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).

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.

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.

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.

Coexisting Epithelioid Trophoblastic Tumor and Placental Site Trophoblastic Tumor During Asymptomatic Relapse: A Case Report and Literature Review.

Gestational trophoblastic neoplasms are a group of trophoblastic tumors that include choriocarcinoma (CC), epithelioid trophoblastic tumors (ETTs), and placental site trophoblastic tumors (PSTTs). Mixed gestational trophoblastic neoplasms include combinations of CCs with ETTs and/or PSTTs; combinations of ETTs and PSTTs have also been described. This report describes the case of a 49-yr-old female with mixed ETT and PSTT discovered due to menstrual delay and a positive beta-human chorionic gonadotropin in serum 11 yr after normal pregnancy; it is an asymptomatic recurrence of the neoplasm after 2 yr. Moreover, only the ETT recurred without evidence of PSTT by biopsy and without any increase in human chorionic gonadotropin levels, even though human chorionic gonadotropin was positive in the first onset of the disease. We also reviewed published English literature, which revealed that there are only 36 cases of mixed trophoblastic tumors to date, of which pure mixed ETT and PSTT were reported only in four cases including our case. The most common combination is CC admixed with an ETT (52%), followed by CC with PSTT in 30.5%. CC admixed with an ETT and/or PSTT account for 83% of the cases, of which pure mixed ETT and PSTT were reported only in 4 cases (11%). The rarity of this condition entails reporting of all cases to facilitate future research and clinical management.

LPCAT1-TERT fusions are uniquely recurrent in epithelioid trophoblastic tumors and positively regulate cell growth.

Gestational trophoblastic disease (GTD) is a heterogeneous group of lesions arising from placental tissue. Epithelioid trophoblastic tumor (ETT), derived from chorionic-type trophoblast, is the rarest form of GTD with only approximately 130 cases described in the literature. Due to its morphologic mimicry of epithelioid smooth muscle tumors and carcinoma, ETT can be misdiagnosed. To date, molecular characterization of ETTs is lacking. Furthermore, ETT is difficult to treat when disease spreads beyond the uterus. Here using RNA-Seq analysis in a cohort of ETTs and other gestational trophoblastic lesions we describe the discovery of LPCAT1-TERT fusion transcripts that occur in ETTs and coincide with underlying genomic deletions. Through cell-growth assays we demonstrate that LPCAT1-TERT fusion proteins can positively modulate cell proliferation and therefore may represent future treatment targets. Furthermore, we demonstrate that TERT upregulation appears to be a characteristic of ETTs, even in the absence of LPCAT1-TERT fusions, and that it appears linked to copy number gains of chromosome 5. No evidence of TERT upregulation was identified in other trophoblastic lesions tested, including placental site trophoblastic tumors and placental site nodules, which are thought to be the benign chorionic-type trophoblast counterpart to ETT. These findings indicate that LPCAT1-TERT fusions and copy-number driven TERT activation may represent novel markers for ETT, with the potential to improve the diagnosis, treatment, and outcome for women with this rare form of GTD.

Urothelial carcinoma with trophoblastic differentiation: Reappraisal of the clinical implication and immunohistochemically features.

PURPOSE: To investigate the clinical implications of identifying urothelial carcinoma (UC) with trophoblastic differentiation (UCTD). MATERIALS AND METHODS: A prospective cohort study was performed from 2010 to 2016 to examine the incidence of UCTD in urinary tract cancer and association with clinicopathological indicators and patient outcome. RESULTS: UCTD was detected in 47 of 859 (5.5%) cases of UC of the bladder and 65 of 635 (10.2%) cases in the upper urinary tract. UCTD of the bladder was significantly associated with non-papillary, multiple, larger size ( > 3 cm), muscle invasion, and nodal metastasis (P ≤ 0.0001, respectively). A higher risk of recurrence (P = 0.005), progression (P < 0.0001), and patient death (P < 0.0001) was observed for UCTD than those with traditional, high-grade UC of the bladder. Among four patterns of expression, focal expression of ß-human chorionic gonadotropin was frequently detected in papillary tumor (P < 0.005) and UCs of smaller than 3 cm (P = 0.03). Significant indicators in predicting poor disease-specific overall survival in multivariate statistical model were tumor staging (P = 0.001), followed by non-focal ß-hCG expression (P = 0.049). CONCLUSION: UCTD is more often identified in the upper urinary tract than in the bladder. UCTD of the bladder was significantly associated with higher risk of recurrence, progression, and patient death. Expression of ß-hCG in non-focal patterns predicts a worse prognosis for patients with UCTD and deserves an individualized treatment planning.

Malignant tumours of the uterus and ovaries with Mullerian and germ cell or trophoblastic components have a somatic origin and are characterised by genomic instability.

AIMS: Tumours of the female genital tract with a combination of malignant Mullerian and germ cell or trophoblastic tumour (MMGC/T) components are usually diagnosed in postmenopausal women, and pursue an aggressive clinical course characterised by poor response to therapy and early relapses. These clinical features suggest that MMGC/T are somatic in origin, but objective molecular data to support this interpretation are lacking. This study evaluates the molecular features of nine MMGC/T, including seven tumours containing yolk sac tumour (YST), one tumour containing choriocarcinoma and one tumour containing epithelioid trophoblastic tumour. The objectives were to: (i) investigate whether MMGC/T show a distinct genetic profile and (ii) explore the relationship between the different histological components. METHODS AND RESULTS: Next-generation sequencing of paired samples demonstrated that the mutational profile of the Mullerian and non-Mullerian components of the tumour were almost identical in all cases. Moreover, the driver mutations identified were those expected in the specific subtype of Mullerian component present in each case. In contrast, variants expected in postpubertal germ cell tumours and gestational trophoblastic tumours were not identified, and FISH for i(12p) was negative in all cases tested. In this study, mismatch repair-proficient MMGC/T (eight of nine) were characterised by a complex copy-number variant profile, including numerous focal, regional, arm-level and chromosome-level events. CONCLUSIONS: Comparison of paired samples supports that the YST and trophoblastic tumour components of MMGC/T have a somatic origin and often show numerous copy-number variants, suggestive of underlying genomic instability.

[Epithelioid trophoblastic tumour with pulmonary metastasis]. / Cas clinique. Tumeur trophoblastique épithélioïde avec métastase pulmonaire.

Epithelioid trophoblastic tumours are rare kind of gestational trophoblastic disease. Their detection is made by repetitive measurement of ?HCG after any gestational period (including spontaneous abortion). Epithelioid trophoblastic tumour can cause pulmonary metastasis. We describe the clinical case of a 44-year old woman with a cystic lesion of the right pulmonary apex following a miscarriage which was an epithelioid trophoblastic tumour. She's still in complete remission after surgery and careful follow up.

Les tumeurs trophoblastiques épithélioïdes sont des maladies rares faisant partie des néoplasies gestationnelles trophoblastiques (comme le choriocarcinome et la tumeur trophoblastique du site placentaire, par exemple). Leur détection repose sur le suivi du taux de ?HCG post-grossesse ou post-fausse couche. Les tumeurs trophoblastiques épithélioïdes ont une propension à causer des métastases pulmonaires. Nous décrivons l'histoire d'une femme de 44 ans présentant une lésion kystique du poumon survenue dans les suites d'une fausse couche et s'avérant être une tumeur trophoblastique épithélioïde. Le suivi attentiste post-chirurgical constate un état de rémission complète prolongée.

Diagnóstico atípico de un tumor trofoblástico del lecho placentario: presentación de un caso y revisión de la literatura / Atypical diagnosis of a trophoblastic tumour of the placental bed: presentation of a case and review of the literatura

El tumor trofoblástico del lecho placentario es una de las formas más raras de neoplasia trofoblástica gestacional. Su manifestación clínica más típica es el sangrado vaginal anormal. Debido a su rareza no existe un tratamiento óptimo estandarizado. Presentamos un caso de tumor trofoblástico del lecho placentario con un diagnóstico atípico asociado a una hemorragia posparto que requirió histerectomía obstétrica de urgencia

Placental site trophoblastic tumour is a rare form of gestational trophoblastic disease. The most common clinical manifestation is abnormal vaginal bleeding. Due to its rarity there is no optimal standardised treatment. A case is presented of placental site trophoblastic tumour after an atypical diagnosis associated with a postpartum haemorrhage that required an emergency peri-partum hysterectomy

BRCA1 promoter hypermethylation in human placenta: a hidden link with ß-hCG expression.

Gestational trophoblastic diseases (GTD) are group of pregnancy-related tumors characterized by abnormal levels of 'ß-hCG' with higher incidence in South-East Asia, especially India. Our laboratory has reported that wild-type BRCA1 transcriptionally regulates ß-hCG in triple negative breast cancers (TNBCs). These factors culminated into analysis of BRCA1 status in GTD, which would emanate into elucidation of BRCA1- ß-hCG relationship and unraveling etio-pathology of GTD. BRCA1 level in GTD is down-regulated due to the over-expression of DNMT3b and subsequent promoter hypermethylation, when compared to the normal placentae accompanied with its shift in localization. There is an inverse correlation of serum ß-hCG levels with BRCA1 mRNA expression. The effects of methotrexate (MTX), which is the first-line chemotherapeutic used for GTD treatment, when analyzed in comparison with plumbagin (PB) revealed that PB alone is efficient than MTX alone or MTX-PB in combination, in showing selective cytotoxicity against GTD. Interestingly, PB increases BRCA1 levels post-treatment, altering DNMT3b levels and resultant BRCA1 promoter methylation. Also, cohort study analyzed the incidence of GTD at Sree Avittom Thirunal (SAT) Hospital, Thiruvananthapuram, which points out that 11.5% of gestational trophoblastic neoplasia (GTN) cases were referred to Regional Cancer Centre, Thiruvananthapuram, for examination of breast lumps. This has lend clues to supervene the risk of GTD patients towards BRCA1-associated diseases and unveil novel therapeutic for GTD, a plant-derived naphthoquinone, PB, already reported as selectively cytotoxic against BRCA1 defective tumors.

A Rare Case of Atypical Placental Site Nodule With an Emerging Intermediate Trophoblastic Tumor.

Placental site nodule (PSN) is a benign lesion composed of chorionic-type intermediate trophoblastic cells and is typically an incidental finding in uterine or endocervical curettage specimens. Epithelioid trophoblastic tumor (ETT) and placental site trophoblastic tumor (PSTT) are intermediate trophoblastic neoplasms of chorionic and implantation site types, respectively. ETT is speculated to be the neoplastic counterpart of PSN. The term atypical placental site nodule (APSN) has been proposed for PSN-type lesions displaying one or more concerning features, including larger size/more abundant lesional tissue, more extensive plaque-like growth, increased cellularity with more cohesive nests and cords of cells, a greater extent/distribution of necrosis, increased atypia, mitotic activity, and/or a Ki-67 proliferation index greater than usually encountered in the typical PSN. It has been proposed that APSN is an intermediary lesion between PSN and intermediate trophoblastic tumors, more commonly ETT but also PSTT. We report a case of a 39-yr-old woman who developed abnormal uterine bleeding 44 mo after her last recognized pregnancy. An endometrial curettage specimen demonstrated an APSN with some features concerning for an intermediate trophoblastic tumor. A hysterectomy specimen demonstrated residual APSN with foci consistent with emerging PSTT and ETT. This case illustrates the earliest form of PSTT and ETT arising in association with an APSN and supports interpretation of APSN as an intermediary lesion between typical PSN and intermediate trophoblastic tumors.