THE IASLC/ERS/ATS ADENOCARCINOMA CLASSIFICATION RATIONALE AND STRENGTHS

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1 THE IASLC/ERS/ATS ADENOCARCINOMA CLASSIFICATION RATIONALE AND STRENGTHS PULMONARY PATHOLOGY SOCIETY USCAP, BALTIMORE, March 2, 2013 William D. Travis, M.D. Dept of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY Worldwide, lung cancer is the most common cause of major cancer mortality in men and the second most common in women. Recent therapeutic advances have led to a revolution in the lung cancer field in discovering therapeutically tractable oncogene dependency, that have major implications for patient evaluation and approach to diagnosis. The 2011 IASLC/ATS/ERS Classification of Lung Adenocarcinoma addresses these issues. 1 This classification was developed based on an evidence-based approach by an international multidisciplinary panel including pathologists, oncologists/respiratory physicians, radiologists, molecular biologists, and thoracic surgeons. 1 Multiple paradigm shifts are outlined that have a major impact on clinical practice for pathologists as well as the entire multidisciplinary team caring for lung cancer patients. Two review articles one on small biopsies/cytology specimens and the other on resection specimens addressed primarily to pathologists are about to be published and are currently available online. 2, 3 Since 70% of lung cancer patients present in advanced stages, their diagnosis is usually established based on small biopsies and/or cytology specimens and the primary therapy is chemotherapy; the remaining patients are usually resectable and surgery is the primary treatment. In order to address all types of cancer patients, there are two major components to the classification based on the type of specimen: 1) small biopsies and cytology or 2) resection. Because previous WHO classifications did not provide specific criteria and terminology for pathologic diagnosis of lung cancer in small biopsies and cytology, 4 this new classification is more clinically relevant as it addresses these small specimens and addresses molecular testing. In recent years, three therapeutic advances for advanced NSCLC have made accurate histologic diagnosis a critical step in developing a personalized approach to management. The first, relates to tyrosine kinase inhibitors as first line therapy in patients with advanced lung adenocarcinoma with EGFR mutations. 5 For this reason, in the new classification EGFR mutation testing is recommended for advanced lung cancer patients with a histologic diagnosis of adenocarcinoma. Second, patients with adenocarcinoma or NSCLC, not otherwise specified (NSCLC-NOS) are more responsive to pemetrexed than those squamous cell carcinoma. 6 Third, squamous cell carcinoma is associated with life threatening hemorrhage in patients treated with bevacizumab therefore it is contraindicated in lung cancer patients with this histology. 7 Fourth, crizotinib is an FDA-approved therapy for advanced adenocarcinomas with ALK rearrangements Both EGFR mutations and ALK rearrangements are almost exclusively seen in lung adenocarcinomas. So a pathologic diagnosis of adenocarcinoma or squamous cell carcinoma will determine patient eligibility for EGFR mutation testing and for specific therapies. In all of these clinical trials the pathologic diagnoses were based on light microscopy with or without mucin stains but not on the basis of immunohistochemical stains. 5-7 While much progress has been made in identifying validated molecular targets for lung adenocarcinoma, only recently have potential targets been identified for squamous cell carcinoma

2 including FGFR1 amplification and DDR2 mutations which may render these patients sensitive to FGFR 11, inhibition and dasatinib respectively. The Cancer Genome Atlas (TCGA) project sponsored by the National Cancer Institute has identified molecular alterations that may represent molecular targets in the majority of lung squamous cell carcinomas. 13 In the future this may lead to effective targeted therapies for lung squamous cell carcinomas, which would only increase the importance of accurate pathologic classification in small biopsies and cytology. CLASSIFICATION BASED ON SMALL BIOPSIES AND CYTOLOGY Now that lung cancer therapy is personalized for individual patients based on the histologic type of lung cancer and molecular status, the pathologist s role and approach to lung cancer diagnosis in small biopsies and cytology have been affected dramatically. The need to classify non-small cell carcinoma (NSCLC) further to distinguish squamous cell carcinoma from adenocarcinoma has not existed until recently so the frequency of NSCLCnot otherwise specified (NOS) has been increasing up to 20-40%. Now pathologists need to make an effort to make a more specific diagnosis using special stains. Tumors that show morphologic squamous or adenocarcinoma differentiation can be classified as squamous cell carcinoma or adenocarcinoma, respectively. However, for those tumors that lack clear differentiation by morphology and would be classified as NSCLC-NOS in the past, now need to be evaluated by immunohistochemistry. The recommendation is to use a single adenocarcinoma marker such as TTF-1 and a single squamous marker such as the recently described p40 antibody. 14 If a NSCLC-NOS by light microscopy shows a staining pattern that clearly points to adenocarcinoma (TTF-1 positive, p40 negative), the tumor can be classified as NSCLC, favor adenocarcinoma. If such a tumor stains with a squamous pattern (p40 positive, TTF-1 negative), then it can be called NSCLC, favor squamous cell carcinoma. If the tumor does not show clear differentiation by immunohistochemistry, it should remain as NSCLC-NOS. These terms and criteria will help track the former NOS tumors that are being reclassified with the addition of special stains for future clinical trials. Advanced stage tumors classified as adenocarcinoma, NSCLC, favor adenocarcinoma or NSCLC-NOS should be tested for EGFR mutation; mutation positive patients are eligible for tyrosine kinase inhibitor therapy. If there is no EGFR mutation, recent data suggests these patients are candidates for EML4-ALK fusion testing and if positive they can receive the FDA approved drug crizotinib, 10 and if negative these patients are eligible for pemetrexed or bevacizumab based chemotherapeutic regimens. In the new classification, a limited use of special stains is recommended for NSCLC- NOS by light microscopy in order to try to classify these tumors further. Minimizing special stains is helpful to maximize the amount of tissue available for molecular testing. 1 A new responsibility for pathologists, in addition to making a correct diagnosis, is to manage these small biopsies and cytology specimens strategically so there is sufficient tissue preserved for molecular studies. A new emphasis is made on the need for a multidisciplinary approach to lung cancer diagnosis. One of the central proposals in this classification is that each institution needs to have a multidisciplinary strategy that addresses how to obtain these small specimens, how to process them in the pathology laboratory, how to preserve material for molecular testing, sending specimens to the molecular laboratory for expedited testing and the reporting the results in a pathology report. It may be useful to have a multidisciplinary committee to develop this strategy and to monitor issues in an ongoing fashion. 2

3 CLASSIFICATION BASED ON RESECTION SPECIMENS Major changes are also recommended for adenocarcinomas diagnosed in resection specimens: 1 1) the term bronchioloalveolar carcinoma (BAC) should not be used anymore, because tumors previously classified under as BAC are represented by five different tumors in this classification; 2), for solitary tumors measuring 3cm, new concepts of adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) have been introduced for lesions that have no invasion or 5mm invasion, respectively; these patients should have 100% or near 100% disease free survival (DFS); 3) for invasive adenocarcinomas, comprehensive histologic subtyping is recommended for evaluation with classification according to the predominant subtype; 4) micropapillary adenocarcinoma is proposed as a new subtype with a poor prognosis; 5) the term lepidic replaces BAC for tumors with a predominant component formerly called nonmucinous BAC, and the term lepidic predominant adenocarcinoma is recommended along with discontinuing the term mixed subtype ; 6) invasive mucinous adenocarcinoma (IMA) is the term used to replace those formerly classified as mucinous BAC. IMA are strongly correlated with KRAS mutation Recently strong survival correlations were demonstrated using this classification in Stage I adenocarcinomas with the following 5-year DFS: AIS and MIA (100%), lepidic (90%), acinar (84%), papillary (83%), and there was a poor prognostic group: micropapillary (67%), solid (70%), colloid (71%) predominant tumors as well as invasive mucinous adenocarcinoma (75%). 15 Comprehensive histologic subtyping is performed by making semiquantitative estimation of each of the patterns in 5% increments. A deliberate choice needs to be made to give one pattern the largest percentage. It is useful to record in diagnostic reports each adenocarcinoma subtype that is present with the percentages. This approach may also provide a basis for architectural grading of lung adenocarcinomas Early reproducibility studies have shown moderate to substantial inter-observer agreement among pathologists for the predominant pattern. A reproducibility study of classical and difficult selected images of the major lung adenocarcinoma subtypes circulated among a panel of 26 expert lung cancer pathologists documented kappa values of / and /- 0.14, respectively. 18 A recent study of reproducibility for predominant pattern showed moderate to good κ-values of 0.44 to 0.72 for pulmonary pathologists. For untrained pathologists κ-values were expectedly lower ranging from 0.38 to 0.47, but these improved after a training session to 0.51 to 0.66 and reevaluation by the same reviewers led to very high κ-values between Reproducibility improves after training sessions. However, work is needed to improve separation of difficult problems such as lepidic versus acinar or papillary and micropapillary versus papillary patterns. 18, Since this classification was initially published, there are a growing number of studies of resected lung adenocarcinomas that have demonstrated its utility in identifying significant prognostic subsets and molecular correlations according to the predominant 15, 16, patterns. In summary this classification outlines many paradigm shifts in lung cancer diagnosis that crystalize the importance of histology and genetics in personalized medicine for lung cancer patients. Evidence-based recommendations are made that will transform the clinical practice of all physicians involved with lung cancer diagnosis. Reference List 1. Travis WD, Brambilla E, Noguchi M et al. The New IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification. J Thoracic Oncol 2011;6(2):

4 2. Travis WD, Brambilla E, Noguchi M et al. Lung Cancer Diagnosis in Small Biopsies and Cytology: Implications of the 2011 IASLC/ATS/ERS. Arch Pathol Lab Med 2013;e pub ahead. 3. Travis WD, Brambilla E, Noguchi M et al. Diagnosis of Lung Adenocarcinoma in Resected Specimens: Implications of the 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society Lung Classification. Arch Pathol Lab Med 2013;e pub ahead. 4. Travis WD, Brambilla E, Müller-Hermelink HK, Harris CC. Pathology and Genetics: Tumours of the Lung, Pleura, Thymus and Heart. Lyon: IARC; Mok TS, Wu YL, Thongprasert S et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361(10): Scagliotti GV, Parikh P, von PJ et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 2008;26(21): Johnson DH, Fehrenbacher L, Novotny WF et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 2004;22(11): Sasaki T, Janne PA. New Strategies for Treatment of ALK Rearranged Non-Small Cell Lung Cancers. Clin Cancer Res 2011;17(23): Shaw AT, Solomon B. Targeting anaplastic lymphoma kinase in lung cancer. Clin Cancer Res 2011;17(8): Kwak EL, Bang YJ, Camidge DR et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 2010;363(18): Dutt A, Ramos AH, Hammerman PS et al. Inhibitor-Sensitive FGFR1 Amplification in Human Non- Small Cell Lung Cancer. PLoS ONE 2011;6(6):e Weiss J, Sos ML, Seidel D et al. Frequent and focal FGFR1 amplification associates with therapeutically tractable FGFR1 dependency in squamous cell lung cancer. Sci Transl Med 2010;2(62):62ra Hammerman PS, Hayes DN, Wilkerson MD et al. Comprehensive genomic characterization of squamous cell lung cancers. Nature 2012;489(7417): Bishop JA, Teruya-Feldstein J, Westra WH, Pelosi G, Travis WD, Rekhtman N. p40 (DeltaNp63) is superior to p63 for the diagnosis of pulmonary squamous cell carcinoma. Mod Pathol 2012;25(3): Yoshizawa A, Motoi N, Riely GJ et al. Impact of proposed IASLC/ATS/ERS classification of lung adenocarcinoma: prognostic subgroups and implications for further revision of staging based on analysis of 514 stage I cases. Mod Pathol 2011;24(5):

5 16. Sica G, Yoshizawa A, Sima CS et al. A grading system of lung adenocarcinomas based on histologic pattern is predictive of disease recurrence in stage I tumors. Am J Surg Pathol 2010;34(8): Kadota K, Suzuki K, Kachala SS et al. A grading system combining architectural features and mitotic count predicts recurrence in stage I lung adenocarcinoma. Mod Pathol 2012;25(8): Thunnissen FB, Beasley MB, Borczuk A et al. Reproducibility of histopathological subtypes and invasion in pulmonary adenocarcinoma. An international interobserver study. Mod Pathol 2012;25(12): Warth A, Stenzinger A, von Brunneck AC et al. Interobserver variability in the application of the novel IASLC/ATS/ERS classification. Eur Respir J 2012;40(5): Warth A, Stenzinger A, von Brunneck AC et al. Interobserver variability in the application of the novel IASLC/ATS/ERS classification. Eur Respir J 2012;40(5): Warth A, Cortis J, Fink L et al. Training increases concordance in classifying pulmonary adenocarcinomas according to the novel IASLC/ATS/ERS classification. Virchows Arch 2012;461(6): Warth A, Muley T, Meister M et al. The novel histologic IASLC/ATS/ERS classification system of invasive pulmonary adenocarcinoma is a stage-independent predictor of survival. J Clin Oncol 2012;30(13): Russell PA, Wainer Z, Wright GM, Daniels M, Conron M, Williams RA. Does lung adenocarcinoma subtype predict patient survival?: A clinicopathologic study based on the new International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society international multidisciplinary lung adenocarcinoma classification. J Thorac Oncol 2011;6(9): Yoshizawa A, Sumiyoshi S, Sonobe M et al. Validation of the IASLC/ATS/ERS Lung Adenocarcinoma Classification for Prognosis and Association with EGFR and KRAS Gene Mutations: Analysis of 440 Japanese Patients. J Thorac Oncol 2013;8(1): Shim HS, Lee dh, Park EJ, Kim SH. Histopathologic characteristics of lung adenocarcinomas with epidermal growth factor receptor mutations in the international association for the study of lung cancer/american thoracic society/european respiratory society lung adenocarcinoma classification. Arch Pathol Lab Med 2011;135(10): Sterlacci W, Savic S, Schmid T et al. Tissue-Sparing Application of the Newly Proposed IASLC/ATS/ERS Classification of Adenocarcinoma of the Lung Shows Practical Diagnostic and Prognostic Impact. Am J Clin Pathol 2012;137(6):