Surgical resection for indeterminate pulmonary nodules in patients with prior breast cancer: diagnostic value and biomarker reassessment

Abstract

Background

Pulmonary nodules detected during postoperative surveillance in breast cancer survivors present a diagnostic challenge because imaging findings alone often cannot reliably distinguish pulmonary metastases from primary lung cancer. Surgical resection provides definitive pathological diagnosis while simultaneously enabling biomarker reassessment in metastatic lesions. This study evaluated the diagnostic value and clinical significance of pulmonary resection for indeterminate pulmonary nodules in patients with prior breast cancer.

Methods

We retrospectively reviewed 33 pulmonary resections performed in 32 consecutive patients with a history of breast cancer who underwent pulmonary resection for indeterminate pulmonary nodules between 2016 and 2025. Clinicopathological findings, imaging characteristics, perioperative outcomes, and receptor discordance between primary breast tumors and pulmonary metastatic lesions were analyzed. Paired biomarker data were available for 18 patients with pulmonary metastases.

Results

Final pathological diagnoses included metastatic breast cancer in 23 lesions (69.7%), primary lung cancer in 9 lesions (27.3%), and benign disease in 1 lesion (3.0%), indicating that more than one-quarter of lesions suspected preoperatively to represent pulmonary metastases were actually primary lung cancers. Most procedures were performed using video-assisted thoracoscopic surgery (87.9%). Among patients with paired biomarker data, substantial discordance in hormone receptor and human epidermal growth factor receptor 2 (HER2) expression was observed, including frequent conversion between HER2-0 and HER2-low categories. Biomarker reassessment resulted in modification of subsequent systemic treatment in three patients. Perioperative outcomes were favorable, with no operative mortality and low postoperative morbidity.

Conclusions

Surgical resection for indeterminate pulmonary nodules in selected patients with prior breast cancer provides definitive pathological diagnosis, appropriate local treatment, and sufficient tissue for biomarker reassessment. Histological confirmation should be considered when imaging findings remain inconclusive because pulmonary nodules in breast cancer survivors are not necessarily metastatic disease. Biomarker reassessment may directly influence individualized systemic treatment strategies in the HER2-low era.

Highlight box.

Key findings

• Surgical resection for indeterminate pulmonary nodules in breast cancer survivors provided definitive pathological diagnosis, appropriate local treatment, and sufficient tissue for biomarker reassessment with acceptable perioperative outcomes.

• More than one-quarter of resected pulmonary lesions were diagnosed as primary lung cancer rather than metastatic breast cancer.

• Biomarker reassessment of surgically resected lung metastases demonstrated substantial discordance in hormone receptor and human epidermal growth factor receptor 2 (HER2) expression, including frequent conversion between HER2-0 and HER2-low categories.

What is known and what is new?

• Differentiating pulmonary metastases from primary lung cancer based on imaging findings alone is often difficult in breast cancer survivors. Receptor discordance between primary and metastatic breast cancer has been reported previously.

• This study demonstrated that surgical resection provides definitive pathological diagnosis while simultaneously enabling clinically relevant biomarker reassessment in patients with indeterminate pulmonary nodules. A substantial proportion of lesions initially suspected to represent metastatic breast cancer were pathologically diagnosed as primary lung cancer.

What is the implication, and what should change now?

• Pulmonary nodules in breast cancer survivors should not automatically be regarded as metastatic disease; histological confirmation should be considered when imaging findings are inconclusive.

• Minimally invasive surgical approaches such as video-assisted thoracoscopic surgery can provide adequate tissue for both diagnosis and biomarker reassessment with low morbidity.

• Reassessment of HER2 status in metastatic lesions may become increasingly important for treatment selection in the HER2-low era.

Introduction

Pulmonary nodules are increasingly detected during postoperative surveillance in breast cancer survivors owing to prolonged survival and advances in systemic therapy. However, differentiating pulmonary metastases from primary lung cancer or benign lesions remains clinically challenging, as imaging findings are often inconclusive. Accurate diagnosis is essential because treatment strategies and prognostic implications differ substantially according to the underlying pathology (1-3).

Histological confirmation can be achieved by bronchoscopic biopsy, computed tomography (CT)-guided percutaneous biopsy, or surgical resection. However, bronchoscopic and CT-guided biopsy may be limited by small tissue samples, technical difficulty, or procedure-related complications. In contrast, minimally invasive pulmonary resection using video-assisted thoracoscopic surgery (VATS) provides definitive diagnosis while simultaneously allowing adequate tissue acquisition for biomarker reassessment and comprehensive pathological evaluation (1,4-6). In addition, surgically resected specimens allow reassessment of hormone receptor and human epidermal growth factor receptor 2 (HER2) status in metastatic lesions, which may influence systemic treatment selection, particularly in the HER2-low era (7-12).

The present study aimed to evaluate the diagnostic and clinical significance of pulmonary resection for indeterminate pulmonary nodules in patients with prior breast cancer, with particular focus on pathological diagnosis, perioperative outcomes, and biomarker reassessment between primary breast tumors and pulmonary metastatic lesions. Although imaging modalities have improved substantially, differentiating pulmonary metastases from primary lung cancer based on radiological findings alone remains challenging in many patients. Furthermore, biomarker reassessment of metastatic lesions has gained increasing importance because receptor conversion, particularly HER2-low expression, may influence subsequent systemic treatment strategies. However, studies evaluating both the pathological diagnosis of indeterminate pulmonary nodules and the clinical impact of biomarker reassessment using surgically resected pulmonary specimens remain limited. Although pulmonary metastasectomy has been reported previously and may provide therapeutic benefit in carefully selected patients with isolated pulmonary metastases (13-15), few studies have comprehensively evaluated both its diagnostic value and its role in biomarker reassessment in the HER2-low era. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1302/rc).

Methods

Study design and patient selection

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Institutional Review Board of Fukuoka University Hospital (approval No. H26-04-006). Because this study used only existing clinical data and involved no intervention, the requirement for written informed consent was waived. This retrospective study included patients with a history of breast cancer who underwent surgical resection of pulmonary lesions at Fukuoka University Hospital between January 2016 and December 2025. Clinical records, imaging findings, operative reports, and pathological data were reviewed.

Two analytical cohorts were established according to the study objectives:

1. Pulmonary resection cohort (33 resections in
32 patients), used to evaluate radiologic characteristics, diagnostic diversity, and surgical feasibility of pulmonary lesion resection.

2. Metastatic breast cancer cohort (23 resections in
22 patients), consisting of patients with pathologically confirmed breast cancer lung metastases. Clinicopathological characteristics of the primary tumor were analyzed in this cohort on a per-patient basis.

Receptor comparison analyses were performed in patients with paired biomarker data available for both the primary tumor and the metastatic lesion. ER and PgR comparison was available in 18 patients, and HER2 comparison was available in 18 patients.

Indications for pulmonary resection

Pulmonary resection was considered for patients with newly detected pulmonary nodules when imaging studies could not reliably distinguish metastatic breast cancer from primary lung cancer or benign disease and complete surgical resection was considered feasible. Pulmonary metastasectomy was also considered for patients with isolated pulmonary metastases amenable to complete resection.

The extent of pulmonary resection was determined according to tumor size, anatomical location, and the feasibility of preserving lung parenchyma while achieving complete resection. Wedge resection was preferred whenever feasible, whereas segmentectomy or lobectomy was selected when wedge resection was unlikely to achieve an adequate surgical margin or was technically unsuitable. Our institutional management algorithm for indeterminate pulmonary nodules is shown in Figure S1.

Preoperative tissue diagnosis

Preoperative tissue diagnosis was considered when clinically indicated. Bronchoscopic biopsy under general anesthesia with intermittent CT confirmation of the biopsy forceps position was available at our institution; however, because the procedure required a hybrid operating room and general anesthesia, it was reserved for selected patients in whom preoperative pathological confirmation was expected to alter subsequent management.

This procedure was therefore selectively performed only in patients in whom a reasonable diagnostic yield was anticipated, such as those with a visible lesion on chest radiography or a bronchus sign on CT.

Bronchoscopy was not routinely performed because its diagnostic yield was considered limited for small peripheral nodules, and surgical resection was generally preferred when definitive diagnosis and potential curative treatment could be achieved simultaneously. Preoperative bronchoscopic biopsy was performed in four patients; however, a definitive pathological diagnosis could not be established in any case. Final surgical pathology demonstrated pulmonary metastasis in two patients and primary lung cancer in the remaining two patients. For centrally located or large pulmonary lesions requiring anatomical resection, thoracoscopic needle biopsy followed by intraoperative frozen-section examination was performed before proceeding to anatomical resection when no preoperative pathological diagnosis had been established and intraoperative confirmation was considered necessary.

Pathological evaluation

Resected pulmonary specimens were examined by dedicated pulmonary and breast pathologists. Histological diagnosis was established using routine hematoxylin and eosin staining supplemented by immunohistochemistry (IHC) when necessary. The diagnosis of metastatic breast cancer was based on histological morphology together with IHC findings, including estrogen receptor (ER), progesterone receptor (PgR), HER2, GATA3, mammaglobin, gross cystic disease fluid protein-15 (GCDFP-15), thyroid transcription factor-1 (TTF-1), and Napsin A, as appropriate. HER2 status was assessed according to the contemporaneous American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines applicable at the time of pathological evaluation.

Biomarker reassessment

Receptor comparison was performed between the primary breast tumor and the corresponding pulmonary metastatic lesion in patients with paired pathological data. ER and PgR expression were recorded as the percentage of positively stained tumor cells. Receptor conversion for ER and PgR was defined as an absolute difference of ≥10 percentage points between the primary and metastatic lesions. HER2 IHC score change was defined as any change in IHC score. In addition, clinically relevant HER2 category conversion was evaluated by classifying tumors as HER2-0 (IHC 0), HER2-low [IHC 1+ or IHC 2+ with negative in situ hybridization (ISH)], or HER2-positive (IHC 3+ or IHC 2+ with positive ISH).

Statistical analysis

Continuous variables are presented as median (range), and categorical variables as number (percentage). Comparisons between groups were performed using the Mann-Whitney U test for continuous variables and Fisher’s exact test for categorical variables, as appropriate. Correlations between receptor change and recurrence interval were evaluated using Spearman’s rank correlation coefficient. Because this retrospective study included all consecutive eligible patients during the study period, no formal sample size calculation was performed. Statistical analyses were performed using R software (version 4.5.2; R Foundation for Statistical Computing, Vienna, Austria). A two-sided P value <0.05 was considered statistically significant. Analyses were performed using complete-case data, and missing values were not imputed.

Results

Patient selection

Between January 2016 and December 2025, 33 pulmonary resections were performed in 32 consecutive patients with a history of breast cancer who underwent surgery for newly detected pulmonary lesions (Figure 1). Final pathological diagnoses included metastatic breast cancer in 23 lesions (69.7%), primary lung cancer in 9 lesions (27.3%), and benign disease in 1 lesion (3.0%). Thus, more than one-quarter of lesions initially suspected to represent pulmonary metastases were ultimately diagnosed as primary lung cancer. Twenty-two patients with pathologically confirmed breast cancer lung metastases constituted the metastatic breast cancer cohort because one patient underwent two sequential pulmonary resections for metastatic disease (Table S1). Paired biomarker analyses were available for 18 patients for ER, PgR, and HER2.

Figure 1.

Study flow of pulmonary lesion resections in breast cancer survivors. Between 2016 and 2025, 33 pulmonary resections were performed in 32 breast cancer patients with newly detected lung lesions. Final pathological diagnoses included metastatic breast cancer in 23 resections, primary lung cancer in 9, and benign disease in 1. Twenty-two patients with pathologically confirmed breast cancer lung metastases were included in the metastatic cohort. Paired receptor analyses were available in 18 patients for ER/PgR and in 18 patients for HER2. ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; PgR, progesterone receptor.

Clinicopathological characteristics

Clinicopathological characteristics are summarized in Table 1.

Table 1. Clinicopathological characteristics.

Variable	N (%)
(a) Pulmonary resection cohort (per resection, n=33)
Final pathological diagnosis
Metastatic breast cancer	23 (69.7)
Primary lung cancer	9 (27.3)
Benign lesion	1 (3.0)
Lesion number
Solitary	22 (66.7)
Multiple	11 (33.3)
CT appearance
Solid	23 (69.7)
Part-solid	10 (30.3)
Ground-glass opacity	0
Margin
Smooth	7 (21.2)
Non-smooth	26 (78.8)
(b) Metastatic breast cancer cohort† (per patient, n=22)
Histological type (available in 22 patients)
DCIS	1 (4.5)
IDC	20 (90.9)
ILC	1 (4.5)
Pathological stage at initial diagnosis (22 patients)
0	1 (4.5)
I	7 (31.8)
II	11 (50.0)
III	1 (4.5)
IV	2 (9.1)
Pathological nodal status (22 patients)
pN0	12 (54.5)
pN1	7 (31.8)
pN2	2 (9.1)
pN3	1 (4.5)
Primary breast cancer subtype (classification available in 20 patients with complete HER2 data)
HR-positive/HER2-negative	15 (68.2)
HR-positive/HER2-positive	2 (9.1)
Triple-negative	3 (13.6)
HER2 unknown (HR-positive)	2 (9.1)
Adjuvant systemic therapy after primary surgery (available in 22 patients)
No adjuvant therapy	2 (9.1)
Chemotherapy alone	3 (13.6)
Endocrine therapy alone	10 (45.5)
Chemotherapy + endocrine therapy	7 (31.8)
With anti-HER2 therapy	2
Without anti-HER2 therapy	5

Pathological stage and nodal status are based on the initial breast cancer diagnosis. Intrinsic subtype was determined according to ER, PgR, and HER2 status of the primary tumor. HER2 status was unavailable in two patients. Median age: primary lung cancer, 70 (range, 51–77) years; pulmonary metastasis, 56 (range, 25–83) years; P=0.38. HR positivity was defined as ER and/or PgR positivity. HER2 status was evaluated according to the contemporaneous ASCO/CAP guidelines. ^†, median age at pulmonary surgery: 64 (range, 25–83) years; median recurrence interval to pulmonary metastasectomy: 81.6 (range, 2.0–230.8) months. ASCO/CAP, American Society of Clinical Oncology/College of American Pathologists; DCIS, ductal carcinoma in situ; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; IDC, invasive ductal carcinoma; ILC, invasive lobular carcinoma; PgR, progesterone receptor; pN, pathological lymph node.

Among the 33 pulmonary resections, solitary pulmonary nodules were more common than multiple lesions (66.7% vs. 33.3%). On CT, solid nodules accounted for 69.7% of lesions, whereas 30.3% demonstrated part-solid morphology. No pure ground-glass nodules were observed. Most lesions showed non-smooth margins (78.8%), emphasizing that radiological appearance alone was insufficient to distinguish pulmonary metastases from primary lung cancer.

Among the 22 patients with pulmonary metastases, the median age at pulmonary surgery was 56 years (range, 25–83 years), and the median interval from primary breast cancer surgery to pulmonary metastasectomy was 81.6 months (range, 2.0–230.8 months). Histologically, invasive ductal carcinoma accounted for 90.9% of primary breast cancers, whereas one patient each had ductal carcinoma in situ (DCIS) and invasive lobular carcinoma. Stage II disease was the most frequent pathological stage (50.0%), and more than half of the patients were node-negative at the initial diagnosis (54.5%). HR-positive/HER2-negative tumors represented the predominant intrinsic subtype (68.2%).

Regarding adjuvant systemic therapy, endocrine therapy alone was administered in 45.5% of patients, chemotherapy plus endocrine therapy in 31.8%, chemotherapy alone in 13.6%, and no adjuvant systemic therapy in 9.1%. Among patients receiving combined chemotherapy and endocrine therapy, two had also received anti-HER2 therapy.

Radiologic characteristics and diagnostic diversity

Representative CT images are shown in Figure S2. Considerable overlap in imaging findings was observed between pulmonary metastases and primary lung cancer. Both entities frequently demonstrated irregular or spiculated margins and, in some cases, part-solid morphology, making reliable preoperative differentiation difficult based on imaging alone.

Final pathological examination demonstrated marked diagnostic diversity (Figure 2). Of the 33 resected pulmonary lesions, only 23 (69.7%) represented metastatic breast cancer, whereas 9 lesions (27.3%) were diagnosed as primary lung cancer and one lesion (3.0%) was benign. These findings indicate that pulmonary nodules detected during breast cancer follow-up should not automatically be regarded as metastatic disease.

Figure 2.

Final pathological diagnosis of pulmonary lesions detected during breast cancer follow-up. Pulmonary lesions resected in breast cancer survivors showed heterogeneous diagnoses, including metastatic breast cancer (69.7%), primary lung cancer (27.3%), and benign disease (3.0%).

Surgical outcomes

Perioperative outcomes are summarized in Table 2.

Table 2. Surgical outcomes of pulmonary resection in breast cancer patients.

Variable	Value
Surgical approach
VATS	29 (87.9)
RATS	2 (6.1)
Open thoracotomy	2 (6.1)
Type of pulmonary resection
Wedge resection	19 (57.6)
Segmentectomy	6 (18.2)
Lobectomy	7 (21.2)
Combined resection (segmentectomy + wedge)	1 (3.0)
Operative time, min	134 [45–369]
Blood loss, mL	0 [0–275]
Postoperative length of stay, days	7 [3–17]
Postoperative complications	1 (3.0)
Clavien-Dindo ≥ Grade II (pneumonia)	1 (3.0)

Data are presented as n (%) or median [interquartile range]. RATS, robot-assisted thoracic surgery; VATS, video-assisted thoracoscopic surgery.

Minimally invasive surgery was performed in the vast majority of patients. VATS was used in 29 procedures (87.9%), and robot-assisted thoracic surgery in two (6.1%), whereas thoracotomy was required in only two patients (6.1%). Wedge resection was the most common procedure (57.6%), reflecting the diagnostic intent of surgery, followed by lobectomy (21.2%), segmentectomy (18.2%), and combined segmentectomy plus wedge resection (3.0%). Two patients with pulmonary metastases underwent lobectomy. In one patient, the metastatic lesion measured 4.6 cm and was located in the right middle lobe. In the other patient, the lesion was centrally located adjacent to the pulmonary vein. In both patients, thoracoscopic needle biopsy followed by intraoperative frozen-section examination confirmed metastatic breast cancer before lobectomy was performed. However, limited resection was considered technically inappropriate because of the tumor size or anatomical location, despite the lesions being solitary pulmonary metastases.

Median operative time was 134 minutes (range, 45–369 minutes), median blood loss was 0 mL (range, 0–275 mL), and the median postoperative hospital stay was 7 days (range, 3–17 days). Only one patient (3.0%) developed a postoperative complication (Clavien-Dindo grade II pneumonia), which resolved with antibiotic treatment. No perioperative mortality occurred, indicating that pulmonary resection was performed safely in this selected patient population.

Biomarker reassessment

Individual paired biomarker data are provided in Table S2. Paired biomarker data were available for 18 patients. Receptor change is summarized in Table 3.

Table 3. Receptor change between primary breast tumors and lung metastases.

Marker	Evaluable cases, n	No change, n (%)	Change, n (%)
ER	18	7 (38.9)	11 (61.1)
PgR	18	9 (50.0)	9 (50.0)
HER2 (IHC score)	18	3 (16.7)	15 (83.3)

Change in ER and PgR was defined as an absolute difference of ≥10 percentage points between the primary tumor and the metastatic lesion. HER2 IHC score change was defined as any change in HER2 IHC score between primary and metastatic tumors. Detailed patterns of receptor status shifts are illustrated in Figure 3. ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemical; PgR, progesterone receptor.

ER change was observed in 11 patients (61.1%), whereas PgR change occurred in 9 patients (50.0%). HER2 IHC score changed in 15 patients (83.3%), indicating substantial biological heterogeneity between primary breast tumors and pulmonary metastases.

Scatter plots comparing receptor expression between primary breast tumors and pulmonary metastases are presented in Figure 4. Although receptor expression remained similar in several patients, marked changes in ER, PgR, and HER2 expression were observed in others. Sankey diagrams illustrating receptor transitions are shown in Figure 3.

Figure 4.

Scatter plots comparing receptor expression between primary breast tumors and corresponding lung metastases. (A) ER expression (%). (B) PgR expression (%). (C) HER2 immunohistochemical score. The diagonal line indicates identical receptor expression between the primary tumor and the metastatic lesion. ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; PgR, progesterone receptor.

Figure 3.

Receptor status shifts between primary breast tumors and lung metastases. Sankey diagrams illustrate transitions in receptor status between primary tumors and corresponding lung metastases. ER (A) and PgR (B) are classified as positive or negative. HER2 (C) is categorized as HER2-0, HER2-low, or HER2-positive. The widths of the connecting bands represent the number of cases in each transition category, and numbers on the bands indicate the exact number of cases. ER and PgR positivity was defined as ≥1% expression. ER and PgR status shifts were evaluated in patients with available positive/negative receptor status, regardless of availability of exact percentage values. ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; PgR, progesterone receptor.

Clinically relevant HER2 category conversion

Clinically relevant HER2 category conversion is summarized in Table S3.

Overall, clinically relevant HER2 category conversion occurred in 9 of 18 patients (50.0%). Conversion from HER2-0 to HER2-low was the most common pattern (33.3%), whereas conversion from HER2-low to HER2-0 occurred in two patients (16.7%). One patient converted from HER2-positive to HER2-low following anti-HER2 therapy, whereas no patients converted from HER2-low or HER2-0 to HER2-positive. These findings suggest that reassessment of HER2 status may have increasing clinical relevance in the HER2-low era.

Clinical impact of biomarker reassessment

Biomarker reassessment influenced subsequent systemic treatment in three patients. Two patients demonstrated conversion from HR-positive/HER2-negative disease to triple-negative disease, whereas one patient converted from triple-negative disease to HR-positive/HER2-negative disease, resulting in modification of subsequent systemic treatment strategies.

Association between receptor change and recurrence interval

Correlation analyses are summarized in Table 4 and illustrated in Figure S3.

Table 4. Correlation between receptor change and recurrence interval.

Receptor	n	Spearman’s ρ	P value
ER	18	0.21	0.41
PgR	18	0.32	0.20
HER2	17	0.28	0.29

Spearman’s rank correlation analysis was performed to evaluate the association between receptor change (absolute difference in ER or PgR expression, or change in HER2 IHC score) and the interval between primary breast cancer surgery and pulmonary resection. ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemical; PgR, progesterone receptor.

No significant association was observed between recurrence interval and changes in ER expression (Spearman’s ρ=0.21, P=0.41), PgR expression (ρ=0.32, P=0.20), or HER2 IHC score (ρ=0.28, P=0.29).

Similarly, subgroup analysis according to recurrence interval (<5 versus ≥5 years) demonstrated no significant differences in the frequency of ER, PgR, or HER2 conversion (Table S4).

Additional findings

One patient initially diagnosed with DCIS subsequently developed pulmonary metastasis despite the absence of documented microinvasion in the primary breast specimen. The clinicopathological and receptor findings for this patient are included in Table S2.

Discussion

Principal findings

The present study demonstrated three clinically important findings. First, more than one-quarter of pulmonary nodules detected in patients with a history of breast cancer were ultimately diagnosed as primary lung cancer rather than metastatic disease, highlighting the diagnostic value of surgical resection for indeterminate pulmonary lesions. Second, receptor discordance between primary breast tumors and pulmonary metastases was frequently observed, particularly for HER2 status in the HER2-low era. Third, biomarker reassessment altered subsequent systemic treatment in several patients, supporting the clinical significance of pathological confirmation beyond diagnosis alone.

Diagnostic value of surgical resection

Differentiating pulmonary metastases from primary lung cancer remains a common clinical challenge during postoperative surveillance of breast cancer patients (1-3).
Although CT provides valuable morphological information, radiological findings frequently overlap between these entities (2,3). In the present series, 27.3% of surgically resected pulmonary lesions proved to be primary lung cancer, despite preoperative suspicion of metastatic disease.

Previous studies have similarly reported that pulmonary nodules detected after breast cancer treatment represent a heterogeneous group of diseases, including metastatic tumors, second primary lung cancers, and benign lesions (2,3). Because therapeutic strategies differ substantially according to pathological diagnosis (1), establishing a definitive diagnosis is essential before initiating systemic treatment whenever feasible.

Our findings therefore support an active role for surgical biopsy or limited pulmonary resection in carefully selected patients with resectable indeterminate pulmonary nodules, particularly when imaging findings are inconclusive and pathological confirmation may alter subsequent management. Notably, preoperative bronchoscopic biopsy failed to establish a definitive diagnosis in all four patients in whom it was attempted, further highlighting the limitations of tissue diagnosis for selected indeterminate pulmonary nodules.

Safety and feasibility of surgery

Pulmonary resection was safely performed in our cohort using predominantly minimally invasive approaches. Nearly 90% of procedures were completed by VATS, postoperative morbidity was low, and no perioperative mortality occurred. Most patients underwent wedge resection, which provided sufficient tissue for definitive diagnosis while minimizing surgical invasiveness.

These results suggest that minimally invasive pulmonary resection represents a practical diagnostic strategy with acceptable perioperative risk in appropriately selected patients (6,13,14).

Receptor discordance between primary and metastatic tumors

Receptor discordance between primary and metastatic breast cancer has been well documented, although reported frequencies vary among studies according to metastatic site and methodology. In a systematic review and meta-analysis including 39 studies and 6,118 paired primary and metastatic breast cancer samples, Schrijver et al. reported pooled discordance rates of 19.3% for ER, 30.9% for PgR, and 10.3% for HER2 (10). Consistent with these previous reports, we also observed substantial alterations in ER, PgR, and HER2 expression.

Notably, HER2 IHC scores changed in more than 80% of paired specimens, reflecting the dynamic biological evolution of metastatic breast cancer. Although this frequency appears higher than that reported in previous studies, direct comparison should be interpreted cautiously because earlier studies primarily evaluated conversion between HER2-positive and HER2-negative disease, whereas we evaluated HER2 IHC score change and additionally evaluated clinically relevant HER2 category conversion in the HER2-low era. These findings emphasize that metastatic lesions cannot always be assumed to retain the biological characteristics of the primary tumor and highlight the increasing clinical importance of reassessing HER2 expression.

Several mechanisms may contribute to receptor discordance, including intratumoral heterogeneity, clonal selection under systemic therapy, treatment-induced biological evolution, and technical variability in biomarker assessment (10,11).

Clinical significance in the HER2-low era

The emergence of HER2-low breast cancer as a therapeutically relevant category has increased the importance of accurately reassessing HER2 expression in metastatic lesions (7,8).

Half of our patients demonstrated clinically relevant HER2 category conversion, with conversion from HER2-0 to HER2-low representing the most common pattern. Such changes may influence eligibility for antibody-drug conjugates, including trastuzumab deruxtecan, which has demonstrated significant clinical benefit in patients with HER2-low metastatic breast cancer (7,8).

Conversely, one patient converted from HER2-positive to HER2-low following anti-HER2 therapy, illustrating that HER2 expression may also decrease during disease progression. These observations support repeat pathological evaluation whenever metastatic tissue can be safely obtained.

Clinical impact of biomarker reassessment

Importantly, biomarker reassessment resulted in modification of systemic treatment in three patients. Although the number was small, these cases illustrate the potential clinical consequences of receptor conversion. Without pathological confirmation, treatment decisions would have relied solely on the biological characteristics of the primary tumor, potentially resulting in suboptimal systemic therapy.

Therefore, the value of pulmonary resection extends beyond establishing the diagnosis of metastatic disease and includes providing updated biological information that may guide individualized treatment strategies.

Recurrence interval and tumor biology

We observed no significant correlation between recurrence interval and changes in ER, PgR, or HER2 expression.

This finding suggests that receptor evolution may occur independently of recurrence timing and may instead reflect complex interactions among tumor heterogeneity, treatment-related selective pressure, and clonal evolution. Larger studies are warranted to clarify factors associated with receptor conversion (9-11).

Rare presentation of pulmonary metastasis after DCIS

An unusual finding in our cohort was pulmonary metastasis arising after an initial diagnosis of DCIS without documented microinvasion. Although exceedingly uncommon, similar cases have been reported previously (16).
The underlying mechanism remains uncertain and may involve occult microinvasion or dissemination of tumor cells before definitive treatment. Because of its rarity, this finding should be interpreted cautiously but highlights the biological diversity of breast cancer progression.

Limitations

This study has several limitations. First, it was a retrospective single-center study with a relatively small sample size, which may limit the generalizability of our findings. Second, biomarker analyses were available only for patients with paired pathological specimens, introducing the possibility of selection bias. Third, HER2 status was evaluated according to the contemporaneous ASCO/CAP guidelines applicable at the time of diagnosis, and changes in guideline criteria over the study period may have influenced HER2 classification. Finally, because pulmonary resection was performed only in selected patients with resectable lesions, our findings may not be applicable to all patients with metastatic breast cancer.

Nevertheless, this study reflects contemporary clinical practice in the HER2-low era and includes detailed paired biomarker analyses together with evaluation of their impact on subsequent systemic treatment.

Conclusions

Surgical resection using minimally invasive approaches provides important diagnostic and clinical information for indeterminate pulmonary nodules in patients with a history of breast cancer. In addition to establishing a definitive pathological diagnosis, reassessment of ER, PgR, and HER2 expression in pulmonary metastases may influence systemic treatment decisions, particularly in the HER2-low era. These findings support consideration of surgical tissue acquisition in carefully selected patients when pathological confirmation has the potential to modify subsequent management.

Supplementary

The article’s supplementary files as

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. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Institutional Review Board of Fukuoka University Hospital (approval No. H26-04-006). Because this study used only existing clinical data and involved no intervention, the requirement for written informed consent was waived.

Data Sharing Statement

Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1302/dss

jtd-18-9-1046-dss.pdf ^{(70KB, pdf)}

DOI: 10.21037/jtd-2026-1302