Original ArticlesComprehensive Histologic Assessment Helps to Differentiate Multiple Lung Primary Nonsmall Cell Carcinomas From MetastasesGirard, Nicolas MD*; Deshpande, Charuhas MD, PhD†; Lau, Christopher PhD‡; Finley, David MD§; Rusch, Valerie MD§; Pao, William MD, PhD* ∥ ¶ ♯; Travis, William D. MD†Author Information *Pao Lab, Human Oncology and Pathogenesis Program †Department of Pathology ‡Diagnostic Molecular Pathology Laboratory §Thoracic Surgery Service ∥Thoracic Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center ¶Department of Medicine, Weill Medical College of Cornell University, New York, NY ♯Vanderbilt-Ingram Cancer Center, Nashville, TN Supported by the National Cancer Institute (CA124504; CBB), the HOPP Lung Cancer Research Fund (W.P.), the Rosalind Warren Memorial Fund (W.P.), and the MSKCC Geoffrey Beene Cancer Research Center (W.P.). Correspondence: William D. Travis, MD, Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065 (e-mail: [email protected]). Nicolas Girard is a recipient of travel grants from the College des Professeurs de Pneumologie (CEP)/AstraZeneca, the National Federation of French Comprehensive Cancer Centers/Fondation de France, and the Philippe Foundation. Disclosure: The authors declare no conflict of interest. The American Journal of Surgical Pathology: December 2009 - Volume 33 - Issue 12 - p 1752-1764 doi: 10.1097/PAS.0b013e3181b8cf03 Buy Metrics Abstract The pathologic classification of nonsmall cell lung cancer (NSCLC) is evolving. Lung adenocarcinoma is morphologically heterogeneous, with mixtures of acinar, papillary, bronchioloalveolar, and solid patterns in more than 80% of cases. In case of synchronous or metachronous multiple NSCLC, the distinction of intrapulmonary metastases from independent primary tumors is of great clinical importance as it influences staging and potentially the therapeutic strategy. Here we took advantage of a cohort of 20 patients with 42 multiple NSCLC tumors (24 potential pair comparisons) that were annotated molecularly using genomic and mutational profiling to evaluate the value of comprehensive histologic assessment in this setting. Using the Martini-Melamed criteria, paired tumors were characterized as multiple primary NSCLCs in 21 cases and as intrapulmonary metastases in 3 cases. Genomic and mutational data led to a diagnosis of multiple primaries in 14 cases and of metastases in 8 cases; 2 cases could not be assessed. This molecular characterization contradicted the Martini-Melamed diagnosis in 7 (32%) of the 22 assessable comparisons. Adenocarcinoma was found in 32 (76%) of the 42 tumors. After review in a blinded fashion, semiquantitative comprehensive histologic assessment of paired tumors was different in 16 and similar in 8 paired tumors. We found that comparing adenocarcinomas is a complex issue that requires assessment not only of percentages of the histologic subtypes, but also the recording of additional histologic details such as cytologic features, patterns of stroma, necrosis, discrete nodularity versus miliary growth and variants such as clear cell, signet ring, mucinous, and fetal patterns. We also found that paired squamous cell carcinomas could be compared based on histologic subtyping in addition to cytologic and stromal characteristics. Considering histologically different tumors as multiple primaries, and similar tumors as metastases, comprehensive histologic subtyping was consistent with the molecular characterization in 20 (91%) of the 22 pairs comparisons. In summary, based on a well characterized cohort with detailed clinical, pathologic and molecular data, we found comprehensive histologic assessment is a powerful tool that seems to be a promising way to determine whether multiple lung adenocarcinomas or squamous cell carcinomas are metastatic or multiple primaries. This has great clinical implications for staging and therapeutic management of lung cancer patients with multiple tumors. Given its high correlation with molecular characterization of such tumors, it may provide a much cheaper and faster method to address this problem. © 2009 Lippincott Williams & Wilkins, Inc.