Misdiagnosis and Reflections on Two Cases of Placental Site Trophoblastic Tumors

Placental site trophoblastic tumor (PSTT) is a rare subtype of gestational trophoblastic disease that is often misdiagnosed because of non-specific clinical symptoms, normal or mildly elevated β-hCG levels, and inconclusive imaging findings.¹ Preoperative pathological diagnosis is often challenging, the safety of hysteroscopy remains controversial, and prognostic factors are complex. Given the limited clinical experience with this rare tumor, this article reports two cases of PSTT that were initially misdiagnosed to explore diagnostic pitfalls, the safety of hysteroscopy, and prognostic factors, supplemented by a targeted literature review.

A 30-year-old woman (gravida 1, para 1) with a 10-year history of polycystic ovary syndrome (PCOS) conceived after ovulation induction and delivered a full-term infant via cesarean section in December 2023. Six months postpartum, she developed persistent scant vaginal spotting that continued for 1 year before she sought medical attention. Urine human chorionic gonadotropin (hCG) test results were negative. Transvaginal ultrasonography detected a 2.7 × 1.4 cm heterogeneous echogenic lesion on the right side of the uterine cavity, with an ill-defined myometrial border, as well as polycystic changes in both ovaries. Routine blood work and chest radiography were unremarkable. She was initially diagnosed with abnormal uterine bleeding suspicious for a submucosal uterine fibroid with concomitant PCOS.

The patient underwent hysteroscopic myomectomy and diagnostic curettage. Postoperative histopathology and immunohistochemistry confirmed PSTT, with positive staining for human placental lactogen (hPL), CD146, and Ki-67 (> 10%) and negative staining for p63 (Figure 1). On readmission, her serum hCG level was 4.3 IU/L, which was within the normal range. Contrast-enhanced chest and abdominal computed tomography (CT), non-contrast brain magnetic resonance imaging (MRI), and contrast-enhanced pelvic MRI excluded distant metastases. After counseling regarding the risks and benefits of treatment, the patient and her family elected to undergo total hysterectomy with bilateral salpingectomy. Final pathology confirmed PSTT with superficial myometrial invasion. At the 1-year follow-up, her serum hCG level remained below 2.3 IU/L, with no evidence of recurrence or metastasis.

Figure 1.

(a, b) The tumor cells are arranged in sheets or clusters, with abundant bichromatic cytoplasm, and infiltrate the smooth muscle of the muscularis layer. (c) Immunohistochemistry showed CD146-positive cells; (d) immunohistochemistry showed Ki67-positive cells (> 10%+).

A 24-year-old healthy woman (gravida 1, para 1) underwent a full-term vaginal delivery 1 year before presentation. She reported 1 month of amenorrhea with a positive urine hCG test; serum hCG levels fluctuated between 80 and 100 IU/L. No gestational sac was visualized on pelvic ultrasonography, leading to a misdiagnosis of ectopic pregnancy and treatment with herbal medicine, specifically a customized compound decoction of traditional Chinese medicine. Her hCG level failed to decline and gradually increased to 103.1 IU/L. Repeat transvaginal ultrasonography identified a 2.3 × 1.7 cm heterogeneous hypoechoic intrauterine lesion, which was misdiagnosed as retained products of conception. Treatment with mifepristone plus herbal medicine was administered. This treatment constituted off-label, empirical use of the medication and was administered after thorough discussion between the physician and patient and with the patient’s consent. However, her hCG levels did not decrease.

The patient then underwent hysteroscopic excision of the focal lesion. Postoperative histopathology and immunohistochemistry confirmed PSTT, with patchy hPL positivity, CD146 positivity, Ki-67 expression of approximately 30% in hot spots, and negative p63 staining (Figure 2). Imaging, including contrast-enhanced chest and abdominal CT, non-contrast brain MRI, and contrast-enhanced pelvic MRI, confirmed the absence of distant metastases. Following an informed discussion of management options, the patient underwent total hysterectomy with bilateral salpingectomy. Pathology confirmed superficial myometrial invasion by PSTT. Her serum hCG level decreased to below 2.3 IU/L shortly after surgery. At the 1-year follow-up, she remained disease-free, with no signs of recurrence or distant metastasis.

Figure 2.

(a, b) The tumor cells are arranged in sheets or clusters, with abundant bichromatic cytoplasm, and infiltrate the smooth muscle of the muscularis layer. (c) Immunohistochemistry showed CD146-positive cells; (d) immunohistochemistry showed Ki67 positivity, with a positivity rate of 30% in the hotspot regions.

Both cases described above reflected the typical clinical misdiagnosis of PSTT. As a rare type of gestational trophoblastic neoplasia, PSTT accounts for only 0.2% of all gestational trophoblastic disease cases, with an incidence of approximately 1 per 100,000 pregnancies.^{1, 2} First, its core clinical manifestations, including irregular vaginal bleeding and secondary amenorrhea, overlap substantially with those of common benign gynecological diseases, creating considerable challenges for early differential diagnosis.³ In terms of serological characteristics, PSTT originates from intermediate trophoblasts; accordingly, most patients have normal or mildly elevated β-hCG levels, which differs markedly from the substantially elevated hCG concentrations observed in choriocarcinoma and invasive hydatidiform mole.^{1, 4} In addition, pelvic ultrasonography lacks pathognomonic imaging features, making it difficult to distinguish PSTT from uterine fibroids or adenomyosis.⁵ The gold standard for definitive PSTT diagnosis is histopathological examination combined with immunohistochemical staining. Unfortunately, PSTT lesions often invade deeply into the myometrium while the endometrium maintains a nearly normal appearance, so routine curettage and hysteroscopic biopsy may yield limited tissue samples for diagnosis.² Coupled with clinicians’ insufficient understanding and limited practical experience with this rare disease, the rate of definitive preoperative diagnosis of PSTT remains extremely low, posing a widespread clinical challenge.

As can be seen from this, histopathological examination is indispensable for confirming PSTT. Diagnostic tissue specimens are mainly obtained through uterine curettage, hysteroscopic biopsy, or surgical excision of focal lesions.⁶ Nevertheless, targeted clinical studies remain scarce regarding whether hysteroscopic surgery increases the risk of pelvic or abdominal tumor implantation, seeding, or distant metastasis in patients with PSTT. From the perspective of biological behavior, PSTT is an indolent trophoblastic tumor with a tendency toward localized progression; the vast majority of lesions are confined to the uterus, and the incidence of distant metastasis is relatively low.^{7, 8} Consistent with this clinical feature, both patients at our center received a confirmed diagnosis through hysteroscopic tissue sampling before undergoing total hysterectomy. Importantly, neither intraoperative tumor seeding nor postoperative pathological evidence of metastasis was observed in either case. For young patients with PSTT who desire fertility preservation, fertility-sparing surgery can be considered after a comprehensive preoperative risk assessment, and hysteroscopic surgery may be a viable option for patients with small PSTT lesions confined to the endometrium or partially protruding into the uterine cavity.¹ Moreover, accumulated long-term follow-up data have supported the safety of this fertility-sparing strategy: multiple patients with PSTT have successfully conceived after hysteroscopic conservative surgery, and no tumor recurrence or distant metastasis was reported during prolonged surveillance.⁹ Taken together, existing clinical evidence and practical experience with fertility-sparing procedures indirectly suggest that hysteroscopic intervention does not increase the risk of pelvic or abdominal tumor implantation or distant metastasis in patients with PSTT.

Due to the rarity of PSTT, most prognostic analyses are limited by small sample sizes, and relevant retrospective studies have conducted only preliminary investigations of high-risk prognostic factors. To date, two independent adverse prognostic indicators have been widely recognized. On the one hand, an interval of ≥ 48 months from the last pregnancy to PSTT diagnosis predicts poor overall survival;¹⁰ Froeling et al.¹¹ confirmed that such patients have a markedly increased risk of death (hazard ratio = 14.57, p < 0.001). On the other hand, extrauterine metastasis is closely associated with an unfavorable prognosis.¹⁰ A retrospective analysis conducted by Liu et al.⁴ demonstrated that FIGO stage IV is an independent high-risk factor for poor PSTT outcomes. Moreover, multiple univariate studies have identified several other risk factors associated with adverse prognosis, including a high mitotic count (> 5 mitoses per 10 high-power fields), deep myometrial invasion (involving more than half of the myometrial layer), serosal infiltration, extensive tumor necrosis, and lymphovascular space invasion.^{2, 10} Notably, no existing studies have confirmed that hysteroscopic surgery is an independent risk factor affecting the prognosis of patients with PSTT.