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W.D. Travis

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    P1.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 233)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      P1.04-010 - Pilot Internet Survey of Interobserver Variability in Pathology Diagnoses of Multiple Tumor Nodules (ID 2851)

      09:30 - 17:00  |  Author(s): W.D. Travis

      • Abstract
      • Slides

      The distinction between separate primary lung cancers (SPLC) or intrapulmonary metastases (IM) is of great clinical importance because of the substantial staging and prognostic implications. With the broad implementation of CT screening for lung cancer, the recognition of multiple tumor nodules is increasingly common. Currently, similarities and differences in histology between two tumors provide the most definitive distinction between SPT and IM. However, the level of agreement among pathologists regarding this question has not been tested. The IASLC Pathology Committee and the Multidisciplinary SPT Working Group has addressed this issue through a pilot online survey. This study assesses the feasibility and reports preliminary results of a web-based survey to determine interobserver variation in distinguishing SPT and IM.

      A pilot study was conducted to test whether multiple observers could assess a collection of 50 cases of multiple tumors through a digital web-based system. Five pairs of resected nodules were assembled from the University of Colorado and scanned into an image database using an Aperio AT2 slide scanner (Leica Biosystems) with a 40X objective. Reviewers were asked to review slide images, to provide a histological diagnosis according to WHO criteria, to answer questions regarding specific histological details related to each nodule and to determine whether the multiple nodules were SPT and IM. Combined results were evaluated for level of concordance on the central question of primary or metastatic status. Results were also correlated with EGFR, KRAS, ALK and TP53 mutational status.

      A total 21 pulmonary pathology subspecialists completed the survey, evaluating 10 nodules from 5 patients. Ten of the reviewers were from the US, 3 from Japan, 2 from the UK, and one each from Canada, France, Germany, the Netherlands, Korea and Sweden. On the question of SPLC vs IM, 10 reviewers agreed on all cases and these determinations were regarded the histological consensus. There was 85% overall concordance with the consensus diagnosis. Most of dissenting opinions related to a single case. In all but one instance, tumors from the same individual with different histological diagnoses were designated SPLC. However, in 30% of the cases, tumors from the same individual with identical histological diagnoses were determined to be SPLC. The histological attributes regardless of WHO diagnostic category that significantly (each p>0.0001) contributed to this conclusion included lepidic growth, cell size, nuclear pleomorphism and nucleolar prominence. The mutational status of these cases was in complete agreement with the histological consensus. Mutations that distinguished SPT included KRAS, EGFR or TP53 mutation in only one member of a tumor pair or different EGFR mutations in each member of a pair. In IM, identical KRAS mutation was found in both members of a tumor pair.

      In this pilot study a high level of consensus was achieved in separating SPLC vs or IM. A large minority (30%) of tumor pairs with identical histological diagnoses were determined to be SPLC suggesting that histological features beyond those used for WHO classification are taken into account when determining SPT status.

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    PLEN 02 - Lung Cancer: IASLC Global Initiatives (ID 51)

    • Event: WCLC 2015
    • Type: Plenary
    • Track: Plenary
    • Presentations: 1
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      PLEN02.01 - 2015 WHO Classification of the Pathology and Genetics of Tumors of the Lung (ID 2041)

      08:15 - 09:45  |  Author(s): W.D. Travis

      • Abstract
      • Presentation

      The 2015 WHO Classification of Tumors of the Lung, Pleura, Thymus and Heart has just been published with numerous important changes from the 2004 WHO classification, due in part to remarkable advances in lung cancer genetics and therapy.[1] Multiple major changes for the common lung cancers mostly follow the 2011 lung adenocarcinoma classification sponsored by the International Association for the Study of Lung Cancer (IASLC), American Thoracic Society (ATS) and European Respiratory Society (ERS).[2 ] This 2015 edition follows previous WHO Classifications of Lung Tumors in 1967 and 1981, of Lung and Pleural Tumors in 1999 and Tumors of the Lung, Pleura, Thymus and Heart in 2004.[3, 4] Through support of its Pathology Committee, the IASLC has played a key role in the last three WHO Classifications.[5] With each subsequent classification, new techniques were introduced resulting in increased complexity, but greater ability to personalize therapeutic strategies that are now frequently dependent on histology and genetics. The most significant changes in the 2015 Classification involve: 1) Use of immunohistochemistry throughout the classification, when possible, not only for small biopsies/cytology, but also for resected specimens in certain settings such as solid adenocarcinoma, nonkeratinizing squamous cell carcinoma, large cell carcinoma, neuroendocrine tumors and sarcomatoid carcinomas. 2) A new emphasis on genetic studies, in particular integration of molecular testing to help personalize treatment strategies for advanced lung cancer patients. Due to the therapeutic implications, molecular testing for EGFR mutation and ALK rearrangement is today recommended in tumors classified as adenocarcinoma and in cases where an adenocarcinoma component cannot be excluded.[2, 6] 3) A new classification for small biopsies and cytology similar to that proposed in the 2011 IASLC/ATS/ERS Classification[2] proposes that tumors that have clear morphologic patterns of adenocarcinoma or squamous cell can be diagnosed as adenocarcinoma or squamous cell carcinoma, respectively, without immuhistochemistry, unless a pneumocyte marker such as TTF-1 is desired to address primary versus metastatic adenocarcinoma. However, in the setting of poorly differentiated tumors that do not show clear differentiation by routine microscopy, a limited immunohistochemical workup is recommended to allow for an accurate diagnosis and also to preserve as much tissue for molecular testing as possible. Most tumors can be classified using a single adenocarcinoma marker (e.g. TTF-1) and a single squamous marker (e.g. p40 or p63). Nonsmall cell carcinomas (NSCC) that show no clear adenocarcinoma or squamous cell carcinoma morphology or immunohistochemical markers are regarded as NSCC not otherwise specified (NOS). If a tumor with this morphology stains with pneumocyte markers (i.e. TTF-1), it is classified as NSCC, favor adenocarcinoma and if it stains only with squamous markers (i.e. p40) it is classified as NSCC, favor squamous cell carcinoma. Using this approach, a diagnosis of NSCC-NOS can be avoided in up to 90% of cases.[7, 8 ] 4) According to the 2011 IASLC/ATS/ERS Classification of lung adenocarcinoma, adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) were defined as entities to have 100% or near 100% disease free survival if completely resected, respectively. Also, invasive adenocarcinomas are classified according to the predominant pattern using comprehensive histologic subtyping (CHS). Multiple studies have shown prognostic significance to this approach with favorable outcome for lepidic adenocarcinomas and poor outcome for solid and micropapillary adenocarcinomas. CHS can be helpful in staging as well: 1) along with other morphologic features, it can be useful in comparing multiple lung adenocarcinomas in a single patient in order to distinguish multiple primary tumors from intrapulmonary metastases and 2) it can also help in measuring invasive size in lepidic adenocarcinomas. Micropapillary or solid predominant subtyping also appears to predict improved responsiveness to adjuvant chemotherapy compared to acinar or papillary predominant tumors in surgically resected lug adenocarcinoma patients when analyzed by disease free survival and specific disease free survival.[9] 5) The diagnosis of large cell carcinoma is restricted only to resected tumors that lack any clear morphologic or immunohistochemical differentiation with reclassification of the remaining former large cell carcinoma subtypes into different categories. 6) Squamous cell carcinomas are reclassified into keratinizing, nonkeratinizing and basaloid subtypes with the non-keratinizing tumors requiring immunohistochemistry proof of squamous differentiation. 7) Neuroendocrine tumors are grouped together in one category, although new genetic data supports previous clinical, epidemiologic and pathologic data showing that low and intermediate grade typical (TC) and atypical carcinoids (AC) are distinct from the high grade small cell carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC). Ki-67 is useful to distinguish carcinoids from SCLC and LCNEC especially in small crushed biopsies. However, published data do not support incorporation into the classification, particularly in separating TC from AC. Spread through air spaces (STAS) is a newly recognized pattern of invasion which consists of micropapillary clusters, solid nests or single cells beyond the edge of the tumor into air spaces in the surrounding lung parenchyma, It probably contributes to the significantly increased recurrence rate for patients with small stage 1 adenocarcinomas who undergo limited resections.[10] Future clinical trials and large scale genetic studies such as The Cancer Genome Atlas (TCGA) need to incorporate the new pathologic criteria for both small biopsies and resection specimens which now require immunohistochemistry to precisely classify poorly differentiated tumors such as solid adenocarcinoma or nonkeratinizing squamous cell carcinoma. Despite promising preliminary data, additional work is needed to develop a histological grading system for lung cancer. Acknowledgement: This abstract is presented with gratitude on behalf of the WHO Panel and the IASLC Pathology Committee. References: 1. Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. Lyon: International Agency for Research on Cancer; 2015. 2. Travis WD, Brambilla E, Noguchi M, et al. The New IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification. JThoracic Oncol 2011;6:244-85. 3. Travis WD, Colby TV, Corrin B, Shimosato Y, Brambilla E, in collaboration with LHS, Countries pf. Histological Typing of Lung and Pleural Tumors. Berlin: Springer; 1999. 4. Travis WD, Brambilla E, Mller-Hermelink HK, Harris CC. Pathology and Genetics: Tumours of the Lung, Pleura, Thymus and Heart. Lyon: IARC; 2004. 5. Tsao MS, Travis WD, Brambilla E, Nicholson AG, Noguchi M, Hirsch FR. Forty years of the international association for study of lung cancer pathology committee. J Thorac Oncol 2014;9:1740-9. 6. Lindeman NI, Cagle PT, Beasley MB, Chitale DA, Dacic S, Giaccone G, Jenkins RB, Kwiatkowski DJ, Saldivar JS, Squire J, Thunnissen E, Ladanyi M. Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors: Guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. J ThoracOncol 2013. 7. Nicholson AG, Gonzalez D, Shah P, Pynegar MJ, Deshmukh M, Rice A, Popat S. Refining the Diagnosis and EGFR Status of Non-small Cell Lung Carcinoma in Biopsy and Cytologic Material, Using a Panel of Mucin Staining, TTF-1, Cytokeratin 5/6, and P63, and EGFR Mutation Analysis. JThoracOncol 2010;5:436-41. 8. Loo PS, Thomas SC, Nicolson MC, Fyfe MN, Kerr KM. Subtyping of Undifferentiated Non-small Cell Carcinomas in Bronchial Biopsy Specimens. JThoracOncol 2010;5:442-7. 9. Tsao MS, Marguet S, Le Teuff G, Lantuejoul S, Shepherd FA, Seymour L, Kratzke R, Graziano SL, Popper HH, Rosell R, Douillard JY, Le-Chevalier T, Pignon JP, Soria JC, Brambilla EM. Subtype Classification of Lung Adenocarcinoma Predicts Benefit From Adjuvant Chemotherapy in Patients Undergoing Complete Resection. J Clin Oncol 2015. 10. Kadota K, Nitadori JI, Sima CS, Ujiie H, Rizk NP, Jones DR, Adusumilli PS, Travis WD. Tumor Spread Through Air Spaces is an Important Pattern of Invasion and Impacts the Frequency and Location of Recurrences Following Limited Resection for Small Stage I Lung Adenocarcinomas. J Thorac Oncol 2015;10:806-14.

      Lepidic adenocarcinoma
      Acinar adenocarcinoma
      Papillary adenocarcinoma
      Micropapillary adenocarcinoma
      Solid adenocarcinoma
      Invasive mucinous adenocarcinoma Mixed invasive mucinous and non-mucinous adenocarcinoma
      Colloid adenocarcinoma
      Fetal adenocarcinoma
      Enteric adenocarcinoma
      Minimally invasive adenocarcinoma Non-mucinous Mucinous
      Preinvasive lesions Atypical adenomatous hyperplasia Adenocarcinoma in situ Nonmucinous Mucinous
      Squamous cell carcinoma
      Keratinizing squamous cell carcinoma
      Non-keratinizing squamous cell carcinoma
      Basaloid squamous cell carcinoma
      Preinvasive lesion Squamous cell carcinoma in situ
      Neuroendocrine tumors
      Small cell carcinoma Combined small cell carcinoma
      Large cell neuroendocrine carcinoma Combined large cell neuroendocrine carcinoma
      Carcinoid tumors Typical carcinoid Atypical carcinoid
      Preinvasive lesion Diffuse idiopathic pulmpnary neuroendocrine cell hyperplasia
      Large cell carcinoma

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