Mediastinal Germ Cell Tumors Research Articles

Primary Mediastinal Germ Cell Tumors-The University of Western Ontario Experience.

Extragonadal germ cell tumors account for 2–5.7% of germ cell tumors (GCTs). Of these, primary mediastinal GCTs (PMGCTs) are responsible for 16–36% of cases. Given the rarity of these tumors, specific treatment strategies have not been well defined. We report our experience in treating these complex patients. In total, 318 men treated at our institution with chemotherapy for GCTs between 1980 and 2016 were reviewed. PMGCT was defined as clinically diagnosed mediastinal GCT with no evidence of testicular GCT (physical exam/ultrasound). We identified nine patients diagnosed with PMGCT. All patients presented with an anterior mediastinal mass and no gonadal lesion; four patients also had metastatic disease. Median age at diagnosis was 30 years (range, 14–56) and median mass size at diagnosis was 9 cm (range, 3.4–19). Eight patients had non-seminoma and one had pure seminoma. All patients received cisplatin-based chemotherapy initially. Surgical resection was performed in four patients; three patients had a complete resection and one patient was found to have an unresectable tumor. At a median follow-up of 2 years (range, 3 months–28 years) six patients had progressed. Progression-free survival was short with a median of 4.1 months from diagnosis (range 1.5–122.2 months). Five patients died at a median of 4.4 months from diagnosis. One and 5-year overall survivals were 50% and 38%, respectively. PMGCT are rare and aggressive. Our real-life Canadian experience is consistent with current literature suggesting that non-seminoma PMGCT has a poor prognosis despite prompt cisplatin-based chemotherapy followed by aggressive thoracic surgery.

Mediastinal germ cell tumors: cohort of patients with this rare entity.

BackgroundExtragonadal germ cell tumors are infrequent and represent between 1–10% of all mediastinal tumors. It presents differences to those of gonadal location in terms of clinical presentation, behavior and prognosis which is poor even with treatment.MethodsRetrospective and descriptive cohort study on 16 patients with diagnosis of mediastinal germ cell tumor surgically treated at Maria Ferrer Respiratory Rehabilitation Hospital and Alexander Fleming Specialized Medical Institute.ResultsNine men and 7 women were analyzed over a period of 10 years. The median age was significantly lower among men (22 vs. 38 years, P<0.01). The most common initial symptom was pain in 43.75%. Chest tomography was the diagnostic method used in 13 patients (81.25%). Tumor marker levels were raised in 7 patients (43.75%), and decreased after surgery. All women had a mature teratoma, however, no statistically significant difference was found at the histological distribution by gender (P=0.336). The median tumor size was 9.50 centimeters. The most frequent surgical approach was sternotomy. No woman in the series received treatment before or after surgery, while 88.90% of men received neoadjuvant treatment for invasion or intimate contact with neighboring structures (P=0.001). Chemotherapy was indicated in 33.30% of the male population due to relapse. The median follow-up was 36 months (range, 1–95 months). No statistically significant differences were observed in the median follow-up (P=0.950), the percentage of relapses (P=0.091) and overall survival by gender (P=0.335). Overall survival was 75%.ConclusionsTumors were predominantly primary and not seminomatous. Multimodal treatment was a useful tool to improve the chances of resection and overall survival. There was a percentage of women higher than the published literature, teratomas predominated in them, and surgery was the only necessary treatment.

Three distinct hematological malignancies from a single germ cell tumor: a case report

BackgroundThe association between non seminomatous germ cell tumors (GCTs) and hematological malignancies of rare lineage has been described in the literature. In some of these cases there is evidence that the leukemia derives from a pluripotent primitive clone present in the original germ cell tumor.Case presentationWe present a highly unusual case of a 23-year-old man of South Asian origin with a history of Klinefelter’s syndrome who initially developed mediastinal non seminomatous GCT. Following treatment with surgery and standard chemotherapy he went on to develop three different hematological malignancies of distinct lineages in sequential fashion over a short time period. Despite treatment with multiple intensive chemotherapy regimens and a matched unrelated donor allogeneic stem cell transplant, he died 41 months after initial diagnosis of his GCT and 10 months after the first diagnosis of hematological malignancy.ConclusionsThis is an extreme case that highlights the pluripotency and aggressiveness of these GCT-derived hematological malignancies, and the need for novel therapeutic approaches.

Mediastinal germ cell tumors: many questions and perhaps an answer.

Some germ cell tumors (GCTs) in men develop into hematologic malignancies; however, the clonal origins of such malignancies remain unknown. In this issue of the JCI, Taylor, Donoghue, et al. unravel the clonal relationship between primary mediastinal nonseminomas (PMNs) and hematologic somatic-type malignancies (HSTMs). Whole-exome sequencing was used to construct phylogenetic trees of the PMNs and the ensuing HSTM clones. HSTMs were derived from multiple distinct clones not detected within the PMNs. Clones from PMNs and HSTMs shared a common precursor, arguably an embryonal carcinoma cell resulting from a reprogrammed primordial germ cell from the thymus. Mutational and copy number variation analysis of a large cohort of patients with PMNs also demonstrated a high prevalence of TP53 mutations not found in testicular nonseminomas. These data likely explain why patients with PMNs are frequently resistant to platinum-based chemotherapy and provide TP53 mutations as potential targets.

Germ cell tumors and associated hematologic malignancies evolve from a common shared precursor.

Germ cell tumors (GCTs) are the most common cancer in men between the ages of 15 and 40. Although most patients are cured, those with disease arising in the mediastinum have distinctly poor outcomes. One in every 17 patients with primary mediastinal nonseminomatous GCTs develop an incurable hematologic malignancy and prior data intriguingly suggest a clonal relationship exists between hematologic malignancies and GCTs in these cases. To date, however, the precise clonal relationship between GCTs and the diverse additional somatic malignancies arising in such individuals have not been determined. Here, we traced the clonal evolution and characterized the genetic features of each neoplasm from a cohort of 15 patients with GCTs and associated hematologic malignancies. We discovered that GCTs and hematologic malignancies developing in such individuals evolved from a common shared precursor, nearly all of which harbored allelically imbalanced p53 and/or RAS pathway mutations. Hematologic malignancies arising in this setting genetically resembled mediastinal GCTs rather than de novo myeloid neoplasms. Our findings argue that this scenario represents a unique clinical syndrome, distinct from de novo GCTs or hematologic malignancies, initiated by an ancestral precursor that gives rise to the parallel evolution of GCTs and blood cancers in these patients.

Vasculogenic Mesenchymal Tumor: A Clinicopathologic and Molecular Study of 55 Cases of a Distinctive Neoplasm Originating From Mediastinal Yolk Sac Tumor and an Occasional Precursor to Angiosarcoma.

We report 55 postchemotherapy resections of primary nonseminomatous mediastinal germ cell tumors with prominent vasculogenic features showing the formation of rudimentary to well-developed neoplastic vessels within primitive mesenchyme. These cases represented 25% of a cohort of 221 such specimens. The patients were 19 to 49 years old (mean, 28 y) and 98% had serological evidence of yolk sac tumor. The vasculogenic lesions, felt to represent a neoplastic reiteration of embryonic vasculogenesis in the splanchnic mesoderm of the yolk sac, were further subdivided into teratoma with vasculogenic stroma (n=9), vasculogenic mesenchymal tumor (VMT) (n=42, further classified into low grade [n=24] and high grade [n=18]), and angiosarcoma (n=4). The distinction of teratoma with vasculogenic stroma from VMT was based solely on the greater extent of VMT (exceeding 1 low power [×4 objective] microscopic field), with both categories showing a spectrum of vessels lined by atypical endothelium in a nonendothelial neoplastic stroma that often also generated vascular walls comprised of atypical smooth muscle. The angiosarcomas showed stratification of highly atypical endothelial cells or anastomosing vessels lined by nonstratified but cytologically similar endothelium. Immunohistochemical studies supported the generation of neoplastic vessels from the tumor stroma, most commonly by the development of stromal clefts showing reactivity for podoplanin, CD34, and occasionally ERG, followed by the gradual development from the clefts of thin-walled vessels that later became encircled by stromal cells showing smooth muscle differentiation by immunohistochemistry. Occasionally, round collections of stromal erythrocytes became surrounded by stromal cells to generate blood vessels. Fluorescence in situ hybridization showed chromosome 12p copy number increase in both the endothelial component and stromal component in 8/9 VMT cases and in 1/1 angiosarcoma. On follow-up, no patient with teratoma with vasculogenic stroma had evidence of a subsequent vascular tumor or sarcoma, whereas 8 of the 35 (23%) patients with VMTs (2 low grade and 6 high grade) and meaningful follow-up developed sarcoma (1 angiosarcoma, 2 rhabdomyosarcomas, and 5 not further characterized). The difference between low-grade and high-grade tumors was of borderline significance (P=0.058). Two of the 4 patients with angiosarcoma died of metastatic angiosarcoma, with the other 2 disease-free at 6.8 and 7 years. Compared with the 165 patients with follow-up and no vasculogenic lesions, there was a highly significant (P=4.3×10-5) association of any vasculogenic lesion with sarcomatoid tumors during the clinical course of VMT patients. In addition, 5/46 patients with follow-up and vasculogenic lesions (11%) died of either leukemia or myelodysplastic syndrome compared with 2 of 166 (1%) lacking them (P=0.0012). Three of the 5 patients had identifiable immature hematopoietic cells within their vasculogenic lesions, but 4 other VMT patients with these did not develop leukemia or myelodysplasia. We conclude: (1) vasculogenic lesions are frequent in postchemotherapy resections of primary mediastinal germ cell tumors with yolk sac tumor components; (2) they mostly consist of neoplastic vessels in a stroma that also generates neoplastic vascular walls of smooth muscle; (3) VMTs are associated with an increased incidence of sarcomas, even though most vasculogenic lesions in this context do not meet criteria for angiosarcoma; (4) the presence of vasculogenic lesions in postchemotherapy resections of primary mediastinal germ cell tumors place patients at increased risk for leukemia or myelodysplasia.

Disorder of sex development with germ cell tumors: Which is uncovered first?

Background Disorders of sex development (DSD) are rare conditions. Although they are known to predispose to germ cell tumors (GCT), there is a paucity of information regarding the circumstances of DSD discovery. Design/methods All patients with DSD registered in two French pediatric GCT protocols (TGM95 and 13) were analyzed. Results Sixteen patients were identified among 276 ovarian, 160 testicular, and 24 mediastinal GCT. Eleven phenotypic females (median age 15 years) exhibited gonadal GCT, including 10 with a 46,XY karyotype and gonadal dysgenesis and one with 46XX,45X0 mosaicism. None had genital anomalies, seven had spontaneous pubertal changes, and one had spontaneous menarche. The tumors were bilateral in four cases. DSD was diagnosed after the GCT diagnosis in seven cases. The reasons for karyotyping were bilateral tumors (3), gonadoblastoma/streak gonad/absence of egg follicles (3), or systematic for GCT (1). The karyotyping was performed before the GCT diagnosis in four cases: for polymalformative syndrome (2) or primary amenorrhea (2). Four males (median age 14 years) exhibited mediastinal GCT (metastatic in two cases) indicative of Klinefelter syndrome, despite typical phenotypes in all cases. The remaining patient had severe hypospadias, leading to the discovery of 46,XY/45,X0 mosaicism before the diagnosis of testicular nonseminomatous GCT at 16 years of age. Conclusion DSD are often uncovered at the time of GCT diagnosis (11/16 cases). This should prompt oncologists to rule out a DSD in patients with GCT, even in case of pubertal development. Earlier recognition of Klinefelter syndrome could potentially lead to GCT detection at an earlier stage.

Multimodality treatment outcome in patients with primary malignant mediastinal germ cell tumor in adults.

BackgroundMalignant mediastinal germ cell tumor (MGCT) is rare and has poor outcomes even after multimodality treatment. Data from resource‐poor countries are scarce in the literature.AimsTo evaluate the clinicopathologic features and treatment outcome of primary malignant MGCT at our center.Methods and ResultsSingle institutional data review of patients aged ≥18 years, treated with a diagnosis of malignant MGCT between Nov'2013 and Nov'2019. Risk stratification was done as per International Germ Cell Cancer Collaborative Group (IGCCCG) classification. Patients were treated with platinum based chemotherapy and surgical resection for the residual disease was performed in non‐seminomatous histology.28 patients had MGCT with a median age of 25 years (range:18‐36) and all were male. Seven patients had superior vena cava obstruction (SVCO) at diagnosis and pre‐treatment histological diagnosis was available in 23 (82%) patients. Seven (25%) patients had seminoma histology, all were of good risk as per IGCCCG risk criteria, whereas others had non‐seminoma histology with poor‐risk group. Seven patients with seminoma histology achieved a complete response after initial treatment. Six patients with non‐seminoma histology underwent complete resection of residual disease post‐chemotherapy and five revealed residual viable tumors. After a median follow‐up of 10.8 months (range:2.9‐75), 3‐year progression‐free survival (PFS) and overall survival (OS) estimate was 61.2% and 94.7% in the whole cohort, respectively and 3‐year PFS and OS estimate was 100% in patients with seminoma histology.ConclusionsThis is the largest data set of MGCT patients' outcomes reported from India with multi‐modality treatment. All patients were male and one‐fourth had SVCO at presentation. Seminoma histology patients had a 100% outcome after initial platinum based chemotherapy. But, those with non‐seminoma histology had a poor outcome even with chemotherapy and surgery.

PRIMARY MEDIASTINAL CHORIOCARCINOMA (PMC) IN A YOUNG WOMAN WITH HEMOPTYSIS AND A LUNG MASS

SESSION TITLE: Medical Student/Resident Lung Cancer Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Primary mediastinal choriocarcinoma (PMC) is an extra gonadal, non-gestational, angioinvasive rare germ cell neoplasm that mostly arises along the midline structures. PMC contains syncytiotrophoblastic cells which secrete human chorionic gonadotropin hormone (hCG). An elevated hCG is considered an important serologic tumor marker in the diagnosis of mediastinal germ cell tumor, in the absence of gestation and with no previous gynecologic malignancy. CASE PRESENTATION: A 39 year-old woman with no past medical history was admitted to the hospital with severe right sided chest pain associated with hemoptysis that started 2 weeks prior to admission. Physical exam revealed decreased breath sounds on the right hemithorax with dullness to percussion. Bloodwork was significant for β-HCG of 6,566 mlU/ml with negative alpha fetoprotein, and normal lactate dehydrogenase. A CT scan of the chest revealed a large necrotic solid mass with numerus enlarged vessels located in the anterior mediastinum (Figure 1). PET scan was negative for any metastatic lesions. Transvaginal ultrasound was negative for intrauterine or ectopic pregnancy. Transthoracic core biopsy showed poorly differentiated choriocarcinoma. Immunohistochemistry staining was positive for β-HCG, placental alkaline phosphatase, and pancytokeratin AE1/AE3 (Figure 2). The tumor was not amenable to surgical resection due to its large size and high vascularity. The patient was started on cisplatin and etoposide followed by etoposide, MTX, Act-D, cyclophosphamide, and vincristine (EMA-CO). After the first course of chemotherapy, the levels of β-HCG markedly decreased. DISCUSSION: PMC is a rare malignancy in both genders, more prevalent in men than in women. The natural process of PMC has been poorly understood. Possible theories include: (1) trophoblastic embolus related to a gestational event after a long period of latency; (2) metastases from a primary gonadal choriocarcinoma; (3) retained primordial germ cells that migrated during embryogenesis. An extensive workup is required to exclude other β-HCG-positive tumors from PMC, such as primary poorly differentiated non-small cell carcinoma of the lung, and gestational metastatic choriocarcinoma. Our patient was found to have a large highly vascular mass in the presence of elevated β-HCG, and absence of primary genital tumor. The histological features showed extensive areas of hemorrhage and necrosis and biphasic cellular population including cytotrophoblastic and syncytiotrophoblastic cells. In contrast to gestational choriocarcinoma, PMC is rapidly progressive and fatal in the great majority of cases with a dismal 5 years survival of less than 5%. CONCLUSIONS: Due to the rarity of PMC, currently there is no consensus regarding treatment guidelines. Thus, case reports such as this contribute to the scant literature to raise the profile of this rare and devastating disease. Reference #1: Ruan Z, Wang S, Wang Z, Jing Y. A rare case of bilateral massive hemothorax from spontaneous rupture of a primary mediastinal mixed germ cell tumor. Ann Thorac Surg. 2012;93:664–666 Reference #2: Bachmann J, Ernestus K, Werner T, et al. Detection of primary choriocarcinoma in the mediastinum by F-18 FDG positron emission tomography. Clin Nucl Med. 2007;32:663–665. Reference #3: Serno J, Zeppernick F, Jakel J, Primary pulmonary choriocarcinoma; cas report and the review of the literature, Gynecologic nad obstetric investigation, vol. 74, no. 2, pp. 171-176,2012 DISCLOSURES: No relevant relationships by Marwah Abduljabbar, source=Web Response No relevant relationships by Sara Mehrsefat, source=Web Response No relevant relationships by jorge otoya, source=Web Response No relevant relationships by Noman Subhani, source=Web Response no disclosure on file for Maria Wallis-Crespo

MIXED GERM CELL TUMOR PRESENTING AS LARGE MEDIASTINAL MASS

SESSION TITLE: Fellows Disorders of the Mediastinum Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: October 18-21, 2020 INTRODUCTION: Extragonadal Germ cell tumors involving the mediastinum are rare and accounts for 3-4% of all germ cell tumors1.Literature review showed only small number of case reports about mixed germ cell tumors involving mediastinum or lungs. We present a rare case of young female presented with very large mediastinal mass. CASE PRESENTATION: 27-year-old female with no significant past medical history presented to the emergency room for the complaint of left-sided chest. She states she has been having intermittent chest pain for the last 2 months with pain radiates to left upper back, describes pain as sharp and stabbing in nature, gets worse with breathing movement and progressively getting worse. She also had night sweats and productive cough but denied any fevers, chills, weight loss, hemoptysis. Patient is never smoker and denied any second hand smoke exposure. Blood work-up was unremarkable, EKG showed sinus tachycardia. Chest x-ray showed left hemithorax opacification concerning for mass, she had CT chest done which showed massive left hilar mass. Patient underwent CT-guided biopsy which showed possible teratoma versus pulmonary hamartoma. Cardiothoracic surgery was consulted and patient underwent left thoracotomy with excision of left-sided intrathoracic mass. Pathology results consistent with mixed germ cell tumor comprised of teratoma with yolk sac tumor. Patient did well after surgery and discharged home with oncology follow-up. DISCUSSION: The differential diagnosis of mediastinal tumors is challenging and includes thymomas, esophageal/thyroid cancers, lymphomas, bronchogenic cysts and extra gonadal germ cell tumors. Germ cell tumors include Teratoma (mature and immature), Yolk sac tumor, Seminoma, Choriocarcinoma, Embryonal carcinoma and Mixed germ cell tumors. Germ cell tumors account for 20% of mediastinal tumors with teratoma and seminomas being most common cause. Because of multiple components of tumor, sampling of mediastinal germ cell tumors can be misleading. In one case report the germ cell tumor was misdiagnosed as hemangioma and in other case report, biopsy led to life threatening bleeding resulting in death of patient. Presenting symptoms include chest pains, shortness of breath, hemoptysis, and trichoptysis (expectoration of hair).Treatment options include complete surgical resection and chemotherapy. Complete resection is important as survival rate is low for patients with residual tumors. Mixed germ cell tumors with malignant components are more aggressive with survival rate less than 2 years. CONCLUSIONS: Extra gonadal Germ cell tumor involving mediastinum are rare, physicians need to be aware of difficulties and complications associated with diagnosis. Germ cell tumors should be considered in differential diagnosis of mediastinal mass especially in young patients. Reference #1: Moreira AL, Ströbel P, Chan JKC et al. Germ cell tumours of the mediastinum. Seminoma. In: WHO Classification of Tumours of Lung, Pleura, Thymus and Heart, 4th edn. IARC, Lyon 2015; 244–8. Reference #2: Sakane T, Okuda K, Murase T, Watanabe T, Oda R, Tatematsu T, Yokota K, Haneda H, Inagaki H, Nakanishi R. Mixed-type primary germ cell tumor of the mediastinum in a young adult male with a sudden life threatening condition: A case report. Thorac Cancer. 2020 Jan;11(1):166-169. doi: 10.1111/1759-7714.13231. Epub 2019 Nov 6.PMID: 31693305 DISCLOSURES: No relevant relationships by Imran Amer, source=Web Response No relevant relationships by Adnan Khan, source=Web Response No relevant relationships by Sana Khan, source=Web Response No relevant relationships by Thomas Maloney, source=Web Response No relevant relationships by Moeez Qureshi, source=Web Response

PRIMARY MEDIASTINAL SEMINOMA FOUND ON EVALUATION FOR WEIGHT LOSS

SESSION TITLE: Medical Student/Resident Disorders of the Mediastinum Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Extragonadal germ cell tumors (GCTs) typically arise in midline locations such as mediastinum and retroperitoneum. They are formed either due to failure of primordial germ cells to migrate to the gonadal ridges [1] or reverse migration of the transformed germ cells in the testes [2]. Mediastinal seminomas are rare tumors constituting about 1/3rd of malignant mediastinal GCTs and 2-4 percent of mediastinal masses [3]. CASE PRESENTATION: A 55-year-old man with a history of active smoking (½ pack cigarettes per day), hepatitis C, bipolar disorder, prior alcohol/intravenous drug use (heroin and cocaine) presented with shortness of breath and 50-pound weight loss. Chest computed tomography (CT) revealed a 3.0 x 1.1 cm para-aortic lymph node. Positron emission tomography (PET/CT) scan showed hypermetabolic activity (maximum standardized uptake value of 10). Bronchoscopy with EBUS (endoscopic ultrasound) and mediastinoscopy were considered as methods to obtain tissue but discarded due to the location of the mass. He underwent a left Video-assisted thoracoscopic surgery (VATS) which showed seminoma. H&E (hematoxylin and eosin) slides revealed pale tumor cells with distinct nuclei and prominent central nucleoli in a background of lymphocytic infiltrate. The tumor cells stained positive for germ cell markers CD117, Oct 3/4 and Sall 4; but were negative for melanoma markers (Mart1a, S100), as well as CK20, CK7, Pancytokeratin, CD30, CD15, TTF1 and CDX2. DISCUSSION: Mediastinal seminomas occur mainly in men aged 20 to 40 years. They are typically slow growing and can be very bulky by the time they cause symptoms. Serum beta subunit of human chorionic gonadotropin (beta-hCG) is elevated in approximately one-third of patients. They do not produce alpha-fetoprotein (AFP). Ultrasound is advised in all cases to evaluate for any testicular primary. Seminomas are exquisitely sensitive to both cisplatin-based chemotherapy and radiotherapy (RT) but local control with surgery and RT only have modest success due to their typically later presentation. The commonly used chemotherapy regimens are 3 cycles of bleomycin/etoposide/cisplatin (BEP) or 4 cycles of etoposide/cisplatin (EP) (in patients who have previously received RT, who have underlying lung disease or age more than 50 years to avoid bleomycin lung toxicity). Long-term disease-free survival is achieved in roughly 90 percent of patients treated with chemotherapy. CONCLUSIONS: Primary mediastinal seminoma is a malignant extragonadal GCT most commonly found in the anterior mediastinum. Usually, young men in their 20-40s present with large 4-11cm anterior mediastinal masses which cause symptoms by compressing local structures. Or, as in our case, they are found incidentally. Surgery/RT can be considered but many patients present late so local control is not possible. However, these tumors respond well to chemotherapy with complete response rates of 90% Reference #1: Intracranial germ cell tumors: a comprehensive review of proposed embryologic derivation; Glenn OA, Barkovich AJ; Pediatr Neurosurg. 1996;24(5):242; PMID 8933567 Reference #2: Genetics and biology of adult human male germ cell tumors; Chaganti RS, Houldsworth J; Cancer Res. 2000;60(6):1475; PMID 10749107 Reference #3: Primary germ cell tumors of the mediastinum: II. Mediastinal seminomas--a clinicopathologic and immunohistochemical study of 120 cases; Moran CA, Suster S, Przygodzki RM, Koss MN; Cancer. 1997;80(4):691; PMID 9264352 DISCLOSURES: No relevant relationships by William Han, source=Web Response No relevant relationships by Sahib Singh, source=Web Response

The mutational landscape of histiocytic sarcoma associated with lymphoid malignancy.

Histiocytic sarcoma and tumors with dendritic cell differentiation (HDT) are uncommon neoplasms often with an aggressive clinical course that may occur in association with another hematologic malignancy or mediastinal germ cell tumor (secondary HDT, sHDT). Previous studies have shown mutations in the RAS/MAPK pathway in HDT and have demonstrated a clonal relationship between HDT and associated lymphoid malignancies through common translocations or identical immunoglobulin or T-cell receptor gene rearrangements. We performed whole exome sequencing on 16 cases of sHDT to further evaluate the spectrum of mutations that occur in sHDT in the context of an associated lymphoid malignancy, including cases associated with follicular lymphoma (FL), chronic lymphocytic leukemia/small lymphocytic lymphoma, B- and T-cell acute lymphoblastic leukemia/lymphoma and peripheral T-cell lymphoma, NOS. In addition, we assessed the clonal relationship between the HDT and the associated lymphoid malignancy in three cases for which matched samples were available. We found mutations in RAS/MAPK pathway genes in 14/16 cases of sHDT associated with diverse mature and precursor B-cell and T-cell neoplasms, involving KRAS (8/16), BRAF (2/16), NRAS (2/16), MAP2K1 (1/16), and NF1 (1/16). In addition, we note that FL-associated sHDT frequently shares a similar mutational profile to the associated malignancy, identifying mutations in CREBBP or KMT2D in all cases and "aberrant" somatic hypermutation in 5/6 cases. Our study confirms the role of the RAS/MAPK pathway in the pathogenesis of sHDT, provides further evidence of a common neoplastic precursor and, in the case of FL, gives additional insight into the stage in lymphomagenesis at which transdifferentiation may occur.

Mixed Mediastinal Germ Cell Tumor: A Case Report

Germ cell tumors constitute a heterogeneous group of neoplasms derived from primitive germ cells, arising as a consequence of an embryogenic error. A clinical case of a 16-year-old white male patient, with no previous pathological history or toxic habits, who was admitted to the internal medicine room for presenting a clinical picture of asthenia and anorexia was added, to whom light fever was added in evening schedule. Several examinations were performed, including: Immunohistochemistry, biopsy, Computed Axial Tomography, X-ray of the chest and Mixed germ cell tumor of Mediastinum was diagnosed. Chemotherapy was started. The prognosis of the disease depends on the precociousness with which the diagnosis and treatment are made.

Clinical Characteristics and Outcomes of Patients With Primary Mediastinal Germ Cell Tumors: A Single-Center Experience.

Purpose: Primary mediastinal germ cell tumors (PMGCTs) are rare. The natural history and optimal treatment strategies still need to be defined. The aim of the study was to summarize the clinical characteristics, treatment outcomes, and prognostic factors of PMGCTs.Methods: Twenty-four patients with PMGCTs who were treated from December 2008 to January 2019 were evaluated retrospectively. The Kaplan–Meier method and Cox regression analysis were used to evaluate factors associated with prognosis.Results: The study population consisted of 23 male patients and 1 female patient. Five patients were diagnosed with seminoma and 19 patients were diagnosed with nonseminoma. The median follow-up time for all patients was 15.8 (3.9–114.5) months. The 5-year overall survival (OS) and progression free survival (PFS) rates for all patients were 65.2 and 44.3%. For nonseminoma and seminoma, the 5-year OS rates were 54.1 and 100% (P = 0.093), respectively, and the 5-year PFS rates were 28.7 and 100%, respectively (P = 0.044). In patients with nonseminoma, first-line radiotherapy indicated superior OS and PFS (P = 0.037 and 0.027, respectively). The median survival time after recurrence was 4.3 months and the 1-year survival rate after recurrence was 23.4%.Conclusion: These results indicated that in PMGCTs, the prognosis of seminoma is superior to that of nonseminoma. Radiotherapy may be an essential treatment in patients with nonseminoma. Patients with relapse have unfavorable prognosis.

Response to guadecitabine (SGI-110) combined with cisplatin and gemcitabine (GCG) in platinum refractory germ cell tumors (GCTs).

e17057 Background: Treatment options for platinum refractory GCTs are limited. Platinum resistance derives, in part, from tumour suppressor gene promotor methylation. In vitro, this reverses on co-administration of a DNA hypomethylating agent. Guadecitabine is a next generation hypomethylating agent. SPIRE is a phase Ib/IIa clinical trial to establish a GCG dose/schedule. Methods: We report 2 platinum refractory GCT patients (pts) treated (txd) in SPIRE with GCG (guadecitabine 20 mg/m2, SC, day (D) 1-5; cisplatin 70 mg/m2, IV, D8; gemcitabine 1000 mg/m2, IV, D8 + 15; filgrastim 300 μg, SC, D15-21; q21). Results: Pt 1: 21 yo man, testicular mixed GCT (seminoma/malignant teratoma intermediate). Prior tx: 2001, orchidectomy; 2005, 3 x BEP (bleomycin, etoposide, cisplatin) + retroperitoneal lymph node dissection. 2015, 2 x TI (paclitaxel, ifosfamide), 3 x TIP (cisplatin, ifosfamide, paclitaxel); 2016, 3 x HDCE (high dose carboplatin/ etoposide + autologous stem cell transplantation); 2017, 6 x GOP (gemcitabine, oxaliplatin, paclitaxel). In 2017, received 6 x GCG in SPIRE for CT confirmed lung metastases (mets) and rising β-hCG (human chorionic gonadotropin). Response: RECIST stable disease with metabolic CR on PET in lungs and &gt; 90% β-hCG reduction. In Cycle 6, pt developed symptomatic brain mets, treated with WBRT (40Gy, 20#) + cyberknife to the six mets completed 2018. Since 2018, ongoing complete marker and radiologic (brain and systemic) remission (20 months). Pt 2: 44 yo man, primary mediastinal non-seminomatous GCT. Prior tx: 2008, 4 x BEP + mediastinal mass resection; 2015, 4 x TIP; 2016, 1 x HDCE. In 2017, received 5 x GCG in SPIRE for a PET avid mediastinal/pulmonary relapse and AFP (alpha-fetoprotein) rise. Response: RECIST stable and &gt; 50% AFP reduction for 6 months (subsequent progression with intracerebral metastasis). Treatment was well tolerated. Grade 4 neutropenia/ thrombocytopenia occurred in both and febrile neutropenia in pt 1. Both required a 25% dose reduction in Cis/Gem. Conclusions: GCG produced exceptional clinical responses in both platinum refractory GCT pts. Prospective evaluation is warranted. Clinical trial information: 16332228.

Characteristics and One Year Survival of Mediastinal Germ Cell and Its Influencing Factors

Backgorunds: Mediastinal germ cell tumors are relatively rare. These tumors can be benign or malignant, which has a poor prognosis malignant. Nowadays, multimodality therapy can improve the survival rate of patients’ mediastinal germ cell tumors. This study aims to determine the characteristics and factors affecting the 1-year survival rate of mediastinal germ cell tumors patients in the Persahabatan Hospital, Jakarta.&#x0D; Methods: The study was conducted using retrospective cohort of mediastinal germ cell tumors patients medical records in Persahabatan Hospital, Jakarta from January 1, 2007 to December 31, 2012. Data obtained were analyzed using Kaplan Meier analysis of survival.&#x0D; Results: As much as 60 subjects participated in this study. Mediastinal germ cell tumors were found more in male (80%) with a median age of 21 years and especially in the age group of 20-29 years (43.3%). Most clinical symptoms found were shortness of breath (66.7%), most patients came with performance status (PS) 2 (50%). The majority of the mediastinal germ cell tumors found were teratomas (53.3%), followed with nonseminoma (40%) and seminomas (6.7%). Factors affecting the survival rate of mediastinal germ cell tumors were performance status of, the patients, treatment, complications and location of the tumors. One-year survival rate of mediastinal germ cell tumors in this study was 41.67% and affected by patients’ performance status, tumor location, complications and treatment.&#x0D; Conclusion: Mediastinal germ cell tumors were mostly found in male, with the chief complain of dypnea and mostly was teratoma. Mediastinal germ cell tumors have high mortality rate. The 1-year survival was influenced by patient’s performance status, tumor location, complications and treatment. (J Respir Indo. 2020; 40(2): 97-102)

Outcomes following surgery for primary mediastinal nonseminomatous germ cell tumors in the cisplatin era

ObjectiveTreatment of primary mediastinal nonseminomatous germ cell tumors involves cisplatin-based chemotherapy followed by surgery to remove residual disease. We undertook a study to determine short and long-term outcomes. MethodsA retrospective analysis of patients with primary mediastinal nonseminomatous germ cell tumors who underwent surgery at our institution from 1982 to 2017 was performed. ResultsA total of 255 patients (mean age, 29.2 years) were identified. Acute respiratory distress syndrome occurred postoperatively in 27 patients (10.9%), which was responsible for all 11 (4.3%) postoperative deaths. Of patients who developed acute respiratory distress syndrome, more patients received bleomycin-containing chemotherapy (25 out of 169; 14.8%) than non-bleomycin regimens (2 out of 77; 2.6%) (P = .004). With respect to variables independently predictive of long-term survival, evidence of choriocarcinoma before chemotherapy (n = 12) was determined to be an adverse factor (P = .006). In contrast, biopsy-proven elements of seminoma (n = 34) were predictive of improved survival (P = .04). The worst pathology identified in the residual mediastinal mass after chemotherapy was necrosis in 61 patients (25.0%), teratoma in 84 patients (34.4%), and malignant (persistent germ cell or non–germ cell cancer) in 97 patients (39.8%), which influenced overall survival (P < .001). Additionally, teratoma with stromal atypia (n = 18) demonstrated decreased survival compared with teratoma without atypia (n = 66; P = .031). Patients with malignancy involving >50% of the residual mass (n = 47) had a 2.3-fold increased risk of death compared with ≤50% malignancy (n = 45; P = .008). Finally, elevated postoperative serum tumor markers (n = 40) was significantly predictive of adverse survival (P < .001). ConclusionsIn the treatment of primary mediastinal nonseminomatous germ cell tumors, avoiding bleomycin-containing chemotherapy is important. Pre- and postchemotherapy pathology and postoperative serum tumor markers are independent predictors of long-term survival.

Analysis of extra-cranial germ cell tumors in male children: Experience from a single centre in India

BackgroundExtra-cranial germ cell tumors (GCT) are rare malignancies in children. There is paucity of data on presentation and outcomes of extra-cranial GCT in male children from India. MethodsThe study included all extra-cranial GCT in male children <18 years of age treated at our centre from January 2000 to December 2018. Baseline demographics, clinical manifestations, pathology, treatment details and outcomes of these patients were analysed retrospectively from the case records. ResultsThe study included 35 male children with extracranial GCT. Of these, 28 patients had testicular GCT, 1 had retroperitoneal nodal GCT, 1 had paraspinal mass diagnosed as GCT, 1 had mediastinal GCT and 4 had sacrococcygeal teratoma. Mixed germ cell tumor was the commonest histological subtype. 16/28 (57.1%) patients with testicular GCT were diagnosed with stage IV disease. PEb (Cisplatin, etoposide, bleomycin) chemotherapy was the most common regimen administered. Among the patients with testicular GCT, the 4 year event free survival (EFS) was 73.3% and the overall survival (OS) was 87.9%. In Children’s Oncology Group (COG) system of stages I, II and III, the 4 year OS was 100% and in stage IV it was 78.8%. ConclusionGerm cell tumors of the testis are the most common extracranial GCT in childhood. Despite presentation in advanced stages, the majority can be cured with platinum based chemotherapy.

The Role of Surgical Resection as A Salvage Therapy and Immunohistochemical Stain to Confirm Mediastinal Yolk Sac Tumor

Background: Mediastinal germ cell tumors are uncommon, representing less than 1% of all malignancies. They mostly occur in young men after puberty and have a poor prognosis with over all long term survival rate 42%. Case Report: We reported a case report in Saiful Anwar Malang Hospital, Indonesia, a young man, 26 years old with an anterior mediastinum tumor and VCSS The CT scan of the chest showed an anterosuperior mediastinal mass which compress the superior vena cava. The result from transthoracic FNAB with USG guidance showed an extragonadal germ cell tumor which resemble an Embryonal Carcinoma from mediastinum. The AFP serum level was elevated. Patient underwent a radiotherapy and a surgical debulking. The biopsy showed an Endodermal Sinus Tumor (Yolk Sac). Immunohistochemical stain for cytokeratin was positive in the tumor cells while stain for CD30 was negative. These were confirming the diagnosis of primary mediastinal yolk sac tumor. Patient received a combination chemotherapy for a total 6 cycles.Conclusion: Some procedures like biopsy, tumor marker, immunohistochemical stain, could differentiate the subtype of mediastinal germ cell tumor. The multimodality treatment by combining chemotherapy with surgical therapy or radiotherapy could increase the survival outcome of patients.

Successful Therapy on Patients with Yolksac and Embrional Carcinoma by Surgery and Chemotherapy

Background: Malignant mixed germ cell tumors account for 13-25% of all non seminoma germ cell tumors, almost all cases were found in males (85%), increased in the third decade, and had an average survival rate of 40-45%. With modern management the average 5-year survival rate can be over 80%.Case Report: We reported a case report in Saiful Anwar Malang Hospital, Indonesia, a young man, 26 years old with an malignant epithelial tumor derived from mediastinal or lung. The CT scan of the chest showed an lobulated solid mass of iso-hipodens on the anterior superior mediastinum, mass encompassing the aortic arch, left pulmonalis artery, subclavian artery. The result from transthoracic FNAB with USG guidance showed an malignant epithelial tumor derived from mediastinal or lung, impression of an adeno squamous carcinoma. The AFP, LDH, and NSE serum level was elevated. Patient underwent a surgical sternotomy and tumor debulking. The biopsy showed an malignant mixed germ cell tumor (yolksac and embrional carcinoma). These were confirming the diagnosis of malignant mixed germ cell mediastinal tumor (yolksac and embrinonal carcinoma). Patient received a combination bleomycin, etoposid, cisplatin 3 series chemoteraphy  and evaluated.Conclusion: Some procedures like biopsy, tumor marker, could differentiate the subtype of mediastinal germ cell tumor. The multimodality treatment by combining surgical therapy (surgical sternotomy and tumor debulking) with chemotherapy could increase the survival rate of patients.