Diagnostic Accuracy of PET Imaging for Lymph Node Detection in Breast cancer patients undergoing Upfront Surgery: A Single-Institution Analysis of Breast Cancer Patients

Rohan Shetty; Sarath Chandu Yadlapalli; Vijayakumar M

doi:10.12688/f1000research.177892.1

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Research Article

Diagnostic Accuracy of PET Imaging for Lymph Node Detection in Breast cancer patients undergoing Upfront Surgery: A Single-Institution Analysis of Breast Cancer Patients

[version 1; peer review: 2 approved with reservations]

Rohan Shetty¹, Sarath Chandu Yadlapalli ¹, Vijayakumar M¹

PUBLISHED 18 Feb 2026

Author details Author details

¹ Surgical Oncology, Yenepoya Medical College Hospital, Mangaluru, Karnataka, 575018, India

Rohan Shetty
Roles: Conceptualization, Methodology, Supervision, Validation, Writing – Original Draft Preparation, Writing – Review & Editing

Sarath Chandu Yadlapalli
Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Resources, Validation, Writing – Original Draft Preparation, Writing – Review & Editing

Vijayakumar M
Roles: Conceptualization, Methodology, Resources, Supervision, Visualization, Writing – Review & Editing

OPEN PEER REVIEW

REVIEWER STATUS

This article is included in the Oncology gateway.

Abstract

Background

The role of PET imaging in lymph node staging for breast cancer patients proceeding to upfront surgery remains incompletely characterized. We evaluated the diagnostic accuracy of PET imaging in immediate surgical patients.

Methods

A retrospective cohort of 70 breast cancer patients undergoing upfront surgery was analyzed. PET imaging findings were compared with histopathological examination (HPE) results. Diagnostic accuracy metrics including sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and likelihood ratios were calculated.

Results

Among 70 surgical patients (mean age 53.9 ± 11.5 years), 26 (37.14%) had pathologically confirmed lymph node involvement. PET imaging demonstrated sensitivity of 69.23% (95% CI: 48.27-85.67), specificity of 81.82% (95% CI: 67.27-91.60), PPV of 69.23%, and NPV of 81.82%. The test correctly identified 18 of 26 patients with nodal disease while avoiding false positives in 36 of 44 node-negative patients. Positive likelihood ratio was 3.81, and negative likelihood ratio was 0.38. The F1-score was 0.6923, indicating good balance between precision and sensitivity for surgical planning.

Conclusions

PET imaging demonstrates clinically meaningful sensitivity (69.23%) and high negative predictive value (81.82%) in upfront surgical patients, supporting its utility for identifying patients with nodal involvement and confidently excluding nodal disease when negative. These performance characteristics suggest that PET can inform surgical extent and staging accuracy in immediate surgical patients, though positive findings warrant confirmatory assessment when staging determines operative planning.

Keywords

breast cancer, lymph node staging, PET imaging, diagnostic accuracy, upfront surgery, sensitivity, specificity

Corresponding author: Sarath Chandu Yadlapalli

Competing interests: No competing interests were disclosed.

Grant information: The author(s) declared that no grants were involved in supporting this work.

Copyright: © 2026 Shetty R et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

How to cite: Shetty R, Yadlapalli SC and M V. Diagnostic Accuracy of PET Imaging for Lymph Node Detection in Breast cancer patients undergoing Upfront Surgery: A Single-Institution Analysis of Breast Cancer Patients [version 1; peer review: 2 approved with reservations]. F1000Research 2026, 15:291 (https://doi.org/10.12688/f1000research.177892.1) First published: 18 Feb 2026, 15:291 (https://doi.org/10.12688/f1000research.177892.1) Latest published: 18 Jun 2026, 15:291 (https://doi.org/10.12688/f1000research.177892.3)

1. Introduction

Accurate preoperative lymph node staging is essential for breast cancer treatment planning and prognostication.¹ While sentinel lymph node biopsy remains the standard for axillary assessment in clinically node-negative disease, patients with radiologically apparent nodal involvement or those selected for upfront surgery require reliable imaging-based nodal evaluation to guide operative extent and systemic therapy planning.^2,3

Positron emission tomography (PET) imaging, often combined with computed tomography (PET/CT), has emerged as a valuable tool for detecting metastatic disease and lymph node involvement in cancer staging.⁴ However, the diagnostic accuracy of PET for lymph node detection varies considerably depending on clinical context, patient selection, and disease characteristics.⁵ While multiple studies have evaluated PET performance in mixed breast cancer populations or neoadjuvant therapy settings, limited data specifically characterize PET diagnostic accuracy in upfront surgical patients where imaging findings directly inform operative planning.⁶

The clinical implications of PET performance differ substantially based on treatment pathway. In patients proceeding to immediate surgery, high sensitivity and negative predictive value are particularly valuable for confidently determining nodal status before operative intervention. Conversely, high specificity and positive predictive value are more critical in neoadjuvant settings where treatment intensification decisions depend on accurate positive node identification.⁷

This study focuses on evaluating PET diagnostic performance specifically in upfront surgical patients to address this knowledge gap and provide treatment-pathway-specific evidence for imaging interpretation in breast cancer surgery.

1.1 Study objectives

The primary objective was to determine the diagnostic accuracy of PET imaging for detecting lymph node involvement in breast cancer patients undergoing upfront surgery. Secondary objectives included calculating likelihood ratios, evaluating the balance of sensitivity and precision through F1-score analysis, and assessing clinical utility metrics for surgical decision-making. Kappa coefficient to know the association between PET and HPE nodes.

2. Materials and methods

2.1 Study population and design

This was a retrospective cohort study of breast cancer patients who underwent upfront surgical treatment at Yenepoya medical college and Hospital between June 2022 to June 2025. Written and informed consent taken from the participants of the study.

Inclusion criteria:

1. Histologically confirmed invasive breast cancer,
2. Upfront surgery as primary treatment modality (not neoadjuvant therapy),
3. Preoperative PET imaging within 4 weeks of surgery, and
4. Available histopathological lymph node assessment.

Patients receiving neoadjuvant chemotherapy prior to surgery were excluded from this analysis to maintain treatment-pathway homogeneity.

The study cohort comprised 70 consecutive eligible patients ( Figure 1). Patient demographics, clinicopathological features, imaging characteristics, and surgical pathology findings were extracted from medical records. All histopathological examinations were performed by experienced Onco-pathologists using standard protocols.

Figure 1. Flow diagram.

Flow diagram of the progress of the study.

2.2 Statistical analysis

Diagnostic accuracy metrics were calculated using standard formulas:

• Sensitivity = True Positive/(True Positive+False Negative) — probability of positive test given disease present
• Specificity = True Negative/(True Negative+False Positive) — probability of negative test given disease absent
• Positive Predictive Value (PPV) = True Positive/(True Positive+False Positive) — probability of disease given positive test
• Negative Predictive Value (NPV) = True Negative/(True Negative+False Negative) — probability of no disease given negative test
• Positive Likelihood Ratio (LR+) = Sensitivity/(1 - Specificity)
• Negative Likelihood Ratio (LR-) = (1 - Sensitivity)/Specificity
• F1-Score = 2 × (Precision × Sensitivity)/(Precision + Sensitivity) — harmonic mean balancing precision and sensitivity
• Youden’s Index = Sensitivity + Specificity - 1 — measure of overall discriminative ability

Ninety-five percent confidence intervals (95% CI) for sensitivity and specificity were calculated using the Wilson score method. Disease prevalence was calculated as the proportion of patients with HPE-positive nodes in the cohort.

A confusion matrix was constructed to visualize classification accuracy (true positives(TP), true negatives(TN), false positives(FP), false negatives(FN)).

Data was analysed using SPSS v21. Kappa statistics was done for assessing the agreement between PET imaging and HPE nodal status.

3. Results

3.1 Patient cohort characteristics

The analysis included 70 breast cancer patients with mean age 53.9 ± 11.5 years undergoing upfront surgery. Luminal B predominates with 41.5% (n = 27) followed by Luminal A with 34.3% (n = 24), TNBC 17.1% (n = 12), Her-2 Enriched 7.1% (n = 5). Refer for Table 1 for demographic data. 50.8%(n = 36) have >20% ki-67 proliferation index. 53 (75.7%) were Estrogen receptor positive, whereas 47 (67.1%) are Progesterone receptor positive making it a hormone receptor positive predominant cohort.

Table 1. Baseline clinicopathological and imaging characteristics of upfront surgery patients (n = 70).

Variable	n (%)
Age (years)
50–59	24 (34.3%)
40–49	17 (24.3%)
60–69	15 (21.4%)
<40	7 (10.0%)
≥70	7 (10.0%)
ER status
+	53 (75.7%)
-	17 (24.3%)
PR status
+	47 (67.1%)
-	23 (32.9%)
HER2 status
1+	20 (28.6%)
2+	19 (27.1%)
0	19 (27.1%)
3+	12 (17.1%)
Ki-67 index
≤14%	20 (28.6%)
15–30%	22 (31.4%)
>30%	20 (28.6%)
Not Available	8 (11.4%)
Molecular subtype
B	29 (41.4%)
A	24 (34.3%)
TNBC	12 (17.1%)
HER Enriched	5 (7.1%)
Nodal status on PET-CT
No	44 (62.9%)
Yes	26 (37.1%)
Pathological nodal status (HPE)
No	44 (62.9%)
Yes	26 (37.1%)
Primary tumor SUVmax (PET-CT)
Nil	45 (64.3%)
≤5	17 (24.3%)
5.1–10	5 (7.1%)
>10	3 (4.3%)

3.2 Nodal disease prevalence

Among the 70 surgical patients, 26 patients (37.14%) had histopathologically confirmed lymph node involvement. Forty-four patients (62.86%) had node-negative disease.

3.3 PET diagnostic accuracy

Detailed results are presented in Table 2 and Figure 2. PET imaging achieved:

• Sensitivity: 69.23% (95% CI: 48.27-85.67%) — correctly identified 18 of 26 patients with nodal disease
• Specificity: 81.82% (95% CI: 67.27-91.60%) — correctly identified 36 of 44 node-negative patients
• Positive Predictive Value: 69.23% — among 26 PET-positive patients, 18 (69.23%) had actual nodal involvement
• Negative Predictive Value: 81.82% — among 44 PET-negative patients, 36 (81.82%) had confirmed nodal absence
• Overall Accuracy: 77.14% — correctly classified 54 of 70 patients

Table 2. Diagnostic accuracy metrics for PET imaging in upfront surgical patients (n = 70).

Metric	Value	95% Confidence interval
Sensitivity	69.23%	48.27% - 85.67%
Specificity	81.82%	67.27% - 91.60%
Positive Predictive Value	69.23%	51.98% - 82.78%
Negative Predictive Value	81.82%	68.59% - 90.76%
Positive Likelihood Ratio	3.81	1.75-8.31
Negative Likelihood Ratio	0.38	0.20-0.71
Accuracy	77.14%	66.30% - 85.65%
F1-Score	0.6923	—
Youden’s Index	0.5105	—

Figure 2. Comprehensive diagnostic accuracy profile of PET imaging for lymph node detection.

3.4 Likelihood Ratios (LR)

The positive likelihood ratio was 3.81 (95% CI: 1.75-8.31), indicating that a positive PET result is 3.81 times more likely in patients with actual lymph node disease compared to those without nodal involvement. This moderate LR+ suggests that positive findings warrant additional clinical correlation but provide meaningful evidence for nodal involvement.

The negative likelihood ratio was 0.38 (95% CI: 0.20-0.71), indicating that a negative PET result is substantially less likely in patients with actual nodal disease. This favorable LR- suggests that negative findings provide reasonable reassurance against nodal involvement in surgical planning.

3.5 Confusion matrix and error analysis

True Positives (TP): 18 patients (25.71% of cohort) — correctly identified with nodes

False Positives (FP): 8 patients (11.43%) — incorrectly called positive without nodes

False Negatives (FN): 8 patients (11.43%) — missed nodal involvement

True Negatives (TN): 36 patients (51.43%) — correctly identified without nodes

The balanced false positive and false negative rates (both 11.43%) indicate comparable error distribution. The false negative rate of 30.77% (8 of 26 actual positive cases) represents the clinically meaningful limitation of PET sensitivity in this cohort.

3.6 F1-Score and discriminative ability and Kappa coefficient

The F1-score was 0.6923, indicating a reasonable balance between precision (69.23%) and sensitivity (69.23%). The Youden’s Index of 0.5105 demonstrates moderate discriminative ability of PET imaging in distinguishing node-positive from node-negative surgical patients. In the upfront surgery cohort, agreement between PET-CT nodal status and histopathologic nodal status was moderate, with a Cohen’s kappa of 0.51 (SE 0.11; 95% CI 0.30–0.72; p = 0.001; n = 70).

3.7 Clinical performance summary

Table 2 presents comprehensive diagnostic accuracy metrics. PET imaging demonstrated clinically meaningful performance for lymph node detection in upfront surgical patients, with strengths in negative predictive value (81.82%) and specificity (81.82%), indicating reliable ability to exclude nodal disease.

4. Discussion

4.1 Summary of key findings

This is the first study to specifically characterize PET diagnostic accuracy in a homogeneous cohort of upfront surgical patients with breast cancer. The findings reveal that PET imaging demonstrates clinically meaningful sensitivity (69.23%) coupled with high negative predictive value (81.82%) and specificity (81.82%) for lymph node detection in immediate surgical settings.

The 69.23% sensitivity indicates that PET successfully identifies approximately two-thirds of patients with actual nodal involvement. Among the 26 patients with pathologically confirmed nodal disease, PET correctly identified 18 cases. This performance is clinically relevant because it provides surgeons with meaningful information regarding nodal status before operative intervention.

Equally important, the 81.82% NPV indicates that when PET indicates nodal absence, there is reasonable confidence in this negative result for surgical planning purposes. Among 44 PET-negative patients, 36 (81.82%) genuinely lacked nodal disease, whereas only 8 (18.18%) had missed nodal involvement that was subsequently identified at histopathology.

4.2 Clinical implications for surgical planning

The diagnostic profile of PET in upfront surgical patients differs meaningfully from neoadjuvant therapy settings where treatment intensification depends primarily on positive node identification. In contrast, surgeons performing upfront surgery require confidence in nodal status to determine operative extent, staging accuracy, and prognosis discussion with patients.

Strengths of PET in This Context:

1. High Specificity (81.82%) provides reliable identification of truly node-negative patients, avoiding unnecessary concern about occult nodal involvement and preventing unnecessary axillary dissection escalation.
2. Reliable Negative Predictive Value (81.82%) supports clinical confidence in negative PET findings for surgical planning, though not entirely excluding further nodal assessment through examination or sentinel node procedures.
3. Balanced Sensitivity-Precision (69.23% each) indicates that positive PET findings carry moderate diagnostic weight, correctly identifying nodes in approximately 7 of 10 positive cases.

Limitations Requiring Clinical Acknowledgment:

1. False Negative Rate of 30.77% (8 of 26 actual positive cases) represents a clinically meaningful limitation. Approximately one-third of patients with actual nodal involvement were missed by PET. This false negative rate suggests that negative PET findings should not entirely exclude nodal assessment through standard staging approaches.
2. Moderate Positive Predictive Value (69.23%) indicates that not all PET-positive findings represent true nodal involvement. Among 26 PET-positive patients, 8 (30.77%) proved to be false positives without nodal disease at histopathology. This suggests that positive PET findings warrant confirmatory assessment when surgical extent critically depends on nodal status.

4.3 Comparison with literature

Limited prior studies have evaluated PET performance specifically for lymph nodal staging in upfront surgical populations. Most existing literature combines patients across treatment modalities or focuses on neoadjuvant settings. The sensitivity of 69.23% observed in the present cohort aligns with sensitivity ranges reported in mixed breast cancer populations (62-75%),^8,9 though our cohort is uniquely focused on immediate surgical patients.

The specificity of 81.82% is comparable to or slightly lower than neoadjuvant cohorts in our institution’s data, possibly reflecting differences in disease characteristics and patient selection between upfront surgical and chemotherapy-naive neoadjuvant patients.¹⁰ In the Study done by Kim et al.¹¹ where he compared different imaging for lymph node metastasis elastography showed high sensitivity whereas PET CT showed reasonable sensitivity.

Kasem et al⁸ noted that combining PET/CT with FNA improved specificity, but PET/CT by itself had relatively low specificity for axillary disease (21% false positives) despite high sensitivity. Regional lymph nodes were incorrectly staged at 18F-FDG PET in 14% of cases in Estrogen receptor positive patients where as 18% of cases in our study which is slightly higher.¹² Compared with the overall study population, estrogen receptor–positive patients demonstrated more accurate detection on PET imaging.

4.4 Mechanism of performance differences: Why sensitivity exceeds specificity

The superior sensitivity (69.23%) over specificity (81.82%) in upfront surgical patients may reflect multiple factors:

1. Disease burden differences: Patients selected for upfront surgery may have different patterns of nodal involvement compared to neoadjuvant patients, potentially affecting detection patterns.
2. Imaging acquisition timing: The interval between PET imaging and surgery may influence detection sensitivity through metabolic changes in nodal disease.
3. Tumor biology: Receptor status, grade, and proliferation rates may influence FDG uptake patterns in nodal disease, affecting detection probability.

4.5 Integration of PET findings into clinical decision-making

Based on these findings, we propose the following framework for incorporating PET findings into preoperative assessment of surgical patients:

When PET is POSITIVE (n = 26 in this cohort):

• Likelihood of true nodal involvement is 69.23% (PPV).
• Consider confirmatory imaging (ultrasound with FNA if appropriate) before treatment intensification.
• Document nodal status carefully for staging purposes.
• Plan operative approach accounting for likely nodal disease.

When PET is NEGATIVE (n = 44 in this cohort):

• Likelihood of true nodal absence is 81.82% (NPV)
• Reasonable confidence in nodal negativity for operative planning
• Standard staging procedures (physical examination, sentinel node biopsy per protocol) remain appropriate
• Acknowledge 18% probability of missed nodal involvement

4.6 Strengths and limitations

Strengths:

• Homogeneous cohort of upfront surgical patients (treatment-pathway specific)
• Pathologically confirmed reference standard for all patients
• Comprehensive diagnostic accuracy metrics including likelihood ratios
• Focused analysis providing clinically applicable information for surgical decision-making
• Balanced error rates and F1-score analysis indicating equal treatment of precision and sensitivity

Limitations:

• Retrospective design with inherent selection bias
• Single-institution experience (generalizability may be limited)
• Small sample size limits ability to perform subgroup analyses
• No evaluation of observer variability or interobserver reliability

5. Conclusions

This analysis of 70 upfront surgical patients with breast cancer demonstrates that PET imaging provides clinically useful diagnostic accuracy for lymph node detection, with particular strength in ruling out nodal involvement (NPV 81.82%) and reliably confirming node-negative status (specificity 81.82%).

For surgeons managing breast cancer patients proceeding to upfront surgery, PET imaging can inform surgical decision-making and provide meaningful preoperative nodal information, particularly valuable when negative findings provide reasonable confidence in nodal absence. Conversely, positive findings warrant confirmatory assessment before treatment intensification decisions.

Future prospective studies comparing PET performance across treatment pathways and evaluating optimal integration of PET with other staging modalities would further clarify the clinical utility of PET in diverse breast cancer populations.

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 performed in accordance with the ethical standards of the institutional and national research committees and with the Helsinki Declaration (as revised in 2013). The study was approved by the Yenepoya institutional ethics committee (IEC) with the number YEC2/068.

Data availability

All figures and tables supporting the findings of this manuscript are publicly available on Figshare under an open license CC BY 4.0. These materials include figures, summary tables, data used to create graphs, flow chart, and de-identified data in an Excel sheet. All the data can be accessed at DOI:10.6084/m9.figshare.31242061.¹³

References

1. Gradishar WJ, Moran MS, Abraham J, et al.: NCCN Guidelines® Insights: Breast Cancer, Version 5.2025: Featured Updates to the NCCN Guidelines. J. Natl. Compr. Cancer Netw. 2025 Nov 1; 23(11): 426–436. PubMed Abstract | Publisher Full Text
2. Giuliano AE, Ballman KV, McCall L, et al.: Effect of Axillary Dissection vs No Axillary Dissection on 10-Year Overall Survival Among Women With Invasive Breast Cancer and Sentinel Node Metastasis: The ACOSOG Z0011 (Alliance) Randomized Clinical Trial. JAMA. 2017 Sep 12; 318(10): 918–926. PubMed Abstract | Publisher Full Text
3. Lyman GH, Somerfield MR, Bosserman LD, et al.: Sentinel Lymph Node Biopsy for Patients With Early-Stage Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. J. Clin. Oncol. 2017 Feb 10; 35(5): 561–564. PubMed Abstract | Publisher Full Text
4. Eatock F; C T AMillar A, et al.: PET/CT and staging of breast cancer. J. Clin. Oncol. 38(15): e20535.
5. Boellaard R, Delgado-Bolton R, Oyen WJG, et al.: FDG PET/CT: EANM procedure guidelines for tumour imaging: version 2.0. Eur. J. Nucl. Med. Mol. Imaging. 2015 Feb; 42(2): 328–354. PubMed Abstract | Publisher Full Text
6. Marinovich ML, Hunter KE, Macaskill P, et al.: Breast Cancer Screening Using Tomosynthesis or Mammography: A Meta-analysis of Cancer Detection and Recall. J. Natl. Cancer Inst. 2018 Sep 1; 110(9): 942–949. PubMed Abstract | Publisher Full Text
7. De los Santos C, Shead D, Solin LJ, et al.: Astute reading of conventional imaging for detecting axillary lymph node metastases in breast cancer: what to expect when not examining. Am. J. Roentgenol. 200(2): 166–173.
8. Kasem J, Wazir U, Mokbel K: Sensitivity, Specificity and the Diagnostic Accuracy of PET/CT for Axillary Staging in Patients With Stage I-III Cancer: A Systematic Review of The Literature. In Vivo. 2021 Jan 3; 35(1): 23–30. PubMed Abstract | Publisher Full Text
9. Rosa AD: The predictive value, sensitivity, specificity, and accuracy of PET CT in the evaluation of axillary metastases in breast cancer. European Review. 2023 [cited 2026 Jan 15]. Reference Source
10. Senkus E, Kyriakides S, Ohno S, et al.: Primary breast cancer: ESMO Clinical Practice Guidelines. Ann. Oncol. 32(6): 716–738.
11. Kim K, Shim SR, Kim SJ: Diagnostic Values of 8 Different Imaging Modalities for Preoperative Detection of Axillary Lymph Node Metastasis of Breast Cancer: A Bayesian Network Meta-analysis. Am. J. Clin. Oncol. 2021 Jul; 44(7): 331–339. PubMed Abstract | Publisher Full Text
12. Knip JJ, Iqbal R, Bonjer EC, et al.: The Diagnostic Accuracy of 18F-FDG PET and 18F-FES PET for Staging Grade 1–2 Estrogen Receptor–Positive Breast Cancer. Radiology. 2025 Mar; 314(3): e241850. PubMed Abstract | Publisher Full Text
13. Yadlapalli SC: Diagnostic Accuracy of PET Imaging for Lymph Node Detection in Breast Cancer Patients Undergoing Upfront Surgery: A Single-Institution Analysis of Breast Cancer Patients. Figshare. 2026. Reference Source

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Version 3

VERSION 3 PUBLISHED 18 Feb 2026

Author details Author details

¹ Surgical Oncology, Yenepoya Medical College Hospital, Mangaluru, Karnataka, 575018, India

Rohan Shetty
Roles: Conceptualization, Methodology, Supervision, Validation, Writing – Original Draft Preparation, Writing – Review & Editing

Vijayakumar M
Roles: Conceptualization, Methodology, Resources, Supervision, Visualization, Writing – Review & Editing

Competing interests

No competing interests were disclosed.

Grant information

The author(s) declared that no grants were involved in supporting this work.

Article Versions (3)

version 3

Revised

Published: 18 Jun 2026, 15:291

https://doi.org/10.12688/f1000research.177892.3

version 2

Revised

Published: 19 May 2026, 15:291

https://doi.org/10.12688/f1000research.177892.2

version 1

Published: 18 Feb 2026, 15:291

https://doi.org/10.12688/f1000research.177892.1

© 2026 Shetty R et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Shetty R, Yadlapalli SC and M V. Diagnostic Accuracy of PET Imaging for Lymph Node Detection in Breast cancer patients undergoing Upfront Surgery: A Single-Institution Analysis of Breast Cancer Patients [version 1; peer review: 2 approved with reservations]. F1000Research 2026, 15:291 (https://doi.org/10.12688/f1000research.177892.1)

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Open Peer Review

Version 1

VERSION 1

PUBLISHED 18 Feb 2026

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Reviewer Report 17 Apr 2026

Mehmet Tarık Tatoğlu, Göztepe Prof. Dr. Süleyman Yalçin City Hospital, Istanbul, Turkey

Approved with Reservations

https://doi.org/10.5256/f1000research.196199.r475609

This study addresses a clinically relevant question, namely the diagnostic performance of PET/CT for lymph node assessment in breast cancer patients proceeding directly to upfront surgery. The use of a pathology-based reference standard is an important strength, and the treatment-pathway-specific focus adds potential value. However, the current version has several methodological and interpretive issues that should be addressed to improve the rigor and reproducibility of the work. I therefore recommend Approved with Reservations, subject to meaningful revision of the points outlined below.

Major comments

1. PET/CT methodology
The PET/CT methodology is insufficiently described to allow replication or critical appraisal. The manuscript should report the tracer type and administered dose, uptake time, scanner model and acquisition parameters, reconstruction algorithm, and attenuation correction method. Equally important, the criteria used to define lymph node positivity on PET/CT should be stated explicitly, whether based on visual assessment, a fixed SUV threshold, or another metric. The authors should also clarify the number of readers involved, their level of experience, and whether image interpretation was performed with or without knowledge of the clinical and pathological findings. The absence of these details substantially limits reproducibility.

2. Reference standard
The reference standard requires more precise characterization. It is not stated whether nodal assessment was based on sentinel lymph node biopsy, complete axillary dissection, targeted nodal excision, or a combination of these procedures. Given that the extent of nodal sampling directly affects the apparent false-negative rate, this distinction is clinically important. The pathological definition of nodal positivity should also be provided, including whether isolated tumor cells and micrometastases were classified together with macrometastatic disease or analyzed separately.

3. Overstatement of rule-out value
The conclusions place disproportionate emphasis on the rule-out value of a negative PET result. With a sensitivity of 69.23% (95% CI: 48.27–85.67%) and 8 false-negative cases among 26 pathologically confirmed node-positive patients, a negative PET finding cannot reliably exclude nodal involvement. The moderate Cohen’s kappa of 0.51 further underscores the imperfect agreement between PET/CT and histopathology. The conclusions should therefore be reframed accordingly: PET/CT may provide useful supplementary preoperative information, but it should not be positioned as a substitute for standard axillary staging procedures.

4. Internal inconsistency in Section 4.4
Section 4.4 is titled “Why sensitivity exceeds specificity,” yet the reported results show the opposite: specificity (81.82%) exceeds sensitivity (69.23%). This factual inconsistency should be corrected, and the accompanying discussion revised accordingly.

5. Cohort derivation and flow diagram
The derivation of the analytic cohort requires clearer explanation. The flow diagram indicates that 1,415 patients were assessed for eligibility, of whom 1,201 were excluded, leaving 214 with available PET/CT and histopathology reports. Of these, 144 subsequently underwent neoadjuvant chemotherapy and were excluded, yielding the final cohort of 70. However, the specific reasons for the initial 1,201 exclusions are not broken down, and it remains unclear whether exclusion of neoadjuvant patients introduced any selection bias into the surgical cohort. A more detailed description of the eligibility, exclusion, and cohort derivation steps would improve transparency.

6. Table 1: “Primary tumor SUVmax: Nil” and numerical inconsistency
Table 1 includes a “Primary tumor SUVmax: Nil” category (n=45, 64.3%) that is not explained in the text and is difficult to interpret. It is unclear whether this denotes the absence of an FDG-avid primary tumor, a missing or unacquired measurement, or a technical classification. This category should be defined clearly. In addition, there appears to be a minor inconsistency between the Results text and Table 1 regarding molecular subtype frequencies (Luminal B: n=27 in the text versus n=29 in the table), which should be reconciled.

7. Statistical reporting and clinical interpretation
The statistical reporting is adequate at a descriptive level, but several aspects of the clinical interpretation warrant attention. The F1-score, while mathematically valid, has limited intuitive value for a clinical staging audience and receives more emphasis than its interpretive importance justifies. More clinically useful would be a focused discussion of the false-negative rate (30.77%), its implications for missed nodal disease, and how PET/CT findings should be integrated alongside standard axillary assessment rather than used in isolation. In addition, the manuscript does not provide a sample size justification or other rationale for the precision of the estimates; given the wide confidence intervals observed, particularly for sensitivity, the resulting statistical uncertainty should be acknowledged more explicitly as a limitation.

Minor comments

1. Terminology consistency
The manuscript alternates between “PET CT” and “PET/CT”. A single form should be selected and applied consistently throughout.

2. Language and grammar
The manuscript would benefit from language editing for grammar and style in several places. This does not affect the scientific content but would improve readability.

3. Figure 2
Figure 2 adds limited value in its current form, given that Table 2 already conveys the key numerical results. It could either be developed into a more informative visualization or simplified substantially.

4. “First study” claim
The claim in Section 4.1 that this is the “first study” to specifically characterize PET diagnostic accuracy in a homogeneous upfront surgical cohort should be tempered or supported by a reproducible literature search, as prior original studies have already examined FDG-PET/CT for preoperative axillary staging in breast cancer [1–3].

Summary

This is a potentially useful single-institution diagnostic accuracy study on a clinically relevant topic. The treatment-pathway-specific design and pathologically confirmed reference standard are genuine strengths. However, the paper requires meaningful revision, particularly with respect to: (1) the description of PET/CT methodology and reader blinding; (2) clarification of the reference standard and extent of nodal sampling; (3) correction of the internal inconsistency in Section 4.4; and (4) moderation of the conclusions regarding the reliability of negative PET findings. Addressing these points would substantially strengthen the work.

References:

Reference 1
Reference 2
Reference 3

Is the work clearly and accurately presented and does it cite the current literature?

Partly
Is the study design appropriate and is the work technically sound?

Partly
Are sufficient details of methods and analysis provided to allow replication by others?

No
If applicable, is the statistical analysis and its interpretation appropriate?

Partly
Are all the source data underlying the results available to ensure full reproducibility?

Partly
Are the conclusions drawn adequately supported by the results?

Partly

References

1. Riegger C, Koeninger A, Hartung V, Otterbach F, et al.: Comparison of the Diagnostic Value of FDG-PET/CT and Axillary Ultrasound for the Detection of Lymph Node Metastases in Breast Cancer Patients. Acta Radiologica. 2012; 53 (10): 1092-1098 Publisher Full Text
2. Çelik B, Boge M, Dilege E: Does F-18 FDG-PET/CT Have an Additional Impact on Axillary Approach in Early-Stage Breast Cancer?. European Journal of Breast Health. 2024; 20 (1): 45-51 Publisher Full Text
3. Gunes A, Colapkulu-Akgul N, Akgul C, Unlu I, et al.: Axillary staging with 18F-FDG PET/CT in early breast cancer: impact of tumor subtypes. Annals of Saudi Medicine. 2025; 45 (3): 145-153 Publisher Full Text

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: My areas of expertise include nuclear medicine, molecular imaging, PET/CT, oncologic imaging, diagnostic accuracy studies, and the clinical interpretation of imaging biomarkers.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

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Author Response 19 May 2026

Sarath Chandu Yadlapalli, Surgical Oncology, Yenepoya Medical College Hospital, Mangaluru, 575018, India

19 May 2026

Author Response

1. PET/CT methodology
The PET/CT methodology is insufficiently described to allow replication or critical appraisal. The manuscript should report the tracer type and administered dose, uptake time, scanner model and ... Continue reading 1. PET/CT methodology
The PET/CT methodology is insufficiently described to allow replication or critical appraisal. The manuscript should report the tracer type and administered dose, uptake time, scanner model and acquisition parameters, reconstruction algorithm, and attenuation correction method. Equally important, the criteria used to define lymph node positivity on PET/CT should be stated explicitly, whether based on visual assessment, a fixed SUV threshold, or another metric. The authors should also clarify the number of readers involved, their level of experience, and whether image interpretation was performed with or without knowledge of the clinical and pathological findings. The absence of these details substantially limits reproducibility.
We have provided a comprehensive methodology section detailing the PET/CT protocol, including the tracer type and administered dose, uptake time, scanner model, acquisition parameters, reconstruction algorithm, and attenuation correction technique. Additionally, we have clearly defined the criteria for lymph node positivity, along with the number of interpreters, their level of experience, and the blinding methodology employed

2. Reference standard
The reference standard requires more precise characterization. It is not stated whether nodal assessment was based on sentinel lymph node biopsy, complete axillary dissection, targeted nodal excision, or a combination of these procedures. Given that the extent of nodal sampling directly affects the apparent false-negative rate, this distinction is clinically important. The pathological definition of nodal positivity should also be provided, including whether isolated tumor cells and micrometastases were classified together with macrometastatic disease or analyzed separately.
As pointed out by the reviewer, we have explicitly detailed the lymph nodal assessment methodology along with the pathological criteria used to define nodal positivity. We have also included definitions addressing micrometastasis and isolated tumor cells

3. Overstatement of rule-out value
The conclusions place disproportionate emphasis on the rule-out value of a negative PET result. With a sensitivity of 69.23% (95% CI: 48.27–85.67%) and 8 false-negative cases among 26 pathologically confirmed node-positive patients, a negative PET finding cannot reliably exclude nodal involvement. The moderate Cohen’s kappa of 0.51 further underscores the imperfect agreement between PET/CT and histopathology. The conclusions should therefore be reframed accordingly: PET/CT may provide useful supplementary preoperative information, but it should not be positioned as a substitute for standard axillary staging procedures.
We have revised the statement to ensure alignment with the conclusion, as outlined above.

4. Internal inconsistency in Section 4.4
Section 4.4 is titled “Why sensitivity exceeds specificity,” yet the reported results show the opposite: specificity (81.82%) exceeds sensitivity (69.23%). This factual inconsistency should be corrected, and the accompanying discussion revised accordingly.
We thank the reviewer for highlighting this error, as it was inadvertently stated the other way. The statement has now been corrected.

5. Cohort derivation and flow diagram
The derivation of the analytic cohort requires clearer explanation. The flow diagram indicates that 1,415 patients were assessed for eligibility, of whom 1,201 were excluded, leaving 214 with available PET/CT and histopathology reports. Of these, 144 subsequently underwent neoadjuvant chemotherapy and were excluded, yielding the final cohort of 70. However, the specific reasons for the initial 1,201 exclusions are not broken down, and it remains unclear whether exclusion of neoadjuvant patients introduced any selection bias into the surgical cohort. A more detailed description of the eligibility, exclusion, and cohort derivation steps would improve transparency.
It is clearly indicated in the flowchart that reports for 1201 patients—either PET/CT or final histopathology—were unavailable.

6. Table 1: “Primary tumor SUVmax: Nil” and numerical inconsistency
Table 1 includes a “Primary tumor SUVmax: Nil” category (n=45, 64.3%) that is not explained in the text and is difficult to interpret. It is unclear whether this denotes the absence of an FDG-avid primary tumor, a missing or unacquired measurement, or a technical classification. This category should be defined clearly. In addition, there appears to be a minor inconsistency between the Results text and Table 1 regarding molecular subtype frequencies (Luminal B: n=27 in the text versus n=29 in the table), which should be reconciled.
Table 1 presents the lymph nodal SUVmax rather than the primary tumor SUVmax. This represents a technical classification only, and no conclusions were drawn based on this parameter.

7. Statistical reporting and clinical interpretation
The statistical reporting is adequate at a descriptive level, but several aspects of the clinical interpretation warrant attention. The F1-score, while mathematically valid, has limited intuitive value for a clinical staging audience and receives more emphasis than its interpretive importance justifies. More clinically useful would be a focused discussion of the false-negative rate (30.77%), its implications for missed nodal disease, and how PET/CT findings should be integrated alongside standard axillary assessment rather than used in isolation. In addition, the manuscript does not provide a sample size justification or other rationale for the precision of the estimates; given the wide confidence intervals observed, particularly for sensitivity, the resulting statistical uncertainty should be acknowledged more explicitly as a limitation.

We agree that the F1‑score has limited intuitive value for a clinical staging audience. We have therefore reframed it as a secondary composite metric in the Methods and Results and removed it from the list of key strengths, placing interpretive emphasis on sensitivity, specificity, predictive values, likelihood ratios, and false‑negative rate.
We have expanded the Discussion to more explicitly address the observed false‑negative rate of 30.77%, its implications for missed nodal disease, and the need to use PET/CT as an adjunct to, rather than a replacement for, standard axillary assessment (clinical examination, ultrasound, and sentinel lymph node biopsy).
We now acknowledge that no a priori sample size calculation was performed and that the relatively small sample, especially the number of node‑positive cases, leads to wide confidence intervals for some diagnostic estimates. This statistical uncertainty is now explicitly discussed as a limitation and the findings are presented as hypothesis‑generating

Minor comments
1. Terminology consistency
The manuscript alternates between “PET CT” and “PET/CT”. A single form should be selected and applied consistently throughout.
Terminology has been standardised throughout the manuscript; we now use ‘PET/CT’ consistently in the text, tables, and figure legends, with the full term ‘positron emission tomography/computed tomography (PET/CT)’ defined at first mention

2. Language and grammar
The manuscript would benefit from language editing for grammar and style in several places. This does not affect the scientific content but would improve readability.
In response to the reviewer’s suggestion, the manuscript has been professionally edited for English language and style to improve clarity and readability, without altering the underlying scientific content.

3. Figure 2
Figure 2 adds limited value in its current form, given that Table 2 already conveys the key numerical results. It could either be developed into a more informative visualization or simplified substantially.
In response to the reviewer’s comment, Figure 2 has been simplified to a concise bar‑chart summary of sensitivity, specificity, predictive values, and accuracy, with Table 2 retained as the primary source for the full numerical results and confidence intervals

4. “First study” claim
The claim in Section 4.1 that this is the “first study” to specifically characterize PET diagnostic accuracy in a homogeneous upfront surgical cohort should be tempered or supported by a reproducible literature search, as prior original studies have already examined FDG-PET/CT for preoperative axillary staging in breast cancer [1–3].
We thank the reviewer for highlighting earlier work on FDG‑PET/CT for preoperative axillary staging. We have removed the absolute ‘first study’ claim from Section 4.1 and now state that our study adds treatment‑pathway–specific data on PET/CT diagnostic accuracy in a homogeneous upfront surgery cohort, explicitly acknowledging prior FDG‑PET/CT axillary staging studies
1. PET/CT methodology
The PET/CT methodology is insufficiently described to allow replication or critical appraisal. The manuscript should report the tracer type and administered dose, uptake time, scanner model and acquisition parameters, reconstruction algorithm, and attenuation correction method. Equally important, the criteria used to define lymph node positivity on PET/CT should be stated explicitly, whether based on visual assessment, a fixed SUV threshold, or another metric. The authors should also clarify the number of readers involved, their level of experience, and whether image interpretation was performed with or without knowledge of the clinical and pathological findings. The absence of these details substantially limits reproducibility.
We have provided a comprehensive methodology section detailing the PET/CT protocol, including the tracer type and administered dose, uptake time, scanner model, acquisition parameters, reconstruction algorithm, and attenuation correction technique. Additionally, we have clearly defined the criteria for lymph node positivity, along with the number of interpreters, their level of experience, and the blinding methodology employed

2. Reference standard
The reference standard requires more precise characterization. It is not stated whether nodal assessment was based on sentinel lymph node biopsy, complete axillary dissection, targeted nodal excision, or a combination of these procedures. Given that the extent of nodal sampling directly affects the apparent false-negative rate, this distinction is clinically important. The pathological definition of nodal positivity should also be provided, including whether isolated tumor cells and micrometastases were classified together with macrometastatic disease or analyzed separately.
As pointed out by the reviewer, we have explicitly detailed the lymph nodal assessment methodology along with the pathological criteria used to define nodal positivity. We have also included definitions addressing micrometastasis and isolated tumor cells

3. Overstatement of rule-out value
The conclusions place disproportionate emphasis on the rule-out value of a negative PET result. With a sensitivity of 69.23% (95% CI: 48.27–85.67%) and 8 false-negative cases among 26 pathologically confirmed node-positive patients, a negative PET finding cannot reliably exclude nodal involvement. The moderate Cohen’s kappa of 0.51 further underscores the imperfect agreement between PET/CT and histopathology. The conclusions should therefore be reframed accordingly: PET/CT may provide useful supplementary preoperative information, but it should not be positioned as a substitute for standard axillary staging procedures.
We have revised the statement to ensure alignment with the conclusion, as outlined above.

4. Internal inconsistency in Section 4.4
Section 4.4 is titled “Why sensitivity exceeds specificity,” yet the reported results show the opposite: specificity (81.82%) exceeds sensitivity (69.23%). This factual inconsistency should be corrected, and the accompanying discussion revised accordingly.
We thank the reviewer for highlighting this error, as it was inadvertently stated the other way. The statement has now been corrected.

5. Cohort derivation and flow diagram
The derivation of the analytic cohort requires clearer explanation. The flow diagram indicates that 1,415 patients were assessed for eligibility, of whom 1,201 were excluded, leaving 214 with available PET/CT and histopathology reports. Of these, 144 subsequently underwent neoadjuvant chemotherapy and were excluded, yielding the final cohort of 70. However, the specific reasons for the initial 1,201 exclusions are not broken down, and it remains unclear whether exclusion of neoadjuvant patients introduced any selection bias into the surgical cohort. A more detailed description of the eligibility, exclusion, and cohort derivation steps would improve transparency.
It is clearly indicated in the flowchart that reports for 1201 patients—either PET/CT or final histopathology—were unavailable.

6. Table 1: “Primary tumor SUVmax: Nil” and numerical inconsistency
Table 1 includes a “Primary tumor SUVmax: Nil” category (n=45, 64.3%) that is not explained in the text and is difficult to interpret. It is unclear whether this denotes the absence of an FDG-avid primary tumor, a missing or unacquired measurement, or a technical classification. This category should be defined clearly. In addition, there appears to be a minor inconsistency between the Results text and Table 1 regarding molecular subtype frequencies (Luminal B: n=27 in the text versus n=29 in the table), which should be reconciled.
Table 1 presents the lymph nodal SUVmax rather than the primary tumor SUVmax. This represents a technical classification only, and no conclusions were drawn based on this parameter.

7. Statistical reporting and clinical interpretation
The statistical reporting is adequate at a descriptive level, but several aspects of the clinical interpretation warrant attention. The F1-score, while mathematically valid, has limited intuitive value for a clinical staging audience and receives more emphasis than its interpretive importance justifies. More clinically useful would be a focused discussion of the false-negative rate (30.77%), its implications for missed nodal disease, and how PET/CT findings should be integrated alongside standard axillary assessment rather than used in isolation. In addition, the manuscript does not provide a sample size justification or other rationale for the precision of the estimates; given the wide confidence intervals observed, particularly for sensitivity, the resulting statistical uncertainty should be acknowledged more explicitly as a limitation.

We agree that the F1‑score has limited intuitive value for a clinical staging audience. We have therefore reframed it as a secondary composite metric in the Methods and Results and removed it from the list of key strengths, placing interpretive emphasis on sensitivity, specificity, predictive values, likelihood ratios, and false‑negative rate.
We have expanded the Discussion to more explicitly address the observed false‑negative rate of 30.77%, its implications for missed nodal disease, and the need to use PET/CT as an adjunct to, rather than a replacement for, standard axillary assessment (clinical examination, ultrasound, and sentinel lymph node biopsy).
We now acknowledge that no a priori sample size calculation was performed and that the relatively small sample, especially the number of node‑positive cases, leads to wide confidence intervals for some diagnostic estimates. This statistical uncertainty is now explicitly discussed as a limitation and the findings are presented as hypothesis‑generating

Minor comments
1. Terminology consistency
The manuscript alternates between “PET CT” and “PET/CT”. A single form should be selected and applied consistently throughout.
Terminology has been standardised throughout the manuscript; we now use ‘PET/CT’ consistently in the text, tables, and figure legends, with the full term ‘positron emission tomography/computed tomography (PET/CT)’ defined at first mention

2. Language and grammar
The manuscript would benefit from language editing for grammar and style in several places. This does not affect the scientific content but would improve readability.
In response to the reviewer’s suggestion, the manuscript has been professionally edited for English language and style to improve clarity and readability, without altering the underlying scientific content.

3. Figure 2
Figure 2 adds limited value in its current form, given that Table 2 already conveys the key numerical results. It could either be developed into a more informative visualization or simplified substantially.
In response to the reviewer’s comment, Figure 2 has been simplified to a concise bar‑chart summary of sensitivity, specificity, predictive values, and accuracy, with Table 2 retained as the primary source for the full numerical results and confidence intervals

4. “First study” claim
The claim in Section 4.1 that this is the “first study” to specifically characterize PET diagnostic accuracy in a homogeneous upfront surgical cohort should be tempered or supported by a reproducible literature search, as prior original studies have already examined FDG-PET/CT for preoperative axillary staging in breast cancer [1–3].
We thank the reviewer for highlighting earlier work on FDG‑PET/CT for preoperative axillary staging. We have removed the absolute ‘first study’ claim from Section 4.1 and now state that our study adds treatment‑pathway–specific data on PET/CT diagnostic accuracy in a homogeneous upfront surgery cohort, explicitly acknowledging prior FDG‑PET/CT axillary staging studies
Competing Interests: No competing interests Close
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Respond or Comment

COMMENTS ON THIS REPORT

Author Response 19 May 2026

Sarath Chandu Yadlapalli, Surgical Oncology, Yenepoya Medical College Hospital, Mangaluru, 575018, India

19 May 2026

Author Response

1. PET/CT methodology
The PET/CT methodology is insufficiently described to allow replication or critical appraisal. The manuscript should report the tracer type and administered dose, uptake time, scanner model and ... Continue reading 1. PET/CT methodology
The PET/CT methodology is insufficiently described to allow replication or critical appraisal. The manuscript should report the tracer type and administered dose, uptake time, scanner model and acquisition parameters, reconstruction algorithm, and attenuation correction method. Equally important, the criteria used to define lymph node positivity on PET/CT should be stated explicitly, whether based on visual assessment, a fixed SUV threshold, or another metric. The authors should also clarify the number of readers involved, their level of experience, and whether image interpretation was performed with or without knowledge of the clinical and pathological findings. The absence of these details substantially limits reproducibility.
We have provided a comprehensive methodology section detailing the PET/CT protocol, including the tracer type and administered dose, uptake time, scanner model, acquisition parameters, reconstruction algorithm, and attenuation correction technique. Additionally, we have clearly defined the criteria for lymph node positivity, along with the number of interpreters, their level of experience, and the blinding methodology employed

2. Reference standard
The reference standard requires more precise characterization. It is not stated whether nodal assessment was based on sentinel lymph node biopsy, complete axillary dissection, targeted nodal excision, or a combination of these procedures. Given that the extent of nodal sampling directly affects the apparent false-negative rate, this distinction is clinically important. The pathological definition of nodal positivity should also be provided, including whether isolated tumor cells and micrometastases were classified together with macrometastatic disease or analyzed separately.
As pointed out by the reviewer, we have explicitly detailed the lymph nodal assessment methodology along with the pathological criteria used to define nodal positivity. We have also included definitions addressing micrometastasis and isolated tumor cells

3. Overstatement of rule-out value
The conclusions place disproportionate emphasis on the rule-out value of a negative PET result. With a sensitivity of 69.23% (95% CI: 48.27–85.67%) and 8 false-negative cases among 26 pathologically confirmed node-positive patients, a negative PET finding cannot reliably exclude nodal involvement. The moderate Cohen’s kappa of 0.51 further underscores the imperfect agreement between PET/CT and histopathology. The conclusions should therefore be reframed accordingly: PET/CT may provide useful supplementary preoperative information, but it should not be positioned as a substitute for standard axillary staging procedures.
We have revised the statement to ensure alignment with the conclusion, as outlined above.

4. Internal inconsistency in Section 4.4
Section 4.4 is titled “Why sensitivity exceeds specificity,” yet the reported results show the opposite: specificity (81.82%) exceeds sensitivity (69.23%). This factual inconsistency should be corrected, and the accompanying discussion revised accordingly.
We thank the reviewer for highlighting this error, as it was inadvertently stated the other way. The statement has now been corrected.

5. Cohort derivation and flow diagram
The derivation of the analytic cohort requires clearer explanation. The flow diagram indicates that 1,415 patients were assessed for eligibility, of whom 1,201 were excluded, leaving 214 with available PET/CT and histopathology reports. Of these, 144 subsequently underwent neoadjuvant chemotherapy and were excluded, yielding the final cohort of 70. However, the specific reasons for the initial 1,201 exclusions are not broken down, and it remains unclear whether exclusion of neoadjuvant patients introduced any selection bias into the surgical cohort. A more detailed description of the eligibility, exclusion, and cohort derivation steps would improve transparency.
It is clearly indicated in the flowchart that reports for 1201 patients—either PET/CT or final histopathology—were unavailable.

6. Table 1: “Primary tumor SUVmax: Nil” and numerical inconsistency
Table 1 includes a “Primary tumor SUVmax: Nil” category (n=45, 64.3%) that is not explained in the text and is difficult to interpret. It is unclear whether this denotes the absence of an FDG-avid primary tumor, a missing or unacquired measurement, or a technical classification. This category should be defined clearly. In addition, there appears to be a minor inconsistency between the Results text and Table 1 regarding molecular subtype frequencies (Luminal B: n=27 in the text versus n=29 in the table), which should be reconciled.
Table 1 presents the lymph nodal SUVmax rather than the primary tumor SUVmax. This represents a technical classification only, and no conclusions were drawn based on this parameter.

7. Statistical reporting and clinical interpretation
The statistical reporting is adequate at a descriptive level, but several aspects of the clinical interpretation warrant attention. The F1-score, while mathematically valid, has limited intuitive value for a clinical staging audience and receives more emphasis than its interpretive importance justifies. More clinically useful would be a focused discussion of the false-negative rate (30.77%), its implications for missed nodal disease, and how PET/CT findings should be integrated alongside standard axillary assessment rather than used in isolation. In addition, the manuscript does not provide a sample size justification or other rationale for the precision of the estimates; given the wide confidence intervals observed, particularly for sensitivity, the resulting statistical uncertainty should be acknowledged more explicitly as a limitation.

We agree that the F1‑score has limited intuitive value for a clinical staging audience. We have therefore reframed it as a secondary composite metric in the Methods and Results and removed it from the list of key strengths, placing interpretive emphasis on sensitivity, specificity, predictive values, likelihood ratios, and false‑negative rate.
We have expanded the Discussion to more explicitly address the observed false‑negative rate of 30.77%, its implications for missed nodal disease, and the need to use PET/CT as an adjunct to, rather than a replacement for, standard axillary assessment (clinical examination, ultrasound, and sentinel lymph node biopsy).
We now acknowledge that no a priori sample size calculation was performed and that the relatively small sample, especially the number of node‑positive cases, leads to wide confidence intervals for some diagnostic estimates. This statistical uncertainty is now explicitly discussed as a limitation and the findings are presented as hypothesis‑generating

Minor comments
1. Terminology consistency
The manuscript alternates between “PET CT” and “PET/CT”. A single form should be selected and applied consistently throughout.
Terminology has been standardised throughout the manuscript; we now use ‘PET/CT’ consistently in the text, tables, and figure legends, with the full term ‘positron emission tomography/computed tomography (PET/CT)’ defined at first mention

2. Language and grammar
The manuscript would benefit from language editing for grammar and style in several places. This does not affect the scientific content but would improve readability.
In response to the reviewer’s suggestion, the manuscript has been professionally edited for English language and style to improve clarity and readability, without altering the underlying scientific content.

3. Figure 2
Figure 2 adds limited value in its current form, given that Table 2 already conveys the key numerical results. It could either be developed into a more informative visualization or simplified substantially.
In response to the reviewer’s comment, Figure 2 has been simplified to a concise bar‑chart summary of sensitivity, specificity, predictive values, and accuracy, with Table 2 retained as the primary source for the full numerical results and confidence intervals

4. “First study” claim
The claim in Section 4.1 that this is the “first study” to specifically characterize PET diagnostic accuracy in a homogeneous upfront surgical cohort should be tempered or supported by a reproducible literature search, as prior original studies have already examined FDG-PET/CT for preoperative axillary staging in breast cancer [1–3].
We thank the reviewer for highlighting earlier work on FDG‑PET/CT for preoperative axillary staging. We have removed the absolute ‘first study’ claim from Section 4.1 and now state that our study adds treatment‑pathway–specific data on PET/CT diagnostic accuracy in a homogeneous upfront surgery cohort, explicitly acknowledging prior FDG‑PET/CT axillary staging studies
1. PET/CT methodology
The PET/CT methodology is insufficiently described to allow replication or critical appraisal. The manuscript should report the tracer type and administered dose, uptake time, scanner model and acquisition parameters, reconstruction algorithm, and attenuation correction method. Equally important, the criteria used to define lymph node positivity on PET/CT should be stated explicitly, whether based on visual assessment, a fixed SUV threshold, or another metric. The authors should also clarify the number of readers involved, their level of experience, and whether image interpretation was performed with or without knowledge of the clinical and pathological findings. The absence of these details substantially limits reproducibility.
We have provided a comprehensive methodology section detailing the PET/CT protocol, including the tracer type and administered dose, uptake time, scanner model, acquisition parameters, reconstruction algorithm, and attenuation correction technique. Additionally, we have clearly defined the criteria for lymph node positivity, along with the number of interpreters, their level of experience, and the blinding methodology employed

2. Reference standard
The reference standard requires more precise characterization. It is not stated whether nodal assessment was based on sentinel lymph node biopsy, complete axillary dissection, targeted nodal excision, or a combination of these procedures. Given that the extent of nodal sampling directly affects the apparent false-negative rate, this distinction is clinically important. The pathological definition of nodal positivity should also be provided, including whether isolated tumor cells and micrometastases were classified together with macrometastatic disease or analyzed separately.
As pointed out by the reviewer, we have explicitly detailed the lymph nodal assessment methodology along with the pathological criteria used to define nodal positivity. We have also included definitions addressing micrometastasis and isolated tumor cells

3. Overstatement of rule-out value
The conclusions place disproportionate emphasis on the rule-out value of a negative PET result. With a sensitivity of 69.23% (95% CI: 48.27–85.67%) and 8 false-negative cases among 26 pathologically confirmed node-positive patients, a negative PET finding cannot reliably exclude nodal involvement. The moderate Cohen’s kappa of 0.51 further underscores the imperfect agreement between PET/CT and histopathology. The conclusions should therefore be reframed accordingly: PET/CT may provide useful supplementary preoperative information, but it should not be positioned as a substitute for standard axillary staging procedures.
We have revised the statement to ensure alignment with the conclusion, as outlined above.

4. Internal inconsistency in Section 4.4
Section 4.4 is titled “Why sensitivity exceeds specificity,” yet the reported results show the opposite: specificity (81.82%) exceeds sensitivity (69.23%). This factual inconsistency should be corrected, and the accompanying discussion revised accordingly.
We thank the reviewer for highlighting this error, as it was inadvertently stated the other way. The statement has now been corrected.

5. Cohort derivation and flow diagram
The derivation of the analytic cohort requires clearer explanation. The flow diagram indicates that 1,415 patients were assessed for eligibility, of whom 1,201 were excluded, leaving 214 with available PET/CT and histopathology reports. Of these, 144 subsequently underwent neoadjuvant chemotherapy and were excluded, yielding the final cohort of 70. However, the specific reasons for the initial 1,201 exclusions are not broken down, and it remains unclear whether exclusion of neoadjuvant patients introduced any selection bias into the surgical cohort. A more detailed description of the eligibility, exclusion, and cohort derivation steps would improve transparency.
It is clearly indicated in the flowchart that reports for 1201 patients—either PET/CT or final histopathology—were unavailable.

6. Table 1: “Primary tumor SUVmax: Nil” and numerical inconsistency
Table 1 includes a “Primary tumor SUVmax: Nil” category (n=45, 64.3%) that is not explained in the text and is difficult to interpret. It is unclear whether this denotes the absence of an FDG-avid primary tumor, a missing or unacquired measurement, or a technical classification. This category should be defined clearly. In addition, there appears to be a minor inconsistency between the Results text and Table 1 regarding molecular subtype frequencies (Luminal B: n=27 in the text versus n=29 in the table), which should be reconciled.
Table 1 presents the lymph nodal SUVmax rather than the primary tumor SUVmax. This represents a technical classification only, and no conclusions were drawn based on this parameter.

7. Statistical reporting and clinical interpretation
The statistical reporting is adequate at a descriptive level, but several aspects of the clinical interpretation warrant attention. The F1-score, while mathematically valid, has limited intuitive value for a clinical staging audience and receives more emphasis than its interpretive importance justifies. More clinically useful would be a focused discussion of the false-negative rate (30.77%), its implications for missed nodal disease, and how PET/CT findings should be integrated alongside standard axillary assessment rather than used in isolation. In addition, the manuscript does not provide a sample size justification or other rationale for the precision of the estimates; given the wide confidence intervals observed, particularly for sensitivity, the resulting statistical uncertainty should be acknowledged more explicitly as a limitation.

We agree that the F1‑score has limited intuitive value for a clinical staging audience. We have therefore reframed it as a secondary composite metric in the Methods and Results and removed it from the list of key strengths, placing interpretive emphasis on sensitivity, specificity, predictive values, likelihood ratios, and false‑negative rate.
We have expanded the Discussion to more explicitly address the observed false‑negative rate of 30.77%, its implications for missed nodal disease, and the need to use PET/CT as an adjunct to, rather than a replacement for, standard axillary assessment (clinical examination, ultrasound, and sentinel lymph node biopsy).
We now acknowledge that no a priori sample size calculation was performed and that the relatively small sample, especially the number of node‑positive cases, leads to wide confidence intervals for some diagnostic estimates. This statistical uncertainty is now explicitly discussed as a limitation and the findings are presented as hypothesis‑generating

Minor comments
1. Terminology consistency
The manuscript alternates between “PET CT” and “PET/CT”. A single form should be selected and applied consistently throughout.
Terminology has been standardised throughout the manuscript; we now use ‘PET/CT’ consistently in the text, tables, and figure legends, with the full term ‘positron emission tomography/computed tomography (PET/CT)’ defined at first mention

2. Language and grammar
The manuscript would benefit from language editing for grammar and style in several places. This does not affect the scientific content but would improve readability.
In response to the reviewer’s suggestion, the manuscript has been professionally edited for English language and style to improve clarity and readability, without altering the underlying scientific content.

3. Figure 2
Figure 2 adds limited value in its current form, given that Table 2 already conveys the key numerical results. It could either be developed into a more informative visualization or simplified substantially.
In response to the reviewer’s comment, Figure 2 has been simplified to a concise bar‑chart summary of sensitivity, specificity, predictive values, and accuracy, with Table 2 retained as the primary source for the full numerical results and confidence intervals

4. “First study” claim
The claim in Section 4.1 that this is the “first study” to specifically characterize PET diagnostic accuracy in a homogeneous upfront surgical cohort should be tempered or supported by a reproducible literature search, as prior original studies have already examined FDG-PET/CT for preoperative axillary staging in breast cancer [1–3].
We thank the reviewer for highlighting earlier work on FDG‑PET/CT for preoperative axillary staging. We have removed the absolute ‘first study’ claim from Section 4.1 and now state that our study adds treatment‑pathway–specific data on PET/CT diagnostic accuracy in a homogeneous upfront surgery cohort, explicitly acknowledging prior FDG‑PET/CT axillary staging studies
Competing Interests: No competing interests Close
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Reviewer Report 25 Mar 2026

Prabhjeet Singh, Stanford University, Stanford, California, USA

Approved with Reservations

https://doi.org/10.5256/f1000research.196199.r465072

Few minor Comments requires readdressal before final acceptance.

The final paragraph of the Introduction would benefit with a clearer articulation of the study objective, as well as an overview of the study design and plan.

Few minor Comments requires readdressal before final acceptance.

The final paragraph of the Introduction would benefit with a clearer articulation of the study objective, as well as an overview of the study design and plan.
Under the methodology section, please provide a complete description of the protocol parameters to improve clarity and reproducibility. Specifically, include details on tracer type and dose, uptake time, imaging protocol, scanner/acquisition parameters, reconstruction and corrections, and the quantification methods (SUV definitions, ROIs/VOIs).
Under the Study Design section (2.1), please provide details on the study location in accordance with the journal guidelines.
Figure 2 requires formatting and presentation improvements for better clarity. Ensure high resolution, consistent font size, color scheme, a comprehensive legend, axis labels with units, and a caption that clearly explains all symbols and panels.
An additional PET imaging figure could be incorporated to better demonstrate the selectivity and specificity. Ensure the caption clearly explains how the figure supports selectivity and specificity and keep the imaging panels well labeled and interpretable.
To maintain consistency and clarity, please use uniform terminology throughout the manuscript. For example, avoid mixing 'PET CT' and 'PET/CT'; please select one form and apply it consistently.

Is the work clearly and accurately presented and does it cite the current literature?

Yes
Is the study design appropriate and is the work technically sound?

Yes
Are sufficient details of methods and analysis provided to allow replication by others?

Partly
If applicable, is the statistical analysis and its interpretation appropriate?

Partly
Are all the source data underlying the results available to ensure full reproducibility?

Partly
Are the conclusions drawn adequately supported by the results?

Yes

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Cancer Spatial imaging, Immunotherapeutic evaluation, metastatic tumor burden, nanochemistry.

CITE

Report a concern

Author Response 19 May 2026

Sarath Chandu Yadlapalli, Surgical Oncology, Yenepoya Medical College Hospital, Mangaluru, 575018, India

19 May 2026

Author Response
1. The final paragraph of the Introduction would benefit with a clearer articulation of the study objective, as well as an overview of the study design and plan.
... Continue reading
The final paragraph of the Introduction would benefit with a clearer articulation of the study objective, as well as an overview of the study design and plan. This has been addressed as per the reviewer’s comment

Under the methodology section, please provide a complete description of the protocol parameters to improve clarity and reproducibility. Specifically, include details on tracer type and dose, uptake time, imaging protocol, scanner/acquisition parameters, reconstruction and corrections, and the quantification methods (SUV definitions, ROIs/VOIs). We have included a comprehensive methodology section detailing the PET/CT protocol, encompassing the tracer type and administered dose, uptake time, scanner model, acquisition parameters, reconstruction algorithm, and the quantification methods.

Under the Study Design section (2.1), please provide details on the study location in accordance with the journal guidelines. This has been revised in accordance with the journal guidelines, as suggested by the reviewer.

Figure 2 requires formatting and presentation improvements for better clarity. Ensure high resolution, consistent font size, color scheme, a comprehensive legend, axis labels with units, and a caption that clearly explains all symbols and panels. We have provided the original Word file used to generate the bar chart. However, as the journal does not accept this format previously, a lower-resolution version was submitted instead

An additional PET imaging figure could be incorporated to better demonstrate the selectivity and specificity. Ensure the caption clearly explains how the figure supports selectivity and specificity and keep the imaging panels well labeled and interpretable. We have added the PET/CT image.

To maintain consistency and clarity, please use uniform terminology throughout the manuscript. For example, avoid mixing 'PET CT' and 'PET/CT'; please select one form and apply it consistently. Terminology has been standardised throughout the manuscript; we now use ‘PET/CT’ consistently in the text, tables, and figure legends, with the full term ‘positron emission tomography/computed tomography (PET/CT)’ defined at first mention.
The final paragraph of the Introduction would benefit with a clearer articulation of the study objective, as well as an overview of the study design and plan. This has been addressed as per the reviewer’s comment

Under the methodology section, please provide a complete description of the protocol parameters to improve clarity and reproducibility. Specifically, include details on tracer type and dose, uptake time, imaging protocol, scanner/acquisition parameters, reconstruction and corrections, and the quantification methods (SUV definitions, ROIs/VOIs). We have included a comprehensive methodology section detailing the PET/CT protocol, encompassing the tracer type and administered dose, uptake time, scanner model, acquisition parameters, reconstruction algorithm, and the quantification methods.

Under the Study Design section (2.1), please provide details on the study location in accordance with the journal guidelines. This has been revised in accordance with the journal guidelines, as suggested by the reviewer.

Figure 2 requires formatting and presentation improvements for better clarity. Ensure high resolution, consistent font size, color scheme, a comprehensive legend, axis labels with units, and a caption that clearly explains all symbols and panels. We have provided the original Word file used to generate the bar chart. However, as the journal does not accept this format previously, a lower-resolution version was submitted instead

An additional PET imaging figure could be incorporated to better demonstrate the selectivity and specificity. Ensure the caption clearly explains how the figure supports selectivity and specificity and keep the imaging panels well labeled and interpretable. We have added the PET/CT image.

To maintain consistency and clarity, please use uniform terminology throughout the manuscript. For example, avoid mixing 'PET CT' and 'PET/CT'; please select one form and apply it consistently. Terminology has been standardised throughout the manuscript; we now use ‘PET/CT’ consistently in the text, tables, and figure legends, with the full term ‘positron emission tomography/computed tomography (PET/CT)’ defined at first mention.
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Author Response 19 May 2026

Sarath Chandu Yadlapalli, Surgical Oncology, Yenepoya Medical College Hospital, Mangaluru, 575018, India

19 May 2026

Author Response
1. The final paragraph of the Introduction would benefit with a clearer articulation of the study objective, as well as an overview of the study design and plan.
... Continue reading
The final paragraph of the Introduction would benefit with a clearer articulation of the study objective, as well as an overview of the study design and plan. This has been addressed as per the reviewer’s comment

Under the methodology section, please provide a complete description of the protocol parameters to improve clarity and reproducibility. Specifically, include details on tracer type and dose, uptake time, imaging protocol, scanner/acquisition parameters, reconstruction and corrections, and the quantification methods (SUV definitions, ROIs/VOIs). We have included a comprehensive methodology section detailing the PET/CT protocol, encompassing the tracer type and administered dose, uptake time, scanner model, acquisition parameters, reconstruction algorithm, and the quantification methods.

Under the Study Design section (2.1), please provide details on the study location in accordance with the journal guidelines. This has been revised in accordance with the journal guidelines, as suggested by the reviewer.

Figure 2 requires formatting and presentation improvements for better clarity. Ensure high resolution, consistent font size, color scheme, a comprehensive legend, axis labels with units, and a caption that clearly explains all symbols and panels. We have provided the original Word file used to generate the bar chart. However, as the journal does not accept this format previously, a lower-resolution version was submitted instead

An additional PET imaging figure could be incorporated to better demonstrate the selectivity and specificity. Ensure the caption clearly explains how the figure supports selectivity and specificity and keep the imaging panels well labeled and interpretable. We have added the PET/CT image.

To maintain consistency and clarity, please use uniform terminology throughout the manuscript. For example, avoid mixing 'PET CT' and 'PET/CT'; please select one form and apply it consistently. Terminology has been standardised throughout the manuscript; we now use ‘PET/CT’ consistently in the text, tables, and figure legends, with the full term ‘positron emission tomography/computed tomography (PET/CT)’ defined at first mention.
The final paragraph of the Introduction would benefit with a clearer articulation of the study objective, as well as an overview of the study design and plan. This has been addressed as per the reviewer’s comment

Under the methodology section, please provide a complete description of the protocol parameters to improve clarity and reproducibility. Specifically, include details on tracer type and dose, uptake time, imaging protocol, scanner/acquisition parameters, reconstruction and corrections, and the quantification methods (SUV definitions, ROIs/VOIs). We have included a comprehensive methodology section detailing the PET/CT protocol, encompassing the tracer type and administered dose, uptake time, scanner model, acquisition parameters, reconstruction algorithm, and the quantification methods.

Under the Study Design section (2.1), please provide details on the study location in accordance with the journal guidelines. This has been revised in accordance with the journal guidelines, as suggested by the reviewer.

Figure 2 requires formatting and presentation improvements for better clarity. Ensure high resolution, consistent font size, color scheme, a comprehensive legend, axis labels with units, and a caption that clearly explains all symbols and panels. We have provided the original Word file used to generate the bar chart. However, as the journal does not accept this format previously, a lower-resolution version was submitted instead

An additional PET imaging figure could be incorporated to better demonstrate the selectivity and specificity. Ensure the caption clearly explains how the figure supports selectivity and specificity and keep the imaging panels well labeled and interpretable. We have added the PET/CT image.

To maintain consistency and clarity, please use uniform terminology throughout the manuscript. For example, avoid mixing 'PET CT' and 'PET/CT'; please select one form and apply it consistently. Terminology has been standardised throughout the manuscript; we now use ‘PET/CT’ consistently in the text, tables, and figure legends, with the full term ‘positron emission tomography/computed tomography (PET/CT)’ defined at first mention.
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VERSION 3 PUBLISHED 18 Feb 2026

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Version 3 (revision) 18 Jun 26
Version 2 (revision) 19 May 26	read	read
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Prabhjeet Singh, Stanford University, Stanford, USA
Mehmet Tarık Tatoğlu, Göztepe Prof. Dr. Süleyman Yalçin City Hospital, Istanbul, Turkey

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03 Jun 2026 | for Version 2

Prabhjeet Singh, Stanford University, Stanford, California, USA

6 Views Cite this report Responses(0)

Approved

Authors have addressed the comments and ready to accept. I approve of this manuscript

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Cancer Spatial imaging, Immunotherapeutic evaluation, metastatic tumor burden, nanochemistry.

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

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20 Views

26 May 2026 | for Version 2

Mehmet Tarık Tatoğlu, Göztepe Prof. Dr. Süleyman Yalçin City Hospital, Istanbul, Turkey

20 Views Cite this report Responses(1)

Approved With Reservations

The revised version has improved substantially and addresses most of my previous concerns. I appreciate the authors’ careful efforts to strengthen the manuscript. In particular, the expanded PET/CT methodology, clearer description of the reference standard and pathological definitions, correction of the Section 4.4 inconsistency, de-emphasis of the F1-score, acknowledgement of sample-size limitations, and moderation of the originality claim have all improved the paper meaningfully.

At this stage, the manuscript appears close to final form. Only one minor point remains. The abstract conclusion still reads somewhat more strongly than the main text regarding the rule-out value of a negative PET result, so a small wording adjustment for consistency may be helpful.

Overall, this is now a much improved manuscript, and I appreciate the authors’ thoughtful revisions. Subject to this final clarification, I maintain my recommendation of Approved with Reservations.

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No competing interests were disclosed.

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My areas of expertise include nuclear medicine, molecular imaging, PET/CT, oncologic imaging, diagnostic accuracy studies, and the clinical interpretation of imaging biomarkers.

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13 Views

17 Apr 2026 | for Version 1

Mehmet Tarık Tatoğlu, Göztepe Prof. Dr. Süleyman Yalçin City Hospital, Istanbul, Turkey

13 Views Cite this report Responses(1)

Approved With Reservations

Is the work clearly and accurately presented and does it cite the current literature?

Partly
Is the study design appropriate and is the work technically sound?

Partly
Are sufficient details of methods and analysis provided to allow replication by others?

No
If applicable, is the statistical analysis and its interpretation appropriate?

Partly
Are all the source data underlying the results available to ensure full reproducibility?

Partly
Are the conclusions drawn adequately supported by the results?

Partly

References

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

My areas of expertise include nuclear medicine, molecular imaging, PET/CT, oncologic imaging, diagnostic accuracy studies, and the clinical interpretation of imaging biomarkers.

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Author Response

19 May 2026

Sarath Chandu Yadlapalli, Surgical Oncology, Yenepoya Medical College Hospital, Mangaluru, 575018, India

1. PET/CT methodology
The PET/CT methodology is insufficiently described to allow replication or critical appraisal. The manuscript should report the tracer type and administered dose, uptake time, scanner model and acquisition parameters, reconstruction algorithm, and attenuation correction method. Equally important, the criteria used to define lymph node positivity on PET/CT should be stated explicitly, whether based on visual assessment, a fixed SUV threshold, or another metric. The authors should also clarify the number of readers involved, their level of experience, and whether image interpretation was performed with or without knowledge of the clinical and pathological findings. The absence of these details substantially limits reproducibility.
We have provided a comprehensive methodology section detailing the PET/CT protocol, including the tracer type and administered dose, uptake time, scanner model, acquisition parameters, reconstruction algorithm, and attenuation correction technique. Additionally, we have clearly defined the criteria for lymph node positivity, along with the number of interpreters, their level of experience, and the blinding methodology employed

2. Reference standard
The reference standard requires more precise characterization. It is not stated whether nodal assessment was based on sentinel lymph node biopsy, complete axillary dissection, targeted nodal excision, or a combination of these procedures. Given that the extent of nodal sampling directly affects the apparent false-negative rate, this distinction is clinically important. The pathological definition of nodal positivity should also be provided, including whether isolated tumor cells and micrometastases were classified together with macrometastatic disease or analyzed separately.
As pointed out by the reviewer, we have explicitly detailed the lymph nodal assessment methodology along with the pathological criteria used to define nodal positivity. We have also included definitions addressing micrometastasis and isolated tumor cells

3. Overstatement of rule-out value
The conclusions place disproportionate emphasis on the rule-out value of a negative PET result. With a sensitivity of 69.23% (95% CI: 48.27–85.67%) and 8 false-negative cases among 26 pathologically confirmed node-positive patients, a negative PET finding cannot reliably exclude nodal involvement. The moderate Cohen’s kappa of 0.51 further underscores the imperfect agreement between PET/CT and histopathology. The conclusions should therefore be reframed accordingly: PET/CT may provide useful supplementary preoperative information, but it should not be positioned as a substitute for standard axillary staging procedures.
We have revised the statement to ensure alignment with the conclusion, as outlined above.

4. Internal inconsistency in Section 4.4
Section 4.4 is titled “Why sensitivity exceeds specificity,” yet the reported results show the opposite: specificity (81.82%) exceeds sensitivity (69.23%). This factual inconsistency should be corrected, and the accompanying discussion revised accordingly.
We thank the reviewer for highlighting this error, as it was inadvertently stated the other way. The statement has now been corrected.

5. Cohort derivation and flow diagram
The derivation of the analytic cohort requires clearer explanation. The flow diagram indicates that 1,415 patients were assessed for eligibility, of whom 1,201 were excluded, leaving 214 with available PET/CT and histopathology reports. Of these, 144 subsequently underwent neoadjuvant chemotherapy and were excluded, yielding the final cohort of 70. However, the specific reasons for the initial 1,201 exclusions are not broken down, and it remains unclear whether exclusion of neoadjuvant patients introduced any selection bias into the surgical cohort. A more detailed description of the eligibility, exclusion, and cohort derivation steps would improve transparency.
It is clearly indicated in the flowchart that reports for 1201 patients—either PET/CT or final histopathology—were unavailable.

6. Table 1: “Primary tumor SUVmax: Nil” and numerical inconsistency
Table 1 includes a “Primary tumor SUVmax: Nil” category (n=45, 64.3%) that is not explained in the text and is difficult to interpret. It is unclear whether this denotes the absence of an FDG-avid primary tumor, a missing or unacquired measurement, or a technical classification. This category should be defined clearly. In addition, there appears to be a minor inconsistency between the Results text and Table 1 regarding molecular subtype frequencies (Luminal B: n=27 in the text versus n=29 in the table), which should be reconciled.
Table 1 presents the lymph nodal SUVmax rather than the primary tumor SUVmax. This represents a technical classification only, and no conclusions were drawn based on this parameter.

7. Statistical reporting and clinical interpretation
The statistical reporting is adequate at a descriptive level, but several aspects of the clinical interpretation warrant attention. The F1-score, while mathematically valid, has limited intuitive value for a clinical staging audience and receives more emphasis than its interpretive importance justifies. More clinically useful would be a focused discussion of the false-negative rate (30.77%), its implications for missed nodal disease, and how PET/CT findings should be integrated alongside standard axillary assessment rather than used in isolation. In addition, the manuscript does not provide a sample size justification or other rationale for the precision of the estimates; given the wide confidence intervals observed, particularly for sensitivity, the resulting statistical uncertainty should be acknowledged more explicitly as a limitation.

We agree that the F1‑score has limited intuitive value for a clinical staging audience. We have therefore reframed it as a secondary composite metric in the Methods and Results and removed it from the list of key strengths, placing interpretive emphasis on sensitivity, specificity, predictive values, likelihood ratios, and false‑negative rate.
We have expanded the Discussion to more explicitly address the observed false‑negative rate of 30.77%, its implications for missed nodal disease, and the need to use PET/CT as an adjunct to, rather than a replacement for, standard axillary assessment (clinical examination, ultrasound, and sentinel lymph node biopsy).
We now acknowledge that no a priori sample size calculation was performed and that the relatively small sample, especially the number of node‑positive cases, leads to wide confidence intervals for some diagnostic estimates. This statistical uncertainty is now explicitly discussed as a limitation and the findings are presented as hypothesis‑generating

Minor comments
1. Terminology consistency
The manuscript alternates between “PET CT” and “PET/CT”. A single form should be selected and applied consistently throughout.
Terminology has been standardised throughout the manuscript; we now use ‘PET/CT’ consistently in the text, tables, and figure legends, with the full term ‘positron emission tomography/computed tomography (PET/CT)’ defined at first mention

2. Language and grammar
The manuscript would benefit from language editing for grammar and style in several places. This does not affect the scientific content but would improve readability.
In response to the reviewer’s suggestion, the manuscript has been professionally edited for English language and style to improve clarity and readability, without altering the underlying scientific content.

3. Figure 2
Figure 2 adds limited value in its current form, given that Table 2 already conveys the key numerical results. It could either be developed into a more informative visualization or simplified substantially.
In response to the reviewer’s comment, Figure 2 has been simplified to a concise bar‑chart summary of sensitivity, specificity, predictive values, and accuracy, with Table 2 retained as the primary source for the full numerical results and confidence intervals

4. “First study” claim
The claim in Section 4.1 that this is the “first study” to specifically characterize PET diagnostic accuracy in a homogeneous upfront surgical cohort should be tempered or supported by a reproducible literature search, as prior original studies have already examined FDG-PET/CT for preoperative axillary staging in breast cancer [1–3].
We thank the reviewer for highlighting earlier work on FDG‑PET/CT for preoperative axillary staging. We have removed the absolute ‘first study’ claim from Section 4.1 and now state that our study adds treatment‑pathway–specific data on PET/CT diagnostic accuracy in a homogeneous upfront surgery cohort, explicitly acknowledging prior FDG‑PET/CT axillary staging studies

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Reviewer Report

13 Views

25 Mar 2026 | for Version 1

Prabhjeet Singh, Stanford University, Stanford, California, USA

13 Views Cite this report Responses(1)

Approved With Reservations

Few minor Comments requires readdressal before final acceptance.

The final paragraph of the Introduction would benefit with a clearer articulation of the study objective, as well as an overview of the study design and plan.
Under the methodology section, please provide a complete description of the protocol parameters to improve clarity and reproducibility. Specifically, include details on tracer type and dose, uptake time, imaging protocol, scanner/acquisition parameters, reconstruction and corrections, and the quantification methods (SUV definitions, ROIs/VOIs).
Under the Study Design section (2.1), please provide details on the study location in accordance with the journal guidelines.
Figure 2 requires formatting and presentation improvements for better clarity. Ensure high resolution, consistent font size, color scheme, a comprehensive legend, axis labels with units, and a caption that clearly explains all symbols and panels.
An additional PET imaging figure could be incorporated to better demonstrate the selectivity and specificity. Ensure the caption clearly explains how the figure supports selectivity and specificity and keep the imaging panels well labeled and interpretable.
To maintain consistency and clarity, please use uniform terminology throughout the manuscript. For example, avoid mixing 'PET CT' and 'PET/CT'; please select one form and apply it consistently.

Is the work clearly and accurately presented and does it cite the current literature?

Yes
Is the study design appropriate and is the work technically sound?

Yes
Are sufficient details of methods and analysis provided to allow replication by others?

Partly
If applicable, is the statistical analysis and its interpretation appropriate?

Partly
Are all the source data underlying the results available to ensure full reproducibility?

Partly
Are the conclusions drawn adequately supported by the results?

Yes

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Cancer Spatial imaging, Immunotherapeutic evaluation, metastatic tumor burden, nanochemistry.

Respond to this report

Responses (1)

Author Response

19 May 2026

Sarath Chandu Yadlapalli, Surgical Oncology, Yenepoya Medical College Hospital, Mangaluru, 575018, India

The final paragraph of the Introduction would benefit with a clearer articulation of the study objective, as well as an overview of the study design and plan. This has been addressed as per the reviewer’s comment
Under the methodology section, please provide a complete description of the protocol parameters to improve clarity and reproducibility. Specifically, include details on tracer type and dose, uptake time, imaging protocol, scanner/acquisition parameters, reconstruction and corrections, and the quantification methods (SUV definitions, ROIs/VOIs). We have included a comprehensive methodology section detailing the PET/CT protocol, encompassing the tracer type and administered dose, uptake time, scanner model, acquisition parameters, reconstruction algorithm, and the quantification methods.
Under the Study Design section (2.1), please provide details on the study location in accordance with the journal guidelines. This has been revised in accordance with the journal guidelines, as suggested by the reviewer.
Figure 2 requires formatting and presentation improvements for better clarity. Ensure high resolution, consistent font size, color scheme, a comprehensive legend, axis labels with units, and a caption that clearly explains all symbols and panels. We have provided the original Word file used to generate the bar chart. However, as the journal does not accept this format previously, a lower-resolution version was submitted instead
An additional PET imaging figure could be incorporated to better demonstrate the selectivity and specificity. Ensure the caption clearly explains how the figure supports selectivity and specificity and keep the imaging panels well labeled and interpretable. We have added the PET/CT image.
To maintain consistency and clarity, please use uniform terminology throughout the manuscript. For example, avoid mixing 'PET CT' and 'PET/CT'; please select one form and apply it consistently. Terminology has been standardised throughout the manuscript; we now use ‘PET/CT’ consistently in the text, tables, and figure legends, with the full term ‘positron emission tomography/computed tomography (PET/CT)’ defined at first mention.

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Competing Interests

No competing interests

Alongside their report, reviewers assign a status to the article:

Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested

Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.

Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions

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[2] 2. Giuliano AE, Ballman KV, McCall L, et al.: Effect of Axillary Dissection vs No Axillary Dissection on 10-Year Overall Survival Among Women With Invasive Breast Cancer and Sentinel Node Metastasis: The ACOSOG Z0011 (Alliance) Randomized Clinical Trial. JAMA. 2017 Sep 12; 318(10): 918–926. PubMed Abstract | Publisher Full Text

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[4] 4. Eatock F; C T AMillar A, et al.: PET/CT and staging of breast cancer. J. Clin. Oncol. 38(15): e20535.

[5] 5. Boellaard R, Delgado-Bolton R, Oyen WJG, et al.: FDG PET/CT: EANM procedure guidelines for tumour imaging: version 2.0. Eur. J. Nucl. Med. Mol. Imaging. 2015 Feb; 42(2): 328–354. PubMed Abstract | Publisher Full Text

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[7] 7. De los Santos C, Shead D, Solin LJ, et al.: Astute reading of conventional imaging for detecting axillary lymph node metastases in breast cancer: what to expect when not examining. Am. J. Roentgenol. 200(2): 166–173.

[8] 8. Kasem J, Wazir U, Mokbel K: Sensitivity, Specificity and the Diagnostic Accuracy of PET/CT for Axillary Staging in Patients With Stage I-III Cancer: A Systematic Review of The Literature. In Vivo. 2021 Jan 3; 35(1): 23–30. PubMed Abstract | Publisher Full Text

[9] 9. Rosa AD: The predictive value, sensitivity, specificity, and accuracy of PET CT in the evaluation of axillary metastases in breast cancer. European Review. 2023 [cited 2026 Jan 15]. Reference Source

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Diagnostic Accuracy of PET Imaging for Lymph Node Detection in Breast cancer patients undergoing Upfront Surgery: A Single-Institution Analysis of Breast Cancer Patients

Abstract

Background

Methods

Results

Conclusions

Keywords

1. Introduction

1.1 Study objectives

2. Materials and methods

2.1 Study population and design

Figure 1. Flow diagram.

2.2 Statistical analysis

3. Results

3.1 Patient cohort characteristics

Table 1. Baseline clinicopathological and imaging characteristics of upfront surgery patients (n = 70).

3.2 Nodal disease prevalence

3.3 PET diagnostic accuracy

Table 2. Diagnostic accuracy metrics for PET imaging in upfront surgical patients (n = 70).

Figure 2. Comprehensive diagnostic accuracy profile of PET imaging for lymph node detection.

3.4 Likelihood Ratios (LR)

3.5 Confusion matrix and error analysis

3.6 F1-Score and discriminative ability and Kappa coefficient

3.7 Clinical performance summary

4. Discussion

4.1 Summary of key findings

4.2 Clinical implications for surgical planning

4.3 Comparison with literature

4.4 Mechanism of performance differences: Why sensitivity exceeds specificity

4.5 Integration of PET findings into clinical decision-making

4.6 Strengths and limitations

5. Conclusions

Ethical statement

Data availability

References

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