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A. Yoshizawa



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    O17 - Anatomical Pathology I (ID 128)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Pathology
    • Presentations: 1
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      O17.05 - Accuracy and Interobserver Agreement in Identifying Histologic Subtypes in Stage I Lung Adenocarcinomas ≤3 cm Using Frozen Section (ID 2590)

      11:15 - 11:25  |  Author(s): A. Yoshizawa

      • Abstract
      • Presentation
      • Slides

      Background
      The new IASLC/ATS/ERS classification of lung adenocarcinoma (ADC) histologic subtypes is now recommended for prognostic stratification. The ability to determine histologic subtype accurately by frozen section (FS) may help surgeons to choose limited resection versus anatomic resection in the management of lung ADC. The aim of this study is to investigate the accuracy and interobserver agreement of FS for predicting histologic subtype.

      Methods
      FS and permanent section slides from 361 surgically resected stage I lung ADCs ≤3 cm were reviewed for predominant histologic subtype and presence or absence of lepidic, acinar, papillary, micropapillary, and solid patterns. To determine interobserver agreement, 50 cases were additionally reviewed by 3 pathologists. To test the accuracy of FS in determining degree of invasion in cases with predominantly lepidic growth pattern, 5 pathologists reviewed FS slides from 35 patients and attempted to discriminate between adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and lepidic predominant adenocarcinoma (LPA).

      Results

      Parameter Accuracy, % (95% CI) Sensitivity, % (95% CI) Specificity, % (95% CI) κ
      Predominant histologic subtype
      Overall 68 (63–73) Not applicable Not applicable 0.565
      Lepidic 90 (86–92) 75 (64–84) 93 (90–96) 0.681
      Acinar 76 (71-80) 70 (61–77) 79 (73–84) 0.481
      Papillary 85 (81-88) 62 (50–72) 91 (87–94) 0.527
      Micropapillary 94 (91-96) 21 (9–40) 99 (97–100) 0.277
      Solid 91 (88-94) 79 (67–87) 94 (90–96) 0.700
      Presence or absence of each histologic pattern
      Lepidic 80 (76–84) 75 (69–80) 91 (84–96) 0.588
      Acinar 89 (85–92) 90 (86–93) 67 (35–90) 0.252
      Papillary 72 (67–77) 70 (64–75) 79 (69–87) 0.397
      Micropapillary 67 (62–72) 37 (30–45) 94 (89–97) 0.321
      Solid 84 (80–88) 69 (61–76) 96 (92–98) 0.670
      The accuracy of FS for predicting histologic subtype is shown in the Table. There was moderate agreement on the predominant histologic subtype between FS diagnosis and final diagnosis (κ=0.565). FS had high specificity for micropapillary and solid patterns (94% and 96%, respectively), but sensitivity was low (37% and 69%, respectively). The interobserver agreement was satisfactory (κ > 0.6, except for acinar pattern). All cases of AIS were correctly diagnosed using FS. For MIA, only 41.3% of FS diagnoses were correct, and 52% were overdiagnosed as LPA; for cases of LPA, 79% of FS diagnoses were correct.

      Conclusion
      FS can provide information on the presence of aggressive histologic patterns—micropapillary and solid—with high specificity but low sensitivity. FS is not suitable for determining the predominant pattern or degree of invasion. Although FS can be helpful in diagnosing AIS, it has poor accuracy in distinguishing MIA from LPA.

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    P3.18 - Poster Session 3 - Pathology (ID 177)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Pathology
    • Presentations: 1
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      P3.18-006 - Non-terminal respiratory unit lung adenocarcinoma: can have 3 subtypes and is associated with poor prognosis (ID 1727)

      09:30 - 09:30  |  Author(s): A. Yoshizawa

      • Abstract

      Background
      Terminal respiratory unit (TRU) adenocarcinoma, which is proposed as a distinct subset of lung adenocarcinomas, develops in periphery of the lung parenchyma, is similar in cell morphology to type II pneumocytes or Clara cells, is positive for the expression of thyroid transcription factor-1 (TTF-1), and harbors mutations in the gene encoding the epidermal growth factor receptor (EGFR). The clinicopathological characteristics are generally well defined. In contrast, few studies have focused on non-TRU type adenocarcinomas. We herein analyzed clinicopathologic and prognostic findings of non-TRU type adenocarcinomas.

      Methods
      We selected 244 consecutive patients with lung adenocarcinomas underwent pulmonary resection at Kyoto University Hospital between January 2001 and December 2007. All cases were classified according to IASLC/ATS/ERS criteria. Findings of significant prognostic factors for lung adenocarcinomas prompted analyses of lymphatic invasion, vascular invasion, pleural invasion, tumor grade. We annalyzed immunohistochemical expression of the mucins MUC5B, MUC5AC, as well as TTF-1 using TMA blocks comprising lung adenocarcinoma specimens from the 244 patients. The presence of mutations in EGFR and KRAS was also determined.

      Results
      TTF-1, MUC5B, and MUC5AC were detected in 219 (89.6%), 75 (30.7%) and 33 cases (13.5%), respectively. Cluster analysis of the protein expression and EGFR and KRAS mutations yielded four classes of tumors as follows: TRU-type (TTF-1(+), MUC5B(-), MUC5AC(-)); Combined-type (TTF-1(+), MUC5B(+) and/or MUC5AC(+)); Bronchiolar-type (TTF-1(-), MUC5B(+) and/or MUC5AC(+)); and Null-type (TTF-1(-), MUC5B(-), MUC5AC(-), EGFR mutations(-), KRAS mutations(-)). TRU-type tumors were significantly associated with non-mucinous adenocarcinoma in situ (AIS), whereas Bronchiolar-type tumors were associated with mucinous AIS. Combined-type cases were intermediate in morphology between TRU-type and Bronchiolar-type cases (P < 0.001). TRU-type was associated with significantly better prognosis (5-year disease free survival rate (5y-DFS-rate) = 75.2%, 5-year overall survival rate (5y-OS-rate) = 83.8%), followed by Combined-type (5y-DFS-rate = 61.7%, 5y-OS-rate = 73.2%), Bronchiolar-type (5 y-DFS-rate = 53.6%, 5y-OS-rate = 53.9%), and Null-type (5y-DFS-rate = 40.0%, 5 y-OS-rate = 40.0%). Multivariate analyses indicated that non-TRU type significantly correlated with poorer prognosis for DFS (hazard ratio (HR) = 1.946; 95% confidence interval (CI) 1.139-3.322; P = 0.015) and OS (HR = 1.933; 95% CI 1.072-3.491; P = 0.030).

      Conclusion
      The present study demonstrates that lung adenocarcinomas expressing MUC5B and MUC5AC could represent the non-TRU type and have a poorer prognosis than that of TRU-type lung adenocarcinomas. In addition, three distinct subtypes of non-TRU type adenocarcinomas were discovered. There are no effective treatments for patients with non-TRU type lung adenocarcinoma, while patients with TRU-type lung adenocarcinoma can be treated with EGFR inhibitors. Therefore, the characterization of non-TRU type lung adenocarcinomas described here, suggests that patients with this disease can be identified as candidates for receiving treatments that will hopefully be developed in the future.