Synchronous Bilateral Breast Cancer with Heterogeneous Histology: Invasive Ductal and Lobular Carcinoma – A Case Report

Abstract

Introduction

Synchronous bilateral breast cancer (SBBC) is rare, comprising 2–5% of all breast cancer cases. Even more uncommon is the presence of discordant histologies in each breast. This report discusses a case involving invasive ductal carcinoma (IDC) in the left breast and invasive lobular carcinoma (ILC) in the right breast.

Case Presentation

A 46-year-old Arab woman presented with a 6-month history of a growing lump in the left breast and a newly noticed nodule in the right breast. Imaging and biopsy confirmed IDC (Grade 2, ER+/PR+/HER2−) in the left breast and ILC with LCIS in the right breast. Bilateral axillary lymphadenopathy was observed. She underwent neoadjuvant chemotherapy (doxorubicin/cyclophosphamide followed by paclitaxel), followed by a left radical mastectomy with axillary dissection. Hormonal therapy (goserelin and exemestane) and adjuvant radiotherapy were initiated. Right-breast surgery is pending.

Conclusion

SBBC with discordant histology necessitates a multidisciplinary, individualized treatment approach. Hormone receptor status, tumor biology, and extent of disease all influence treatment decisions. This rare clinical scenario highlights the need for further research and specific management guidelines.

Introduction

Breast cancer is the most common cancer in women in roughly every country, and about half of these women have no specific risk factors besides sex and age [1]. Furthermore, the primary cancer is adenocarcinoma, which is divided into ductal carcinoma (85%) and lobular carcinoma (15%) [2]. Several studies have compared these two subtypes and discovered that they are clinically and molecularly different [3]. The most important difference is that in invasive lobular carcinoma (ILC), the cells lose their adhesion due to loss of E-cadherin expression [4]. Clinically, this subtype has a worse prognosis and requires surgery in most cases [5], where this cancer benefits from neoadjuvant chemotherapy (NACT) less [6]. With the improvement of diagnostic and early detection techniques, the rate of women diagnosed with synchronous breast cancer has increased by 40% [7]. A bilateral synchronous breast cancer incidence is unique, accounting for 2–5% of all types of breast cancer [8]. However, the most important risk factors for the development of bilateral breast cancer are family history and aggressive tumors, which have negative estrogen receptor and positive epidermal growth factor receptor-2 [9].

Here, a case of synchronous bilateral breast cancer in a female is being presented: invasive ductal carcinoma (IDC) in the right breast and ILC in the left breast [10].

Case Presentation

A 46-year-old Arab woman presented to our department with a 6-month history of a progressively enlarging, tender lump in her left breast. Shortly thereafter, she noticed a smaller, firm nodule in her right breast. She denied skin changes, nipple discharge, unexplained weight loss, drenching night sweats, or fever, and had no personal or family history of breast or ovarian malignancy.

On admission, her vital signs were within normal limits. Physical examination of the left breast revealed a firm, irregular mass in the upper outer quadrant; non-tender at rest but tender on palpation; with no skin dimpling or nipple retraction. The right breast contained several mobile, firm nodules without overlying skin or nipple changes. Bilateral axillary examination uncovered palpable lymphadenopathy (left nodes up to 2.3 cm; right nodes up to 2.0 cm).

Bilateral Doppler ultrasound and contrast-enhanced computed tomography demonstrated a heterogeneous, dense area in the left breast featuring an irregular hypoechoic mass measuring 1.8 × 2.1 cm behind the nipple (BI-RADS 6), multiple small cysts (≤0.7 cm), and enlarged axillary nodes lacking a normal hilum. On the right, several irregular hypoechoic masses (3.2 × 4.2 cm at 9 o’clock; 1.8 × 3.0 cm at 2 o’clock; BI-RADS 5) were seen alongside reactive-appearing axillary nodes. Pelvic imaging showed a heterogeneous uterus with endometrial thickening of 1.2 cm (Fig. 1).

Fig. 1.

Axial contrast-enhanced computed tomography (CT) scan of the chest demonstrating bilateral irregular hypoechoic masses involving both the right and left breasts. The lesions are visualized as dense, heterogeneous areas consistent with malignant features. No significant chest wall invasion is observed. This image corresponds to the initial diagnostic workup of synchronous bilateral breast cancer.

Standard breast imaging modalities such as mammography and breast magnetic resonance imaging (MRI) were not available for this patient. Due to the ongoing conflict and limited healthcare resources in Syria, there was no accessible medical archive to retrieve or provide adequate mammography or MRI images. Consequently, diagnostic workup relied primarily on ultrasound and computed tomography findings.

A left-breast Tru-Cut biopsy revealed Grade 2 IDC (Nottingham score 7: tubular formation 3, nuclear pleomorphism 2, mitotic rate 2) with lymphovascular emboli; immunohistochemistry was ER+/PR+/HER2−. The Ki-67 proliferation index was 25%, indicating a moderately proliferative tumor.

The right-breast biopsy demonstrated ILC with an LCIS component; two of 19 axillary nodes were positive with extracapsular extension. Immunohistochemistry showed ER positivity in 95% of tumor cells, PR positivity in 70%, HER2 negativity (0), and a Ki-67 proliferation index of 15%, consistent with a low-proliferative tumor.

She completed four cycles of AC (doxorubicin/cyclophosphamide) followed by four cycles of paclitaxel (with supportive Neupogen), and has been maintained on monthly goserelin (Zoladex) and daily exemestane. After a month, she underwent an uncomplicated left radical mastectomy with Level I–II axillary dissection. Postoperatively, drains were removed by Day 7 (output < 50 mL/24 h), wound healing was uneventful, and she has begun adjuvant radiotherapy to the left chest wall and axilla, with right-breast surgical planning pending.

Patient’s Perspective

“When I first learned that I had cancer in both breasts, I was shocked and afraid. The doctors explained that each tumor was different, which made the treatment more complex. Despite the difficult circumstances and limited resources, I felt reassured by the team’s clear plan. After completing chemotherapy and surgery, I am relieved that my health has improved, and I am hopeful about the future.”

Discussion

Synchronous bilateral breast cancer (SBBC), the presentation of two primary malignancies in each breast diagnosed concurrently, is an uncommon clinical entity that poses significant diagnostic and therapeutic challenges [11]. While its incidence is reported to be between 0.2% and 7.5% of all breast cancers, this wide range reflects a critical and often overlooked issue in the literature: the lack of a standardized definition for “synchronous” [12]. Various studies define the interval between diagnoses from within 1 month to as long as 12 months, which directly impacts reported incidence rates and complicates the comparison of outcomes across different cohorts [13].

This definitional ambiguity is not merely a semantic point; it may obscure true biological differences between tumors diagnosed nearly simultaneously versus those found several months apart, hindering the development of robust, evidence-based management guidelines. The increasing use of high-sensitivity imaging modalities like MRI and improved long-term survival for breast cancer patients are leading to a higher detection rate of contralateral disease, making a more precise understanding of SBBC clinically imperative [14].

The complexity of SBBC is magnified exponentially when the tumors exhibit discordant histology, as presented in this case of a 46-year-old woman with IDC in the left breast and ILC in the right [11]. Such cases, where the two most common yet biologically distinct subtypes of breast cancer arise simultaneously, are rarer still, representing a “disease of diseases” that fundamentally challenges conventional oncological paradigms [15].

The management of a single patient harboring two separate tumor biologies invalidates a “one-size-fits-all” approach. Treatment decisions must navigate the differing natural histories, molecular drivers, metastatic potential, and therapeutic sensitivities of each cancer. This creates profound dilemmas in the selection and sequencing of systemic therapy, surgical strategy, and prognostic assessment that are not encountered in unilateral disease or even in histologically concordant SBBC [13, 16]. This case, therefore, serves as a valuable model for exploring the necessity of a highly individualized, multidisciplinary treatment strategy tailored to the unique characteristics of each tumor.

Comparison with Previously Reported Cases

To contextualize the unique challenges presented by our patient, it is instructive to critically compare her case with other published reports of SBBC with discordant histology. The literature, though composed primarily of case reports and small series, reveals a spectrum of clinical presentations and management strategies that underscore the profound heterogeneity of this condition. A comparative analysis highlights the key variables that influence decision-making, including molecular subtype discordance, nodal status, and response to therapy (Table 1).

Table 1.

Comparative analysis of synchronous bilateral breast cancer cases with discordant histology

Case (reference)	Age	Left breast (histology and receptor status)	Right breast (histology and receptor status)	Nodal status	Treatment strategy	Key finding/outcome
Present case	46	IDC, Grade 2; ER+/PR+/HER2−	ILC with LCIS; ER+/PR+/HER2−	Bilateral axillary node positive	NACT > left mastectomy > adjuvant RT/ET	Management of two distinct HR+ tumors; highlights challenges in low-resource settings
Copur et al. [17]	48	ILC; ER+/PR+/HER2−	IDC; triple-negative (ER–/PR–/HER2–)	Right axillary node positive	NACT > bilateral mastectomy	Discordant response to NACT: complete response in IDC, residual disease in ILC.
Brock et al. [16]	N/A	IDC; ER+/PR–/HER2−	ILC; ER+/PR–/HER2–	Left node positive (triple-negative)	N/A	Discordance between primary tumor (ER+) and nodal metastasis (triple-negative)
Aranda-Gutierrez et al. [13]	35	Hormone-sensitive (HR+) tumor, Stage IIB	IDC; triple-negative, Stage IIA	N/A	Bilateral mastectomy > adjuvant chemo/RT/ET	Treatment guided by the most aggressive tumor (triple-negative), followed by endocrine therapy for the other
Peshin et al. [18]	61	ILC, Grade 1	IDC, Grade 2	Left: node negative; Right: one positive SLN	Bilateral mastectomy > adjuvant RT/ET/CDK 4/6 inhibitors	Management in a patient with significant family history and comorbidities
Ojo et al. [12]	45	IDC; triple-negative (TNBC)	IDC with medullary features; HER2–positive (ER–/PR–/HER2+)	Initially left axillary node positive; ypN0 post-NACT	NACT > bilateral mastectomy	Complete pathological response to NACT in a BRCA1 carrier with TNBC and contralateral HER2+ disease
El Amrani et al. [19]	56	Mucinous carcinoma (T3N1M0)	Multifocal multicentric ILC (T2N0M0)	Left: N1; right: N0	Bilateral mastectomy > adjuvant chemo	Coexistence of mucinous carcinoma and ILC. Prognosis correlated with the most advanced tumor

Our patient presented with two hormone receptor-positive (HR-positive), HER2-negative tumors: a Grade 2 IDC and an ILC. This presentation is similar in its HR-positivity to the case described by Brock et al. [16] which involved a left IDC (ER+/PR–) and a right ILC (ER+/PR–). However, the case by Brock et al. [16] introduced an additional layer of complexity: discordance between the primary tumor's receptor status and that of its nodal metastasis, where the left axillary node was found to be triple-negative. This finding points toward the potential for significant intra-patient tumor evolution and heterogeneity, a factor that can have deleterious effects on survival and complicates adjuvant therapy decisions [16].

In stark contrast stands the case reported by Copur et al. [17] involving a 48-year-old woman with a right-sided triple-negative IDC and a left-sided HR-positive ILC. This profound discordance in molecular subtype led to a dramatically discordant response to NACT. The aggressive, triple-negative IDC achieved a complete pathological response, whereas the more indolent, HR-positive ILC showed significant residual disease after the same systemic treatment. This outcome powerfully illustrates the central therapeutic dilemma in discordant SBBC: a standard chemotherapy regimen may be optimal for one tumor but suboptimal or even unnecessary for the other.

Further highlighting the spectrum of molecular discordance, Aranda-Gutierrez et al. [13] reported on a 35-year-old woman with a stage IIA triple-negative IDC in the right breast and a stage IIB HR-positive tumor in the left. The management of such cases forces clinicians to adopt a strategy based on the most aggressive tumor, often exposing the patient to the toxicities of comprehensive chemotherapy for the triple-negative component, followed by long-term endocrine therapy for the HR-positive component.

Collectively, these cases demonstrate that SBBC with discordant histology is not a single entity but a collection of unique clinical scenarios. While our patient’s concordant HR-positive status simplified the choice of endocrine therapy, the decision to administer NACT still had to balance the expected benefits for the moderately proliferative IDC (Ki-67 25%) against the potentially limited response of the low-proliferative ILC (Ki-67 15%). This comparative analysis solidifies the principle that management cannot be generalized; it must be meticulously tailored to the specific histological and molecular profile of each individual tumor.

Prognostic Considerations in Discordant SBBC

The prognosis for patients with SBBC is a subject of considerable debate, with historical data often suggesting worse outcomes compared to unilateral breast cancer (UBC). An early study by Jobsen et al. [20] found that patients with SBBC had significantly higher rates of distant metastasis and worse disease-specific survival at 10 years compared to their UBC counterparts.

However, this perspective has been challenged by more recent, carefully controlled studies. The prevailing view is now shifting toward the idea that the presence of a second tumor may not be an independent adverse prognostic factor in itself. Instead, the overall outcome is likely dictated by the clinicopathological features of the constituent tumors [21].

This has led to the development of the “reference lesion” hypothesis, which posits that the prognosis of an SBBC patient is determined by the tumor with the more aggressive biological profile. This reference lesion is typically defined as a tumor with the more advanced stage, larger size, higher histological grade, or adverse receptor status. A case-control study that matched SBBC patients to UBC patients based on the characteristics of their reference lesion found no significant difference in disease-specific survival, concluding that the contralateral second tumor had no additional impact on the outcome. Applying this model to the present case, the prognostic drivers would be sought by comparing the two tumors. Although both are Grade 2, the left-sided IDC exhibited a higher proliferation index (Ki-67 25% vs. 15%) and the presence of lymphovascular emboli, features that might designate it as the reference lesion dictating the patient's overall risk [21].

However, a more sophisticated understanding of prognosis in SBBC is emerging, suggesting that the “reference lesion” model may be an oversimplification. Recent large-scale cohort studies propose that the discordance between the two tumors may itself be an independent prognostic variable. An analysis of the SEER database revealed that patients with discordant molecular subtypes in their bilateral tumors had significantly worse breast cancer-specific survival and overall survival compared to patients with concordant subtypes. This effect was observed specifically in the SBBC group, not in metachronous cases, suggesting that the simultaneous presence of two biologically distinct tumor environments has a uniquely negative prognostic impact. This finding was further supported by reports linking hormone receptor discordance specifically to an increased rate of metastasis and higher 5-year mortality [13, 22].

This evolution in prognostic understanding reflects a conceptual shift. The initial model compared SBBC as a single entity to UBC. The “reference lesion” hypothesis refined this by deconstructing SBBC into two separate events, with the worse of the two driving the outcome. The latest “discordance hypothesis” takes a more systemic view, suggesting that the relationship between the two tumors – their biological heterogeneity – is a critical factor. This implies that the underlying genetic predisposition that permits two different tumors to arise, or the complex interplay between two distinct tumor microenvironments within a single host, may create a more aggressive systemic disease state. Therefore, a comprehensive prognostic assessment for a patient with discordant SBBC should not only identify the reference lesion but must also consider the very fact of molecular discordance as a potential adverse factor.

Management and Individualized Therapeutic Strategies

The management of SBBC with discordant histology is fraught with clinical dilemmas that necessitate a departure from standard, guideline-driven protocols toward a highly individualized, multidisciplinary approach. These challenges span the entire treatment continuum, from the selection of systemic therapy to surgical decision-making.

The Neoadjuvant Chemotherapy Paradox

The decision to administer NACT, as was done in this case, exemplifies a central management dilemma. The primary goals of NACT include downstaging tumors to improve surgical outcomes, potentially enabling breast-conserving surgery, and providing an in vivo assessment of chemosensitivity that can inform prognosis and subsequent adjuvant choices [15].

However, in a discordant IDC/ILC setting, this strategy is complicated by the well-documented differential chemosensitivity of the two histologies. Numerous studies have shown that ILC responds less favorably to NACT compared to IDC. This is attributed to the biological characteristics of ILC, which is typically HR-positive, low-grade, and has a lower proliferative rate [14]. The case from Copur et al.’s study [17] provides a stark illustration of this “NACT paradox”: a standard chemotherapy regimen resulted in a complete response for the triple-negative IDC but left significant residual disease in the HR-positive ILC.

This highlights the risk of simultaneously overtreating one tumor while undertreating the other. In our patient, the use of an anthracycline- and taxane-based regimen was a reasonable choice for the Grade 2, moderately proliferative IDC. However, a more modest response was to be expected in the low-proliferative ILC. This inherent tension justifies the individualized decision-making process and underscores the importance of counseling patients about the potentially divergent responses of their two distinct cancers [17].

Selection of Systemic Agents and Surgical Strategy

When molecular subtypes are discordant – for instance, one tumor being triple-negative and the other HR-positive – the choice of systemic agents becomes even more complex. The current, albeit not evidence-based, consensus is to design the systemic therapy plan around the most aggressive tumor. This often means that a patient receives a full course of aggressive chemotherapy tailored to the triple-negative or HER2-positive cancer, followed by years of endocrine therapy for the HR-positive cancer. This sequential approach, while logical, can lead to significant cumulative toxicity and highlights the need for research into more nuanced therapeutic strategies [12, 16].

Surgical management also requires careful consideration. Bilateral mastectomy is the most frequently performed surgery for SBBC, chosen for oncologic safety, to simplify follow-up surveillance, and to address patient anxiety [23].

However, the paradigm is shifting. For multifocal and multicentric unilateral disease, breast-conserving surgery, often involving oncoplastic techniques, is increasingly considered an oncologically safe option for selected patients [24].

This principle could be cautiously extrapolated to some SBBC cases, particularly if both tumors are small and favorably located. The decision-making process must be a shared one, balancing oncologic risk, cosmetic outcomes, and patient preferences, as was done for our patient, who underwent a left radical mastectomy with plans for the right breast surgery pending. Finally, even the extent of initial staging is a point of debate. While metastatic workup is standard for advanced unilateral cancer, its routine use in all SBBC cases is questionable. Recent data suggest that for patients with clinically node-negative SBBC, full metastatic staging could potentially be omitted, representing another area where clinical judgment must be individualized to avoid over-investigation [25].

Multifocality in Ductal and Lobular Carcinomas

Clarification of Findings in the Present Case

First, it is important to clarify the findings in our patient’s case as documented by the imaging and pathology reports. The right breast, which was diagnosed with ILC, presented with “several irregular hypoechoic masses.” This finding of multiple lesions is entirely consistent with the well-established biological behavior of ILC. In contrast, the left breast, diagnosed with IDC, presented as a single, unifocal “irregular hypoechoic mass measuring 1.8 × 2.1 cm.” Therefore, the multifocal presentation was associated with the lobular carcinoma, not the ductal carcinoma, in this specific case.

The Biological Basis of Multifocality in ILC

Multifocality and multicentricity (the presence of multiple tumor foci in the same or different breast quadrants, respectively) are classic hallmarks of ILC, occurring more frequently than in IDC. As previously discussed, this phenomenon is a direct biophysical consequence of the loss of E-cadherin (CDH1) function [26–28].

Without this critical cell adhesion molecule to hold them together in a cohesive mass, ILC cells can easily detach and disseminate as individual cells or small, non-cohesive clusters through the stromal planes and ductal system of the breast. This discohesive infiltration pattern allows for the establishment of multiple, geographically separate tumor deposits, leading to the characteristic multifocal or diffuse presentation of the disease [29].

The Biological Basis of Multifocality in IDC

While less common than in ILC, multifocality is, nevertheless, a well-documented and clinically important feature in a subset of IDC cases, with reported incidence rates ranging widely from 6% to over 60% depending on the definition and imaging modality used. The underlying biological mechanisms for multifocal IDC are believed to be different from those in ILC and are primarily explained by two competing, though not mutually exclusive, hypotheses supported by clonality studies [30–32].

• 1.Intramammary spread (monoclonal origin): This model posits that multiple tumor foci arise from a single primary tumor through intramammary metastasis. Cancer cells from the index lesion spread via the ductal system (intraductal spread) or through lymphatic or vascular channels within the breast, seeding new, clonally related satellite tumors. Whole-exome sequencing and cytogenetic analyses have provided strong evidence for this mechanism in some cases by demonstrating that distinct tumor foci share identical or highly similar clusters of mutations and chromosomal aberrations, confirming a common clonal origin [33, 34].
• 2.Synchronous independent primaries (polyclonal origin): This model proposes that multiple foci are truly separate, independent tumors that arise synchronously from different progenitor cells within a breast that is subject to “field cancerization.” This suggests a widespread genetic or epigenetic predisposition within the breast tissue that allows for multiple, independent carcinogenic events to occur. Studies have also found evidence supporting this mechanism, identifying multifocal tumors that are histologically similar but immunocytochemically or genetically distinct, indicating they are clonally unrelated [33–35].

Thus, multifocal IDC is not a single biological entity but can result from at least two distinct pathways. Regardless of the underlying histology or mechanism, the clinical significance of multifocality is clear. The presence of multiple tumor foci represents a greater total tumor burden. This increased tumor load has been consistently associated with a higher risk of axillary lymph node involvement and is considered a marker of a more aggressive phenotype, which can impact staging, treatment decisions, and prognosis [36].

This case of synchronous bilateral breast cancer with discordant invasive ductal and lobular histologies exemplifies a rare but clinically significant oncological challenge that defies standardized treatment protocols. The simultaneous management of two biologically distinct malignancies within a single patient necessitates a highly individualized therapeutic strategy, formulated by a multidisciplinary team, that accounts for the unique molecular drivers, proliferative potential, and therapeutic sensitivities of each tumor. Our experience underscores that beyond simply reiterating the rarity of this condition, the key lesson lies in appreciating and responding to the profound clinical implications of inter-tumoral heterogeneity.

The critical analysis of this case in the context of the existing literature illuminates several key principles and future directions. The prognosis of SBBC is complex, likely determined not only by the most aggressive “reference lesion” but also by the very presence of molecular discordance, which may itself be an independent adverse factor. Management is fraught with dilemmas, particularly regarding the use of NACT, where the differential sensitivities of IDC and ILC can lead to divergent outcomes.

To advance the care of this unique patient population, several collaborative efforts are needed. First, the establishment of multi-institutional registries is essential to amass sufficient data on these rare cases, enabling more robust analysis of treatment strategies and outcomes. Second, there is a pressing need for a consensus definition of “synchronous” to standardize research and allow for meaningful cross-study comparisons. Third, the routine molecular characterization of both tumors in all cases of bilateral breast cancer should be strongly considered, as identifying discordance has clear prognostic and potential therapeutic implications. Finally, continued research using advanced genomic and molecular techniques is crucial to further unravel the clonal relationships and field cancerization effects that predispose patients to developing discordant bilateral tumors. The ultimate goal of these efforts is to move beyond management based on extrapolation and expert opinion toward the development of evidence-based guidelines that can optimize treatment and improve survival for women facing this complex diagnosis.

Conclusion

SBBC with heterogeneous histology represents a rare clinical scenario that challenges diagnostic and therapeutic decision-making. Our case emphasizes the need for individualized, multidisciplinary planning, particularly in low-resource settings where access to standard imaging and pathology tools may be limited. Beyond reiterating the rarity, the key lesson lies in the importance of considering histological and molecular heterogeneity when tailoring treatment strategies.

Statement of Ethics

The Ethics Committee at Damascus University does not require ethical approval for reporting individual cases or case series. Written informed consent was obtained from the patient for publication of this case report and any accompanying images. The work has been reported in line with the CARE checklist criteria, available as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000548545).

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This study was not supported by any sponsor or funder.

Author Contributions

Ahmad Al-Bitar led the clinical assessment, patient follow-up, and surgical planning and contributed significantly to case documentation and manuscript supervision. Ahmad Bishr Nasra participated in literature review, data analysis, and radiological interpretation; co-wrote the discussion; and helped structure the case presentation. Lama Alsaoub managed patient data collection and pathological report synthesis, contributed to drafting the introduction, and structured abstract. Mohammad Alaa Aldakak finalized the manuscript, ensured compliance with ethical and publication standards, and assisted in editing and critical revisions. Maher Saifo provided oncologic expertise, contributed to treatment planning, and critically revised the manuscript for intellectual and clinical accuracy.

Funding Statement

This study was not supported by any sponsor or funder.

Data Availability Statement

All data generated or analyzed during this study are included in this article and its online supplementary material files. Further inquiries can be directed to the corresponding author.