A Diagnostic Dilemma in a Breast Cancer Patient on Tamoxifen: Perihepatic Endometriosis Masquerading as Metastatic Disease

Breast cancer metastasis to the liver carries a poor prognosis, and the identification of hypermetabolic hepatic or perihepatic lesions on 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in a patient with a known oncological history typically raises immediate concern for disease progression. We report the case of a 49-year-old woman with a prior history of breast cancer, managed on tamoxifen, in whom PET/CT and conventional CT imaging demonstrated findings highly suggestive of widespread osseous and peritoneal metastases. Surgical excision of the dominant perihepatic lesion revealed endometriosis on histopathological examination, with no evidence of malignancy. The coexisting skeletal lesions, by contrast, represented true osseous metastases and were treated with systemic therapy. This case illustrates the potential for endometriosis, particularly in the context of tamoxifen-associated endometrial stimulation, to generate false-positive findings on functional imaging, and underscores the essential role of tissue biopsy in guiding oncological decision-making.

18F-FDG PET/CT, false-positive imaging, selective estrogen receptor modulator, histopathology, case report

Breast cancer represents the most prevalent malignancy and the leading cause of cancer-related mortality among women globally.1 Distant metastasis develops in approximately 25–30% of patients, with the liver constituting one of the most frequently involved sites.2,3 Breast cancer liver metastasis (BCLM) is associated with a median overall survival of three to six months in the absence of treatment, rendering accurate and timely staging of critical therapeutic importance.4 Contemporary oncological practice relies extensively on 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) for lesion characterization and disease restaging, given its high sensitivity for detecting metabolically active foci.5 However, PET/CT is not entirely specific. Elevated 18F-FDG uptake reflects increased glucose transporter activity and glycolytic metabolism, features shared not only by aggressive neoplasms but also by a range of inflammatory and benign pathological processes. Among these, endometriosis is a recognized diagnostic mimic, capable of generating hypermetabolic lesions that are indistinguishable from metastatic deposits on functional imaging.6 Endometriosis is a chronic, estrogen-dependent inflammatory disorder defined by the ectopic implantation of endometrial glands and stroma beyond the uterine cavity. While predominantly a pelvic disease, extrapelvic manifestations have been reported in the lungs, diaphragm, and, exceedingly rarely, the liver.7,8 Hepatic and perihepatic endometriosis is documented in fewer than 40 cases in the English-language literature, and correct preoperative identification occurs in only approximately 16% of reported cases, reflecting the considerable diagnostic challenge it poses.9 The complexity of this diagnostic landscape is further compounded in patients receiving tamoxifen, a selective estrogen receptor modulator (SERM) widely employed in adjuvant breast cancer therapy. Although tamoxifen exerts anti-estrogenic effects within breast tissue, it acts as a partial estrogen agonist at the level of the endometrium. This paradoxical agonism, particularly pronounced in the postmenopausal hormonal milieu, has been associated with a nearly twofold increase in the risk of endometriosis and may stimulate the proliferation of pre-existing or de novo endometriotic foci.10,11 The resulting lesions may achieve sufficient metabolic activity to resemble metastatic recurrence on PET/CT.6 We present a case that illustrates these diagnostic challenges, with the aim of raising awareness of this rare but clinically important pitfall in the oncological evaluation of breast cancer patients on tamoxifen. Case Presentation A 49-year-old woman presented with right shoulder pain. Her medical history was significant for left modified radical mastectomy (MRM) performed nearly nine years prior for breast cancer, right breast augmentation performed concurrently, and ongoing adjuvant therapy with tamoxifen 20 mg orally daily. The primary tumor was a grade 2 invasive ductal carcinoma, staged as ypT1c N1(mi) M0. It was estrogen receptor-positive and HER2-positive, and adjuvant tamoxifen was prescribed on this basis. Her initial liver magnetic resonance imaging (MRI) at that time was unremarkable (Figure 1). In the evaluation of her presenting complaint, 18F-FDG PET/CT was performed and demonstrated multiple intensely hypermetabolic osseous lesions involving the right shoulder and multiple vertebral bodies, findings considered highly suspicious for skeletal metastases. An additional intensely hypermetabolic hepatic lesion was identified, similarly interpreted as consistent with metastatic disease (Figure 2). Subsequent contrast-enhanced computed tomography (CT) of the abdomen and pelvis revealed a right subdiaphragmatic/perihepatic soft tissue mass, reported as likely representing peritoneal metastasis (Figure 3). | Figure 3 Axial contrast-enhanced CT of the abdomen demonstrating right subdiaphragmatic/perihepatic soft-tissue thickening (white arrows) corresponding to the FDG-avid focus identified on PET/CT (Figure 2). | Given the apparent imaging burden of disease, the patient was referred for surgical evaluation. The decision was made to proceed with excision of the right subdiaphragmatic peritoneal lesion prior to initiating systemic therapy, in order to obtain histopathological confirmation. Pathological examination of the surgical specimen demonstrated endometriosis. No evidence of metastatic breast carcinoma was identified. Follow-up CT of the abdomen confirmed complete resolution of the right subdiaphragmatic/perihepatic soft tissue abnormality following excision (Figure 4). The intensely FDG-avid osseous lesions involving the right shoulder and vertebral bodies were consistent with true skeletal metastases, in contrast to the perihepatic lesion, which proved to be benign endometriosis. The patient received systemic oncological therapy for the skeletal metastatic disease and remains under oncology follow-up, with stable disease to date.

The Diagnostic Limitations of 18F-FDG PET/CT in Oncological Staging The identification of new hypermetabolic lesions in a breast cancer survivor with an established treatment history raises concern for disease progression, an interpretation that carries immediate and important therapeutic implications. In this case, the PET/CT findings were both anatomically and metabolically compelling and met conventional radiological criteria for metastatic disease. However, the histopathological findings were discordant and revealed a benign inflammatory etiology. This discordance illustrates a well-recognized limitation of functional imaging: 18F-FDG uptake is a marker of cellular metabolic activity rather than a specific indicator of malignancy. False-positive findings are documented across a spectrum of benign conditions, including infectious foci, granulomatous disease, post-procedural inflammatory changes, and endometriosis.5 Published data indicate that endometriotic lesions demonstrate a variable maximum standardized uptake value (SUVmax) ranging from 1.8 to 5.3, with a median of 3.8, values that overlap substantially with those observed in low-grade malignancies and are sufficient to generate clinically significant false-positive interpretations, particularly in the perihepatic and subdiaphragmatic compartments where peritoneal metastases are routinely suspected.6 Tamoxifen as a Contributory Factor in Endometriosis Presentation The pathogenesis of this patient’s perihepatic endometriosis cannot be considered in isolation from her pharmacological background. Tamoxifen remains a cornerstone of adjuvant therapy for estrogen receptor-positive breast cancer, where its anti-estrogenic mechanism substantially reduces the risk of locoregional and distant recurrence.12 However, its tissue-specific pharmacodynamics present a clinically important paradox: while functioning as an estrogen antagonist in the breast, tamoxifen exerts partial estrogen agonist activity at the endometrium, uterus, and potentially at ectopic endometrial implants.13,14 This agonistic effect is particularly amplified in the postmenopausal hormonal environment, where the absence of circulating endogenous estrogen renders endometrial tissue more sensitive to the weak estrogenic stimulus provided by tamoxifen. Epidemiological evidence suggests that postmenopausal women receiving tamoxifen carry a 1.9-fold increased risk of developing endometriosis relative to untreated controls.15 Tamoxifen exposure has also been shown to stimulate both de novo formation and accelerated proliferation of pre-existing endometriotic foci, which may drive the development of metabolically active, space-occupying lesions that resemble metastatic deposits on imaging.16,17 The Rarity and Diagnostic Difficulty of Hepatic and Perihepatic Endometriosis Extrapelvic endometriosis represents a diagnostically demanding entity in its own right; hepatic and perihepatic involvement constitutes one of its rarest manifestations. Fewer than 40 cases have been reported in the English-language literature to date.9 The clinical presentation is characteristically non-specific: a systematic review identified right upper quadrant pain as the predominant symptom in 87.5% of affected patients, yet correct preoperative diagnosis was achieved in only 16% of cases.18 The majority of patients in reported series received an initial working diagnosis of primary hepatic malignancy, most commonly hepatic epithelioid hemangioendothelioma (HEHE), or metastatic disease, which underscores the degree to which this condition eludes clinical recognition prior to tissue sampling.18,19 The radiological features of hepatic and perihepatic endometriosis on conventional cross-sectional imaging are similarly non-discriminating, with lesions demonstrating variable morphology, enhancement characteristics, and signal intensity that do not reliably distinguish them from malignant processes. In the absence of a clinical history suggestive of endometriosis or pathognomonic imaging features, the diagnosis is almost invariably established only through histopathological examination.20 The Imperative of Histopathological Confirmation This case reinforces a principle that, although foundational to oncological practice, warrants reemphasis in the current era of advanced imaging: histopathological verification remains the reference standard for diagnosis, particularly when imaging findings would prompt a transition from curative to palliative intent. The clinical consequences of misclassifying endometriosis as metastatic carcinoma are substantial and include unnecessary exposure to systemic cytotoxic or hormonal therapies, deterioration in quality of life, and failure to provide definitive surgical management for a condition that may be curable by excision.21,22 In patients with a prior oncological history, the pressure to act quickly on concerning imaging findings is understandable. This case demonstrates that tissue biopsy, even when it requires a surgical approach, can refine the assessment of disease extent. Here, biopsy showed the perihepatic lesion to be benign endometriosis rather than peritoneal metastasis, and it was excised with complete resolution, while the coexisting osseous lesions were confirmed as true metastases and managed with systemic therapy. The Risk of Malignant Transformation An important caveat in the management of endometriosis in this clinical context is the documented, albeit low, risk of malignant transformation. Endometriosis is associated with transformation to endometrioid adenocarcinoma or adenosarcoma in approximately 1% of premenopausal and 1–2.5% of postmenopausal women.23,24 This risk may be further potentiated by the proliferative estrogenic stimulus conferred by tamoxifen. While the lesion in this patient was confirmed as benign, the possibility of malignant transformation in tamoxifen-exposed endometriotic foci warrants vigilant long-term surveillance in this patient population.11

This case report documents a clinically significant false-positive oncological finding in a breast cancer patient on tamoxifen, in whom perihepatic endometriosis generated imaging appearances indistinguishable from peritoneal metastatic disease. The case highlights several convergent diagnostic challenges: the inherent metabolic non-specificity of 18F-FDG PET/CT, the paradoxical endometrial stimulatory effects of tamoxifen, and the rarity and diagnostic difficulty of extrapelvic hepatic endometriosis. The principal lesson of this case is that histopathological confirmation remains the gold standard in oncology, particularly when imaging findings would fundamentally alter the therapeutic intent. For breast cancer patients receiving tamoxifen, the differential diagnosis of newly identified hypermetabolic abdominal or perihepatic lesions should be broadened to include treatment-related benign proliferative conditions. A structured multidisciplinary approach that integrates oncology, radiology, surgery, gynecology, and pathology is essential to ensure diagnostic accuracy, prevent inappropriate therapeutic escalation, and deliver definitive management when a surgically curable etiology is identified. Ethics and Consent Statement Written informed consent was obtained from the patient for the publication of this case report and the accompanying images. Ethical approval was not required for the publication of this case report; a formal exemption (reference number 09348203) was granted by King Saud University, King Saud University Medical City. Disclosure The authors report no conflicts of interest in this work.

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