Diagnostic challenges of epithelioid trophoblastic tumor in a patient with elevated beta-human chorionic gonadotropin (β-hCG) levels: a case description

Introduction

Epithelioid trophoblastic tumor (ETT) is a rare gestational trophoblastic neoplasm (GTN), with serum beta-human chorionic gonadotropin (β-hCG) levels typically below 2,500 mIU/mL (1). Markedly elevated β-hCG is highly atypical and often leads to an initial misdiagnosis of choriocarcinoma, a distinction with critical therapeutic implications as ETT is primarily managed surgically whereas choriocarcinoma is treated with chemotherapy. We present an exceptional case of histologically pure ETT with a β-hCG level exceeding 59,000 mIU/mL. The case provided the first description of contrast-enhanced ultrasound (CEUS) features in ETT, performed due to a contraindication to magnetic resonance imaging (MRI), offering valuable complementary information for characterizing such rare entities and underscoring the importance of recognizing this atypical biochemical presentation to guide correct clinical management.

Case presentation

A 37-year-old woman (gravida 9, para 2) presented with a 3-month history of irregular vaginal bleeding. Her last pregnancy had ended in an induced abortion 4 years prior to the current presentation. Transvaginal ultrasound revealed a rapidly growing, well-circumscribed mass (from 2.5 to 6.6 cm during 3 months) in the lower uterus, featuring a hypoechoic halo, internal calcifications and rich vascularity (Figure 1A,1B). Serum β-hCG was strikingly elevated at 59,364.62 mIU/mL. Her history included no molar pregnancy. Due to a documented gadolinium allergy, CEUS was subsequently performed. It demonstrated early, intense, and heterogeneous enhancement of the solid components with well-defined margins and extensive central necrosis (Figure 1C). Staging computed tomography (CT) showed no evidence of distant metastasis; however, it could not definitively characterize the nature of the primary uterine lesion (Figure 1D). These features are concerning and do not exclude the presence of a malignant uterine tumor. A diagnosis of stage I GTN was made according to the International Federation of Gynecology and Obstetrics (FIGO) staging system. The patient received five cycles of neoadjuvant multi-agent chemotherapy with a modified EMA-CO regimen (etoposide, methotrexate, and actinomycin D). Serum β-hCG levels declined from 12,764.4 to 13.5 mIU/mL over the course of five cycles of chemotherapy. Following total hysterectomy, histopathology confirmed pure ETT, showing epithelioid morphology, necrosis, and hyalinized stroma (Figure 1E). Immunohistochemistry was positive for CK18, p63, and focally for hCG, with a Ki-67 index of 40% (Figure 1F). No choriocarcinoma component was identified. Postoperatively, β-hCG normalized and has remained within the normal range after completion of consolidation therapy. 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 Declaration of Helsinki and its subsequent amendments. Written informed consent was provided by the patient for the publication of this article and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Figure 1 Imaging and histopathological findings of epithelioid trophoblastic tumor. (A) Grayscale ultrasound shows a hypoechoic mass (×) with clear boundaries and hypoechoic halo (arrows) between the lower anterior uterine wall and cervix, containing internal punctate hyperechoic foci (calcifications). (B) Color Doppler imaging demonstrates rich internal vascularity within the mass (×). (C) Contrast-enhanced ultrasound reveals early, intense, and heterogeneous enhancement with well-defined borders (arrows) and extensive non-enhancing necrotic areas (*). (D) Axial contrast-enhanced CT shows a hypodense mass (×) with heterogeneous density and marked heterogeneous enhancement. (E) Microscopic examination reveals epithelioid tumor cells arranged in nests and nodules, with necrosis and hyalinized stroma, and absence of features typical of choriocarcinoma (HE, ×100). (F) Immunohistochemistry demonstrates a Ki-67 proliferation index of approximately 40% (×100). CT, computed tomography; HE, hematoxylin and eosin.

Discussion

This case challenges the conventional biochemical profile of ETT and highlights the complementary role of imaging in the integrated diagnostic work-up. The presented β-hCG level is extraordinarily high for a pure ETT, a range typically pathognomonic for choriocarcinoma (1-3). This expands the recognized biochemical spectrum of ETT and critically emphasizes that markedly elevated β-hCG alone should not definitively rule out ETT. Misclassification carries significant consequences, as the core treatment for ETT is surgical resection, often preceded by chemotherapy, whereas choriocarcinoma is primarily chemosensitive (1). Therefore, recognizing this atypical presentation is essential to avoid delaying potentially curative surgery.

The ultrasound findings of a well-circumscribed mass with internal calcifications are features documented in ETT but rare in choriocarcinoma (4). Most notably, to our knowledge, this is the first report detailing the CEUS features of ETT. CEUS clearly delineated the tumor’s enhancing solid portions from necrosis and confirmed its well-defined borders, a pattern less consistent with the aggressive, infiltrative growth of choriocarcinoma. This highlights CEUS as an alternative for lesion characterization when contrast-enhanced MRI is contraindicated (5). The definitive diagnosis relied on histopathology confirming pure ETT without a choriocarcinoma component. The findings suggest that extremely high β-hCG can originate from ETT itself, or that preoperative chemotherapy eradicated a potential high-hCG-producing focus.

The significant decline in β-hCG during neoadjuvant chemotherapy demonstrates the regimen’s effectiveness in reducing tumor burden. However, the persistence of a radiographically visible mass and the final histopathological confirmation of pure ETT are noteworthy. In cases of mixed trophoblastic tumors, chemotherapy may effectively eliminate choriocarcinoma components, potentially leaving behind less responsive ETT. This underscores the necessity of histologic confirmation following neoadjuvant therapy, as residual disease may indicate chemotherapy-resistant ETT requiring surgical resection.

Distinguishing ETT from choriocarcinoma pathologically is crucial due to differing treatments. ETT typically shows nests of monomorphic epithelioid cells with modest atypia, necrosis and hyalinized stroma, and is immunohistochemically positive for p63 and cytokeratins (e.g., CK18), with focal hCG staining and a Ki-67 index generally between 10% and 25%. In contrast, choriocarcinoma exhibits a biphasic pattern with marked atypia, hemorrhage, no stroma, diffuse strong hCG expression, p63 negativity, and a high Ki-67 index (>50%). In our case, the findings—p63 positivity, focal hCG staining, a Ki-67 of 40%, and absence of choriocarcinoma elements—confirmed pure ETT, underscoring the need for careful pathological assessment (3,6). The elevated Ki-67 index aligns with the tumor’s aggressive clinical behavior (rapid growth and very high β-hCG) and does not conflict with the diagnosis given its otherwise classic pathological profile.

Conclusions

In conclusion, this report highlights that ETT can present with choriocarcinoma-range β-hCG levels. A comprehensive evaluation integrating atypical imaging features—particularly via modalities such as CEUS—and histopathology is crucial for accurate diagnosis and for guiding the correct therapeutic strategy toward surgery.

Acknowledgments

None.

Footnote

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1-2800/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. 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 Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this article and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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