Abstract
Introduction: The American Thoracic Society is a cosponsor of a newly published lung adenocarcinoma classification.
Methods: An international multidisciplinary panel of experts was formed. A systematic review was performed and recommendations were graded by strength and quality of the evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.
Results: The classification addresses both resection specimens and small biopsies/cytology. The terms bronchioloalveolar carcinoma and mixed subtype adenocarcinoma are no longer used. For resection specimens, new concepts are introduced such as adenocarcinoma in situ and minimally invasive adenocarcinoma for small solitary adenocarcinomas with pure lepidic growth and predominant lepidic growth with ≤ 5 mm invasion, respectively. Invasive adenocarcinomas are classified by predominant pattern after using comprehensive histologic subtyping with lepidic, acinar, papillary, and solid patterns; micropapillary is added. In the new aspect of this classification that provides guidance for small biopsies and cytology specimens, non-small cell lung carcinomas (NSCLC), in patients with advanced stage disease, are to be classified into more specific types, such as adenocarcinoma or squamous cell carcinoma, whenever possible, for several reasons: (1) adenocarcinoma or NSCLC not otherwise specified should be tested for EGFR mutations, because the presence of these mutations is predictive of responsiveness to EGFR tyrosine kinase inhibitors, (2) adenocarcinoma histology is a strong predictor for improved outcome with pemetrexed therapy, and (3) squamous histology is a risk factor for life-threatening hemorrhage with bevacizumab therapy. NSCLC- not otherwise specified by light microscopy alone should be studied with immunohistochemistry and/or mucin stains.
Conclusions: This classification is intended to support clinical practice as well as research investigation and clinical trials.
A new international multidisciplinary classification has just been published in the Journal of Thoracic Oncology under the sponsorship of the American Thoracic Society (ATS), the International Association for the Study of Lung Cancer (IASLC), and the European Respiratory Society (ERS) (1). In this article, an Executive Summary of the new classification is presented.
Due to the rapid advances in clinical, radiologic, pathologic, and molecular aspects of lung adenocarcinoma, there is a need to improve the existing World Health Organization (WHO) classification using a multidisciplinary approach. Among the pitfalls of the existing 2004 WHO classification system are the following:
The term bronchioloalveolar carcinoma (BAC) is used for widely divergent clinical, radiologic, pathologic, and molecular subsets of patients.
The “mixed subtype” category accounts for more than 90% of all resected lung adenocarcinomas, despite great heterogeneity in clinical, radiologic, pathologic, and molecular features.
Previous WHO classifications have addressed histologic classification, primarily based on resection specimens.
The current classification system inadequately addresses the diagnostic issues and strategic management of tissues associated with molecular testing of small biopsy and cytology specimens. This is particularly important because the vast majority of patients with lung cancer present with advanced disease and are diagnosed based on small biopsy and cytology specimens. Due to the recent understanding that histologic typing and EGFR mutation status are important for selection of chemotherapy for patients with advanced lung adenocarcinoma, there is a great need for a new classification that addresses diagnostic issues and strategic management of tissue to allow for molecular testing in small biopsy and cytology specimens.
The new International Multidisciplinary Lung Adenocarcinoma Classification is sponsored by the ERS, the IASLC, and the ATS (1). This classification is now published in the Journal of Thoracic Oncology, the official journal of the IASLC. Under the scientific oversight of the ATS and ERS, the classification project involved a systematic review to provide an evidence-based foundation with specific recommendations.
The IASLC, ATS, and ERS developed an international core panel of experts with oncologists/respiratory physicians, pathologists, radiologists, molecular biologists, and thoracic surgeons. The new classification was developed based on discussions at a series of meetings between March 2008 and December 2009 and a systematic review supported by members of the ATS Documents Development and Implementation Committee. We used the Grading of Recommendations, Assessment, Development and Evaluation approach to rate the quality of evidence and to grade the recommendations. Recommendations were expressed as either strong or weak (also known as conditional), and the evidence was graded as high, moderate, low, or very low quality. The latter was based on the assessment of eight criteria that influence the confidence in the estimates of effect for the evaluated outcomes. Official notification of approval of the document by the Board of Directors of the ATS and ERS was received on November 8, 2010.
The goals of this project were:
To develop a multidisciplinary subclassification of lung adenocarcinoma that (a) resolves the ongoing discrepancy in the pathologic versus clinical use of the term BAC, which currently defines 100% versus 5 to 20% 5-year survival, respectively, depending on the definition being used; (b) achieves an international standard for histologic subclassification of lung adenocarcinomas; and (c) defines clinical/histologic/radiologic/molecular subtypes of lung adenocarcinoma.
To achieve an international consensus that will result in widespread acceptance of this classification.
This classification outlines multiple major changes in lung adenocarcinoma classification. First, the diagnosis is best established using a multidisciplinary approach. Second, this classification addresses terminology and criteria for diagnosis of lung cancer in small biopsies and cytology, due to the need for EGFR mutation testing in patients with advanced lung adenocarcinoma and the need to avoid using bevacizumab and pemetrexed chemotherapy in patients with squamous cell carcinoma (Table 1). Also due to the need for EGFR mutation testing in patients with advanced lung cancer, optimal tissue management in these small tissue samples is essential to allow for not only diagnosis but also molecular testing. This requires institutional multidisciplinary coordination to streamline the procurement and processing of specimens for timely diagnosis and molecular testing. Third, use of the term BAC is discontinued, and concepts of adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) are introduced (Table 2). Fourth, for overtly invasive adenocarcinomas, comprehensive histologic subtyping and classification by the predominant subtype is recommended to better stratify tumors previously classified as mixed subtype. Fifth, overtly invasive tumors previously classified as mucinous BAC are now classified as invasive mucinous adenocarcinoma. Finally, implications of this classification for tumor-node-metastasis staging include potential improvement in predicting prognosis using invasive size, rather than total size, in tumors with a lepidic component and better comparison of multiple adenocarcinomas to distinguish metastases from multiple primaries with the aid of comprehensive histologic subtyping.
| 2004 WHO Classification | Small Biopsy/Cytology: IASLC/ATS/ERS |
| Adenocarcinoma (mixed subtype, acinar, papillary, solid) | Morphologic adenocarcinoma patterns clearly present: |
| Adenocarcinoma, describe identifiable patterns present (including micropapillary pattern not included in 2004 WHO classification) | |
| Comment: If pure lepidic growth, mention an invasive component cannot be excluded in this small specimen | |
| ?Bronchioloalveolar carcinoma (nonmucinous) | Adenocarcinoma with lepidic pattern (if pure, add note: an invasive component cannot be excluded) |
| ?Bronchioloalveolar carcinoma (mucinous) | Mucinous adenocarcinoma (describe patterns present) |
| ?Fetal | Adenocarcinoma with fetal pattern |
| ?Mucinous (colloid) | Adenocarcinoma with colloid pattern |
| ?Signet ring | Adenocarcinoma with (describe patterns present) and signet ring features |
| ?Clear cell | Adenocarcinoma with (describe patterns present) and clear cell features |
| ?No 2004 WHO counterpart—most will be solid adenocarcinomas | Morphologic adenocarcinoma patterns not present (supported by special stains): Non-small cell carcinoma, favor adenocarcinoma |
| Squamous cell carcinoma (papillary, clear cell, small cell, basaloid) | Morphologic squamous cell patterns clearly present: Squamous cell carcinoma |
| ?No 2004 WHO counterpart | Morphologic squamous cell patterns not present (supported by stains): Non-small cell carcinoma, favor squamous cell carcinoma |
| Small cell carcinoma | Small cell carcinoma |
| Large cell carcinoma | Non-small cell carcinoma, not otherwise specified (NOS) |
| ?Large cell NE carcinoma (LCNEC) | Non-small cell carcinoma with NE morphology (positive NE markers), possible LCNEC |
| ?Large cell carcinoma with NE morphology (LCNEM) | Non-small cell carcinoma with NE morphology (negative NE markers)—see comment |
| Comment: This is a non-small cell carcinoma where LCNEC is suspected, but stains failed to demonstrate NE differentiation. | |
| Adenosquamous carcinoma | Morphologic squamous cell and adenocarcinoma patterns present: Non-small cell carcinoma, with squamous cell and adenocarcinoma patterns |
| Comment: this could represent adenosquamous carcinoma. | |
| ?No counterpart in 2004 WHO classification | Morphologic squamous cell or adenocarcinoma patterns not present but immunostains favor separate glandular and adenocarcinoma components |
| Non-small cell carcinoma, NOS, (specify the results of the immunohistochemical stains and the interpretation) | |
| Comment: this could represent adenosquamous carcinoma. | |
| Sarcomatoid carcinoma | Poorly differentiated NSCLC with spindle and/or giant cell carcinoma (mention if adenocarcinoma or squamous carcinoma are present) |
| Preinvasive lesions |
| ?Atypical adenomatous hyperplasia |
| ?Adenocarcinoma in situ (≤ 3 cm formerly BAC) |
| ??Nonmucinous |
| ??Mucinous |
| ??Mixed mucinous/nonmucinous |
| Minimally invasive adenocarcinoma (≤ 3 cm lepidic predominant tumor with ≤ 5 mm invasion) |
| ?Nonmucinous |
| ?Mucinous |
| ?Mixed mucinous/nonmucinous |
| Invasive adenocarcinoma |
| ?Lepidic predominant (formerly nonmucinous BAC pattern, with > 5 mm invasion) |
| ?Acinar predominant |
| ?Papillary predominant |
| ?Micropapillary predominant |
| ?Solid predominant with mucin production |
| Variants of invasive adenocarcinoma |
| ?Invasive mucinous adenocarcinoma (formerly mucinous BAC) |
| ?Colloid |
| ?Fetal (low and high grade) |
| ?Enteric |
The committee makes the following recommendations:
We recommend discontinuing the use of the term “BAC” (strong recommendation, low-quality evidence).
For small (≤ 3 cm), solitary adenocarcinomas with pure lepidic growth, we recommend the term “adenocarcinoma in situ” (AIS), which defines patients who should have 100% disease-specific survival if the lesion is completely resected (strong recommendation, moderate-quality evidence). Remark: Most AIS are nonmucinous; rarely are they mucinous.
For small (≤ 3cm), solitary adenocarcinomas with predominant lepidic growth and small foci of invasion measuring 0.5 cm or less, we recommend a new concept of “minimally invasive adenocarcinoma” (MIA) to define patients who should have near 100% disease-specific survival if completely resected (strong recommendation, low-quality evidence). Remark: Most MIA are nonmucinous; rarely are they mucinous.
For invasive adenocarcinomas, we suggest comprehensive histologic subtyping be used to assess histologic patterns semiquantitatively in 5% increments, choosing a single predominant pattern. We also suggest that individual tumors be classified according to the predominant pattern and that the percentages of the subtypes be reported (weak recommendations, low-quality evidence).
In patients with multiple lung adenocarcinomas, we suggest comprehensive histologic subtyping in the comparison of the complex, heterogeneous mixtures of histologic patterns to determine if the tumors are metastases or separate synchronous or metachronous primaries (weak recommendation, low-quality evidence).
For nonmucinous adenocarcinomas previously classified as mixed subtype, in which the predominant subtype consists of the former nonmucinous BAC, we recommend use of the term “lepidic predominant adenocarcinoma” (LPA) and discontinuing the term “mixed subtype” (strong recommendation, low-quality evidence).
In patients with early-stage adenocarcinoma, we recommend the addition of “micropapillary predominant adenocarcinoma,” when applicable, as a major histologic subtype due to its association with poor prognosis (strong recommendation, low-quality evidence).
For adenocarcinomas formerly classified as mucinous BAC, we recommend they be separated from the adenocarcinomas formerly classified as nonmucinous BAC and depending on the extent of lepidic versus invasive growth that they be classified as mucinous AIS, mucinous MIA, or for overtly invasive tumors “invasive mucinous adenocarcinoma” (weak recommendation, low-quality evidence).
For small biopsies and cytology, we recommend that non-small cell lung cancer (NSCLC) be further classified into a more specific type, such as adenocarcinoma or squamous cell carcinoma, whenever possible (strong recommendation, moderate-quality evidence).
We recommend that the term NSCLC not otherwise specified (NOS) be used as little as possible, and we recommend it be applied only when a more specific diagnosis is not possible by morphology and/or special stains (strong recommendation, moderate-quality evidence).
When a diagnosis is made in a small biopsy or cytology specimen in conjunction with special studies, it should be clarified whether the diagnosis was established based on light microscopy alone or if special stains were required.
Tissue specimens should be managed not only for diagnosis but also to maximize the amount of tissue available for molecular diagnostic studies.
To guide therapy for patients with advanced lung adenocarcinoma, each institution should develop a multidisciplinary team that coordinates the optimal approach to obtaining and processing biopsy/cytology specimens to provide expeditious diagnostic and molecular results.
The terms AIS or MIA should not be used in small biopsies or cytology specimens. If a noninvasive pattern is present in a small biopsy, it should be referred to as lepidic growth.
The term “large cell carcinoma” should not be used for diagnosis in small biopsy or cytology specimens and should be restricted to resection specimens in which the tumor is thoroughly sampled to exclude a differentiated component.
When paired cytology and biopsy specimens exist, they should be reviewed together to achieve the most specific and nondiscordant diagnoses.
Cell blocks should be prepared from cytology samples including pleural fluids.
The term “non-squamous cell carcinoma” should not be used by pathologists in diagnostic reports. It is a categorization used by clinicians to define groups of patients with several histologic types who can be treated in a similar manner; in small biopsies/cytology pathologists should classify NSCLC as adenocarcinoma, squamous cell carcinoma, NSCLC-NOS, or other terms outlined in Table 1.
The above strategy for classification of adenocarcinoma versus other histologies and the terminology in Table 1 should be used in routine diagnosis as well as future research and clinical trials, so that there is uniform classification of disease cohorts in relation to tumor subtypes and data can be stratified according to diagnoses made by light microscopy alone versus diagnoses requiring special stains.
Tumors that show sarcomatoid features, such as marked nuclear pleomorphism, malignant giant cells, or spindle cell morphology, should be preferentially regarded as adenocarcinoma or squamous cell carcinoma if clear glandular or squamous features are present, respectively, as this is apt to influence management. If such features are not present, the term “poorly differentiated non-small cell carcinoma with giant and/or spindle cell features” (depending on what feature is present) should be used.
Neuroendocrine immunohistochemical markers should only be performed in cases in which there is suspected neuroendocrine morphology. If neuroendocrine morphology is not suspected, neuroendocrine markers should not be performed.
In patients with advanced lung adenocarcinoma, we recommend testing for EGFR mutation (strong recommendation, moderate-quality evidence).
Remarks: This is a strong recommendation because the potential benefits clearly outweigh harms. This recommendation assumes that correct classification by EGFR mutation status is associated with important benefit based on randomized phase 3 clinical trials of EGFR TKI therapy, which demonstrate a predictive benefit for response rate and progression-free survival, but not overall survival, as well as subset analyses of multiple additional studies.
If molecular testing is planned, appropriate biopsy methods should be used to obtain sufficient tissue for both pathologic diagnosis and molecular analyses, and the specimens should be handled appropriately.
When an opacity in the lung adenocarcinoma spectrum is either a pure ground glass nodule or part-solid nodule with a predominant ground-glass component, we recommend that the term BAC no longer be used (strong recommendation, low-quality evidence). These tumors should be classified by the new terms: AIS, MIA, and LPA.
For overtly invasive adenocarcinomas previously classified as “mucinous BAC,” we recommend they be separated from nonmucinous adenocarcinomas and be classified as “invasive mucinous adenocarcinoma” (strong recommendation, moderate-quality evidence).
Remark: At computed tomography (CT) scan, this entity is usually solid or mostly solid, has frequent air bronchograms, shows a lobar or multilobar distribution, and frequently consists of multiple nodular or consolidative opacities (former term, “multicentric BAC”).
Radiologists performing biopsies should obtain sufficient tissue not only for traditional microscopic analysis but also for immunohistochemical and molecular analysis.
Thin-section CT technique should be used for part-solid lesions to record the size of (a) the solid component, and (b) total tumor size, including both solid and ground-glass components.
Changes in shape, size, and attenuation help determine follow-up and when intervention is appropriate.
In the rapidly progressing field of lung adenocarcinoma, this classification brings together many recent advances that will significantly impact diagnosis and management for these patients. A multidisciplinary team approach is needed, particularly for the vast majority of patients with lung adenocarcinoma who present in advanced stage where small biopsies and cytology specimens need to be obtained and processed in such a way to assure not only accurate histologic diagnosis but also expedited processing for molecular testing. For the first time, standardized terminology and criteria are provided for diagnosis of adenocarcinoma in small biopsy and cytology specimens. For patients with resected lung adenocarcinomas, the old term “BAC” is discontinued and new terms of AIS, MIA, and LPA are introduced. The old term “mixed subtype” is also no longer used, and overtly invasive tumors are classified according to the predominant subtype. This approach needs to be tested to validate preliminary data suggesting it may help stratify prognostic subsets of overtly invasive tumors and that the size T-factor may be best measured based on size of the invasive component rather than total size in tumors cases with lepidic components.
For TNM staging there are several important implications of this classification: (1) comprehensive histologic subtyping along with other histologic characteristics can be very helpful in determining if multiple pulmonary nodules are separate primaries or intrapulmonary metastases showing good correlation with molecular findings and clinical outcome, and (2) it may be possible to improve the tmor-node-metastasis staging for lung adenocarcinomas that have a lepidic component by using the invasive size to predict tumor size rather than total size both by pathologic and CT scan assessment.
The authors thank other contributors to this project, including: Hisao Asamura, Japan; Giorgio Scagliotti, Italy; Tetsuya Mitsudomi, Japan; Rudolf M. Huber, Germany; Yuichi Ishikawa, Japan; Montserrat Sanchez-Cespedes, Spain; Jean-Paul Sculier, Belgium; Takashi Takahashi, Japan; Masahiro Tsuboi, Japan; Johan Vansteenkiste, Belgium; Ignacio Wistuba, United States; Denise Aberle, United States; Christian Brambilla, France; Douglas Flieder, United States; Wilbur Franklin, United States; Adi Gazdar, United States; Philip Hasleton, UK; Douglas Henderson, Australia; Bruce Johnson, United States; David Johnson, United States; Keith Kerr, UK; Keiko Kuriyama, Japan; Jin Soo Lee, Korea; Vincent A. Miller, United States; Iver Petersen, Germany; Victor Roggli, United States; Rafael Rosell, Spain; Nagahiro Saijo, Japan; Erik Thunnissen, Netherlands; Ming Tsao, Canada; David Yankelewitz, United States; Holger Schuneman, United States.
| 1. | Travis WD, Brambilla E, Noguchi M, Geisinger KR, Beer D, Powell CA, Johnson B, Riely GJ, Rusch VW, Asamura H, et al.. The new IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification. J Thorac Oncol 2011;6:244–285. |
Funding for this project was provided by the International Association for the Study of Lung Cancer (IASLC), American Thoracic Society (ATS), and European Respiratory Society (ERS).
Author disclosures