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      High tumor mutation burden predicts favorable outcome among patients with aggressive histological subtypes of lung adenocarcinoma: A population-based single-institution study


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          Tumor mutation burden (TMB) is an emerging predictive cancer biomarker. Few studies have addressed the prognostic role of TMB in non-small cell lung carcinoma, with conflicting results. Moreover, the association of TMB with different histological subtypes of lung adenocarcinoma has hitherto not been systematically evaluated. Here we studied the prognostic value of TMB and its distribution in different histological subtypes of lung adenocarcinomas in a retrospective cohort using the most recent updated classification guidelines.

          Materials and methods

          176 surgically resected stage I–IV lung adenocarcinomas were histologically reclassified according to WHO 2015 guidelines. A modified classification subdividing the acinar subtype into classic acinar, complex glandular and cribriform subtypes was further applied and potentially prognostic histopathological characteristics such as tumor-infiltrating lymphocytes were evaluated. 148 patients with stage I–III tumors and complete follow-up data were included in the survival analyses. TMB was determined by a commercial next generation sequencing panel from 131 tumors, out of which 105 had survival data available.


          Predominant micropapillary, solid and complex glandular as well as nonpredominant cribriform histological subtypes were associated with significantly shorter survival. High TMB concentrated in micropapillary, solid and acinar predominant subtypes. Interestingly, TMB ≥ 14 mutations/MB conferred a stage- and histology-independent survival benefit compared to TMB < 14 in multivariable analysis for overall (HR 0.284, 95% CI 0.14–0.59, P=0.001) and disease-specific survival (HR 0.213, 95% CI 0.08–0.56, P=0.002).


          TMB was an independent biomarker of favorable prognosis in our cohort of lung adenocarcinoma despite being associated with predominant histological subtypes considered aggressive.

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          Most cited references10

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          Prognostic Effect of Tumor Lymphocytic Infiltration in Resectable Non-Small-Cell Lung Cancer.

          Tumor lymphocytic infiltration (TLI) has differing prognostic value among various cancers. The objective of this study was to assess the effect of TLI in lung cancer.
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            Prognostic Impact of Tumor Mutation Burden in Patients With Completely Resected Non-Small Cell Lung Cancer: Brief Report.

            Tumor mutation burden (TMB) is thought to be associated with the amount of neoantigen in the tumor and to have an important role in predicting the effect of immune checkpoint inhibitors. However, the relevance of TMB to prognosis is not yet fully understood. In this study, we investigated the clinical significance of TMB in patients with NSCLC and examined the relationship between TMB and prognosis.
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              • Article: not found

              Evaluation of tumor-infiltrating lymphocytes using routine H&E slides predicts patient survival in resected non–small cell lung cancer


                Author and article information

                Neoplasia (New York, N.Y.)
                Neoplasia Press
                22 June 2020
                September 2020
                22 June 2020
                : 22
                : 9
                : 333-342
                [a ]Institute of Biomedicine, University of Turku and Department of Pathology, Turku University Hospital, Kiinamyllynkatu 10, 20520 Turku, Finland
                [b ]University of Turku, Department of Pulmonary Diseases and Clinical Allergology and Division of Medicine, Department of Pulmonary Diseases, Turku University Hospital, Hämeentie 11, 20521 Turku, Finland
                [c ]Auria Biobank, University of Turku and Turku University Hospital, Kiinamyllynkatu 10, 20520 Turku, Finland
                [d ]Department of Pathology, University of Helsinki, Haartmaninkatu 3, 00014 Helsingin yliopisto, Finland
                [e ]Roche Oy, Klovinpellontie 3, 02180 Espoo, Finland
                Author notes
                [* ]Corresponding author. heikki.vilhonen@ 123456tyks.fi

                Authors contributed equally to this publication

                © 2020 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                : 18 March 2020
                : 18 May 2020
                : 20 May 2020
                Original article

                lvi, lymphovascular invasion,stas, spread through air spaces,tmb, nonsynonymous tumor mutation burden defined as mutations per megabase of coding dna,vpi, visceral pleural invasion,non-small cell lung cancer,lung adenocarcinoma,tumor mutation burden,histological subtype,prognostic biomarker


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