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S. Dacic



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    MS21 - Practical Problems in Lung Cancer Diagnosis - Application of the 2011 Adenocarcinoma Classification (ID 38)

    • Event: WCLC 2013
    • Type: Mini Symposia
    • Track: Pathology
    • Presentations: 1
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      MS21.5 - Molecular Analysis for Distinction Second Primary of the Lung vs Lung Metastasis? (ID 560)

      14:00 - 15:30  |  Author(s): S. Dacic

      • Abstract
      • Presentation
      • Slides

      Abstract
      Background: The development of high-resolution chest imaging techniques and screening of smokers for lung cancer resulted in increased detection of multiple lung cancers. The challenge for pathologists and treating physicians is to determine whether multiple lung cancers represent separate primary tumors or metastasis, as this affects the stage, treatment and prognosis. The clinical and pathological criteria used to define multiple lung tumors were initially published by Martini and Melamed in 1975. These criteria are based on tumor morphology and location and may not predict prognosis. The AJCC 7[th] edition staging of lung adenocarcinoma recognized shortcomings of this proposal and incorporated changes in the staging of multiple lung cancer, but molecular genetic analysis was not recommended as a standard approach. Methods: PubMed available peer-reviewed original articles and experience of the author. Results: Distinction between primary tumors and intrapulmonary metastasis becomes challenging when tumors are morphologically similar. Since the original Martini and Melamed proposal, many molecular approaches have been utilized in the evaluation of clonal relationships between multiple lung nodules including DNA microsatellite analysis, PCR assays for common somatic mutations, aCHG, and gene expression analysis. Molecular classification of multiple lung cancers is concordant with pathological classification in about two-thirds of the cases. It is difficult to determine the precise percentage because of the relatively small number of analyzed cases, mixed analysis of synchronous and metachronous tumors, and use of different methods and interpretation criteria. Early studies used two types of clonality assays: a panel of variable number of polymorphic microsatellite markers and X-chromosome inactivation analysis (Am J Surg Pathol 2005; 29(7):897;Ann Diagn Pathol 2001;5(6):321; Clin Cancer Res 2000; 6(10):3994; J Natl Cancer Inst 2009;101:560) . Tumors with largely concordant results were considered clonal in origin (metastases), and those with discordant findings were considered to be independent primary tumors. The main weakness of earlier studies was a limited number of analyzed genes. Recently, more comprehensive approaches analyzing a large number of single nucleotide polymorphic loci in a single assay or large-scale DNA sequencing of tumors were used (Clin Cancer Res 2009; 15(16):5184; Lung Cancer 2012;77:281). Although more comprehensive molecular approaches were used, a proportion of cases with discordant molecular and morphological results remained similar. Furthermore, molecular profiling only slightly improved prognostic classification of multiple lung tumors. Standard practice is to test non-resectable adenocarcinomas for common actionable somatic mutations (e.g. EGFR) and gene rearrangements (e.g. ALK) as predictors of response to targeted therapies. This information can also be used for improved staging of multiple lung nodules (Eur Resp J 2012; 39:1437; Lung Cancer 2012; 77:281). Based on similar or different mutational profile synchronous tumors may be classified as independent primaries or intrapulmonary metastases. It is very likely that surgically non-resectable tumors with different mutational profiles such as EGFR and KRAS will show different treatment responses, further emphasizing the need for separate analysis of multifocal tumors. In contrast to morphologic classification, molecular profiling can be performed on the cytology specimens. This approach can be used in adenocarcinoma only, and currently no standard molecular testing in squamous cell carcinoma is in practice. Conclusions: Molecular approaches to classification of multiple lung tumors have not been standardized, and their performance in routine clinical practice remain to be established. Testing for common activating oncogenic mutations and translocations is likely to provide information about clonal relationship between multifocal lung tumors. Implementation of molecular information to current histologic staging could improve the accuracy of staging in patients with multifocal tumors and improve therapeutic decision making.

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    O04 - Molecular Pathology I (ID 126)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Pathology
    • Presentations: 1
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      O04.08 - DISCUSSANT (ID 3983)

      10:30 - 12:00  |  Author(s): S. Dacic

      • Abstract
      • Presentation
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      Abstract not provided

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

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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 - 16:30  |  Author(s): S. Dacic

      • 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.