The cribriform pattern identifies a subset of acinar predominant tumors with poor prognosis in patients with stage I lung adenocarcinoma: a conceptual proposal to classify cribriform predominant tumors as a distinct histologic subtype

Modern Pathology (2014) 27, 690–700 690 & 2014 USCAP, Inc All rights reserved 0893-3952/14 $32.00 The cribriform pattern identifies a subset of acinar predominant tumors with poor prognosis in patients with stage I lung adenocarcinoma: a conceptual proposal to classify cribriform predominant tumors as a distinct histologic subtype Kyuichi Kadota1,2,3, Yi-Chen Yeh1, Camelia S Sima4, Valerie W Rusch1, Andre L Moreira2, Prasad S Adusumilli1,5 and William D Travis2 1Division of Thoracic Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; 2Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; 3Department of Diagnostic Pathology, Faculty of Medicine, Kagawa University, Kagawa, Japan; 4Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA and 5Center for Cell Engineering, Memorial Sloan-Kettering Cancer Center, New York, NY, USA The 2011 International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/ European Respiratory Society (ERS) lung adenocarcinoma classification emphasizes the prognostic significance of histologic subtypes. However, one limitation of this classification is that the highest percentage of patients (B40%) is classified as acinar predominant tumors, and these patients display a spectrum of favorable and unfavorable clinical behaviors. We investigated whether the cribriform pattern can further stratify prognosis by histologic subtype. Tumor slides from 1038 patients with stage I lung adenocarcinoma (1995–2009) were reviewed. Tumors were classified according to the IASLC/ATS/ERS classification. The percentage of cribriform pattern was recorded, and the cribriform predominant subtype was considered as a subtype for analysis. The log-rank test was used to analyze the association between histologic variables and recurrence-free probability. The 5-year recurrence-free probability for patients with cribriform predominant tumors (n ¼ 46) was 70%. The recurrence-free probability for patients with cribriform predominant tumors was significantly lower than that for patients with acinar (5-year recurrence-free probability, 87%; P ¼ 0.002) or papillary predominant tumors (83%; P ¼ 0.020) but was comparable to that for patients with micropapillary (P ¼ 0.34) or solid predominant tumors (P ¼ 0.56). The recurrence-free probability for patients with Z10% cribriform pattern tumors (n ¼ 214) was significantly lower (5-year recurrence-free probability, 73%) than that for patients with o10% cribriform pattern tumors (n ¼ 824; 84%; Po0.001). In multivariate analysis, patients with acinar predominant tumors with Z10% cribriform pattern remained at significantly increased risk of recurrence compared with those with o10% cribriform pattern (P ¼ 0.042). Cribriform predominant tumors should be considered a distinct subtype with a high risk of recurrence, and presence (Z10%) of the cribriform pattern is an independent predictor of recurrence, identifying a poor prognostic subset of acinar predominant tumors. Our findings highlight the important prognostic value of comprehensive histologic subtyping and recording the percentage of each histologic pattern, according to the IASLC/ATS/ERS classification with the addition of the cribriform subtype. Modern Pathology (2014) 27, 690–700; doi:10.1038/modpathol.2013.188; published online 1 November 2013 Keywords: cribriform; histologic subtype; lung adenocarcinoma; recurrence Correspondence: Dr WD Travis, MD, Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Room C563E, New York, NY 10065, USA. E-mail: Received 28 June 2013; revised 14 August 2013; accepted 15 August 2013; published online 1 November 2013 Lung cancer is the leading cause of cancer mortality worldwide.1,2 In most countries, adenocarcinoma is the most common histologic type of lung cancer.3 Accumulating evidence suggests that the architectural pattern of lung adenocarcinoma can be used www.modernpathology.org Cribriform in lung adenocarcinoma 691 K Kadota et al to stratify tumors with respect to prognosis.4–8 The newly proposed International Association for the Study of Lung Cancer (IASLC), American Thoracic Society (ATS), and European Respiratory Society (ERS) international multidisciplinary classification of lung adenocarcinoma emphasizes the prognostic significance of the predominant histologic subtype in lung adenocarcinoma,9 a finding that has been validated in independent cohorts.10–12 For stage I tumors, histologic subtyping can be used to stratify patients into three prognostic groups (low, intermediate, and high architectural grade).6,10,13 In the 2011 IASLC/ATS/ERS classification of lung adenocarcinoma, acinar pattern is defined as glandular structures that are round to oval shaped, with a central luminal space surrounded by tumor cells; cribriform arrangements are also regarded as a pattern of acinar adenocarcinoma.9 The word cribriform is derived from the Latin cribrum (for ‘sieve’) and is used to describe tumors characterized by evenly spaced ‘back-to-back’ glands lacking intervening stroma. The cribriform pattern has been well recognized in various tumors, including adenoid cystic adenocarcinoma of the salivary gland,14,15 lung,16,17 and breast.18,19 In addition, the cribriform arrangement has been recognized as a pattern of conventional adenocarcinoma in various organs.20–27 To our knowledge, however, the prognostic significance of the cribriform pattern for lung adenocarcinoma has not been established. In this study, we determined (1) whether presence of the cribriform pattern correlates with higher risk of recurrence; (2) whether the cribriform predominant subtype can be used to further stratify prognosis, in addition to the IASLC/ATS/ERS classification; and (3) whether the cribriform pattern correlates with cliniopathologic factors in patients with stage I lung adenocarcinoma. As we addressed these questions, we considered whether the cribriform pattern should be added as a new subtype of lung adenocarcinoma. Materials and methods Patients This retrospective study was approved by the Memorial Sloan-Kettering Cancer Center Institutional Review Board (WA0269-08). We reviewed all patients with pathologically confirmed stage I solitary lung adenocarcinoma who underwent surgical resection at Memorial Sloan-Kettering Cancer Center between 1995 and 2009. Tumor slides were available for histologic evaluation from 1038 patients. Clinical data were collected from the prospectively maintained Thoracic Surgery Service lung adenocarcinoma database. Disease stage was assigned on the basis of the seventh edition of the American Joint Committee on Cancer TNM Staging Manual.28 Subsets of the cases in this study have been previously published in manuscripts focused on architectural grading,6 histologic classification,10 nuclear grading,29 and immune microenvironment in lung adenoca (...truncated)