Concurrent human epidermal growth factor receptor 2-positive breast cancer with axillary nodal metastasis in a patient with pituitary prolactinoma: a case report

Introduction

Pituitary prolactinoma represents the most common functional pituitary adenoma, most frequently managed effectively with continuous dopamine agonists such as cabergoline (1,2). While prolactin (PRL) plays a multifaceted biological role in normal mammary development and potential carcinogenesis, the clinical reality of optimizing treatment for patients who develop early, aggressive breast cancer (BC) while under active neuro-endocrine control remains severely underexplored.

Small-sized BCs (T1b, ≤1cm) generally carry a highly favorable prognosis characterized by a remarkably low risk of early lymphatic dissemination (3,4). However, when exceptionally aggressive tumor biological features—such as human epidermal growth factor receptor 2 (HER2) amplification and a high Ki-67 index—intersect with a systemic endocrine comorbidity, distinctly uncharacteristic clinical behaviors may emerge. Contemporary authoritative guidelines, such as the 2024 National Comprehensive Cancer Network (NCCN) updates and European Society for Medical Oncology (ESMO) consensus, provide robust treatment frameworks for HER2-positive BC (5,6). Nevertheless, they lack specific actionable evidence evaluating polypharmacy safety [combining dual-HER2 blockade, tyrosine kinase inhibitors (TKIs), and continuous dopamine agonists] and biological disease evolution in this specific endocrine patient subset (7).

Herein, we successfully managed a unique clinical scenario: a postmenopausal woman presenting with a minuscule primary breast tumor (0.8 cm) that had already established robust axillary node spread, entirely discordant with its physical size. Strikingly, this progression occurred despite her serum PRL levels being strictly maintained within the normal reference range through active medication. Stripping away broad epidemiological debates regarding uncontrolled hyperprolactinemia, this case report aims to validate the safety of concurrent multidisciplinary treatments and contextually scrutinize the specific biological mechanisms of early nodal metastasis. We present this article in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-2026-0018/rc).

Case presentation

Patient and clinical history

A 56-year-old postmenopausal woman presented to Breast Disease Diagnosis and Treatment Center, Shanghai Baoshan Hospital of Integrated Traditional Chinese and Western Medicine with a chief complaint of a painless, palpable mass in the outer quadrant of her left breast, which she had noticed growing extremely slowly over approximately 2 years. Her past medical history was highly significant for a pituitary prolactinoma diagnosed 5 years prior, for which she was stably maintained on cabergoline (0.5 mg daily). Under this regimen, serial measurements over the exact 5 years preceding her BC diagnosis demonstrated that her serum PRL was strictly controlled between 8 and 15 ng/mL. Explicitly, there were no documented transient PRL elevations or spikes during the 2-year history of her breast mass development.

Examination: comprehensive physical examination revealed a firm, mobile, approximately 1 cm mass located in the upper outer quadrant of the left breast. Crucial negative findings included the absolute absence of spontaneous or induced galactorrhea, nipple discharge, skin tethering, and clinical visual field defects—all of which confirmed strong ongoing control of her prolactinoma. Palpation of the axilla identified slightly enlarged, firm, and mobile left axillary lymph nodes. She actively declined germline BRCA1/2 genetic testing.

All procedures performed in this case 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 case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Diagnostic work-up

Pituitary imaging: contrast-enhanced pituitary magnetic resonance imaging (MRI) confirmed a stable, small (3 mm × 1 mm) non-enhancing cystic-appearing lesion in the mid-posterior pituitary without stalk deviation or suprasellar extension (Figure 1A).

Figure 1 Imaging and histopathological findings of concurrent pituitary prolactinoma and HER2-positive BC with axillary nodal metastasis. (A) Pituitary MRI showing a stable, small (3 mm × 1 mm) non-enhancing cystic-appearing lesion in the mid-posterior pituitary without stalk deviation or suprasellar extension, consistent with pharmacologically treated prolactinoma. (B) Breast MRI reveals a small enhancing nodule (3 mm × 5 mm) posterior to the left nipple exhibiting irregular spiculated margins, early enhancement and washout, and restricted diffusion, coupled with enlarged left axillary nodes, categorized as clinical BI-RADS 4a. (C) Axillary MRI demonstrating metastatic lymph node(s) in BC with pathologic enhancement. (D) BC tissue stained with H&E at a magnification of 40×10, showing characteristic features of invasive ductal carcinoma, Nottingham grade 2. (E) Metastatic lymph node tissue stained with H&E at a magnification of 40×10, independently confirming the breast origin of metastatic adenocarcinoma cells. BC, breast cancer; BI-RADS, Breast Imaging Reporting and Data System; H&E, hematoxylin and eosin; HER2, human epidermal growth factor receptor 2; MRI, magnetic resonance imaging.

Breast imaging: breast MRI revealed a small, enhancing nodule (3 mm × 5 mm) posterior to the left nipple exhibiting irregular spiculated margins, early enhancement with rapid washout, and restricted diffusion. Coupled with functionally enlarged left axillary lymph nodes, this lesion was categorized radiologically as Breast Imaging Reporting and Data System (BI-RADS) 4a (Figure 1B,1C).

Surgery and pathology

On January 31, 2023, the patient initially underwent an excisional biopsy of the left breast mass. Intraoperative frozen section analysis definitively confirmed the lesion as an invasive carcinoma. Concurrently, a sentinel lymph node biopsy was performed, which revealed metastasis in one sentinel lymph node.

Consequently, the surgical plan was expanded to a left breast modified radical mastectomy with a completion axillary lymph node dissection (ALND). Although breast-conserving surgery was technically debated, the conversion to a modified radical mastectomy was chosen for two primary reasons: the tumor’s physical proximity to the nipple, and the patient’s explicit refusal to undergo breast-conserving surgery.

Final meticulous pathology demonstrated an invasive carcinoma of no special type (NST), Nottingham grade 2, measuring precisely 0.8 cm (pT1b). The associated high-grade ductal carcinoma in situ (DCIS) component constituted ~10% of the localized lesion and, critically, exhibited the exact same HER2-amplified status (3+) as the highly active invasive component. The completion ALND yielded a total of 2 positive nodes out of 27 evaluated (Figure 1D,1E). Therefore, the final pathologic stage was definitively calculated as pT1bN1aM0. Complete biomarker profiling confirmed: estrogen receptor (ER) 40% (2+), progesterone receptor (PR) 3% (1+), HER2 uniformly positive [3+ and fluorescence in situ hybridization (FISH) amplified], and a dangerously high Ki-67 index of 40% (Table 1).

Adjuvant therapy and outcome

A comprehensive, aggressive adjuvant strategy was pursued. From February to July 2023, the patient received a standard anthracycline-taxane based chemotherapy regimen (epirubicin + cyclophosphamide followed by docetaxel) (8). Concurrently, dual anti-HER2 targeted therapy with trastuzumab and pertuzumab was initiated and administered for one full year. Adjuvant chest wall and regional axillary radiotherapy were additionally administered.

To maintain her endocrine health, the patient explicitly continued the use of cabergoline (0.5 mg daily) uninterrupted throughout this exhausting oncological sequence. For BC endocrine therapy, she was eventually transitioned to the aromatase inhibitor letrozole (2.5 mg daily). At the 36 months post-surgery milestone, the patient remains completely disease-free with highly stable pituitary function. Her serum PRL levels have remained consistently in the 8–15 ng/mL range at all follow-up visits (Tables 2,3).

Discussion

Tumor biology and early nodal dissemination

This case presents a clinically striking scenario: a 56-year-old patient with a primary breast lesion of only 0.8 cm (pT1b) who nonetheless exhibited early axillary nodal dissemination (pN1a). While recent large-scale registry data suggest that treated hyperprolactinemia does not significantly increase the overall incidence of BC (9), the biological intersection between PRL signaling and HER2-positive tumor behavior warrants a case-specific analysis. Conventional paradigms suggest that small T1b tumors are associated with a favorable prognosis; however, the presence of HER2 amplification and a high Ki-67 index (40%) shifts the focus toward an aggressive, biology-first model of metastasis (10).

At the molecular level, the PRL receptor (PRLR) represents a compelling therapeutic and diagnostic target in BC (11). PRL signaling has been shown to regulate transcriptional programs that enhance tumor resistance and invasiveness (12). Specifically, PRL-driven pathways can promote physiological “stemness” within the tumor microenvironment, potentially conferring a high capacity for early lymphatic escape and therapeutic resistance, even when systemic PRL levels are pharmacologically suppressed (13). In this patient, the historical endocrine milieu—marked by long-standing treated prolactinoma—may have primed the mammary stroma or activated localized PRLR-mediated signaling, facilitating nodal spread despite a small primary tumor volume.

Treatment compatibility and clinical management

The successful management of this patient involved reconciling intensive anti-HER2 regimens with ongoing pituitary-directed therapy. Current frameworks for HER2-positive early BC emphasize the necessity of dual-targeted blockade combined with taxane-based chemotherapy, particularly in node-positive disease (14,15). Given the contemporary landscape of BC statistics, where early detection and aggressive biology often overlap (16), the priority is to maintain adherence to these high-intensity protocols without compromising the management of comorbid conditions.

Integrating cabergoline with modern oncological agents requires a nuanced understanding of potential overlapping toxicities. While a 2023 international consensus provides clear guidelines for the diagnosis and management of prolactin-secreting adenomas (17), it offers limited guidance on navigating concurrent oncological treatment. For instance, the rigorous cardiac monitoring essential for patients receiving trastuzumab and pertuzumab must be maintained regardless of the pituitary status. Furthermore, as the patient transitioned to extended adjuvant therapy with neratinib—a strategy recommended by the latest 2024/2025 clinical guidelines for high-risk HER2-positive patients (5)—new practical challenges emerged. Neratinib management requires proactive strategies to mitigate adverse effects, most notably diarrhea (18), which must be carefully balanced with the patient’s existing endocrine stability.

Contemporary evidence and synthesis

This case demonstrates that the “knowledge gap” regarding the safety of combining intensive dual-HER2 blockade and neratinib with dopamine-agonist therapy can be bridged through multidisciplinary surveillance. The stability of the patient’s pituitary function throughout chemotherapy and radiotherapy confirms the feasibility of these concurrent treatments. Future directions should prioritize characterizing individualized PRLR-pathway activity within tumor tissue to better predict which patients with endocrine comorbidities are at risk for early metastatic spread. Ultimately, this report establishes a safe clinical precedent for the integrated use of modern oral targeted therapies and standard-of-care adjuvant regimens in the presence of stable pituitary prolactinomas.

Limitations and future directions

This single case report establishes a clinical association rather than absolute causality between local PRL-receptor crosstalk and accelerated metastatic phenotypes. Retrospectively, specialized immunohistochemical staining specifically evaluating tumor-intrinsic PRLR expression or downstream phosphorylated signal transducer and activator of transcription 5 (STAT5) was technically unavailable. To fully understand these paradoxical presentations, future translational algorithms must firmly shift towards scrutinizing the integrated cellular crosstalk between HER2 and local PRLR signaling exclusively within the specific tumor microenvironment, investigating tissue-level interactions independently of circulating PRL volume.

Conclusions

We describe an exceptionally rare clinical phenomenon demonstrating robust early axillary lymphatic metastasis from a sub-centimeter, HER2-positive (3+) BC concurrent with a pharmacologically neutralized pituitary prolactinoma. This case establishes the critical safety, therapeutic compatibility, and physiological stability of continuously maintaining dopamine agonists un-interrupted alongside intensive multidisciplinary systemic anti-cancer therapies. To logically decode the early dissemination of highly proliferative minute tumors under strictly normal PRL parameters (8–15 ng/mL), clinical oncology must evaluate localized tumor microenvironment pathway crosstalk and heavily individualize polypharmacy care.

Acknowledgments

The authors thank the patient for providing written informed consent for publication of this case report.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-2026-0018/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-2026-0018/prf

Funding: This study was supported by Youqing (Yucai) Program of Shanghai Baoshan District Health Commission (No. BSWSYC-2024-05); Medical and Health Project of Baoshan District Science and Technology Committee in Shanghai (No. 21-E-59); Shanghai Municipal Health Commission & Shanghai Administration of Traditional Chinese Medicine Shanghai General Hospital Integrated Chinese-Western Collaborative Guidance Program (No. ZXXT-202404); Zhang Weihong Baoshan District Famous TCM Master Inheritance Studio (No. BSMZYGZS-2024-03); National Natural Science Foundation of China (No. 82505584); and Clinical Research Special Project of Health Industry, Shanghai Municipal Health Commission (No. 20234Y0203).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-2026-0018/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 case 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 case report 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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