2 years since the time of diagnosis.ConclusionsWhile there are recognized risks associated with estrogen therapy less is known about the extent to which exogenous estrogen can serve as a driver of malignancy. With recent experimental evidence revealing a pro-growth impact of estrogen on human testicular cells, continued reporting of similar cases in the literature is imperative to see if a link between exogenous estrogen exposure and testicular cancer exists.

Alpha-fetoprotein-producing ovarian clear cell adenocarcinoma with fetal gut differentiation: a rare case report and literature review

BackgroundAlpha-fetoprotein (AFP) is a useful tumor marker for ovarian germ cell tumors, particularly yolk sac tumor (YST). It is valuable for both diagnosis and further follow-up. Epithelial ovarian carcinoma (EOC) rarely secretes AFP, especially for clear cell type and in the postmenopausal women. Based on the limited knowledge about AFP-producing clear cell type EOC, a case and literature review on this topic is extensively reviewed.Case presentationWe report a 55-year-old postmenopausal woman experienced vaginal spotting for one month, and serum level of AFP was 60,721 ng/ml initially. Histological examination was clear cell type EOC. Tumor cells revealed strong immunoreactivity for glypican-3 (GPC3) and AFP and weak for hepatocyte nuclear factor-1 beta (HNF-1 beta), but negative for CD30, making the diagnosis of AFP-producing clear cell type EOC with fetal gut differentiation in focal areas, FIGO (International Federation of Gynecology and Obstetrics) IIIc. Although the patient underwent an intensive treatment, including optimal debulking surgery and multi-agent chemotherapy, the patient died of disease. To provide a better understanding of clinical and molecular characteristics of the AFP-producing clear cell type EOC, we conducted a systematic literature review.ConclusionsA total of three papers described the AFP-producing clear cell type EOC are available. The overall survival rate of these cases, including the current case is 50%. Although immunohistochemical examination is not always needed in routine for the diagnosis of clear cell type EOC, to distinguish from other tumors, especially germ cell tumors, or to provide the better way to monitor therapeutic response or to evaluate the disease status, immunostaining, including GPC3, HNF-1 beta, CD30, cytokeratin 7 or 20, and AFP is taken into account. Due to rarity, the appropriate chemotherapy regimen and the biological behavior of AFP-producing clear cell type EOC are still unclear.

Genes associated with testicular germ cell tumors and testicular dysgenesis in patients with testicular microlithiasis.

Testicular microlithiasis (TM) is one of the symptoms of testicular dysgenesis syndrome (TDS). TM is particularly interesting as an informative marker of testicular germ cell tumors (TGCTs). KIT ligand gene (KITLG), BCL2 antagonist/killer 1 (BAK1), and sprouty RTK signaling antagonist 4 (SPRY4) genes are associated with a high risk of TGCTs, whereas bone morphogenetic protein 7 gene (BMP7), transforming growth factor beta receptor 3 gene (TGFBR3), and homeobox D cluster genes (HOXD) are related to TDS. Using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis, we investigated allele and genotype frequencies for KITLG (rs995030, rs1508595), SPRY4 (rs4624820, rs6897876), BAK1 (rs210138), BMP7 (rs388286), TGFBR3 (rs12082710), and HOXD (rs17198432) in 142 TGCT patients, 137 TM patients, and 153 fertile men (control group). We found significant differences in the KITLG GG_rs995030 genotype in TM (P = 0.01) and TGCT patients (P = 0.0005) compared with the control. We also revealed strong associations between KITLG_rs1508595 and TM (G allele, P = 0.003; GG genotype, P = 0.01) and between KITLG_rs1508595 and TGCTs (G allele, P = 0.0001; GG genotype, P = 0.0007). Moreover, there was a significant difference in BMP7_rs388286 between the TGCT group and the control (T allele, P = 0.00004; TT genotype, P = 0.00006) and between the TM group and the control (T allele, P = 0.04). HOXD also demonstrated a strong association with TGCTs (rs17198432 A allele, P = 0.0001; AA genotype, P = 0.001). Furthermore, significant differences were found between the TGCT group and the control in the BAK1_rs210138 G allele (P = 0.03) and the GG genotype (P = 0.01). KITLG and BMP7 genes, associated with the development of TGCTs, may also be related to TM. In summary, the KITLG GG_rs995030, GG_rs1508595, BMP7 TT_rs388286, HOXD AA_rs17198432, and BAK1 GG_rs210138 genotypes were associated with a high risk of TGCT development.