A rare case of multifocal/multicentric breast cancer in a young female: a case report and literature review

Introduction

Multifocal (MF) and multicentric (MC) breast cancers, collectively termed MMBC, refer to the presence of more than two synchronous ipsilateral breast carcinomas (1). MF breast cancer is defined as two or more tumors located within the same breast quadrant, and MC breast cancer refers to lesions involving more than one quadrant. MMBC demonstrates variability among different foci and relatively aggressive behavior and worse survival compared to unifocal breast cancer. Considering the heterogeneity and the rarity of MMBC, its surgical strategy and other treatments require comprehensive clinical evaluation supported by extended imaging assessment and overall pathological results. We present this article in accordance with the CARE reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-1-570/rc).

Case presentation

Medical history

The patient was a 38-year-old woman who accidentally discovered a self-palpable mass in the upper outer quadrant of her left breast, approximately 1 cm in size, with no associated discomfort. She presented to our hospital for evaluation. Her breast ultrasound before admission revealed more than ten hypoechoic nodules in the left breast. The largest one, located at the 12 o’clock position approximately 4 cm from the nipple, measured about 1.6 cm × 1.4 cm × 0.8 cm. It was irregular in shape with indistinct margins, and several punctate hyperechoic foci were noted at its periphery. It was assessed as Breast Imaging Reporting and Data System (BI-RADS) 5. The clinical and radiological findings indicated a need for operative intervention. The patient had no significant past medical history. She has a normal obstetrical and menstruation history and denied any family history of breast cancer or other malignancies.

Breast physical examination

In the patient’s physical examination, multiple masses were palpated in the upper quadrant (extending from the 11 to 1 o’clock position) of the left breast, measuring approximately 0.5 to 1.5 cm in diameter (Figure 1). The largest mass, approximately 1.5 cm in size, was located in the upper outer quadrant, about 4 cm from the nipple. All the masses were firm, poorly-defined, moderately mobile, and exhibiting no significant tenderness. No enlarged or hardened lymph nodes were palpated in either axilla or the supraclavicular fossae.

Figure 1 The patient’s physical examination images: (A) the anterior perspective; (B) the 45-degree oblique perspective. Multiple masses were palpated in the upper quadrant (extending from the 11 to 1 o’clock position) of the left breast, measuring approximately 0.5 to 1.5 cm in diameter. The largest mass, approximately 1.5 cm in size, was located in the upper outer quadrant, about 4 cm from the nipple. All the masses were firm, poorly-defined, moderately mobile, and exhibiting no significant tenderness.

Imaging examinations and laboratory tests

All the preoperative laboratory results were within normal limits. In the breast ultrasound, the left breast demonstrated more than ten hypoechoic nodules. The largest one, located at the 12 o’clock position approximately 4 cm from the nipple, measured about 1.6 cm × 1.4 cm × 0.8 cm. It appeared irregular in shape with indistinct margins, and several punctate hyperechoic foci were noted at its periphery. It was assessed as BI-RADS 5 (Figure 2). In the mammography, there was an irregular nodular opacity observed in the upper inner quadrant of the left breast, measuring approximately 15.6 mm × 17.5 mm, with surrounding architectural distortion of the parenchyma, and also categorized as BI-RADS 5 (Figure 3). In the dynamic contrast-enhanced breast magnetic resonance imaging (MRI), multiple nodules and mass-like enhancements could be more clearly seen in the upper aspect of the left breast. The largest one, located superior to the nipple, measured approximately 9 mm × 16 mm, exhibited reduced apparent diffusion coefficient (ADC) values, and demonstrated a predominantly plateau-type kinetic curve on dynamic enhancement (Figure 4). This was rated as BI-RADS 4b. Additionally, several small lymph nodes were noted in bilateral axillae.

Figure 2 The patient’s preoperative breast ultrasound images. There were more than ten hypoechoic nodules in the left breast. Among them, the largest nodule is located at the 12 o’clock position approximately 4 cm from the nipple, measured about 1.6 cm × 1.4 cm × 0.8 cm (yellow arrow). (A) and (B) show the sizes of the tumors in different measurement directions under the ultrasound probe. It appeared irregular in shape with indistinct margins, and several punctate hyperechoic foci were noted at its periphery. It was assessed as BI-RADS 5. BI-RADS, Breast Imaging Reporting and Data System.

Figure 3 The patient’s mammography images: (A) the CC position; (B) the MLO position. There was an irregular nodular opacity (yellow arrow) observed in the upper inner quadrant of the left breast, measuring approximately 15.6 mm × 17.5 mm, with surrounding architectural distortion of the parenchyma (red arrow). It was categorized as BI-RADS 5. BI-RADS, Breast Imaging Reporting and Data System; CC, craniocaudal; MLO, mediolateral oblique.

Figure 4 The patient’s MRI images: (A) multiple enhancing nodules and masses (yellow arrows) in the left breast upper outer quadrant; (B) the masses (red arrows) demonstrate reduced ADC values and a plateau-type dynamic enhancement curve, indicative of malignant potential. ADC, apparent diffusion coefficient; MRI, magnetic resonance imaging.

Operation

Given the patient’s young age, breast conservation was the first surgical approach under consideration. However, given the high suspicion of malignancy in multiple masses and complying with the patient’s request, we decided to proceed multiple mass biopsies, left simple mastectomy, and sentinel lymph node biopsy (SLNB) (using methylene blue mapping) under general anesthesia. Through an arcuate incision in the left breast, several ill-defined, irregular nodules measuring approximately 0.5–1.5 cm in diameter were palpated, distributed from the upper inner to the upper outer quadrant. These nodules, together with surrounding normal glandular tissue, were completely excised (Figure 5). Frozen pathology confirmed MF malignant disease. Masses 1 and 2 showed invasive carcinoma with ductal carcinoma in situ (DCIS); mass 3, invasive carcinoma, and mass 4, DCIS with intraductal papilloma. All blue-stained and palpably enlarged sentinel lymph nodes were removed; no other suspicious nodes were found. Frozen section of the SLNB specimens confirmed no carcinoma (0/5).

Figure 5 The patient’s surgical specimens’ images: (A) gross multifocal specimens from the upper quadrant; (B) four relatively large individual masses after dissection.

Postoperative formalin-fixed paraffin-embedded (FFPE) pathologic diagnosis

The left breast masses were all pathologically diagnosed as moderately differentiated invasive mammary carcinoma of no special type (NST) (Figure 6A,6B, compared to the normal breast tissue in Figure 6C, and Table 1). Masses 1 and 2 (1.1 cm × 0.7 cm × 1.1 cm and 0.6 cm × 0.6 cm × 0.6 cm, respectively) exhibited lymphovascular invasion and were associated with surrounding intermediate-grade DCIS. Masses 3 and 4 were also moderately differentiated invasive mammary carcinoma of NST (1.3 cm × 1.1 cm × 0.9 cm and 0.6 cm × 0.6 cm × 0.6 cm, respectively) showed no lymphovascular or perineural invasion; mass 4 was associated with adjacent DCIS and an intraductal papilloma. Immunohistochemistry (IHC) on the invasive carcinoma revealed consistently positive staining for estrogen receptor (ER) (90%), androgen receptor (AR) (90%), and a Ki-67 index of 10% across all the masses. Differential findings were as follows in IHC staining: masses 1 & 2: progesterone receptor (PR) (strongly positive, 60%), human epidermal growth factor receptor-2 (HER2) (2+); masses 3 & 4: PR (moderately positive, 70%), HER2 (3+) (Figure 6D,6E, compared to the normal breast tissue in Figure 6F). FISH was not performed. All tumors showed scattered P53 positivity and were negative in CK14, CK5/6, EGFR, P63, chromogranin A (CgA), and synaptophysin (Syn).

Figure 6 The patient’s pathological H&E staining images of tumors in (A,B) multifocal specimens from the upper quadrant (400×), compared to (C) the normal adjacent breast tissue (400×) and (D,E) the HER2 staining of the multifocal tumors (IHC staining; 200×) compared to (F) the HER2 staining result of normal breast tissue (IHC staining; 200×). H&E, hematoxylin and eosin; HER2, human epidermal growth factor receptor-2; IHC, immunohistochemistry.

In the simple mastectomy specimen, the left breast tissue showed MF intermediate-grade DCIS with focal microinvasive carcinoma (the largest focus <1 mm, NST, moderately differentiated) without definite lymphovascular or perineural invasion. The nipple, skin, and deep inferior surgical margins were free of cancer infiltration. In the axillary sentinel lymph nodes, several lymph nodes were identified, measuring 0.4 to 0.8 cm in diameter. They showed chronic inflammation, and no metastatic carcinoma was identified (0/5). The pathological tumor-node-metastasis (TNM) stage of this patient is pT1N0M0.

Postoperative course and treatment plan

The patient’s cut healed satisfactorily. The postoperative treatment plan consists of six cycles of TC chemotherapy (docetaxel 120 mg + cyclophosphamide 1,000 mg, administered every 3 weeks) concurrently with HER2-targeted therapy (trastuzumab every 3 weeks for 1 year). Ovarian protection with goserelin will be administered during chemotherapy. Radiotherapy is not required following chemotherapy. Subsequent endocrine therapy is planned (goserelin + anastrozole + calcium carbonate for 5 years, with re-assessment upon completion to determine the necessity for extended therapy).

In her follow-up for evaluation, the patient tolerated the adjuvant treatment regimen well. Follow-up clinical and radiological examinations at 6 months showed no evidence of local recurrence or distant metastasis; however, further long-term follow-up is needed to confirm sustained response.

Ethical consideration

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 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.

Discussion

In clinical practice, due to challenges in precise measurement and diagnostic accuracy, MF and MC are often studied together as MMBC. Most studies showed that about 10% to 20% of breast cancer patients could demonstrate MMBC (2), while the reported prevalence of MMBC varies widely, ranging from approximately 1% to 75% (2-6), primarily due to inconsistent definitions, lack of standardized diagnostic criteria and an increase in detection rates due to improved imaging technology. The most common age of onset in MMBC patients was 35–64 years old (median age more than 50 years old), and MMBC is more prevalent in premenopausal or younger women (2). Most MMBC has two lesions, and the TNM staging of MMBC mostly depends on the diameter of the largest lesion (2). Notably, significant intertumoral heterogeneity is frequently observed among different foci within MMBC, including variations in histologic or molecular subtype, grade, biomarker expression, and other pathological and imaging features.

The standard imaging assessment for MMBC primarily includes mammography, ultrasound, and MRI. Mammography has limited sensitivity for detecting cancerous lesions in dense breasts, and even when combined with ultrasound—which offers higher sensitivity in dense tissue—up to approximately 50% of MMBC cases may be missed (7). Breast MRI plays a valuable role in the preoperative identification of MF lesions, particularly when ultrasound or mammography suggests multiple nodules but cannot establish a definitive diagnosis (8,9). In this case, the display of multiple lesions by mammography was atypical. Ultrasound could show multiple lesions in the upper quadrant but had limited diagnostic significance. However, MRI provided a crucial supplementary basis for preoperative assessment. However, the routine use of MRI in MMBC patients remains controversial, mainly due to its limited specificity in differentiating benign from malignant lesions. MRI can detect additional MMBC in up to 16% of patients (10). The high sensitivity of MRI is accompanied by low specificity, which can lead to the detection of more benign findings and potentially result in unnecessary surgical interventions, such as wider excisions or even mastectomy—as may occur in over 10% of MMBC patients due to false-positive MRI findings (10,11). Therefore, accurate identification of all lesions is critical for breast-conserving surgery. In current clinical practice, ultrasound and mammography are routinely applied together for initial screening, supplemented by MRI when necessary, to improve the detection rate of MMBC. However, completely avoiding missed lesions remains challenging. Advances in imaging techniques such as contrast-enhanced mammography, dynamic contrast-enhanced MRI (12), and diffusion-weighted imaging [sensitivity of MRI + diffusion-weighted imaging (DWI): 96.6% to 100%; sensitivity of DWI + dynamic contrast-enhanced (DCE)-MRI: increasing from 51.2% to 73.1%] (13) are expected to further enhance the sensitivity and specificity of MMBC detection, thereby providing more reliable support for clinical diagnosis.

MMBC can exhibit clonal heterogeneity among different foci. Notably, 7–37% of MMBC cases display significant intertumoral heterogeneity in histology, grade, immunohistochemical markers (e.g., ER, PR, HER2, Ki-67), and molecular subtypes across different tumor foci (2,14,15). Their similar pathological presentations often indicate related or identical oncogenic processes. While in about 37.5% cases, minor lesions are likely to be more aggressive than the primary tumor, suggesting that if the treatment based solely on the dominant focus could lead to undertreatment or poor response in heterogeneous cases could result in significantly worse survival (15,16). Thus, a systematic evaluation of all lesions—including hormone receptor status, HER2 status (17), and genetic profiling (18,19) across all lesions may guide tailored therapeutic strategies and improve clinical outcomes (14,15). In this case, FISH testing was not performed on the HER2 2+ foci, as HER2 3+ positivity had already been confirmed in other tumor foci by IHC. Given this finding and the established treatment strategy for MMBC, the addition of anti-HER2 therapy was indicated irrespective of FISH results. Thus, FISH was not deemed essential per our institutional practice. Nevertheless, we acknowledge the reviewer’s important observation regarding the value of FISH in characterizing HER2 heterogeneity across different foci in MMBC. This highlights a current limitation in the completeness of our diagnostic workflow. Moving forward, we aim to incorporate such testing when clinically warranted and economically feasible for the patient. Moreover, the adjuvant therapy decision was based not solely on the “largest” focus’s pT1N0 status as MMBC usually dose, but also on the aggregate tumor burden and high-risk pathological features present across the multiple synchronous invasive foci. Relatively consistent IHC biomarker profiles and molecular subtypes across all foci supported the use of a unified treatment approach based on pathological findings. According to the patient’s request, as the HER2 expression in some lesions was positive, anti-HER2 targeted therapy and chemotherapy were administered, followed by long-term endocrine treatment. Although some tumor foci were HER2 2+, basing the treatment regimen on the HER2 3+ status of other foci ensures that no eligible foci are left untreated. This broader indication for therapy offers a more comprehensive approach and may contribute to improved patient outcomes. As research on breast carcinogenesis advances, future management of MMBC will likely incorporate more precise molecular biomarkers to better assess tumor heterogeneity and guide personalized therapy.

MMBC possesses unique clinical and biological profiles distinct from unifocal breast cancer, driving the need for specific prognostic indicators to guide treatment strategies. There are various opinions on how to define the tumor size and T stage of MMBC. Evidence has shown that the maximum diameter of the largest lesion may best reflect patient survival (20,21), while other research viewpoints suggest that the overall size or volume estimate may more accurately reflect the biological behavior and prognosis of the tumor (2). The independent prognostic value of multifocality itself is controversial (22,23). While early studies indicated higher local recurrence rates, increased lymph node metastasis, and poorer prognosis in MMBC, recent research demonstrates comparable outcomes between MMBC and unifocal disease when treated with standardized surgery and adequate margins (1,24,25). Over the past two decades, numerous studies and meta-analyses have confirmed that breast-conserving surgery and mastectomy yield comparable outcomes in terms of overall survival, local control, and distant metastasis rates in MMBC (6,26). The 2017 St. Gallen International Breast Cancer Conference expressed support for breast-conserving surgery in MMBC cases. Furthermore, the 2022 National Comprehensive Cancer Network (NCCN) Guidelines note that MMBC is no longer considered an absolute contraindication for breast-conserving surgery. The 2023 ACOSOG Z11102 prospective trial reported a 5-year cumulative recurrence rate of merely 3.1%. Notably, patients undergoing preoperative MRI evaluation achieved a 5-year local recurrence rate of 1.7%, significantly lower than the 22.6% in non-MRI patients, demonstrating that thoroughly evaluated MMBC patients can achieve satisfactory outcomes with breast-conserving surgery (27). Nevertheless, real-world data indicate that MMBC patients may still experience higher rates (up to 26.1%) of re-excision or conversion to mastectomy (28). And it should be noted that multifocality may increase the risk of positive margins (based on the “≥1 mm” rule), and resection of multi-quadrant tumors may affect cosmetic outcomes. In summary, with advancements in multidisciplinary care and growing patient emphasis on cosmetic outcomes, breast-conserving surgery has emerged as a viable option for MMBC. Our patient ultimately underwent mastectomy instead of breast-conserving surgery. This decision was based on the small breast size, relatively large tumor dimensions, and their close proximity, which would have led to a suboptimal cosmetic outcome. This approach is consistent with real-world clinical decision-making, and her prognosis requires further follow-up.

The key feature of this case is the extremely rare, simultaneous occurrence of multiple distinct tumor foci. Most of the MMBC cases reported domestically and internationally are composed of two foci (mostly a larger main focus and a smaller secondary focus within the same area), while in this case, there are as many as 10 foci, with each lesion having a similar volume, making it difficult to distinguish the main focus from the secondary foci. Moreover, the total volume of the foci is relatively large. The multiple foci are located in the outer upper quadrant and the inner upper quadrant, and they are also multi-focal and multi-centered breast cancer. The patient is only 38 years old, which is younger than the average age of the domestic and international cohorts (3,21,25). With the increasing incidence and younger onset of breast cancer, patients often mistake malignant masses for benign lesions and underestimate their significance. Moreover, rare MF and MC cancers are prone to be missed, misdiagnosed, or diagnosed late in high-volume outpatient settings with limited physical and imaging evaluations. MMBC in young women is generally associated with a poorer prognosis, making timely diagnosis and treatment critical. Given the potential pathological heterogeneity among MMBC foci, comprehensive evaluation of all lesions—including minor ones—is essential for individualized treatment planning and may justify escalation of therapy when appropriate. From a surgical perspective, breast-conserving surgery is feasible for MMBC when negative margins and acceptable cosmetic outcome can be achieved. To ensure oncologic safety, appropriate margin width and thorough margin assessment are essential. Recent prospective trial data provide strong support for breast-conserving surgery in MMBC. However, further high-quality evidence with long-term follow-up is needed, incorporating refined evaluation metrics such as breast-to-tumor volume ratio, T-staging criteria (based on total tumor size vs. largest focus diameter) (21), and tumor location, to fully validate the safety of this approach.

In summary, this case is distinctive for its occurrence in a young woman with a high number of MMBC foci, and its diagnostic and therapeutic course offers valuable clinical insights that help define the impact of such cases on clinical decision-making. It underscores the critical necessity of comprehensive pre-operative imaging (especially contrast-enhanced MRI) in cases with multiple suspicious findings on initial assessment, to fully map the disease extent and avoid underestimation. Moreover, the case highlights the paramount importance of individual pathological verification of each distinct focus, as demonstrated by the heterogeneous IHC profiles (including HER2 heterogeneity) we observed. This directly informs surgical planning (extent of resection) and adjuvant therapy selection (e.g., the need for targeted anti-HER2 therapy for HER2-positive foci).

Conclusions

MMBC refer to the presence of more than two synchronous ipsilateral breast carcinomas. In a young female patient with a rare MMBC including more than ten potential foci, the mastectomy surgical strategy was chosen according to the patient’s request and cosmetic outcome. Early and accurate diagnosis of MMBC is critical, and more accurate preoperative diagnosis relies on breast MRI beyond ultrasound and mammography. When the margin is clean and there are no other suspicious lesions, breast-conserving surgery could be safe and meet the cosmic need. In the case of multiple lesions, extensive lesions, multi-center lesions and small breasts, mastectomy is first under consideration, while the false positivity from imaging evaluation requires attention.

Acknowledgments

We would like to thank the patient and her family for permitting us to share this case. We would also like to thank the Department of Pathology at our center for its valuable guidance and assistance in the pathological diagnosis.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-1-570/rc

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-1-570/prf

Funding: This study was supported by Undergraduate Education and Teaching Reform Project of Peking Union Medical College (No. 2024bkjg014, to X.Z.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-1-570/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 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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