2025+AABIP循证指南：肺癌的支气管镜诊断与分期

Methodology

The guideline development process integrated a sys-tematic literature review through March 2023, utilizing the Grading of Recommendations, Assessment, Development and Evaluation(GRADE) framework for evidence assess-ment and National Institute for Health and Care Excellence(NICE) methodology for recommendation formulation. A modified Delphi consensus process(≥80% agreement threshold) was used for recommendation validation. The multidisciplinary panel comprised pulmonologists, interven-tional radiologists, thoracic surgeons, and allied health professionals.

# Minimum Threshold for Evidence-Based Guideline Process

The minimum criteria for producing an evidence-based recommendation and meta-analysis were at least 2 well-designed studies-randomized controlled trials(RCTs) or observational studies-that quantitatively addressed comparable interventions and outcomes, each assessed as fair or good quality.

Core Objectives

1. Standardization of diagnostic approaches for PPNs.

2. Optimization of CP-EBUS-guided mediastinal staging protocols.

3. Reduction of care variability across diverse clinical settings.

4. Mitigation of geographic and institutional outcome disparities.

5. Identification of critical research priorities.

# Implementation of Framework

● Recommendations utilize NICE-guided terminology:

●“Offer” or“Use”: Interventions where empirical evidence demonstrates clear benefit-to-risk superiority, and which should be routinely offered/used in eligible patients.

Advisory board, AXANA-Honoraria/Advisory board, BeiGene-Hono-Advisory/Advisory board, Boehringer Ingelheim-Honoraria/Advisory board,BMS-Honoraria/Advisory board, EQRx-Honoraria/Advisory board,Fujilm-Honoraria/Advisory board, Guardant Health-Honoraria/Advi-sory board, Intuitive-Honoraria/Advisory board, Janssen-Honoraria/Advisory board, Lily-Honoraria/Advisory board, Merck Sharp \&Dohme-Honoraria/Advisory board, Olympus-Honoraria/Advisory board, R.C.: Optellum-Research support; R.G.: Olympus-Consulting fees/Speaking honoraria/Clinical research-institutional CME support,Delective News/Speaking honoraria/Clinical research institu-institutional CME support, Johnson& Johnson/Ethicon-Sociating fees/Speaking honoraria/Clinical research/institutional CME support, Johnson& Johnson/Ethicon-Sociating fees/Speaking honoraria/Clinical research/institutional CME support; V.K.H.:Ambu-Consulting fees;Y.B.G.:Lead Optik-Consulting fees, Intensive Surgical-Honoraria, Olympus-Honoraria/Advisory Board, Patient Power-Medial board membership, M.S.(Shafiq): Ambu A/S-Consulting fees, PulmonX-Research grants, Olympus-Research grants; A.C.:Intuitive-Consulting fees. Russell J. Miller, MD, CAPT, MC, USN is a military service member or federal/contracted employee of the United States government. This work was prepared as part of his official duties.Title 17 U.S.C.105 provides that‘copyright protection under this title is

<EndOfPara>not available for any work of the United States Government' Title 17 U.S.C.101 defines US Government work as work prepared by a military service member or employee of the US Government as part of that per-son's official duties. The views expressed in this article reflect the results of research conducted by the author and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense,nor the United States Government. For the remaining authors, there is no conflict of interest or other disclosures.

Correspondence: Russell J. Miller, MD, CAPT, MC, USN, Uniformed Services University of the Health Sciences(USUHS), Bethesda,MD; Department of Pulmonary Medicine, Naval Medical Center San Diego, San Diego, CA 92134,(e-mail: russell.j.miller32,mil@health.mil).

Supplemental Digital Content is available for this article. Direct URL citations are provided in the HTML and PDF versions of this article on the journal's website, www.bronchology.com.

Written work prepared by employees of the Federal Government as part of their official duties, is under the U.S. Copyright Act, a“work of the United States Government" for which copyright protection under Title 17 of the United States Code is not available. As such,copyright does not extend to the contributions of employees of the Federal Government.

DOI:10.1097/L.BR.0000000000001034

| Bronchol Intervul Pulmonol● Volume 32, Number 4, October 2025

ABIP Guidelines: Bronchoscopic Diagnosis, Staging

●“Consider”: Interventions where evidence suggests prob-able benefit for most patients, but the balance of risks/benefits or patient preferences indicates individualized decision-making.

● "Make No Recommendation": situations where the available evidence is insufficient(either in quantity or quality) to support a definitive "use" or "do not use"statement.

●“Do Not Routinely Offer” or“Do Not Routinely Use”:Interventions where the evidence does not support routine use, or where harms may outweigh benefits for the general patient population.

●“Do Not Offer” or“Do Not Use”: Interventions where the evidence demonstrates a clear lack of benefit and harms clearly outweigh benefits.

Recommendations and Key Rationale

1. Recommendation 1: Evidence-Informed(Meta-analysis)Consider peripheral navigational bronchoscopy(PNB)with biopsy, rather than computed tomography-guided transthoracic needle biopsy (CT-TTNB), for evaluating indeterminate PPNs, taking into account patient factors,nodule characteristics, local expertise, and costs.1-10 Remark: Although the meta-analysis showed higher diagnostic yield with CT-TTNB based on studies of older bronchoscopic platforms, emerging data on contemporary bronchoscopic guidance techniques dem-onstrate comparable diagnostic yields with lower pneumothorax rates and offer procedural flexibility for concurrent lymph node staging.

2. Recommendation 2: Evidence-Based(Meta-analysis) Con-sider using multiple biopsy tools, rather than a single tool,during bronchoscopy to sample indeterminate PPNs.11-20 Remark: A meta-analysis of 10 studies demonstrates improved diagnostic yield with multiple biopsy tools without increased complications. Effect sizes remain modest, and implementation should be individualized based on patient characteristics and institutional capabilities.

3. Recommendation 3: Evidence-Based(Meta-analysis) Con-sider using Rapid On-Site Evaluation(ROSE) during bronchoscopy for nonsurgical biopsy of indeterminate PPNs,based on local resource availability and clinical context.21-26 Remark: A meta-analysis demonstrates that ROSE improves diagnostic yield without prolonging procedural time, while facilitating specimen triage for molecular testing. However,implementation requires consideration of institutional cyto-pathology support capabilities.

4. Recommendation 4. Evidence-Based(Meta-analysis) We make no recommendation regarding the use of diagnos-tic peripheral bronchoscopy versus CT-TTNB specifi-cally to obtain tumor tissue for molecular analysis in patients with malignant PPNs.2,27,28 Remark: A meta-analysis of 3 comparative studies showed no significant difference between modalities for obtaining adequate tumor tissue; both methods demonstrated high success rates for molecular testing.

5. Recommendation 5: Evidence-Informed(Systematic Review) Use a systematic staging examination, rather than examining only radiographically suspicious lymph nodes, during CP-EBUS for mediastinal staging in presumed lung cancer.29-37 Remark: Systematic reviews demonstrate that systematic CP-EBUS staging detects 5% to 15% more occult mediastinal disease compared

with targeted sampling of radiographically abnormal nodes alone.

6. Recommendation 6: Evidence-Based(Meta-analysis) Do not routinely offer properative surgical mediastinoscopy to patients with a negative CP-EBUS-guided mediastinal staging examination who have risk factors for occult N2/N3 disease but no overt radiographic involvement.38-40 Remark: A meta-analysis indicates that post-CP-EBUS mediastinoscopy provides only marginal improvement in detecting occult N2/N3 disease without significantly reducing unexpected nodal metastases at surgery.

7. Recommendation 7: Evidence-Based(Meta-analysis)Clinicians should recognize a primary tumor size>3 cm as a significant risk factor for occult mediastinal metastasis and consider invasive nodal staging in patients with peripheral tumors and a radiographically normal hilum and mediastinum.41-44 Remark: A meta-analysis demonstrates that tumors larger than 3 cm have approximately twice the likelihood of harboring occult mediastinal metastasis compared with smaller tumors.This recommendation includes risk-stratification guid-ance rather than a direct“use/do not use” statement.

8. Recommendation 8: Evidence Informed(Systematic Review) Do not routinely offer invasive mediastinal staging for patients with pure ground-glass nodules(GGNs) and a radiographically normal mediastinum on computed tomography(CT) and positron emission tomography(PET).45-53 Remark: Retrospective analyses demonstrate that pure GGNs carry an extremely low risk of mediastinal lymph node metastasis, making routine invasive staging of limited diagnostic benefit relative to procedural risks.

9.Recommendation 9: Evidence Informed(Systematic review) We make no recommendation regarding the routine use of CP-EBUS to detect occult N1 disease before stereotactic body radiation therapy(SBRT) in patients with early-stage nonsmall cell lung cancer(NSCLC) who do not meet criteria for invasive staging.45,54-60 Remark: Current evidence lacks sufficient methodological rigorous to demonstrate meaningful improvements in clinical outcomes, while procedural risks and potential treatment delays must be considered.

INTRODUCTION

For decades, lung cancer survival rates remained abysmal despite incremental progress in treatment. Recent advances in cancer detection and therapeutic modalities are helping to improve overall survival and reduce recurrence.61 Despite this positive trend, there are marked variations in patient outcomes between centers, regions,and socioeconomic groups.62-70 Much of this heterogene-ity can be attributed to inconsistent adherence to best practices and guideline-concordant care.71,72 While varia-tion in therapeutic approach is frequently identified as a primary determinant of disparate outcomes, appropriate use of invasive diagnostic procedures for tissue acquisition and mediastinal staging is a prerequisite for implementing optimal treatment.

The American Association for Bronchology and Interventional Pulmonology(AABIP) assembled an expert panel to develop comprehensive evidence-informed recom-mendations addressing 2 critical domains:

1. Nonsurgical biopsy approaches for peripheral pulmo-nary nodules(PPNs).

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2. Convex probe endobronchial ultrasound(CP-EBUS)-guided mediastinal staging in nonsmall cell lung cancer(NSCLC).

This document synthesizes our rigorous systematic review with meta-analysis, supplemented by expert con-sensus where data proved insufficient for formal evidence-based guidance.

Nine distinct recommendations were formulated-6 supported by meta-analysis and 3 by systematic reviews.One meta-analysis-supported recommendation diverged from initial findings due to recent technological advances and newer data that were initially not available for inclusion into the meta-analysis. These guidelines also highlight several areas requiring further investigation, including robotic bronchoscopy, real-time intracopural imaging techniques,and innovative tools such as peripheral cryobiopsy.

Clinicians are urged to implement these recommenda-tions within the context of their local expertise, patient-specific factors, and available resources. Our expectation is that these evidence-based and evidence-informed recom-mendations will help reduce disparities in lung cancer outcomes while improving diagnostic yield and sensitivity for PPNs and mediastinal staging assessments.

METHODOLOGY

Panel Selection

The guideline development process incorporated an executive committee from AABIP, an expert panel, and a dedicated writing group. Six pulmonologists (including 2 methodologies) comprised the executive committee that oversaw the entire guideline development process. The expert panel consisted of 9 pulmonologists, 2 interventional radiologists, and 2 thoracic surgeons.

Fourteen pulmonologists and 3 allied health profes-sionals(2 nurse practitioners and 1 respiratory therapist)formed the writing group. Both the expert panel and writing group participated in recommendation voting, while the expert panel additionally reviewed and suggested manu-script edits for assigned Population, Intervention, Compa-rator, Outcome(PICO) questions.

Conflict of Interest(COI)

All nominees submitted disclosure forms before selec-tion. Individuals holding patents or significant stock positions that might benefit from these guidelines were automatically disqualified. The executive committee managed lesser con-flicts on a case-by-case basis to maintain integrity.

PICO Question Development

Initial Question Generation

Each expert panel member proposed 5 clinically relevant questions for each category:

Nonsurgical biopsy of PPNs.

Evaluation of pulmonary nodules when mediastinal staging is warranted.

Question Ranking

After reviewing for redundancy, questions were ranked 1 to 9(1 to 3=unimportant, 4 to 6=important, 7 to 9=critically important). Questions scoring 7 to 9 received automatic selection, with additional 4 to 6 scoring questions added until reaching a total of 15.

Refining PICO Questions(Modified Delphi)

The writing group drafteded Delphi process followed with the expert panel; panelists could accept, reject, or propose revisions in round one, then voted to include or reject in round 2.Questions required 70% approval for inclusion. Nine final PICO questions emerged that targeted key aspects of diagnosing and staging pulmonary nodules.

Systematic Review and Meta-Analysis

Literature Search

Literature searches for each PICO question were conducted in 2021 with updates in March 2023 across multiple databases(including PubMed and Embase) using predefined strategies. Given the rapid pace of technological advancement in this field, a post-hoc decision was made to also consider pivotal, high-impact studies that became available after the formal literature search cutoff to ensure recommendations reflect the most current evidence. Pre-ferred Reporting Items for Systematic Reviews and Meta-Analyses(PRISMA) flow diagrams in the supplementary materials detail the screening methodology.

Screening and Selection

The writing group performed initial title screening.Two independent reviewers evaluated potentially relevant abstracts using Covidence software. Abstracts advanced to full-text review when both reviewers deemed them relevant;the guideline chair and co-chairs(RM, AC, FK, and MS)resolved disagreements. Inclusion criteria required studies to address the respective PICO elements, include>50 partic-ipants, and report specified outcomes. Two reviewers assessed full-text articles for eligibility before data extraction.

Risk of Bias and Quality Appraisal

Each included full-text article underwent bias assess-ment using appropriate validated tools:

Quality Assessment of Diagnostic Accuracy Studies-2(QUADAS-2) for diagnostic accuracy studies.

Newcastle-Ottawa Scale for observational studies.

A Meaurement Tool to Assess Systematic Reviews-2(AMSTAR-2) for existing systematic reviews.

Two independent reviewers assessed bias risk for each study. Disagreements were resolved through discussion or consultation with a third reviewer. Poor-quality articles were excluded. Complete risk of bias assessments appear in Supplementary Tables S1-S7, Supplemental Digital Con-tent 1, http://links.lww.com/LBR/A364.

Data Extraction and Synthesis

Data extraction for each PICO question utilized standardized Excel spreadsheets capturing study design,population characteristics, interventions, comparators, out-comes, and effect measures. Due to the variable definitions of diagnostic yield, we extracted final diagnostic outcomes as determined by the individual study authors. We acknowl-edge that definitions of yield varied across studies (strict,intermediate, or liberal definitions) and are not necessarily consistent with the recent American Thoracic Society(ATS)/American College of Chest Physicians (ACCP)consensus definitions of diagnostic yield or accuracy.73 When feasible, meta-analyses were conducted using R(version 4.4.2) and RStudio (version 2024.12.1 Build 563),employing the meta package (version 8.0-2) for both

|Rec. #|Outcome & Comparison|# Studies|Study Design Breakdown|Risk of Bias|Inconsistency|Indirectness|Publication Bias|Overall Certainty|Comment/Rationale| |---|---|---|---|---|---|---|---|---|---| |1|Diagnostic Yield: Bronchoscopy vs. TTNB|10|●RCT:3 ●Retrospective:7|Not serious|Not serious|Serious|Serious|Very Low|Older bronchoscopy studies show lower yields compared to CT-guided TTNB. Newer bronchoscopic methods may narrow this gap. Bronchoscopy is consistently associated with significantly lower pneumothorax rates.| |1|Pneumothorax (Any): Bronchoscopy vs. TTNB|10|●RCT:3 ●Retrospective:7|Not serious|Not serious|Not serious|Not serious|Not serious|consistently associated with significantly lower pneumothorax rates. Limited events result in wide confidence intervals.| |2|Diagnostic Yield: Single vs. Multiple Biopsy Tools|10|● Prospective: 4 ●Retrospective:6|Not serious|Not serious|Not serious|Not serious|Not serious|Adding an additional biopsy tool increases yield by $\sim 10\%$ (absolute improvement).| |3|Diagnostic Yield: ROSE vs. No ROSE|6|●RCT:3 ●Prospective: 1 ●Retrospective:2|Not serious|Not serious|Not serious|Not serious|Moderate|ROSE consistently improves diagnostic yield without significantly increasing procedure duration. Marked heterogeneity (P $\approx$ 95%) due to variable definitions of procedure time across studies.| |3|Procedure Time: ROSE vs. No ROSE|4|●RCT:3 ●Retrospective:1|Not serious|Not serious|Not serious|Not serious|Serious|Marked heterogeneity (P $\approx$ 95%) due to variable definitions of procedure time across studies.| |4|Molecular Testing Adequacy: Bronchoscopy vs. TTNB|3|●Prospective: 1 ●Retrospective:2|Not serious|Not serious|Serious|Not serious|Suspected|Very Low| |5|Surgically Detected Occult|8|●RCT:1 ●Prospective: 3 ● Retro2: 4|Very serious|Serious|Not serious|Serious|Systematic CP-EBUS detects 5-15% more occult N2/N3 disease. Data primarily from small, retrospective studies with broad variability.|| |6|Missed N2/N3 Disease: CP-EBUS alone vs. CP-EBUS + Mediastinoscopy|3 3 ●RCT: 1 ● Prospective: 2|Not serious|Not serious|Not serious|Not serious|Suspected|Minimal additional benefit from routine mediastinoscopy after negative CP-EBUS in high-risk patients. Tumors >3 cm|| |7|Occult Mediastinal(N2) Metastases: Tumor Size >3cm|4|● Retrospective: 4 ●Retrospective:4|Serious|Not serious|Not serious|Suspected|Tumors >3 cm approximately double the risk of occult N2||

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 random and fixed-effects models. Results were compiled into evidence summaries.

Delphi-Based Consensus for Recommendations

Following a systematic review and quality appraisal,the writing group drafted recommendations that underwent a modified Delphi voting process involving both the expert panel and writing group. Consensus required ≥80% agree-ment (Agree/Strongly Agree) with ≥75% panel participa-tion. Up to 3 rounds were planned if necessary. If consensus remained below 80% after 3 rounds, statements were reframed as comments (if ≥67% agreement) or excluded(<67%). All recommendations in this guideline achieved consensus without requiring maximum rounds.

Evidence Grading and Recommendation Framework

Grading of Recommendations Assessment,Development, and Evaluation(GRADE) and National Institute for Health and Care Excellence(NICE):Basic Differences

GRADE assesses overall certainty(high, moderate,low, and very low) and helps determine strong versus conditional recommendations based on benefits, harms-values, and resources. NICE employs more direct, action-oriented wording to guide clinical practice. We applied GRADE principles for evidence certainty rating but presented final recommendations using NICE terminology.

Implementation of the NICE Framework

Recommendations utilized the following NICE-guided terms:

“Offer” or“Use”: Interventions where empirical evidence demonstrates clear benefit-to-risk superiority, and which should be routinely offered/used in eligible patients.

“Consider”: Interventions where evidence suggests probable benefit for most patients, but the balance of risks/benefits or patient preferences indicates individualized decision-making.

“Make No Recommendation”: Situations where the avail-able evidence is insufficient (either in quantity or quality) to support a definitive “use” or “do not use” statement.

“Do Not Routinely Offer” or“Do Not Routinely Use”:Interventions where the evidence does not support routine use, or where harms may outweigh benefits for the general patient population.

“Do Not Offer” or“Do Not Use”: Interventions where the evidence demonstrates a clear lack of benefit and harms clearly outweigh benefits.

Combining GRADE evaluation with NICE language provided both robust evidence assessment and practical guidance. The certainty of evidence for each key outcome across all recommendations was assessed using the GRADE framework and is summarized in Tables 1 and 2.

Ethical Considerations

This guideline relied solely on published studies; there-fore, no institutional review board approval was required. No patient-identifiable data were collected, and no new inter-ventions were introduced. All participants adhered to ethical standards throughout the literature review process.

www.bronchology.com

TABLE 2. Summary of Included Studies: Bronchoscopy Versus CT-TTNB*

|References|Design and size|Interventions/tools|Diagnostic yield|Pneumothorax/chest tube|Population / Inclusion| |---|---|---|---|---|---| |Atkins et al (2020)^{10}|Retrospective cohort; n=135 (ENB=135; CT-TTNB=23)|ENB (21-22G needle) vs. CT-TTNB (17-19G coaxial)|ENB: 51.9%; CT-TTNB: CT-TTNB: 87.0%|ENB: PTX 3%; Chest tube 2%. CT-TTNB: PTX 13%; Chest tube 0%.|● Single-center; retrospective ● SPN $\sim$ 28 mm average ● CT-TTNA group consist of patients with- ENB followed by CT-TTNB| |Bhatt et al (2018)^2|Retrospective cohort; n=300 (ENB=150; CT-TTNB=150)|ENB (21-22G needle) vs. CT-TTNB (coaxial needle)|ENB: 66.0%; CT-TTNB: coaxial|ENB: PTX 4%; Chest tube 27.9%; CT-TTNB: CT-TTNB: 86.0%|● Excluded advanced disease or known diagnosis. ● Peripheral nodules(~22-24 mm) Single institution| |Herath et al (2023)^3|Prospective randomized; n=36 (rEBUS- cryo=20; CT-TTNB=16)|rEBUS +cryobiys vs. CT-TTNB (coaxial needle)|rEBUS-cryo: 85%; CT-TTNB: CT-TTNB: CT-20TTNB: CT-10.9%|rEBUS-cryo: PTX 4.2%; Chest tube 0%. CT-TTNB: CT-TTNB: CT12.5%; 93.8%|● Established venousles $\geq 1$ cm $\bullet$ No central lesions or bulky $\geq 1$ cm $\bullet$ No central lesions or bulky mediastinal lymph nodes| |Hur et al (2010)^4|Retrospective cohort; n=77 (CT-F-TTNB=53; TBLB=24)|Repeat TBLB (standard) vs. CT-F-TTNB (20-22G Chiba)|CT-F-TTNB: TBLB: CT-5.7%|TBLB: PTX 0%; Chest tube 0%. CT-F-TTNB: PTX 13.2%; Chest tube 5.7%|Suspected malignant lesions with nondiagnostic initial bronchoscopy ● Central and peripheral lesions (mean 27±11 mm)| |Steinfort et al (2011)^5|Prospective RCT; n=48 (rEBUS-GS=32; CT-TTNB=16)|rEBUS + guide sheath vs. CT-TTNB (coaxial needle)|rEBUS-GS: 87.5%; CT-TTNB: CT-TTNB: PTX 18.8%; Chest tube 0% 93.8%|rEBUS-GS: PTX 3.2%; Chest tube 0%. CT-TTNB: PTX 18.8%; Chest tube 0% 93.8%|Single-center RCT. Small sample size. ● Significant difference in lesion size (CT-PNB: 41±21 mm vs.rEBUS-GS: CT-PNTB: PTX 0%; Chest tube 0% ●Mean nodule size $\sim$ 27 mm| |Wang et al (2016)^10|Retrospective matched; n=108 (rEBUS-GS=54; CT-TTNB=54)|rEBUS-GS (20 MHz) vs. CT-TTNB (coaxial needle)|rEBUS-GS: 81.5%; CT-TTNB: CT-TTNB: 87.0%|rEBUS-GS: PTX 9.3%; Chest tube 3.7%. CT-TTNB: PTX 0%; Chest tube 0%|● Propensity-matched by lesion size location ●Mean nodule size $\sim$ 27 mm| |Wang et al (2018)^6|Retrospective; n=160 (rEBUS-GS=80; CT-TTNB=80)|rEBUS-GS vs. CT-TTNB (standard coaxial needle)|rEBUS-GS: 65.0%; rEBUS-GS: PTX 1.3%; Chest tube 0%. CT-TTNB: CT-TTNB: CT-5.0%|rEBUS-GS: PTX 1.3%; Chest tube 0%. CT-TTNB: CT-TTNB: CT-10.9%; rEBUS-GS: PTX 1.5%; Chest tube 4.3% 84.6%|● Peripheral nodules < 3 cm, suspicious for malignancy ● No bulky lymph nodes or advanced disease. ● Single station 10-50 mm, peripheral ● No advanced disease ● Large single-center cohort ● LEBUS primarily for lesions>80 mm| |Zhang et al (2019)^9|Retrospective; n=522 (rEBUS-GS=262; CT-TTNB=260) (rEBUS-GS=250; CT-TTNB=279)|rEBUS-GS vs. CT-TTNB (standard coaxial needle)|rEBUS-GS: 78.2%; CT-TTNB: CT-TTNB: CT-4.6%|rEBUS-GS: PTX 0.4%; Chest tube 19.7%; LEBUS-GS: PTX 0.4%; Chest tube NR. CT-TTNB: CT-TTNB: CT-4.6%|● Large single-center cohort ● Large single-center cohort ● LEBUS primarily for lesions>80 mm ● Nodules in“middle third” of lung ● Lesion size 8-40 mm ● Single center; small ENB sample ● Peripheral nodules (1-3 cm) ● Multicenter; randomized design ● Key modern ENB trial| |Zhang et al (2023)^8|Retrospective; n=114 (ENB=21; CT-TTNB=93)|ENB vs. CT-TTNB (standard coaxial needle)|ENB: 76.1%; CT-TTNB: CT-TTNB: CT-73.1%|ENB: PTX 0%; Chest tube 0%. CT-TTNB: CT-TTNB: PTX 16.1%; Chest tube 6.5% 73.1%|● Nodules in“middle third” of lung ● Lesion size 8-40 mm ● Single center; small ENB sample ● Peripheral nodules (1-3 cm) ● Multicenter; randomized design ● Key modern ENB trial| |Lentz et al (2025)^74†|Prospective multicenter RCT; n=234 (ENB=121; CT-TTNB=113)|ENB with digital tomosynthesis vs. CT-TTNB (coaxial needle)|ENB: 79.0%; CT-TTNB: CT-TTNB: CT-TTNB: CT-73.6%|ENB: PTX 3.3%; Chest tube 0.8% . Multicenter; randomized design ● Key modern ENB trial|● Peripheral nodules (1-3 cm) ● Multicenter; randomized design ● Key modern ENB trial|

*CT-guided procedure terminology varies in source studies; cited papers may refer to it as CT-TTNA (Aspiration); CT-PNB (Percutaneous Needle Biopsy); CT-NAB (Percutaneous Needle Aspiration) CT-TTB (Transthoracic Biopsy); CT-guided lung puncture; or CT-guided biopsy/sampling.

tStudy published after the March 2023 literature search cutoff, included by post-hoc panel consensus due to high relevance and impact. Study not included in the main meta-analysis.

CT-F-TTNB indicates computed tomography with fluoroscopy-guided transthoracic needle biopsy; CT-TTNB, computed tomography-guided transthoracic needle biopsy; ENB, electromagnetic navigational bronchoscopy; GS, guide sheath; NR, not reported; PTX, pneumothorax; rEBUS, radial endobronchial ultrasound; RCT, randomized controlled trial; SPN, solitary pulmonary nodule; TBLB, transbronchial lung biopsy.

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     FIGURE 1.(A)(Recommendation 1). Diagnostic Yield(All Modalities)-CT-TTNB vs. Bronchosopy. Forest plot showing the odds ratios(ORs) with 95% Cls comparing the diagnostic yield of CT-guided transthoracic needle biopsy(CT-TTNB) vs.

Bronchosity 推荐 across 10 studies. The squares represent individual study estimates, with the size reflecting each study's weight under the common-effect model. The horizontal lines through the squares indicate the 95% CI. The diamonds at the bottom represent the pooled effect estimate using a random-effects

model. Heterogeneity was moderate $\left({}^{2}=34.9\%\right)$ . Overall, CT-TTNB demonstrated a significantly higher diagnostic yield compared with bronchoscopy [random-effects OR: 3.24(2.20-4.79),P<0.0001] (B). [Recommendation 1). Diagnostic yield(Radial EBS-Only)-CT-TTNB vs. Bronchoscopy. Forest plot displaying ORs and 95% Cls for diagnostic yield of CT-TTNB versus bronchoscopy in 6 studies using radial endobronchial ultrasound(rEBUS). The squares indicate study-specific estimates,sized according to the weight under the common-effect model;whiskers show the 95% CI. The diamond indicates the pooled effect under a random-effects model. Heterogeneity was minimal(P=0.00%). Overall, CT-TTNB had a higher diagnostic yield than rEBUS bronchoscopy alone[random-effects OR: 3.32(2.37-4.66),P=0.0003]. (C) Recommendation 1). Diagnostic yield(ENB-Only)-CT-TTNB vs. Bronchoscopy. Forest plot comparing diagnostic yield of CT-TTNB vs. electromagnetic navigation bronchoscopy(ENB) alone across 3 studies. Each square indicates an individual study's odds ratio(OR) with 95% CI. The diamond represents the random-effects estimate. Heterogeneity was moderate(P=6.7%). Under the random-effects model, the pooled OR was 25.0(24-27.39), P=0.2328, reflecting high variance and no significant difference in yield.(D)(Recommendation 1). Preunethorax Incidence- CT-TTNB vs.266.0(27-39).25.4(100.0)100.0%100.0%100.0%100.0%100.0%100.0%100.0%100.0%100.0%100.0%100.0%100.0%100.0%100.0%100.0%100.0%100.0%100.0%100.0%100.0%100.0%100.0%100.0%100.0%100.0%100.0%100.0%100.0%100.0%100.0%100.0%100.0%100.0%100.0%100.0%100.0%100.0%100.0%100.0%100.0%100.0%100.0%100.0%100.0%100.0%100.0%100.0%100.0%100.0%100.0%100.0%100.0%10

SECTION IV: RECOMMENDATIONS

Recommendation 1: Evidence-Informed(Meta-Analysis)

PICO Question

In patients with indeterminate PPNs, should peripheral navigational bronchography(PNB) or computed tomogra-phy(CT)-guided transthoracic needle biopsy(CT-TTNB) be used for tissue diagnosis?

Recommendation

Consider PNB with biopsy, rather than CT-TTNB, for evaluating indeterminate PPNNs, taking into account patient factors, nodule characteristics, local expertise, and costs.

Background

PPNs can represent either benign or malignant entities,and accurately characterizing the lesion is essential for appropriate and timely management. ${}^{75}$ CT-TTNB has

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AABIP Guidelines: Bronchoscopic Diagnosis, Staging

|A|Multiple Tools|Single Tool| |---|---|---| |Study|Events Total Events Total|Odds Ratio| |Arimura 2017|91|105| |Boonsarngsuk 2015|90|112| |Kim 2023|87|110| |Kuo 2014†|106|132| |Matsumoto 2021|231|257| |Oberg 2022|108|120| |Oki 2023|37|50| |Orr 2022|164|324| |Reichenberger 1999±|87|172| |Sumi 2021|44|51| |Common effect model|1433|1420|

Prediction interval

#

OR

OR 95%-Cl (common) (random)

|1.62|0.78;3.40]|5.4%|5.8%| |---|---|---|---| |1.71|0.92;3.17]|7.7%|8.1%| |2.00|1.09;3.65]|8.1%|8.5%| |2.08|1.20;3.63]|9.6%|10.0%| |3.07|1.88;5.02]|12.2%|12.4%| |1.19|0.53;2.69]|4.4%|4.8%| |1.74|0.74;4.09]|4.1%|4.4%| |1.35|0.99;1.84]|30.8%|27.9%| |1.86|1.19;2.90]|14.8%|14.8%| |2.38|0.87;6.51]|2.9%|3.2%| |1.77|1.49;2.10]|100.0%|$$\begin{array}{c}\\ \\ \\ \\ \\ \\ \end{array}$$| |1.78|1.49;2.14]|1.49;2.14]|$$\begin{array}{c}\\ \\ \\ \\ \\ \end{array}$$| |1.36|2.34]||100.0%|

Favours Single Favours Multiple Odds Ratio(95% CI)

|B Study|Multiple-tool Events Total Events Total|Single-tool Events Total Events Total|Weight 95%-CI(common) (random)|Weight Weight||||| |---|---|---|---|---|---|---|---|---| |B Study|Arima 2017|91 105|84|105|1.62[0.78;3.40]|7.6%|8.0%|| |Boonsarungsuk 2015|90 112|79 112|112|1.71[0.92;3.17]|10.6%|11.3%||| |Kuo 2014†|106 132|92|139|2.08[0.99;1.84]|12.0%|13.9%||| |Orr 2022|164 324|140|324|1.35[0.99;1.84]|47.1%|41.4%||| |Reichenberger 1999†|87 172|54|152|1.86[1.19;2.90]|19.3%|21.0%||| |Sumi 2021|44 51|37|51|2.38[0.87;6.51]|3.5%|4.3%||| |Common effect model|896|883||1.63[1.33;2.00]|100.0%|||| |Random effects model||||1.64[1.33;2.02]||100.0%||| |Prediction interval||||1.20;2.24]||||| |Heterogeneity:l2=0.0%,T2=0.0031,p=0.6847||0.1 0.2 0.5|1 2|5 10||||| |Favors Single Favors Multiple 1.49;2.14] 100.0%||||||||| |Odds Ratio (95% CI)|Odds Ratio (95% CI)|Odds Ratio (95% CI)|Odds Ratio (95% CI)|Odds Ratio (95% CI)|Odds Ratio (95% CI)|Odds Ratio (95% CI)|Odds Ratio (95% CI)|| |C Multiple Tools Single Tool|Weight|||||||| |Study|Events Total Events Total|OR|95%-CI (common)|(random)||||| |Kim 2023|87|110|72|110||2.00[1.09;3.65]|28.4%|| |Matsumoto 2021|231|257|191|257||3.07[1.88;5.02]|36.4%|| |Oberg 2022|108|120|106|120||1.19[0.53;2.69]|20.0%|| |Oki 2023|37|50|31|50||1.74[0.74;4.09]|15.2%|| |Common effect model 537 537 2.19[1.59;3.00] 100.0%||||||||| |Prediction interval 2.06[1.10;3.88]||||||||| |Prediction interval 2.0.5 1 2 5 10||||||||| |Favors Single Favors Multiple 0.1 0.2 0.5 1 2 5 10||||||||| |Odds Ratio (95% CI)|Odds Ratio (95% CI)|Odds Ratio (95% CI)|Odds Ratio (95% CI)|Odds Ratio (95% CI)|Odds Ratio (95% CI)|Odds Ratio (95% CI)|Odds Ratio (95% CI)||

|Study|Multiple Tools Events Total Events Total|Single Tool Events Total Events Total| |---|---|---| |Kim 2023 Matsumoto 2021|87 231|72 257| |Oberg 2022|108 120|108 120| |Oki 2023|37 37|50 31|

|| |---| |Random effects model| |Prediction interval| |Heterogeneity:12=30.5%,T=0.0587,P=0.2290|

Heterogeneity:12=30.5%,T=0.0587,P=0.2290

OR

|2.00[1.09;3.65]| |---| || |3.07[1.88;5.02]| |1.19[0.53;2.69]| |1.74[0.74;4.09]| |2.19[1.59;3.00]| |2.06[1.10;3.88]| |$[0.75;5.70]$|

modalities used for PNB have evolved significantly.Radial-probe endrochial ultrasound(rEBUS) with 2-dimensional(2D) fluoroscopy, electromagnetic navigation bronchoscopy(ENB), and, more recently, robotic-assisted platforms have progressively allowed for more precise targeting and accurate diagnosis of PPNs during

Miller et al

/ Bronchol Intervent Pulmonol● Volume 32, Number 4, October 2025

FIGURE 2. A(Recommendation 2). Diagnostic yield: single vs. multiple tools(overall). Forest plot of odds ratios(ORs) and 95% CIs comparing the diagnostic yield of a single-tool approach vs. a multiple-tool(combined) approach, based on 10 studies(n=1572).Squares illustrate individual study ORs, with size proportional to study weight. The diamond represents the random-effects estimate.Heterogeneity was low(2=6.5%). Both pooled estimates indicated higher diagnostic yield with multiple tools[random-effects OR: 1.78(1.49-2.14), P<0.0001]."single tool" arm represents the diagnostic yield reported for the single highest-performing tool in each study,compared against the overall diagnostic yield achieved using all tools combined in the"multiple tools" arm.↑ Single-tool yield(TBBW+ Brushing: 103/132) were derived from 2 separate patient cohorts, explaining the different denominators.$ Single-tool yield(TBNA: 54/152) reflects only the subset of 172 total lesions where TBNA was performed and assessed(attempted in 153). Multitool yield(full work-up: 87/172) includes all lesions. The denominator mismatch arises because TBNA was not attempted in all cases. B(Recommendation 2). Diagnostic yield(conventional tools subset): multiple vs. single tools. Forest plot of 6 studies evaluating single vs. multiple conventional biopsy tools. The squares reflect each study's OR and 95% Cl; the diamond represents the random-effects pooled estimate. Heterogeneity was low(12=0.0%). The combined approach demonstrated superior diagnostic yield(random-effects OR: 1.64(1.33-2.02), P=0.0018."Single tool" arm represents the diagnostic yield reported for the single highest-performing tool in each study, compared against the overall diagnostic yield achieved using all tools combined in the"multiple tools" arm.↑ Single-tool yield(TBBW: 92/139) and multitool yield(TBBW+ Brushing: 103/132) were derived from 2 separate patient cohorts,explaining the different denominators.$ Single-tool yield(TBNA: 54/152) reflects only the subset of 172 total lesions where TBNA was performed and assessed(attempted in 153). Multitool yield(full work-up: 87/172) includes all lesions. The denominator mismatch arises because TBNA was not attempted in all cases. C(Recommendation 2). Cryobiopysis subset: multiple vs. single tools. Forest plot comparing single-tool to multiple-tool approaches specifically using cryobiopysis in 4 studies. Squares show study-level ORs with 95% Cls. The diamond represents the random-effects estimate. There was minimal heterogeneity(2=30.5%). Overall, using multiple tools with cryobiosply yielded a higher diagnostic success(random-effects OR: 2.06(1.10-3.88), P=0.0356." Single tool" arm represents the diagnostic yield reported for the single highest-performing tool in each study, compared against the overall diagnostic yield achieved using all tools combined in the"multiple tools" arm.

bronchoscopy. Incorporation of real-time imaging techni-ques such as digital tomosynthesis(DT) and cone-beam computed tomography(CBCT) has further enhanced procedural capabilities. ${}^{77}$

Summary of Evidence

Ten comparative studies(n= 2043) were included in the meta-analysis-7 retrospective and 3 prospective, including 2 randomized controlled trials(RCTs)(Supplementary Fig. S1,Supplemental Digital Content 1, http://links.lww.com/LBR/A364),3,5,6 All transthoracic interventions utilized CT guid-ance. Peripheral bronchoscopic procedures used rEBUS guidance in 6 studies and electromagnetic navigation in 3,1,2,8 Risk of bias varied, reflecting differences in study design and patient selection criteria.

(1) Diagnostic yield: The pooled yield for CT-TTNB proce-dures reached 87.0%, versus 67.0% for PNB. In our analysis, CT-TTNB had higher odds of diagnostic success[OR:3.24(2.20-4.79),P<0.0001;Fig.1A].1-10 Two RCTS,both utilizing rEBUS guidance, reported equivalent diagnostic rates compared with CT-TTNB(Fig. 1B).However, these RCTs were small and enrolled patients with relatively large lesions, averaging over 3 cm.3,5 In 5 studies that evaluated nodules≤2 cm, CT-TTNB main-tained a proportional diagnostic yield advantage of~20%over PNB.2,4,6-8 Fig.1C summarizes ENB studies, and relevant details of all studies appear in Table 2.

(2) Complications: Pheumothorax was the most common complication, occurring significantly more frequently with CT-TTNB procedures than with PNB, with a pooled risk difference of 0.18(0.12-0.25), P=0.0002(Fig.1D). Nine studies further stratified pneumothorax rates based on chest tube requirements. While the trend again favored PNB, the effect did not reach statistical significance[RD: 0.02(-0.00 to 0.05), P=0.096;Fig.1E].1,2,4,8,10

(3)Recent advances: A recently completed multicenter RCT(VERITAS) compared ENB with DT to CT-TTNB. This study demonstrated a 79% overall diag-nostic yield with ENB compared with 73.6% for CT-TTNB.74 However, CT-TTNB had a significantly higher risk of complications, including pneumothorax

requiring intervention(11.5% vs. 0.8% with PNB).When this trial was incorporated into the meta-analysis,CT-TTNB maintained a higher overall yield(85.7% vs.68.4% for PNB), though the gap narrowed relative to earlier data[OR: 2.64(1.53-4.56), P=0.0002; Fig. 1F].

Early data on robotic-assisted bronchoscopy(RAB)suggest improved diagnostic yields and reduced pneumo-thorax rates compared with earlier PNB modalities. A key difference between the VERITAS study and previous ENB studies was the addition of real-time intraprocedural imaging with DT. As technologies like CBCT become further integrated into PNB practice, the diagnostic yield gap between bronchoscopic and transthoracic biopsy modalities may further narrow. The additional cost and radiation exposure of these techniques warrant careful consideration.

Rationale

Although older data show CT-TTNB provides a higher diagnostic yield, newer bronchoscopic modalities and appli-cations may help achieve comparable yields while maintaining a lower risk of pneumothorax. Bronchoscopy also provides the flexibility of simultaneous mediastinal staging with CP-EBUS and multinode sampling in a single procedure. The panel's recommendation drew on a meta-analysis of existing literature largely reflecting older PNB technologies. However, the factors detailed above justify a more nuanced recommenda-tion, prompting an“Evidence-Informed” stance.

Implementation Considerations

● Clinical efficacy: Newer PNB modalities with real-time imaging may narrow the diagnostic gap with lower complications; additional data are needed.

● Multitarget capabilities: Bronchoscopy enables sampling of multiple lesions in one session(including additional lung nodules and CP-EBUS-guided lymph node staging).

● Combining procedures: PBN can be paired with CP-EBUS and surgical resection under a single anesthesia event, improving efficiency of lung cancer management.78

● Cost and resource utilization: Consider institutional resour-ces before large equipment and staffing investments.79

$\overline{J}\text{BroncholIntervPulmonol}\bullet\text{Volume\,32,\,Number\,4,\,October\,2025}$

AABIP Guidelines: Bronchoscopic Diagnosis, Staging

![A Study\nROSE\nEvents Total Events Total\nNo ROSE\nChen 2015\n242\n279\n385\n536\n43\n52\n2.57\n[1.73; 3.80]\n34.2% 32.0% 4.7% 4.0% 9.8% 40.8% 8.0% 10.15; 5.59] 7.7% 8.0% 2.54[1.15; 5.59] 7.7% 8.0% 10.62; 11.10] 4.3% 5.4%\nChen 2015\n2022\n242\n279\n385\n536\n43\n52\n1.74[0.57; 5.30] 1.61[0.79; 3.27] 3.21[2.27; 4.55] 3.21[2.15; 5.59] 7.7% 8.0% 4.24[1.62; 11.10] 4.3% 5.4%\nRandom effects model Prediction interval\nHeterogeneity: l^2=0.0%, t^2=0, p=0.4780\nFavors No ROSE Favors NO ROSE Odds Ratio (95% CI)\nB Study\nROSE\nNo ROSE Events Total Events Total\nLiu 2022\n25202\n477\n528\n393\n528\n274\n84\n105\n122\n0.1\n0.2\n0.5\n1\n2\n5\n10\nFavors No ROSE Favors NO ROSE Odds Ratio (95% CI)\nB Random effects model Prediction interval\nXud2022\nStudy 2023\n5025\n435\n525\n40058\nQi 2022\nLiu 2022\n50566084\n43552022\n84100\n75598\nQi 2022\n1.74[0.57; 5.30] 1.61[0.79; 3.27] 72.54\n1.15; 5.59] 2.54[1.15; 5.59] 31.9%\nQi 2022\n50566084\n2400\n224\n1.20\n1.93[1.20; 3.11] 1.93[1.02; 3.66] 100.0% 100.0% 100.0% 800.68\nFavors No ROSE Favors ROSE 95% -CI (common) Random results\nData Help\nRos\n0.1 0.2\n0.5 1\n2\n5\n10\nFavors No ROSE Favors ROSE 95% -CI (common) Random (95% CI)\n](2/aj0YEe4oUhYkBdfpda0fYP/figuree9fdc255cc1c45d8b0b11aafe67ceac3_0_2.png)  FIGURE 3.(A)(Recommendation 3). Diagnostic yield: ROSE vs. No ROSE(All Studies). Forest plot comparing rapid on-site cytologic evaluation(ROSE) vs. no ROSE in 6 studies(n=2710) for diagnostic yield. Individual ORS and 95% Cls are shown as squares with whiskers; the diamond is the random-effects pooled estimate. Heterogeneity was negligible( $l^{2}=0.0\%$ ). Overall, ROSE significantly improved diagnostic yield[random-effects OR: 2.71(2.06-3.58), P=0.0002].(B)(Recommendation 3). Diagnostic yield: ROSE vs. No ROSE(RCTs Only).Forest plot of 3 randomized controlled trials(RCTs) comparing ROSE with no ROSE for diagnostic yield. Squares display study-level ORS with 95% Cls; the diamond indicates the random-effects pooled estimate. Heterogeneity was negligible( $l^{2}=0.0\%$ ). The random-effects model suggests a significant benefit for ROSE[OR: 1.93(1.02-3.66), P=0.0475].(C)(Recommendation 3). Procedure duration(ROSE vs. No ROSE). Forest plot comparing procedure duration(mean difference, MD) in minutes for ROSE vs. no ROSE in 4 studies. Each square shows the study-specific MD with 95% Cl; the diamond represents the random-effects pooled estimate. Substantial heterogeneity was observed( $l^{2}=94.9\%$ ). Neither analysis showed a statistically significant difference in procedure time[random-effects MD:-1.11(-7.83 to 5.61), P=0.6368].

12|www.bronchology.com

Miller etal

TABLE 3. Summary of Included Studies: Single Versus Multiple Biopsy Tools for Peripheral Pulmonary Lesions

|References|Study design and sample size|Interventions/tools|Diagnostic yield (single best vs. all combined)|Complications/ adverse events|Key population / inclusion| |---|---|---|---|---|---| |Arimura et al (2017)11|Prospective; n=130 suspected lung CA|TBB + brush + TBNA|TBB 80% All 86.7% TBB 70.5% + BAL|Not described|● Mean lesion ~30 mm Adequate for molecular testing| |Boonsarngsuk et al (2015)12|12Prospective; n=112 PPLs|TBB + brush smear + cell block + rinse + BAL|TBB 70.5% All:80.4%|Pneumonia (1); no severe complications|● Mean lesion ~23.5 mm BAL also used for infection screening| |Kim et al (2023)13|Retrospective; n=110 PPNs ≤30 mm|TBB, Brush, TBNA (PeriView FLEX) + Cryobiopsy (1.1 mm)|Cryo 65.5% All: 79.1% TBB 66.2% All: 80.3%|PTX (1), infection (1), bleeding (9)|● Mean lesion ~22 mm ~8.6% had moderate bleeding requiring tamponade| |Kuo et al (2014)14|Retrospective; n=271 PPLs|TBB + Wash ± Brush|TBB 66.2% All: 80.3%|PTX (7), significant bleeding (22)|● Mean lesion ~35 mm Combined brushing/wash →+10% yield| |Matsumoto et al (2021)15|Retrospective; n=257 PPLs|TBB + TBNA + Brush + Cryobiopsy (1.9 mm)|Cryo 74.3% All 89.9%|Severe bleeding (3), PTX (2), abscess (2)|● Mean lesion ~23 mm +23 mm erin 9% incremental yield from adding cryobiopsy| |Oberg et al (2022)16|Retrospective; n=112 (robotic-assisted)|TBNA + TBB + Cryobiopsy (1.1 mm)|Cryo 88.3% All 90%|PTX (6), chest tube (3), bleeding (3)|● Mean lesion 22 mm High specimen adequacy with cryobiopsy| |Oki et al (2023)17|Prospective; n=50 PPNs ≤30 mm|TBB + Cryobiopsy (1.1 mm)|Cryo 62% All 74% TBB 43.2% All 50.6%|Minor bleeding in 94% (self-limited), 1, admission PTX (5), bleeding (2)|● Mean lesion ~18 mm Manageable cryo-related bleeding testin ● Tissue adequate for advanced testing| |Orr et al (2022)18|Prospective; n=324 PPLs|GenCut Core Needle + TBB|TBB 43.2% All 50.6%|PTX (5), bleeding (2)|● Tissue adequate for advanced testing| |Reichenberger et al (1999)19|Retrospective; n=172 PPLs|TBNA + TBB + wash + brush|TBB 35.5% All:50.6%|PTX (1), self-limited bleeds (12)|● TbNA significantly helps yield in certain sizes/locations| |Sumi et al (2021)20|Retrospective; n=51 PPNs ≤30 mm|Ultrathin + TBNA (PeriView FLEX) + TBB|TBB 72.5% All 86.3%|PTX (2), no chest tube|● Mean lesion ~23 mm ● TBNA + TBB synergy for “Adjacent” lesions|

BAL indicates bronchoalveolar lavage; Cryo, cryobiopsy; PPL, peripheral pulmonary lesion; PPN, peripheral pulmonary nodule; PTX, pneumothorax; TBB, transbronchial biopsy; TBNA, transbronchial needle aspiration.

$\overline{}$ Bronchol Intervul Pmonol $\bullet$ Volume 32, Number 4, October 2025

ABIP Guidelines: Bronchoscopic Diagnosis, Staging

Bronchoscopy CT-TTNB Events Total Events Total OR 95%-CI(common)(random)Study OR 95%-CI(common)(random)Bhatt 20183236415051.76[0.50; 6.22]44.5%39.1%Kunimasa 20228912174.88[1.33; 17.87]18.5%38.4%Zhu 2018778'0.28[0.03; 2.78]36.9%22.5%Common effect model 2021551.79[0.79; 4.04]100.0%Random effects model 1.72[0.07; 45.05]1.79[0.01; 45.05]Prediction interval[0.01;263.57]Heterogeneity: $I^{2}=57.0\%,\tau^{2}=0.8654,p=0.0977$ 0.050.51210 2010 203 Favors CT-TTNB Favors Bronchoscopy Odds Ratio(95% CI)

FIGURE 4.(Recommendation 4). Molecular testing adequacy- bronchoscopy vs. CT-TTNB. Forest plot of 3 studies(n=357) comparing adequacy for molecular testing in bronchoscopic samples vs. CT-TTNB specimens. Squares illustrate individual ORs and 95% Cl; the diamond represents the random-effects pooled estimate. Moderate heterogeneity $(P^{2}=57.0\%)$ . Neither model reached statistical significance favoring one approach over the other[random-effects OR: 1.72(0.07-45.05), P=0.55].

Recommendation 2: Evidence-Based(Meta-Analysis)

PICO Question

During bronchoscopic evaluation of indeterminate PPNs, should multiple biopsy tools, rather than a single biopsy tool, be used when sampling the lesion?

Recommendation

Consider using multiple biopsy tools, rather than a single tool, during bronchoscopy to sample indeterminate PPNs.

Background

Bronchoscopic sampling of PPNs has evolved since the introduction of flexible bronchoscopy in the 1970s.80 Traditional tools like transbronchial biopsy (TBB), trans-bronchial needle aspiration (TBNA), brushing, and bronchoalveolar lavage (BAL) offer complementary advantages. ${ }^{81,82}$ Forceps bioscopy may yield lower diagnos-tic rates in nodules without a "bronchus sign," 20 while needle-based approaches can sample airway-adjacent lesions more effectively. Cryobiopsy provides larger,better-preserved tissue samples. ${ }^{13}$

Summary of Evidence

A total of 10 studies(n=1572) comparing single-tool with multitool PPN sampling were included for pooled analysis (Fig. S2, Supplemental Digital Content 1, http://links.lww.com/LBR/A364). Overall, adding a second or third tool increased diagnostic yield from ~63% to ~73%, an absolute improvement of about 10% [OR: 1.78 (1.49-2.14),P<0.0001; Fig. 2A]. Table 3 provides further details of the included studies. ${ }^{11-20}$

In a subgroup analysis of 6 studies using only traditional tools (forceps, needle, and brush), multitool strategies again outperformed single-tool approaches [OR: 1.64 (1.33-2.02),$P=0.0018$; Fig. 2B].11,12,14,18-20 TBB was the highest-yield tool in 5 of the studies. Despite evidence elsewhere,82,83 only 1 of 4 studies using TBNA found it to be the top performer. ${}^{19}$

Cryobiopsy was utilized in 4 studies, and it was the highest-yield single tool for all 4 (range: 65% to 88%).Adding another tool increased yield by 2% to 14%. This was confirmed by a subgroup analysis (Fig. 2C), which favored using multiple tools over cryobiopsy alone [OR: 2.06 (1.10-3.88), P=0.036].13.15-17

Rationale

Despite heterogeneity across studies, the additional cost and time required for multiple tools are likely outweighed by the need to prevent repeat biopsy procedures after a nondiagnostic result. Lesion location appears to influence tool efficacy, with TBNA and cryobiopsy perform-ing better for lesions adjacent to the airway compared with TBB or brushing. Registry data(AQuIRE) show that TBB exclusively diagnosed~11% of cases, with TBNA adding an additional 6%.83 As demonstrated in the NAVIGATE trial,omitting either method from a multitool approach can significantly reduce true-positive rates.84

Implementation Considerations

● Diagnostic yield: A multitool approach should increase diagnostic yield by ~10% compared with a single tool,likely reducing costs and complications associated with repeat procedures.

● Performance comparison: Cryoprobe and TBNA may outperform TBB and brushing when lesions are adjacent to rather than within the airway. The primary tool's baseline yield influences the magnitude of the benefit(eg,2% to 17% gain).

● Individualized approach: A universal approach is likely unnecessary; tool choice should be individualized based on lesion location, size, onsite cytologic analysis, molecular marker needs, and oper-ator experience.

Recommendation 3: Evidence-Based(Meta-Analysis)

PICO Question

Should rapid on-site evaluation(ROSE) be used during bronchoscopy for the evaluation of indeterminate PPNs?

Recommendation

Consider using ROSE during bronchoscopy for non-surgical biopsy of indeterminate PPNs, based on local resource availability and clinical context.

Background

Prior investigations have established that ROSE improves both diagnostic yield and tissue optimization for ancillary testing

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/ Bronchol Intervon Pulmonol● Volume 32, Number 4, October 2025

|Time w/o ROSE|Time w/o ROSE|Time w/o ROSE|Time w/o ROSE|W(min) (min) (min) 27.8±4.7|17.4±3.4|17.4±3.4|17.4±3.4|17.4±3.4|15.4±5.7|15.4±5.7|15.4±5.7|15.4±5.7|15.4±5.7|15.4±5.7|15.4±5.7|15.4±5.7|15.4±5.7|15.4±5.7|15.4±5.7|15.4±5.7|||| |---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---| |W(min) (min)|W(min) (min)|W(min) (min)|W(min) (min)|W(min) (min)|W(min) (min)|W(min) (min)|W(min) (min)|W(min) (min)|W(min) (min)|W(min) (min)|W(min) (min)|W(min) (min)|W(min) (min)|W(min) (min)|W(min) (min)||||||||| |Time|||||||||||||||||||||||| |Time||||||||||||||||||||||||

during mediastinal lymph node sampling with CP-EBUS.85,86 However, its precise utility for peripheral pulmonary nodules(PPNs) remains less defined, owing to concerns regarding resource utilization, procedural cost, and potential extension of procedure time by on-site cytopathological review.87-90 More-over, it is uncertain how direct tool-in-lesion confirmation provided by contemporary localization technologies such as CBCT might impact the incremental value of ROSE.

Summary of Evidence

Six studies were analyzed(n=2710)-3 RCTs, 2 retro-spective studies, and 1 prospective observational investigation(Supplementary Fig. S3, Supplemental Digital Content 1,http://links.lww.com/LBR/A364).21-26 Meta-analysis demon-strated that ROSE significantly enhanced diagnostic yield compared with procedures without ROSE[OR: 2.71(2.06-3.58),P=0.0002; Fig. 3A]. Examination of the RCT subset revealed a significant benefit for ROSE[OR: 1.93(1.02-3.66),P=0.048; 0.0002; Fig. 3B]. Procedure duration showed negligible overall difference under random-effects analysis(Fig. 3C), with a mean difference of-1.11 minutes(-7.83 to 5.61), P=0.637 and high heterogeneity. Complication occurrence, including pneumothorax and mild hemoptysis, varied across studies. A summary of these studies is provided in Table 4.

Rationale

ROSE appears to enhance diagnostic yield without significantly extending procedural time. Nevertheless, sev-eral important contextual factors warrant consideration. All analyzed studies were conducted in Asian centers and amid increasing adoption of real-time imaging for“tool-in-lesion”confirmation. While ROSE offers immediate assessment of specimen adequacy, advanced imaging modalities may provide similar confidence of lesion access, potentially limiting ROSE's incremental benefit. Only 2 studies specifically utilized CT-TTNB, leaving this question unre-solved. Institutions with robust cytopathology services may derive particular value from ROSE implementation, espe-cially for high-risk diagnostic cases.

Implementation Considerations

● Staffing and workflow integration: ROSE requires a trained on-site cytopathologist(or tele-ROSE support)for timely slide preparation and interpretation.91,92

●Resource allocation analysis: Initial implementation costs require evaluation against potential reductions in repeat procedures.

● Expertise assessment: Centers lacking sufficient cytopa-thology personnel might explore tele-ROSE solutions or emerging artificial intelligence(AI)-driven cytology platforms.93

●Research priorities: Further investigation is warranted regarding the interaction between ROSE and intra-procedural advanced lesion localization technologies.

Recommendation 4: Evidence-Based(Meta-Analysis)

PICO Question

In patients with malignant PPNs, should bronchoscopy or CT-TTNB be used for obtaining tumor tissue for molecular analysis?

www.bronchology.com/15

TABLE 5. Bronchoscopy Versus TTNB for Molecular Analysis in Malignant PPNs

||Study design and comparison|Platform and handling|Genes interrogated|Dx yield for molecular analysis|Major complications|Key findings| |---|---|---|---|---|---|---| |Bhatt et al(2018)2|Retrospective; n=86(50 CT-TTNB, 36 ENB)|Sanger and allele-specific PCR; FISH(ALK); ISH(HER2)|EGFR; KRAS; BRAF; HER2 amplification; ALK fusion|CT-TTNB: 41/50 (82.0%) ENB: 32/36 (88.9%)|CT-TTNB: PTX 28.7%; bleed 16.7% ENB: PTX 4.0; bleed 3.3%|All 5 targets successfully assayed; ENB showed higher adequacy despite smaller samples| |Kunimasa et al(2022)27|Retrospective; n=116 (17 CT- TTNB, 99 TBB)|Oncomine Comprehensive Assay v3 (DNA+ RNA NGS; 161 genes); AllPrep extraction; Qubit QC; ROSE + H&E for bronchoscopy|161-gene DNA/RNA panel(SNVs, CNVs, fusions) ERX 87, ROSI|CT-TTNB: 12/17 (70.6%) TBB:82/99 (82.8%) CT-TTTA: 87/88 (98.9%) rEBUS-GS: 74/77 (96.1%)|Not reported 12/17 (70.6%) ET-TTTA: 87/88 (98.9%) REBUS-GS: 20.9% rEBUS-GS: PTX 0.7; hemorrhage 0.7%|Driver mutations in 54% overall (EGFR 24%, KRAS 11%, MET 3.5%); tissue- confirmation workflow improved adequacy| |Zhu et al(2018)28|Prospective; n=155 (88 CT TTNA, 77 rEBUS)|RT-PCR/ARMS; break-apart FISH|EGFR ex 18-21; ALK; ROSI|CT-TTTA: 87/88 (98.9%) rEBUS-GS: 74/77 (96.1%)|CT-TTTA: PTX 37.9; hemorrhage 20.9% rEBUS-GS: PTX 0.7% hemorrhage|EGFR mutations in 31 cases; ALK/ ROSI≤2%|

ARMS indicates amplification refractory mutation system; CNV, copy-number variation: CT-TTN, CT-guided Transthoracic Needle an Spiration; CT-TTN, CT-guided transthoracic needle biopsy; ENB,electromagnetic navigation bronchoscopy; FISH, Fluorescence; In Situ Hybridization; rEBUS-Gs, guide-shear radial endobronchial ultrasound; H&E, hematoxylin and eosin(stain); ISH, in situ hybridization; NGS next-generation sequencing; NSCLC, nonsmall cell lung cancer; PTX, pneumothorax; ROSE, rapid on-site evaluation; RT-PCR, reverse-transcriptase polymerase chain reaction; rEBUS, radial endobronchial ultrasound;SNV, single-nucleotide variant; TBB, transbronchial biopsy.

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Miller et al

TABLE 6. Levels of Systematic Staging for CP-EBUS-Guided Mediastinal Assessment

|Level of thoroughness|Definition|Key criteria/features|Rationale|| |---|---|---|---|---| |Targeted||Biopsy only nodal stations that appear morphologically abnormal (CT≥ 10 mm) or FDG avid.|- Sample every clearly abnormal node. - No biopsies from morphologically normal / PET-negative stations - Sample 4R, 4L, 7 (± 2R/2 L if feasible) when PET-positive or ≥ 5 mm short-axis on EUSB.|Simplifies staging \R≤| |sampling||Diagonal sampling of the core mediastinal chain in descending order N3 → N2 → N1 whenever a node is≥5 mm or PET-positive.|- Sample every clearly abnormal node. - No biopsies from morphologically normal / PET-negative stations - Sample 4R, 4L, 7 (± 2R/2 L if feasible) when PET-positive or ≥ 5 mm short-axis on EUSB.|Balances sensitivity and efficiency, recommended by multiple guidelines.102-104| |Minimum standard (systematic)|Sequential sampling of the core mediastinal chain in descending order N3 → N2 → N1 whenever a node is≥5 mm or PET-positive.|- feasible) when PET-positive or ≥ 5 mm short-axis on EUSB. - ≥ 3 passes or ROSE per nodal station* . Cease deeper sampling after a malignant higher-level node (optional). - Biopsy all nodes ≥ 5 mm plus < 5 mm if any suspicious sonographic traits. - Include hilar 10/11 when accessible.|- Increases sensitivity for occult N3 / disease at the cost of longer procedure time.101, 105-107|| |Thorough exam|As per Level 2, plus a systematic evaluation of every accessible mediastinal and hilar station (i.e., biopsy all nodes ≥ 5 mm and < 5 mm if sonographically suspicious) in the same N3 → N2 → N1 sequence.|- Include hilar 10/11 when accessible.|Increases sensitivity for occult N2/N3 /600.10, 105-107|| |Complete systematic staging|As per Level 3, plus posterior/inferior nodes accessed by EUS-B/EUS after the CP-EBUS sequence (adds stations 8 and 9; optional 5/6).|- All Level 3 steps, plus: - Switch to esophageal route after CP-EBUS to sample stations 8 & 9 (± 5/6).|Provides the highest sensitivity, detecting ~5-15% additional occult disease versus CP-EBUS alone, but requires dual modality skills and added time.30,104,108||

*With ROSE: the onsite cytologist may reduce unnecessary extra passes only after confirming both a definite diagnosis and enough cellularity for downstream testing (eg, molecular profiling). In practice that still means at least 3--and frequently 4 or more passes per nodal station. $^{192}$

↑Suspicious sonographic features for nodes <5 mm include: (1) round morphology (short to long axis ≈ 1); (2) sharply demarcated margin; (3) heterogeneous or mottled echotexture; (4) coagulation necrosis sign (avascular hypoechoic focus); (5) loss of central hilar structure; and/or (6) abnormal Doppler vascularity-grade II/III chaotic flow or bronchial artery inflow-adapted from Nakajima et al.109

CP-EBUS, convex-probe endobronchial ultrasound; EUS, endoscopic ultrasound; EUS-B, esophageal ultrasound performed with an EBUS scope; CT, computed tomography; FDG, fluorodeoxyglucose; N1/ N2/ N3,nodal Levels; PET, positron emission tomography; ROSE, rapid on-site cytologic evaluation.

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TABLE 7. Systematic Versus Targeted CP-EBUS

||Study design|Sample size|Key population|Tools/ interventions compared|Systematic definition|Targeted definition|Diagnostic yield/efficacy|Complications/ adverse events|Additional key outcomes| |---|---|---|---|---|---|---|---|---|---| |Block et al (2010)$29|Retrorespective cohort|93|NSCLC needing mediastinal staging|CP-EBUS # LN|LN $\geq$ 5 mm from stations tested|Only FDG-avid LN on PET/CT|Systematic sampling detected all mediastinal disease once $\geq 4$ LN stations were biopsised (60% found at 1st station; 90% by the third) 95% sensitivity vs. 80% CP- E BN $3\rightarrow N 1$|Not specifically reported|Feasibility of multistation sampling| |Cordovilla et al (2021)$^{30}$|Retrorespective cohort|45|iN0-N1 NSCLC|CP-EBUS $\pm$ EUS|LN $\geq$ 5 mm from N3 $\rightarrow$ N1 plus EUS if negative|CP-EBUS alone, suspicious LN only|CP-EBUS alone, EBS alone; EUS found extra 6.6% missed by CP- EBUS|No severe complications|Combining CP-EBUS +EUS beneficial in PET-CT-normal mediastinum Single scope systematic CP- EBUS+ EUS B detects one extra clinically important 100% at 100% patients| |Cordovilla et al (2019)$^{31}$|Prospective prospective multicenter|229|Suspected resectable NSCLC|CP-EBUS+EUS - netected CP- EBUS|LN $\geq$ 8 mm in stations 2R,2L,4R,4L,7 nodes|Sample only PET/ CT abnormal nodes|Sensitivity $\sim 73\%$ targeted $\rightarrow$ 77% systematic (+4%) $\rightarrow$ 82% EBUS + EUS B +9%); clinically relevant extra info in 10% of patients|Not specifically reported|Combining CP-EBUS +EUS beneficial in PET-CT-normal mediastinum Single scope systematic CP- EBUS + EUS B detects one extra clinically important 100% at 100% patients| |Evison et al (2016)$^{32}$|Prospective multicenter|642|NSCLC, pre/ post ESTS quality standard|CP-EBUS with or w/o formal LN sampling|Minimum of 3 LN stations (4R,4L,7) targeted|Only LN suspicious on imaging|Sensitivity $\sim 85\%$ ; only 16% met $\geq 3$ station sampling; no overall sensitivity improvement|Not reported|Standardization reduced variability, but not absolute sensitivity| |Sanz-Santos et al (2018)$^{34}$|Retrospective|107|NSCLC with PET- suspected N2|Systematic CP- EBUS vs. hypothetical targeted|LN $\geq$ 5 mm from on PET-CT terminalal N3 $\rightarrow$ N1|LN if FDG-avid on PET-CT|94% sensitivity, 96% accuracy, discovered 13% additional N3/N2b vs. targeted|1.8% complication rate|Systematic approach changed management by revealing more advanced disease| |Serra et al (2020)$^{35}$|Retrospective|174|cN0-N1 NSCLC|Systematic CP- EBUS|LN $\geq$ 5 mm from contralateral (N3) to N1 LN|Not applicable|12% unsuspected N2; 0% N3; 3% sensitivity 84%, specificity 100%, NPV 96.7%|No major complications No serious CP- EBUS changed rate|High negative predictive value for cN0-N1| |Steinfort et al (2024)$^{36*}$|Prospective multicenter|155|Locally advanced (cIII) NSCLC for RT|Systematic CP- EBUS $\pm$ EUS-B vs. PET-based staging|LN $\geq$ 6 mm from LN vs. PET-based staging|Only FDG-avid LN $|~12% had suspected N2; 0% N $3\rightarrow N1$ N $100\%$ , NPV 96.7%|No serious CP- EBUS-related events|Endosonography more accurate than PET alone for RT planning| |Sullivan et al (2022)$^{37}$|Prospective RCT|38|cN0-N1 NSCLC needing CP- EBUS staging|Targeted (omit T triple-normal LN) vs. systematic|LN stations 4R, 4L, 7 Systematically|Skip LN if normal by CT, PET, CP-EBUS stage|Missed disease 5.45% (targeted) vs. 0% (systematic); procedure time 3 vs. 19 min|No adverse events reported|Feasibility data for omitting biopsy in “triple-normal” LN|

*Study published after the March 2023 literature search cutoff; included by post-hoc panel consensus due to high relevance and impact.

CP-EBUS indicates convex probe endobronchial ultrasound; EUS, endoscopic ultrasound; EUS-B, endoscopic ultrasound performed with an EBUS scope; LN, lymph node; FDG, fluorodeoxyglucose; iN0: Imaging node-negative; cN0: Clinically node-negative; PET-CT, positron emission tomography-computed tomography; NSCLC, nonsmall cell lung cancer; N2/N3, advanced nodal disease; ESTS, European Society of Thoracic Surgeons; NPV, negative predictive value; RCT, randomized controlled trial; RT, radiotherapy.

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J/ Bronchol Intervent Pulmonol● Volume 32, Number 4, October 2025

![Study\nEBUS only Events Total\nEBUS + Med Events Total\nRisk Difference\nRD\n95%–CI (common) (random)\n0.010 [-0.049;0.070] 51.5% 44.1% 0.020 [-0.071;0.112] 14.7% 18.8% 0.052 [-0.013;0.118] 33.8% 37.0% 0.026 [-0.014;0.066] 100.0% 0.028 [-0.031;0.086] 100.0% 0.028 [-0.059;0.115] 0.059; 0.115] 0.4\nBousema 2023\n15\n171\n12\n155\nLucena 2023\n3\n47\n4\n2\n4\n1\n0\n9\n2\n4\n6\n1\n0\n0.020 [-0.071;0.112] 14.7% 18.8% 0.052 [-0.013;0.118] 33.8% 37.0% 0.026 [-0.014;0.066] 100.0% 0.028 [-0.031;0.086] 100.0% 0.028 [-0.059;0.115] 10\n0.059; 0.115] 0.4\n0.026 [-0.014;0.066] 100.0% 0.028 [-0.031;0.086] 100.0% 0.028 [-0.059;0.115] 10\n0.059; 0.115] 0.4\n0.026 [-0.031;0.086] 100.0% 0.028 [-0.059;0.115] 10\n0.059; 0.115] 10\n0.059; 0.115] 10\n0.059; 0.115] 10\n0.059; 0.115] 10\n0.059; 0.115] 10\n0.059; 0.115] 10\n0.059; 0.115] 10\n0.059; 0.115] 10\n0.059; 0.115] 10\n0.059; 0.115] 10\n0.059; 0.115] 10\n0.059; 0.115] 10\n0.059; 0.115] 10\n0.059; 0.115] 10\n0.059; 0.115] 10\n0.059; 0.115] 10\n0.059; 0.115] 10\n0.059; 0.115] 10\n0.059; 0.115] 10\n0.059; 0.115] 10\n0.059; 0.115] 10\n0.059; 0.115] 10\n0.05\n](2/aj0YEe4oUhYkBdfpda0fYP/figure783c4966200146429994bc012edc5417_0_2.png) FIGURE 5.(Recommendation 6). Missed N2/N3 Disease-EBUS-only vs. combined approach. Forest plot assessing the risk difference(RD) in missed N2/N3 nodal disease when using CP-EBUS-only staging versus a combined approach, across 3 studies(EBUS only n=328;combined n=305; total across arms n=633; 562 unique patients). Squares denote study-level RDs with 95% Cls. The diamond represents the random-effects pooled estimate. Heterogeneity was minimal $(\bar{I}^{2}=0.00\%)$ . There was no statistically significant difference in missed N2/N3 disease between CP-EBUS alone and a combined strategy[RD: 0.03(-0.03 to 0.09), P=0.18].

Recommendation

We make no recommendation regarding the use of PNB versus CT-TTNB specifically to obtain tumor tissue for molecular analysis in patients with malignant PPNs.

Background

Efficient and comprehensive tumor characterization at diagnosis is critical for maximizing the benefits of targeted and immunotherapies. As personalized treatments advance into earlier-stage disease, minimally invasive diagnostic methods must reliably provide adequate samples for genetic and molecular testing. Insufficient tissue can delay or compromise optimal management.

Summary of Evidence

A meta-analysis of 3 studies $(n=357,\text{ Fig. S4},$ Supplemental Digital Content 1, http://links.lww.com/LBR/A364) comparing PNB with CT-TTNB for providing adequate tumor tissue for molecular analysis showed no significant difference between the approaches [OR: 1.72(0.07-45.05), P=0.55, Fig. 4].2,27,28 The overall evidence certainty was considered very low due to heterogeneous methods, small sample sizes, and nonrandomized designs(Table 5). All 3 studies reported comparable success rates,with bronchoscopy showing a small nonsignificant advant-age in 2,27 and CT-TTNB in the third.28 Tissue adequacy for molecular testing exceeded 90% in both groups.

Rationale

<BeginOfPara>On the basis of this limited evidence, PNB and CT-TTNB appear to have high and comparable tissue adequacy rates for molecular studies, though these results apply to cases with positive biopsies.(For detailed discussion of diagnostic efficacy,see Recommendation 1.) While CT-TTNB might yield larger core samples for molecular testing, tissue adequacy depends on multiple factors, such as tumor size, location, necrotic proportion, and procedural aspects, including needle choice,number of passes, and efficiency of immunohistochemical staining.94-96 This suggests the specific method (bronchoscopic or transthoracic) may be less important than optimizing lesion selection, procedural protocols, and operator expertise.94,97-100 Randomized trials are needed to clarify which approach

<EndOfPara>provides the best balance of diagnostic yield, tissue adequacy for molecular marker testing, safety, and cost-effectiveness.

Implementation Considerations

● Choice of sampling approach: Limited evidence suggests no clear advantage for either modality; choice should be guided by the likelihood of obtaining adequate diagnostic material with minimal patient risk.

● Concurrent mediastinal evaluation: Bronchoscopy may be preferable when mediastinal staging (CP-EBUS) is required in the same procedure.

● Advanced molecular panels: Both approaches can achieve advanced molecular diagnostics in experienced hands. Careful attention to patient selection and proce-dural details(including multiple passes and meticulous tissue handling) is crucial.

● Future directions: Additional high-quality, prospective data are needed to define the optimal tissue acquisition strategy for molecular testing.

Recommendation 5: Evidence-Informed(Systematic Review)

PICO Question

Does systematic CP-EBUS evaluation improve impor-tant clinical outcomes compared with targeted CP-EBUS evaluation in patients with presumed lung cancer?

Recommendation

Use a systematic staging examination, rather than examining only radiographically suspicious lymph nodes,during CP-EBUS for mediastinal staging in presumed lung cancer.

Background

Studies reveal significant variability in the thorough-ness of CP-EBUS-directed mediastinal staging across centers and operators.34,101,102 This variation can lead to missed occult metastases in normal-sized or nonfluoro-dyosegluocine(FDG)-avid nodes, potentially affecting treatment decisions and outcomes.29,32 Guidance is needed about the extent of CP-EBUS evaluation required to

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AABIP Guidelines: Bronchoscopic Diagnosis, Staging

||||||||| |---|---|---|---|---|---|---|---| |Complications AES|Complications AES|Complications AES|Complications AES|Major morbidity 1.2%(immediate) vs.15.4%(Mede) None|||| |NZ3N|missed by EUS-BUS CP-EP-BUS CPM|1.9%(15)|91.5%|49.1|No EBUS-Related (minmediate) non-catalytic diagnosis (2.6%)||19.1| |NZ2N3|one BUS-BUS CPM|1.7%(15)|7.7%(15)|49.2|19.9||10.4%| |NZ2N3|one BUS-BUS CPM|1.8%(15)|8.8%(15)|6.4%(34/4)|4.3%(24/6)||10.9(10)| |NZ2N3|one BUS-BUS CPM|1.8%(15)|7.7%(15)|6.4%(34/4)|4.3%(24/6)||11.1(10)| |NZ2N3|one BUS-BUS CPM|1.8%(15)|8.8%(15)|6.4%(34/4)|4.3%(24/6)||11.1(10)| |NZ2N3|one BUS-BUS CPM|1.8%(15)|8.8%(15)|6.4%(34/4)|4.3%(24/6)||10.9(10)| |NZ2N3|one BUS-BUS CPM|1.8%(15)|7.7%(15)|6.4%(34/4)|4.3%(24/6)||11.1(10)| |NZ2N3|one BUS-BUS CPM|1.8%(15)|8.8%(15)|6.4%(34/4)|4.3%(24/6)||11.1(10)| |NZ2N3|one BUS-BUS CPM|1.8%(15)|8.8%(15)|6.4%(34/4)|4.3%(24/6)||10.9(10)| |NZ2N3|one BUS-BUS CPM|1.8%(15)|7.7%(15)|6.4%(34/4)|4.3%(24/6)||11.1(10)| |NZ2N3|one BUS-BUS CPM|1.8%(15)|8.8%(15)|6.4%(34/4)|4.3%(24/6)||11.1(10)| |NZ2N3|one BUS-BUS CPM|1.8%(15)|8.8%(15)|6.4%(34/4)|4.3%(24/6)||10.9(10)| |NZ2N3|one BUS-BUS CPM|1.8%(15)|8.8%(15)|6.4%(34/4)|4.3%(24/6)||11.1(10)| |NZ2N3|one BUS-BUS CPM|1.8%(15)|8.8%(15)|6.4%(34/4)|4.3%(24/6)||11.1(10)| |NZ2N3|one BUS-BUS CPM|1.8%(15)|8.8%(15)|6.4%(34/4)|4.3%(24/6)||11.1(10)| |NZ2N3|one BUS-BUS CPM|1.8%(15)|8.8%(15)|6.4%(34/4)|4.3%(24/6)||11.1(10)| |NZ2N3|one BUS-BUS CPM|1.8%(15)|8.8%(15)|8.8%(10)|||11.1(10)| |NZ2N3|one BUS-BUS CPM|1.8%(15)|8.8%(15)|8.8%(10)|||11.1(10)| |NZ2N3|one BUS-BUS CPM|1.8%(15)|8.8%(15)|8.8%(10)|||11.1(10)| |NZ2N3|one BUS-BUS CPM|1.8%(15)|8.8%(15)||||11.1(10)| |NZ2N3|one BUS-BUS CPM|1.8%(15)|8.8%(15)||||11.1(10)| |NZ2N3|one BUS-BUS CPM|1.8%(15)|||||11.1(10)| |NZ2N3|one BUS-BUS CPM|1.8%(15)|||||11.1(10)| |NZ2N3|one BUS-BUS CPM|1.8%(15)|||||11.1(10)| |NZ2N3|one BUS-BUS CPM|1.8%(15)|||||11.1(10)|

<EndOfPara>optimize mediastinal staging in the setting of possible lung cancer.

Levels of Thoroughness for Mediastinal Staging

CP-EBUS[and when applicable, endoscopic ultra-sound(EUS)] sampling for staging purposes can be categorized into 4 levels of breadth: targeted sampling,minimum standard(Systematic), thorough exam, and complete systematic staging. These range from sampling only abnormal or highly suspicious lymph nodes to sampling any lymph node in every accessible station through both CP-EBUS and EUS(Table 6).30,34,102-109

While debate persists about whether more exhaustive staging justifies the added procedural complexity, consensus exists that at least the “Minimum Standard” (ie, systematic)approach should be performed in most cases. More extensive methods might be reserved for higher-risk scenarios.30,110

Summary of Evidence

A systematic review identified 5 articles for qual-itative synthesis, but criteria for pooled analysis were not met(Fig. S5, Supplemental Digital Content 1, http://links.lww.com/LBR/A364). Consequently, a broader review discovered 8 studies of variable methodology that demonstrated consistent findings: systematic CP-EBUS approaches detect 5% to 15% more occult N2/N3 disease compared with targeted sampling.29,31,34 Even among patients with a radiographically normal mediastinum(cN0-N1), occult nodal metastases can occur in up to 24% of cases.30,35 Although sampling multiple nodal stations may slightly prolong procedures, it helps avoid missing disease that could alter treatment plans.29,32,36 One small feasibility RCT suggested that deferring biopsy of“triple-normal” lymph nodes(normal size, no PET uptake, negative ultrasound features) might be safe, but larger trials are needed to confirm this approach.37 Table 7 provides more details on relevant studies.

Rationale

While evidence supporting systematic CP-EBUS stag-ing comes largely from retrospective and observational studies, findings consistently suggest increased detection of nodal metastasis with systematic sampling compared with targeting only suspicious nodes. Patients with radiograph-ically normal mediastina may still harbor occult disease, and earlier identification can significantly influence treatment decisions. Though systematic staging demands greater technical skill and adds procedural time, it improves overall staging accuracy, alters treatment plans, and decreases the risk of discovering unexpected N2/N3 disease during surgery.

Implementation Considerations

● Standardization requirements: Systematic CP-EBUS necessitates comprehensive massive mediastinal anatomic knowl-edge and adherence to standardized protocols.32,34

● Competency considerations: Systematic mediastinal stag-ing requires more advanced training than targeted sampling. Not all CP-EBUS operators need full com-petency in systematic staging but should clearly docu-ment the sampling approach used.

● Resource implications: Sampling additional stations increases procedural time, sedation requirements, and overall costs. High-volume centers typically demonstrate

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/ Bronchol Intervent Pulmonol● Volume 32, Number 4, October 2025

Study 30cm 53cm 95%-CI(common)(random)Study Events Total 87& 66& 0.07[-0.04; 0.19]+14.9%9.7%Cho 2018 3 432 2030.06[-0.02;0.14]+14.1%21.3%Farjah 2013 40 44904490.05[-0.01;0.10]+50.3%39.0%Gao 2017 78231410.06[-0.00;0.13]20.6%30.1%Common effect model 38885950.06[0.02;0.09]100.0%Random effects model 0.06[0.04;0.07]-0.00;0.07]Prediction interval[-0.00;0.12]{-0.4}-0.20.20.4$0.2$0.4$Lower Risk≤3cm Higher Risk>3cm Risk Difference(95% CI)

FIGURE 6.(Recommendation 7). Lesion size $\leq 3$ cm vs.> 3 cm. Forest plot of risk differences(RDs) in a dichotomized lesion size comparison(>3 cm vs.≤3 cm) across 4 studies(n=1247). Squares denote individual study estimates with 95% Cls; the diamond represents the random-effects pooled estimate. No heterogeneity was detected(2=0.0%). Overall, the larger lesion size group(>3 cm)had a higher event rate[RD: 0.06(0.04-0.07), P=0.0016].

better adherence to systematic sampling and improved staging performance. ${ }^{30}$

● Patient selection criteria: Systematic CP-EBUS is gen-erally recommended for patients with abnormal lymph nodes on imaging, central tumors, or tumors larger than 3 cm, given a higher risk for nodal metastases.110,111 Systematic staging may be omitted in select cases, such as small peripheral T1N0 lesions without CT/PET abnor-malities or when there is obvious mediastinal infiltration(in which specific nodal sampling is less relevant).111

Impact of the 9th Edition TNM Classification

New categories: The 9th edition International Association for the Study of Lung Cancer(IASLC) Tumor, Node, Metastasis(TNM) system distinguishes between single-station (N2a) and multistation (N2b) involvement, reinforcing the importance of comprehensive mediastinal staging. $112,113$

Impact on sampling approach: Under older guidelines,operators may have concluded CP-EBUS staging after confirming one positive N2 station by ROSE. Changes with the 9th edition emphasize the need to sample additional N2 nodes regardless of the initial ROSE result to distinguish between single-station and multistation disease. ${}^{113}$

Practical changes:

ROSE and fresh needles may be increasingly used to reduce cross-contamination once a malignant node is identified.

Future protocols may require systematically sampling all N2 stations rather than stopping at the first positive station to ensure accurate staging, prognosis, and treatment decisions.

Recommendation 6: Evidence-Based(Meta-Analysis)

PICO Question

Should mediastinoscopy be performed after a negative CP-EBUS in patients with risk factors for occult mediastinos disease but no overt radiographic involvement?

Recommendation

Do not routinely offer preoperative surgical mediastino-scopy to patients with a negative CP-EBUS-guided media-stinal staging examination who have risk factors for occult N2/N3 disease but no overt radiographic involvement.

Background

Accurate mediastinal staging is crucial for guiding NSCLC treatment. While cervical mediastinoscopy was once the gold standard for preoperative invasive staging,CP-EBUS has largely replaced it, demonstrating compara-ble accuracy with lower morbidity.110,111,114 The negative predictive value of CP-EBUS varies across studies and settings. Very high-probability lymph nodes(large and FDG-avid) with a negative CP-EBUS result(no cancer or an alternative diagnosis like granuloma) should be followed by mediastinoscopy for confirmation. However, there is less clarity regarding confirmatory mediastinoscopy in patients at high-risk of occult disease(eg,cN1 nodes, central tumors,or lesions larger than 3 cm). Balancing the small false-negative risk of CP-EBUS against the costs, risks, and potential surgical delays associated with mediastinoscopy is key.

Summary of Evidence

Three studies(n=562) were identified for quantita-tive synthesis(Fig. S6, Supplemental Digital Content 1,http://links.lww.com/LBR/A364)-1 RCT38 and 2 high-quality prospective observational study(Table 8).39,40 The studies evaluated immediate surgical resection versus confirmatory mediastinoscopy after negative CP-EBUS staging. CP-EBUS generally demonstrated relatively high negative predictive values exceeding 90%. In the largest study by Bousae et al,38 unforeseen N2 disease was discovered in 8.8% of patients undergoing immediate resection compared with 7.7% in those undergoing mediastinoscopy, indicating CP-EBUS alone was non-inferior to combined CP-EBUS and mediastinoscopy.Similarly, Lucena et al39(2023) noted only a 2%additional detection rate with mediastinoscopy in a population with moderate risk for occult metastasis.Finally, Yasufuku et al40(2011) observed similar sensi-tivity(81% vs. 79%) and negative predictive value(91%vs. 90%) when comparing CP-EBUS alone to CP-EBUS plus mediastinoscopy. With pooled analysis, there was no significant difference in missed N2/N3 disease between the 2 approaches [RD: 0.03(-0.03 to 0.09), P=0.18, Fig. 5].The number needed to treat (NNT) ranged from 24 to 77,underscoring limited clinical benefit from adding media-stinoscopy in this patient population.

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AABIP Guidelines: Bronchoscopic Diagnosis, Staging

|Tumor|Key findings|Key findings|Key findings|Key findings| |---|---|---|---|---| |Tumor|Key findings|33 cm (n)|7.54 [1,224-4657] 1.61 [0,942.71] 8.9% 2.1%|Risk rose with tumor size.| |$$\leq 3\,cm\,(n)\,U_{2}^{2}$$|12.1%|1.0%|8.9% 2.1%|| |$$\leq 3\,cm\,(n)\,U_{2}^{2}$$|66|203|449|| |$$\leq 3\,cm\,(n)\,U_{2}^{2}$$|19.5%|7.0%|13.6%|| |$$\geq 3\,cm\,(n)\,U_{2}^{2}$$|43|176|8.5%|| |$$\begin{array}{l}\\ \\ \\ \\ \\ \\ \\ \\ \\ \end{array}$$|5|176|82|| |$$\begin{array}{l}\\ \\ \\ \\ \\ \\ \\ \\ \\ \end{array}$$|CT|43|176|| |Study Study|295|19.5% 3 cm (n)|87 43||

Rationale

Although mediastinoscopy may slightly increase the detection of occult mediastinal disease, its additional yield remains small. Given procedural risks, costs, and potential surgical delays, most patients with negative CP-EBUS and no overt radiographic mediastinal disease will not benefit from routine preoperative mediastinoscopy. Instead, surgi-cal resection with intraoperative lymph node dissection is generally preferred. Confirmatory mediastinoscopy may be selectively performed for patients with particularly high-risk imaging features(eg, intense FDG-avid nodes) or incom-plete CP-EBUS examination.

Implementation Considerations

● Patient selection: Reserve mediastinoscopy for cases with discordant CP-EBUS-to-imaging results(eg, nondiagnos-tic CP-EBUS of large or FDG-avid lymph nodes in a high-risk patient) or suspicious findings not thoroughly sampled by CP-EBUS.

●CP-EBUS protocol: A systematic CP-EBUS-guided approach(sampling multiple nodal stations) should be performed to minimize false negatives; see Recommen-dation 5 for details.

● Resource utilization: In centers with high CP-EBUS expertise, routine mediastinoscopy offers minimal added value and can be safely omitted.

●Postoperative management: If unexpected N2/N3 disease is discovered after resection, established adjuvant therapy protocols apply.

Recommendation 7: Evidence-Based(Meta-Analysis)

PICO Question

Does tumor size using a 3 cm cutoff affect the likelihood of occult mediastinal metastasis in patients with peripheral tumors and a radiographically normal hilum and mediastinum?

Recommendation

Clinicians should recognize a primary tumor size>3 cm as a significant risk factor for occult mediastinal metastasis and consider invasive nodal staging in patients with peripheral tumors and a radiographically normal hilum and and mediastinum.

Note: This recommendation includes risk-stratification guidance rather than a direct "use/do not use" statement.The following uses NICE's "Consider" to convey that invasive nodal staging should be individualized based on tumor size and clinical context.

Background

While there is general agreement among societies and previous guidelines regarding the indications for invasive lung cancer staging, contention exists about how primary tumor size impacts risk for occult mediastinal involvement.According to the 2013 ACCP guidelines, tumor size is not an independent criterion for invasive staging, while the 2014 European Society of Thoracic Surgeons(ESTS) guidelines specifically include tumor size>3 cm as an indication. ${}^{110,111}$

Summary of Evidence

A meta-analysis of 4 retrospective cohort studies(n=1247; Table 9) found a significantly higher risk of occult

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TABLE 10. Key Studies Examining LN Metastasis in Ground-Glass and Subsolid Nodules

|Study|Design / Sample Size|Population / Inclusion|Nodule Characteristics|LN Metastasis Rate|Key Findings| |---|---|---|---|---|---| |Hayashi 2017120|Retrospective; n=188|Pathologic T1 adenocarcinoma $\leq 3\,cm$|Solid component on mediastinal-window CT $\leq 5\,mm$ vs. $>5\,mm$|0% when solid$\leq 5\,mm$|Nearly pure-GGO lesions show no nodal spread;solid thickness is the critical predictor.| |Lin 202046|Retrospective; n=768|Stage I lung adenocarcinoma with any GGO|Pure-GGO, GGO-predominant(CTR\leq 0.5), Solid- predominant(CTR>0.5) GGO-predominant vs. Solid-predominant|0%/3.8%/6.9% . 0.8% vs.10.9%|Pure-GGO group had zero LN spread; risk rises with increasing solid ratio; lymphadenectomy may be unnecessary for pure-GGO. LN-positive disease restricted to solid- predominant tumors; mediastinal LN evaluation provides no benefit in GGO- predominant cases.| |Moon 201647|Retrospective; n=358|cT1N0M0 NSCLC $\leq 3\,cm$|Pure-GGO only|0%|Systemic node sampling revealed no nodal involvement in any pure-GGO patient.| |Sim 201448|Retrospective; n=48|Surgically resected pure GGO nodules(median 12 mm) GGO-dominant(>3 cm total size)|CTR $\leq 0.25$ (Type A), 0.25-0.5 (Type B), 0.5 (Type C)|0%(Types A\& B);32% in Type C|Even large(>3 cm) GGO-dominant lesions remain node-negative until the solid portion exceeds 50%.| |Wang 202050|Retrospective; n=327|Stage IA peripheral adenocarcinoma presenting as GGO|Pure-GGO, GGO- predominant, Solid-dominant, Pure-solid|0%/0% /7.5%/14.9% (pooled); 0.0-1.5% vs 30.4% (pooled); 0% vs 6.6% (own cohort)|All LN-positive cases occurred in lesions with substantial solid components.| |Xu51 2023|Two-center retrospective cohort n=864+ pooled review(35 studies)|NSCLC≤3 cm (pure & semisolid GGOs)|CTR≤0.5 vs. >0.5|0-0.1% vs 30.4% (pooled); 0% vs 6.6% (own cohort)|Large, pooled data set confirms near-zero LN risk below CTR 0.5 and sharp rise above that threshold.| |Ye 201952|Retrospective; n=911|Stage I adenocarcinoma (part-solid, pure-GGO, pure-gGO, pure-solid) Invasive NSCLC up to 5 cm|Part-solid, Pure-GGO, Pure-solid, Pure-solid CTR≤0.5 vs. >0.5|2.2% /0% /27% 0% vs.24.1%|Part-solid nodules carry modest LN risk; pure-GGO again zero. Large series demonstrating CTR≤0.5 as a reliable surrogate for node-negative status.|

cT1N0M0 indicates clinical T1 N0 M0 stage(TNM classification); CT, computed tomography; CTR, consolidation-to-tumor ratio(solid-portion diameter÷ overall lesion diameter); GGO, ground-glass opacity; LN,lymph node; NSCLC, nonsmall cell lung cancer.

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N2 disease in peripheral NSCLC tumors>3 cm compared with those≤3 cm[RD: 0.06(0.04-0.07), P=0.0016, Fig. 6].Across individual studies, unsuspected N2 prevalence ranged from~3% to 19%. Other reports suggest alternate size cutoffs(eg,2.5 cm) or note additional risk factors, including subsolid lesions and adenocarcinoma subtype.7,115-117 Relevant liter-ature review and quality evaluations are summarized in Supplementary Figure S7, Supplemental Digital Content 1,http://links.lww.com/LBR/A364.

Rationale

Larger tumors generally demonstrate more aggres-sive biological behavior and increased lymphatic spread.43 Conventional imaging often fails to detect micrometa-static disease in tumors>3 cm.44 Adopting the 3 cm threshold aligns with TNM staging and helps ensure that higher-risk patients receive thorough nodal assessment.Subgroup analyses suggest features like central location,lower-lobe position, or large solid components further elevate risk.42

Implementation Considerations

● Patient selection: Tumors larger than 3 cm should be considered an independent criterion for invasive media-stinal staging, even in the absence of other known risk factors for mediastinal metastasis.

● Additional risk factors: Other risk factors, such as suspicious N1 uptake and central tumor location, further heighten concern for nodal involvement.

Future directions: Emerging AI and radiomics approaches may refine thresholds for invasive staging and risk stratification.

Recommendation 8: Evidence-Informed(Systematic Review)

PICO Question

Should invasive mediastinal staging be performed for patients with pure ground-glass nodules(GGNs) and a radiographically normal mediastinum?

Recommendation

Do not routinely offer invasive mediastin staging for patients with pure GGNs and a radiographically normal mediastinum by CT and PET scan.

Background

GGNs are increasingly detected through incidental findings and screening programs.118 Most pure GGNs represent preinvasive or minimally invasive adenocarcinomas with an indolent course and favorable prognosis.119 Current guidelines focus on tumor size, location, and suspicion of N1 disease to assess a patient's need for mediastinal staging, but offer limited attention to nodule density.110,111 Aggressive staging practices for low-risk lesions such as GGNs may lead to unnecessary invasive procedures.

Summary of Evidence

A systematic review was conducted(Supplementary Fig. S8, Supplemental Digital Content 1, http://links.lww.com/LBR/A364). Three studies were included in the qualitative synthesis, with only one providing quantitative data. A broader review of 9 retrospective studies(n=48 to 2749) consistently demonstrated negligible or absent

mediastinal lymph node(LN) metastases(0\% to 1\%) from pure GGNs.46-53,120 In contrast, part-solid nodules showed a slightly higher-though still low-metastatic LN inci-dence(~1.6% to 8%), particularly in nodules with larger solid components[consolidation-to-tumor ratio(CTR)>0.5]. Table 10 summarizes these findings, illustrating near-zero metastasis risk for pure GGNs and highlighting the low, yet higher, risk in part-solid nodules.

Rationale

Pure GGNs typically represent preinvasive or mini-mally invasive adenocarcinomas with a very low chance of lymphatic spread, rendering additional invasive staging(CP-EBUS, mediastinoscopy) unlikely to alter management.Part-solid nodules with CTR≤0.5 similarly show very low LN metastatic potential. However, part-solid nodules with CTR>0.5 demonstrated substantially greater risk and generally warrant standard staging approaches.

Implementation Considerations

Accurate radiologic assessment: Use high-resolution thin-section CT to precisely measure the nodule's total diameter and the solid component, thus determining the CTR.

Risk stratification: Invasive staging can likely be omitted for pure ground-glass nodules or those with a small solid component(CTR $\leq 0.5$ ). Conversely, if CTR is $>0.5$ or CT/PET suggests nodal disease, standard mediastinal staging (CP-EBUS, mediastinoscopy) should be performed.Multidisciplinary coordination: Ensure standardized termi-nology and measuring techniques are used by radiologists,thoracic surgeons, and oncologists regarding CT.Future Directions: AI and radiomics may improve risk stratification and refine invasive staging thresholds.

Future Directions: AI and radiomics may improve risk stratification and refine invasive staging thresholds.

Recommendation 9: Evidence-Informed(Systematic Review)

PICO Question

Should CP-EBUS be performed to detect occult N1 disease before osteaticoroid body radiation therapy(SBRT) in patients with early-stage NSCLC?

Recommendation

We make no recommendation regarding the routine use of CP-EBUS to detect occult N1 disease before SBRT in patients with early-stage NSCLC who do not meet criteria for invasive staging.

Background

SBRT is a favored treatment option for many patients with early-stage NSCLC, particularly those who have significant comorbidities or may not be suitable surgical candidates. While outcomes for well-selected SBRT candidates are typically excellent, roughly 10% to 20% will develop locoregional recurrence.121,122 A primary difference between these patients and those undergoing surgery is that the latter benefit from pathologic nodal assessment, whereas SBRT patients generally do not receive invasive staging. Although risk factors for occult N2/N3 disease are well documented, the same is not true for occult N1.123 Undetected N1 disease, which would remain untreated with SBRT, may be a significant driver of recurrence. 60,124

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TABLE 11. Key Retrospective Studies Evaluating EBUS Before SBRT for Early-Stage NSCLC

|Study|Design/sample size|Population/key,Inclusion criteria|Study focus and methods|Comparator groups|Diagnostic yield/ treatment efficacy|Key outcomes|Summary/conclusions|| |---|---|---|---|---|---|---|---|---| |Akthar et al (2018)54|Retrorespective; N=92|cStage I (T1-T2, N0, M0) NSCLC; all received SBRT; some underwent CP-EBUS|Compared CP-EBUS-staged vs. no CP-EBUS-staged for regional control, DFS, and OS|CP-EBUS(n=37) vs. No CP-EBUS(n=55)|Up-staging not reported; 2 y FFRF 86% vs.88%, OS 88% vs. 77%|No difference in regional failure, DFS, or OS|Routine EBUS offered no outcome benefit when imaging was cN0; inability to assess occult N + because EBUS group was node- negative by design Universal EBUS not supported; advocate selective use|| |George et al (2024)55*|Retrorespective; N=376|Stage IA-II(T1-T2, N0) by imaging; all received SBRT; median follow-up ~43 mo|Examined the correlation of CP-EBUS-based nodal staging with OS, recurrences Used propensity/ instrumental (CP-EBUS±med), all treated with SABR (2004-2014)|EXN (CP-EBUS-staged vs. No OS, recurrences Used propensity/ instrumental (CP-EBUS±med), all assess the OS impact of INS|INS (CP-EBUS only) (n=142) vs. No INS (n=234)|No recurrence benefit; multivariable OS HR:1.66 (1.17-2.35)|INS associated with worse OS, likely selection bias|Universal EBUS not supported; advocate selective use| |Kennedy et al (2020)56|Retrorespective; N=651|cT1-T2, N0, M0 NSCLC (PET-CT negative nodal disease), all received SBRT|cT1-T2, N0, M0 NSCLC (PET-CT with vs. without invasive staging|INS (CP-EBUS or med) vs. No INS|inversative 2 y/ nodal+ distant control, OS INS. without invasive staging|Median OS 2.8 y vs 2.7 y; IV-adjusted HR:1.0|No survival benefit|Large cohort supports selective rather than routine INS| |Mullins et al (2021)57|Retrorespective; N=158|cT1-T2, N0, M0 NSCLC by imaging; all treated with SBRT|Compared event-free/ OS outcomes for CP-EBUS vs. imaging staging using CalP-EBUS sensitivity vs. imaging; no separate "no CP-EBUS" group|CP-EBUS vs. No CP-EBUS for all)|NS (CP-EBUS or Med) vs. No INS|Three year nodal- failure freedom 84% vs.69% (P=0.10); OS 65% vs. 67%|Nonsignificant trend to better nodal control; no OS gain|Authors favour selective staging only| |Ong et al (2015)58|Retrorespective; N=220|cT1-2a, N0, M0 (<5 cm) by integrated PET-CT; all underwent CP-EBUS|cT1-2a, N0, M0 sensitivity vs. imaging; no separate "no CP-EBUS" group|Single cohort (CP-EBUS for all)|Sens 36.7%, Spec (CP-EBUS for all)|Sens 36.7%, Spec occult nodes but 22% overall occult an $+8\%$ detected by EBUS) Isolated nodal failure|EBUS detects some occult nodes but misses many in inaccessible stations|Useful adjunct before ablative therapy, yet limited by reach| |Schonewolf et al (2018)59|Retrorespective; N=236|cT1-T2, N0, M0 NSCLC;~24% had method) pre-SBRT cT1-2a, N0, M0 (<5 cm) by PET-CT; all potential SABR candidates|IMNS (CP-EBUS or med) pre-SBRT clT-2a, N0, M0 (<5 cm) by PET-CT; all potential SABR staging; single- cohort|IMNS vs. No, nodal, distant failures& OS for IMNS vs.no IMNS Compared PET-CT vs. CP-EBUS for nodal (up/down) staging; single- cohort|Isolated nodal failure 14% vs. 8% (NS); OS HR 0.70 (0.43-1.12) 19% stage shift; in PET-N0 pts 3.4% occult N+ found by EBUS|IMNS did not improve recurrence or OS recurrence or OS HR 0.70 (0.43-1.12) Stage migration|Restrict invasive staging to selected high-risk cases||

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On this basis, routine CP-EBUS assessment-even for patients with small, peripheral tumors and seemingly minimal risk of occult N2 disease-has been adopted at many institutions as a means of detecting N1 disease and potentially reducing the risk of SBRT failure. However,there is no conclusive evidence that identifying N1 disease by CP-EBUS staging improves overall survival or reduces recurrence. Moreover, CP-EBUS adds cost,procedural risks, and the possibility of delaying definitive therapy.

Summary of Evidence

No studies met criteria for a quantitative synthesis(Supplementary Fig. S9, Supplemental Digital Content 1, http://links.lww.com/LBR/A364). A review of 8 retrospective evaluations(Table 11) involving patients with clinically node-negative (cNO) NSCLC who received SBRT with or without invasive nodal staging (INS) was performed. Among studies that specifically evaluated outcomes for INS versus no INS in cN0 patients (as determined by PET/CT), there was no consistent evidence of a survival advantage or a decrease in recurrence attributable to INS.45,55,57,59 In most of these cohorts, patients were either deemed N0 through CP-EBUS or received no staging at all, so the actual detection rates of occult N1 N were not extensively documented.

In 2 studies, roughly 2% to 5% of cN0 patients were upstaged by CP-EBUS to N1.58,60 In the series by Ong and colleagues, which included surgical patients with cN0 disease, CP-EBUS uncovered N1 disease in 5%, whereas intraoperative assessments eventually revealed N1 involve-ment in~20% of patients. Notably, 70% of these“missed”nodal stations were intralobar(stations 12, 13, 14) and therefore beyond CP-EBUS reach.

Rationale

Although CP-EBUS can detect occult N1 disease in a subset of clinically node-negative(cN0) patients, the available evidence is currently limited and does not conclusively show whether doing so solely to rule out N1 disease before SBRT improves survival or reduces recurrence. Many patients undergoing SBRT have significant comorbidities or cannot tolerate surgery; thus, identifying isolated N1 disease may not substantially alter management or impact outcomes in this setting. Any potential benefit must also be weighed against the time, cost, and procedural risks of invasive staging in a population often at higher procedural risk.

Importantly, this review does not address patients whose imaging is suspicious for N2/N3 disease or who meet standard invasive staging criteria. In addition, patients who opt for SBRT over surgery despite having fewer comorbid-ities and a longer expected survival may represent a distinct population where the impact of occult N1 disease could differ; however, these groups were beyond the scope of the current analysis. Due to the limited number and quality of studies, we cannot make a definitive recommendation for or against routine CP-EBUS staging in patients who appear to have early-stage disease on imaging.

Implementation Considerations

● Limited impact on management: While identifying occult N1 disease may alter treatment strategies in certain cases,current data do not conclusively show that routine CP-EBUS staging improves survival or disease control for early-stage NSCLC patients treated with SBRT.

● Risk/benefit assessment: Any benefit gained from detect-ing occult nI disease must be balanced against the time,cost, and procedural risks associated with CP-EBUS-especially in patients with multiple comorbidities who are already considered poor surgical candidates.

● Select populations: For individuals with established risk factors for N2/N3 disease(eg, suspicious lymph node features on imaging, central tumor location,tumor size>3 cm), standard invasive staging is still recommended before SBRT, in accordance with exist-ing guidelines.

Future Research: Further data are needed to define CP-EBUS's full utility in this patient population, partic-ularly as newer, smaller-footprint CP-EBUS scopes become available. Future investigations should examine whether more comprehensive sampling of intralobar nodes(eg, stations 12 to 14) can improve detection rates and ultimately translate to better outcomes for patients with early-stage NSCLC.

CONCLUSIONS

These evidence-based and evidence-informed guide-lines represent the first comprehensive AABIP recom-mendations focusing specifically on the bronchoscopic diagnosis and staging of lung cancer. Topics for evalua-tion were chosen based on clinical and potentially actionable relevance and target those who are most likely to perform invasive tissue evaluation of lung cancer. The goal was to provide a framework based on the best available evidence and, where data were lacking, expert consensus. To ensure an unbiased, scientifically valid,standards-compliant, and trustworthy resource, a meth-odologically rigorous process combining GRADE evi-dence appraisal with NICE-structured recommendations was utilized.

We acknowledge several limitations to our recom-mendations. Much of the supporting evidence for the recommendations stems from retrospective analyses and observational studies, with relatively few high-quality randomized controlled trials. This limited the strength of several recommendations. Therefore, it is important to emphasize that a lack of strict adherence to these guide-lines should not be viewed as a deviation from the standard of care.

A significant limitation of our meta-analysis is the variable methodology used to define and calculate diagnostic yield and accuracy across studies. As noted by Gonzalez et al.,73 the reported diagnostic yield can vary by more than 20% depending on whether strict, intermediate,or liberal definitions are used. This methodological heterogeneity limits the interpretability of our pooled estimates and highlights the importance of adherence to standardized outcome reporting in future bronchoscopy studies.

The rapid evolution of PNB guidance technology concurrent with and subsequent to our literature search parameters resulted in various methodologic constraints and may limit the longevity of some conclusions. We addressed these by updating the literature review and analysis as new data became available, incorporating indirect evidence when applicable, and discussing relevant knowledge and evidence gaps. Also, a substantial proportion of our guidelines addresses CP-EBUS practice, which has an established evidence base that was not subject to as many rapid changes

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as PNB. Furthermore, many of our recommendations address sampling concepts that are mostly modality-neutral for PNB guidance, preserving the relative applicability and relevance of the guideline. Nevertheless, future iterations will likely require recalibration as more robust performance data on these and other emerging technologies relevant to advanced diagnostic bronchoscopy and PPN evaluation become available.

Since the completion of our search(March 2023),several high-impact studies have evaluated robotic-assisted bronchoscopy, real-time cone-beam CT, and digital tomo-synthesis. Preliminary results suggest diagnostic yields approaching those of CT-guided biopsy with lower compli-cation rates. Although promising, these data remain insufficiently mature for an evidence-graded recommenda-tion. We acknowledge this evidence gap as a significant limitation of the current guidelines, and the panel has prioritized a focused future update to address this question.

Our guideline working and expert group panel lacked a medical oncologist, pathologist, and patient advocate. We recognize that diversifying representation is a fundamental aspect of guideline development and that these stakeholders would contribute valuable perspectives to lung cancer diagnosis and management in general. However, this effort uniquely focused on specific technical aspects of and approaches to diagnostic procedures for lung nodules and cancer, which were most relevant to those performing them.A broader inclusion of lung cancer stakeholders who would provide insight into therapeutic implications, long-term clinical trajectories, and quality-of-life endpoints is encour-aged for guidelines of a broader scope.

Our process identified multiple areas in need of more rigorous investigation. While the randomized VERITAS trial74 represents a major advancement in providing high-quality data on the diagnostic performance of minimally invasive techniques,comparing newer PNB technologies with percutaneous sampling remains a high priority. Standardization of tissue acquisition protocols for optimal molecular testing likewise warrants further exploration. Prospective evaluation of optimal staging thresh-olds for patients with a radiographically normal mediastinum, as well as the utility of systematic versus targeted sampling strategies, is another critical domain for future research.

The AABIP intends this guideline to function as a living document. A formal evidence update is planned within 3 to 5 years, with consideration for an earlier targeted revision should a sufficient quantity of high-quality comparative data on robotic-assisted bronchoscopy or real-time intraproce-dural imaging become available.

In conclusion, these guidelines were developed to provide practical and useful assistance to clinicians perform-ing diagnosis and staging in patients with suspected or confirmed lung cancer. We encourage adaptation of these recommendations in accordance with local expertise, institu-tional capabilities, and patient-specific factors. Recognizing that this field is rapidly evolving, the periodic reassessment and updating of these guidelines will be needed. We hope this document provides a valuable summary of existing evidence and expert-based perspectives, stimulates future investigation,and facilitates more robust, evidence-based guidance.

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