Subtypes Of Germ Cell Tumors Research Articles

Dysgerminomas: germ cell tumors exhibit high expression of PD-L1 and associated with high TILs and good prognosis

Ovarian germ cell tumors (OVGCTs) account for 28% of all diagnosed ovarian cancers, and malignant germ cell tumors specifically account for approximately 13% of diagnosed ovarian cancers in Saudi Arabia. Although most germ cell tumor patients have a high survival rate, patients who experience tumor recurrence have a poor prognosis and present with more aggressive and chemoresistant tumors. The use of immunotherapeutic agents such as PD-L1/PD-1 inhibitors for OVGCTs remains very limited because few studies have described the immunological characteristics of these tumors. This study is the first to investigate PD-L1 expression in ovarian germ cell tumors and explore the role of PD-L1 expression in tumor microenvironment cells and genetic alterations. A total of 34 ovarian germ cell tumors were collected from pathology archives. The collected tumor tissues included ten dysgerminomas, five yolk sac tumors, five immature teratomas, and one mature teratoma, and the remaining samples were mixed germ cell tumors. The tumors were analyzed using immunohistochemical analysis to determine PD-L1 expression, immune cell infiltration and cancer stem cell populations and their correlation with clinical outcome. Furthermore, the genetic alterations in different subtypes of germ cell tumors were correlated with PD-L1 expression and clinical outcome. Datasets for testicular germ cells (TGCTs) were retrieved from The Cancer Genome Atlas (TCGA) and analyzed using cBioPortal (cbioportal.org) and Gene Expression Profiling Interactive Analysis (GEPIA). Compared with yolk sac tumors, dysgerminomas highly express PD-L1 and are associated with high levels of tumor infiltrating lymphocytes (TILs) and stem cell markers. In addition, compared with PD-L1-negative yolk sac tissue, dysgerminomas/seminomas with high PD-L1 expression are associated with more genetic alterations and a better prognosis. Our findings will contribute to the knowledge about the potential benefits of ovarian cancer immunotherapy in specific subsets of germ cell tumor patients and the risk factors for resistance mediated by tumor microenvironment cells.

Clinical and pathological characteristics of extra-cranial germ cell tumors: A 30-year single-center experience in Saudi Arabia.

To investigate the clinical and pathological characteristics of extracranial germ cell tumors (GCTs) in children aged 0-168 months treated at the National Guard Hospital, Jeddah, Saudi Arabia from 1990 to 2020. In this retrospective analysis, the data for all cases of GCTs were collected from 1990 to 2020. Statistical analyses were carried out using JMP software. The data was divided into 4 main categories: demographics, pathological/clinical features, recurrence, treatment and outcome. The study included 50 patients, with a mean age at diagnosis of 56.52 months. The median follow-up duration was 30 months. Most tumors were in the gonads, and among the extragonadal tumors, the sacro-coccyx was the most frequent site of the disease.The most common histological subtype of GCTs is yolk sac tumor, accounting for 28% of cases. Of the 50 patients, 46% received chemotherapy, and 54% underwent surgery without chemotherapy. Ten (20%) patients experienced recurrence after treatment. At the last follow-up, 96% of the patients were alive, and only 2 of the patients died due to advanced disease. Our findings were comparable to international data, but improvement in surveillance is required for long-term survivors.

S2626 Metastatic Testicular Choriocarcinoma Causing Gastrointestinal Bleeding in a Young Adult Male

Introduction: Testicular germ cell tumors are rare and account for less than 1% of malignancies in males. Although there are multiple subtypes of germ cell tumors, choriocarcinoma is the most aggressive and least common subtype. Metastasis typically occurs via hematogenous spread, usually affecting the lungs, liver and brain. We present a case of a 34-year-old male with metastatic testicular choriocarcinoma presenting with melena due to metastatic foci of disease involving the stomach. Case Description/Methods: A 34-year-old male with recently diagnosed stage IIIC metastatic germ cell tumor with known metastasis to the brain, lung, and liver presented to the hospital for initiation of cisplatin-based chemotherapy. He reported a two-week history of melena for which gastroenterology was consulted. His abdomen was soft and non-tender. Digital rectal exam did not reveal any overt bleeding. Labs were notable for a hemoglobin of 6.8 g/dL and a hematocrit of 22.3%. Esophagogastroduodenoscopy was performed revealing numerous nodular islands of abnormal tissue in the gastric body. Biopsies of the tissue were obtained and sent to pathology. Biopsies of the mucosa were positive for cytokeratin7, human-chorionic-gonadotropin (HCG), and a minimal number of cells expressing CD30. The tumor cells were negative for cytokeratin 20, alpha-fetoprotein (AFP), and placental-alkaline-phosphatase (PLAP) on immunohistochemistry staining. These findings supported the diagnosis of metastatic germ cell tumor with predominant choriocarcinoma component. Following esophagogastroduodenoscopy, the patient was placed on acid suppression therapy and proceeded with chemotherapy. Discussion: Testicular choriocarcinoma is a rare subtype of germ cell tumor that affects young adult males. It is an aggressive tumor that metastasizes early via hematogenous spread. Patients can present with hemorrhage from metastatic lesions which can be spontaneous or in response to chemotherapy. Metastasis to the gastrointestinal tract is seen in less than 5% of cases involving primary testicular choriocarcinoma. In such cases, the stomach is the most common location of metastasis. This case highlights the importance of knowing that malignant germ cell tumors can present with gastrointestinal bleeding and should be placed in the differential when a young man presents with gastrointestinal bleeding.

Pediatric Extracranial Germ Cell Tumors: Expression of microRNA.

Germ cell tumors (GCTs) may occur from the neonatal period to late adulthood, characterized by extensive clinical and pathologic heterogeneity. MicroRNAs are a family of small noncoding RNAs that regulate a wide array of biological processes including carcinogenesis. MicroRNAs may be used for many purposes in clinical diagnostics. Numerous studies have proven the diagnostic value of microRNA371-373 and microRNA302/367 expression in malignant GCT. The diagnostic value of microRNA375 is disputable, because while its value is confirmed by some research data, there are still others denying it. The results of our own research on the relative expression of 10 microRNAs, including microRNA375, associated with GCT in the tumor tissues of 84 children and adolescents are presented. In our research, overexpression of microRNA 371-373, 302/367 detected in the group of malignant GCT subtypes. Statistically significant expression of microRNA375 have been defined not only in the group of malignant GCT subtypes, but also in the group of immature teratomas. Among malignant GCTs, high expression of microRNA375 is specific for yolk sac tumors. In the group of seminomas, embryonic carcinomas, and mature teratomas expression of microRNA375 was observed imperceptible, even so the results were statistically insignificant. Expression of microRNA 371-373, 302/367 is representative of malignant GCT subtypes. Statistically significant and high expression of microRNA375 attributable for yolk sac tumors and immature teratomas.

The value of CXorf67 and H3K27me3 for diagnosing germ cell tumors in central nervous system

Objective: To investigate immunohistochemical patterns of CXorf67 and H3K27me3 proteins in central nervous system germ cell tumors (GCTs) and to assess their values in both diagnosis and differential diagnosis. Methods: A total of 370 cases of central nervous system GCTs were collected from 2013 to 2020 at Huashan Hospital of Fudan University, Shanghai, China. The expression of CXorf67, H3K27me3 and commonly-used GCT markers including OCT4, PLAP, CD117, D2-40, and CD30 by immunohistochemistry (EnVision method) was examined in different subtypes of central nervous system GCTs. The sensitivity and specificity of each marker were compared by contingency table and area under receiver operating characteristic (ROC) curve. Results: Of the 370 cases there were 282 males and 88 females with a mean age of 19 years and a median age of 17 years (range, 2-57 years). Among the GCTs with germinoma, the proportions of male patients and the patients with GCT located in sellar region were both higher than those of GCTs without germinoma (P<0.05), respectively. CXorf67 was present in the nuclei of germinoma and normal germ cells, but not in other subtypes of GCT. H3K27me3 was negative in germinoma, but positive in the nuclei of surrounding normal cells and GCTs other than germinoma. In the 283 GCTs with germinoma components, the expression rate of CXorf67 was 90.5% (256/283), but no cases were positive for H3K27me3. There was also an inverse correlation between them (r2=-0.831, P<0.01). The expression rates of PLAP, OCT4, CD117 and D2-40 were 81.2% (231/283), 89.4% (253/283), 73.9% (209/283) and 88.3% (250/283), respectively. In 63 mixed GCTs with germinoma components, the expression rate of CXorf67 was 84.1% (53/63), while all cases were negative for H3K27me3. The expression rates of PLAP, OCT4, CD117 and D2-40 were 79.4% (50/63), 79.4% (50/63), 66.7% (42/63) and 87.3% (55/63), respectively. The 6 markers with largest area under ROC curve in ranking order were H3K27me3, CXorf67, D2-40, OCT4, PLAP and CD117 (P<0.05). Conclusions: CXorf67 and H3K27me3 have high sensitivity and high specificity in diagnosing germinoma. There is a significant inverse correlation between them. Therefore, they can both be used as new specific immunohistochemical markers for the diagnosis of GCTs.

Primary immature teratoma of the thigh: a review.

Teratomas are a subtype of germ cell tumors composed of a variety of somatic tissues derived from more than one of the three germinal layers (ectoderm, endoderm and mesoderm). They can be classified as mature tumors and immature tumors. Teratomas most commonly arise at the sacrococcygeal region and the gonads. The occurrence of a teratoma outside the common gonadal and midline locations is exceptional. This review article lists the reported primary and metastatic malignant teratomas in extragonadal locations and discusses the possible explanation for the atypical location, their treatment and prognosis.

PRIMARY MEDIASTINAL YOLK SAC TUMOR: A RARE CASE

&lt;p&gt;&lt;strong&gt;Background&lt;/strong&gt;. Yolk sac tumor is a subtype of germ cell tumor which is highly malignant. Mediastinal Yolk sac tumor is also an extragonadal germ cell tumor which is extremely rare and is common in children and young adults. We report a case of a Yolk Sac Tumor in the anterior mediastinum in a 21-year-old male patient.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Case&lt;/strong&gt;. A case of Yolk Sac Tumor in a 21-year-old man with complaints of shortness of breath and chest pain experienced for ± 2 weeks. The CT scan showed the soft tissue with high-density thorax in the anterior mediastinum. The Levels of Alpha Feto Protein (AFP) 2,000 ng / mL and Beta-Human Chorionic Gonadotropin (B-HCG) 1.20 mIU / mL. Macroscopically, it appears brownish-gray tissue with a volume of 0.5 ccs. Typical histopathological examination reveals a Yolk Sac tumor.&lt;strong&gt;&lt;/strong&gt;&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion&lt;/strong&gt;. Yolk Sac Tumor as a Mediastinal primary tumor is a rare tumor. The diagnosis must be made not only based on histopathological examination but also based on the patient's age and elevated serum alpha-fetoprotein (AFP) and Beta-Human Chorionic Gonadotropin (B-HCG). Despite there is modern chemotherapy, the prognosis for these tumors is highly poor.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Keywords&lt;/strong&gt; . Yolk sac tumor, mediastinum, germ cell.&lt;strong&gt;&lt;/strong&gt;&lt;/p&gt;

High Expression of microRNA-371a-3p in Cystic Fluid of Post-Chemotherapy Teratoma with Concurrent Normal Serum Levels in Patients with Non-Seminomatous Testicular Germ Cell Tumours

Background: MicroRNA-371a-3p (miR-371), the novel serum biomarker of testicular germ cell tumours (GCTs), is produced by undifferentiated subtypes of GCTs but not by teratoma. Cystic teratoma developing from retroperitoneal metastases of GCT subsequent to chemotherapy had been shown to contain high levels of classical serum tumour markers of GCT in the presence of normal marker levels in serum. To date, no information is available regarding the presence of miR-371 in the cystic fluid of residual teratoma after chemotherapy. Methods: Four patients (age 18–26 years) undergoing retroperitoneal lymph node dissection (RPLND) for cystic residual masses resulting from chemotherapy of bulky retroperitoneal GCT had measurements of miR-371 in both serum and cystic fluid aspirated from surgical specimens. Measurement of the miR was performed with quantitative real-time PCR using miR-30b-5p as reference. Results were tabulated and analysed in a descriptive manner. Results: Histologically, all of the surgical specimens involved teratoma only with no evidence of vital undifferentiated GCT tissue. All patients were cured. Prior to RPLND, miR-371 serum levels were not measurable or close to zero in all of the patients. Cystic fluid revealed elevated levels of miR-371 in 3 patients and traces of miR in one. Conclusions: The detection of miR-371 in the cystic fluid of teratoma is somewhat enigmatic since this GCT subtype usually does not express the miR. Two hypotheses may explain the finding: First, miR-371 molecules were released into the cystic fluid by active GCT tissue prior to chemotherapy. High levels were kept after regression of vital GCT tissue because the cystic lumen is without a specific drainage system. Second, teratoma cells lining the interior cyst wall may shed small amounts of miR-371 into the lumen. Because of the lacking drainage system, even small levels may accumulate. The present finding adds to the understanding of the biology of the novel biomarker of GCT.

Novel Diagnostic Methods and Posttreatment Clinical Phenotypes Among Intracranial Germ Cell Tumors.

Central nervous system (CNS) germ cell tumors (GCT) are rare and complex pediatric neoplasms, the optimal management of which remains an area of active investigation. To present an updated cohort study, with particular attention to novel diagnostic methods and posttreatment clinical phenotypes. A single-institution cohort study of 80 primary, neurosurgically managed, CNS GCTs was conducted at Mayo Clinic, 1988-2017. Postchemotherapy resection (eg, second-look surgery) was frequently required (27.0%), especially after adjuvant therapies for nongerminomatous GCTs (NGGCTs; 14 of 28 cases, excluding mature teratoma) and significantly associated with pineal lesions, as compared to neurohypophyseal or bifocal lesions (43.6%vs 5.9% vs 6.7%, P=.004), a finding that retained statistical significance after adjusting for index extent of resection and histology (P=.04). Essentially every NGGCT case underwent at least 1 craniotomy, either on presentation, as second-look surgery, or following local recurrence. Mature teratomatous tissue was highly incident in second-look specimens (84.2%), even among lesions initially diagnosed as germinomas. Pretreatment cerebrospinal fluid (CSF) cell fraction analysis demonstrated an association between single lesions and neutrophil predominance, whereas nongerminomatous GCTs were associated with increased monocyte fractions. CNS GCTs are clinically heterogeneous lesions, resulting in numerous opportunities for improved understanding and clinical management via novel diagnostic and therapeutic protocols. Samples from second-look surgeries for recurrent germinomas frequently demonstrate teratomatous tissue, suggesting possible underdiagnosis of mixed GCTs-particularly among pineal lesions. GCT subtypes demonstrate differential cell fraction distributions on CSF analysis, a novel and perhaps diagnostically helpful finding that requires validation in external cohorts.

Differential expression of DNA methyltransferases and demethylases among the various testicular germ cell tumor subtypes.

Aim: Characterize DNA methyltransferases/demethylases expression in testicular germ cell tumors (TGCTs). Methods:In silico analysis of TCGA database, assessment of transcript levels of most relevant enzymes in four TGCT cell lines and validation in patient cohort (real-time quantitative polymerase chain reaction; immunohistochemistry). Results:DNMT3A, DNMT3B and TET2 were the most differentially expressed between seminomas (SEs) and nonseminomas (NSs). DNMT3B was significantly overexpressed in NS-related cell lines, and the opposite was found for TET2. Significantly higher DNMT3A/B mRNA expression was observed in NS, indicating a role for de novo methylation in reprogramming. Significantly higher TET2 protein expression was observed in SEs, suggesting active demethylation contributes for SE hypomethylated state. More differentiated histologies disclosed distinct expression patterns. Conclusion: DNA-modifying enzymes are differentially expressed between TGCT subtypes, influencing reprogramming and differentiation.

18F-Flourodeoxy glucose PET-computed tomography in testicular carcinoma: diagnostic and prognostic value.

This study aims to assess the diagnostic role of F-FDG PET/computed tomography in primary staging and restaging of testicular cancer in comparison with contrast-enhanced diagnostic thoracic-abdominopelvic computed tomography. Thirty-two consecutive male patients with testicular carcinoma (median age: 29, min-max: 17-65) who were referred to the nuclear medicine department for F-FDG PET/computed tomography were retrospectively included in the study. Patients were evaluated based on the F-FDG PET/computed tomography indications and germ cell tumor subtypes. On patient-based analysis, overall sensitivity, specificity, PPV, NPV and accuracy of 18F-FDG PET/computed tomography were 71%, 100%, 100%, 30% and 75%. On lesion-based analysis, for evaluation of lymph node metastasis they were 76%, 100%, 100%, 57% and 81%, and for detection of distant metastasis 85%, 100%, 100%, 90% and 93%, respectively. Median SUVmax for seminomas were calculated as 14.2 and for nonseminomas 7.8 (P = 0.62) Mean time to progression and overall survival were calculated as 76.6 ± 10.7 and 111 ± 7.5 months, respectively. Mean overall survival and time to progression for PET-positive and negative groups was not found significant (P = 0.69 and P = 0.81). The only significant factor in predict overall survival was the presence of distant organ metastases in PET/computed tomography (124.6 ± 5.2 vs. 78.7 ± 14.0 months, P = 0.02). In this single-center experience with a limited number of patients, F-FDG PET/computed tomography appears to have a value of staging and restaging for both seminomatous and non-seminomatous GCTs.

Primary germ cell tumors of the central nervous system

The study objective is to describe current views on pathogenesis, molecular biology, diagnosis, treatment of primary germ cell tumors of the central nervous system, as well as treatment prognosis.Materials and methods. The review includes 51 literature sources (4 in Russian, 47 in English). All articles were published in the last 20 years.Results and conclusion. The review reflects both established principles and characteristics of the national protocol of treatment of germ cell tumors, treatment nuances determined by histological type of the tumor. The most effective treatment method for germ cell tumors are radiation and neoadjuvant chemotherapy. For non-germinal germ cell tumors chemotherapy with subsequent complete removal is optimal. Total tumor resection by itself is the ideal treatment of mature teratomas. In the future, molecular and cytogenetic studies will allow to additionally identify subtypes of germ cell tumors of the central nervous system which will become the basis of new directions for therapy, improved treatment results and methods of prognosis.

An up-date on novel molecular targets in testicular germ cell tumors subtypes.

Testicular germ cell tumors (TGCTs) are the most frequent solid malignant tumors in men 20-34 years of age and the most frequent cause of death from solid tumors in this age group. In addition, the incidence of these tumors has significantly increased over the last few decades. Testicular germ cell tumors are classified into seminoma and nonseminoma germ cell tumors (NSGCTs). NSGCTs can be further divided into embryonal carcinoma, Teratoma, yolk sac tumor, and choriocarcinoma. There are noteworthy differences about therapy and prognosis of seminomas and nonseminoma germ cell tumors, even though both share characteristics of the primordial germ cells (PGCs). Many discovered biomarkers including HMGA1, GPR30, Aurora-B, estrogen receptor β, and others have given further advantage to discriminate between histological subgroups and could represent useful molecular therapeutic targets.

Immunotherapeutic Targeting of GPC3 in Pediatric Solid Embryonal Tumors.

Glypican 3 (GPC3) is a heparan sulfate proteoglycan and cell surface oncofetal protein which is highly expressed on a variety of pediatric solid embryonal tumors including the majority of hepatoblastomas, Wilms tumors, rhabdoid tumors, certain germ cell tumor subtypes, and a minority of rhabdomyosarcomas. Via both its core protein and heparan sulfate side chains, GPC3 activates the canonical Wnt/β-catenin pathway, which is frequently overexpressed in these malignancies. Loss of function mutations in GPC3 lead to Simpson-Golabi-Behmel Syndrome, an X-linked overgrowth condition with a predisposition to GPC3-expressing cancers including hepatoblastoma and Wilms tumor. There are several immunotherapeutic approaches to targeting GPC3, including vaccines, monoclonal antibodies, antibody-drug conjugates, bispecific antibodies, cytolytic T lymphocytes, and CAR T cells. These therapies offer a potentially novel means to target these pediatric solid embryonal tumors. A key pediatric-specific consideration of GPC3-targeted immunotherapeutics is that GPC3 can be physiologically expressed in normal tissues during the first year of life, particularly in the liver and kidney. In summary, this article reviews the current evidence for targeting childhood cancers with GPC3-directed immunotherapies.

DNA methylation profiling as a tool for testicular germ cell tumors subtyping.

Assess differential patterns of selected five genes' promoter methylation among testicular germ cell tumors (TGCT) subtypes. CRIPTO, HOXA9, MGMT, RASSF1A and SCGB3A1 promoter methylation levels were evaluated by quantitative methylation-specific PCR in 161 TGCT and 16 controls. Associations between clinicopathological parameters and promoter methylation levels were assessed, and receiver operating characteristics curve analysis was performed. Promoter methylation of CRIPTO/HOXA9/SCGB3A1 panel and RASSF1A best discriminated between controls and nonseminomatous tumors or seminomas, respectively, whereas HOXA9/RASSF1A panel displayed the best discriminative performance between nonseminomatous tumor and seminomas. Significant differences in CRIPTO, MGMT and RASSF1A methylation levels were depicted between pure forms and matched mixed components of seminomas and embryonal carcinoma. HOXA9, RASSF1A and SCGB3A1 promoter methylation significantly associated with tumor stage. Different combinations of five genes' promoter methylation levels discriminate among TGCT subtypes. Methylation patterns may also assist in identification of more clinically aggressive tumors.

A CASE REPORT OF A PRIMARY YOLK SAC TUMOR OF THE ANTERIOR MEDIASTINUM

SESSION TITLE: Disorders of the Mediastinum SESSION TYPE: Fellow Case Report Posters PRESENTED ON: 10/09/2018 01:15 pm - 02:15 pm INTRODUCTION: Primary Yolk Sac Tumor (YST) of the anterior mediastinum in adult is extremely rare and usually has a poor prognosis. Yolk sac tumor is a subtype of Germ Cell Tumor that is commonly seen in young adult that when found outside the gonads are called extragonadal germ cell tumors (EGGCTs). CASE PRESENTATION: A 27-year-old male non hypertensive and non-diabetic was admitted due to difficulty of breathing associated with chest pain for 2 months. Intermittent fever was also noted. After performing Chest CT scan with contrast and laboratory studies, the results indicated an anterior mediastinal mass. Biopsy and immunohisto-chemical staining revealed a primary yolk sac tumor. Debulking of the mass was done and the procedure was tolerated. Chemotherapy with Cisplatin and Etoposide was given. During the course of this process, there were lesser shortness of breath and no complaints of chest pain. DISCUSSION: Yolk sac tumours appear in both men and women and are usually associated with the testes and ovaries. When the testes and ovaries are not the primary site, the tumours are called extragonadal yolk sac tumours and these are usually located in the mediastinum. In an international study by Bokemeyer et al. with 381 mediastinal GCTs, the most common symptoms on presentation were dyspnea (25%), chest pain (23%), cough (17%), fever (13%), night sweat, or weight loss (11%). Night sweat, fatigue, hemoptysis, and symptoms of superior vena cava compression were seen in <10% of patients with mediastinal GCT. Histologically, extragonadal GCTs and mediastinal GCTs have many similarities. Microcystic/reticular pattern is the most common histological presentation. Schiller-Duval bodies are pathognomonic and are helpful for identification. The treatment regimens of extragonadal and gonadal YSTs are similar since they share histological patterns. Extragonadal nonseminomatous germ cell tumors have considerably poorer prognosis. Chemotherapeutic schemes based on cisplatin have shown significant results with up to 50% of patients achieving long-term survival. CONCLUSIONS: This is the first report of a Primary Yolk Sac Tumor of the anterior mediastinum in Philippine Heart Center. Overall, there are few reports on Primary YST of the anterior mediastinum. Up to date, resection with chemotherapy is the treatment of choice. Reference #1: Woodward PJ, Mostofi FK, Talerman A. Germ cell tumors. In: Eble JN, Sauter G, Epstein JI, Sesterhenn IA, editors. WHO classification of tumors. Pathology & Genetics. Tumors of the Urinary system and Male Genital Organs. Lyon: IARC Press; 2004. p. 237-40. Reference #2: Kuzur ME, Cobleigh MA, Greco FA, Einhorn LH, Oldham RK. Endodermal sinus tumour of the mediastinum. Cancer 1982;50:766-74. Reference #3: A. Papaioannou, K. Porpodis, D. Spyratos, and K. Zarogoulidis, “Yolk sac tumour in the anterior mediastinum,” Pneumon, vol. 26, no. 4, pp. 361–365, 2013. DISCLOSURES: No relevant relationships by CRISTIA MAYSOL MORALES, source=Web Response

Identification of diagnostic tumour markers and therapeutic targets in testicular tumours

Today, tumour classification has been expanded due to immunohistochemical and molecular-pathological analyses due to corresponding patterns/profiles of protein and gene expression. The latter analyses often include growth factors and their ligands, intracellular signalling pathways, DNA-binding proteins, and oncogenes and suppressor genes, thus functionally including primarily the regulation of growth including angiogenesis and apoptosis as well as the induction of metastases to adhesion and migration disorders. Based on observations that testicular tumours often show microcalcifications, possibly due to impaired calcium metabolism, we focused on calcium-dependent transmembrane proteins, particularly cadherins, in the search for new tumour markers and therapeutic targets. N‑cadherin is expressed differently in the various subtypes of germ cell tumours and is useful in N‑cadherin-positive germ cell tumours as anovel therapeutic targeting structure, particularly in cisplatin resistance, due to functional analysis. In the tumours of the sex cord stroma beta-catenin and the transcription factor SOX-9 give aclear classification of these tumours. Thus, morphological investigations prove to be pilot experiments to purposefully narrow the spectrum of functionally important proteins and thus to establish promising new differential diagnostic markers or target structures.

Primary Central Nervous System Germ Cell Tumors: A Review and Update.

Primary central nervous system (CNS) germ cell tumors (GCT) are a heterogeneous group of tumors that are still poorly understood. In North America, GCTs comprise approximately 1% of primary brain tumors in pediatric and young adult patients. GCTs can occur as pure or mixed subtypes; they are divided into germinomas, which are the most common subtype, and non-germinomatous germ cell tumors (NGGCTs), which consist of approximately one-third of GCTs and include teratomas, embryonal carcinomas, choriocarcinomas, and yolk sac tumors. While the etiology of primary CNS GCT is not entirely clear, the various subtypes are lineage-related and may involve progenitor germ cells that fail to migrate and become trapped in midline locations. Primary CNS GCT most commonly arises in the pineal region but also occur in other areas. Presenting symptoms can include headache, Parinaud syndrome, diabetes insipidus, precosious puberty, ataxia, or hemiparesis. Diagnosis of primary CNS GCTs can be difficult and is often delayed. Various imaging studies and tumor markers can assist in specific diagnosis. Treatment plans differ depending on the subtype of GCT and may vary among physicians and institutions. Germinomas have a favorable prognosis with a greater than 90% overall survival, while NGGCTs only have survival rates ranging from 40-70%. Germinomas seem to be most effectively treated with chemotherapy and radiation, while NGGCT usually require surgical resection, chemotherapy, and radiation with the exception of mature teratomas frequently curable with surgery alone. Gamma knife radiosurgery is a promising treatment that may be an effective additional treatment option. Cytogenic and molecular analyses are attempting to further specify the different GCT subtypes and are helping to direct the development of distinct therapeutic targets to improve treatment and prognosis.

Detailed pathologic analysis on the co-occurrence of non-seminomatous germ cell tumor subtypes in matched orchiectomy and retroperitoneal lymph node dissections.

The frequency of co-occurrence between germ cell tumor (GCT) components in non-seminomatous germ cell tumor (NSGCT) orchiectomy specimens and their correlation with histologic findings in subsequent retroperitoneal lymph node dissection (RPLND) specimens have not been well characterized. The objective of the study was to report the first detailed clinicopathologic analysis of NSGCT orchiectomy and RPLND samples to determine the likelihood and agreement of the co-occurrence of GCT components. A total of 118 consecutive patients with NSGCT treated between 1988 and 2012 who underwent both orchiectomy and RPLND at a single academic tertiary care center were analyzed. Statistical analysis of co-occurrence likelihood and agreement of GCT components was performed, both within and between orchiectomy and RPLND specimens. Embryonal carcinoma was the most frequent component present in orchiectomy specimens, and there were multiple significant associations between orchiectomy GCT components; seminoma occurred less frequently with embryonal carcinoma (OR 0.29 [95% confidence interval (CI) 0.11-0.75]; p<0.01), and teratoma more frequently occurred with choriocarcinoma (OR 9.64 [95% CI 1.22-76.12]; p=0.01). Presence of teratoma in the orchiectomy specimen predicted for a fourfold increase in distant metastasis on multivariate analysis (HR 4.92 [1.14-18.9]; p=0.02). The only significant association of co-occurrence in the RPLND specimen was between embryonal carcinoma and teratoma (OR 0.01 [95% CI 0-0.07]; p<0.001), where it was significantly less likely for them to occur together. Our findings are limited by their retrospective nature. The co-occurrence of GCT components within orchiectomy specimens does not appear to be a completely random process. However, there is less agreement and more randomness between the occurrence of the GCT components in matched orchiectomy and RPLND samples. In this report, we look at the co-occurrence of different GCT components within matched orchiectomy and RPLND pathology specimens and show that co-occurrence is not a completely random process.

MRI features of pediatric intracranial germ cell tumor subtypes

Intracranial germ cell tumors differ in histology and location, and require different clinical management strategies. We characterized the imaging features that may aid pre-operative differentiation of intracranial germinomas and non-germinomatous germ cell tumors (NGGCTs). This retrospective study analyzed 85 patients with intracranial germ cell tumors and adequate preoperative or pretreatment MRIs between 2000 and 2013 at our institution. Pretreatment MRI characteristics, apparent diffusion coefficient (ADC) values, tumor histopathology, and patient outcomes were compared. NGGCTs occurred in the pineal region and cerebral hemispheres more often than germinomas; all bifocal lesions were germinomas. NGGCTs (36.6 ± 17.0mm) were significantly larger than germinomas (25.7 ± 11.6mm; P = 0.002). The presence of pure solid tumor (45.5 vs. 20.0%, P = 0.033) and an infiltrative margin (20.0 vs. 3.3%, P = 0.035) were significantly more common in germinomas than NGGCTs. The presence of intratumoral T1 hyperintense foci (66.7 vs. 10.9%, P < 0.001) and moderate/marked enhancement (86.7 vs. 50.9%, P < 0.001) were significantly more common in NGGCTs than in germinomas. Mean ADCmean values (×10-3mm2/s) were significantly lower in germinomas (1.113 ± 0.415) than in NGGCTs (2.011 ± 0.694, P = 0.001). Combined a lack of T1 hyperintense foci and an ADCmean threshold value (1.143 × 10-3 mm2/s) had the highest specificity (91.3%) and positive predictive value (92.3%), while the combination of lack of a T1 hyperintensense foci, no/mild enhancement, and an ADCmean threshold value had 100% sensitivity and 100% negative-predictive value for discriminating germinomas from NGGCTs. Pre-operative conventional MRI characteristics and diffusion-weighted MRI help clinicians to assess patients with intracranial germ cell tumors. Tumor size, location, T1 hyperintense foci, intratumoral cystic components, tumor margin and enhancing patterns demonstrate contrast between germinomas and NGGCTs. Serum tumor markers and adjunctive combination with T1 hyperintensity and/or enhancing pattern with ADC offer potential in preoperative differentiating intracranial germinomas and NGGCTs.