Lung cancer associated with cystic airspaces in the perioperative immunotherapy era: radiologic and pathologic pitfalls, surgical extent, and management implications

Introduction

Advances in perioperative immunotherapy and targeted therapy for stage II–III non-small cell lung cancer (NSCLC) have reshaped treatment paradigms and pushed multimodal management toward increasingly earlier disease stages (1-5). In this evolving context, precise radiologic and pathologic staging of atypical early lung cancers becomes critical because radiologic overstaging may expose patients to unnecessary systemic therapy, whereas understaging may jeopardize curative resection.

Lung cancer associated with cystic airspaces (LCCA) refers to a spectrum of lung malignancies characterized by air-filled cystic spaces within or adjacent to the tumor on computed tomography (CT). Unlike cavitary lung cancer, which typically shows central necrosis and air bronchograms representing preserved airway structures, LCCA is characterized by tumor growth along or around cystic airspaces, with variable wall thickening, mural nodules, or multicystic architecture (6,7). With the expanded use of screening and thin-slice CT, LCCA is increasingly recognized in clinical practice. Most cases are adenocarcinomas, while squamous cell carcinoma is less common. Radiologically, LCCA may present as thin- or thick-walled cystic lesions, mural nodules, internal septations, or honeycomb-like changes, often overlapping with benign cystic or cavitary lung diseases, including tuberculosis, bullae, and simple lung cysts.

Multiple studies have proposed classification systems for LCCA based on CT morphological characteristics (8-10). Among these, the classification proposed by Shen et al. offers a useful morphology-based framework for describing cyst features and facilitating radiologic-pathologic correlation (11), categorizing LCCA into four distinct types: Type I (thin-walled), defined by cystic airspaces with wall thickness <2 mm; Type II (thick-walled), characterized by circumferential wall thickening ≥2 mm; Type III (mural nodule), defined by the presence of endophytic or exophytic nodular components within the cyst wall; and Type IV (multicystic/complex), characterized by clustered cystic airspaces with intermixed solid or subsolid components (Figure 1).

Figure 1 Radiologic classification of lung cancer associated with cystic airspaces (LCCA). (A) Type I (thin-walled): cystic lesions characterized by an average wall thickness of less than 2 mm. (B) Type II (thick-walled): cystic lesions demonstrating circumferential wall thickening of 2 mm or greater. (C) Type III (mural nodule): cystic lesions featuring mural nodules with either endophytic or exophytic growth patterns. (D) Type IV (mixed type): lesions consisting of solid or subsolid components intermixed with multiple clustered cystic airspaces, exhibiting reticular changes. LCCA, lung cancer associated with cystic airspaces.

Although the majority of LCCA cases are resectable at initial evaluation, major uncertainties persist regarding radiologic measurement, T-staging accuracy, and the applicability of surgical and perioperative strategies established for solid or part-solid NSCLC. To address these decision-critical issues in the perioperative era, we performed a narrative synthesis of the current literature and incorporated insights from our ongoing single-center prospective registry (NCT07066813), which includes more than 300 CT-defined LCCA cases with systematic radiologic-pathologic correlation. Rather than a formal meta-analysis, this perspective integrates published evidence with illustrative clinical cases to focus on decision-critical controversies in staging, prognostic evaluation, imaging-based classification, and management of LCCA. Beyond synthesizing current knowledge, we aim to identify key evidence gaps and outline forward-looking research priorities, including potential study designs and analytical strategies to address unresolved clinical questions.

Radiologic definition and T-staging pitfalls in LCCA

Radiologic T-staging in LCCA presents unique challenges due to the presence of intralesional cystic airspaces. Accurately assessing tumor size is essential for surgical planning and for determining indications for neoadjuvant therapy, yet current guidelines remain ambiguous. Previous studies have demonstrated notable discrepancies between CT-measured lesion size and actual pathological tumor size in LCCA (12). The ninth edition of the tumor-node-metastasis (TNM) classification does not specify whether to measure the solid component or the entire lesion, including cystic areas (13). Current guidelines (14) do not provide explicit recommendations for the measurement of atypical cystic lesions associated with LCCA. As a result, radiologic size assessment remains challenging, and the incorporation of air-containing components may not accurately reflect the true tumor burden, potentially affecting staging and treatment decisions. Recent deep learning-based component segmentation tools may further support standardized classification and objective measurement in LCCA (14). In the era of neoadjuvant immunochemotherapy, such overestimation may negatively influence therapeutic decision-making, potentially compromising patient outcomes. To address this, some studies advocate measuring only the solid components (e.g., mural nodules or solid portions of the cyst wall) to better reflect the actual tumor burden and prognosis. However, given the morphological heterogeneity of LCCA, certain lesions, particularly Types I and II, may lack identifiable solid nodules, rendering such measurements challenging or infeasible.

Furthermore, as clinical recognition of pure ground-glass opacity (GGO) and part-solid component nodules continues to evolve, it is increasingly recognized that a significant subset of LCCA lesions harbor subsolid-predominant lesions within the cyst wall, or are even predominantly subsolid. For these subsolid-predominant LCCA lesions, key clinical questions remain unresolved: should patients undergo upfront surgical resection even when radiologic T-staging exceeds T3? What are the optimal indications and timing for neoadjuvant therapy in this distinct subgroup? (Figure 2).

Figure 2 Heterogeneity and clinical controversies in T3-stage LCCA. This figure demonstrates four representative cases of T3-stage LCCA located in the left lower lobe. Despite sharing the same T-stage, these LCCA lesions demonstrate substantial heterogeneity due to variations in cystic airspace presence and wall composition, potentially reflecting significant differences in tumor burden. Such variability leads to considerable divergence in real-world clinical decision-making, highlighting ongoing controversies and challenges in the accurate staging and management of LCCA. (A) A 65-mm lesion in the left lower lobe, displaying central cavitation and liquefactive necrosis on CT. Needle biopsy indicated poorly differentiated squamous cell carcinoma (TPS 20%), clinically staged as cT3N0M0, stage IIb by PET-CT. The patient underwent radical surgical resection after neoadjuvant chemoimmunotherapy. (B) A 58-mm lesion in the left lower lobe. Needle biopsy revealed moderately differentiated adenocarcinoma (micropapillary 40%, lepidic 30%, acinar 30%) with a TPS of 5%, and the tumor was clinically staged as cT3N0M0; PET-CT showed stage IIb. Genetic analysis identified Kirsten rat sarcoma viral oncogene homolog (KRAS p.G12C) and Fanconi anemia complementation group M (FANCM p.S724) mutations. The patient received neoadjuvant chemoimmunotherapy followed by radical surgical resection. (C) A 55-mm Type II LCCA lesion in the left lower lobe, predominantly part-solid cyst-wall components. PET-CT staging indicated cT3N0M0, stage IIb. The patient underwent primary curative resection, and postoperative pathology revealed pT3N1M0, stage IIIa. (D) A 60-mm Type II LCCA lesion in the left lower lobe, predominantly solid in cyst-wall composition. Needle biopsy confirmed squamous cell carcinoma, clinically staged as cT3N0M0, stage IIb by PET-CT. Similar controversy persists regarding the optimal management strategy, involving either immediate radical resection or neoadjuvant therapy followed by surgery. CT, computed tomography; LCCA, lung cancer associated with cystic airspaces; PET-CT, positron emission tomography-computed tomography; TPS, tumor proportion score.

To date, no direct comparative studies have validated the concordance between radiologic and pathologic T-staging in LCCA. It remains unclear whether LCCA and non-LCCA lesions of the same radiologic T-stage represent comparable tumor burden or share similar prognostic implications. The relative clinical value of radiologic versus pathologic staging in guiding therapy is likewise undefined. In addition to challenges in radiologic assessment, obtaining a definitive tissue diagnosis can also be difficult. Bronchoscopic biopsy, including robotic-assisted approaches, may have a limited diagnostic yield because tumor cells are often confined to focal regions of the cyst wall rather than forming a solid mass. This spatial heterogeneity increases the risk of sampling error and false-negative results. As a result, in selected cases with high radiologic suspicion, clinical decision-making may need to rely on integrated imaging and clinical judgment rather than preoperative histologic confirmation alone.

These knowledge gaps underscore the urgent need for well-designed, high-quality studies to refine staging criteria and support personalized treatment strategies. To address this, we have initiated a prospective clinical study of radiologic T-staging in LCCA (NCT07066813), enrolling more than 300 patients. The registry systematically captures radiologic features (e.g., cyst morphology, wall thickness, mural nodules, and subsolid components), pathologic findings, molecular data when available, and longitudinal clinical outcomes. These data are prospectively integrated to evaluate radiologic-pathologic concordance, refine staging accuracy, and assess subtype-specific prognosis.

Prognostic value of cyst-wall composition and mural nodules

In early-stage lung cancer, solid-predominant lesions are consistently associated with worse prognosis compared to lesions with subsolid-predominant components (15). GGO lesions typically exhibit indolent behavior and slow growth. Part-solid components suggest intermediate aggressiveness, whereas solid components are associated with poorer differentiation and shorter tumor doubling times (16,17). Whether this paradigm applies to LCCA remains an open question.

Clinically, many LCCA lesions demonstrate cyst walls containing GGO or part-solid components, or appear as part-solid nodules encompassing a prominent air-filled cavity. It is unclear whether such subsolid-predominant LCCA lesions similarly indicate a less aggressive biological phenotype. Emerging evidence suggests a potential progression model in which cyst wall composition evolves from GGO to part-solid components and ultimately to solid components, reflecting a stepwise increase in tumor aggressiveness. The development of solid mural nodules within the cyst wall has been associated with disease progression and significantly worse outcomes (6,18). Shen et al. demonstrated that the presence of a solid component within the cyst wall was a strong predictor of histologic invasiveness across all four LCCA subtypes. Type III lesions showed a significantly higher proportion of moderately to poorly differentiated histologies compared to the other subtypes (11,12). These findings highlight the prognostic value of cyst wall features on imaging, suggesting that the presence and morphology of solid components may serve as key indicators of tumor aggressiveness.

Notably, Figure 2 illustrates four LCCA cases with identical radiologic T-stages but divergent cyst-wall compositions; one patient with a predominantly part-solid component-walled cyst had pathologically confirmed N1 metastasis, indicating that cyst-wall appearance alone does not reliably reflect biological behavior. Larger, pathologically correlated cohorts are required to validate cyst-wall features as prognostic markers and to refine risk stratification in LCCA.

Imaging-based classification shows prognostic potential but requires further refinement

Emerging evidence suggests that imaging subtypes of LCCA may correlate with tumor biology and clinical outcomes. Compared to Type I (thin-walled) and Type IV (mixed type) lesions, Type II (thick-walled) and Type III (mural nodule) LCCAs are more frequently associated with poorer tumor differentiation and worse prognosis (11,12,19), supporting the prognostic potential of imaging-based classification and the need for more intensive evaluation and management in higher-risk subtypes. However, current classification systems lack standardization, with different institutions adopting varying criteria (8-10). Even within the same framework, interobserver variability and overlapping imaging features limit consistency. Some LCCA lesions exhibit mixed morphologic features, such as thickened walls with mural nodules (Type II + III) or mural nodules combined with multicystic changes (Type III + IV), which reduces reproducibility and limits the clinical utility of current classification systems for decision-making (Figure 3).

Figure 3 Radiological presentation of LCCA lesions exhibiting multiple classification features simultaneously. (A) A lesion in the right lower lobe with a maximum radiological diameter of 40.5 mm, demonstrating thick-walled characteristics consistent with Type II LCCA, accompanied by mixed reticular changes characteristic of Type IV, predominantly featuring part-solid components. Postoperative pathology revealed moderately differentiated adenocarcinoma (predominantly papillary subtype), with a maximum pathological tumor diameter of 30 mm, without lymph node metastasis. (B) A lesion in the right lower lobe with a maximum radiological diameter of 28.0 mm, displaying Type II thick-walled characteristics alongside typical nodular changes of Type III, predominantly solid components. Postoperative pathology confirmed moderately differentiated squamous cell carcinoma, with a maximum pathological tumor diameter of 28 mm, without lymph node metastasis. (C,D) A lesion in the right lower lobe with a maximum radiological diameter of 37.0 mm, exhibiting thick-walled changes (Type II), with typical nodular features (Type III) observed on an alternate CT plane, predominantly solid in composition. Postoperative pathology identified moderately differentiated adenocarcinoma, with a maximum pathological tumor diameter of 25 mm, with N1 lymph node metastasis. (E,F) A lesion in the left lower lobe with a maximum radiological diameter of 38.5 mm, demonstrating mixed reticular changes (Type IV) along with nodular features (Type III) observed on an alternate CT plane. The nodular components were predominantly solid, accompanied by thin cystic walls. Postoperative pathology revealed moderately differentiated adenocarcinoma (40% acinar, 40% papillary, and 20% micropapillary subtypes), with visceral pleural invasion, maximum pathological tumor diameter 25 mm, and N2 lymph node metastasis. CT, computed tomography; LCCA, lung cancer associated with cystic airspaces.

Advances in artificial intelligence (AI) and radiomics offer an opportunity to refine this approach. Quantitative, model-based extraction of wall thickness, mural nodule configuration, cyst architecture, and subsolid components may provide more objective and reproducible characterization than visual assessment alone. When integrated with pathology and outcome data, such imaging signatures could underpin a standardized, prognostically relevant classification system for LCCA and support individualized treatment strategies (10).

Are current surgical, targeted, and immunotherapy guidelines applicable to LCCA?

To date, major clinical trials that define surgical strategies and perioperative systemic therapy for early-stage NSCLC, such as JCOG0802 (20), JCOG0804 (21), JCOG1211 (22) and CALGB140503 (23) for surgical strategy; ADAURA (3) and ALINA (1) for targeted therapy; and CheckMate816 (5), KEYNOTE-671 (4) and Impower010 (2) for immunotherapy, have not identified LCCA as a distinct subgroup. Consequently, significant gaps remain in our understanding of optimal surgical and perioperative management strategies specifically for LCCA.

Surgical resection remains the cornerstone of treatment for stage I LCCA, yet several crucial questions remain unresolved. For LCCA lesions approximately 2 cm on CT, is sublobar resection, such as segmentectomy, oncologically sufficient given the complex morphology of these tumors? Moreover, how should the consolidation-to-tumor ratio (CTR) be precisely calculated in the presence of cystic airspaces? Should wider surgical margins be considered for Type II and Type III LCCA lesions, given their association with less favorable prognoses? Finally, for larger (>3 cm) but GGO-predominant lesions, could segmentectomy represent a feasible and oncologically safe alternative to lobectomy in carefully selected cases? (Figure 4A-4D).

Figure 4 Controversies in treatment decision-making for LCCA lesions. (A-D) Four representative cases illustrating the uncertainty regarding optimal surgical resection extent for LCCA. Each lesion exceeds 30 mm (T2 stage), with cyst-wall components predominantly characterized by GGO. It remains unclear whether lobectomy is mandatory or if segmentectomy is oncologically sufficient, as robust evidence is currently lacking. (A) A Type II LCCA lesion in the left upper lobe, maximum radiological diameter 36.0 mm, demonstrating thick-walled features, with cyst-wall components predominantly GGO. Postoperative pathology revealed moderately differentiated adenocarcinoma (predominantly lepidic), maximum pathological tumor diameter 20 mm, and lymph node-negative. (B) A Type IV LCCA lesion in the right upper lobe, maximum radiological diameter 38.6 mm, displaying mixed reticular features with cyst-wall predominantly part-solid components. Pathology confirmed moderately differentiated adenocarcinoma (acinar 80%, lepidic 20%), maximum pathological tumor diameter 22 mm, and lymph node-negative. (C) A Type II LCCA lesion in the right upper lobe, maximum radiological diameter 31.7 mm, exhibiting thick-walled characteristics, predominantly GGO. Pathological examination demonstrated adenocarcinoma with high-to-moderate differentiation (lepidic 60%, acinar 40%), maximum pathological tumor diameter 18 mm, and lymph node-negative. (D) A Type II LCCA lesion in the right upper lobe, maximum radiological diameter 32.2 mm, showing thick-walled changes, predominantly GGO. Pathology revealed well-differentiated adenocarcinoma (predominantly lepidic), maximum pathological tumor diameter 25 mm, and lymph node-negative. (E-H) Representative cases illustrating ongoing therapeutic controversies for LCCA lesions radiologically staged as T3. Due to the presence of cystic airspaces, clear, high-level clinical evidence is lacking regarding whether these lesions should undergo immediate radical surgical resection or receive neoadjuvant therapy before surgery. (E) Type II LCCA lesion in the left lower lobe, maximum radiological diameter 55.6 mm, characterized by thick-walled cystic features predominantly composed of solid components. Postoperative pathology revealed moderately to poorly differentiated squamous cell carcinoma with visceral pleural invasion, maximum pathological tumor diameter 42 mm, and lymph node-negative. (F) Type II + IV LCCA lesion in the right middle lobe, maximum radiological diameter 62.5 mm, demonstrating mixed radiological features combining Type II thick-walled characteristics and Type IV reticular changes, predominantly composed of part-solid components. Pathology confirmed poorly differentiated squamous cell carcinoma, with a maximum pathological tumor diameter of 55 mm, and lymph node-negative. (G) Type II + III LCCA lesion in the left lower lobe, maximum radiological diameter 57.5 mm, exhibiting combined thick-walled (Type II) and nodular (Type III) features, predominantly solid. Postoperative pathology demonstrated moderately to poorly differentiated adenocarcinoma (acinar 80%, solid 20%), maximum pathological tumor diameter 50 mm, and lymph node-negative. Genetic testing detected no actionable mutations. (H) Type III LCCA lesion in the right upper lobe, maximum radiological diameter 55 mm, characterized by nodular features with predominantly GGO composition. Pathology revealed moderately differentiated adenocarcinoma (lepidic 20%, acinar 75%, micropapillary 5%), maximum pathological tumor diameter 25 mm, and lymph node-negative. GGO, ground-glass opacity; LCCA, lung cancer associated with cystic airspaces.

For LCCA with radiologic staging approaching T3, indications for neoadjuvant therapy are particularly ambiguous. In lesions with predominantly GGO or part-solid components, upfront surgery may be sufficient, but robust evidence is lacking. In contrast, Type II and III LCCA, characterized by thickened solid walls or mural nodules, may biologically resemble higher-risk invasive tumors, raising the question of whether neoadjuvant chemoimmunotherapy should be selectively considered (Figure 4E-4H). An exploratory study from an Italian group reported lesion shrinkage in advanced multifocal LCCA treated with immune checkpoint inhibitors (ICIs), suggesting potential sensitivity to immunotherapy (24). However, these findings are preliminary and lack support from systematic, high-level clinical evidence.

Collectively, these uncertainties highlight the urgent need for LCCA-specific clinical studies. It remains unclear whether existing surgical, targeted, and immunotherapy algorithms can be applied directly or require modification to reflect the distinctive imaging patterns and biological behavior of LCCA. A key unresolved issue is the management of small lesions, particularly those with subsolid cyst-wall components or minimal solid mural nodules. Some of these lesions appear indolent and may resemble GGO-predominant lung cancers. However, distinguishing indolent from aggressive cystic tumors remains difficult. Cyst-wall composition is highly heterogeneous, and solid invasive components may emerge abruptly. Prospective natural-history studies and longitudinal radiologic-pathologic correlation are therefore essential. Such evidence is needed to establish risk-stratification criteria, define surveillance intervals, and determine appropriate intervention thresholds for small LCCA lesions.

Multifocal LCCA: when to suspect intrapulmonary metastasis (IPM)

Current oncologic principles increasingly support classifying multifocal GGOs as independent clonal lesions, favoring a diagnosis of multiple primary lung cancers (MPLC) rather than IPM (25). However, when multiple lesions display highly similar, characteristic cystic features, the possibility of IPM should not be overlooked.

We present two compelling cases suggestive of IPM in the setting of multifocal LCCA. In the first case, the patient was initially diagnosed with a Type IV LCCA in the right upper lobe, with a cyst wall dominated by part-solid components. One year after curative resection, multiple GGO lesions emerged in the right lower lobe and rapidly evolved into lesions with solid and cystic components. Histopathological examination and next-generation sequencing (NGS) provided strong support for a diagnosis of IPM (Figure 5A-5I). In the second case, a patient with a primary right upper lobe LCCA underwent curative resection. One year later, a new Type I LCCA lesion developed in the right middle lobe, closely resembling the original tumor’s cystic morphology. Surgical resection and subsequent pathological and molecular analysis again strongly suggested IPM (Figure 5J-5L). The details of these two cases are provided in the file available at https://cdn.amegroups.cn/static/public/tlcr-2025-1-1488-1.pdf.

Figure 5 Radiological, histopathological, and genomic profiling of two multiple LCCA patients. (A) Chest CT scan of case 1 showing a mass (T1) in the right upper lobe with cystic changes. No satellite nodules were detected in the ipsilateral lobes. (B) H&E staining of T1 reveals moderately differentiated adenocarcinoma (acinar-predominant, IASLC grade 2, ×100). (C,E,G) Interval CT imaging of tumors 2, 3, and 4, respectively, located in the right lower lobe, showing gradual enlargement and cystic change during follow-up. (D,F,H) Histopathology confirmed that all three lesions are moderately differentiated adenocarcinoma (H&E staining, ×100). (I) Genomic profiling of the four tumors revealed 18 shared driver gene mutations. (J) Chest CT scan of case 2 showing a cystic mass (T1) in the right upper lobe. Follow-up CT imaging revealed a thin-walled cystic nodule in the right middle lobe near the mediastinum (T2) and a GGO nodule (T3) in the posterior basal segment of the right lower lobe. (K) Postoperative histopathology of T1, T2, and T3 in case 2 confirmed moderately to poorly differentiated squamous cell carcinoma, moderately to poorly differentiated squamous cell carcinoma, and minimally MIA, respectively (H&E staining, ×100). (L) Phylogenetic tree map of the three lesions confirms monoclonal origin of T1 and T2 squamous carcinomas, with T3 as a genetically distinct primary. CT, computed tomography; GGO, ground-glass opacity; H&E, hematoxylin and eosin; IASLC, International Association for the Study of Lung Cancer; LCCA, lung cancer associated with cystic airspaces; MIA, minimally invasive adenocarcinoma; TMB, tumor mutational burden.

One of the fundamental principles of biology is that structure reflects function and, in turn, the underlying genotype. Lesions arising from a common clonal origin often share similar genetic alterations, growth dynamics, and invasive behavior (26). Consequently, multiple pulmonary lesions derived from monoclonal tumor cells may display strikingly consistent morphologic features, including cystic architecture, mural configuration, and GGO or part-solid components. In clinical practice, the presence of multiple pulmonary lesions with highly similar cystic patterns and evolution should raise suspicion for a shared biological origin and support consideration of IPM rather than MPLC. In this context, structural similarity is not merely a visual observation but also a potential phenotypic expression of tumor clonality and evolutionary trajectory.

This concept requires integration of imaging, histopathology, clinical behavior, and, when available, molecular profiling. Although not universally applicable, it highlights the importance of multidisciplinary evaluation. When multiple lesions share highly similar cystic architecture and growth kinetics, IPM should be considered alongside MPLC. In such cases, NGS can provide objective evidence of clonality, thereby refining classification and informing staging and treatment decisions.

Conclusions

Future work in LCCA should focus on resolving the central challenge of accurate staging and treatment selection. Key priorities include establishing radiologic-pathologic correlations to inform LCCA-specific measurement approaches, developing pragmatic algorithms that link imaging features to surgical and perioperative strategies, and integrating molecular profiling to distinguish MPLC from IPM. Together with emerging radiomics and AI tools, these efforts may enable a unified framework that aligns morphology with biology and supports more precise, individualized management of LCCA.

Acknowledgments

The authors sincerely thank the multidisciplinary team (MDT) of thoracic oncology at The Second Xiangya Hospital of Central South University for caring for all the patients.

During the preparation of this work, the authors used ChatGPT in order to enhance the clarity, language, and readability of the text. After using this service, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.

Footnote

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1488/prf

Funding: This study was funded by the Natural Science Foundation of Hunan Province (Nos. 2020SK53419, 2021JJ30926, and 2026JJ60080), the Guangxi Natural Science Foundation (No. 2026GXNSFAA00640295), the National Natural Science Foundation of China (No. 82302449), the Scientific Research Launch Project for New Employees of The Second Xiangya Hospital of Central South University, the Health Research Project of Hunan Provincial Health Commission (No. W20243115), the Shanghai Health and Medical Development Science and Technology Promotion Program (No. PMY202410110097), and the Scientific Research Program of FuRong Laboratory (No. 2025PT5020).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1488/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Written informed consent was obtained from all patients to permit researchers to analyze clinical features and tissue samples.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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