Correlation between multimodality imaging features and molecular subtypes in breast cancer: a comparative study between young (≤30 years) and middle-aged (45–55 years) women

Introduction

Breast cancer emerged as the most prevalent malignancy among women worldwide in 2020 (1), with incidence rates demonstrating a marked age-dependent increase (2). Notably, significant geographical disparities exist related to the age-specific incidence patterns. In Western nations, <1% of breast cancer cases occur in women under 30 years of age, while in Asia, this proportion exceeds 3% (3). Within China specifically, the mean age at diagnosis is approximately a decade younger than that in Western countries (4), and within the Chinese epidemiological context, the operational definition of “young breast cancer” is a case diagnosed before 30–35 years.

This younger demographic faces distinct clinical challenges, including body image concerns, fertility preservation, childcare responsibilities, and occupational reintegration posttreatment (5). Furthermore, molecular subtype heterogeneity significantly influences therapeutic approaches and prognostic outcomes (6), underscoring the critical need for precise preoperative subtype characterization to optimize treatment strategies and improve survival in younger patients.

Despite these clinical imperatives, research investigating the correlation between immunohistochemical molecular subtypes and imaging characteristics in patients with breast cancer under 30 years of age remains scarce globally. The existing literature on this demographic primarily focuses on the low incidence rate in this age group and does not provide a systematic analysis of the relationship between tumor biology imaging features. This study therefore aimed to characterize the imaging features of breast cancer in women <30 years of age and analyze their associations with molecular subtypes as determined by immunohistochemical profiling. To contextualize findings within China’s unique epidemiologic profile, we strategically selected patients with breast cancer 45–55 years old, as the comparator cohort, reflecting the national incidence peak (7). We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-434/rc).

Methods

Study population and clinicopathological data

This retrospective study was approved by the Ethics Committee of Affiliated Hospital of Qingdao University (No. QYFY WZLL 30287) and was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The requirement for individual consent was waived due to the retrospective nature of the analysis.

Molecular subtypes were defined according to the 2015 St. Gallen International Expert Consensus and included estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and Ki-67 expression.

All participants had previously provided written informed consent for their mammographic examinations. The study cohort comprised Chinese female patients diagnosed with breast cancer at Affiliated Hospital of Qingdao University between January 2015 and March 2025. Clinical records and imaging data were systematically retrieved from two primary sources: the Picture Archiving and communication system (PACS; Centricity PACS Radiology RA1000 Workstation, GE HealthCare, Chicago, IL, USA) for mammography images [including digital breast tomosynthesis (DBT) and digital mammography (DM)] and the Hospital Information System (HIS) for clinicopathological data.

Patients with prior mastectomy history, breast implants, or recurrent or bilateral breast malignancies, as well as those lacking immunohistochemical profiles, were excluded. The study population consisted of 146 young women (<30 years; median age 29 years; age range 20–30 years) and 292 middle-aged women (45–55 years; median age 48 years; age range 45–55 years) matched at a 1:2 ratio according to molecular subtype prevalence during the study period. Breast Cancer Susceptibility Gene (BRCA) mutation analysis, performed in four selected cases (three young and one middle-aged patient), revealed no pathogenic variants.

All enrolled patients underwent the bilateral breast ultrasound examination. For lesions classified as Breast Imaging Report and Data System (BI-RADS) category 4 or higher, supplemental imaging with DBT/DM of the ipsilateral breast was implemented before core needle biopsy to delineate lesion characteristics and detect multifocal disease. Following histological confirmation of malignancy, contralateral breast DBT/DM was systematically performed. Preoperative breast magnetic resonance imaging was excluded from the standardized imaging protocol due to insufficient utilization rates among younger patients in our cohort.

Imaging acquisition

Ultrasound images were obtained with a 10 to 14-MHz linear probe (Acuson S2000, Siemens Healthineers, Erlangen, Germany) and a 3.5 to 7.5-MHz linear probe (EBU-7500, Hitachi Medical, Tokyo, Japan).

DBT and DM images were simultaneously acquired via a Selenia Dimensions mammography system (Marlborough, MA, USA) in combination mode. The X-ray tube was rotated 15° (−7.5° to 7.5°) during standard breast compression. Images were reconstructed into 1-mm slices. Standard mediolateral oblique and craniocaudal views of the affected breast were obtained.

Imaging interpretation

All imaging interpretations were conducted in accordance with the fifth edition of the BI-RADS criteria of the American College of Radiology (ACR) (8). Mammographic breast density was classified via DM images: “almost entirely fatty” (ACR category a) and “scattered fibroglandular densities” (ACR category b) classification were categorized as non-dense breasts, while “heterogeneously dense” (ACR category c) and “extremely dense” (ACR category d) were categorized as dense breasts.

Ultrasonographic lesions were categorized into mass lesions (with or without calcifications) or intraductal calcifications. Mass morphology was systematically evaluated across four parameters: shape, margin, posterior features, Doppler vascularity. For DBT and DM assessments, mass lesions were analyzed based on morphological characteristics (shape, margin, and density), while isolated microcalcifications were characterized by their geometric configuration and distribution patterns.

Two dedicated breast radiologists (5–13 years of subspecialty experience) conducted double-blind interpretations using standardized high-resolution workstations (Coronis 5MP, Barco, Kortrijk, Belgium). Prior to analysis, consensus training sessions were conducted to ensure uniform application of the BI-RADS criteria. All readers remained blinded to clinical outcomes, histopathological results, and colleagues’ interpretations throughout the evaluation process. Discordant interpretations within a single imaging modality were resolved through discussion.

Clinical and histopathological data

Clinical parameters, including age, breast cancer family history (first-degree relatives), and presenting symptoms, were extracted from electronic medical records. Histopathological evaluation of surgical specimens served as the diagnostic reference standard, with documentation of tumor histotype, immunohistochemical subtype, histological grade, tumor stage, and axillary lymph node status. Histopathological classification encompassed five categories: invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), invasive micropapillary carcinoma (IMPC), mucinous carcinoma (MC), and metaplastic breast carcinoma (MBC).

Molecular subtypes were defined in accordance with the 2015 St. Gallen International Expert Consensus Recommendation (9), the 2020 American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines (10), and the 2025 Chinese Breast Cancer Diagnosis and Treatment Guidelines (11). Molecular subtype classification included the expression of ER, PR, HER2, and Ki-67 expression. PR positivity was defined as an expression level exceeding 20%. HER2 overexpression was considered positive when the membrane staining was graded 3+ on immunohistochemistry. A score of 0 or 1+ ruled out HER2 gene amplification, while a score of 2+ and further corroboration by fluorescence in situ hybridization confirmed HER2 gene amplification. Ki-67 positivity was defined as an expression level exceeding 20%. Cancers were categorized into four groups: (I) luminal A [ER+, PR++ (≥20%), HER2−, and Ki67− or + (<20%)]; (II) luminal B [a: ER+, PR− or + (<20%), HER2−, and Ki-67++ (≥20%); b: ER+, PR+, HER2+, and any Ki-67 expression]; (III) HER2 overexpression (ER−, PR−, and HER2+); and (IV) triple negative (TN; ER−, PR−, and HER2−).

Statistical analysis

All statistical analyses were performed with SPSS software version 22.0 (IBM Corp., Armonk, NY, USA). Categorical variables are expressed as frequencies and percentages. The Chi-squared test and Fisher exact test were applied to compare categorical variables. A P value less than 0.05 indicated a statistically significant difference.

Results

Clinicopathological features

Immunohistochemical subtypes in the younger and middle-aged groups respectively included luminal B in 70 and 140 cases (48.0%), TN in 32 and 64 cases (21.9%), HER2 overexpression in 25 and 50 cases (17.1%), and luminal A in 19 and 38 cases (13.0%). A palpable mass was the primary clinical presentation in middle-aged group, whereas nipple discharge occurred more frequently in younger group (P=0.007). Tumor size distribution exhibited variation between cohorts (P=0.009), with lesions >5.0 cm occurring more commonly in the younger group and smaller tumors (≤2.0 cm) being more common in the middle-aged group. IDC was the most common histotype among the younger and middle-aged groups (91.8% and 90.1%, respectively). T2 was the most common stage in both groups (both 58.2%), but younger patients exhibited a significantly higher of T3 stage tumors, whereas middle-aged patients demonstrated a prevalence of T1 stage (P<0.001); grade II tumors predominated in both cohorts (57.5% and 57.9%), while the rate of axillary lymph node metastasis was markedly higher in younger patients (P<0.001) (Table 1 and Figure 1).

Figure 1 Clinicopathological features. IDC, invasive ductal carcinomas; ILC, invasive lobular carcinoma; IMPC, invasive micropapillary carcinoma; MBC, metaplastic breast carcinoma; MC, mucinous carcinoma; T, tumor.

Imaging features

Ultrasound

Younger patients demonstrated significantly higher rates of mass with calcification lesions (P=0.009), whereas noncalcified masses predominated in the middle-aged group. Middle-aged patients exhibited more irregular morphologies (P=0.044), while younger patients tended to have an oval/round morphology. Margin characteristics differed: younger patients had more angular margins, whereas middle-aged patients had more spiculated and microlobulated margins (P=0.001). In terms of posterior features, enhanced signals predominated in younger patients, while shadowing occurred more commonly in middle-aged patients (P=0.001). Blood flow signals were predominantly rich in younger patients but low in middle-aged patients (P=0.01).

For luminal B tumors, masses with calcification lesions were more common in the younger group, while noncalcified masses were more common in the middle-aged group (P=0.004) (Figures 2,3). Younger patients also demonstrated higher rates of indistinct margins (P=0.004), while spiculated margins were more common in the middle-aged group. For TN tumors, round/oval lesions were more common in the younger group (P=0.008) (Figures 4,5), while noncalcified masses were more common in the middle-aged group (P=0.046). No statistically significant differences were observed between the two groups for luminal A or HER2-overexpression tumors (all P values >0.05) (Table 2 and Figure 6).

Figure 2 A 28-year-old patient with the luminal B subtype. (A) DM revealed an irregular hyperdense mass with microlobulated margins and fine linear or linear branching calcifications distributed segmentally within and around the lesion. (B) DBT demonstrated a spiculated hyperdense mass containing similar segmentally distributed calcifications. (C) Ultrasonography identified an irregular hypoechoic mass with spiculated margins, shadowing posterior features, high blood flow, and internal calcifications. DBT, digital breast tomosynthesis; DM, digital mammography.

Figure 3 A 45-year-old patient with the luminal B subtype. (A,B) Both DM and DBT imaging displayed an irregular slightly hyperdense mass with spiculated margins (circle). (C) Ultrasound examination revealed an irregular hypoechoic lesion with spiculated margins, shadowing posterior features, and low blood flow. DBT, digital breast tomosynthesis; DM, digital mammography.

Figure 4 A 25-year-old patient with the triple-negative subtype. (A) DM detected an irregular hyperdense mass with indistinct margins (arrow). (B) DBT demonstrated an oval-shaped hyperdense mass with obscured margins (arrow). (C) Ultrasound imaging showed an oval hypoechoic mass with circumscribed and microlobulated margins, enhancement posterior features, and high blood flow. DBT, digital breast tomosynthesis; DM, digital mammography.

Figure 5 A 55-year-old patient with the triple-negative subtype. (A,B) Both DM and DBT imaging revealed an irregular slightly hyperdense mass with indistinct margins (arrows). (C) Ultrasonographic evaluation identified an irregular hypoechoic mass with angular margins, combined posterior features, and low blood flow. DBT, digital breast tomosynthesis; DM, digital mammography.

Figure 6 Ultrasonography features. HER2, human epidermal growth factor receptor 2; TN, triple-negative.

Digital breast tomosynthesis

Younger patients exhibited significantly higher rates of microcalcifications (P=0.002) and had a higher proportion of lesions with oval or round morphologies (P<0.001), isodensity (P=0.003), and microlobulated margins (P<0.001); meanwhile, while middle-aged patients predominantly presented with high-density lesions (P=0.003) and indistinct margins (P<0.001). Younger patients displayed finer linear or branching calcifications (P=0.003), while the middle-aged group demonstrated a predominance of amorphous calcifications. No significant difference was found in calcification distribution between the two groups (P>0.05).

Luminal B tumors showed age-specific variability: younger patients had more isodense lesions, whereas lesions in middle-aged patients tended to be hyperdense (P=0.008), with a greater proportion of microlobulated margins than indistinct margins (P=0.003). TN tumors in younger patients exhibited higher rates of oval/round morphology (P<0.001) (Figures 4,5) and microlobulated margins (P=0.03). For tumors with HER2 overexpression, isolated calcifications were more frequently observed in younger patients (P=0.02) (Figures 7,8), who exhibited finer linear or branching calcifications, while middle-aged patients tended to have fine pleomorphic or coarse calcifications (P=0.006). Notably, the luminal subtypes demonstrated higher spiculated margin rates than did TN and HER2-overexpression types (Figures 2,3,9-11; Table 3).

Figure 7 A 29-year-old patient with the HER2-overexpression subtype. (A,B) Both DM and DBT imaging exhibited linear and segmental fine linear or linear branching calcifications (circles). (C) Ultrasound demonstrated an irregular hypoechoic mass with indistinct margins, shadowing posterior features, high blood flow, and internal calcifications. DBT, digital breast tomosynthesis; DM, digital mammography; HER2, human epidermal growth factor receptor 2.

Figure 8 A 46-year-old patient with the HER2-overexpression subtype. (A) DM displayed clustered coarse heterogeneous calcifications (circle). (B) DBT revealed an irregular slightly hyperdense mass with microlobulated margins containing internal coarse heterogeneous calcifications in a grouped distribution (circle). (C) Ultrasonography indicated an irregular hypoechoic mass with microlobulated margins, combined posterior features, high blood flow, and internal calcifications. DBT, digital breast tomosynthesis; DM, digital mammography; HER2, human epidermal growth factor receptor 2.

Figure 9 A 28-year-old patient with the luminal A subtype. (A,B) DM and DBT imaging demonstrated an irregular isodense mass with spiculated margins (circles). (C) Ultrasound examination revealed an irregular hypoechoic mass with spiculated margins, shadowing posterior features, and low blood flow. DBT, digital breast tomosynthesis; DM, digital mammography.

Figure 10 A 45-year-old patient with the luminal A subtype. (A) DM showed an irregular isodense mass with indistinct margins and grouped amorphous calcifications (circle). (B) DBT revealed an irregular isodense mass with spiculated margins and grouped amorphous calcifications (circle). (C) Ultrasonographic evaluation demonstrated an irregular hypoechoic mass with spiculated margins, shadowing posterior features, low blood flow, and internal calcifications. DBT, digital breast tomosynthesis; DM, digital mammography.

Figure 11 Digital breast tomosynthesis features. HER2, human epidermal growth factor receptor 2; TN, triple-negative.

DM

The prevalence of dense breast tissue (ACR c-d) was significantly higher in younger patients than in middle-aged patients (P=0.03), as was that of isolated calcifications (P=0.047). However, there were no statistically significant differences related to molecular subtype between the groups (all P values >0.05) (Table 4 and Figure 12).

Figure 12 Digital mammography features. a, ACR category a (almost entirely fatty); b, ACR category b (scattered fibroglandular densities); c, ACR category c (heterogeneously dense); d, ACR category d (extremely dense). ACR, American College of Radiology; HER2, human epidermal growth factor receptor 2; TN, triple-negative.

Discussion

Mammography remains the primary noninvasive modality for diagnosing breast disease, yet its utility in young women is limited due to the density of breast tissue and concerns for radiation, complicating early cancer detection in this age group. Although ultrasound serves as the initial imaging choice for young patients, its operator-dependent nature precludes standalone use for cancer screening. This diagnostic gap underscores the clinical need to determine the correlations between imaging features and molecular subtypes, particularly given the therapeutic implications of immunohistochemical profiles.

The diagnostic limitations of DM in dense breasts are compounded by tissue overlap artifacts and reduced contrast resolution from minimal X-ray attenuation differences between benign and malignant tissues (12). DBT, which received the United States Food and Drug Administration (FDA) approval in 2011 (13), demonstrates superior diagnostic performance through improved detection of subcentimeter masses (7–8 mm) under low-contrast conditions (14) and is particularly advantageous for dense-breasted younger women.

In our study, we included 45- to 55-year-old patients as comparators due to China’s unique epidemiologic profile, with breast cancer incidence peaking in this age range (7). Some studies have indicated there to be similar tumor biology and prognosis between patients <35 and <40 years of age (15,16), others have reported there to no significant differences in molecular subtype distribution, hormone receptor expression (ER and PR), or histologic grade between those <35 years old and those 35–50 years old (17).

Younger patients with breast cancer typically present with self-detected palpable masses and exhibit aggressive histopathological and biological features, including elevated proliferation indices, vascular invasion (18), and advanced tumor stages and poorer prognoses. Our findings align with those of Schlichting et al. (19), who reported that 56% of patients <40 years of age in the Surveillance, Epidemiology, and End Results (SEER) database had stage T3 tumors. Moreover, the younger cohort in this study demonstrated higher rates of grade III histology and lymph node metastasis, which is consistent Anders et al.’s (20) observations of increased biological aggressiveness in young-onset breast cancer.

These aggressive clinicopathological profiles manifest distinctively on imaging modalities. Ultrasonographic analysis revealed morphological patterns among luminal B tumors characteristic to each age group. Younger patients predominantly exhibited calcified masses with indistinct margins and enhanced posterior features, whereas middle-aged patients more frequently presented with noncalcified masses with spiculated margins and shadowing posterior features. These distinct posterior feature patterns may reflect variations in calcification extent and composition of stromal fibrosis.

The imaging features of TN breast cancer (TNBC) vary significantly according to age. In our study, younger patients displayed a higher prevalence of circumscribed oval/round lesions on ultrasound and DBT, aligning with established TNBC features of benign-mimicking morphology (e.g., well-defined margins) and absence of calcifications (21,22). Therefore, a comprehensive evaluation of different imaging modalities is essential to ensuring no malignant lesions are overlooked. The characteristic enhancement posterior features observed in both cohorts likely reflects tumor biology, with dense cellularity in high-grade malignancies and necrotic liquefaction generating differences in ultrasound signal (23). Furthermore, we found a weak association between TN tumors and microcalcifications. Notably, younger patients demonstrated increased vascularity, linked to higher estrogen levels, which can stimulate the production of vascular endothelial growth factor at both the protein and messenger RNA levels in tumor cells, thereby promoting tumor angiogenesis (24).

DBT analysis revealed spiculated margins as a common feature of the luminal subtypes across both cohorts. These radiographic features included either radial linear shadows extending from tumor margins (indicative of peritumoral infiltration) or stellate patterns emerging from a central focus (suggestive of desmoplastic reaction) when tumor demarcation was indistinct. The fibrotic spiculations likely result from neoplastic cells invading adjacent stromal tissue, where subsequent collagen deposition may paradoxically impede tumor progression and potentially contribute to improved clinical outcomes (25,26); meanwhile, their lower rate of detection in the DM images of younger patients is likely due to the technical limitations imposed by dense parenchyma.

The pathophysiological basis of calcification patterns reflects tumor microenvironment dynamics. Calcification analysis showed modality-independent consistency between DM and DBT, while the morphological patterns varied according to age. Younger patients exhibited a higher prevalence of calcification, particularly fine linear or linear branching calcification patterns. This observation aligns with established pathophysiological mechanisms in which malignant transformation induces localized metabolic disturbances, leading to abnormal calcium-phosphate deposition (27) and potentially indicating more aggressive tumor biology in younger populations. Certain subtype-specific patterns emerged in our study: there were variations in luminal B tumors that were age dependent (i.e., calcified masses in younger patients and noncalcified masses in middle-aged patients), while tumors with HER2 overexpression demonstrated a higher frequency of isolated calcifications as compared with the other three subtypes, aligning with previous reports (28). Another study found that among younger patients, invasive malignancies manifesting as calcifications are commonly associated with extensive IDC (29). These diffuse intraductal proliferations often demonstrate indistinct boundaries and complex spatial distribution, contributing to increased positive surgical margin rates and elevated local recurrence risks. The pathognomonic calcification patterns likely reflect necrotic debris from rapid cellular turnover under hypoxic conditions and insufficient blood supply, explaining the association between intraductal malignancies and fine linear or linear branching or coarse microcalcifications. These findings collectively suggest that the presence of microcalcification in younger patients with breast cancer may serve as an imaging biomarker for adverse clinicopathological features and a worse prognosis, thereby supporting the diagnostic value of mammography in this population.

Certain limitations to this study should be acknowledged. The sample size for patients under 30 years of age was relatively small, and recruitment only involved a single center, potentially limiting the generalizability of our findings. These constraints necessitate validation through prospective multicenter studies with expanded cohort sizes. Additionally, the multicenter studies should incorporate standardized imaging protocols and central pathology review to control for institutional variability.

Conclusions

Breast cancer imaging features show age-specific associations with molecular subtypes, with marked differences between young (≤30 years) and middle-aged (45–55 years) patients. These radiologic–pathological correlations may predict molecular subtypes and thus facilitate personalized treatment and prognosis.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-434/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-434/dss

Funding: This work was supported by the National Key Research and Development Program of China (No. 2016YFC 1303004).

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-434/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. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments and was approved by the Ethics Committee of Affiliated Hospital of Qingdao University (No. QYFY WZLL 30287). The requirement for individual consent was waived due to the retrospective nature of the analysis.

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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