Postmenopausal mixed gestational trophoblastic neoplasia: a case report and review of the literature.

A 65-year-old Chinese woman, gravida 3 para 2, presented with a pelvic mass that had been present for four months and abnormal vaginal bleeding for seven days. She had been menopausal for 14 years and had not experienced any abnormal vaginal bleeding prior to this presentation. She had experienced two normal full-term vaginal deliveries, 41 and 40 years ago, respectively. Her latest pregnancy ended in an artificial abortion 38 years ago, which was successful with no complications. Additionally, she has complications including hypertension, sequelae of cerebral infarction, mild anemia, hypoproteinemia, and varicosity. Upon admission, we conducted a detailed examination. The abdominal examination showed an irregular and huge mass with limited mobility and mild tenderness. The ultrasound (US) revealed an inhomogeneous texture of the uterine myometrium, with asymmetric thickening of the anterior and posterior walls. Additionally, a 14.4 cm × 10.7 cm heterogeneous hypoechoic mass was observed near the posterior wall of the uterus. The uterine artery pulsatility index (PI), resistivity index (RI), and systolic/diastolic ratio (S/D) were measured by Doppler flow velocimetry (left: PI, 0.49; RI, 0.36; S/D, 1.56; right: PI, 0.33; RI, 0.26; S/D, 1.36) ( Figure 1 ). The abdominal and pelvic computed tomography (CT) image demonstrated the mass adhering to the uterus, with uneven enhancement during the contrast-enhanced scan. Peritoneal thickening, retroperitoneal and pelvic lymphadenopathy, and bilateral ureter lesions were all considered metastatic tumors, and the lesions obscured the ureter and caused bilateral hydroureteronephrosis ( Figure 2 ). The chest CT image showed multiple nodules and the CT scan of the brain showed no evidence of metastatic lesions. The endometrial biopsy indicated poorly differentiated carcinoma. The colposcopy biopsy indicated cervical stromal invasion, and the possibility of metastasis from ovarian or uterine was being considered. The patient’s serum β-hCG level was 1,525 mIU/mL, which was detected incidentally. The ultrasound examination performed before treatment. Top left: the uterine myometrium has an inhomogeneous texture, along with asymmetric thickening of the anterior and posterior walls. Power Doppler image of the region of mass showing high vascularity. Top right: a 14.4 cm × 10.7 cm heterogeneous hypoechoic mass located behind the posterior wall of the uterus. Bottom left, Spectral Doppler image of left uterine artery showing low-resistance blood flow (PI, 0.49; RI, 0.36; S/D, 1.56). Bottom right, Spectral Doppler image of right uterine artery showing low resistance (PI, 0.33; RI, 0.26; S/D, 1.36). 1D, 2D, 3D indicate the length, width and height of the lesion. ED, end-diastolic velocity; Lt Ut, left uterine; MD, mean diastolic flow velocity; PI, pulsatility index; PS, peak systolic velocity; RI, resistivity index; Rt Ut, right uterine; S/D, systolic/diastolic ratio; TA max , time-averaged maximum velocity; Ut-HR, uter ine artery heart rate. CT scan prior to the treatment. There is a large mass behind the uterus, accompanied by peritoneal thickening, retroperitoneal and pelvic lymphadenopathy. The enhancement during the contrast-enhanced scan is uneven. CT, computed tomography; FOV, field-of-view. The clinical symptoms and elevated serum hCG level led to a clinical suspicion of GTN, although a precise diagnosis could not be established at the time. Additionally, the possibility of concurrent primary ovarian cannot be ruled out. The first cycle of MTX-based chemotherapy (including methotrexate, fluorouracil, and etoposide) was initiated after the initial diagnosis. Granulocyte-colony stimulating factor (G-CSF) was administered post-chemotherapy to prevent delay of chemotherapy. On the 7th day of the chemotherapy interval, the β-hCG level was down to 156.0 mIU/mL, but she developed grade-4 myelosuppression and severe stomatitis. Consequently, she was admitted to receive symptomatic supportive treatments, which included blood transfusions, nutritional support therapy, etc. Despite the scheduled chemotherapy being delayed, the β-hCG level showed a downward trend. By the fourteenth day, it had decreased further to 96.3 mIU/mL. On the 28th day of the chemotherapy interval, the patient’s vital signs stabilized and the blood routine was generally normal. She was scheduled for further treatment. But the serum β-hCG level re-elevated to 1,294.0 mIU/mL. Given the heavy tumor burden and the unknown definitive diagnosis, after consulting with the family, it was decided to proceed with exploratory laparotomy to alleviate the tumor load and to further clarify the diagnosis. Intraoperatively, the uterus was found to be the size of a 12-week pregnancy, and an 8 cm hemorrhagic necrosis mass lesion, tan to dark-brown, was discovered on the posterior uterine wall, extending from the uterine fundus to the pouch of Douglas, invading the surface of the rectum. The right ovary increased in size to approximately 10 cm × 10 cm × 8 cm, appearing as a brown, crispy mass. Multiple nodules with a diameter of 0.5 cm were visible on the surface of the right pelvic sidewall, bladder peritoneum, greater omentum, liver, spleen, and diaphragm ( Figure 3 ). The right ovary and the huge mass were fully excised and sent for intraoperative frozen section pathological analysis. They were interpreted as epithelial-like malignant tumor and malignant trophoblastic neoplasm, but the specific type has not been defined. Subsequently, a total abdominal hysterectomy, bilateral salpingo-oophorectomy, right pelvic peritonectomy, right pelvic lymph node dissection, and greater omentum resection, along with excision of peritoneal implants, were performed. Cytoreduction to no gross residual disease was achieved. All the lesions were sent for the permanent pathological analysis. The postoperative β-hCG level was 797 mIU/mL. Immunohistochemical staining results are shown in Table 1 . Intra-operative findings. Multinodular mass extending from the the posterior uterine wall. +, the antigen is expressed in tested sample; partial+, in the tissue samples tested, only some cells or regions exhibited antigen-positive expression; −, the antigen was absent in the tested samples. CC, choriocarcinoma; ETT, epithelioid trophoblastic tumor; GTN, gestational trophoblastic neoplasia; PSTT, placental site trophoblastic tumor. Based on morphological and immunohistochemical results, the diagnosis concluded by the pathologist was mixed GTN (CC + PSTT + ETT), involving the cervix, both fallopian tubes and ovaries, the greater omentum, the pelvic peritoneum, and pelvic lymph nodes, as well as the liver surface. Following the surgery, a cycle of TP/TE regimen chemotherapy (alternating paclitaxel and cisplatin with paclitaxel and etoposide) was administered, resulting in a minimum reduction of the β-hCG level to 31.6 mIU/L during the intermittent phase of chemotherapy. On the 12th day of the chemotherapy interval, she was shown at hospital with a fever, low blood pressure and severe malnutrition. Sepsis was diagnosed after examinations. Additionally, grade-3 myelosuppression, electrolyte imbalance, coagulation disorder and bilateral deep vein thromboses in the calves were also diagnosed. Therefore, chemotherapy was suspended and the patient was transferred to intensive care unit for symptomatic supportive treatment. On the 26th day of the interval, β-hCG re-elevated to 1,320 mIU/L. The enhanced CT scan revealed the progression of peritoneal dissemination of the tumor. On the 36th day of the interval, the family decided to forgo treatment due to financial difficulties and requested to be discharged. The patient passed away on the third day following discharge. The treatment process and corresponding hCG changes are depicted in Figure 4 . The treatment process and corresponding hCG changes. GTN, gestational trophoblastic neoplasia; hCG, human chorionic gonadotropin; MTX, methotrexate; TP/TE, alternating paclitaxel and cisplatin with paclitaxel and etoposide.

Gestational trophoblastic neoplasia (GTN) is a group of rare malignant tumors that originate from pregnancy, including invasive mole (IM), choriocarcinoma (CC), and intermediate trophoblastic tumor (ITT). Specifically, ITT consists of placental site trophoblastic tumor (PSTT) and epithelioid trophoblastic tumor (ETT). GTN primarily affects patients of reproductive age and is relatively uncommon in postmenopausal women ( 1 , 2 ). CC, characterized by markedly elevated serum human chorionic gonadotropin (hCG), constitutes the majority of GTN. In contrast, ITTs are rare, accounting for only about 1–2% of GTN. Serum hCG levels in patients with ITT are often normal or only mildly elevated ( 3 ). In exceptionally rare cases, some patients may be diagnosed with mixed GTN, which is primarily characterized by the coexistence of CC and PSTT and/or ETT components, sometimes it presents without CC components ( 3 - 6 ). The serum hCG level of mixed GTN is determined by the proportion of these different components and their optimal therapeutic regimen also require further research to be defined ( 3 ). Here, we report a 65-year-old postmenopausal woman with mixed GTN which includes CC, ETT and PSTT. The patient underwent multi-agent chemotherapy combined with surgery and experienced a partial response, but unfortunately developed extensive metastases shortly thereafter and succumbed to the disease. We discuss the challenges in early diagnosis and treatment management, present the controversy over chemotherapy timing and regimen, as well as the necessity and timing of surgery. In addition, data of 45 patients diagnosed with mixed GTN reported available has been collected and further analyzed, which can enhance the clinicians’ understanding of the disease and formulate better treatment approaches. The effective strategy to enhance prognosis of mixed GTN still need to explore in the future. We present this article in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-2025-290/rc ).

From 1998 to 2025, 45 cases of mixed GTN were reported. Databases, including PubMed/MEDLINE, Web of Science, the Cochrane Library, and Embase, were searched for all cases using the keywords “mixed gestational trophoblastic neoplasia”, “mixed choriocarcinoma”, “combined choriocarcinoma”, “coexisting choriocarcinoma”, “placental site trophoblastic tumor”, and “epithelioid trophoblastic tumors”. No language restrictions were applied. The clinical characteristics of patients with mixed GTN reported in the literature are summarized in Table 2 . AP, abdominal pain; CC, choriocarcinoma; CR, complete remission; ETT, epithelioid trophoblastic tumor; FIGO, International Federation of Gynecology and Obstetrics; GTN, gestational trophoblastic neoplasia; hCG, human chorionic gonadotropin; HM, hydatidiform mole; NA, not available; PSTT, placental site trophoblastic tumor; VB, vaginal bleeding. Among the published cases, only three patients reported to be CC + PSTT + ETT (3/45, 6.70%). Most mixed GTN occurred in reproductive age, with an average age of 37.2 years (range, 15–66 years), only four patients were older than 50 years. The previous gestational events were documented in 43 cases. A prior normal pregnancy accounted for 48.8% (21/43), abortions for 37.2% (16/43), and hydatidiform moles for 20% (6/43), none of them were hydatidiform mole and coexisting fetus (HMCF). The time interval between antecedent pregnancy was known for 24 patients, 11 (45.8%) cases were >48 months. The longest time interval was reported as 38 years ( 7 ). Abnormal vaginal bleeding was the most common presenting symptom. Pretreatment serum β-hCG levels were available for 40 cases, with 39 exhibiting elevated serum β-hCG levels; the sole exception was a case of mixed ETT and PSTT, which had a serum β-hCG level of 1 mIU/mL ( 8 ). The production of β-hCG is mainly by the syncytiotrophoblast in CC or syncytiotrophoblast-like cells in PSTT and ETT. The serum β-hCG levels in patients with pure CC are usually very high, generally exceeding 10,000 mIU/mL, whereas serum β-hCG levels are lower in patients with PSTT or ETT, ranging from <1,000 mIU/mL to undetectable. Serum β-hCG levels in patients with mixed GTN vary widely, depending on the tumor composition and proportion ( 3 ) (1–625,924 mIU/mL, mean of 55,681 mIU/mL). Higher initial serum β-hCG levels are mostly seen in mixed GTN with a CC component (CC + ETT—mean: 69,839 mIU/mL; CC + PSTT—mean: 73,069 mIU/mL; CC + ETT + PSTT—mean: 3,348 mIU/mL). The mean level of mixed ETT and PSTT was 1,701 mIU/mL. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration and its subsequent amendments. Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Mixed GTN is the rarest form of GTN. Our report is the 46th case of mixed GTN. The antecedent pregnancy was an abortion 38 years ago, marking the longest interval among the previous cases. Previous studies have found that almost none of the patients with mixed GTN could be diagnosed correctly upon their initial visit ( 5 ). The nodules or masses of GTN always located in the uterine myometrium or within the uterine cavity ( 26 ). But in this case, based on the enhanced CT scan, the large mass located outside the uterus, with extensive pelvic lymph node involvement, was considered to be an ovarian malignant tumor. At the same time, the asymmetric myometrial thickening was easy to be considered as adenomyosis. Moreover, the patient has been menopausal and her last pregnancy occurred a long time ago, making it easy to overlook the diagnosis of GTN. In terms of the initial serum β-hCG level of 1,525 mIU/mL, the possibility of a special type of GTN was considered, but the specific subtype could not be defined. Doppler measurement of the uterine artery revealed significantly lower resistance and higher blood-flow velocity, but it still cannot distinguish the specific type. Recent studies indicate that the uterine artery PI plays a significant role in the differential diagnosis between PSTT and other GTNs, with PSTT patients exhibiting significantly higher PI values compared to other subtypes of GTN ( 27 ). However, the value of uterine artery blood flow index in the differential diagnosis of mixed GTN still needs further study. The final diagnosis could only rely on gross pathological examination. According to the International Federation of Gynecology and Obstetrics (FIGO) 2000 criteria ( 2 ), the patient we report was initially diagnosed with stage IV, scoring 18 points, which indicates an extremely high risk. However, the FIGO Prognostic Scoring System is not completely applicable to PSTT and ETT, and the poor prognostic factors for survival are FIGO stage III/IV and an interval of more than 48 months from the previous pregnancy ( 2 ). Consequently, the patient was considered to have a poor survival prognosis both before and after the pathological examination. In previous cases, 43 patients were available for FIGO staging, of whom 21 were at stage I–II (48.8%), 22 at stage III–IV (51.2%). Regarding the interval, 11 cases (11/24, 40.9%) had an interval of more than 48 months. Therefore, 44 cases were available for prognosis evaluation, and 28 cases (63.6%) were considered to have a poor survival prognosis. As for the clinical outcomes, 3 patients died, all of whom were considered to have a poor survival prognosis. The first-line treatment for GTN remains conventional chemotherapy, particularly for CC, which is highly sensitive to chemotherapy, allowing most patients to achieve complete remission ( 28 ). In contrast, PSTT or ETT are relatively chemo-resistant, surgery is the primary treatment modality. The stage I PSTT or ETT confined to the uterus can be cured with hysterectomy alone, but chemotherapy should still be given to those with poor prognostic indicators or advanced disease ( 2 ). Mixed GTN present complex therapeutic challenges, which has a certain response to chemotherapy due to the presence of CC component. The treatment is proposed to combine chemotherapy with surgery ( 9 ). In the case we report, β-hCG level decreased significantly after one cycle of preoperative chemotherapy and further minimized with TP/TE regimen chemotherapy post-surgery, indicating a good response to chemotherapy. Apart from chemotherapy and surgery, immunotherapy has shown positive therapeutic effects on special types and chemoresistant GTD ( 25 ). During normal pregnancy, trophoblastic cells secrete programmed cell death-ligand 1 (PD-L1) to suppress the semi-allogeneic immune reaction. PD-L1 is also highly expressed within different GTN subtypes, which helps evade immune responses and allows for the proliferation of premalignant and malignant cells ( 29 ). Inhibiting programmed death-1 (PD-1)/PD-L1 pathway among chemorefractory GTN cases has become popular recently, with successful therapeutic outcomes achieved in several series ( 30 - 32 ). The National Comprehensive Cancer Network (NCCN) also adds PD-1/PD-L1 inhibitors to its list of therapies for multi-agent chemotherapy-resistant GTN that are “useful in certain circumstances” ( 2 ). In our series, three patients received pembrolizumab as adjuvant therapy. Emlein et al. reported the use of first-line pembrolizumab in combination with chemotherapy for treatment of stage III PSTT + ETT, and the patient achieved complete remission ( 6 ). Matthews et al. published a case of stage IV mixed chemo-resistant PSTT + ETT that responded well to single-agent pembrolizumab ( 7 ). However, Ghorani et al. reported that a case of stage IV mixed ETT + PSTT, who had failed multiple therapies over seven years, experienced disease progression after five cycles of pembrolizumab and died four months later ( 25 ). Previous study has confirmed that tumor-infiltrating lymphocytes (TILs) are correlated with the anti-PD-1 response ( 33 ). The absence of TILs in the third patient may explain why she did not respond. The application of immunotherapy in mixed GTD is still limited. The best biomarker to predict immunotherapy response remains uncertain, and its efficacy also requires further investigation. The patient we report progressed rapidly through treatment and succumbed within less than 3 months. Drawing upon the literature we reviewed and the experience gained from the diagnostic and treatment processes, the following insights are proposed. First and foremost, postmenopausal patients with abnormal vaginal bleeding or pelvic mass should also be tested for β-hCG levels to differentiate the possibility of GTN. Secondly, the spectral and power/color Doppler techniques combined with traditional US are expected to be an essential tool in the near future, providing reference for differential diagnosis ( 26 ). Thirdly, the older women we reported, who had underlying diseases, was initially considered to be at ultra-high risk, may not tolerate aggressive chemotherapy. Considering induction with low-dose etoposide and cisplatin (EP) for 1–3 cycles before starting multiple chemotherapy as NCCN guideline recommended ( 2 ). Fourthly, the NCCN guideline recommends chemotherapy combined with surgery for stage II–IV PSTT and ETT ( 2 ). Mixed GTN also requires surgical resection of chemo-resistant lesions, but the timing of surgery must be carefully considered. Feng et al. suggested that β-hCG should be controlled at low levels before operation ( 34 ). Considering that the β-hCG level had rebounded prior to surgery, the patient should undergo an additional cycle of chemotherapy or attempt immunotherapy before proceeding with surgery. Last but not least, palliative care should be provided whenever possible for patients with relapse or progression ( 2 ).

In conclusion, mixed GTN is an exceptionally rare malignant neoplasm of the trophoblastic tissue, particularly in postmenopausal women. Hence the risk of misdiagnosis is high and definitive treatment protocols remain elusive. Previous literature and our cases underscore the importance of early diagnosis, identifying cases with poor prognosis, and carefully considering chemotherapy and surgical treatment regimens and timing. Future research and clinical trials are necessary to further explore the method to promote differential diagnosis, novel therapeutic modalities and personalized treatment approaches to improve treatment outcomes.

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