Ovarian non-gestational placental site trophoblastic tumor with lung metastasis: further evidence for a distinct category of trophoblastic neoplasm.

We previously described a series of cases which characterize a distinct group of primary ovarian placental site trophoblastic tumor (PSTT) and epithelioid trophoblastic tumor (ETT) as a non-gestational set consistent with germ cell type/origin. Here we report a new case of ovarian non-gestational PSTT. The patient was a 13 year-old young female admitted for a spontaneous pneumothorax of the left lung. The pathology of lung wedge excision specimen demonstrated metastatic PSTT and ovarian biopsy showed atypical intermediate trophoblastic proliferation which was found to be PSTT in the subsequent salpingo-oophorectomy specimen. In the ovary, the tumor was composed of singly dispersed or small clusters of predominantly mononuclear cells and rare multinucleated cells extensively infiltrating the ovarian parenchyma, tubal mucosa, and paraovarian/paratubal soft tissue. A minor component of mature cystic teratoma (less than 5% of total tumor volume) was present. Immunohistochemically, the neoplastic cells of main tumor were diffusely immunoreactive for hPL, Gata3 and AE1/AE3, and had only rare hCG-positive or p63-positive cells. The morphology and immunohistochemical results support a PSTT. Molecular genotyping revealed an identical genotype pattern between the normal lung tissue and the metastatic PSTT, indicating its non-gestational nature of germ cell type/origin. This case represents the first case of such tumor with distant (lung) metastasis. This case also provides further evidence to support our recommendation that primary ovarian non-gestational intermediate trophoblastic tumors of germ cell type/origin, including PSTT and ETT, should be formally recognized in classification systems.

Placental site trophoblastic tumor (PSTT): a case report and review of the literature.

Placental site trophoblastic tumor (PSTT), also known as atypical choriocarcinoma, syncytioma, chorioepitheliosis or trophoblastic pseudotumor, is a rare gestational trophoblastic disease (0.25-5% of all trophoblastic tumors) and it is composed by neoplastic proliferation of intermediate trophoblasts at placental implantation site. It consists of aggregates or sheets of large, polyhedral to round, predominantly mononucleated cells with a characteristic vascular and myometrial invasion. Main differential diagnoses are gestational choriocarcinoma (GC) and epitelioid trophoblastic tumor (ETT). We present a case of PSTT in a 25-year-old woman. Neoplastic cells showed moderate/high nuclear pleomorphism, abundant amphophilic, eosinophilic and clear cytoplasm, numerous mitotic figures (10 mitoses/10 HPF), and myometrial invasion. Other features are necrosis, vascular invasion with replacement of myometrial vessels by tumor cells and hemorrhage. The patient showed typical low serum ß-hCG levels and high serum humane placental lactogen (hPL) levels.

Epithelioid trophoblastic tumor: A case series.

An epithelioid trophoblastic tumor (ETT) is an extremely rare gestational trophoblastic tumor. Cases of ETT present with abnormal vaginal bleeding in women of reproductive age group with marginally elevated beta human chorionic gonadotrophin (B-hCG) levels. Here, we describe a series of four patients (all were females) including histomorphology, immunoprofiles, and diagnostic difficulty of this rare entity. All cases were in their reproductive age group. The mean pre-treatment hCG level was 665.24 (mIU/mL). Microscopically, all cases had a tumor showing an epithelioid appearance arranged in large nests and sheets. Individual tumor cells were round to polygonal with abundant eosinophilic cytoplasm, with central vesicular nuclei and prominent nucleoli. Areas of hemorrhage, necrosis, and intercellular hyaline-like material deposition were identified in all cases (100%). Immunohistochemically, tumor cells in all cases showed diffuse positivity for AE1/AE3 and p63 (100%). GATA3 was available in one case (25%), which was positive in the tumor cells. In one case (25%), hPL was focally positive, and in one case (25%), it was negative. SALL4 was performed in two cases (50%) and was negative in tumor cells. The mean Ki67 labeling index was 19.2 (range 10-30%). All four patients underwent surgical intervention and were treated with hysterectomy. The mean follow-up in this series was 39.4 months (range 6-70), and all patients are alive to date with a mean survival of 32.8 months (range, 4-67).

Epithelioid Trophoblastic Tumor Presenting as an Adnexal Mass: Report of a Diagnostically Challenging Case.

Epithelioid trophoblastic tumor (ETT) is a rare neoplasm derived from chorionic intermediate trophoblast cells, representing less than 2% of all gestational trophoblastic neoplasms. Classically, ETT presents as a uterine mass in women of reproductive age following a term pregnancy. The time from pregnancy to tumor development varies from months to several years. ETT most often arises in the endometrium, followed by the cervix. Extrauterine ETT are extremely infrequent, with few cases reported in the literature. We report a case of a 41-year-old woman, with history of three term pregnancies who presented with abdominal pain and elevated beta human chorionic gonadotropin (ß-hCG) level, ten years after her last pregnancy. Imaging reported a 3.5 cm adnexal mass, suspicious for ectopic pregnancy. Hysterectomy and mass resection revealed a 4.7 cm, tan-yellow, necrotic mass adjacent to the broad ligament. Histologic evaluation in conjunction with immunohistochemical stains revealed a tumor consistent with ETT. No connection to the endometrium was found grossly or microscopically. DNA fingerprinting analysis revealed the tumor to have two copies of paternal alleles, as seen in molar gestations. One of the primary differential diagnoses for ETT is squamous cell carcinoma due to similar morphologic features. In challenging cases, genetic analysis demonstrating paternally derived genes can establish the diagnosis. In this report, we discuss the challenges in the diagnosis of extrauterine ETT, due to its rarity and highly variable presentation, given that appropriate diagnosis is critical for correct patient management.

Non-choriocarcinomatous trophoblastic tumors of testis in postchemotherapy retroperitoneal lymph node dissections.

Non-choriocarcinomatous trophoblastic tumors (NCTTs) are seldomly diagnosed in male genital tract. As they have been recently described among the testicular germ cell tumor (TGCT) variants, pathologists' familiarity with their morphology is limited. We searched our electronic hospital records covering the years 2000-2017 for post-chemotherapy retroperitoneal TGCT metastectomies. Slides of all cases with viable tumor were retrieved from the archives and reviewed. Cases suspected of N-CTT morphologies were subjected to immunohistochemistry. Twelve NCTTs were identified, 9 of which were unseen or misdiagnosed by the original pathologists: Cystic trophoblastic tumor (CTT) (n = 5), placental site trophoblastic tumor (n = 2), epithelioid trophoblastic tumor (ETT) (n = 4), and coinciding PSTT + ETT (n = 1). Eight of these were associated with mature teratoma components, and one case (ETT) contained embryonal carcinoma and yolk sac tumor in addition to teratoma. Ten patients were clinically N1 at the time of primary tumor detection and orchiectomy. One patient had burned-out primary testicular tumor. Six patients were clinical M1a at presentation, while one male was cM1b. Six patients had mildly elevated ß-HCG (≤ 410 mIU/ml) just prior to retroperitoneal lymph node dissections (RPLND), while the others had normal ß-HCG levels. All patients had follow-ups ranging from 8 to 118 months (mean 42.3 months). Three patients died of disease-related and two of unrelated causes. In conclusion, because NCTTs are rare and newly described tumor types, their diagnosis is difficult and most of them are missed in post-chemotherapy RPLNDs. The majority of patients exhibit normal or slightly elevated ß-HCG levels. N-CTTs are usually accompanied by other components of TGCT, the most common being teratoma. Despite the high survival rate of the patients, our study points to the unpredictable evolution of NCTT cases, which may concur with a high-stage or progressive disease.

Cystic trophoblastic tumour of the testis: Case report.

Cystic trophoblastic tumor (CTT) is a rare non-aggressive germinative neoplasm from the group of non-choriocarcinomatous trophoblastic tumors, which is presented by cystic spaces lined with mononuclear degenerative-looking trophoblastic cells. CTT has been most often described as a residual disease in dissected retroperitoneal lymph nodes of patients with metastatic germ cell testicular tumours after chemotherapy. There were published only sporadic cases of primary testicular mixed germ cell tumour with CTT component. Hereby, the authors present a case of a 22-year-old man with a mixed germ cell tumour composed of postpubertal teratoma, embryonal carcinoma and CTT. Immunohistochemically, the CTT tumour cells were positive for cytokeratins (AE1/AE3, CK8/18), GATA3, p63 and focally also for beta-hCG and alpha-inhibin. CTT may be presented as a rare component of primary testicular mixed germ cell tumour and it represents very likely an evolutionary intermediate stage of transition from choriocarcinoma into teratoma during the process of regression.

O papel da ultrassonografia na doença trofoblástica gestacional / The role of ultrasonography in gestational trophoblastic disease

A doença trofoblástica gestacional (DTG) agrupa um conjunto de anomalias do desenvolvimento trofoblástico, que incluem formas clínicas benignas como a mola hidatiforme completa e parcial, o nódulo do sítio placentário atípico e o sítio trofoblástico exagerado, e malignas, caracterizando a neoplasia trofoblástica gestacional (NTG). De modo geral, seu diagnóstico precoce antecipa complicações clínicas que podem estar associadas a near miss obstétrico. Diante da suspeição clínica, é a ultrassonografia (US) precoce o exame de escolha pa ra o diagnóstico, associado à dosagem sérica de gonadotrofina coriônica humana, capaz de minimizar a ocorrência de complicações clínicas associadas à gravidez molar. Nos casos de NTG, é a US também de grande valia para estadiamento, avaliação de prognóstico e acompanhamento da mulher tratada para DTG. Este estudo faz uma revisão sobre o papel da US na DTG, sendo importante para familiarizar os tocoginecologistas com essa doença e salientar o papel da US consoante as melhores práticas clínicas.(AU)

Gestational trophoblastic disease (GTD) includes a set of trophoblastic developmental anomalies, which include benign forms such as complete and partial hydatidiform mole, atypical placental site nodule and exaggerated trophoblastic site, and malignant forms, characterizing gestational trophoblastic neoplasia (GTN). In general, its early diagnosis anticipates clinical complications that could be associated with obstetric near miss. In view of clinical suspicion, early ultrasonography (US) and serum levels of human chorionic gonadotropin are the best diagnostic screening techniques, able to minimizing the occurrence of medical complications associated with molar pregnancy. In cases of GTN, US is also of great value for staging, assessment of prognosis and follow-up of women treated for GTN. This study reviews the role of US in GTD, being important to familiarize tocogynecologists with this disease and highlight the role of US according to best clinical practices to minimize the morbidity of these patients and maximize the remission rates of this disease.(AU)

Analysis of the Outcome of Treatment of Brain Metastases from Malignant Trophoblastic Tumours and Risk Factors for Prognosis during Pregnancy.

Temozolomide combined with whole-brain radiotherapy has good near-term efficacy and safety in the treatment of brain metastases from nonsmall cell lung cancer. In this study, we analyzed the risk factors for treatment and prognosis of brain metastases in gestational trophoblastic neoplasm (GTN) during pregnancy. Thirty-one patients with brain metastases were included in the study. All patients had a pathological diagnosis of primary lesions, including 23 adenocarcinomas, 7 squamous carcinomas, and 1 adenosquamous carcinoma, and had ≥3 intracranial metastases, controlled primary lesions (including resected primary lesions or unresectable primary lesions in partial remission (PR)/complete remission (CR) for ≥2 months) by cranial enhancement MRI and no extracranial metastases. Presence or control of extracranial metastases was for ≥2 months. The common adverse toxic effects were nausea, vomiting, neutropenia, and thrombocytopenia, but most patients tolerated them with symptomatic management.

Clinical features and management of trophoblastic epithelioid tumors: A systematic review.

BACKGROUND: This study aimed to systematically review the existing literature on epithelioid trophoblastic tumors (ETTs), the rarest type of gestational trophoblastic neoplasia. METHODS: A systematic review according to PRISMA guidelines was performed, using ScienceDirect, Web of Science, and Scopus databases. The only filter used was the English language. Eligibility/inclusion criteria: retrospective observational studies (case reports, case series) including full case description of epithelioid trophoblastic tumor lesions. RESULTS: Seventy studies were assessed for synthesis, including 147 cases. 66.7% of patients with ETT presented with irregular vaginal bleeding. Pretreatment ß-hCG levels ranged up to 1000 mIU/mL in 58.5% patients. Of most patients, 42.2% had stage I disease, 10.9% stage II, 25.2% stage III, and 21.8% of patients had stage IV. The most common sites of metastatic disease were the lungs, followed by the liver and brain. After treatment, complete remission was achieved in 75.5% of patients, partial remission in 10.2% of patients, and 14.3% of patients died. On univariate and multivariate analyses, stage IV disease was an independent prognostic factor for overall and disease-free survival. CONCLUSIONS: Hysterectomy and metastatic lesion resection are essential for controlling ETT. Investigational studies on molecules like EGFR, VEGF, PD-1, CD105, and LPCAT1 are potential therapeutic targets for metastatic ETT.

Complete hydatidiform mole in higher-order multiple pregnancies.

Molar degeneration of the trophoblast is a rare, yet possible, complication of pregnancies. Complete hydatidiform mole is the most common histological type among all trophoblastic tumors and it is the result of the fertilization of an empty oocyte from two sperms or by one sperm that then duplicates. Complete mole is characterized by hydropic degeneration of abnormal chorionic villi, diffused trophoblast hyperplasia and the absence of identifiable embryonic or fetal tissue; the hyperplastic trophoblast justifies the common finding of high serum beta HCG levels. Twin molar pregnancy is an uncommon obstetric event, and even less frequent are triplet/quadruplet molar pregnancies. We hereby report a case of a complete hydatidiform mole with two coexistent fetuses in a triplet pregnancy after in vitro fertilization procedure; the pregnancy ended with a therapeutic abortion. During the follow-up, the serum beta human chorionic gonadotropin concentration started to rise, and the diagnosis of post-molar gestational trophoblastic neoplasia was made and consequently methotrexate treatment was started. Due to the rarity of this condition, there are no specific guidelines for the management of multiple pregnancies complicated by complete hydatidiform mole. We therefore performed a review of the literature including all reported cases of triplets/quadruplets pregnancies complicated by complete mole of a fetus focusing on ultrasound diagnosis, treatment and outcomes of this rare and life-threatening condition.

Recurrent Metastatic Choriocarcinoma Responsive to Etoposide and Cisplatin with Etoposide, Methotrexate, and Dactinomycin: A Case Report.

Choriocarcinoma is a malignant trophoblastic tumour usually of placental origin. It is characterized by early metastasis to the brain and lungs. With early detection, it has a better prognosis with treatment. We report a case of 18 years female at 26 weeks of gestation in her third pregnancy who had a history of treatment for metastatic gestational trophoblastic neoplasm with chemotherapy and radiotherapy two years back. Therefore, she was managed as a case of recurrent choriocarcinoma with brain metastasis with chemotherapy (etoposide and cisplatin with etoposide, methotrexate, and dactinomycin) and was responsive. Her symptoms resolved and ß-human chorionic gonadotropin dropped to normal value (<2.39 mIU/ml) which has shown that timely diagnosis and management can be vital for the successful treatment of brain metastasis. Keywords: chemotherapy; choriocarcinoma; metastasis; recurrence.

MALIGNANT TUMORS IN PEDIATRIC POPULATION OF UKRAINE: TRENDS AND STRUCTURAL FEATURES.

The creation of a central bank of personalized information of cancer patients, including children, allowed to obtain objective data and establish continuous cancer surveillance in the child population in Ukraine. The aim of the study was to analyze the dynamics of cancer incidence (1989-2019) and mortality (1999-2019) based on the 3rd revision of International Classification of Childhood Cancer (ICCC-3). MATERIALS AND METHODS: A study cohort includes 31,537 patients aged 0-19 years at the time of diagnosis in 1989-2019, registered in Ukrainian population. RESULTS: The major groups of malignancies in the child population are presented by leukemia, lymphomas, central nervous system (CNS) tumors, epithelial neoplasms, bone cancer and soft tissues sarcomas. There were observed no gender differences in cancer incidence, except germ cell tumors and trophoblastic tumors, gonadal malignancies, as well as some other malignant epithelial neoplasms, with their proportion being twice higher in the female population. Our analysis showed a trend towards increase in the incidence of leukemia, CNS neoplasms, neuroblastoma, trophoblastic tumors and epithelial malignancies; decrease in the incidence of lymphomas and bone neoplasms; stabilization in the incidence of malignancies of liver and kidneys. The dynamic changes in cancer mortality in the studied cohort were observed, namely, the decrease of mortality from leukemias and lymphomas in males (but not in females), along with the increase of mortality from CNS neoplasms, neuroblastoma, soft tissues sarcomas and germ cell tumors, regardless of gender. CONCLUSIONS: The analysis and presentation of the epidemiological data on children's malignancies implementing ICCC-3 classification for all relevant records in the National Cancer Registry of Ukraine allows for evaluating the major trends of cancer incidence and mortality in Ukrainian pediatric population, taking into account tumor morphology, topography, gender and age.

Bizarre Chorionic-type Trophoblast in Second-trimester and Third-trimester Placentas: Clinicopathologic Characterization of a Placental Pseudoneoplastic Lesion.

Bizarre (atypical/symplastic) cells have been described in various gynecologic normal tissues and benign neoplasms. This type of bizarre cytologic change is usually an incidental finding and is regarded as a benign process. We describe 17 cases of bizarre chorionic-type trophoblast in second-trimester and third-trimester placentas that created concern for an underlying/undersampled or incipient intraplacental trophoblastic neoplasm, predominantly found in intervillous trophoblastic islands (11/17), placental septae (6/17), chorionic plate (1/17), and/or the chorion layer of fetal membranes (2/17). The bizarre trophoblastic cells exhibited sheet-like or nested architecture, had a multifocal/patchy distribution, and/or were present as individual cells within hyaline stroma; they were characterized by large nuclei with smudgy chromatin and occasional intranuclear pseudoinclusions. The degree of atypia was classified as mild (0/17), moderate (3/17), or severe (14/17). Mitotic figures and necrosis were not identified. A dual immunohistochemical stain for trophoblast (hydroxyl-delta-5-steroid dehydrogenase) and a proliferation marker (Ki-67), performed in 15 cases, demonstrated 0% to very low proliferative activity within the bizarre trophoblast (0% to 2% [10/15], 3% to 8% [5/15]). Immunohistochemical stains for fumarate hydratase showed intact/retained expression in the bizarre cells in 7 of 7 cases. Clinical follow-up ranged from 1 to 45 months, and all patients were alive and well without subsequent evidence of a gestational trophoblastic or other neoplasms. We conclude that bizarre chorionic-type trophoblast in second-trimester or third-trimester placentas have the potential to mimic an intraplacental trophoblastic neoplasm but are likely a benign degenerative change. This study expands the spectrum of bizarre cells that occur in the gynecologic tract.

Case Report: Tubal Atypical Placental Site Nodule.

Placental site nodule (PSN) is a benign proliferation of chorionic-type intermediate trophoblastic cells that forms a tumor-like lesion. Most PSNs are intrauterine, but a few have been reported outside the uterus, including in fallopian tubes. PSN is related to epithelioid trophoblastic tumor (ETT) in that both are composed of chorionic-type intermediate trophoblastic cells, while ETT is hypercellular and contains trophoblastic cells with increased nuclear atypia and a higher Ki-67 proliferation index as compared with PSN. Occasionally, an intermediate stage between a PSN and an ETT is observed, and such a lesion is often recognized as an atypical PSN (aPSN) characterized by trophoblastic cells exhibiting morphologic features in transition from a conventional PSN to an ETT. aPSN has been thought to exhibit benign behavior; however, it has also been reported that up to 15% of aPSN lesions either coexist with, or subsequently develop into, ETT. To the best of our knowledge, there has been no case report of an aPSN in an extrauterine site. Here, we reported a highly unusual case of tubal aPSN, which illustrates several key features associated with PSN and its possible pathogenesis.

Placental Site Trophoblastic Tumor in a Pulmonary Vascular Malformation With Spontaneous Pneumothorax.

Placental site trophoblastic tumor, a rare variety of gestational trophoblastic disease, is traditionally limited to the uterus, found within the placental implantation site where it can lead to arteriovenous malformations. Gestational trophoblastic diseases are known to metastasize to the lungs, of which choriocarcinomas are the most common. However arteriovenous malformations related to such metastatic lesions are extremely rare. The occurrence of spontaneous pneumothorax in pulmonary arteriovenous malformations, under any circumstances, is rarely reported. Herein we report a rare case of metastatic placental site trophoblastic tumor found within pulmonary arteriovenous malformations uniquely presenting with spontaneous pneumothorax.