A rare case of gestational ovarian choriocarcinoma coexistent with intrauterine pregnancy.

OBJECTIVE: To report the rare case of gestational primary ovarian choriocarcinoma coexistent with intrauterine pregnancy, successfully treated with surgery and systemic chemotherapy. We also describe the utility of short tandem repeat (STR) genotyping in the diagnosis of choriocarcinoma. CASE REPORT: A 38-year-old woman at 17 gestational weeks presented with an ovarian tumor rupture in the left ovary. Left salpingo-oophorectomy was performed and the patient was diagnosed with gestational ovarian choriocarcinoma via histopathology and STR genotyping. After artificial abortion, the patient underwent 8 cycles of chemotherapy. Abdominal hysterectomy was performed because of the presence of low levels of human chorionic gonadotropin and the tumor that developed behind the uterus. However, no viable choriocarcinoma cells were found in the residual tumor, suggesting that the patient achieved full remission. CONCLUSIONS: Early detection is crucial in treating choriocarcinomas; thus, clinicians should consider the possibility of choriocarcinoma at the presence of an ovarian tumor during pregnancy. Gestational and non-gestational choriocarcinomas differ in prognosis and sensitivity to chemotherapy due to their different etiologies. Therefore, STR genotyping may be beneficial in predicting the patient's prognosis or selecting the appropriate regimen.

Frequent EGFR expression/EGFR amplification and lack of activating mutation in testicular choriocarcinoma.

Choriocarcinoma (CC) is the rarest but most aggressive histological component of adult testicular germ cell tumor (TGCT). Although we previously reported a putative role of epidermal growth factor receptor (EGFR) alterations in the progression of CC, little is known about the kinase-activating mutation status of EGFR, which predicts the response to EGFR-tyrosine kinase inhibitors. In this study, we clinicopathologically reviewed a total of 12 cases of mixed TGCTs with CC components. Immunohistochemistry, fluorescence in situ hybridization, and direct sequencing was performed to investigate EGFR expression, EGFR copy number alterations, and functional mutation of EGFR in these CC components, respectively. Four (33%) of 12 cases exhibited predominant CC components (>50%), and all these patients died due to disease within 62 months. Overexpression of EGFR, higher copy number of EGFR, and amplification of EGFR was observed in 12 (100%), 10 (83%), and 9 (75%) of 12 CC components, respectively. None of the cases showed any mutational events in exons 18 to 24, which encode the tyrosine kinase domain of EGFR. These results confirm an important role of EGFR in the tumor aggressiveness of testicular CCs and may suggest its possible innate resistance against conventional anti-EGFR therapies.

Ovarian Intermediate Trophoblastic Tumors: Genotyping Defines a Distinct Category of Nongestational Tumors of Germ Cell Type.

Trophoblastic neoplasms involving the ovary are uncommon and include gestational tumors, which are either metastatic from the uterus or ectopic and nongestational tumors, which include those of germ cell type/origin and somatic tumors with trophoblastic differentiation; in all these types, most are pure choriocarcinoma. Intermediate trophoblastic tumors, which include placental site trophoblastic tumor (PSTT) and epithelioid trophoblastic tumor (ETT), are rare in the ovary, with most assumed to be gestational; this is the only category formally recognized in 2014 World Health Organization (WHO) classification, likely due to few well-documented nongestational examples. We report the clinicopathologic features of 6 ovarian intermediate trophoblastic tumors, including 3 PSTTs, 2 ETTs, and 1 ETT with choriocarcinomatous differentiation. DNA-based short tandem repeat genotyping identified 4 of these as nongestational (3 PSTTs and 1 ETT), as evidenced by sharing of alleles between tumor and normal tissue at all informative loci. Interestingly, all 3 of the nongestational PSTTs coexisted with mature cystic teratoma. The remaining 2 tumors (1 ETT and 1 ETT with some choriocarcinomatous differentiation) were gestational (likely ectopic due to lack of evidence of a uterine tumor), as evidenced by the presence of both maternal and novel/nonmaternal alleles at informative loci in tumor compared with normal tissue. It is important to recognize a distinct category of primary ovarian nongestational intermediate trophoblastic tumors of germ cell type/origin, including PSTT and ETT, in classification systems to guide clinical management, as gestational and nongestational tumors have different genetic origins and may require different therapy. Genotyping is useful for classification as nongestational versus gestational, particularly as traditional clinicopathologic findings cannot always predict the nature of a trophoblastic tumor.

Fluorescence In Situ Hybridization for the X and Y Chromosome Centromeres Helps Differentiate Between Gestational and Nongestational Choriocarcinoma in Clinically Ambiguous Cases.

CONTEXT.­: Gestational choriocarcinoma usually presents during the reproductive years, typically within 1 year of pregnancy, although presentation remote from pregnancy also occurs and may cause confusion with other tumors, including choriocarcinoma of germ cell origin and somatic carcinomas with choriocarcinomatous differentiation. It is important to separate these tumors for treatment and prognostic reasons. OBJECTIVE.­: To assess the utility of fluorescence in situ hybridization for the X and Y chromosome centromeres in determining the gestational origin of clinically ambiguous extrauterine choriocarcinomas in women. DESIGN.­: A review of female patients with extrauterine choriocarcinomas who had no evidence of prior gestational trophoblastic disease was performed. Samples were analyzed by fluorescence in situ hybridization for the X and Y chromosome centromeres using standard methodologies. RESULTS.­: Five cases met the criteria, all of which displayed trophoblastic cells and necrosis. Three cases (60%) had Y chromosomes by fluorescence in situ hybridization, which confirmed gestational origin. Although the 2 cases without a Y chromosome would ordinarily require molecular genotyping for paternal genetic material to establish gestational origin, in one of these cases a subsequent recurrence of yolk sac tumor allowed confirmation of its mediastinal origin. CONCLUSIONS.­: Fluorescence in situ hybridization for detection of the X and Y chromosome centromeres is an effective screening test for gestational choriocarcinoma. It provided a definitive diagnosis of metastatic gestational choriocarcinoma in 3 of 5 potential cases that lacked a clinical history of gestational trophoblastic disease. An additional benefit is that more laboratories have the capability to perform fluorescence in situ hybridization than can perform molecular genotyping for definitive diagnosis.

Using short tandem repeat analysis for choriocarcinoma diagnosis: a case series.

BACKGROUND: Choriocarcinoma is a highly aggressive, malignant trophoblastic neoplasm that can be gestational or non-gestational in origin. Accurate discrimination between these two subtypes, the causative pregnancy type, and the pregnancy-to-treatment interval for gestational choriocarcinoma are vital for clinical management. METHODS: Fifteen choriocarcinomas were genotyped using multiplex fluorescent polymerase chain reaction amplification of 15 short tandem repeat (STR) loci and the amelogenin locus (XY determination). Genotype patterns at each locus from tumoral and maternal tissues were compared, and any prior or concurrent mole/placenta was also compared when available. According to STR results showing the presence or absence of the paternal chromosomal complement, the gestational or non-gestational origin of the tumor and the nature of the causative pregnancy was identified. RESULTS: Fourteen tumors were gestational. Of these, seven were androgenetic/homozygous XX, and two were androgenetic/heterozygous XX, indicating that the causative pregnancies were molar pregnancies. Among the nine molar pregnancies, five were of the occult type. A menopausal patient developed a tumor from a mole that occurred seven years ago, identified by the genetically identical allele from the tumor and prior mole. One tumor originating from a previous mole was interrupted by term delivery. Two tumors found eight weeks postpartum were identified as originating from a prior occult mole. A pelvic choriocarcinoma was separated from a genetically distinct third trimester intrauterine placenta. Five gestational tumors were biparental: 2 XX, 3 XY. Of three ovarian tumors, two were confirmed gestational (1 androgenetic/homozygous XX; 1 biparental XY), and one was an ovarian tumor (XX) with a complete match of the genotype for all 15 loci, therefore ascertaining its non-gestational origin. CONCLUSION: Gestational choriocarcinoma can originate in an androgenetic or biparental manner. The majority are androgenetic/homozygous XX, while a large number of them might be occult molar pregnancies. The origin of ectopic androgenetic choriocarcinoma with concurrent intrauterine placenta might be from either dispermic twin gestation (mole and coexistent nonmolar fetus) or an antecedent molar pregnancy. Choriocarcinoma shortly postpartum might not be associated with the last placenta. STR analysis can be useful in distinguishing gestational choriocarcinoma from non-gestational, as well as the causative pregnancy, and serve as a helpful examination tool for guiding clinical management.

[Testicular germ cell tumors: Histopathological and molecular features]. / Tumeurs germinales du testicule : caractéristiques histopathologiques et moléculaires.

In 2016, the WHO classification of testicular germ cell tumors was revised considering advances in the understanding of their tumorigenesis and molecular features. This restructuring led to a division into two major groups with, on one hand, prepubertal-type tumors, not derived from germ cell neoplasia in situ (GCNIS), and on the other hand, postpubertal-type tumors, GCNIS-derived, which occur in youg men (seminoma and non seminomatous germ cell tumors - embryonal carcinoma, yolk sac tumor, teratoma and choriocarcinoma essentially). The term germ cell neoplasia in situ is consensually accepted as a new terminology for the precursor lesion. In this new classification, the term "spermatocytic seminoma" is replaced by "spermatocytic tumor", reclassified among non-GCNIS-derived tumors. The purpose of this change of nomenclature is to reflect the usually non-aggressive behaviour of this tumor and to avoid any confusion with usual seminoma. The spectrum of trophoblastic tumors continues to expand with the description of new rare entities such as the cystic trophoblastic tumor, the placental site trophoblastic tumor and the epithelioid trophoblastic tumor. This review aims to provide a focus on testicular germ cell tumors highlighting the new immunohistochemical and molecular features responsible for the restructuring of classification. The TNM staging is presented according to the AJCC 8th edition 2017 update.

Short tandem repeat analysis for confirmation of uterine non-gestational choriocarcinoma in a postmenopausal Taiwanese woman.

RATIONALE: Rare uterine choriocarcinoma can be differentiated gestational from nongestational choriocarcinoma by using short tandem repeats (STRs). PATIENT CONCERNS: A 56-year-old Taiwanese woman underwent staging surgery because of suspicion of high-grade endometrial cancer. The pathology-confirmed uterine tumor with syncytiotrophoblasts and decidual change of the endometrium was harvested. DIAGNOSIS: Uterine nongestational choriocarcinoma. INTERVENTIONS: The tumor specimen, the patient's blood, and her husband's blood were drawn for STRs analysis using polymerase chain reaction amplification kit. The genotype of the tumor cells was solely maternal and made the diagnosis of uterine nongestational choriocarcinoma. OUTCOME: Adjuvant chemotherapy with etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine regimen achieved good response in the patient. The patient is now recurrence-free for 12 months. LESSONS: STRs aid precise classification of rare choriocarcinoma. We encourage using the method to analyze suspicious choriocarcinoma.

Choriocarcinoma in Women: Analysis of a Case Series With Genotyping.

Choriocarcinoma is an uncommon malignant neoplasm, which can be either gestational or nongestational in origin. Distinction of these subtypes has prognostic and therapeutic implications. Twenty-two tumors were genotyped using polymerase chain reaction amplification of 15 short tandem repeat loci and the amelogenin locus (XY determination). DNA patterns from tumor and maternal tissue, as well as villous tissue from any available prior or concurrent gestation, were compared, to determine gestational versus nongestational nature (containing vs. lacking a paternal chromosome complement, respectively) and the relationship between the tumor and any prior or concurrent gestation. Nineteen tumors were gestational. Of these, 14 were purely androgenetic/homozygous XX: 6 uterine tumors with a concurrent or prior genetically related complete hydatidiform mole (CHM), 4 uterine tumors without an accompanying villous component, 1 uterine cornual tumor separate from a genetically distinct second trimester intrauterine placenta, 1 ectopic ovarian tumor separate from a genetically distinct third trimester intrauterine placenta, and 2 ectopic fallopian tube tumors. Five gestational tumors were biparental: 3 (2 XX, 1 XY) intraplacental choriocarcinomas genetically related to the placenta and 2 uterine tumors without accompanying placental tissue after term deliveries (1 XX 4 weeks postpartum and 1 XYY with allelic imbalances 1 year postpartum; prior placentas not available for analysis). Three tumors were nongestational: all XX with allelic imbalances; 2 ovarian, 1 pelvic. Gestational choriocarcinoma can be androgenetic or biparental. Most are androgenetic/homozygous XX, often associated with a genetically related concurrent or prior CHM, and thus of molar-associated type. These findings support that homozygous XX CHMs are associated with some risk of significant gestational trophoblastic disease. Intraplacental choriocarcinomas are biparental and genetically related to the placenta. Biparental choriocarcinoma detected in a postpartum uterine sample is consistent with undetected intraplacental choriocarcinoma. Eutopic or ectopic androgenetic choriocarcinoma separate from a concurrent intrauterine placenta is not derived from intraplacental tumor and is consistent with either a form of dispermic twin gestation (molar-type choriocarcinoma and coexistent nonmolar fetus) or origin from an antecedent molar pregnancy. While fallopian tube tumors are usually gestational, tumors in other sites (ovary, pelvis) can be nongestational and should not be assumed to be metastatic from a regressed or occult intrauterine or intraplacental gestational tumor.

Genomic profile in gestational and non-gestational choriocarcinomas.

INTRODUCTION: Gestational (GC) (derived from the placenta) and non-gestational (NGC) choriocarcinomas are trophoblastic diseases originated from abnormal proliferation of trophoblastic cells. These rare tumors share similar morphology and pathological features and differ on chemotherapy response, genetic origin and prognosis. In this study, the genomic profile of choriocarcinomas was performed according to their origin (GC or NGC) aiming to better understand these poorly characterized diseases. METHODS: Thirteen patients were included in this study; 10 presented previous history of hydatidiform mole and six developed metastasis. Twelve polymorphic microsatellite markers (D15S659, APOC2, D5S816, BAT25, D3S1614, D3S1311, D1S1656, APC-D5S346, D3S1601, D18S70, D8S1110 and D11S1999) were investigated to distinguish GC from NGC. All choriocarcinomas were evaluated by copy number alterations using array CGH. RESULTS: Eight cases were classified as GC and five as NGC. Although potentially polymorphic, NGC exhibited significant gain of 21p11. Rare copy number alterations (CNA) were detected as a frequent event in GC including gains of 1p36.33-p36.32 (3 cases), 17q25.3 (4 cases), and losses of 9q33.1 (5 cases), 17q21.3 (3 cases) and 18q22.1 (4 cases) (varying from 724 to 3,053 Kb). DISCUSSION: Two tumor suppressor genes are candidates to be involved in GC: TRIM32 (9q33.1) and CDH19 (18q22.1). Gains of CBX2, CBX4 and CBX8 were frequently found in high risk prognostic score in GC. The in silico functional interaction analysis revealed the involvement of PTEN and PI3K-Akt signaling pathways. These data pointed out significant genomic alterations in GC, opening new avenues to better characterize the pathobiology of this disease.

Primary Choriocarcinoma of the Bladder: A Case Report and Review of Literature.

Primary choriocarcinoma of the urinary bladder is a rare entity, and should be distinguished from urothelial carcinoma with trophoblastic differentiation. The leading treatment modalities include surgical extirpation, chemotherapy, and radiation; however, survival remains poor. Herein we describe a rare case of choriocarcinoma of the bladder in a man who presented for evaluation with hematuria and subsequently underwent radical cystectomy with urinary diversion. Diagnosis of extragonadal germ cell tumor was confirmed using fluorescence in situ hybridization identification of isochromosome 12p.

Ovarian nongestational choriocarcinoma and associated adenocarcinoma with the same germ cell origin determined by a molecular genetic approach: A case report.

Ovarian non-gestational choriocarcinomas co-existing with adenocarcinoma are extremely rare and have been reported as epithelial ovarian carcinomas of a "non-germ cell origin" with "choriocarcinomatous differentiation". Although the cellular origin of non-gestational choriocarcinoma may be post-meiotic ovarian germ cells or the dedifferentiation of epithelial ovarian carcinoma, detailed genetic evidence has not yet been obtained to support this. We herein present a case of ovarian non-gestational choriocarcinoma co-existing with adenocarcinoma in a 29-year-old woman. The tumor rapidly increased in size and lung metastases appeared soon after parturition. We genetically demonstrated that the cellular origin of ovarian non-gestational choriocarcinoma was a post-meiotic germ cell derivation using a short tandem repeat analysis. The co-existing adenocarcinoma component was also shown to be of the same germ cell origin. These tumors showed the same homozygous pattern. A molecular genetic approach may be important for understanding the clinicopathological features of such tumors.

Pure non-gestational choriocarcinoma arising in the ovary.

Non-gestational choriocarcinoma (NGCO) is a rare primary ovarian cancer with poor prognosis. It is important to distinguish it from gestational ovarian choriocarcinoma (GCO), because there are different treatment options. However, it is difficult to distinguish the two types by routine histologic, ultrastructural, or immunohistochemical examination. The authors present NGCO in a 41-year-old woman, which was confirmed by DNA polymorphism analysis. All tested microsatellite markers had identical DNA profiles with the same allelic sizes between tumor and normal myometrium of the patient, indicating that both tissues originated from the same person. The results confirmed that the tumor was non-gestational in origin. Although the tumor was large, the authors performed hand- assisted laparoscopic surgical (HALS) staging. After three cycles of combination chemotherapy and surgery, the patient has not had any evidence of disease 48 months after treatment. This case demonstrates the usefulness of HALS staging and DNA polymorphism analysis in NGCO.

Pure nongestational uterine choriocarcinoma in a postmenopausal Chinese woman confirmed with short tandem repeat analysis.

Nongestational choriocarcinomas have been observed in the ovaries but rarely the uterus in postmenopausal women. Choriocarcinomas of gestational and nongestational origin have distinct prognoses but cannot be distinguished with routine histologic examination. We report a case of nongestational uterine choriocarcinoma in a 62-year-old Chinese woman that was confirmed with short tandem repeat analysis.

Genotyping diagnosis of nongestational choriocarcinoma involving fallopian tube and broad ligament: a case study.

A 22 year-old G1P1 woman presented to the emergency room with clinical impression of "ruptured right adnexal mass" and underwent a right salpingo-oophorectomy to rule out ectopic pregnancy. Instead, gross and microscopic examination revealed a pure choriocarcinoma involving the right fallopian tube and broad ligament. On the basis of the patient's age, recent history of delivery, last menstrual period for 10 weeks, large tumor mass, and possible pelvic lymph node metastasis, the patient promptly started to receive 8 cycles of multiagent chemotherapy regimen with a working diagnosis of high-risk gestational choriocarcinoma. Subsequent DNA genotyping analysis showed that the tumor cells had an identical genetic profile to that of the normal tissue of the patient, therefore establishing a final diagnosis of nongestational choriocarcinoma. Six months after the initial presentation, a second surgery was performed to remove a persistent right para-adnexal mass, which showed only necrotic tissue upon microscopic examination. The patient received 1 additional cycle of multiagent chemotherapy. She was alive without evidence of recurrence 26 months after the initial diagnosis.

Molecular genetic analysis of nongestational choriocarcinoma in a postmenopausal woman: a case report and literature review.

Choriocarcinoma is a highly malignant tumor of trophoblastic origin. Most cases occur in association with preceding gestational events. However, on very rare occasions, nongestational choriocarcinoma arises from germ cell or trophoblastic differentiation in different types of carcinoma. This article reports the case of a 58-year-old woman with primary nongestational choriocarcinoma of the uterus that developed 19 years after her final pregnancy and 4 years after menopause. A total abdominal hysterectomy and bilateral salpingo-oophorectomy was performed. Histopathological examination showed choriocarcinoma of the uterus without components of other germ cell tumors. Karyotype analysis of the tumor cells demonstrated XX. We confirmed its nongestational origin by DNA polymorphism analysis at 15 short tandem repeat loci. After surgery, the patient was given four courses of combination chemotherapy. She is still alive and there has been no evidence of recurrence 3 years after surgery.

Pure non-gestational ovarian choriocarcinoma in a 45,XO/46,XX SRY-negative true hermaphrodite.

Non-gestational ovarian choriocarcinoma (NGCO) is an extremely rare malignant tumor with a poor prognosis and is difficult to distinguish from gestational choriocarcinoma. True hermaphrodite (TH) is genetically a heterogenous condition causing ovarian and testicular tissue development in the same individual. We report here the first case of pure NGCO in the right ovotestis of a 23-year-old 45,XO/46X,X sex-determining region Y chromosome (SRY)-negative TH. The diagnosis of non-gestational origin was confirmed by testing five short tandem repeats (STR). The patient responded well to radical surgery with bleomycin, etoposide, cisplatin (BEP) regimen. We also hypothesize that some mutations of an X-linked or autosomal gene lead to testicular determination in SRY-negative TH patients.

Ovarian choriocarcinoma as the first manifestation of 46,XY pure gonadal dysgenesis.

We report a case of 46,XY pure gonadal dysgenesis (Swyer syndrome) in a phenotypically normal 12-year-old girl with a history of vaginal bleeding and early breast development, with ovarian choriocarcinoma as the first manifestation. The clues leading to the diagnosis included the failure to establish any relationship between normal menstrual cycles postoperatively and a small remaining contralateral ovary. The correct diagnosis is important for cancer prophylaxis and hormonal replacement therapy. Prepubertal and peripubertal girls presenting with gonadal germ cell tumors should be carefully evaluated for the possibility of underlying gonadal dysgenesis. A history of vaginal bleeding or early signs of puberty does not exclude the diagnosis.

[Genetic genesis of choriocarcinoma].

OBJECTIVE: To distinguish choriocarcinoma from gestational or non-gestational choriocarcinoma and also identify the causative pregnancy of gestational choriocarcinoma by the genetic origin through molecular genetic analysis. METHODS: Twelve patients with choriocarcinoma, who had experienced surgery prior to chemotherapy were enrolled in this study. All 12 cases were diagnosed pathologically as choriocarcinoma. Peripheral venous blood samples and formalin-fixed paraffin-embedded blocks of choriocarcinoma tissue microdissected from haematoxylin and eosin-stained sections of tissue by microdissection method were available from the patient and (or) her husband. DNA was then prepared from the couples' blood samples and choriocarcinoma tissue by using standard techniques. PCR amplification and fluorescent microsatellite genotyping were performed by using DNA from the couples and captured choriocarcinoma tissues. The genetic contributions to the choriocarcinoma tissue were determined by comparing the fragments of genes from the choriocarcinoma tissue to those from blood samples of the couples. RESULTS: The primary lesion was ovary in 7 cases, but only 4 of them had the maternal contribution, indicating a non-gestational origin; the other three were gestational choriocarcinoma. The primary lesion was uterus in 5 cases, which were all gestational choriocarcinoma confirmed by genetic analyses. The causative pregnancies of the 8 cases with gestational choriocarcinoma were identified as androgenetic complete hydatidiform mole (AnCHM) in six cases and normal pregnancies in two cases, respectively. CONCLUSION: Microsatellite polymorphism analysis is a molecular approach for distinguishing the non-gestational choriocarcinoma from the gestational one, and also be used to identify the causative pregnancy of gestational choriocarcinoma.

Coexistence of a choriocarcinoma and a gonadoblastoma in the gonad of a 46,XY female: a single nucleotide polymorphism array analysis.

Females with 46,XY complete gonadal dysgenesis are at significant risk of developing germ cell tumors, mostly gonadoblastomas. We present here the case of 2 half-sisters, sharing the same father, diagnosed with 46,XY complete gonadal dysgenesis. The 1st sister developed a gonadoblastoma and an invasive dysgerminoma, whereas the 2nd sister developed a gonadoblastoma and an invasive choriocarcinoma within the same gonad. No SRY mutation, chromosome abnormalities, or mosaicism were detected in blood. Single nucleotide polymorphism (SNP) profiling of the choriocarcinoma revealed a complex hyperdiploid pattern with gains of 1 to 4 copies of material from several autosomes, as well as the loss of the Y chromosome and a homozygous SNP profile without copy number change for the X chromosome. Our results are in agreement with the recurrent chromosome gains and losses previously published in germ cell tumors, and the coexistence of both tumors within the same gonad suggests that choriocarcinomas may derive from gonadoblastomas.