title: Tumor Budding Correlates With the Protumor Immune Microenvironment and Is an Independent Prognostic Factor for Recurrence of Stage I Lung Adenocarcinoma.
abstract: BACKGROUND
  Immune cell infiltration associated with tumor capsule disruption and tumor budding has been shown to reflect invasiveness, metastasis, and unfavorable prognosis in colorectal cancer. We investigated the influence of tumor budding on prognosis and its association with the immune microenvironment in lung adenocarcinoma.
  
  
  METHODS
  Tumor slides from resected stage I lung adenocarcinomas were reviewed (n = 524 and n = 514, for training and validation cohorts, respectively) for assessment of tumor budding. CD3+ and forkhead box P3+ (FoxP3+) lymphocytes, CD68+ macrophages, IL-7 receptor, and IL-12 receptor β2 were analyzed using tissue microarrays constructed from tumor and stroma. Probability of recurrence was calculated using the competing risks method.
  
  
  RESULTS
  In the training cohort, risk of recurrence for high-grade tumor budding was higher than it was for low-grade tumor budding (32% vs 12%, P < .001), which was confirmed in the validation cohort (P = .005). Tumor budding stratified the risk of recurrence for acinar-predominant (22% vs 9%, P < .001), papillary-predominant (22% vs 13%, P = .045), and solid-predominant (39% vs 19%, P = .022) tumors. Tumor budding was associated with higher stromal FoxP3+ lymphocyte infiltration, higher stromal FoxP3/CD3 risk index, higher tumoral and stromal CD68+ macrophage infiltration, and IL-7 receptor overexpression (P < .001, all associations). Tumor budding remained independently associated with recurrence on multivariate analysis (hazard ratio, 1.61; P = .008).
  
  
  CONCLUSIONS
  Tumor budding is an independent prognostic factor of stage I lung adenocarcinoma and correlates with the protumor immune microenvironment. Our findings advocate investigating tumor-immune cell interactions at the invading edge as a biologic driver of tumor aggressiveness.
authors.affiliation: Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY; Department of Diagnostic Pathology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Kyuichi
authors.initials: K
authors.lastname: Kadota
authors.affiliation: Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Yi-Chen
authors.initials: YC
authors.lastname: Yeh
authors.affiliation: Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Villena-Vargas
authors.affiliation: Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Leonid
authors.initials: L
authors.lastname: Cherkassky
authors.affiliation: Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Esther N
authors.initials: EN
authors.lastname: Drill
authors.affiliation: Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Camelia S
authors.initials: CS
authors.lastname: Sima
authors.affiliation: Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: David R
authors.initials: DR
authors.lastname: Jones
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: William D
authors.initials: WD
authors.lastname: Travis
authors.affiliation: Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY. Electronic address: adusumip@mskcc.org.
authors.forename: Prasad S
authors.initials: PS
authors.lastname: Adusumilli
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology* / Q000473:pathology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000032:analysis; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis; D014408:Biomarkers, Tumor / Q000032:analysis*; D017252:CD3 Complex / Q000032:analysis; D005260:Female; D051858:Forkhead Transcription Factors / Q000032:analysis; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000473:pathology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000276:immunology* / Q000473:pathology*; D009367:Neoplasm Staging; D011379:Prognosis; D053707:Receptors, Interleukin-12 / Q000032:analysis; D020395:Receptors, Interleukin-7 / Q000032:analysis; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D015996:Survival Rate; D046888:Tissue Array Analysis; D059016:Tumor Microenvironment; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D014408:Biomarkers, Tumor; D017252:CD3 Complex; D051858:Forkhead Transcription Factors; D053707:Receptors, Interleukin-12; D020395:Receptors, Interleukin-7; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C508439:IL12RB2 protein, human
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