Yolk Sac Tumor Component Research Articles

Pulmonary metastases revealing a mixed germ cell tumor with a predominant yolk sac tumor component: A case report

Yolk sac tumor of the testis is rare in adults. Its diagnosis is histological, reproducing an extra-embryonic structure (endodermal sinus tissue). It can be present alone or associated with another component, thus forming a mixed germ cell tumor. Treatment involves orchiectomy and chemotherapy in extratesticular stages. Lymph node dissection is indicated if residual masses persist. These tumors are characterized by a poor prognosis at an advanced metastatic stage. However, we report the clinical case of a 69-year-old man who presented with pulmonary metastases from a mixed germ cell tumor of the testis with a predominant Yolk Sac Tumor component, treated by orchiectomy, chemotherapy, and lymph node dissection.

Diagnostic incidence and pitfalls of rete testis hyperplasia and hyaline globules in a multi-institutional study of 348 testicular germ cell tumors.

The concept of rete hyperplasia with hyaline globules simulating testicular yolk sac tumor was first reported in a mostly retrospective review over 30 years ago. Nonetheless, we continue to encounter examples where this scenario resulted in misdiagnosis. Herein, we sought to investigate the incidence of rete hyperplasia/hyaline globules in germ cell tumors and their associated subtypes and hypothesize an etiology. A consecutive series of 348 germ cell tumor orchiectomies was evaluated for the presence of rete hyperplasia and hyaline globules, with clinicopathologic features recorded. The incidence of rete hyperplasia and/or hyaline globules in our cohort was 30%, with 56% of specimens with rete hyperplasia containing concomitant hyaline globules. Hyaline globules were more often identified in specimens with nonfocal rete hyperplasia (78%) vs focal rete hyperplasia (22%). Absence of a yolk sac tumor component was seen in over half (61%) of orchiectomies with concurrent rete hyperplasia/hyaline globules (n = 105), inclusive of tumors with "pure" subtypes (ie, pure seminoma, pure teratoma, or pure embryonal carcinoma). Of these 105 specimens, rete invasion was seen in only 48%; notably, Paneth cell-like metaplasia was identified in efferent ductules/epididymis in 13%. Rete hyperplasia and hyaline globules are not uncommon findings in the setting of germ cell tumors (including occurrences in various pure/mixed germ cell tumors) and can show striking overlap with yolk sac tumor. We hypothesize that these histologic pitfalls evolve secondary to testicular obstruction by the tumor mass. Recognition of and distinguishing this morphologic mimicry is fundamental to guide appropriate clinical management.

Mediastinal Teratoma with Angiosarcomatous Overgrowth in a Background of Vasculogenic Mesenchymal Tumor

Abstract Introduction/Objective Vasculogenic mesenchymal tumor refers to neoplastic reiteration of embryonic vasculogenesis. It is most commonly associated with nonseminomatous germ cell tumors of the mediastinum, in particular yolk sac tumor. In rare instances these lesions progress to angiosarcoma. Herein, we describe a case of angiosarcoma in a background of vasculogenic mesenchymal tumor in the setting of a mediastinal teratoma. Methods/Case Report A 33-year-old male, with a past medical history of anxiety, and right orchiectomy for testicular torsion, presented with shortness of breath, chest pain, and left arm swelling. Imaging studies demonstrated a mediastinal mass. Biopsy of the mass showed a germ cell tumor most compatible with a teratoma in the limited specimen. The patient received two rounds of chemotherapy and additional treatments were discontinued due to poor tolerance. Subsequent imaging showed continued increase in the size along with mass effect causing moderate to severe compression of the superior vena cava. Subsequently, the patient underwent resection of the mass. Grossly the mass was predominantly encapsulated with areas of capsular disruption. Sectioning revealed heterogeneous cut surfaces with fleshy, cystic, and necrotic areas. Morphologically the tumor was composed predominantly of teratomatous elements with areas of anastomosing atypical vascular channels within a hypocellular stroma suggestive of vascular genic mesenchymal as well as areas reminiscent of Masson lesion. Focally within these areas were malignant spindle cell proliferations compatible with angiosarcoma. The patient had an elevated AFP; however, no yolk sac tumor component was identified after thorough sampling. Final diagnosis of teratoma with angiosarcoma in a background of vasculogenic mesenchymal tumor was rendered after expert consultation. Results (if a Case Study enter NA) NA Conclusion Somatic-type malignancy and sarcomatous overgrowth are known to occur in mediastinal germ cell tumors; however, classification of the sarcomatous overgrowth can be challenging. Vasculogenic mesenchymal tumor is an exceedingly rare sarcomatous overgrowth that can rarely progress to angiosarcoma.

Prognostic implications of distinctive imaging characteristics in primary intracranial germ cell tumors: A retrospective analysis

PurposePrimary central nervous system (CNS) germ cell tumors (GCTs) are rare brain tumors that encompass two subtypes: germinomas and non-germinomatous germ cell tumors (NGGCTs), NGGCTs have less favorable outcome and require multi-modality treatment. Biopsy is recommended for disease diagnosis, the specimen may not adequately reflect the entire tumor. This study aimed to assess distinct imaging characteristics to differentiate between GCT subgroups and to identify possible initial image and subgroup features that influence survival. MethodThis retrospective study, conducted from January 2006 to March 2023, analyzed patient data and MRI findings of primary CNS GCTs. It evaluated tumor characteristics including cysts, seeding, multifocality, and hemorrhage. Tumor volumes and apparent diffusion coefficient (ADC) values of both tumoral and normal-appearing contralateral white matter were measured. These factors were correlated with overall and 5-year survival rates. ResultsThis study included 51 participants with CGTs, comprising 19 germinoma and 32 NGGCTs cases. GCTs with hemorrhage had worse overall (P = 0.03) and 5-year (P = 0.01) survival rates. No survival difference between germinoma and non-hemorrhagic NGGCT. NGGCTs were more likely to bleed (P < 0.001) than germ cell tumor, especially those with choriocarcinoma or yolk sac tumor components (P = 0.001). The ADC ratios of germinomas were significantly lower than those of NGGCTs (P = 0.03 for whole tumor; P < 0.01 or solid part), The ADC ratios of choriocarcinoma were also lower than mixed tumor (P = 0.01; P = 0.02). ConclusionHemorrhage indicates worse prognosis. Intratumoral hemorrhage and ADC ratios differentiate germinoma from NGGCTs. Larger cohorts and advanced MR techniques are needed for future study.

46, XX disorder of sexual development associated with mixed germ cell tumor of the prostate: a rare case report

BackgroundExtragonadal germ cell tumors originating from the prostate are exceptionally rare. To the best of our knowledge, there have been no reported cases of mixed germ cell tumors in individuals with 46 XX disorder of sex development. In this study, we conducted a comprehensive analysis using whole genome sequencing to investigate the clinicopathological and molecular genetic characteristics of a submitted case, with the objective of elucidating its underlying pathogenesis.Case presentationA 40-year-old male patient was diagnosed with a combination of 46, XX disorder of sex development and a primary prostate mixed germ cell tumor with yolk sac tumor and teratoma components. Whole-genome sequencing revealed that the tumor cells had a high somatic mutational load. Analysis of genomic structural variations and copy number variants confirmed the patient's karyotype as 46, XX (SRY +). Additionally, the patient exhibited short stature, small bilateral testes, slightly enlarged breasts, elevated serum alpha-fetoprotein concentrations, elevated follicle-stimulating hormone and luteinizing hormone levels, and low testosterone levels.DiscussionA case of 46, XX disorder of sex development, along with a primary prostatic mixed germ cell tumor, was diagnosed. This diagnosis has contributed to advancing our understanding of the genetic and phenotypic profile of the disease and may provide some insights for its treatment.

Distinct patterns of copy number alterations may predict poor outcome in central nervous system germ cell tumors

We have previously reported that 12p gain may predict the presence of malignant components and poor prognosis for CNS germ cell tumor (GCT). Recently, 3p25.3 gain was identified as an independent predictor of poor prognosis for testicular GCT. Eighty-one CNS GCTs were analyzed. Copy number was calculated using methylation arrays. Five cases (6.2%) showed 3p25.3 gain, but only among the 40 non-germinomatous GCTs (NGGCTs) (5/40, 12.5%; p = 0.03). Among NGGCTs, those with a yolk sac tumor component showed a significantly higher frequency of 3p25.3 gain (18.2%) than those without (1.5%; p = 0.048). NGGCTs with gain showed significantly shorter progression-free survival (PFS) than those without (p = 0.047). The 3p25.3 gain and 12p gain were independent from each other. The combination of 3p25.3 gain and/or 12p gain was more frequent among NGGCTs with malignant components (69%) than among those without (29%; p = 0.02). Germinomas containing a higher number of copy number alterations showed shorter PFS than those with fewer (p = 0.03). Taken together, a finding of 3p25.3 gain may be a copy number alteration specific to NGGCTs and in combination with 12p gain could serve as a marker of negative prognosis or treatment resistance. Germinoma with frequent chromosomal instability may constitute an unfavorable subgroup.

Impact of tumor markers on diagnosis, treatment and prognosis in CNS germ cell tumors: correlations with clinical practice and histopathology

Tumor markers in CNS germ cell tumors (GCTs) include human chorionic gonadotropin (HCG) and alpha fetoprotein (AFP), which have significant diagnostic implications, as elevation of either one leads to clinical diagnosis of non-germinomatous GCTs without histopathological confirmation, justifying intensified chemotherapy and irradiation. The current study, based on an international cohort of histopathologically verified GCTs that underwent biopsy (n = 85) or resection (n = 76), sought to better define the clinical role and prognostic significance of tumor markers from serum and CSF in this challenging patient population. We found that HCG was elevated only in cases with a germinoma or choriocarcinoma component, and there existed a clear cut-off HCG value between the two. AFP was often elevated in GCTs without a yolk sac tumor component, especially immature teratoma. HCG was elevated only in CSF in 3-of-52 cases, and AFP was elevated only in serum in 7-of-49 cases, emphasizing the potential utilization of both serum and CSF studies. Immature teratoma demonstrated unfavorable prognosis independent of tumor marker status, with 56% 5-year overall survival; however, co-existent germinoma components indicated a more favorable prognosis. Taken together, the study findings emphasize the importance for routine assessment and guarded interpretation of tumor markers in CNS GCTs.

A case of vasculogenic mesenchymal tumor in the mediastinum: whole-exome sequencing reveals origin from pre-existing germ cell tumor

Vasculogenic mesenchymal tumor (VMT), a primitive mesenchymal neoplasm enriched by various-sized atypical vessels, is a new entity that develops in mediastinal germ cell tumors (GCTs) with yolk sac tumor (YST) components after chemotherapy. Notably, patients with VMT in the residual GCT have increased risk of developing sarcomas or hematopoietic malignancies. Here, we report a late-teenage male patient with residual teratoma and high-grade VMT after chemotherapy for a mediastinal mixed GCT, including YST. Whole-exome sequencing revealed biallelic inactivation of TP53 and extensive copy number alterations that suggested whole-genome doubling. The biopsy tissue of the mixed GCT before chemotherapy exhibited overlapping genetic alterations to those in the VMT. Immunohistochemical analyses of the VMT showed that the abnormal vessels were positive for cytokeratin, glypican 3, EZH2, and IMP3. The findings that VMT inherits the genetic alterations of pre-existing mixed GCT and exhibits a partly YST-like immunophenotype might contribute to its clinical aggressiveness.

Successful surgical management of massive hemoretroperitoneum caused by spontaneous rupture of retroperitoneal lymph node metastases in a patient with advanced mixed germ cell tumor: a COVID-19 pandemic-related surgical challenge

BackgroundSpontaneous rapture of a germ cell tumor (GCT) metastases causing massive hemoretroperitoneum in a patient without choriocarcinoma component who has not received previous systemic chemotherapy is an exceedingly rare event. In such a devastating case scenario, a high index of clinical suspicion for early diagnosis and appropriate management is crucial.Case presentationWe report on a 25-year-old male patient with a 4-month history of orchiectomy for testicular GCT (tGCT), who presented in the emergency department with acute abdomen and hemodynamic instability. Urgent computed tomography scan depicted a retroperitoneal mass measuring approximately 13 × 11.4 × 15 cm and massive intraperitoneal hemorrhage. Hemoperitoneum caused by spontaneous rapture of the metastatic retroperitoneal mass was suspected. COVID-19 pandemic-related deviation from the oncologic surveillance standards combined with COVID-19-related patient’s emotional distress and self-neglect had led to loss of opportunity for appropriate adjuvant chemotherapy, obviously leading to the development of this devastating complication. An emergency, surgical exploration was decided. The bleeding mass was adequately exposed following a Cattell–Braasch maneuver and active bleeding was controlled by a challenging resection of approximately 80% of the lymph node mass volume. Pathological evaluation of the specimen revealed teratoma with low volume of yolk sac tumor component and extensive necrosis, findings compatible with the patient’s history. Postoperative recovery was uneventful, followed by early start of adjuvant chemotherapy. Two years after the operation the patient is doing well with no evidence of recurrent disease.ConclusionsMassive hemoperitoneum is a devastating event that exceedingly rarely can complicate the clinical course of patients with advanced tGCT. Emergency surgical intervention is usually necessary however, sound judgement and careful surgical techniques are required for a positive and uneventful outcome. During COVID-19 pandemic, first-line medical personnel push their limits further not only to ensure health care services standards but also, to manage unpredictable, life-threatening cancer-related complications, associated with COVID-19-related deviation from appropriate oncologic surveillance and care.

Synchronous Bilateral Testicular Tumors with Different Histology: Case Report and Review of Literature

Abstract Introduction/Objective Germ cell tumor (GCT) is the most common cancer among males in the 20–39 year-old age range, representing 21% of invasive cancer diagnoses. Majority of bilateral testicular tumors are metachronous. The synchronous tumors comprise approximately 0.5%-1% of all cases. Most of the synchronous tumors share the same histologic pattern, predominantly seminoma. The synchronous bilateral testicular GCTs (SBTGCTs) with discordant subtypes are extremely rare. Methods/Case Report A 26-year-old male presented with left testicular pain, the ultrasound revealed bilateral testicular masses with calcifications and microlithiasis in the right side. His serum markers showed elevated alpha-fetoprotein (AFP) and human chorionic gonadotrophin (HCG). Lactate dehydrogenase (LDH) was normal. He underwent bilateral orchiectomy. The pathology report showed a non-seminomatous mixed germ cell tumor, 2.0 cm in greatest dimension, predominantly embryonal carcinoma (90%), with a minor yolk sac tumor component (10%), lymphovascular invasion, Germ-cell neoplasia in situ (GCNIS) and calcifications in the left testicle, and a seminoma, 0.3 cm in greatest dimension with GCNIS and calcifications in the right testicle. The pathologic staging was pT2pNX for the left testicle and pT1pNX for the right testicle. Computed tomography (CT) revealed two mildly enlarged left sided para-aortic retroperitoneal lymph nodes. Radical pelvic lymph node dissection was performed. The pathology report showed four para-aortic lymph nodes positive for metastatic carcinoma. Tumor was positive for CD30 in the embryonal component, positive for Glypican-3 in the yolk sac tumor component, and seminoma was positive for PLAP. The final staging was IIB for the left testicle and IA for the right testicle. He underwent 4 cycles of Etoposide and Cisplatin chemotherapy (EP). He is in complete remission after 10 months of his diagnosis. Results (if a Case Study enter NA) NA. Conclusion The SBTGCTs with discordant subtypes represent a rare entity with no standard therapy. Our patient was treated with 4 cycles of chemotherapy and achieved complete remission.

Yolk Sac Tumor in a Recurrence of Colonic Adenocarcinoma With Shared Mutations in APC and TP53 Genes: A Case Report

Only four cases of colorectal adenocarcinoma with a yolk sac tumor (YST) component have been reported in the English literature. No genetic investigation has been performed in these cases. We report a case of colorectal adenocarcinoma in which the recurrent tumor had a YST component. A 49-year-old woman presented with a pelvic tumor three years after endoscopic mucosal resection of sigmoid colon adenocarcinoma. The pelvic tumor consisted of an undifferentiated carcinoma component and a YST component. The serum alpha-fetoprotein level was elevated to 42 ng/mL. Treatment as conventional colorectal carcinoma produced some anticancer effects, but the patient died 14 months after the recurrence and 49 months after the EMR. With the help of the next-generation sequencing results of the recurrent tumor, APC c.835 - 8A > G and TP53 c.524G > A (p.R175H) mutations were identified by direct sequencing in both the primary and the recurrent tumors, confirming the relationship between the two metachronous tumors.

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.

Malignant Mixed Germ Cell Tumor of the Testis with Associated Nephroblastoma: A Rare Entity

Abstract Introduction/Objective While nephroblastoma is the most common primary childhood renal malignancy, it rarely occurs at extra-renal sites. Testicular nephroblastoma is exceedingly rare, with only 5 previously reported cases arising in association with primary testicular teratoma (4 of which arising in non-atrophic, and 1 arising in atrophic testis). We report a case of testicular nephroblastoma with multiple associated germ cell components. Methods/Case Report The case is that of a 28-year-old male presenting with an enlarging, painless right scrotal swelling. Laboratory results showed elevated serum AFP with normal LDH and beta-HCG, and imaging confirmed the presence of a heterogenous testicular mass. A radical orchiectomy was performed, revealing a tan-white, fleshy, nodular 5.5 cm mass almost entirely replacing the testicular parenchyma. Microscopically, the tumor consisted of multiple components. The nephroblastoma component was associated with teratoma with immature elements and consisted of epithelial tubular structures, small blue blastemal cells, and pale mesenchymal stroma which demonstrated pan-cytokeratin and patchy WT1 expression by immunohistochemistry. Additional components included yolk sac tumor and minor component of seminoma. Foci of germ cell neoplasia in-situ were also identified, supported by immunohistochemical stains for PLAP and OCT3/4. The patient’s post-resection tumor markers normalized, and further assessment for metastasis and chemotherapy is pending. Results (if a Case Study enter NA) NA Conclusion Malignant mixed germ cell tumors of the testis with associated nephroblastoma are exceedingly rare, further studies nand followup are required to determine prognostic values and achieve a more complete understanding of this combination of entities.

Primary hepatic mixed germ cell tumor in an adult.

Primary hepatic mixed germ cell tumor (GCT) is very rare, and less than 10 cases have been reported. We report a case of mixed GCT composed of a choriocarcinoma and yolk sac tumor, which occurred in the liver of a 40-year-old woman. A large mass was detected by computed tomography solely in the liver. Serum β-human chorionic gonadotropin (hCG) was highly elevated, otherwise, other serum tumor markers were slightly elevated or within normal limits. For hepatic choriocarcinoma, neoadjuvant chemotherapy was administered, followed by right lobectomy. Histologic features of the resected tumor revealed characteristic choriocarcinoma features with diffuse positivity for hCG in the syncytiotrophoblasts and diffuse positivity for α-fetoprotein and Sal-like protein 4 in the yolk sac tumor components. Primary malignant GCT in the liver is associated with a poor prognosis and requires specific treatment. Therefore, GCT should be considered during a differential diagnosis of a rapidly growing mass in the liver.

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.

Surgical challenges of excision of retroperitoneal germ cell tumors in children: a single institutional study with literature review

BackgroundRetroperitoneal germ cell tumors (GCTs) are rare, commonly large tumors, often diagnosed in infancy. Complete surgical resection may pose a serious challenge as encasement of major vessels and organ displacement can lead to perioperative complications. This study aims to illustrate the surgical challenges of excising retroperitoneal GCTs.ResultsNine patients were included: six patients with a teratoma, two patients with a mixed GCT with a yolk sac tumor component, and one patient with a pure yolk sac tumor. Six were males and seven were younger than 1 year of age at time of presentation. In all cases, perioperative vascular or organ-related complications occurred in one patient; this resulted in short bowel syndrome. There was no recurrence or mortality during the follow-up period. Relevant literature is reviewed and described.ConclusionsThe anatomical relation of a retroperitoneal GCT to the major vessels and organs is unpredictable. Preoperative radiological evaluation can help to improve the understanding of the vascular anatomy and to plan accordingly. Anteriorly displaced veins may appear insignificant and arteries, such as the superior mesenteric artery may be encased. Preoperative imaging may prevent perioperative complications, leading to safer surgical procedures.Level IV evidenceTherapeutic study

Surveillance alone in stage I malignant ovarian germ cell tumors: a MITO (Multicenter Italian Trials in Ovarian cancer) prospective observational study

ObjectiveThe aim of this study was to analyze the oncological outcome of stage I malignant ovarian germ cell tumors patients included in the MITO-9 study to identify those who might...

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.

Establishment and characterisation of testicular cancer patient-derived xenograft models for preclinical evaluation of novel therapeutic strategies

Testicular cancer (TC) is the most common solid tumour in young men. While cisplatin-based chemotherapy is highly effective in TC patients, chemoresistance still accounts for 10% of disease-related deaths. Pre-clinical models that faithfully reflect patient tumours are needed to assist in target discovery and drug development. Tumour pieces from eight TC patients were subcutaneously implanted in NOD scid gamma (NSG) mice. Three patient-derived xenograft (PDX) models of TC, including one chemoresistant model, were established containing yolk sac tumour and teratoma components. PDX models and corresponding patient tumours were characterised by H&E, Ki-67 and cyclophilin A immunohistochemistry, showing retention of histological subtypes over several passages. Whole-exome sequencing, copy number variation analysis and RNA-sequencing was performed on these TP53 wild type PDX tumours to assess the effects of passaging, showing high concordance of molecular features between passages. Cisplatin sensitivity of PDX models corresponded with patients’ response to cisplatin-based chemotherapy. MDM2 and mTORC1/2 targeted drugs showed efficacy in the cisplatin sensitive PDX models. In conclusion, we describe three PDX models faithfully reflecting chemosensitivity of TC patients. These models can be used for mechanistic studies and pre-clinical validation of novel therapeutic strategies in testicular cancer.

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.