| Abstract|| |
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).
Keywords: Beta hCG, immunohistochemistry, trophoblastic tumor
|How to cite this article:|
Dash SS, Sakhadeo U, Karmarkar S, Mittal N, Menon S, Rekhi B, Deodhar KK. Epithelioid trophoblastic tumor: A case series. Indian J Pathol Microbiol 2023;66:148-51
|How to cite this URL:|
Dash SS, Sakhadeo U, Karmarkar S, Mittal N, Menon S, Rekhi B, Deodhar KK. Epithelioid trophoblastic tumor: A case series. Indian J Pathol Microbiol [serial online] 2023 [cited 2023 Mar 20];66:148-51. Available from: https://www.ijpmonline.org/text.asp?2023/66/1/148/367947
| Introduction|| |
An epithelioid trophoblastic tumor (ETT) is an extremely rare subtype of gestational trophoblastic neoplasia (GTN), accounting for only 1.0–2.0% of all GTN cases. Mazur and Kurman first described the entity in 1994, and Shih and Kurman elaborated on it further in 1998, is a rare gestational trophoblastic tumor of the extravillous trophoblast arising from intermediate trophoblastic cells of the chorionic leave, is characterized by uniform monomorphic nests and cords of mononucleated intermediate trophoblastic cells, which are surrounded by extensive necrosis and are associated with an eosinophilic hyaline-like matrix, creating a “geographical” pattern.
Most ETTs occur in the reproductive age group, and the average age is 36.1 years (range, 15–48 years).About 60% to 70% of the patients have abnormal vaginal bleeding, and some may have amenorrhea. It is not sensitive to chemotherapy, and the mainstay of treatment is hysterectomy. Metastasis and death could occur in about 25% and 10% of patients with ETT, respectively.
The aim of the study is to retrospectively review the cases of this rare diagnosis and assess the clinic-pathological features that help to reach the diagnosis. Due to morphologic and immunohistochemistry, overlapping differential diagnoses are choriocarcinoma (CC), placental site trophoblastic tumor (PSTT), or cervical squamous cell carcinoma (SCC). We present a series of ETT of four cases, evaluating the clinical and pathological parameters reported at our institution.
| Methodology|| |
All cases reported as ETT between January 2016 and December 2021 were retrieved from the archives. Two cases were operated on in our hospital and we received paraffin blocks from two patients. The hematoxylin and eosin-stained slides and immunohistochemistry (IHC) were reviewed by two pathologists. Clinical details were obtained from hospital electronic medical records.
| Results|| |
A total of four cases of ETT were identified in the study period, all (100%) were females. The mean age at diagnosis was 29.7 years (range, 20–40). All cases were in their reproductive age group. The tumor was confined to the uterus in all patients. History of antecedent pregnancy was present in three females (75%) with a history of ectopic pregnancy in two (50%) and molar pregnancy in one (25%). The symptoms at presentation varied; vaginal bleeding in two (50%) and amenorrhea in two (50%) cases. The mean pre-treatment hCG level was 665.2 (mIU/mL) (range, 161–2029).
All four hysterectomy specimens were reviewed [Table 1]. On gross examination, the tumor showed an expansile, nodular, solid lesion with areas of hemorrhage and necrosis. On microscopy, the tumor showed 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 hyaline-like material deposition were identified in all cases (100%). Marked anaplasia was identified in one case (25%). IHC tumor cells in all cases (4/4) showed diffuse positivity for AE1/AE3 and p63 (100%). Inhibin was positive in 3/4 of cases (75%). GATA3 was available in one case 1/4 (25%), which was positive in the tumor cells. In one case, (1/4, 25%) hPL was focally positive and in one case, (1/4, 25%) it was negative. SALL4 was performed in two cases (2/4, 50%) and was negative in tumor cells. The mean Ki67 labeling index was 19.2% (range 10–30%) [Figure 1] and [Figure 2].
|Figure 1: Case no 1. (a and b) [H and E, 200×]. The tumor showed an epithelioid appearance arranged in large nests and sheets. Areas of necrosis, hyaline-like material deposition, and calcification are identified. (c) Tumor cells are diffusely positive for AE1/AE3 (200×). (d) Tumor cells are diffusely positive for GATA3 (200×). (e) Tumor cells are focally positive for hPL (200×). (f) Tumor cells are focally positive for inhibin (100×)|
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|Figure 2: Case no 2. (a and b) [H and E, 200×]. Individual tumor cells are round to polygonal with abundant eosinophilic cytoplasm with central vesicular nuclei and prominent nucleoli. Areas of necrosis and hyaline-like material depositions are identified. (c) Tumor cells are marked by p63 (200×). (d) Ki67 immunostaining (200×). (e) Tumor cells are negative for SALL4 (200×)|
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All four patients underwent surgical intervention and were treated with hysterectomy and one (25%) patient received a preoperative multiagent chemotherapy regimen consisting of etoposide, methotrexate, actinomycin-D, cyclophosphamide, and cisplatin (EMA-CO) for 10 cycles; however, in view of increasing hCG trend, she underwent hysterectomy later on. One patient (25%) developed isolated lung metastasis after 65 months following diagnosis, which was treated by radiofrequency ablation of the lesion and alive after.
The patients were followed up by serial monitoring of hCG levels. 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).
| Discussion|| |
ETT is an extremely rare subtype of GTN, accounting for only 1.0–2.0% of all GTN cases. ETT, a tumor derived from chorionic leave-type extravillous trophoblasts, is characterized by uniform monomorphic nests and cords of mononucleated intermediate trophoblastic cells, with extensive or geographical necrosis and are consistently associated with an eosinophilic hyaline-like material along with stromal hyalinization and decidualization and calcification in some cases.
Although the majority of cases have been reported in women of reproductive age, one case described a 66-year-old postmenopausal woman with ETT. In our series, all patients were in the reproductive age group population., In the first case series by Shih and Kurman, 66.7% of patients with ETT had preceding-term pregnancies. However, in the case series by Zhang et al., among 45 patients whose obstetrics history was available, 51.1% had undergone abortions, 24.4% had complete hydatidiform moles, 8.9% had invasive moles, 4.4% had experienced ectopic pregnancies, and only 8.9% had achieved term pregnancies. In our series, none of the patients were preceded by term pregnancies but by ectopic pregnancy (50%, 2/4) and molar pregnancy (25%, 1/4). Besides occurring in the uterus and cervix, it has also been reported in the extrauterine sites such as broad ligaments, vaginal deposits, fallopian tubes, and lungs. The involvement of the latter is usually metastatic; however, most patients give a history of antecedent molar pregnancies. The possible pathogenesis of this rare clinical phenomenon includes an original transformation of trophoblastic cells passed to the lung during antecedent pregnancy. The other potential hypothesis is that pulmonary lesions may be the consequence of the spontaneous resolution of an antecedent uterine ETT.
Shih described hCG as mildly elevated, where the median is 665 IU/L. It is usually less than 2,500 U/L and only rarely rises to more than 10,000 IU/L. In our series, the mean hCG level was 665.2 (mIU/mL).
The differential diagnoses are CC, PSTT, or cervical SCC. ETT is commonly positive for inhibin and GATA3 along with cytokeratin AE1/AE3, p63, and epithelial membrane antigen, and may be focally positive for trophoblastic proteins including HPL, bhCG, PLAP, and CD146 (Mel-Cam)., P63 is positive in most ETTs and can be particularly useful when the differential diagnosis is with PSTT, which is the closest differential diagnosis. Intermediate cells of PSTT are larger, have more nuclear pleomorphism, and have a more infiltrative growth pattern, and vascular invasion. PSTT has a different immunoprofile, usually strongly immunoreactive for Mel-CAM and hPL and negative for p63.
CC is distinguished from ETT by its biphasic pattern (presence of cytotrophoblasts and syncytiotrophoblasts) along with areas of hemorrhage and necrosis. Serum beta-hCG will be very high. The hyaline-like matrix and necrosis present in ETT are typical features but they are usually not seen in SCC. The hyaline-like material, at times, can resemble keratin; however, SCC is marked by and identified by the presence of keratin pearls, intercellular bridges, and cervical intraepithelial neoplasia (CIN III) in the adjacent epithelium.
Placental site nodules (PSNs) have circumscribed nodules usually <5 mm in size, containing chorionic-type intermediate trophoblasts, displaying focal cytological atypia and absent or low mitotic activity.
Stichelbout et al. described SALL4 was expressed in 100% of CC and it was not detected in any PSTT and ETT. In our series, ETT was positive for AE1/AE3 in 4/4 (100%), p63 4/4 (100%), and inhibin in 3/4 (75%) cases. GATA3 was available in 1/4 (25%) cases, which was positive. In 1/4 (25%) cases, hPL was focally positive, and in 1/4 (25%) cases, it was negative. SALL4 was performed in 2/4 (50%) cases and was negative. The Ki67 index was 10% to 25% in the series by Shih in 1998, which reported a mean Ki67 labeling index of 17.7% (range 10–25%) for ETT; in our case, series it was 19.2%.
Surgical resection is the primary treatment modality for ETT presenting with non-metastatic disease. Although chemotherapy alone is inadequate for advanced-stage and metastatic or locally advanced diseases, it still plays an important role in the management of ETT patients when surgery has failed or is not feasible. The first-line treatment for CC is chemotherapy alone, which is sufficient to cure the majority of patients. Given the chemoresistant nature of PSTT and ETT, surgery is the primary treatment modality, and cervical SCC is managed by radical hysterectomy along with concurrent chemoradiation depending upon the stage. Death rates of 10–13% have been reported for ETT; in our series, all patients are still alive to date with a mean survival of 32.8 months (range, 4–67).
| Conclusion|| |
ETTs are largely chemo-resistant unlike CC, and thus hysterectomy is still the mainstay of treatment. Because of its rarity, limited data have been published regarding follow-up and surveillance for recurrence. Histologically, epithelioid cell nests accompanied by hyaline material deposition and extensive necrosis were important diagnostic clues. Immunohistochemically, diffuse expression of GATA3 and p63, and focal expression of hPL accompanied by non-expression of SALL4 are characteristics of ETT. To the best of our knowledge, this is the first series describing ETT in our country.
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Conflicts of interest
There are no conflicts of interest.
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Kedar Kamalakar Deodhar
Department of Pathology, Annexe Building, 8thFloor, Tata Memorial Hospital, Dr. E Borges Road, Parel, Mumbai - 400 012, Maharashtra
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2]