Reproducibility of Histopathological Subtypes and Invasion in Pulmonary Adenocarcinoma

An International Interobserver Study

Erik Thunnissen; Mary Beth Beasley; Alain C Borczuk; Elisabeth Brambilla; Lucian R Chirieac; Sanja Dacic; Douglas Flieder; Adi Gazdar; Kim Geisinger; Philip Hasleton; Yuichi Ishikawa; Keith M Kerr; Sylvie Lantejoul; Yoshiro Matsuno; Yuko Minami; Andre L Moreira; Noriko Motoi; Andrew G Nicholson; Masayuki Noguchi; Daisuke Nonaka; Giuseppe Pelosi; Iver Petersen; Natasha Rekhtman; Victor Roggli; William D Travis; Ming S Tsao; Ignacio Wistuba; Haodong Xu; Yasushi Yatabe; Maureen Zakowski; Birgit Witte; Dirk Joop Kuik


Mod Pathol. 2012;25(12):1574-1583. 

In This Article

Abstract and Introduction


Histological subtyping of pulmonary adenocarcinoma has recently been updated based on predominant pattern, but data on reproducibility are required for validation. This study first assesses reproducibility in subtyping adenocarcinomas and then assesses further the distinction between invasive and non-invasive (wholly lepidic) pattern of adenocarcinoma, among an international group of pulmonary pathologists. Two ring studies were performed using a micro-photographic image-based method, evaluating selected images of lung adenocarcinoma histologic patterns. In the first study, 26 pathologists reviewed representative images of typical and 'difficult' histologic patterns. A total number of scores for the typical patterns combined (n=94) and the difficult cases (n=21) were 2444 and 546, respectively. The mean kappa score (±s.d.) for the five typical patterns combined and for difficult cases were 0.77±0.07 and 0.38±0.14, respectively. Although 70% of the observers identified 12–65% of typical images as single pattern, highest for solid and least for micropapillary, recognizing the predominant pattern was achieved in 92–100%, of the images except for micropapillary pattern (62%). For the second study on invasion, identified as a key problem area from the first study, 28 pathologists submitted and reviewed 64 images representing typical as well as 'difficult' examples. The kappa for typical and difficult cases was 0.55±0.06 and 0.08±0.02, respectively, with consistent subdivision by the same pathologists into invasive and non-invasive categories, due to differing interpretation of terminology defining invasion. In pulmonary adenocarcinomas with classic morphology, which comprise the majority of cases, there is good reproducibility in identifying a predominant pattern and fair reproducibility distinguishing invasive from in-situ (wholly lepidic) patterns. However, more precise definitions and better education on interpretation of existing terminology are required to improve recognition of purely in-situ disease, this being an area of increasing importance.


The 2004 WHO classification of lung cancer contained four major patterns of adenocarcinoma: bronchioloalveolar, acinar, papillary and solid pattern with the most common pattern consisting of a mixture of these four subtypes.[1] In the recent IASLC/ATS/ERS lung adenocarcinoma classification several major changes are made.[2] First, the mixed subtype category is discontinued and tumors are subtyped according to the predominant pattern following a comprehensive semiquantitatively estimating the percentage of each of the adenocarcinoma histologic patterns. However, evidence for use of predominant patterns to improve reproducibility pattern diagnosis was at the time not available. Therefore, this was put forth as a weak recommendation with low quality of evidence (Pathology Recommendation 4).[1] Second, the term bronchioloalveolar carcinoma (BAC) is no longer used, as BAC was being interpreted in four different ways: (1) adenocarcinoma in situ, (2) minimally invasive adenocarcinoma, (3) overtly invasive adenocarcinoma with a lepidic pattern and (4) invasive mucinous adenocarcinoma (formerly mucinous BAC). In addition, micropapillary adenocarcinoma was added as a fifth major pattern due to its association with poor prognosis.[3,4] Diagnostic inconsistencies may originate from difficulties in interpretation due to subjective application of existing criteria.

In the past, the distinction between small-cell and non-small-cell lung cancers has been shown to have high accuracy and reproducibility.[5,6] Also, in resection specimen, accuracy in distinguishing squamous cell carcinoma from adenocarcinoma has been repeatedly demonstrated, even though cases that are difficult to classify by morphology alone may remain in poorly differentiated tumors.[5–10] However, there remains a lack of data on reproducibility in relation to identifying predominant patterns of adenocarcinoma.

The intention of this study was therefore to assess the reproducibility of histopathological subtyping for adenocarcinomas among pulmonary pathologists from three continents, with respect to both 'histologic patterns' and 'invasion'.