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Takashi Eguchi

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    ES12 - Lung Cancer Pathology in the Age of Genomics (ID 15)

    • Event: WCLC 2019
    • Type: Educational Session
    • Track: Pathology
    • Presentations: 1
    • Now Available
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      ES12.05 - Impact of STAS in Lung Cancer Staging (Now Available) (ID 3222)

      15:15 - 16:45  |  Author(s): Takashi Eguchi

      • Abstract
      • Presentation
      • Slides


      Spread through air spaces (STAS) is an established histologic marker of poor prognosis found in 15-60% of lung cancers. The association with poor prognosis is supported by data from over 3500 patients from multiple multidisciplinary investigative groups worldwide. This prognostic significance has been demonstrated in all major types of lung cancer including adenocarcinoma,1 squamous cell carcinoma,2 small cell carcinoma,3 large cell neuroendocrine carcinoma,3, atypical carcinoid3 and pleomorphic carcinoma.4, 5

      As this large volume of clinical data has accumulated some important issues that have arisen. 1) Importance of processing, 2) Role in Staging? 3) Limited resection vs lobectomy and 4) Frozen section.

      Criteria for STAS

      The original definition of STAS by Kadota et al and the 2015 WHO consisted of tumor cells within the first alveolar air spaces in the lung parenchyma beyond the edge of the main tumor. In adenocarcinoma it can occur as one of three morphologic patterns including 1) micropapillary structures within air spaces; 2) solid nests or tumor islands and 3) scattered discohesive single cells.1, 6 In a recent paper we also proposed to require the presence of more than a single STAS cluster.3 The solid nest pattern is characteristic in other lung cancer histologies such as squamous cell carcinoma and neuroendocrine tumors. 3-dimensional studies with serial histologic sectioning and microCT whole block imaging suggest that there may be two mechanisms of spread into the adjacent lung: 1) detachment, migration through air spaces and reattachment with vessel co-option and 2) tumor islands of continuous tumor spread into adjacent air spaces.

      An important component of the diagnostic criteria is the distinction from artifacts: 1) mechanically induced tumor floaters that are randomly situated often at the edge of the tissue section or out of the plane of section; 2) jagged edges of tumor cell clusters suggesting fragmentation or edges of a knife cut during specimen processing; 3) isolated tumor clusters at a distance from the tumor rather than spreading in a continuous manner from the tumor edge and 4) linear strips of cells lifted off alveolar walls.

      Importance of Processing

      To assess for STAS histologic sections need to be taken in such a way to maximize the interface between the tumor and adjacent non-neoplastic lung parenchyma. For example, sections of subpleural tumors that maximize assessment of the visceral pleura or the interface with dense fibrotic scars or post-obstructive organizing are not well suited for assessment of STAS. This applies to both frozen and permanent sections.

      Role of STAS in Staging?

      Although the prognostic significance of STAS, has led some to suggest it might be included as a factor in staging,7, 8 there is insufficient data at this time to make such a recommendation. Tumor size should continue to be measured according to the gross and/or microscopically recognized edge of lung cancers rather than according to the maximum distance of furthest STAS. Although vascular (V) and lymphatic (L) invasion are recognized in TNM staging, only visceral pleural invasion (VPI) is officially incorporated as a T-factor in the 8th Edition. STAS is regarded as a sign of invasion similar to V, L and VPI, however, more data is needed before introducing this as a T-factor for staging.

      Limited resection vs lobectomy

      Evidence is accumulating that indicates an increased risk of recurrence and worse survival associated with STAS positive tumors treated by limited resection compared to lobectomy.5, 9

      Role of Frozen Sections in Assessing STAS

      There is limited data evaluating pathologist’s ability to recognize STAS in frozen section. Eguchi et al found the sensitivity and specificity of frozen section for prediction of STAS were 71% and 92%. respectively and interrater reliability across 5 pathologists was 0.67.9

      Walts AE et al studied frozen section for evaluation of STAS and recommended that current evidence did not warrant frozen section evaluation for STAS.10 However, frozen section sensitivity to detect STAS positivity was 50%, with a 100% positive predictive value and an 8% negative predictive value. These studies suggest if a pathologist sees STAS on a frozen section there is a 92-100% likelihood it will be present on permanent sections. Both studies were retrospective so attention was not always given to including the tumor edge and adjacent lung. More studies are needed to evaluate the potential role of frozen section in detecting STAS and guiding intraoperative decisions by surgeons.


      1. Kadota K, et al. Tumor Spread through Air Spaces is an Important Pattern of Invasion and Impacts the Frequency and Location of Recurrences after Limited Resection for Small Stage I Lung Adenocarcinomas. J Thorac Oncol 2015;10:806-14.

      2. Lu S, et al. Spread through Air Spaces (STAS) Is an Independent Predictor of Recurrence and Lung Cancer-Specific Death in Squamous Cell Carcinoma. J Thorac Oncol 2017;12:223-34.

      3. Aly RG, et al. Spread Through Air Spaces (STAS) Is Prognostic in Atypical Carcinoid, Large Cell Neuroendocrine Carcinoma, and Small Cell Carcinoma of the Lung. J Thorac Oncol 2019.

      4. Yokoyama S, et al. Tumor Spread Through Air Spaces Identifies a Distinct Subgroup With Poor Prognosis in Surgically Resected Lung Pleomorphic Carcinoma. Chest 2018;154:838-47.

      5. Liu H, et al. Prognostic Impact of Tumor Spread Through Air Spaces in Non-small Cell Lung Cancers: a Meta-Analysis Including 3564 Patients. Pathol Oncol Res 2019.

      6. Travis WD, et al. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. 4th ed. Lyon: International Agency for Research on Cancer; 2015.

      7. Uruga H, et al. Will spread through air spaces be a staging parameter in lung cancer? Journal of thoracic disease 2018;10:593-6.

      8. Dai C, et al. Tumor Spread through Air Spaces Affects the Recurrence and Overall Survival in Patients with Lung Adenocarcinoma >2 to 3 cm. J Thorac Oncol 2017;12:1052-60.

      9. Eguchi T, et al. Lobectomy Is Associated with Better Outcomes than Sublobar Resection in Spread through Air Spaces (STAS)-Positive T1 Lung Adenocarcinoma: A Propensity Score-Matched Analysis. J Thorac Oncol 2019;14:87-98.

      10. Walts AE, et al. Current Evidence Does Not Warrant Frozen Section Evaluation for the Presence of Tumor Spread Through Alveolar Spaces. Arch Pathol Lab Med 2018;142:59-63.

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    OA14 - Update of Phase 3 Trials and the Role of HPD (ID 148)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
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      OA14.03 - Clinical Rationale and Preclinical Evidence for Chimeric Antigen Receptor (CAR) T Cell Therapy Clinical Trial in KRAS-Mutant Lung Cancer (ID 3075)

      11:30 - 13:00  |  Author(s): Takashi Eguchi

      • Abstract
      • Slides


      Chimeric antigen receptor (CAR) T cells are engineered to express a synthetic receptor that redirects specificity to a tumor-associated antigen (TAA). Mesothelin (MSLN) is a TAA expressed by solid tumors, notably in mesothelioma and lung adenocarcinoma (ADC). Our group clinical trial of MSLN-targeted CAR T cells in mesothelioma demonstrated a favorable safety profile and evidence of antitumor activity. In this study, we evaluated the feasibility and utility of MSLN-targeted CAR T cell therapy in advanced, KRAS-mutant lung ADC.


      Tissue microarray from stage I-III lung ADC tumors (n=1438) were reviewed by two pathologists, then stained for MSLN expression on cell-surface and cytoplasm. Of 327 patients with distant recurrences, adequate tissue was available from 34 autologous metastatic sites for MSLN expression evaluation. Healthy donor T cells were retrovirally transduced with a MSLN-targeted CAR. In vitro function against lung ADC cell lines with heterogenous MSLN expression resembling human tumors was assessed via chromium release assay, ELISA, and flow cytometry. In vivo antitumor efficacy (n=30) was evaluated by median survival and tumor bioluminescence in mice bearing lung ADC tumors.


      The incidence of cell-surface MSLN expression was higher in metastases than matched primary tumors (65% vs 38%) and higher in KRAS-mutant than wild type tumors (42% vs 32%). CAR T cells secrete cytokines and lyse lung ADC cell lines in proportion to their cell-surface MSLN expression. No activity against MSLN-very low mesothelial or MSLN-negative lung ADC cell lines was observed. In vivo, a single dose of CAR T cells eradicates established primary and metastatic MSLN-high tumors without evidence of on-target off-tumor toxicity.


      Therapeutically-relevant cell surface MSLN expression is enriched in a population of KRAS-mutant lung ADC patients with poor prognosis and limited treatment options. MSLN-targeted CAR T cells exhibit antigen-specific and antigen density-dependent cytotoxicity against lung ADC cells in vitro and in vivo with no on-target, off-tumor toxicity to normal tissues. These results provide strong rationale for our upcoming MSLN-targeted CAR T cell therapy clinical trial in metastatic, KRAS-mutant lung ADC patients.

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