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P. Illei



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    P2.06 - Poster Session 2 - Prognostic and Predictive Biomarkers (ID 165)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.06-045 - c-Met Expression in Malignant Mesotheliomas (ID 3216)

      09:30 - 09:30  |  Author(s): P. Illei

      • Abstract

      Background
      Met is a receptor tyrosine kinase that is encoded by c-Met a proto-oncogne. Abnormal c-met expression has been described in several solid tumors most notably in non small cell lung carcinoma and gastric carcinoma where tumor growth and survival is driven by met signaling. Furthermore, met is also a resistance pathway for EGFR tyrosine kinase inhibitors. Met-targeted therapies are currently being tested in clinical trials and met IHC is being used as one of the methods to evaluate met expression. Malignant mesothelioma is an aggressive tumor with limited treatment options and short survival. Met-based therapies could be considered in mesotheliomas with deregulated c-Met expression.

      Methods
      The study cohort included 39 malignant mesothelioma (Age 15-91 years; Sex: 11 female and 28 male; Histologic type: 1 sarcomatoid, 7 biphasic and 21 epithelioid, primary location: 8 peritoneal and 31 pleural). Immunohistochemistry was performed using an anti-total c-Met rabbit monoclonal antibody (clone SP-44, Ventana Medical Systems, Tucson, AZ, USA) using 4 micron sections of large biopsies or resection specimens and an automated platform (Ventana Benchmark Ultra, Ventana Medical Systems, Tucson, AZ, USA). The staining was evaluated for intensity (none, week, moderate, strong) and extent (percent of tumor staining) and a score was assigned to each tumor on a scale from 0 to 3+ (0: no staining, 1+: any staining in less than 50% of tumor, 2+: moderate to strong staining in >50% of tumor, 3+: strong staining in >50% of tumor). Tumors with and IHC score of 3+ and 2+ were considered positive.

      Results
      Twenty (20) tumors were scored negative and 19 tumors positive. Strong (3+) staining was seen in 3 epithelioid mesotheliomas (all pleural), 2+ staining was seen in 1 biphasic and 15 epithelioid mesotheliomas, while the remaining 6 biphasic, 1 sarcomatoid and 13 epithelioid mesotheliomas were negative (1+: 19; 0: 1).

      Conclusion
      c-Met positivity (3+ or 2+) is seen in the majority of epithelioid mesothelomas (18 of 21) and in the minority of biphasic mesotheliomas (1 of 7), while the single sarcomatoid mesothelioma was negative. Since the majority of malignant mesotheliomas are of the epithelioid subtype we expect the majority of malignant mesotheliomas be considered met positive as determined by immunohistochemistry and potentially amenable to met-targeted therapy. Correlation with met amplification and activating c-met mutations needs to be investigated to better understand the mechanisms of c-met over expression in malignant mesotheliomas.

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    P2.15 - Poster Session 2 - Thymoma (ID 191)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Thymoma & Other Thoracic Malignancies
    • Presentations: 1
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      P2.15-007 - Digital Microscopy Reproducibility Study of Thymic Epithelial Neoplasms (ID 2883)

      09:30 - 09:30  |  Author(s): P. Illei

      • Abstract

      Background
      Thymic epithelial tumors are rare and morphologically heterogeneous which constitutes interpretive challenges to practicing pathologists. Advances in digital imaging provide an opportunity to disseminate knowledge of these rare tumors, and can be potentially useful as diagnostic and educational tools. However the diagnostic reproducibility utilizing digital slide imaging needs to be validated.

      Methods
      Twenty cases of thymomas or thymic carcinomas with characteristic morphologic features were scanned into the APERIO system. The images were sent to pathologists with expertise in thoracic pathology in 6 different centers. The pathologists were asked to classify the tumors according to the World Health Organization (WHO) 2004 classification and to evaluate invasion on the scanned material. In addition, they were asked to indicate their confidence in the diagnosis using the imaging system. Interobserver agreement was evaluated. After discussions of the first 20 cases, a second round representing 10 cases were evaluated by digital images by the participating pathologists.

      Results
      In the initial phase, there was agreement among pathologists for the diagnosis of thymoma and thymic carcinoma in 75 % of cases (n= 14), in the remaining 6 cases, the disagreement was between cases of B3 thymoma and thymic carcinoma in five and between Type A thymoma and thymic carcinoma in one (kappa=0.43, moderate agreement). Perfect agreement was seen in 4 thymoma cases, where all pathologists diagnosed the same WHO type. These were classical cases with pushing borders and large fibrous bands. In other cases there were disagreements among the classification of the tumor as B2, B3, and AB. The cases with most disagreement were histologically heterogeneous with combined patterns. When invasion was evaluated, the overall k coefficient is 0.49 for the presence of invasion. In the second round of cases, we observed an improvement in interobserver agreement for diagnosis thymoma vs thymic carcinoma (kappa = 0.63) and for determination of invasion (present versus absent) (k=0.57). Most pathologists found that the digital images were comparable with glass slides and the overall confidence in the diagnosis was good.

      Conclusion
      The diagnostic accuracy of thymic epithelial tumors by digital images is equivalent to that reported in prior studies using glass slides. Digital imaging is a good tool for remote consultation and educational purposes. In the majority of specimens, pathologists are able to make the correct diagnosis. Major challenges include distinguishing B3 tumors and carcinomas and tumors with morphologic heterogeneity. The overall agreement can be improved after training. This technology could be used to establish a digital slide bank which could provide a method for training pathologists with less experience in the pathology of thymic epithelial tumors, to foster collaborative work in the field, and diagnostic consultation.

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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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      P2.18-007 - Correlating Histologic and Molecular Features in the Lung Adenocarcinoma TCGA Project (ID 1698)

      09:30 - 09:30  |  Author(s): P. Illei

      • Abstract

      Background
      Our understanding of the molecular landscape of lung adenocarcinoma (ADC) is evolving rapidly. Furthermore, the IASLC/ATS/ERS lung ADC classification was recently published. The histologic and molecular correlations have not yet been thoroughly explored in this rapidly changing field. We sought to investigate the molecular findings according to the IASLC/ATS/ERS classification. .

      Methods
      Aperio© scanned H&E stained slides were reviewed from 230 tumors according to the 2011 IASLC/ATS/ERS lung adenocarcinoma classification criteria. Molecular profiling was performed on 230 resected, untreated lung adenocarcinomas, using mRNA, miRNA and DNA sequencing integrated with copy number, methylation and proteomic analyses. Histologic molecular correlations focused on mRNA and DNA sequencing and TTF-1 proteomic findings.

      Results
      We found 12 lepidic predominant ADC (5%), 21 papillary predominant (9%), 77 acinar predominant (33%), 33 micropapillary predominant (14%), and 58 solid predominant (25%) as well as, 9 invasive mucinous (4%), and 20 unclassifiable ADCs (9%). EGFR mutation and KRAS mutations were found in 8% and 17% of lepidic ADC, respectively. Nine of 12 lepidic ADC (75%) were of the terminal respiratory unit (TRU) gene expression subtype (GES) and 3 (25%)were in the 19p-depleted transcriptional GES, but none were found in the solid-enriched GES (Figure; p=0.007). Most of the papillary ADC were of the TRU (10/21, 47.6%) and 19p-depleted transcriptional (9/21, 42.9%) GES (p=0.026). 46% (41/89) of acinar ADC tumors were in the TRU-GES compared to the solid enriched (18/78, 23.1%) and 19p-depleted transcriptional (18/63, 28.6%) GES (p=0.005). When the oncogene positive group was defined including KRAS, EGFR, ALK, RET, ROS1, BRAF, ERBB2, HRAS and NRAS, there was a higher percentage of solid ADC in the oncogene negative (30/93, 32.3%) compared to the oncogene positive group (28/137, 20.4%, p=0.046). The highest percentage of solid ADC was found in the solid-enriched GES (47/78, 47.4%) compared to the 19p-depleted transcriptional (17/63, 27%) and TRU GES (4/89, 4.5%) (p<0.001). Invasive mucinous ADC correlated with KRAS (but no EGFR) mutations (67%) compared to other ADC (28%, p=0.02) and also lacked elevation of TTF-1 (p=0.007). GES was associated with histologic grade: high grade with solid-enriched GES and intermediate/low grade with TRU GES (p<0.001). Figure 1

      Conclusion
      Our data reveal multiple correlations between molecular (mutation and GES) and histologic (subtyping and grade) features. This reveals insights into the biology of these tumors in particular genetic characteristics of the high grade tumors which may lead to better understanding of why these are more aggressive tumors.

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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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      P3.18-015 - <strong>The Utility of a Novel Triple Marker (combination of TTF, napsin-A and p40) in the Subclassification of Non-small Cell Lung Cancer (NSCLC).</strong> (ID 2911)

      09:30 - 09:30  |  Author(s): P. Illei

      • Abstract

      Background
      Personalized treatment of lung cancers necessitates the subclassification of NSCLC into adenocarcinoma (ADC) and/or squamous cell carcinoma (SqCC). In most cases, NSCLC can be subclassified by routine histomorphological examination of tumors. However, in poorly differentiated tumors or on small biopsy specimens, the subclassification may be difficult by H&E slides alone. Therefore, a panel of immunehistochemical (IHC) markers, including TTF1, Napsin A for adenocarcinoma (ADC) and CK5/6, p63 and p40 for squamous cell carcinoma (SqCC), are usually used to aid in the subclassification, These panels need to be performed on multiple tissue sections, and may result in the exhaustion of tumor tissue for molecular tests. In order to preserve tumor tissue, we investigated the utility of a newly developed triple marker (a combination of TTF, Napsin A and p40) in the subclassification of NSCLC; and compared the sensitivity and specificity of this novel triple marker with commonly used individual markers.

      Methods
      Using pathology archives from Johns Hopkins Hospital, three lung cancer tissue microarrays (TMAs) were constructed using surgical resection material, including 77 cases of ADC, 75 cases of SqCC and 46 cases of metastatic lung ADC. Immunostaining patterns of the triple marker and individual markers were scored semi-quantitatively and compared.

      Results
      In ADC, the sensitivity and specificity of the triple marker showed 93.50% and 77.50%, respectively (Table 1). In SqCC, the sensitivity and specificity of the triple marker showed 100% and 92.50%, respectively (Table 2). In addition, the sensitivity and specificity of the triple marker in metastatic ADC showed 71.74% and 77.50%. Table 1. Immunostaining patterns of different markers in lung ADC (n=77 cases)

      IHCscores
      Markers 0 1 2 3 Sensitivity Specificity P value
      Triple marker 6.5% 10.4% 13.0% 70.1% 93.5% 77.5%
      TTF 14.3% 5.2% 32.5% 48.1% 85.7% 75.0% 0.185
      Napsin A 10.4% 9.1% 22.1% 58.4% 89.6% 90.0% 0.564
      Table 2. Immunostaining patterns of different markers in lung SqCC (n=75 cases)
      IHC scores
      Markers 0 1 2 3 Sensitivity Specificity P value
      Triple marker 0% 29.3% 33.3% 37.3% 100% 92.5%
      p40 0% 32.0% 29,3% 38.7% 100% 90.0% 1.0
      p63 0% 24.0% 45.3% 30.7% 100% 80.5% 1.0
      CK5/6 5.3% 22.7% 36.0% 36.0% 94.7% 80.0% 0.12

      Conclusion
      Our triple marker showed a similar specificity and sensitivity as individual markers and yielded optimal conservation of tissue for molecular testing.