Vascular growth patterns correlate with histological subtypes in human lung adenocarcinoma

ABSTRACT Lung adenocarcinoma, the most common subtype of non-small cell lung cancer (NSCLC), exhibits diverse histopathological and vascular patterns influencing prognosis and therapeutic response. Angiogenesis, the process of new blood vessel formation, has historically been regarded as the predominant mechanism of tumor vascularization in solid cancers. However, vessel co-option, a non-angiogenic process, has emerged as an alternative strategy, involving the hijacking of pre-existing blood vessels by cancer cells rather than the induction of new ones. Furthermore, vessel co-option has been observed in both primary and metastatic cancers. The aim of this study was to determine the vascular patterns of different human adenocarcinoma samples and establish potential correlations between histological subtypes and microvascular growth patterns. Seventy lung adenocarcinoma samples were classified according to the 2021 WHO classification system, and their vascularization patterns were analyzed using CD31 immunohistochemistry and Weigert-Van Gieson staining. A substantial correlation was observed between histological subtypes and vascularization strategies, with solid basal and diffuse tumors exhibiting angiogenesis, and solid alveolar and lepidic tumors associated with vessel co-option. Additionally, papillary and micropapillary patterns exhibited mixed vascularization, while acinar tumors displayed the highest heterogeneity. The combination of staining techniques improved classification accuracy, achieving successful identification in 92.5% of cases. In conclusion, we present a powerful tool that can be used in lung cancer diagnostics to analyze tumor vascularization based on CD31 and elastic fibers staining. The observed correlations highlight the significance of histopathological assessment in determining vascularization mechanisms, which may optimize therapeutic strategies for NSCLC. Highlights Vascular patterns differ among histological subtypes in lung adenocarcinoma. CD31 and WVG staining improves vascular pattern classification. Solid basal and diffuse tumors show angiogenesis, whereas alveolar solid shows co-option. Papillary and micropapillary patterns display mixed angiogenic/co-option features. Vascular profiling may guide NSCLC prognosis and anti-angiogenic therapy effectiveness. Competing Interest Statement The authors have declared no competing interest. Funding Statement This research was funded by the Ministerio de Economia y Competitividad of Spain (PID2022-138765OB-I00 to MP), the Instituto de Salud Carlos III (PI19/01630 and co-funded by FEDER to MP and PI21/01034 to JMM-F), Fundacion Cientifica de la Asociacion Española Contra el Cancer (LABAE234462MUÑO to JMM-F), Fundacion Mutua Madrileña (Ayudas a la Investigacion en Salud 2024 to JMM-F) and Junta de Castilla y Leon (BIO/SA83/13 to MP and SA095P24 to JMM-F). Furthermore, IS-SC were supported by a contract from the Junta de Castilla y Leon (co-funded by the European Social Fund). Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Ethics committee of Universidad de Salamanca gave ethical approval for this work (Regist number 437) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes ↵¥ These authors share senior authorship, and they appear in alphabetic order. Conflict of interest: Authors declare no conflict of interest. Data Availability All data produced in the present study are available upon reasonable request to the authors