Persistently elevated estradiol after bilateral salpingo-oophorectomy in recurrent low-grade endometrial stromal sarcoma: a case report

Abstract

Background

Low-grade endometrial stromal sarcoma (LGESS) is a rare uterine mesenchymal neoplasm that frequently expresses estrogen and progesterone receptors. Endocrine therapy is a cornerstone of treatment for recurrent or metastatic LGESS. In premenopausal patients, bilateral salpingo-oophorectomy (BSO) is commonly performed to reduce endogenous estrogen production and would be expected to result in a postmenopausal hormonal profile.

Case

We report the case of a patient with recurrent, metastatic estrogen receptor (ER)/progesterone receptor (PR)-positive LGESS who had previously undergone BSO. Her disease initially responded to aromatase inhibitor therapy; however, she subsequently experienced pulmonary progression, including a large endobronchial metastasis requiring bronchoscopic cytoreduction. Despite pathologically confirmed BSO, further evaluation revealed a hormone profile more consistent with persistent premenopausal estrogen exposure. Given concern that ongoing estrogen exposure may have been contributing to progression of this hormone-sensitive malignancy, treatment was changed to combined leuprolide and letrozole. Three months after initiation of combined endocrine therapy, imaging demonstrated a partial response, which was confirmed at 6 months, accompanied by estradiol levels in the postmenopausal range.

Conclusion

This case raises the possibility that surgical menopause may not always result in complete estrogen deprivation in LGESS. Potential explanations include assay limitations, undetectable residual gonadotropin-responsive steroidogenic tissue, peripheral aromatization, and tumor-associated estrogenic activity. Biochemical evaluation of estrogen status may be informative in select patients whose disease behavior appears discordant with presumed post-oophorectomy menopausal status.

Highlights

• •Persistently elevated estradiol can occur despite pathologically confirmed BSO.
• •Hormone testing clarified cause of unexpected LGESS progression on endocrine therapy.
• •Leuprolide plus letrozole may overcome resistance mechanisms to aromatase inhibitors.
• •Estradiol level may inform endocrine therapy selection in LGESS.

1. Introduction

Low-grade endometrial stromal sarcoma (LGESS) is a rare uterine mesenchymal neoplasm that frequently expresses estrogen receptor (ER) and progesterone receptor (PR) and is usually responsive to hormonal manipulation (Reich et al., 2000). Ovarian suppression is a key component of management in premenopausal patients, and bilateral salpingo-oophorectomy (BSO) is commonly performed to reduce endogenous estrogen exposure (Stewart et al., 2018). Although BSO would be expected to result in a postmenopausal hormonal profile, data regarding estradiol levels following BSO in LGESS are limited, and persistent elevation of estradiol after pathologically confirmed oophorectomy has rarely been reported. Here, we describe a patient with recurrent ER/PR-positive LGESS who demonstrated a premenopausal hormonal profile despite prior BSO, a finding that influenced subsequent choice of endocrine therapy.

2. Case presentation

A 36-year-old G4P3 Hispanic woman underwent hysterectomy with ovarian preservation 5 years earlier for presumed symptomatic fibroids. She was subsequently lost to follow up, and the pathology report and material from the hysterectomy were unavailable for review. Eighteen months prior to presentation at our institution, she developed abdominal pain and a palpable 5 cm mass in the left lower quadrant. Imaging demonstrated multiple pulmonary lesions, including an 8 cm mass on the right upper lobe. Biopsy was consistent with LGESS. She subsequently underwent a robotic-assisted BSO and resection of the abdominal wall mass. Pathology confirmed LGESS of the abdominal wall lesion, while the ovaries and fallopian tubes were unremarkable. She then started on 2.5 mg per day of letrozole, an aromatase inhibitor.

Follow-up computed tomography (CT) imaging three months later demonstrated a marked response, including reduction of the dominant pulmonary lesion from 7 cm to 4 cm, resolution of a pelvic nodule, and decrease in the size of a vaginal cuff lesion. Despite reported adherence to letrozole, repeat imaging three months later demonstrated pulmonary progression with enlargement of the previously responding lesion to 6 cm, raising concern for aromatase inhibitor resistance. Treatment was then changed to fulvestrant. Serum estradiol was not assessed before fulvestrant initiation. She received two loading doses of fulvestrant before relocating to New York. Subsequent CT imaging performed six weeks following initiation of fulvestrant showed further progression of the pulmonary mass to 7 cm, although pelvic disease had improved.

One month later, she presented to the local emergency department with worsening dyspnea and intermittent hemoptysis. CT imaging demonstrated a 9 cm right upper lobe mass with a 3 cm endobronchial component causing airway obstruction, as well as multiple bilateral pulmonary metastases measuring up to 3 cm, multifocal pleural metastases, and a 2 cm right vaginal cuff mass. Bronchoscopic tumor debulking was performed, and biopsy confirmed metastatic LGESS with retained ER and PR expression. Molecular profiling identified a JAZF1-PHF1 fusion, further supporting this diagnosis.

She then established care at Memorial Sloan Kettering Cancer Center. A hormone panel was sent because of the unexpected progression of disease on appropriate endocrine therapy. Despite prior pathologically confirmed BSO, hormonal evaluation demonstrated a follicle-stimulating hormone level of 20.0 mIU/mL, luteinizing hormone level of 10.6 mIU/mL, and estradiol level of 192 pg/mL as measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) (postmenopausal reference range: <10 pg/mL; premenopausal reference range: 15–350 pg/mL). These findings were more consistent with persistent premenopausal estrogen exposure than with the expected hormonal profile following a BSO. Her body mass index was 28 kg/m². Given concern that ongoing estrogen production was contributing to disease progression, treatment was changed to leuprolide with resumption of letrozole.

At a one-month follow-up visit, she reported hot flashes and resolution of her dyspnea. Three months after initiation of combined endocrine therapy, CT imaging demonstrated a partial response with decreased metastatic burden (Fig. 1). The right upper lobe mass decreased in size by 37%, and all bilateral pulmonary metastases decreased in size and became predominately cavitary. In addition, a previously prominent paratracheal lymph node resolved, and the right vaginal cuff lesion decreased in size. At 6 months, the partial response was confirmed, with estradiol levels confirmed in the postmenopausal range (<5 pg/mL).

Fig. 1.

Radiographic response to combined leuprolide and letrozole. Representative chest computed tomography (CT) images before and after initiation of combined endocrine therapy. A) Baseline CT image of the chest demonstrating a large right upper lobe/endobronchial metastatic lesion (arrow) prior to initiation of leuprolide and letrozole. B) CT image of the chest obtained 3 months after initiation of combined endocrine therapy demonstrating partial response of the dominant pulmonary lesion (arrow) and resolution of additional pulmonary nodules.

3. Discussion

LGESS is a hormone receptor-positive uterine mesenchymal neoplasm that typically follows an indolent clinical course and is responsive to endocrine therapy (Stewart et al., 2018). In contemporary large cohorts of LGESS treated with aromatase inhibitors, median progression-free survival exceeds 6 years, highlighting the importance of estrogen signaling in disease pathogenesis and progression (Maccaroni et al., 2022). Against this background, the finding of persistently elevated estradiol levels despite pathologically confirmed BSO in our patient is particularly notable.

The differential diagnosis of persistent elevated estradiol after bilateral oophorectomy includes residual functional ovarian tissue, assay inaccuracy, exogenous estrogen exposure, adrenal or peripheral estrogen production, and, more rarely, tumor-associated steroidogenesis. In the setting of BSO, ovarian remnant syndrome is usually the first consideration (Colombi et al., 2025); however, it is uncommon and usually associated with technically challenging surgery, most often in the setting of extensive adhesions or endometriosis. In our patient, ovarian remnant syndrome was considered less likely given pathologic confirmation of bilateral oophorectomy and the absence of radiographic evidence of residual ovarian tissue on postoperative imaging. Similarly, although occult ectopic ovarian tissue was a theoretical possibility, it was considered less likely given the absence of suggestive radiographic findings on extensive cross-sectional imaging. Alternative explanations included assay-related inaccuracy, adrenal or peripheral steroidogenesis, or tumor-associated aromatase or estrogenic activity.

Standard estradiol immunoassays have limited accuracy at low hormone concentrations and may yield discordant results compared with LC-MS/MS. The Endocrine Society has highlighted the limitations of routine estradiol assays across a variety of clinical settings (Rosner et al., 2013). In addition, studies in women who are receiving aromatase inhibitors have shown substantial discordance between commercial immunoassays and LC-MS/MS, including spuriously elevated results in samples with very low true estradiol concentrations (Santen et al., 2007). Accordingly, interpretation of unexpected estradiol results following oophorectomy ideally should be confirmed using a sensitive mass spectrometry-based assay (Rosner et al., 2013). Fulvestrant can also interfere with certain estradiol assays (Owen et al., 2019), potentially resulting in falsely elevated estradiol measurements. In our patient, however, estradiol level was measured by LC-MS/MS and was well within the premenopausal range, making immunoassay interference an unlikely explanation.

After menopause, peripheral aromatization of adrenal precursors in adipose tissue and skin becomes an important source of estrogen (Nelson and Bulun, 2001). Although the patient did not have significant obesity, a contribution from peripheral aromatization could not be excluded. Along with this, aromatase expression has been shown in LGESS tumor tissue (Reich and Regauer, 2004), providing a biologic rationale for the activity of aromatase inhibitors in this disease. In a subsequent small clinical series, aromatase expression was identified in the available tumors from patients treated with long-term letrozole (Thanopoulou et al., 2015). These observations raise the possibility that local tumor-associated estrogen production may contribute to disease persistence; however, whether aromatase activity within LGESS contributes meaningfully to circulating estradiol levels remains understudied.

Another potential explanation for disease progression on prior aromatase inhibitor therapy is acquisition of an ESR1 mutation resulting in ligand-independent ER signaling (Dessources et al., 2022). Acquired ESR1 mutations are a recognized mechanism of resistance to aromatase inhibitors in other hormone-driven malignancies and have been reported in LGESS. Such a mechanism could potentially explain disease progression despite aromatase inhibitor therapy, but it would not account for the markedly elevated estradiol concentration observed in our patient.

This framework also helps explain the endocrine strategy selected for our patient. Fulvestrant is a selective ER degrader that accelerates receptor degradation but does not directly suppress estrogen synthesis. In a patient with biochemical evidence of persistent premenopausal hormonal profile despite oophorectomy, reducing estrogen production was considered a more biologically rational strategy than ER blockade alone. Combined treatment with a gonadotropin-releasing hormone (GnRH) agonist and an aromatase inhibitor targets complementary sources of estrogen production. GnRH agonists suppress gonadotropin-dependent steroidogenesis, including estrogen synthesis from any occult ovarian or gonadotropin-responsive steroidogenic tissue, while aromatase inhibitors reduce peripheral conversion of adrenal androgen precursors to estrogen (Stewart et al., 2018).

Another important point from this case is that estrogen dependence in LGESS is generally inferred from tumor behavior and responsiveness to endocrine therapy rather than demonstrated through direct hormonal testing. In clinical practice, treatment decisions are typically guided by hormone receptor expression and radiographic response or progression on endocrine therapy. Although LGESS is widely regarded as a hormone-responsive malignancy, this conclusion is based largely on receptor expression patterns and clinical outcomes rather than direct measurement of circulating estrogen levels (Crowley et al., 2022). Our case raises the possibility that biochemical assessment of estradiol status may be informative in select patients with recurrent hormone-driven LGESS, especially when disease progression appears discordant with the presumed menopausal state following BSO.

The broader clinical implication of this case is that surgical menopause may not reliably result in complete estrogen deprivation in patients with LGESS. In recurrent hormone receptor-positive LGESS with concern for endocrine escape, persistent estrogen exposure should be considered even after bilateral oophorectomy. In such cases, combined GnRH agonist therapy and aromatase inhibition may provide more comprehensive suppression of gonadotropin-dependent and peripheral estrogen production than oophorectomy alone. Consistent with this hypothesis, initiation of leuprolide and letrozole in our patient was associated with a decline in estradiol levels from 192 pg/ml to the postmenopausal range (<5 pg/ml) and a durable partial response. Future reports should consider confirmation of unexpected estradiol values with LC-MS/MS and incorporation of serial hormone measurements, as demonstration of biochemical estradiol suppression following endocrine intervention would help establish whether the elevated estradiol represents a biologically meaningful and therapeutically actionable finding. To our knowledge, this is among the first reports of markedly elevated estradiol levels after pathologically confirmed BSO in LGESS and one of the first to demonstrate how such findings may influence endocrine treatment selection.

CRediT authorship contribution statement

Ali Sanjari Moghaddam: Writing – review & editing, Writing – original draft, Conceptualization. Benjamin Pastore: Writing – review & editing, Writing – original draft, Conceptualization. Maria Fernandez Turzio: Writing – review & editing. Samuel McCash: Writing – review & editing, Formal analysis. Jennifer J. Mueller: Writing – review & editing, Formal analysis. Roisin E. O'Cearbhaill: Writing – review & editing, Writing – original draft, Supervision, Data curation, Conceptualization.

Consent statement

Verbal informed consent for publication of this case report and accompanying images was obtained from the patient and documented in the medical record in accordance with institutional guidelines.

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.

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. Not applicable.

This research follows the CARE guidelines and the CARE checklist.

Funding

None.

Declaration of competing interest

REO reports personal fees from AstraZeneca, Loxo, OnCusp, Cardinal Health, Corcept Pharmaceuticals, Tesaro/GSK, Regeneron, Genmab/Pfizer, Genentech, Gilead, GSK, Gynecologic Oncology Foundation, Mylteni, 2seventybio and Immunogen/Abbvie, travel support for the Gathering Around Cancer, Ireland, all outside the submitted work. Her institute receives funding for clinical research from Alkermes, Bayer/Celgene/Juno, Tesaro/GSK, Merck, Ludwig Cancer Institute, Lyell Therapeutics, Context Therapeutics, Iovance, Fate Therapeutics, Abbvie/StemCentrx, Recursion Therapeutics, Regeneron, TCR2 Therapeutics, Atara Biotherapeutics, MarkerTherapeutics, Syndax Pharmaceuticals, Genmab/Seagen Therapeutics, Sellas Therapeutics, Genentech, Kite Pharma, Lilly, Solve Therapeutics and Gynecologic Oncology Foundation. The remaining authors do not have potential conflicts of interest to declare.