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The New Taxonomy of Lung Adenocarcinoma Stemming from a Multidisciplinary Integrated Approach: Novel Pathology Concepts and Perspectives

2011; Elsevier BV; Volume: 6; Issue: 2 Linguagem: Inglês

10.1097/jto.0b013e31820bfcba

1556-1380

Giuseppe Pelosi,

Lung Cancer Research Studies

Lung cancer is the leading cause of morbidity and death all over the world and a significant burden on healthcare resources of most countries.1Jemal A Siegel R Xu J et al.Cancer statistics, 2010.CA Cancer J Clin. 2010; 60: 277-300Crossref PubMed Scopus (12366) Google Scholar Among the diverse histologic subtypes, adenocarcinoma (AD) is the most common type of lung cancer in both males and females in most countries, even in young people,2Subramanian J Morgensztern D Goodgame B et al.Distinctive characteristics of non-small cell lung cancer (NSCLC) in the young: a surveillance, epidemiology, and end results (SEER) analysis.J Thorac Oncol. 2010; 5: 23-28Crossref PubMed Scopus (142) Google Scholar and in tumors detected in screening low-dose computed tomography programs.3Pelosi G Sonzogni A Veronesi G et al.Pathologic and molecular features of screening low-dose computed tomography (LDCT)-detected lung cancer: a baseline and 2-year repeat study.Lung Cancer. 2008; 62: 202-214Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 4Carter D Vazquez M Flieder DB et al.Comparison of pathologic findings of baseline and annual repeat cancers diagnosed on CT screening.Lung Cancer. 2007; 56: 193-199Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar The characteristic mixture of multiple subtypes has been a major source of inconsistency in subclassification in the past, hence the axiom, the more tumor categories, the more difficulties in the diagnosis. Therefore, new diagnostic criteria and uniform and consistent terminology are needed to improve accuracy and permit correlations between pathology and multiple patient characteristics including clinical features, tumor staging, molecular signatures, prognostic and predictive markers, and imaging data. Morphology still remains an agreed-on gold standard for AD, but a global rethinking of its histopathologic basis by exploiting an integrated multidisciplinary approach could really improve our diagnostic, prognostic, and predictive capabilities. The issue of accurate subtyping of poorly differentiated tumors and limited diagnostic material for predictive purposes is strictly intermingled with this scenario and often presents a difficult challenge,5Hirsch FR Wynes MW Gandara DR et al.The tissue is the issue: personalized medicine for non-small cell lung cancer.Clin Cancer Res. 2010; 16: 4909-4911Crossref PubMed Scopus (65) Google Scholar because most lung cancer patients are discovered with locally advanced or metastatic disease, so cytology or biopsy samples are the only available material. Therefore, in the past, the term “non-small cell lung cancer, not otherwise specified” has been encouraged6Ou SH Zell JA Carcinoma NOS is a common histologic diagnosis and is increasing in proportion among non-small cell lung cancer histologies.J Thorac Oncol. 2009; 4: 1202-1211Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar mainly due to the lack of a clinical reason to classify more precisely. This situation has led to the uncomfortable feeling that histopathology is a finite and imperfect source of diagnostic, prognostic, or predictive information in lung cancers and that molecular studies are more important than histology for prognosis and prediction. For these reasons, this new multidisciplinary classification of AD that is presented in the Journal under the aegis of three outstanding scientific communities devoted to lung cancer, namely the International Association for the Study of Lung Cancer, the American Thoracic Society, and the European Respiratory Society, represents an extraordinary, meritorious, and almost herculean effort by Dr. William D. Travis,7Travis W IASCL/ATS/ERS International multidisciplinary classification of lung adenocarcinoma.J Thorac Oncol. 2011; 6: 244-285Abstract Full Text Full Text PDF PubMed Scopus (3581) Google Scholar which surely will contribute to address many contemporary issues and questions on the subject of pulmonary AD through a close integration of pathologic, clinical, molecular, and radiologic data. There are several innovative aspects of this classification. First, it relies on a multidisciplinary approach with integration of clinical, radiologic, molecular, and imaging features. Second, there is a completely new proposal to provide diagnostic criteria and terminology in small biopsies and cytology, a problem not addressed in previous World Health Organization classifications. Third, for patients with advanced lung AD, epidermal growth factor receptor mutation assessment is recommended, so small biopsy and cytology specimens need to be processed strategically not only for diagnosis but also to preserve tissue for molecular testing. Fourth, for resected ADs, the concepts of AD “in situ” (AIS) and minimally invasive AD (MIA) are introduced to define a subset of patients who should have a 100% disease-free survival. Fifth, in patients with invasive ADs, the introduction of comprehensive histologic subtyping and classification according to the predominant subtype has implications for prognosis and clinical prediction that could help to identify patients for adjuvant therapy even in early stage lung AD.8Motoi N Szoke J Riely GJ et al.Lung adenocarcinoma: modification of the 2004 WHO mixed subtype to include the major histologic subtype suggests correlations between papillary and micropapillary adenocarcinoma subtypes, EGFR mutations and gene expression analysis.Am J Surg Pathol. 2008; 32: 810-827Crossref PubMed Scopus (341) Google Scholar, 9Yoshizawa A, Motoi N, Riely GJ, et al. Prognostic significance of the proposed IASLC/ATS/ERS revised classification of lung adenocarcinoma in 514 stage I lung adenocarcinomas. Mod Pathol In press.Google Scholar Furthermore, it improves stratification of invasive ADs to allow for molecular and radiologic correlations and ultimately may impact on tumor, node, metastasis (TNM) staging if tumor size may be better predicted by the invasive component size rather than the gross diameter. The dogma that AD classification had to rely exclusively on standard hematoxylin and eosin-stained sections rather than under the guidance of findings stemming from immunohistochemistry or molecular assays10Travis W Brambilla E Muller-Hermelink H et al.Tumours of the Lung, Pleura, Thymus and Heart. IARC Press, Lyon2004Google Scholar has been overcome in the present classification, particularly in small biopsies.11Travis WD Rekhtman N Riley GJ et al.Pathologic diagnosis of advanced lung cancer based on small biopsies and cytology: a paradigm shift.J Thorac Oncol. 2010; 5: 411-414Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar Although this classification of AD still uses a rather traditional language, there are significant improvements in comparison with the previous schemes.10Travis W Brambilla E Muller-Hermelink H et al.Tumours of the Lung, Pleura, Thymus and Heart. IARC Press, Lyon2004Google Scholar, 12Travis W Colby T Corrin B et al.Hystological Typing of Lung and Pleural Tumours. Springer Verlag, Berlin, Heidelberg, New York1999Crossref Google Scholar First, a clear subdivision of AD-related lesions into preinvasive and invasive growths, the former comprising atypical adenomatous hyperplasia and the new concept of AIS (nonmucinous and mucinous types) to replace the time-honored and often misinterpreted term of bronchioloalveolar carcinoma (BAC), and the latter made of actually invasive tumors classified according to predominant growth patterns and variants. The sharing of a continuum of morphological changes between adenomatous hyperplasia and nonmucinous AIS, a cytologically low-grade lesion composed of Clara cells and/or type II pneumocytes growing along preexisting alveolar/bronchiolar structures (lepidic pattern) but lacking pleural, stromal, or vascular invasion, makes an unifying concept of preinvasive neoplastic lesions possible with associated risk of progression to invasive tumors.13Noguchi M Stepwise progression of pulmonary adenocarcinoma—clinical and molecular implications.Cancer Metastasis Rev. 2010; 29: 15-21Crossref PubMed Scopus (85) Google Scholar The nosologic position of mucinous AIS still remains debated, and this term should be limited to rare, small-sized, circumscribed, and solitary lesions featuring bland mucinous cells sometimes resembling bronchial goblet cells. The assumption that AIS is a cytologically bland lesion devoid of any invasion but capable of further molecular changes and progression to eventual invasive AD helps us to distinguish this event from lepidic growths of invasive primary or even metastatic AD, which usually are of higher grade. The strict definition of AIS, however, should avoid continuing the improper use of the term BAC abused until recently to indicate both noninvasive and invasive AD with different histologic features and clinical behavior. The upper limit of 3 cm for AIS should allow for complete histologic sampling and avoiding confusion with larger tumors for which there is insufficient evidence that they will have a 100% disease-free survival. When the next TNM revision is developed, AIS should belong to “pTis” category in keeping with the general rules of TNM system. Five-year disease-free survival of AIS is 100% patients because of the absence of any invasive component. Another innovation of the present classification is the introduction of the category of MIA for indicating a usually nonmucinous, lepidic predominant, and low-grade tumor, measuring 3 cm or less, with invasion being limited up to a maximum 5 mm (either showing subtypes other than a lepidic pattern or myofibroblastic stroma). The lack of vascular or pleural invasion or tumor necrosis justifies the excellent prognosis of this tumor type close to 100% just like AIS. In the next TNM revision, MIA may be classified as “pTmi.” In invasive AD where the invasion focus is >5 mm, the approach of this new classification raises the consideration that the size of the invasive components on histologic slides or the solid component on computed tomography scan may be appropriate for sizing T factor, if validated by additional studies. Among invasive AD, quite wise has been the replacement of the confusing mixed subtype AD, by the new approach of classification according to the predominant growth patterns and variants by semiquantitative assessments in 5 to 10% increments to reflect the spectrum of diverse histologic subtypes in these tumors and different molecular properties. This approach could ameliorate the diagnostic reproducibility of AD and allow for data sharing and comparability. Among growth patterns, a new category of invasive AD with predominant nonmucinous lepidic component resembling AIS/MIA has been devised to replace the confusing term AD with BAC features. Other new entries include AD with a predominant micropapillary pattern (similar to analogous life-threatening tumors arising in breast, urinary bladder, or ovary), invasive mucinous AD (formerly known as mucinous BAC), and enteric AD with intestinal differentiation. Signet ring cell and clear cell AD disappear as individual entities because they are regarded as cytological changes occurring in multiple histologic patterns, but when these features are identified even in small amounts, they should be recorded in the diagnosis preferably quantifying them, so the presence of these cytologic features will be reported more often than in prior classifications. This AD classification according to the predominant histologic subtypes has prognostic,7Travis W IASCL/ATS/ERS International multidisciplinary classification of lung adenocarcinoma.J Thorac Oncol. 2011; 6: 244-285Abstract Full Text Full Text PDF PubMed Scopus (3581) Google Scholar, 14Vazquez M Carter D Brambilla E et al.Solitary and multiple resected adenocarcinomas after CT screening for lung cancer: histopathologic features and their prognostic implications.Lung Cancer. 2009; 64: 148-154Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar, 15Anami Y Iijima T Suzuki K et al.Bronchioloalveolar carcinoma (lepidic growth) component is a more useful prognostic factor than lymph node metastasis.J Thorac Oncol. 2009; 4: 951-958Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 16Sakao Y Miyamoto H Sakuraba M et al.Prognostic significance of a histologic subtype in small adenocarcinoma of the lung: the impact of nonbronchioloalveolar carcinoma components.Ann Thorac Surg. 2007; 83: 209-214Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar, 17Finley DJ Yoshizawa A Travis W et al.Predictors of outcomes after surgical treatment of synchronous primary lung cancers.J Thorac Oncol. 2010; 5: 197-205Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar molecular,7Travis W IASCL/ATS/ERS International multidisciplinary classification of lung adenocarcinoma.J Thorac Oncol. 2011; 6: 244-285Abstract Full Text Full Text PDF PubMed Scopus (3581) Google Scholar, 18Bryant CM Albertus DL Kim S et al.Clinically relevant characterization of lung adenocarcinoma subtypes based on cellular pathways: an international validation study.PLoS One. 2010; 5: e11712Crossref PubMed Scopus (47) Google Scholar and predictive7Travis W IASCL/ATS/ERS International multidisciplinary classification of lung adenocarcinoma.J Thorac Oncol. 2011; 6: 244-285Abstract Full Text Full Text PDF PubMed Scopus (3581) Google Scholar implications; may also assist to distinguish multiple lung primaries from metastases19Girard N Deshpande C Lau C et al.Comprehensive histologic assessment helps to differentiate multiple lung primary nonsmall cell carcinomas from metastases.Am J Surg Pathol. 2009; 33: 1752-1764Crossref PubMed Scopus (190) Google Scholar; and is robustly correlated with either radiologic imaging counterparts14Vazquez M Carter D Brambilla E et al.Solitary and multiple resected adenocarcinomas after CT screening for lung cancer: histopathologic features and their prognostic implications.Lung Cancer. 2009; 64: 148-154Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar or TNM staging according to the proportion of AIS component and may support an architectural approach to grading based on the growth patterns.20Sica 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: 1155-1162Crossref PubMed Scopus (274) Google Scholar Commendable is the recommendation to assess any advanced lung AD for epidermal growth factor receptor mutations and the encouragement to be aware of the importance of molecular studies. This is a rapidly evolving field, and hopefully, in the near future, additional molecular biomarkers will be validated in clinical trials testing new target therapies (e.g., crizotinib for anaplastic lymphoma kinase translocation). So, managing appropriately small biopsy and cytology specimens should thus become a strategic goal not only for rendering final diagnoses but also to preserve tissue for further molecular testing. A true paradigm shift of the traditional morphology-based approach and an authentic revolution of this classification regards the recommendation of relying on ancillary tools (immunohistochemistry and multidisciplinary setting) when rendering different diagnoses in small cytology and biopsy specimens,10Travis W Brambilla E Muller-Hermelink H et al.Tumours of the Lung, Pleura, Thymus and Heart. IARC Press, Lyon2004Google Scholar to limit the category of non-small cell lung cancer—not otherwise specified to only those cases in which morphology, immunohistochemistry, and multidisciplinary setting are not contributory. Summing up, I feel that the present classification by Dr. Travis is a valuable global rethinking of lung AD, which finds its strength and innovation in a close integration of improved morphology, clinical and imaging data, immunohistochemistry use, and molecular assays. Thus, this classification is likely to become a common language and denominator among pathologists worldwide, especially those who are engaged with the patient care by moving beyond diagnostics.21Smith BR Therapeutic pathology: time to move beyond diagnostics.Hum Pathol. 2008; 39: 1725-1727Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar This editorial is dedicated to the memory of Carlotta, an extraordinarily lively girl who untimely died of cancer in the prime of life.