Fallopian Tube's Placental Site Nodule: A Case Report

Placental site nodule and characterization of distinctive types of intermediate trophoblast

Placental site nodules (PSNs) and epithelioid trophoblastic tumors (ETTs) respectively represent non-neoplastic and neoplastic lesions of chorionic-type intermediate trophoblasts (ITs). Many patients with a PSN have a history of a cesarean section (CS) or therapeutic abortion. Recent evidence shows that a PSN may progress to an ETT. Herein, we describe a coexisting ETT and placental site trophoblastic tumor (PSTT) intimately associated with PSNs in the post-cesarean lower uterine segment of a 41-year-old woman. The patient presented with abnormal vaginal bleeding 1 year after a cesarean delivery for her most recent pregnancy. We speculated that the neoplasms had transformed from PSNs, the formation of which was related to faulty expulsion of the placental tissue or abnormal colonization of chorionic-type ITs during the CS. Neoplastic trophoblastic cells derived from PSNs displayed differentiation plasticity toward chorionic-type ITs and implantation site ITs that were respectively constituted of an ETT and PSTT.Virtual slidesThe virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1597949195882123

An intermediate trophoblast is a distinctive trophoblastic cell population from which four trophoblastic lesions are thought to arise: exaggerated placental site (EPS), placental site nodule (PSN), placental site trophoblastic tumor (PSTT), and epithelioid trophoblastic tumor (ETT). EPSs and PSTTs are related to the differentiation of the intermediate trophoblast in the implantation site (implantation site intermediate trophoblast), whereas PSNs and ETTs are related to the intermediate trophoblast of the chorion laeve (chorionic-type intermediate trophoblast). EPSs and PSNs are nonneoplastic lesions, whereas PSTTs and ETTs are neoplasms with a potential for local invasion and metastasis. Microscopically, intermediate trophoblastic lesions can be confused with a variety of trophoblastic and nontrophoblastic tumors, but an appreciation of the morphologic features and immunophenotype allows their diagnosis to be relatively straightforward in most instances. Correct diagnosis is important because each of these lesions may require different therapeutic approaches.

Lesions of intermediate trophoblast arising in the uterus include exaggerated placental site, placental site nodule, placental site trophoblastic tumor (PSTT), and epithelioid trophoblastic tumor. Only 12 examples of extrauterine lesions of intermediate trophoblast (ELIT) have been previously reported; 7 new cases are described herein. Six lesions were located in the fallopian tube or paratubal region and one in the ovary. The patients were 25 to 47 (average 36) years of age. The lesions ranged from 0.6 to 4 cm in diameter; four were cystic. The four placental site nodules (three tubal, one paratubal) were composed of small, sharply circumscribed nodules of intermediate trophoblast with no mitotic activity. The three PSTTs (two tubal, one ovarian) exhibited irregular stromal infiltration by intermediate trophoblast, mitotic activity, and necrosis. Chronic salpingitis was seen in the six tubal/paratubal cases, and endometriosis was seen in four cases. Immunoreactivity for human placental lactogen, human chorionic gonadotropin, and cytokeratin in two cases was consistent with an origin from intermediate trophoblast. ELITs presumably arise from previous ectopic pregnancies, a history of which was present in two of these patients. Follow-up, available on two of the three patients with PSTT, was uneventful at 6 and 12 years, but study of additional cases is necessary to reliably determine the behavior of extrauterine PSTTs.

HLA-G is a nonclassical MHC class I antigen that has been shown to be a specific marker for normal intermediate trophoblast (IT). In this study HLA-G immunoreactivity assessed with an HLA-G specific antibody (4H84) was detected in all 14 cases of choriocarcinoma, 14 placental site trophoblastic tumors, 13 epithelioid trophoblastic tumors, 16 placental site nodules, and nine exaggerated placental sites. In contrast, HLA-G immunoreactivity was not detected in 34 nontrophoblastic uterine neoplasms. HLA-G immunoreactivity was present in all the IT cells of exaggerated placental sites and placental site trophoblastic tumors and in 70-100% of IT cells in placental site nodules and epithelioid trophoblastic tumors. The pattern of distribution of HLA-G in different subpopulations of IT confirms the relationship of various trophoblastic lesions to different types of IT (exaggerated placental site and placental site trophoblastic tumor to implantation site IT and placental site nodule and epithelioid trophoblastic tumor to chorionic-type IT) and suggests that choriocarcinoma is related to villous-type IT because the majority of mononucleate cells in this neoplasm were HLA-G immunoreactive. In conclusion, HLA-G immunoreactivity appears to be specific for IT in gestational trophoblastic disease and can serve as a useful marker in the differential diagnosis of these lesions.

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 nodules and plaques: a clinicopathological and immunohistochemical study of 25 cases with ultrastructural findings

The human placenta is an endocrine tissue with a unique capacity for rapid, but tightly controlled proliferation and invasion. Gestational trophoblastic diseases (GTD) are placental pathologies with endocrine activity and partially malignant potential and include hydatidiform moles (HM), placental site nodules (PSN) and tumors such as placental site trophobastic tuor (PSTT) and choriocarcinomas (CC). The AP-1 family of transcription factors (activating protein-1) is composed of the cellular homologs of the Jun and Fos oncoproteins, immediately involved in cellular proliferation, differentiation and invasion processes as well as in the regulation of endocrine genes. We have recently described the expression pattern of the AP-1 factors in the normal human placenta. Their systematic expression in GTD has not been studied so far. For this reason in the present study we investigated the expression pattern of AP-1 family in GTD and compared it to the expression in normal placenta by using immunohistochemistry with specific polyclonal antibodies against all members of the AP-1 family (JunB, JunD, c-Jun, c-Fos, FosB, Fra1, Fra2). Immunohistochemistry was performed on nomal human placentas (positive control) and on 20 cases of GTD including four choriocarcinomas, one PSTT, one PSN and fourteen hydatidiform moles. In the normal placenta and in hydatidiform molar samples most AP-1 factors (especially c-Jun, JunD and Fra2) were expressed in the intermediate (extravillous) trophoblast. In addition, in molar lesions strong expression was found in trophoblast proliferating from the surface of villi. There was only weak expression of JunB and Fra2 in small fractions of villous cyto- and sycytiotrophoblast nuclei. In choriocarcinomas, PSN and especially in PSTT there was a strong expression for c-Jun, JunD, Fra1 and Fra2. The specific localization to extravillous trophoblast and their expression pattern in GTD indicates that the AP-1 family of transcription factors is probably implicated in regulating proliferation and invasion of trophoblast.

Immunohistochemical expression of GATA-3 is seen predominantly in non-neoplastic bladder and breast epithelium and their respective carcinomas; however, data on expression in normal and lesional trophoblastic tissues are limited. Immunohistochemical staining for GATA-3 was assessed in a range of normal/lesional trophoblastic tissues and tumors in the differential diagnosis (n=445), including nonmolar products of conceptions/second and third trimester placentas/ectopic pregnancies, hydatidiform moles, placental site nodules, normal/exaggerated implantation sites, choriocarcinomas, epithelioid trophoblastic tumors, placental site trophoblastic tumors, atypical smooth muscle tumors (including leiomyosarcoma), and cervical and pulmonary squamous cell carcinomas. The extent of expression (0 to 4+) and intensity (weak to strong) were recorded. All cases with developing trophoblast/non-neoplastic trophoblastic proliferation and 81% of trophoblastic neoplasms were positive. Of all non-neoplastic trophoblast cell types, expression was observed in cytotrophoblast in 89% of cases, syncytiotrophoblast in 50%, intermediate trophoblast in 100%, and villous trophoblastic columns in 100%. Increasing gestational age was associated with a decrease in extent/intensity of expression in non-neoplastic cytotrophoblast and syncytiotrophoblast, whereas intermediate trophoblast maintained diffuse and strong expression from early to late gestation (P<0.0001). Eighty-nine percent of normal/exaggerated implantation sites showed 3+ or 4+ expression, whereas staining in 55% of placental site nodules was 1+ or 2+. Staining for GATA-3 was present in 78% of choriocarcinomas, 95% of epithelioid trophoblastic tumors, and 71% of placental site trophoblastic tumors. Although the number of choriocarcinomas and placental site trophoblastic tumors that showed a spectrum of expression ranging from negative to diffuse was relatively evenly distributed, 81% of epithelioid trophoblastic tumors had 3+ or 4+ staining. None of the atypical smooth muscle tumors and 3% of squamous cell carcinomas were positive, all of which exhibited weak staining. We conclude that GATA-3 is frequently expressed in normal and lesional trophoblastic tissues. It is also differentially expressed in intermediate trophoblast and cytotrophoblast/syncytiotrophoblast, which varies according to time during pregnancy. This study expands the spectrum of neoplasms known to express GATA-3. Thus, recognition of expression in trophoblastic tumors is important, because it can present a diagnostic pitfall in the assessment of suspected metastatic bladder or breast carcinomas involving the gynecologic tract. In the evaluation of diagnostically problematic tumors for which trophoblastic neoplasms are in the differential diagnosis, such as leiomyosarcoma and squamous cell carcinoma, GATA-3 can be included as part of an immunohistochemical panel particularly when other trophoblastic markers are either not available or yield ambiguous results.

Epithelioid trophoblastic tumor (ETT) is a relatively uncommon trophoblastic tumor that can be confused with several trophoblastic and nontrophoblastic lesions, notably the placental site nodule and invasive squamous carcinoma of the cervix. In this report, we analyzed the immunoreactivity of two cell cycle-regulated proteins, cyclin E and p16, in ETTs, placental site nodules and cervical squamous carcinomas to determine whether they are useful in their differential diagnosis. Other trophoblastic lesions were also evaluated. Using an H-score based on both percentage of positively stained cells and immunointensity, we found that ETTs demonstrated a much higher cyclin E staining score than placental site nodules (P<0.0001) permitting distinction of ETTs and placental site nodules with a sensitivity of 94.7% at a specificity of 91.7% using a cutoff H-score value of >40. Only two placental site nodules had scores above the cutoff and both showed morphologic features that placed them in an intermediate position between a typical placental site nodule and an ETT, so-called "atypical PSN." p16 immunoreactivity, was not detected in any of the ETTs and placental site nodules, whereas it was strongly and diffusely positive in the vast majority of cervical squamous carcinomas examined (83/87 cases) (P<0.001). Therefore, cyclin E expression is useful in distinguishing an ETT from a placental site nodule and p16 expression is useful in distinguishing an ETT from a cervical squamous carcinoma. The majority of other types of trophoblastic lesions showed diffuse and intense nuclear immunoreactivity for cyclin E whereas none were positive for p16.

The clinicopathological and immunohistochemical features of the second case of placental site nodule (PSN) of extrauterine, tubal location are presented. The lesion was incidentally found in the right tube during a cesarean section and eventual tubal ligation in a 23-year-old women gesta 2 para 1, after an uneventful 39-week intrauterine pregnancy. Grossly, the right Fallopian tube had a 1 cm dilatation filled by necrotic material. Microscopically, the lumen of the Fallopian tube was effaced and replaced by a rim of pleomorphic intermediate trophoblastic (IT) cells with pseudoinvasive parietal features which were positive for human placental lactogen, placental alkaline phosphatase, epithelial membrane antigen and CAM5.2. The Ki67 index was 3%. Due to its bizarre microscopic appearance, this lesion should be included in the differential diagnosis with malignant conditions. Both origins from a previous subclinical extrauterine tubal pregnancy and a possible migration of IT from a uterine implantation are considered.

Placental site nodule (PSN) is a benign lesion representing a nodular aggregate of intermediate trophoblast, embedded in a hyalinized stroma, thought to arise from noninvoluted placental site remaining from a past gestation. Uterus is the most common site of PSN. Occurrence in extrauterine sites is rare, with most examples being reported in the fallopian tubes. Here we report an example of PSN in the ovary. A 35-year-old woman, gravida 4, para 1, with history of adnexal ectopic pregnancy treated with methotrexate, at 39 weeks and 1 day of a subsequent pregnancy, underwent a scheduled C-section. The surgery was successful, and a healthy female infant was delivered. Intraoperative adnexal inspection revealed a small pedunculated mass on the right ovary, which was excised and sent for pathological examination. Gross inspection showed a soft, tan-white tissue fragment measuring 2.0 × 1.0 × 0.2 cm. Microscopic examination showed epithelioid cells with hyperchromatic, mildly atypical nuclei and abundant eosinophilic cytoplasm, embedded in a hyalinized stroma, forming a nodule. A diagnosis of placental site nodule was made. Immunohistochemical stains for keratin AE1/AE3, vimentin, and inhibin were strongly positive in the epithelioid cells, and immunostain for p63 was focally positive, supporting the diagnosis. PSN of the ovary is extremely rare. To our knowledge, there has been only one reported patient in the literature so far. Extrauterine PSNs are thought to arise from ectopic pregnancies. Our patient's ovarian PSN is most likely a consequence of her previous adnexal ectopic pregnancy, which was treated medically.

This report describes the clinical, histological, and immunohistochemical features of 38 cases of placental site nodule (PSN), a recently described lesion of intermediate trophoblast (IT). The patients ranged in age from 20 to 47 years (mean, 31.1 years). PSNs were diagnosed in endometrial (30 cases), endocervical (seven cases), and both endometrial and endocervical specimens (one case). The majority of biopsies were prompted by an abnormal Pap smear (13 cases) or complaints of menorrhagia (21 cases). All PSNs were microscopically detected, lobulated nodules composed of acellular, hyalinized material admixed with IT. Mitotic activity was noted in seven cases. Immunohistochemically, the IT expressed human placental lactogen (hPL) in 78% of cases and human chorionic gonadotropin (hCG) in 42% of cases, but their expression was weak and focal in contrast to uniform, strong staining for placental alkaline phosphatase (PLAP) (100%), cytokeratins (96%), and epithelial membrane antigen (EMA) (84%). Type IV collagen outlined the IT and stained the extracellular material in the cellular areas. Vimentin-positive cells within the lesions were fewer in number and in a different distribution than those expressing PLAP, CK, and EMA. Two consecutive PSNs occurred in one patient, but no patient developed gestational trophoblastic disease or a significant gynecologic neoplasm.

The CCAAT/enhancer-binding protein (C/EBP) family consists of several factors that are important regulators of intracellular processes and hormone action. C/EBP-beta, the most important member of the C/EBP family, was shown recently to be expressed in the normal human placenta where it is localized in villous syncytiotrophoblast and in the extravillous (intermediate) trophoblast but not the villous cytotrophoblast. The purpose of this study was to investigate the expression pattern of C/EBP-beta in gestational trophoblastic disease (GTD) which has not been studied so far. We used immunohistochemistry on a total of 15 cases of GTD including nine complete hydatidiform moles, one placental site nodule (PSN), one placental site trophoblastic tumor (PSTT), and four choriocarcinomas. All our tested specimens showed positivity for C/EBP-beta. The strongest C/EBP-beta expression could be observed in villous syncytiotrophoblast and in the trophoblast proliferations on the villous surface of hydatidiform moles; villous cytotrophoblast was negative. The PSN also showed positive nuclear staining but the expression was not as strong as it was in the hydatidiform moles and the total amount of stained cells was the lowest of all GTD. The PSTT also showed immunoreactivity but with a weaker and more heterogeneous staining than in the choriocarcinomas. The specific expression pattern of C/EBP-beta in GTD indicate that C/EBP-beta could potentially be an additional marker of such lesions.

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.