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Evaluating the risk of underdiagnosis of invasive breast cancer in needle biopsy-diagnosed ductal carcinoma in situ eligible for radiofrequency ablation

World Journal of Surgical Oncology volume 23, Article number: 43 (2025) Cite this article

Abstract

Background

Radiofrequency ablation (RFA) is considered a promising alternative to surgical excision for patients with small, unifocal early-stage breast cancer. A significant concern with the application of RFA in patients diagnosed with ductal carcinoma in situ (DCIS) via needle biopsy is the underdiagnosis of invasive cancer. The extent of this underdiagnosis in DCIS patients eligible for RFA has not been clearly defined.

Methods

This retrospective study assessed lesions diagnosed as DCIS via needle biopsy and eligible for RFA at our institution from April 2009 to March 2024. The eligibility criteria for RFA included a lesion size of ≤ 1.5 cm, unifocality, and clinical node negativity. Underdiagnosis was defined as the presence of invasive cancer in surgical specimens. We evaluated the frequency and risk factors associated with underdiagnosis.

Results

During the study period, 606 lesions were diagnosed as DCIS via needle biopsy. Of these, 209 lesions met the criteria for RFA, with underdiagnosis determined in 40 lesions (19.1%). The distribution of pathological T (pT) stages among these lesions was as follows: DCIS in 169 lesions (80.9%), pT1mi in 20 lesions (9.6%), pT1a in 5 lesions (2.4%), pT1b in 9 lesions (4.3%), pT1c in 5 lesions (2.4%), and pT2 in 1 lesion (0.5%). Multivariate logistic regression analysis identified lesion size ≥ 10 mm as a significant risk factor for underdiagnosis (p = 0.016). Adjuvant endocrine therapy and chemotherapy were administered to 26 (65.0%) and 6 (15.0%) of the underdiagnosed lesions, respectively.

Conclusions

Our findings highlight the risk of underdiagnosing invasive breast cancer in patients undergoing RFA for needle biopsy-diagnosed DCIS. It is crucial to acknowledge the potential for undertreatment when considering RFA as a treatment option.

Background

The detection rate of early-stage breast cancer has increased with the introduction of mammography screening. Glover et al. (2012) and Nelson et al. (2009) reported that the proportion of ductal carcinoma in situ (DCIS) was approximately 20% in screen-detected breast cancer [1, 2]. Breast conserving surgery has become the standard treatment for early breast cancer, including DCIS [3, 4]. However, surgical excision decreases quality of life because it is invasive, causes postoperative pain, and reduces cosmetic outcomes [5]. Therefore, nonsurgical treatments for small early-stage breast cancers that achieve good cosmetic outcomes are under investigation in clinical trials [6,7,8,9,10].

The RAFAELO trial, a single-arm validation study, demonstrated extremely high ipsilateral breast recurrence-free survival rates using radiofrequency ablation (RFA) for early-stage breast cancer with tumor diameters of ≤ 1.5 cm, without axillary lymph node or distant metastasis [11]. RFA can be a promising alternative to surgical excision in early breast cancer that meets eligibility criteria.

Compared to surgical resection, RFA lacks surgical pathological findings. Brennan et al. (2011) reported that a certain proportion of needle biopsy-diagnosed DCIS was found to have invasive cancer on the surgical specimen, indicating underdiagnosis of invasive cancer [12]. Furthermore, inadequate adjuvant therapy in cases of underdiagnosis may lead to poorer long-term prognosis, as highlighted by Curigliano et al. (2023) [13]. However, no study has specified the frequency of underdiagnosis in biopsy-diagnosed DCIS meeting the eligibility criteria for RFA. While numerous studies have investigated the upstaging of biopsy-diagnosed DCIS, there is limited research focusing specifically on the frequency and predictors of underdiagnosis in DCIS cases that meet the eligibility criteria for RFA. Our study aims to address this gap by evaluating the risk of underdiagnosis in this subset of patients, providing insights that are critical for optimizing patient selection for RFA.

In this retrospective observational study, we evaluated the frequency and risk factors for underdiagnosis in needle biopsy-diagnosed DCIS meeting the eligibility criteria for nonsurgical ablation as follows: 1) lesion size of ≤ 1.5 cm, 2) single lesion, 3) and clinical node negativity.

Methods

Study design

This study was approved by the Ethical Committee for Epidemiology of Hiroshima University (no. E2018-1166) and conducted in accordance with the Declaration of Helsinki and the Ethical Guidelines for Medical Research Involving Human Subjects. Given the retrospective observational design of the trial, the requirement for patient written consent was waived. The study included patients with breast cancer diagnosed as DCIS by needle biopsy at the Department of Breast Surgery, Hiroshima University Hospital, from April 2009 to March 2024. In accordance with the eligibility criteria used for other trials on RFA for early breast cancer [6, 7], this study evaluated lesions that met the following criteria:

  • Diagnosed as DCIS via needle biopsy

  • Lesion size of ≤ 1.5 cm in preoperative imaging tests

  • Single lesion

  • Without axillary lymph node metastasis (cN0) and distant metastasis (cM0)

  • Surgical resection of breast lesion with pathological findings

During this period, 606 lesions were diagnosed as DCIS by needle biopsy. Of these, 357 lesions had a lesion size of > 1.5 cm, 26 were multicentric, 6 were cN + , and 8 did not receive surgical resection as they were enrolled in a clinical trial investigating non-surgical therapy for low-risk DCIS (UMIN000028298). Finally, 209 lesions were included in this study (Fig. 1).

Fig. 1
figure 1

Study flowchart. Flowchart depicting the selection process of lesions diagnosed as ductal carcinoma in situ (DCIS) by needle biopsy. A total of 606 lesions were initially identified, of which 397 were excluded based on the following criteria: lesion size > 1.5 cm (n = 357), multicentric lesion (n = 26), clinical node positivity (n = 6), and non-surgical therapy (n = 8). The remaining 209 lesions were included in the study

Full size image

Clinicopathological factors

We evaluated clinical and pathological factors as follows: age at diagnosis, sex, menopausal status, presence of mass lesions on imaging, microcalcifications on mammography, lesion palpability, lesion size, needle biopsy procedure, nuclear grade, estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor 2 (HER2). The size of the lesions was determined based on imaging findings. Breast ultrasound and contrast-enhanced MRI were prioritized for lesion measurement. For lesions primarily presenting as microcalcifications, the extent of calcifications observed on mammography was used to determine the lesion size. These measurements were derived from radiological reports reviewed by experienced radiologists to ensure accuracy and consistency. A cutoff of 10 mm was chosen to categorize clinical lesion size based on evidence from prior studies indicating that lesions ≥ 10 mm are associated with a higher risk of underdiagnosis in ductal carcinoma in situ (DCIS) [14]. Additionally, this threshold aligns with the TNM classification to enhance its clinical utility [15]. Needle biopsy procedure was categorized into core needle biopsy or vacuum-assisted biopsy under the physician’s directions. ER and PgR were assessed by immunohistochemistry, with ≥ 1% considered positive [16]. ER or PgR positivity was considered hormone receptor (HR) positive. HER2 status was assessed using immunohistochemistry, with 3 + classified as positive and 0, 1 + , and 2 + as negative [17]. Fluorescence in situ hybridization was not performed for HER2 + lesions because this study involved needle biopsy-diagnosed DCIS. The nuclear grade classification of DCIS was categorized into low, intermediate, and high according to the consensus classification [18].

The choice of breast surgical procedure was determined by the attending physician's discretion and the patient's preferences. Sentinel lymph node biopsy (SLNB) was routinely performed in patients undergoing mastectomy. Among patients undergoing breast-conserving surgery, SLNB was performed when there was a suspected risk of invasive cancer but was omitted in cases considered to have a low risk of invasive cancer. Presence of invasive disease, pT, and pN were evaluated in surgical specimens. pT and pN were evaluated according to the TNM classification [15]. Underdiagnosis of needle biopsy in the surgical specimens was defined as the identification of invasive disease, including microinvasive carcinoma. A representative case of underdiagnosis was shown in Supplemental Data (Supplemental Fig. 1). The rates of underdiagnosis and distribution of pT and pN were evaluated. After curative surgery, adjuvant chemotherapy and endocrine therapy were administered according to the National Comprehensive Cancer Network guidelines and St. Gallen consensus [13]. These clinicopathological findings were obtained from a prospectively maintained hospital database.

Statistical analysis

To identify predictors of underdiagnosis, the relationship between underdiagnosis and clinicopathological factors was evaluated using logistic regression analysis. All clinicopathological factors were included in the multivariable logistic regression analysis. Odds ratios and 95% confidence intervals were calculated for all variables. A p-value of < 0.05 was considered statistically significant. A p value of < 0.05 was considered statistically significant. All statistical analyses were performed using JMP software (version 13.2.1, SAS Institute Inc., Cary, USA).

Results

Patient characteristics

Patient demographics are shown in Table 1. Median age at diagnosis was 60 years, with an interquartile range of 49–69. All patients were female. Mass-forming lesions were found in 121 (57.9%) cases. Microcalcifications on mammography were present in 93 (44.5%) lesions. Palpable lesions were reported in 46 (22%) cases. Median lesion size was 8 mm, with an interquartile range of 6–12 mm, and lesions of > 10 mm were seen in 80 (38.3%) cases. Needle biopsies were conducted using core needle biopsy in 129 (61.7%) and vacuum-assisted biopsy in 80 (38.3%) lesions. Nuclear grading identified 92 low-grade (44.0%), 86 intermediate-grade (41.1%), and 31 high grade (14.8%) lesions. ER, PgR, and HER2 were positive in 180 (86.1%), 166 (79.4%), and 26 (12.6%) lesions, respectively, with statuses of HR-positive/HER2-negative in 160 (76.6%), HER2-positive in 26 (12.5%), and HR-negative/HER2-negative in 16 (7.7%) lesions. Breast conserving surgery and mastectomy were performed in 149 and 60 patients, respectively. SLNB was performed for axillary staging in 156 patients (74.6%). Adjuvant systemic therapies included chemotherapy in 9 (4.3%) and hormone therapy in 45 (21.5%) patients.

Table 1 Clinicopathological characteristics
Full size table

Frequency of underdiagnosis

Table 1 shows the pathological findings in surgical specimens and adjuvant therapy. Invasive carcinoma was observed in 40/206 (19.1%) lesions. pT stage distribution was as follows: DCIS in 169 (80.9%), pT1mi in 20 (9.6%), pT1a in 5 (2.4%), pT1b in 9 (4.3%), pT1c in 5 (2.4%), and pT2 in 1 (0.5%) lesion. Figure 2 shows the distribution of pT stages in surgical specimens according to HR and HER2 status. In HR-positive/HER2-negative lesions, invasive cancer was found in 33 (20.6%) lesions, with T1b or higher in 12 (7.5%) lesions. In HER2-positive lesions, invasive cancer was present in 5 (19.2%) lesions, and T1b or higher in 1 (6.3%) lesion. For HR-negative/HER2-negative lesions, both invasive cancer and T1b or higher were recorded in 2 (12.5%) lesions. Lymph node metastases were found in 2 (1.0%) lesions, including pN1 in 1 (0.5%) and pN2 in 1 (0.5%) lesion.

Fig. 2
figure 2

Distribution of pT stages in surgical specimens according to HR and HER2 status. Distribution of pT in (a) all subtypes, (b) HR-positive HER2-negative, (c) HER2-positive, and (d) HR-negative HER2-negative lesions. HR, hormone receptor; HER2, human epidermal growth factor 2; DCIS, ductal carcinoma in situ

Full size image

Predictors of underdiagnosis

The association between underdiagnosis and clinicopathological factors is shown in Table 2. In univariate analysis, lesion size, both as a categorical and continuous variable, along with palpability, were significantly associated with underdiagnosis. Age (p = 0.67), mass-forming lesion (p = 0.51), calcification on mammography (p = 0.32), type of needle biopsy (p = 0.12), grade (p = 0.60), ER (p = 0.36), PgR (p = 0.84), and HER2 (p = 0.96) were not significant predictors. In multivariate analysis, lesion size as a categorical variable (odds ratio: 2.47 and 95% confidence interval: 1.15–5.28; p = 0.020) was significantly correlated with underdiagnosis. Other factors, including age, mass formation, microcalcifications, grade, and receptor status, did not show significant associations.

Table 2 Association between clinicopathological factors and underdiagnosis in univariate and multivariate analyses
Full size table

pT stage distribution and adjuvant systemic therapy in underdiagnosed lesions

Table 3 shows the pT distribution and adjuvant systemic therapy in the 40 lesions with underdiagnosis. pT1mi, T1a, T1b, T1c, and T2 were identified in 20 (50.0%), 5 (12.5%), 9 (22.5%), 5 (12.5%), and 1 (2.5%) lesion, respectively. Consequently, T1b or higher was observed in 15 (37.5%) cases. Adjuvant endocrine therapy and chemotherapy were administered to 26 (65.0%) and 6 (15.0%) lesions, respectively.

Table 3 Pathological findings and adjuvant systemic therapy in underdiagnosed lesions
Full size table

Discussion

This retrospective observational study assessed the risk of underdiagnosing invasive cancer in DCIS diagnosed via needle biopsy and meeting eligibility criteria for RFA. Among 209 DCIS lesions evaluated, 40 (19.1%) were found to harbor invasive cancer, with lesion size ≥ 10 mm identified as the most significant predictor of underdiagnosis. These findings provide critical insights into the challenges of accurately diagnosing DCIS and ensuring appropriate patient selection for RFA.

Brennan et al. (2011) conducted a meta-analysis highlighting an underdiagnosis rate of 25% in needle biopsy-diagnosed DCIS [12]. The study identified lesion size, grade, and imaging features as significant predictors of underdiagnosis. Similarly, Carlos Chavez de Paz Villanueva (2017) reported that lesion size > 10 mm was significantly associated with underdiagnosis in a cohort of patients with DCIS [14]. Consistent with these studies, the present study demonstrated that lesion size ≥ 10 mm was associated with a higher risk of underdiagnosis (odds ratio: 2.42; p = 0.017). This finding underscored the importance of lesion size as a robust predictor, particularly in patients considered for nonsurgical treatment modalities such as RFA.

In contrast, some previous studies have suggested that other factors, such as biopsy technique or HR and HER2 status, may have a significantly influence on underdiagnosis. Chavez de Paz Villanueva et al. (2017) found that vacuum-assisted biopsies were associated with lower rates of underdiagnosis compared to core needle biopsies [14]. However, in the present study, no significant difference was observed between these biopsy techniques (p = 0.26). This discrepancy may stem from differences in institutional practices or selection criteria, highlighting the need for standardization in diagnostic protocols. Borgquist et al. (2015) suggested that HER2-positive DCIS is associated with a higher risk of underdiagnosis [19]. Similarly, Iwamoto et al. (2021) found that HR-negative and HER2-positive lesions were more likely to be upstaged [20]. In contrast, our findings did not support these associations, potentially due to the limited statistical power of subgroup analyses. Future multicenter studies with larger cohorts are essential to validate the role of molecular markers as predictors of underdiagnosis.

Predictive models for underdiagnosis have been developed based on preoperative factors. Meurs et al. (2023) and Jakub et al. (2017) created nomograms incorporating variables such as lesion size, grade, and biopsy method to estimate the likelihood of invasive disease [21, 22]. Although these models appear promising, Le Gac et al. (2022) noted a lack of consensus on reliable predictors and their applicability in routine clinical practice [23]. Reported underdiagnosis rates in DCIS eligible for active surveillance trials range from 4 to 25%, highlighting the ongoing challenges of accurate preoperative diagnosis.

The RAFAELO trial (Kinoshita et al., 2024), a landmark study on RFA for early breast cancer, demonstrated excellent local control with an ipsilateral breast recurrence rate of 0.57% over five years [11]. However, one limitation of RFA is the absence of surgical pathological findings, which can obscure the presence of invasive disease. In the present study, a significant proportion (19.1%) of DCIS lesions meeting RFA eligibility criteria were underdiagnosed, raising concerns about the potential for undertreatment. This underscores the need for careful preoperative evaluation and stringent patient selection criteria when considering RFA for needle biopsy-diagnosed DCIS.

While the primary focus of this study is on the diagnosis of DCIS, recent advancements in therapeutic strategies for advanced breast cancer highlighted the evolving landscape of breast cancer management [24,25,26,27,28]. These studies provided important insights into the prognostic factors influencing treatment decisions and long-term outcomes in breast cancer, underscoring the necessity of accurate diagnosis to guide optimal therapy. Chavez de Paz Villanueva et al. (2017) also examined systemic therapy in underdiagnosed cases, reporting that 39.1% of underdiagnosed lesions were ≥ pT1b, with endocrine therapy and chemotherapy administered in 54% and 16.5% of cases, respectively [14]. In the present study, 37.5% of underdiagnosed lesions were ≥ T1b, with endocrine therapy administered in 65.0% and chemotherapy in 15.0%. These findings are consistent with prior research but specifically focus on lesions meeting RFA criteria. HR-positive, HER2-negative pT1a/bN0M0 lesions have a favorable prognosis regardless of endocrine therapy (Sasada et al., 2023) [29]. However, HR-negative lesions require careful evaluation to ensure adequate systemic therapy, given their higher risk of recurrence.

To improve diagnostic accuracy, advanced technologies, such as breast MRI and radiomics-driven artificial intelligence, are emerging as valuable tools. Lee et al. (2022) and Hong et al. (2023) demonstrated the utility of these techniques in predicting invasive disease [30, 31]. Additionally, Hashiba et al. (2023) and Vanni G et al. (2024) highlighted the promise of artificial intelligence in improving diagnostic precision [32]. Future multicenter studies should explore these innovations to develop standardized diagnostic frameworks.

This study has limitations. First, its retrospective design may have introduced selection bias, particularly in the choice of biopsy techniques, which were at the discretion of the treating physician. Second, the relatively small sample size and single-institution setting may limit the generalizability of the findings. Finally, certain variables, such as MRI findings, which are known to influence diagnostic accuracy, were not included in the analysis. To address these limitations, future prospective multicenter studies with larger and more diverse populations are warranted.

The present study highlighted the risk of underdiagnosing invasive cancer in needle biopsy-diagnosed DCIS eligible for RFA, with lesion size ≥ 10 mm identified as a significant predictor. These findings emphasize the need for careful patient selection and advanced diagnostic approaches to mitigate the risk of undertreatment. Incorporating standardized diagnostic protocols and innovative imaging techniques may enhance the safety and efficacy of RFA as a treatment modality for DCIS.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

DCIS:

Ductal carcinoma in situ

ER:

Estrogen receptor

PgR:

Progesterone receptor

HER2:

Human epidermal growth factor 2

HR:

Hormone Receptor

RFA:

Radiofrequency ablation

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Acknowledgements

The authors thank Ulatus (https://www.ulatus.jp) for their assistance with manuscript translation and editing.

Funding

This study was conducted with the support of the National University Corporation Operating Grant.

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Authors and Affiliations

  1. Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, 734-8551, Japan

    Hideo Shigematsu, Mutsumi Fujimoto, Kanako Suzuki, Haruka Ikejiri, Ai Amioka, Emiko Hiraoka, Shinsuke Sasada & Morihito Okada

  2. Department of Anatomical Pathology, Hiroshima University Hospital, Hiroshima, 734-8551, Japan

    Koji Arihiro

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H.S., S.S. and M.O. contributed to the conception and design. H.S., M.F., K.S., H.I., A.A., E.H., and A.K. contributed to the curation, analysis, and interpretation of data. H.S., M.F., and S.S. contributed to the formal analysis. H.S., S.S., and M.O. contributed to drafting and revision of the article. H.S. and M.O. contributed to funding acquisition. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Hideo Shigematsu.

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This study was approved by the Ethical Committee for Epidemiology of Hiroshima University (no. E2018-1166) and conducted in accordance with the Declaration of Helsinki and the Ethical Guidelines for Medical Research Involving Human Subjects.

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The authors declare no competing interests.

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Supplementary Information

12957_2025_3697_MOESM1_ESM.tiff

Additional file 1: Supplemental Fig. 1 A Representative Case of Underdiagnosis. (A) Ultrasound revealed a hypoechoic area measuring 14 mm in diameter. (B) Contrast-enhanced breast MRI identified a 9 mm mass in the E region of the right breast. (C) Needle biopsy specimens showed tumor tissue proliferating and progressing within the ducts or lobules in a cribriform and micropapillary pattern, leading to a diagnosis of ductal carcinoma in situ. (D) Surgical specimens revealed tumor tissue infiltrating the surrounding breast stroma, resulting in a final diagnosis of invasive ductal carcinoma. The pathological diagnosis was pT1b (5 mm) N0M0, ER-positive, PgR-negative, and HER2-positive breast cancer. Postoperative treatments included docetaxel, cyclophosphamide, and trastuzumab therapy, breast-conserving radiotherapy, and adjuvant endocrine therapy.

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Shigematsu, H., Fujimoto, M., Suzuki, K. et al. Evaluating the risk of underdiagnosis of invasive breast cancer in needle biopsy-diagnosed ductal carcinoma in situ eligible for radiofrequency ablation. World J Surg Onc 23, 43 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12957-025-03697-2

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  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12957-025-03697-2

Keywords

World Journal of Surgical Oncology

ISSN: 1477-7819

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