Successful treatment of recurrent epithelioid trophoblastic tumor (ETT) with pembrolizumab after pembrolizumab: A case report and review of literature in treatment of ETT

Abstract

Background

Epithelioid Trophoblastic Tumors (ETT) are rare, which makes an optimal treatment regimen difficult to determine. Since PD-L1 is expressed in placental tissue and in gestational trophoblastic neoplasia (GTN), immunotherapies such as pembrolizumab have been proposed as possible treatments.

Case presentation

The case presented is a 50-year-old postmenopausal female who presented with postmenopausal bleeding and a large, fungating cervical mass. Cervical biopsies confirmed ETT. The patient underwent primary debulking surgery with radical abdominal hysterectomy, bilateral salpingo-oophorectomy, and sigmoid colon resection. The patient was diagnosed with a FIGO Stage IV ETT due to tumor extension to sigmoid colon with a high-risk WHO score of 12. She underwent four cycles of etoposide and cisplatin with etoposide, methotrexate, and dactinomycin (EP-EMA) followed by six months of pembrolizumab maintenance. One year after completion of immunotherapy, the patient was diagnosed with recurrence by vaginal biopsy. PET/CT revealed oligometastatic sites of recurrence, prompting secondary debulking surgery with upper vaginectomy and removal of incisional recurrence. After four cycles of cisplatin/paclitaxel and etoposide/paclitaxel (TP-TE), she received maintenance pembrolizumab for 12 months. Follow-up PET/CT scans revealed no evidence of hypermetabolic activity after 1 year of maintenance therapy.

Conclusion

Use of immunotherapy with anti-PD-1 inhibitors has been successful in cases of GTN due to expression of PD-L1 in placental tissue and in GTN. This case adds to the limited data on immunotherapy in advanced ETT and is the first example of using immunotherapy after immunotherapy in the literature.

Highlights

• •Epithelioid trophoblastic tumor is rare with limited data on treatment.
• •Immunotherapies that target PD-L1 have been used in treatment of ETT.
• •Pembrolizumab may be successful in treatment of advanced/recurrent ETT.
• •Pembrolizumab re-challenge can be considered in recurrence after use in primary treatment.

1. Introduction

Epithelioid Trophoblastic Tumor (ETT) is a rare subtype of gestational trophoblastic neoplasia (GTN) with only approximately 140 cases reported (Pisani et al., 2021). ETTs are thought to arise from chorionic -type intermediate trophoblasts from the chorionic leaf of placental tissue (Buza and Hui, 2010). ETT is often studied with placental site trophoblastic tumor (PSTT), as both have similar characteristics such as originating from intermediate trophoblasts and being grossly similar demonstrating solid and cystic lesions within the uterus, cervix, and within the peritoneal cavity (Buza and Hui, 2010; Horowitz et al., 2016). Both PSTT and ETT typically present in reproductive years with vaginal bleeding and an increase in human chorionic gonadotropin (bHCG) (Buza and Hui, 2010; Shih, et al. 1998). The histologic and immunohistochemical profile of ETT and PSTT differ to allow for distinction for diagnosis (Horowitz et al., 2016) While ETT represents a small proportion of GTN, ETT and PSTT make up a large portion of the mortality rate (Buza and Hui, 2010; Aničić, et al. 2021). Since both PSTT and ETT are known to be more chemo-resistant compared to choriocarcinoma, alternative treatment regimens are actively being explored (Shih, et al. 1998; Bell et al., 2021).

ETT was first described almost 30 years ago. However, due to its rarity, prognosis and management is limited to case reports and case series or extrapolated from reports of GTN or PSTT given the clinical overlap of ETT/PSTT compared to choriocarcinoma (Buza and Hui, 2010; Horowitz et al., 2016). Furthermore, current treatment guidelines for ETT/PSTT are combined in the National Comprehensive Cancer Network (NCCN) guidelines, which recommends surgery as first-line therapy. Chemotherapy is recommended in Stage II-IV or stage I in patients over 4 years from causative gestation. Typical regimens include Etoposide/Methotrexate/Dactinomycin-Etoposide/Cisplatin (EMA-EP), Etoposide/Cisplatin- Etoposide/Methotrexate/Dactinomycin (EP-EMA), or Paclitaxel/Cisplatin-Paclitaxel/Etoposide (TP-TE) per the NCCN guidelines. The mortality rate of ETT is estimated to be between 10 and 24% (Yang et al., 2018), with unfavorable outcomes in ETT similar to PSTT with remission rate only 33% (Zhang et al., 2013).

Here, we present a patient with advanced ETT, who received immunotherapy as part of her initial regimen with recurrence managed with surgical debulking, chemotherapy, and repeat pembrolizumab maintenance.

2. Case presentation

This patient is a 50-year-old female with type 2 diabetes who presented to her gynecologist with postmenopausal bleeding. Obstetric history includes an abortion 20 years prior, a full-term intrauterine fetal demise with vaginal delivery 16 years prior, and most recently a full-term cesarean section from in vitro fertilization 5 years prior to presentation. During the initial exam, the cervix was noted to be grossly abnormal. Cervical biopsies revealed epithelioid trophoblastic tumor, and the patient was referred to gynecologic oncology.

Exam upon referral revealed a fungating mass replacing the cervix and an enlarged, 16-week, non-mobile uterus filling the posterior cul-de-sac. She was admitted to the hospital for an expedited workup. bHCG was elevated to 66.5. Computed tomography (CT) of the chest, abdomen, and pelvis (CAP) showed a soft tissue 14.9 × 7.0 × 12.7 cm mass involving uterus and cervix extending to left pelvis and effacing the contour of bladder (Fig. 1A). Magnetic resonance imaging (MRI) of the brain showed no concerning lesions. MRI of the pelvis revealed a uterus measuring 13.4 × 7.8 × 8.6 cm with mild heterogenous signal at the bladder dome with concern for bladder involvement. There was also a 6.2 × 3.1 × 5.3 cm extension of the mass to the left parametrium. The mass indented but did not involve the sigmoid colon on imaging (Fig. 1B—C). No extra-pelvic disease was identified on imaging (See Table 1).

Fig. 1.

1 A: Sagittal CT scan showing uterus with invading tumor. 1B: T2 weighted sagittal MRI image of tumor. 1C: T2 weighted axial MRI image with extension to left pelvis abutting sigmoid colon.

Table 1.

Timeline of care.

Time from primary surgery (mos)	Activity
−2	Initial presentation
0	Primary debulking surgery
2–4	4 cycles EP-EMA
4–9	Pembrolizumab maintenance for 6 months
14	CT CAP negative during follow up
20	Clinical Recurrence by exam and PET/CT
21	Secondary debulking surgery
22–26	4 cycles TP-TE
25–37	Pembrolizumab
37	PET/CT negative at conclusion of maintenance treatment

Exam under anesthesia and cystoscopy demonstrated no bladder involvement and repeat biopsies confirmed the previous diagnosis of ETT. Immunohistochemical profile was as follows: PCK positive, CAM5.2 positive, GATA3 positive, p63 positive, PLAP positive, Inhibin negative, HCG negative, S100 negative, SALL4 negative, p53 wild type expression, PAX8 negative, HMB 45 negative, SMA negative, RCC focally positive, ki-67 increased. Additional marker HSD3B1 was positive.

The patient underwent a primary debulking surgery with an exploratory laparotomy. The uterine tumor extended to left uterosacral ligament with involvement of sigmoid colon, and a radical abdominal hysterectomy, bilateral salpingo-oophorectomy, bilateral pelvic lymphadenectomy, resection of sigmoid colon with primary anastomosis, omentectomy, left pelvic peritonectomy, and complete debulking was performed.

Pathology of the uterus resulted as a 16 cm epithelioid trophoblastic tumor with full thickness invasion of the myometrium, cervix, and bilateral parametria. Lymphovascular and perineural invasion were identified. Tumor was present in the sigmoid colon serosa and subserosa measuring 8.5 cm extending to one margin, though colon mucosa was free of tumor leading to a diagnosis of International Federation of Gynecology and Obstetrics (FIGO) Stage IV with a high risk WHO prognostic score of 12.

The patient received EP-EMA regimen 4 weeks post-operatively after she was presented at multidisciplinary tumor board and discussed with national experts in GTN. Prior to treatment initiation, Positron Emission Tomography (PET)/CT showed postoperative inflammation but no avid uptake. bHCG decreased to 3.5. After 4 cycles of EP-EMA therapy, bHCG remained below 5. CT CAP obtained post-treatment showed no disease. There were stable pulmonary nodules and a left pelvic sidewall fluid collection, likely representing a lymphocele and not residual disease. She was then transitioned to pembrolizumab maintenance therapy every 3 weeks. This was transitioned to higher dose (400 mg) pembrolizumab every 6 weeks after 2 doses for a total of 6 months of maintenance therapy. Treatment was well tolerated with only mild symptoms of oral mucositis, but no other immune related toxicities. The bHCG remained <2 at follow up appointments after discontinuing pembrolizumab.

The patient presented for follow up 18 months from primary surgery with new onset bilateral forearm pain and periumbilical pain. On pelvic exam, a new 2 mm white solid lesion at the apex of the vagina was biopsied. Pathology confirmed recurrent ETT. bHCG remained negative at 1.7. PET/CT was obtained with new avid uptake in the right axillary lymph nodes in addition to middle anterior pelvic wall and lower anterior pelvic nodules measuring 2.0 × 1.3 cm and 1.0 × 1.0 cm, respectively, consistent with recurrent disease (Fig. 2).

Fig. 2.

PET/CT at time of recurrence with sagittal (A) and axial (B) views.

Axillary nodes were not thought to be recurrence as she had had a recent COVID-19 vaccination prior to the PET scan. The patient underwent an upper vaginectomy and secondary tumor debulking since the remainder of disease was amenable to resection. Notable findings included a 1 cm lesion on the left dome of the bladder, one lesion on the mesentery of the sigmoid colon near the bladder and vaginal cuff, and multiple nodules within the subcutaneous fat of the healed midline vertical incision from the primary debulking, which all correlated with the areas of uptake on the PET/CT. No residual disease was noted at the end of the procedure. The bladder, sigmoid colon, and abdominal wall nodules were all positive for recurrent ETT on pathology. The upper vagina and omental biopsy were negative for ETT. Gestational genotyping was consistent with biparental lineage. HLA-G testing was positive at 2+, indicating possible response to immunotherapy. International consultation suggested consideration of TP-TE with addition of pembrolizumab for at least six months of maintenance.

The patient then completed 4 cycles of TP-TE starting four weeks post-operatively. PET/CT was repeated at completion of TP-TE with no signs of recurrent disease.

The patient was started on pembrolizumab during cycle three of TP-TE for planned maintenance using the 400 mg q6 week regimen. PET/CT obtained six months into repeat pembrolizumab treatment showed no evidence of recurrence. She received a total of ten cycles of pembrolizumab over one year without complications. PET/CT at completion of treatment showed no evidence of disease.

3. Discussion

Given the rarity of ETT, treatment regimens are difficult to establish. NCCN guidelines combine ETT and PSTT treatment and follow-up regimens due to the absence of randomized control trial data to guide management. In the case presented, the patient had multiple poor prognostic factors including age, more than four years from antecedent term pregnancy, involvement of sigmoid colon, and large tumor size resulting in a high risk score of 12. Given the poor prognosis, consultation with national and international experts helped guide treatment. Experts recommended to use pembrolizumab, a PD-1 inhibitor, as part of treatment regimens given successful use in GTN (Ghorani et al., 2017; Baas et al., 2023; Wang et al., 2023).

Immune checkpoint inhibitors, such as pembrolizumab, have revolutionized the treatment of a variety of cancers, and studies have shown their use in the wider treatment of GTN (Bell et al., 2021; Barcellos et al., 2025; Ghorani et al., 2017; Baas et al., 2023; Huang et al., 2017; Wang et al., 2023). PD-L1, the ligand to pembrolizumab's target PD-1, is strongly expressed in GTN and has been shown to be positive in ETT specifically, making it a potential therapeutic target (Yang et al., 2018). The increase of immunotherapy options and the response in gestational trophoblastic disease makes PD-1 inhibitors a promising treatment option, especially in recurrent, resistant, or persistent disease (Ghorani et al., 2017; Barcellos et al., 2025; Baas et al., 2023; Wang et al., 2023).

This case adds to the limited data on the use of pembrolizumab in the treatment of ETT specifically. Gohrani et al. (2017) examined the use of pembrolizumab more widely in GTN, although no ETT case was part of the study. In that study, a patient with mixed PSTT/ETT resistant to chemotherapy underwent five cycles of pembrolizumab; however, the patient died despite treatment. Choi et al. (2019) reported a case of Stage IV ETT with a prognostic score of 14 who received multiple regimens of chemotherapy over a six-year period for continued recurrences. That patient was started on pembrolizumab 200 mg every three weeks with serologic remission after 11 cycles. Pisani et al. (2021) reported a stage 1 disease resected with surgery who was started on pembrolizumab 200 mg every three weeks due to prolonged time between antecedent pregnancy and diagnosis of ETT, which resulted in a 12-month period without recurrence or evidence of distant metastasis. The duration of pembrolizumab was not specified. Bell et al. (2021) reported a patient with Stage IV ETT with unresectable metastasis that underwent seven cycles of EMA-EP chemotherapy with partial response. That patient was started on pembrolizumab with partial response and continued negative bHCG of <2.

Determination of the initiation and duration of immunotherapy in high risk and/or metastatic ETT requires additional investigation. In the meta-analysis by Barcellos et al., cases using pembrolizumab in ETT had various treatment lengths, with many cases still receiving consolidation cycles at the time of reporting (Barcellos et al., 2025). In the case presented, maintenance with pembrolizumab after primary treatment was recommended by experts due to poor prognostic score for 6 months. This is in accordance with the six months of maintenance therapy given after chemotherapy in the Wang et al. study comparing anti-PD-1 treatment alone or in combination with chemotherapy for the treatment of GTN (Wang et al., 2023). During recurrence, it was recommended to continue for at least 6 months by international experts in GTN with the recognition that the duration should be longer than the primary treatment and recognizing that limited data existed to determine length of therapy. Given the high risk nature of the patient's disease, the decision was made to continue therapy for 1 year.

Surgery is considered the cornerstone of treatment of ETT followed by chemotherapy for high risk patients; however, there may be a role for maintenance therapy as part of the treatment regimen of ETT given the recurrence in this case despite no residual disease after primary surgery and completion of initial chemotherapy (Yang et al., 2018; Frijstein et al., 2018). Moreover, this case raises the question of when to initiate pembrolizumab—at time of initial chemotherapy regimen as treatment or after as maintenance. The length of pembrolizumab therapy to prevent recurrence should also be determined, as the patient presented here recurred one year after stopping her six-month maintenance pembrolizumab. Lastly, our ability to evaluate the efficacy of pembrolizumab in treating ETT is limited by the lack of control and the lack of visible disease at initiation of pembrolizumab in each instance. However, given the patient's high-risk disease and positive overall outcome, we can infer that there may be some benefit to anti-PD-1 therapy in ETT in both primary and recurrent settings.

4. Conclusion

The case presented represents a successful approach to treatment of advanced and recurrent epithelioid trophoblastic tumor with pembrolizumab in addition to surgery and chemotherapy, supporting its use for maintenance therapy in addition to its role in recurrence in ETT. Future directions include determining the timing of initiating immunotherapy as well as the duration of maintenance therapy.

CRediT authorship contribution statement

Sarah J. Mokma: Writing – original draft, Data curation. Sarah Alnaif: Writing – review & editing. Nicholas Cardillo: Writing – review & editing, Validation, Supervision, Data curation, Conceptualization.

Ethics declaration

Written informed consent to take part in the study and to publish the article has been obtained from all participants or their legal representatives. The privacy rights of participants have been observed. Written informed consent was obtained from the patient for publication of this case report and accompanying images.

This study was performed in compliance with relevant laws, regulatory frameworks and guidelines where the research took place. Ethics committee approval was not required under relevant laws and institutional guidelines. In accordance with institutional guidelines and federal regulatory frameworks, Institutional Review Board (IRB) review is not required for case reports involving fewer than three patients as they do not meet the statutory definition of research. Written informed consent was obtained from the patient(s) for the publication of this case report and any accompanying images.

This research follows the CARE guidelines and the CARE checklist.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.