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D.H. Chung



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    P2.18 - Poster Session 2 - Pathology (ID 176)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Pathology
    • Presentations: 1
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      P2.18-002 - A comprehensive comparative analysis of the histomorphological features of ALK-rearranged lung adenocarcinoma based on driver oncogene mutations : frequent expression of epithelial-mesenchymal transition markers than other genotype (ID 221)

      09:30 - 09:30  |  Author(s): D.H. Chung

      • Abstract

      Background
      Molecular classification of lung cancer correlates well with histomorphologic features. However, detailed histomorphologic features which differentiate ALK rearranged tumors from ALK wild type has not been fully evaluated. To investigate histomorphologic features of tumors harboring ALK rearrangement to evaluate the predictive significance of morphologic characterization, we compared the histomorphological analysis between ALK-rearranged and ALK negative lung adenocarcinomas based on driver oncogene mutations.

      Methods
      Eighty resected ALK rearranged lung adenocarcinomas and two hundred thirteen resected ALK negative adenocarcinomas (91 EGFR mutated, 29 K-ras mutated and 93 triple-negative) were analyzed for several histomorphological parameters and histologic subtype based on newly proposed IASLC/ATS/ERS classification.

      Results
      ALK rearranged tumors were associated with a younger age at presentation, frequent nodal metastasis and higher stage at diagnosis, compared with patients with other genotypes. ALK rearranged tumors were more likely to show solid predominant pattern (43.8%, 35/80) than other genotypes (p<0.001) and a lepidic predominant histology was not observed in ALK rearranged tumors (p<0.001). In ALK rearranged tumors, considerable number of the tumors (67.5% , 54/80) contained at least 5% solid pattern but only small number of the tumors (12.5%, 12/80) contained at least 5% lepidic pattern, compared with other genotypes (p<0.001). The most significant morphological features distinguishing ALK rearranged tumors from ALK negative tumors were cribriform formation (OR: 3.253, p=0.028), presence of mucin-containing cells (OR: 4.899, p=0.008), close relation to adjacent bronchioles (OR: 5.361, p=0.001), presence of psammoma body (OR: 4.026, p=0.002) and solid predominant histological subtype (OR: 13.685, p=0.023). ALK-rearranged tumors exhibited invasive histomorphological features, aggressive behavior and frequent expression of epithelial-mesenchymal transition markers (loss of E-cadherin and expression of vimentin) compared with other genotype (p =0.015). Spatial proximity between bronchus and ALK-rearranged tumors and frequent solid histologic subtype with p63 expression may cause diagnostic difficulties to differentiate squamous cell carcinoma in the small biopsy, whereas p40 was rarely expressed in ALK-rearranged adenocarcinoma.

      Conclusion
      Knowledge of these features may improve the diagnostic accuracy and lead to a better understanding of the characteristic behavior of ALK-rearranged tumors.

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

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Pathology
    • Presentations: 2
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      P3.18-016 - The usefulness of frozen section diagnosis as for the decision making milestone during the surgery for pulmonary ground glass nodules: embedding medium inflation technique (ID 2946)

      09:30 - 09:30  |  Author(s): D.H. Chung

      • Abstract

      Background
      The appropriate intraoperative decision making of surgical resection for the pulmonary ground glass nodules (GGN) is often difficult. We aimed to evaluate the role of frozen section diagnosis (FSD) as for the intraoperative decision making milestone and compared its accuracy to that of preoperative CT based practice as an interim result.

      Methods
      We retrospectively reviewed FSD of 171 consecutive pulmonary GGN from February 2005 to June 2013 and compared the diagnostic accuracy. Initially, we used only conventional method (Group A) but recently, we adapted a embedding medium inflation method (Group B) for FSD. The qualities of FSD were compared with the final pathologic diagnoses of corresponding permanent paraffin sections. Also, we calculated the sensitivity, specificity, and predictive values of assessing the size of invasive portion in GGN between FSD using the inflation method and preoperative CT based practice.

      Results
      There were no differences in nodule sizes between two groups (1.45±0.6 versus 1.51±0.5, p=0.63). In group A, a correct differential diagnosis between malignancies and benign lesions were made in 138 nodules. Thirteen nodules were erroneously classified and reported as false-positive or false-negative frozen section diagnoses (Sensitivity 95.6%, Specificity 53.8%). Three nodules were under-diagnosed in FSD. One patient required a secondary operation because of false-negative frozen diagnosis at the time of initial surgery. In group B, all of 17 nodules were correctly classified by frozen section. There were no false-positive or false-negative diagnoses in terms of making a diagnosis of malignancy, resulting in 100%-sensitivity and -specificity. (Figure 1) Thirteen nodules were correctly classified as being either minimally invasive adenocarcinoma (MIA) or invasive adenocarcinoma. Three nodules were diagnosed as MIA by frozen section through measuring invasive tumor size (<5mm) concomitantly. With regards to the estimating the size of invasive components of GGN, FSD in group B was superior to measurement of solid component in GGO nodules on HRCT. (Table 1)Figure 1

      Conclusion
      The accuracy of FSD using the embedding medium inflation method in GGO nodules was outstanding compared to the conventional frozen method. Furthermore, this method can help surgeons plan the appropriate surgical treatment after wedge resection of a GGO nodule by providing accurate size estimation of the invasive components of the GGN.

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      P3.18-020 - The mutational profile of lung adenocarcinoma in Korean population (ID 3097)

      09:30 - 09:30  |  Author(s): D.H. Chung

      • Abstract

      Background
      Recent development of molecular target agents encouraged us to investigate the presence of driver mutations in patients with non-small cell lung cancer. As the prevalence of individual driver mutation is different in each ethnic group, understanding of mutational profiles of a specific country is important for clinical practice as well as for decision-making process of health care. Hence, we investigated the genetic profile of lung adenocarcinoma in Korean population.

      Methods
      Among the patients who underwent surgical resection for lung adenocarcinoma between 2001 and 2011, we set up a total of 477 patients whose fresh frozen lung cancer tissues and paraffin blocks were available. We retrospectively searched medical records of the EGFR exons 18-21 mutation tests results. Then, we selected patients who did not harbor EGFR mutations or who had not tested for EGFR mutations. DNA was extracted from those patients’ samples, and EGFR exons 18-21 and KRAS mutation test were performed by Sanger sequencing method. Tissue microarray was made for all 477 patients, and the EML4-Alk fusion was tested by a break-apart FISH method. We also tested KIF5B-RET fusion by using a break-apart FISH method and also by inversion specific long-range PCR. We investigated any correlation between mutational status and clinical variables, such as age, gender, smoking status, stage, and long term survivals.

      Results
      Among 477 patients, 321 patients (67.3%) were harboring at least one of four driver mutations. The EGFR mutations were the most frequently detected (270, 56.6%), followed by KRAS mutations (37, 7.8%), and EML4-Alk fusion (19, 4.0%). We also found five patients who had KIF5B-RET fusion mutations (1.0%). There were 10 patients who had more than two driver mutations; EGFR and KRAS mutations in 4, EGFR and EML4-Alk fusion in 4, KRAS and EML4-Alk fusion in one, and EGFR and KIF5B-RET fusion in one patient. The presences of EGFR mutations were frequently observed in patients with female gender (p=0.000). Although the EGFR mutations were associated with longer overall survival in univariate analysis (log-rank test rank test p=0.007), the presence of EGFR mutation was not a prognostic factor in multivariate analysis (Cox’s regression test p=0.469). The mutational statuses were associated with neither the disease-free survival nor fthe reedom from recurrence.

      Conclusion
      Based on our work, we found as high as 67.3% of lung adenocarcinoma patients in Korean populations were harboring at least one driver mutation, which may get a benefit from target agents. We also found as high as 2% of patients harbored multiple driver mutations. As the target agent will eventually develop resistance, it is recommended to test each driver mutation thoroughly even if one driver mutation was detected. Furthermore, our observation suggests future molecular testing should be based on the next generation sequencing platform.

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    P3.19 - Poster Session 3 - Imaging (ID 181)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Imaging, Staging & Screening
    • Presentations: 1
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      P3.19-014 - CT Morphologic Patterns, Pathologic Subtypes, and Genetic Phenotypes: A Correlation Study in 600 Nodular Lung Adenocarcinomas (ID 2094)

      09:30 - 09:30  |  Author(s): D.H. Chung

      • Abstract

      Background
      Genotype manifests itself as phenotype and that the one may inform the other. In terms of phenotype, imaging has the potential to assist in noninvasively characterizing the tumor, however, there are very few investigators who have pursued that potential connection between imaging features and the genetic characteristics of lung cancer. The purpose of this study was to retrospectively correlate the CT morphologic patterns of nodular lung adenocarcinomas (ADs) with pathological and molecular phenotypes in an East-Asian cohort of patients.

      Methods
      The institutional review board approved this retrospective study, and all patients provided informed consent. 600 primary lung ADs smaller than 3 cm in diameter that were surgically resected from 592 patients (M:F=257:335; mean age, 63) were included. CT morphologic pattern of ADs was evaluated by three board-certified thoracic radiologists and was classified into four patterns: pure GGN, GGO dominant part-solid nodule (PSN), solid dominant PSN, and pure solid nodule. EGFR mutation, ALK rearrangement, and KRAS mutation were evaluated using PCR-based direct DNA sequencing and FISH. Histologic subtype was classified according to IASLC/ATS/ERS classification of lung AD. The Fisher exact test and student t-test were used to assess statistical significance.

      Results
      Figure 1 In terms of CT morphologic patterns, 17.2%,15.2%, 31.8%, and 35.8% of tumors manifested as pure GGN, GGO dominant PSNs, solid dominant PSNs, and pure solid nodules, respectively. EGFR mutation was significantly more often found in ADs that manifested as subsolid nodules (69.9%, 269/385) than in ADs presented as pure solid nodules (46.7%, 100/214) (P<.0001). ALK rearrangement was more frequent in ADs that manifested as pure solid nodule (8.5%, 13/153) than in tumors presented as subsolid nodule (1.8%, 5/281) (P=.001). KRAS mutation showed no significant difference between subsolid nodules (6.6%, 8/121) and pure solid nodules (8.5%, 5/59) (P=.760). The ratio of subsolid nodule vs pure solid nodule was 72.7% vs 27.3% in ADs with EGFR mutation and was 27.8% vs 72.2% in ADs with ALK rearrangement. EGFR mutation was more frequent in minimally invasive ADs (P=.004) and lepidic predominant ADs (P=.018). ALK rearrangement was more frequent in solid predominant ADs (P=.002) and invasive mucinous ADs (P=.030). KRAS mutation was more frequent in invasive mucinous ADs (P=.001).

      Conclusion
      EGFR mutation was significantly more often found in ADs that manifested as subsolid nodules, and ALK rearrangement was more frequent in ADs that manifested as pure solid nodule.