Embryonal Carcinoma Component Research Articles

PD-L1 expression in testicular germ cell tumors undergoing spontaneous regression.

Spontaneous regression of testicular germ cell tumors is a well-known phenomenon; however, the precise mechanisms of spontaneous regression are still unknown. Our study aimed to investigate programmed death-ligand 1 (PD-L1) expression in spontaneously regressed testicular germ cell tumors, exploring the link between the immune response and spontaneous regression. From a sample of 356 testicular germ cell tumors, we singled out 5 completely regressed and 6 partially regressed tumors. In four out of six cases with partial regression, a residual seminoma component was found, while in the remaining two cases, an embryonal carcinoma component was found. Comparisons were made with 20 pure seminomas and 20 mixed germ cell tumors (MGCTs). A semiquantitative immunohistochemical analysis of PD-L1 expression in tumor cells and intra/peritumoral lymphocytes was performed. There was no PD-L1 expression in tumors with complete regression. All partially regressed tumors showed expression in intra/peritumoral lymphocytes within the tumor remnants. Expression was significantly more frequent in pure seminomas compared to MGCTs (P = 0.004). A positive correlation was demonstrated between the seminoma component and the proportion of PD-L1 positive lymphocytes, with a Kendall's Tau-b coefficient of 0.626 (P < 0.001). Tumor cells showed PD-L1 expression in three MGCTs within the embryonal carcinoma component. Our results support an immunological mechanism of spontaneous tumor regression, with the strongest potential in testicular tumors containing seminoma components. However, further research is necessary to determine the role of PD-L1 ligand more precisely in the microenvironment of spontaneously regressed tumors.

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.

Paradoxical Expression of R-10G-reactive Antigen in Human Testicular Embryonal Carcinoma.

Thus far, several monoclonal antibodies directed against cell-surface carbohydrate antigens have been generated. Among them, R-10G reportedly reacts selectively with human embryonic stem and induced pluripotent stem cells, but not with embryonal carcinoma (EC) cells. However, EC cells derived from patients' EC tumors may exhibit varying levels of R-10G-reactive antigen expression. Thus, we asked whether human EC tissues or germ cell tumor (GCT) tissues other than EC express R-10G-reactive antigen. To do so, we quantitatively analyzed R-10G-reactive antigen expression in 83 testicular GCT surgical specimens containing a total of 125 various GCT components. Accordingly, in all EC components examined, the EC cell plasma membrane was immunolabeled with R-10G, while most seminoma components were R-10G-negative. In non-seminomatous GCT (NSGCT) other than EC (non-EC NSGCT), R-10G-reactive antigen expression was variable, but signal distribution was focal, and the average intensity was weaker than that seen in EC. The percentages of R-10G-positive cells in these three groups varied with high statistical significance (p<0.001 for all combinations). These findings indicate that the R-10G-reactive antigen is preferentially expressed in human testicular EC tissues and, thus, could be used as a diagnostic marker for this malignancy.

A RARE OCCURRENCE OF METASTATIC INFILTRATION OF TESTICULAR SEMINOMATOUS MIXED GERM CELL TUMOR CELLS INTOTHE PERITONEAL CAVITY: A CASE REPORT

Undescended testes (UDT) are a common birth anomaly. About 80% of UDT are palpable and 20% are non palpable.1 Palpable UDT are located along the inguinoscrotal descent route. The term non –palpable means that the testis was not found during the patient's examination. In that case we deal with an abdominal testis or with lack of testis. Intraabdominal testes are associated with an increased risk of malignancy. We herein present a recent case in our institution of intraabdominal testis which was histopathologically conrmed as Mixed Germ Cell Tumour (GCT) with a combination of seminoma, yolk sac tumor and embryonal carcinoma components with inltration into the peritoneal cavity.

NONSEMINOMATOUS GERM CELL TUMOR METASTATIC TO THE MAXILLA

<h3>Background</h3> Extragonodal germ cell tumors (GCTs) primarily affect the sacrococcygeal region. Head and neck GCT is rare and accounts for 3% of pediatric neoplasms. Only isolated cases of metastatic GCT have been reported. <h3>Objective</h3> To report a unique case of a metastatic nonseminomatous GCT of mixed phenotype with yolk sac tumor, embryonal carcinoma, and immature teratoma components. <h3>Clinical Findings</h3> A 13-year-old male patient presented with a rapidly enlarging, painless right maxillary tuberosity mass, present for 4 months. The tumor was on the buccal gingiva extending to the hard and soft palate posteriorly. Ipsilateral submandibular lymphadenopathy was evident. No pathology was noted on the panelipse and periapical radiographs. The clinical impression was that of a lymphoma or Kaposi sarcoma. <h3>Pathologic Findings</h3> The histology showed an extensively infiltrative high-grade malignancy composed of small, round, blue discohesive tumor cells demonstrating a solid growth pattern, with areas of adenocarcinoma and squamous differentiation with keratinization. Surface dysplasia was not present. Brisk mitotic activity was noted. Immunohistochemistry revealed positivity with for AE1/AE3, SALL4, Glyplican 3, and OCT3/4, confirming the diagnosis of a metastatic nonseminomatous GCT of mixed phenotype. <h3>Summary</h3> Benign teratomas are the most common childhood extragonodal tumors, followed by yolk sac tumors, which frequently arise in the ovaries and testis. Yolk sac tumors that frequently arise in the ovaries and testis have been reported but continue to be a rare extragonodal tumor and are difficult to diagnose. This report reviews germ cell tumors in the spectrum of metastatic disease to the oral cavity.

GCT-46. MULTI-KINASE INHIBITORS AS NOVEL THERAPEUTIC AGENTS AGAINST INTRACRANIAL NON-GERMINOMATOUS GERM CELL TUMORS

Central nervous system germ cell tumors (CNS GCTs) are rare intracranial malignancies developing in adolescents and young adults which relatively frequently occur in East Asia region of the world including Japan. However, among CNS GCTs, non-germinomatous germ cell tumors (NGGCTs) are highly resistant to the current chemoradiotherapies, and the prognosis of CNS NGGCTs is still extremely poor. Therefore, development of novel therapeutic strategy against CNS NGGCTs is urgently needed. In this study, we screened small molecule inhibitors of kinases specifically targeting cell membrane receptors, such as receptor tyrosine kinases, and their related molecular signaling, which could effectively exert antitumor effects against NGGCT cells. As the NGGCT model cells, the Tcam2 cell, a mixed germ cell tumor cell line composed of germinoma and embryonal carcinoma components, and the YST1 cell, a novel yolk sac tumor cell line established in our institute, were used. As a result, effective induction of cell death in both cell lines was confirmed only by treatment with two multi-kinase inhibitors. Immunoblotting revealed these multi-kinase inhibitors suppressed activation of various kinases concurrently. Furthermore, these multi-kinase inhibitors also triggered cell death in the Tcam2 cell stably expressing mutant KIT, the most common oncogenic driver genes of CNS GCTs, suggesting that these inhibitors would be also effective against CNS GCTs harboring activated KIT mutants. In vivo studies of these multi-kinase inhibitors using CNS GCT xenografts are currently on going.

Malignant Mixed Germ Cell Tumors of the Ovary: An Analysis of 100 Cases Emphasizing the Frequency and Interrelationships of Their Tumor Types.

One hundred malignant mixed germ cell tumors of the ovary that occurred in patients 3 to 55 years (mean: 20 y) of age are described. The clinical presentation was usually that of any highly malignant tumor of the ovary (abdominal pain and distension), but rarely (3 cases) endocrine manifestations were present. The tumors were usually unilateral (96%), ranged from 4 to 38 cm (mean: 16 cm), and were uniformly solid or, more often, solid and cystic; occasionally the typical appearance of dysgerminoma could be appreciated. The most common tumor type was yolk sac tumor (91%), followed by dysgerminoma (61%), immature teratoma (58%), embryonal carcinoma (38%), and choriocarcinoma (11%). A variety of admixtures were encountered; dysgerminoma and yolk sac tumor was the most common combination (25% of the tumors) with the 2 components often being sharply demarcated. Immature teratoma and yolk sac tumor was the next most common pairing (20%) followed by yolk sac tumor and embryonal carcinoma, with or without immature teratoma (16%). Tumors with a choriocarcinoma component had the most varied combinations of tumor types. Embryoid bodies were seen in 21% of the tumors, most often as fragmented forms arranged in a nodular manner with yolk sac tumor and/or embryonal carcinoma; uncommonly they occurred singly or in clusters. Numerous confluent well-formed embryoid bodies (polyembryoma) were prominent in 2 tumors. Three tumors had a focal diffuse embryoma pattern. The specific tumor types showed the known diverse spectrum of microscopic appearances, but the frequent haphazard arrangement of 2 or more subtypes often resulted in complex morphology. Overgrowth of another neoplastic component, most often primitive neuroectodermal tumor, occurred in 10% of the tumors further complicating the histologic picture. This is the largest series of ovarian malignant mixed germ cell tumors reported and details their characteristics including associations of their subtypes and the frequent apparent role of embryoid bodies in giving rise to yolk sac tumor and embryonal carcinoma components.

Metastatic Mixed Germ Cell Tumour with Embryonal Carcinoma and Choriocarcinoma in a Female Eurasian Harvest Mouse (Micromys minutus)

Mixed germ cell tumours occur rarely in veterinary species. This report describes a case of metastatic mixed germ cell tumour in a female Eurasian harvest mouse (Micromys minutus). The tumour was extensive in one ovary and the uterus, and was characterized by two distinct tumour cell populations with features typical of embryonal carcinoma (EC) and choriocarcinoma (CC). Metastases of CC to the lungs and liver were observed. The exact origin of the CC was unclear, but the possibility of a non-gestational CC is favoured, given the context of a mixed germ cell tumour and lack of p53 expression. EC diagnosis was confirmed by immunohistochemical labelling of CD30 and lack of immunoreactivity for c-Kit. In addition, membranous β-catenin expression was present in the EC component, indicating an inactive Wnt/β-catenin pathway, which is required for the maintenance of pluripotency.

Overcoming sociodemographic factors in the care of patients with testicular cancer at a safety net hospital.

The objective of this study was to determine whether standardized treatment of germ cell tumors (GCTs) could overcome sociodemographic factors limiting patient care. The records of all patients undergoing primary treatment for GCTs at both a public safety net hospital and an academic tertiary care center in the same metropolitan area were analyzed. Both institutions were managed by the same group of physicians in the context of multidisciplinary cancer care. Patients were grouped by care center; clinicopathologic features and outcomes were analyzed. Between 2006 and 2018, 106 and 95 patients underwent initial treatment for GCTs at the safety net hospital and the tertiary care center, respectively. Safety net patients were younger (29 vs 33years; P=.005) and were more likely to be Hispanic (79% vs 11%), to be uninsured (80% vs 12%; P<.001), to present via the emergency department (76% vs 8%; P<.001), and to have metastatic (stage II/III) disease (42% vs 26%; P=.025). In a multivariable analysis, an absence of lymphovascular invasion (odds ratio [OR], 0.30; P=.008) and an embryonal carcinoma component (OR, 0.36; P=.02) were associated with decreased use of adjuvant treatment for stage I patients; hospital setting was not (OR, 0.67; P=.55). For patients with stage II/III nonseminomatous GCTs, there was no difference in the performance of postchemotherapy retroperitoneal lymph node dissection between the safety net hospital and the tertiary care center (52% vs 64%; P=.53). No difference in recurrence rates was observed between the cohorts (5% vs 6%; P=.76). Sociodemographic factors are often associated with adverse clinical outcomes in the treatment of GCTs; they may be overcome with integrated, standardized management of testicular cancer.

MP76-11 THE DIAGNOSTIC AND PROGNOSTIC VALUE OF TUMOR MARKER DENSITIES IN MARKER POSITIVE TESTICULAR CANCER

You have accessJournal of UrologyPenile & Testicular Cancer: Penile & Testicular Cancer III (MP76)1 Apr 2020MP76-11 THE DIAGNOSTIC AND PROGNOSTIC VALUE OF TUMOR MARKER DENSITIES IN MARKER POSITIVE TESTICULAR CANCER Naoto Hodotsuka*, Go Kimura, Tatsuro Hayashi, Shuhei Nozaki, Mikio Shibasaki, Hiroya Hasegawa, Ryo Amakawa, Shigehito Minaguchi, Hikaru Mikami, Masato Yanagi, Jun Akatsuka, Yuki Endo, Hayato Takeda, and Yukihiro Kondo Naoto Hodotsuka*Naoto Hodotsuka* More articles by this author , Go KimuraGo Kimura More articles by this author , Tatsuro HayashiTatsuro Hayashi More articles by this author , Shuhei NozakiShuhei Nozaki More articles by this author , Mikio ShibasakiMikio Shibasaki More articles by this author , Hiroya HasegawaHiroya Hasegawa More articles by this author , Ryo AmakawaRyo Amakawa More articles by this author , Shigehito MinaguchiShigehito Minaguchi More articles by this author , Hikaru MikamiHikaru Mikami More articles by this author , Masato YanagiMasato Yanagi More articles by this author , Jun AkatsukaJun Akatsuka More articles by this author , Yuki EndoYuki Endo More articles by this author , Hayato TakedaHayato Takeda More articles by this author , and Yukihiro KondoYukihiro Kondo More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000962.011AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Treatment strategies based on metastatic risk and prognostic factors are important in testicular cancer. Metastatic risk factors of testicular cancer include vascular invasion, more than 50% of embryonal carcinoma component, and a cell proliferation rate of 70% or more. For advanced cases the International Germ Cell Consensus classification is widely used. Currently, there are no recommended indicators to predict prognosis besides this classification. We examined whether we could infer stage and prognosis from AFP density (AFPD) and hCG density (hCGD). METHODS: Among 104 testicular tumors treated in our hospital from May 2008 to May 2018, 29 cases which contains embryonal carcinoma and/or yolk sac tumor with histopathological details were defined as AFP positive group and 40 cases which were hCG positive regardless of histopathological details as hCG positive group.AFPD was defined as AFP value/(resected testicular weight x (proportion of embryonal carcinoma + yolk sac tumor)). hCGD was defined as hCG value/resected testicular weight. We analyzed the correlation of AFPD, AFP, hCGD, hCG, more than 50% of embryonal carcinoma, and vascular invasion with TNM staging and cancer specific survival (CSS) using logistic regression analysis and chi-square test. RESULTS: In AFP positive group, 2 of the 29 cases died of cancer (median observation period 48.5 months). The median AFPD was 2.3 (0.02-815). TNM staging was 6 cases for stage 1A, 9 for stage 1B, 3 for stage 1S, 2 for stage 2A, 2 for stage 2B, 4 for stage 3A, 4 for stage 3A, 6 for stage 3B, 3 for stage 3C. There were 14 cases with more than 50% embryonal carcinoma, and vascular invasion was found in 21 cases. On univariate analyses, AFPD showed significant correlation with TNM staging, and CSS (p=0.049, p=0.0001). On multivariable analysis, AFPD were independent predictor of CSS (p=0.0103).In hCG positive group, 2 of the 40 cases died of cancer (median observation period 52.5 months). The median hCGD was 2.52 (0.01-1168). 13 cases of seminoma and 27 cases of nonseminoma. TNM staging was 8 for stage1A, 12 for stage 1B, 6 for stage 1S, 3 for stage 2A, 3 for stage 3A, 4 for stage 3B, 1 for stage 3C. There were 11 cases with more than 50% embryonal carcinoma, and vascular invasion was found in 29 cases. Vascular invasion showed significant correlation with TNM staging in univariate and multivariable analysis (p=0.020, p=0.022). There were no significant factors for CSS. CONCLUSIONS: In the AFP positive group, only AFPD correlated with TNM staging and CSS, and in the hCG positive group, only vascular invasion correlated with TNM staging. Source of Funding: nothing © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e1155-e1156 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Naoto Hodotsuka* More articles by this author Go Kimura More articles by this author Tatsuro Hayashi More articles by this author Shuhei Nozaki More articles by this author Mikio Shibasaki More articles by this author Hiroya Hasegawa More articles by this author Ryo Amakawa More articles by this author Shigehito Minaguchi More articles by this author Hikaru Mikami More articles by this author Masato Yanagi More articles by this author Jun Akatsuka More articles by this author Yuki Endo More articles by this author Hayato Takeda More articles by this author Yukihiro Kondo More articles by this author Expand All Advertisement PDF downloadLoading ...

Overcoming sociodemographic factors in the care of testicular cancer patients at a safety net hospital.

398 Background: Optimal treatment of GCT in underserved populations is subject to barriers that are associated with worse clinical outcomes. We determine whether standardized treatment of GCT can overcome such sociodemographic factors limiting patient care. Methods: The records of all patients undergoing primary treatment for GCT were analyzed from both a public safety net hospital and an academic tertiary care center in the same metropolitan area. Patients at both institutions were managed by the same group of physicians in the context of multidisciplinary cancer care. Patients were grouped by care center and clinicopathologic features, practice patterns, and outcomes were analyzed. Results: 106 and 95 patients underwent initial treatment for GCT between 2006 and 2018 in the safety net hospital and tertiary care center, respectively. Safety net patients were younger (29 vs 33 years, p=0.005), more likely to be Hispanic (79% vs 11%), more likely to be uninsured (80% vs 12%, p&lt;0.001), and present via the emergency department (76% vs 8%, p&lt;0.001). They were more likely to have metastatic (stage II/III) disease (42% vs 26%, p=0.025). On multivariable analysis, presence of lymphovascular invasion (OR=0.30, p=0.008) and embryonal carcinoma component (OR=0.36, p=0.02) were associated with surveillance vs adjuvant treatment for Stage I patients; hospital setting was not (OR=0.67, p=0.55). For patients with Stage II/III NSGCT, there was no difference in performance of PC-RPLND at the safety net hospital vs tertiary care center (52% vs 64%, p=0.53). No difference in recurrence rates between cohorts (5% vs 6%, p=0.76) was observed. Conclusions: Sociodemographic factors are often associated with adverse clinical outcomes in the treatment of GCT; this may be overcome with integrated, standardized management of testicular cancer.

Mixed Germ Cell Tumor of the Endometrium: A Case Report and Literature Review.

Germ cell tumors (GCTs) localized extragonadally are rare, with only 14 reported cases of a yolk sac tumor in the endometrium. Here we report a case of mixed endometrium GCTs in a 65-year-old postmenopausal woman with abnormal vaginal bleeding. An ultrasound examination showed an oval-shaped mass in the patient’s uterine cavity. Biochemical examination revealed elevated serum α-fetoprotein (AFP) at 359 ng/mL, whereas the tumor markers CA-125, CA-199, and CEA were all within normal range. Total hysterectomy and bilateral salpingo-oophorectomy were performed;. a histological examination revealed that the malignant components contained a yolk sac tumor, embryonal carcinoma, and focal immature teratoma. Immunohistochemical staining showed that AFPs were diffusively distributed in both the yolk sac tumor and embryonal carcinoma. The stem cell marker OCT3/4 was positive in the embryonal carcinoma component and that the pan-cytokeratin AE1/AE3 staining was positive in glandular areas. GFAPs (Glial Fibrillary Acidic Proteins) were positive in neuroectodermal tubules; the Ki-67 protein was positive in 90% of the tumor cells, whereas CD117 and placental alkaline phosphatase (PLAP) were negative. The cumulative evidence indicated mixed GCTs of endometrium as the final histopathological diagnosis. The patient received three courses of adjunct chemotherapy that provided good therapeutic efficacy as evidenced by the decreased serum AFP level. Our report on this rare case of mixed GCTs of the endometrium, supported by associated histological patterns and immunophenotypes and successful adjunct chemotherapy after surgery, could provide insight on future treatment of this rare but lethal disease.

Testicular germ cell tumors: revisiting a series in light of the new WHO classification and AJCC staging systems, focusing on challenges for pathologists

Testicular germ cell tumors (TGCTs) are strikingly heterogeneous, reflecting a complex tumor model, posing serious challenges for pathologists. Accurate classification and staging, according to most recent systems, is fundamental. We aimed to revise a series of consecutively diagnosed TGCTs (2005-2016) in light of the new World Health Organization (WHO) classification and American Joint Committee on Cancer (AJCC) staging systems, discussing dilemmas imposed to pathologists. All 164 patients' clinical files/histological slides were reviewed. Follow-up was last updated on November 2017. Statistical analysis was performed with SPSS (v24). P < 0.05 was considered significant. Non-seminomatous tumors (NSTs) showed more frequently cysts, necrosis, hemorrhage, lymphovascular invasion (LVI) and higher stage than seminomas (SEs) (P < .001, P = .015, P < .001, P = .001, P = .007). Embryonal carcinoma (EC), yolk sac tumor (YST) and teratoma (TE) were the most frequent components in mixed tumors (82.5%, 82.5% and 80.7%). SEs with "atypical features" showed more LVI, higher mitotic count and more extensive necrosis (P = .030, P < .001, P = .016). LVI and >50%EC component, but not rete testis invasion, were associated with higher stage (P < .001, P = .009). Regarding SEs, there was an association between tumor size and both stage (P = .004) and LVI (P < .001). Only four patients disclosed altered stage group when AJCC 8th Edition was employed. Disease recurrence/progression occurred in 5.4% of cases. In two cases, tumor components in metastasectomy specimens were not present in the primary TGCT. Overall survival at 5 years was 98.6%. TGCTs are challenging neoplasms, and pathologists and clinicians alike must be aware of recent updates in classification and staging for adequately tailoring treatment strategies.

Clinicopathological Significance and Antitumor Effect of MPHOSPH1 in Testicular Germ Cell Tumor

MPHOSPH1, which is one of the kinesin superfamily proteins, has been reported to play an essential role in the carcinogenesis and progression of several kinds of cancers. MPHOSPH1 has also been suggested to be involved in STAT3 phosphorylation in hepatocellular carcinoma. However, the biological behavior of MPHOSPH1 in testicular germ cell tumors (TGCTs) is unclear at present. The purposes of this study were to investigate the correlation between the expression of MPHOSPH1 and clinicopathological factors and to examine the efficacy of MPHOSPH1 target therapy in TGCTs. We investigated 75 formalin-fixed paraffin-embedded TGCT samples, containing a total of 86 germ cell tumor components, by immunohistochemistry and 12 frozen samples by Western blotting. Moreover, we carried out in vitro studies to clarify the antitumor effect of MPHOSPH1 knockdown in embryonal carcinoma cell lines, NEC8 and NEC14, using small interference RNA (siRNA). A significantly high expression of MPHOSPH1 was recognized in embryonal carcinoma and yolk sac tumor components compared to the seminoma component (p<0.001, respectively). Clinically, non-seminoma cases are known to have worse prognosis than pure-seminoma cases. Interestingly, high MPHOSPH1 expression was associated with distant metastasis (p=0.001), and thus with advanced-stage disease in this study. High expression of MPHOSPH1 interacted with high expression of phosphorylated STAT3 (p=0.01). The in vitro experiments demonstrated that MPHOSPH1 interruption by siRNA resulted in a significant reduction of cell migration, invasion, proliferation and colony formation in both embryonal carcinoma cell lines (p<0.001, respectively). In conclusion, MPHOSPH1 may be a potential treatment option for TGCTs, and its expression may be a novel biomarker of poor prognosis.

Brentuximab vedotin exerts profound antiproliferative and pro-apoptotic efficacy in CD30-positive as well as cocultured CD30-negative germ cell tumour cell lines.

Prognosis in patients suffering from high‐risk, refractory and relapsed germ cell tumours (GCT) often comprising of CD30‐positive embryonal carcinoma (EC) components remains poor. Thus, novel treatment strategies are warranted. The antibody‐drug conjugate (ADC) brentuximab vedotin delivers the potent antimitotic drug monomethyl auristatin E (MMAE) to CD30‐expressing tumour cells. After CD30 binding, internalization and intracellular linker cleavage cytotoxic MMAE can efflux and eradicate neighbouring CD30‐negative cells. To analyse cytotoxicity and a potential bystander effect of brentuximab vedotin in GCT, we established an in vitro coculture model mimicking GCT of heterogeneous CD30 positivity and measured cell viability, proliferation and apoptosis after exposure to brentuximab vedotin and unbound MMAE by MTS‐ and flow cytometry‐based CFSE/Hoechst assay. CD30 expression being assessed by quantitative RT‐PCR and immunohistochemistry was apparent in all EC cell lines with different intensity. Brentuximab vedotin abrogates cell viability of CD30‐positive GCT27 EC line exerting marked time‐dependent antiproliferative and pro‐apoptotic activity. CD30‐negative JAR cultured alone barely responds to brentuximab vedotin, while in coculture with GCT27 brentuximab vedotin induces clear dose‐dependent cytotoxicity. Cellular proliferation and cell death are significantly enhanced in CD30‐negative JAR cocultured with CD30‐positive GCT27 compared to JAR cultured alone in proof of substantial bystander activity of brentuximab vedotin in CD30‐negative GCT. We present first evidence that in an in vitro model mimicking GCT of heterogeneous histology, brentuximab vedotin exerts potent antiproliferative and pro‐apoptotic activity against both CD30‐positive as well as CD30‐negative GCT subsets. Our results strongly support translational efforts to evaluate clinical efficacy of brentuximab vedotin in high‐risk GCT of heterogeneous CD30 positivity.

GERM-02. IMMUNOHISTOCHEMICAL EVALUATION FOR THE PATHOGENESIS OF INTRACRANIAL GERM CELL TUMORS: EXPRESSION OF PLURIPOTENCY AND CELL DIFFERENTIATION MARKERS

Abstract INTRODUCTION: Primary intracranial germ cell tumors (iGCT) are rare neoplasms that occur in children and adolescents. This study examined both the pathogenesis and the origin of these tumors, as it has been hypothesized that they originate from a totipotent primordial germ cell. MATERIALS AND METHODS: We applied recent knowledge from gonadal germ cell tumors and analyzed expression of a wide panel of stem cell-related proteins(C-KIT, OCT-3/4 (POU5F1), NANOG, SOX2, CD30 and PLAP). Expression shown by immunohistochemistry was analyzed in 12 children and young adults with iGCT, contributing to a careful description of these unusual tumors and adding to the understanding of pathogenesis. RESULTS: Immunohistochemistry showed 5/5 positive in Oct3/4, 5/5 in NANOG, 9/9 in C-KIT and 1/5 in SOX2. All cases that showed positive staining in Oct3/4 or NANOG indicated that the tumors contained germinoma or embryonal carcinoma component. Immunohistochemistry revealed that stem cell related proteins were highly expressed in iGCT, and many similarities were detected with their gonadal equivalents, including a close similarity with primordial germ cells. CONCLUSION: The expression of genes associated with embryonic stem cell pluripotency in CNS germ cell tumors strongly suggests that these tumors are derived from cells that retain, at least partially, an embryonic stem cell-like phenotype, which is a hallmark of primordial germ cells. In addition, these data can be applied to stratify iGCT for treatment strategy in order to provide good survival rate and good functional outcome.

Current Concepts in Management of Stage I NSGCT.

While about 50% of non- seminomatous germ cell tumors of the testes present as clinical stage I (CSI), further management of these patients continues to be mired in controversy. Active surveillance is a frontline option for low- risk CS I patients and according to some, even the high- risk ones with high embryonal carcinoma (ECA) component and vascular invasion (VI). However, it carries the disadvantage of long- term surveillance, the need for prolonged chemotherapy in case of recurrence and the possibility of secondary malignancies due to radiation exposure from frequent CT scans. One or two cycles of BEP chemotherapy is a popular alternative to active surveillance which carries a very low relapse rate, but valid concerns about overtreatment of a majority of patients, with the attendant chemotherapy- related toxicity exist. Retroperitoneal lymph node dissection has been used as a means of avoiding chemotherapy, especially in high- risk patients, but carries the disadvantage of a high surgical morbidity and complications. As with any major surgical procedure, the best results are dependent on the experience and skill of the individual surgeon.

Giant seminoma case with very small yolk sac and embryo carcinoma components, detected by intensive histopathological examination

We experienced the giant seminoma with 18×10×10cm sized and about 2.6kg weight of 25year old patient. We intensively examined the histological tissue type distributions in this giant seminoma. Most of the tumor consisted of seminoma components. In addition, the tumor included the very small fragments of yolk sac tumor and embryonal carcinoma component at the root part of the seminoma mass. This shows that intensive histological examination may contribute to the finding of other embryonic component of the large seminoma. This may show that leaving the seminoma growing may generate the other embryonic tumor component, not always big enough to find out in a routine procedure, during the growth, in the different way from the original mixed cell germ tumor.

Metastatic Treated Malignant Germ Cell Tumors: Is SALL4 a Better Marker Than Placental Alkaline Phosphatase?

Studies have shown that in the metastatic setting and after treatment, expression of immunohistochemical markers may be diminished or lost. Transcription factor SALL4 (sal-like protein 4) has been recognized as a sensitive marker for both primary and metastatic malignant germ cell tumors (MGCTs), but has not been tested in the posttreatment setting. We sought to determine the level of SALL4 expression in treatment-resistant metastatic MGCT in comparison with pan-GCT marker placental alkaline phosphatase (PLAP). Thirty-six previously treated MGCTs, 16 untreated primary testicular MGCTs, and 4 cytology specimens were immunostained for SALL4 and PLAP, and staining characteristics were evaluated. In the treated MGCT group, there was diffuse SALL4 nuclear immunoreactivity in the majority of cases (27/36, 75%), labeling seminoma, yolk-sac tumor, embryonal carcinoma, and primitive neuroectodermal components. No treated metastatic MGCT lacked SALL4 immunoreactivity. In contrast, PLAP was diffusely expressed in only 14/36 (39%) cases of treated MGCTs, showed scattered focal weak to moderate positivity in 13/36 (36%), and was virtually absent in 9/36 (25%) cases. Both markers had scattered expression limited to the epithelial components of teratomatous regions. SALL4 also outperformed PLAP on a small sample of cytology blocks. Although SALL4 is not entirely specific, it is a highly sensitive marker with strong diffuse nuclear reactivity in the majority of MGCTs in the posttreatment setting, at significantly higher levels than PLAP (P<0.001). Persistent expression of SALL4 in metastatic MGCTs resistant to chemoradiation also raises the possibility for targeted systemic therapy as the anti-SALL4 peptide continues to be developed.

Giant Mediastinal Germ Cell Tumour: An Enigma of Surgical Consideration.

We present a case of 16-year-old male, who was referred from private centre for dyspnoea, fatigue, and orthopnea. The chest radiograph revealed complete opacification of left chest which was confirmed by computed tomography as a large left mediastinal mass measuring 14 × 15 × 18 cm. The diagnostic needle core biopsy revealed mixed germ cell tumour with possible combination of embryonal carcinoma, yolk sac, and teratoma. After 4 cycles of neoadjuvant BEP regime, there was initial response of tumour markers but not tumour bulk. Instead of classic median sternotomy or clamshell incision, posterolateral approach with piecemeal manner was chosen. Histology confirmed mixed germ cell tumour with residual teratomatous component without yolk sac or embryonal carcinoma component. Weighing 3.5 kg, it is one of the largest mediastinal germ cell tumours ever reported. We describe this rare and gigantic intrathoracic tumour and discuss the spectrum of surgical approach and treatment of this exceptional tumour.