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International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society International Multidisciplinary Classification of Lung Adenocarcinoma

      Introduction:

      Adenocarcinoma is the most common histologic type of lung cancer. To address advances in oncology, molecular biology, pathology, radiology, and surgery of lung adenocarcinoma, an international multidisciplinary classification was sponsored by the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society. This new adenocarcinoma classification is needed to provide uniform terminology and diagnostic criteria, especially for bronchioloalveolar carcinoma (BAC), the overall approach to small nonresection cancer specimens, and for multidisciplinary strategic management of tissue for molecular and immunohistochemical studies.

      Methods:

      An international core panel of experts representing all three societies was formed with oncologists/pulmonologists, pathologists, radiologists, molecular biologists, and thoracic surgeons. A systematic review was performed under the guidance of the American Thoracic Society Documents Development and Implementation Committee. The search strategy identified 11,368 citations of which 312 articles met specified eligibility criteria and were retrieved for full text review. A series of meetings were held to discuss the development of the new classification, to develop the recommendations, and to write the current document. Recommendations for key questions were graded by strength and quality of the evidence according to the Grades of Recommendation, Assessment, Development, and Evaluation approach.

      Results:

      The classification addresses both resection specimens, and small biopsies and cytology. The terms BAC and mixed subtype adenocarcinoma are no longer used. For resection specimens, new concepts are introduced such as adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) for small solitary adenocarcinomas with either pure lepidic growth (AIS) or predominant lepidic growth with ≤5 mm invasion (MIA) to define patients who, if they undergo complete resection, will have 100% or near 100% disease-specific survival, respectively. AIS and MIA are usually nonmucinous but rarely may be mucinous. Invasive adenocarcinomas are classified by predominant pattern after using comprehensive histologic subtyping with lepidic (formerly most mixed subtype tumors with nonmucinous BAC), acinar, papillary, and solid patterns; micropapillary is added as a new histologic subtype. Variants include invasive mucinous adenocarcinoma (formerly mucinous BAC), colloid, fetal, and enteric adenocarcinoma. This classification provides guidance for small biopsies and cytology specimens, as approximately 70% of lung cancers are diagnosed in such samples. Non-small cell lung carcinomas (NSCLCs), 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 epidermal growth factor receptor (EGFR) mutations as 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 compared with squamous cell carcinoma, and (3) potential life-threatening hemorrhage may occur in patients with squamous cell carcinoma who receive bevacizumab. If the tumor cannot be classified based on light microscopy alone, special studies such as immunohistochemistry and/or mucin stains should be applied to classify the tumor further. Use of the term NSCLC not otherwise specified should be minimized.

      Conclusions:

      This new classification strategy is based on a multidisciplinary approach to diagnosis of lung adenocarcinoma that incorporates clinical, molecular, radiologic, and surgical issues, but it is primarily based on histology. This classification is intended to support clinical practice, and research investigation and clinical trials. As EGFR mutation is a validated predictive marker for response and progression-free survival with EGFR tyrosine kinase inhibitors in advanced lung adenocarcinoma, we recommend that patients with advanced adenocarcinomas be tested for EGFR mutation. This has implications for strategic management of tissue, particularly for small biopsies and cytology samples, to maximize high-quality tissue available for molecular studies. Potential impact for tumor, node, and metastasis staging include adjustment of the size T factor according to only the invasive component (1) pathologically in invasive tumors with lepidic areas or (2) radiologically by measuring the solid component of part-solid nodules.

      Key Words:

      RATIONALE FOR A CHANGE IN THE APPROACH TO CLASSIFICATION OF LUNG ADENOCARCINOMA

      Lung cancer is the most frequent cause of major cancer incidence and mortality worldwide.
      • Boyle P
      • Levin B
      • Parkin DM
      • Bray F
      • Ferlay J
      • et al.
      Global cancer statistics, 2002.
      Adenocarcinoma is the most common histologic subtype of lung cancer in most countries, accounting for almost half of all lung cancers.
      • Curado MP
      • Edwards B
      • Shin HR
      • et al.
      A widely divergent clinical, radiologic, molecular, and pathologic spectrum exists within lung adenocarcinoma. As a result, confusion exists, and studies are difficult to compare. Despite remarkable advances in understanding of this tumor in the past decade, there remains a need for universally accepted criteria for adenocarcinoma subtypes, in particular tumors formerly classified as bronchioloalveolar carcinoma (BAC).
      • Travis WD
      • Brambilla E
      • Muller-Hermelink HK
      • et al.
      • Travis WD
      • Colby TV
      • Corrin B
      • et al.
      As enormous resources are being spent on trials involving molecular and therapeutic aspects of adenocarcinoma of the lung, the development of standardized criteria is of great importance and should help advance the field, increasing the impact of research, and improving patient care. This classification is needed to assist in determining patient therapy and predicting outcome.

      NEED FOR A MULTIDISCIPLINARY APPROACH TO DIAGNOSIS OF LUNG ADENOCARCINOMA

      One of the major outcomes of this project is the recognition that the diagnosis of lung adenocarcinoma requires a multidisciplinary approach. The classifications of lung cancer published by the World Health Organization (WHO) in 1967, 1981, and 1999 were written primarily by pathologists for pathologists.
      • Travis WD
      • Colby TV
      • Corrin B
      • et al.
      • WHO
      • WHO
      Only in the 2004 revision, relevant genetics and clinical information were introduced.
      • Travis WD
      • Brambilla E
      • Muller-Hermelink HK
      • et al.
      Nevertheless, because of remarkable advances over the last 6 years in our understanding of lung adenocarcinoma, particularly in area of medical oncology, molecular biology, and radiology, there is a pressing need for a revised classification, based not on pathology alone, but rather on an integrated multidisciplinary platform. In particular, there are two major areas of interaction between specialties that are driving the need for our multidisciplinary approach to classification of lung adenocarcinoma: (1) in patients with advanced non-small cell lung cancer, recent progress in molecular biology and oncology has led to (a) discovery of epidermal growth factor receptor (EGFR) mutation and its prediction of response to EGFR tyrosine kinase inhibitors (TKIs) in adenocarcinoma patients
      • Mok TS
      • Wu YL
      • Thongprasert S
      • et al.
      Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma.
      • Mitsudomi T
      • Morita S
      • Yatabe Y
      • et al.
      Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial.
      • Maemondo M
      • Inoue A
      • Kobayashi K
      • et al.
      Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR.
      • Zhou C
      • Wu Y-L
      • Chen G
      • et al.
      Efficacy results from the randomized phase III OPTIMAL (CTONG 0802) study comparing first-line erlotinib versus carboplatin (CBDCA) plus gemcitabine (GEM) in Chinese advanced non-small cell lung cancer (NSCLC) patients (PTS) with EGFR activating mutations.
      and (b) the requirement to exclude a diagnosis of squamous cell carcinoma to determine eligibility patients for treatment with pemetrexed, (because of improved efficacy)
      • Scagliotti GV
      • Park K
      • Patil S
      • et al.
      Survival without toxicity for cisplatin plus pemetrexed versus cisplatin plus gemcitabine in chemonaive patients with advanced non-small cell lung cancer: a risk-benefit analysis of a large phase III study.
      • Scagliotti GV
      • Parikh P
      • von Pawel J
      • et al.
      Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer.
      • Ciuleanu T
      • Brodowicz T
      • Zielinski C
      • et al.
      Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study.
      • Scagliotti G
      • Hanna N
      • Fossella F
      • et al.
      The differential efficacy of pemetrexed according to NSCLC histology: a review of two phase III studies.
      or bevacizumab (because of toxicity)
      • Johnson DH
      • Fehrenbacher L
      • Novotny WF
      • et al.
      Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin.
      • Cohen MH
      • Gootenberg J
      • Keegan P
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      FDA drug approval summary: bevacizumab (Avastin) plus Carboplatin and Paclitaxel as first-line treatment of advanced/metastatic recurrent nonsquamous non-small cell lung cancer.
      and (2) the emergence of radiologic-pathologic correlations between ground-glass versus solid or mixed opacities seen by computed tomography (CT) and BAC versus invasive growth by pathology have opened new opportunities for imaging studies to be used by radiologists, pulmonologists, and surgeons for predicting the histologic subtype of adenocarcinomas,
      • Kodama K
      • Higashiyama M
      • Yokouchi H
      • et al.
      Prognostic value of ground-glass opacity found in small lung adenocarcinoma on high-resolution CT scanning.
      • Suzuki K
      • Asamura H
      • Kusumoto M
      • et al.
      “Early” peripheral lung cancer: prognostic significance of ground glass opacity on thin-section computed tomographic scan.
      • Takamochi K
      • Nagai K
      • Yoshida J
      • et al.
      Pathologic N0 status in pulmonary adenocarcinoma is predictable by combining serum carcinoembryonic antigen level and computed tomographic findings.
      • Sakurai H
      • Maeshima A
      • Watanabe S
      • et al.
      Grade of stromal invasion in small adenocarcinoma of the lung: histopathological minimal invasion and prognosis.
      patient prognosis,
      • Kodama K
      • Higashiyama M
      • Yokouchi H
      • et al.
      Prognostic value of ground-glass opacity found in small lung adenocarcinoma on high-resolution CT scanning.
      • Suzuki K
      • Asamura H
      • Kusumoto M
      • et al.
      “Early” peripheral lung cancer: prognostic significance of ground glass opacity on thin-section computed tomographic scan.
      • Takamochi K
      • Nagai K
      • Yoshida J
      • et al.
      Pathologic N0 status in pulmonary adenocarcinoma is predictable by combining serum carcinoembryonic antigen level and computed tomographic findings.
      • Sakurai H
      • Maeshima A
      • Watanabe S
      • et al.
      Grade of stromal invasion in small adenocarcinoma of the lung: histopathological minimal invasion and prognosis.
      • Adler B
      • Padley S
      • Miller RR
      • et al.
      High-resolution CT of bronchioloalveolar carcinoma.
      • Aoki T
      • Tomoda Y
      • Watanabe H
      • et al.
      Peripheral lung adenocarcinoma: correlation of thin-section CT findings with histologic prognostic factors and survival.
      and improve preoperative assessment for choice of timing and type of surgical intervention.
      • Kodama K
      • Higashiyama M
      • Yokouchi H
      • et al.
      Prognostic value of ground-glass opacity found in small lung adenocarcinoma on high-resolution CT scanning.
      • Suzuki K
      • Asamura H
      • Kusumoto M
      • et al.
      “Early” peripheral lung cancer: prognostic significance of ground glass opacity on thin-section computed tomographic scan.
      • Takamochi K
      • Nagai K
      • Yoshida J
      • et al.
      Pathologic N0 status in pulmonary adenocarcinoma is predictable by combining serum carcinoembryonic antigen level and computed tomographic findings.
      • Sakurai H
      • Maeshima A
      • Watanabe S
      • et al.
      Grade of stromal invasion in small adenocarcinoma of the lung: histopathological minimal invasion and prognosis.
      • Adler B
      • Padley S
      • Miller RR
      • et al.
      High-resolution CT of bronchioloalveolar carcinoma.
      • Aoki T
      • Tomoda Y
      • Watanabe H
      • et al.
      Peripheral lung adenocarcinoma: correlation of thin-section CT findings with histologic prognostic factors and survival.
      • El-Sherif A
      • Gooding WE
      • Santos R
      • et al.
      Outcomes of sublobar resection versus lobectomy for stage I non-small cell lung cancer: a 13-year analysis.
      • Nakamura H
      • Kawasaki N
      • Taguchi M
      • et al.
      Survival following lobectomy vs limited resection for stage I lung cancer: a meta-analysis.
      • Okada M
      • Koike T
      • Higashiyama M
      • et al.
      Radical sublobar resection for small-sized non-small cell lung cancer: a multicenter study.
      Although histologic criteria remain the foundation of this new classification, this document has been developed by pathologists in collaboration with clinical, radiology, molecular, and surgical colleagues. This effort has led to the development of terminology and criteria that not only define pathologic entities but also communicate critical information that is relevant to patient management (TABLE 1, TABLE 2). The classification also provides recommendations on strategic handling of specimens to optimize the amount of information to be gleaned. The goal is not only longer to solely provide the most accurate diagnosis but also to manage the tissue in a way that immunohistochemical and/or molecular studies can be performed to obtain predictive and prognostic data that will lead to improvement in patient outcomes.
      TABLE 1IASLC/ATS/ERS Classification of Lung Adenocarcinoma in Resection Specimens
       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
      BAC, bronchioloalveolar carcinoma; IASLC, International Association for the Study of Lung Cancer; ATS, American Thoracic Society; ERS, European Respiratory Society.
      TABLE 2Proposed IASLC/ATS/ERS Classification for Small Biopsies/Cytology
       2004 WHO ClassificationSMALL BIOPSY/CYTOLOGY: IASLC/ATS/ERS
      ADENOCARCINOMA Mixed subtype Acinar Papillary SolidMorphologic 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)
      FetalAdenocarcinoma with fetal pattern
      Mucinous (colloid)Adenocarcinoma with colloid pattern
      Signet ringAdenocarcinoma with (describe patterns present) and signet ring features
      Clear cellAdenocarcinoma with (describe patterns present) and clear cell features
      No 2004 WHO counterpart – most will be solid adenocarcinomasMorphologic adenocarcinoma patterns not present (supported by special stains): Non-small cell carcinoma, favor adenocarcinoma
      SQUAMOUS CELL CARCINOMA Papillary Clear cell Small cell BasaloidMorphologic squamous cell patterns clearly present: Squamous cell carcinoma
      No 2004 WHO counterpartMorphologic squamous cell patterns not present (supported by stains): Non-small cell carcinoma, favor squamous cell carcinoma
      SMALL CELL CARCINOMASmall cell carcinoma
      LARGE CELL CARCINOMANon-small cell carcinoma, not otherwise specified (NOS)
      Large cell neuroendocrine carcinoma (LCNEC)Non-small cell carcinoma with neuroendocrine (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 CARCINOMAMorphologic 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 classificationMorphologic 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 carcinomaPoorly differentiated NSCLC with spindle and/or giant cell carcinoma (mention if adenocarcinoma or squamous carcinoma are present)
      IASLC, International Association for the Study of Lung Cancer; ATS, American Thoracic Society; ERS, European Respiratory Society; WHO, World Health Organization; NSCLC, non-small cell lung cancer; IHC, immunohistochemistry; TTF, thyroid transcription factor.
      For the first time, this classification addresses an approach to small biopsies and cytology in lung cancer diagnosis (Table 2). Recent data regarding EGFR mutation predicting responsiveness to EGFR-TKIs,
      • Mok TS
      • Wu YL
      • Thongprasert S
      • et al.
      Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma.
      • Mitsudomi T
      • Morita S
      • Yatabe Y
      • et al.
      Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial.
      • Maemondo M
      • Inoue A
      • Kobayashi K
      • et al.
      Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR.
      • Zhou C
      • Wu Y-L
      • Chen G
      • et al.
      Efficacy results from the randomized phase III OPTIMAL (CTONG 0802) study comparing first-line erlotinib versus carboplatin (CBDCA) plus gemcitabine (GEM) in Chinese advanced non-small cell lung cancer (NSCLC) patients (PTS) with EGFR activating mutations.
      toxicities,
      • Johnson DH
      • Fehrenbacher L
      • Novotny WF
      • et al.
      Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin.
      and therapeutic efficacy
      • Scagliotti GV
      • Park K
      • Patil S
      • et al.
      Survival without toxicity for cisplatin plus pemetrexed versus cisplatin plus gemcitabine in chemonaive patients with advanced non-small cell lung cancer: a risk-benefit analysis of a large phase III study.
      • Scagliotti GV
      • Parikh P
      • von Pawel J
      • et al.
      Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer.
      • Ciuleanu T
      • Brodowicz T
      • Zielinski C
      • et al.
      Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study.
      • Scagliotti G
      • Hanna N
      • Fossella F
      • et al.
      The differential efficacy of pemetrexed according to NSCLC histology: a review of two phase III studies.
      have established the importance of distinguishing squamous cell carcinoma from adenocarcinoma and non-small cell lung carcinoma (NSCLC) not otherwise specified (NOS) in patients with advanced lung cancer. Approximately 70% of lung cancers are diagnosed and staged by small biopsies or cytology rather than surgical resection specimens, with increasing use of transbronchial needle aspiration (TBNA), endobronchial ultrasound-guided TBNA and esophageal ultrasound-guided needle aspiration.
      • Shah PL
      • Singh S
      • Bower M
      • et al.
      The role of transbronchial fine needle aspiration in an integrated care pathway for the assessment of patients with suspected lung cancer.
      Within the NSCLC group, most pathologists can identify well- or moderately differentiated squamous cell carcinomas or adenocarcinomas, but specific diagnoses are more difficult with poorly differentiated tumors. Nevertheless, in small biopsies and/or cytology specimens, 10 to 30% of specimens continue to be diagnosed as NSCLC-NOS.
      • Scagliotti GV
      • Parikh P
      • von Pawel J
      • et al.
      Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer.
      • Edwards SL
      • Roberts C
      • McKean ME
      • et al.
      Preoperative histological classification of primary lung cancer: accuracy of diagnosis and use of the non-small cell category.
      • Cataluna JJ
      • Perpina M
      • Greses JV
      • et al.
      Cell type accuracy of bronchial biopsy specimens in primary lung cancer.
      Proposed terminology to be used in small biopsies is summarized in Table 2. Pathologists need to minimize the use of the term NSCLC or NSCLC-NOS on small samples and aspiration and exfoliative cytology, providing as specific a histologic classification as possible to facilitate the treatment approach of medical oncologists.
      • Travis WD
      • Rekhtman N
      • Riley GJ
      • et al.
      Pathologic diagnosis of advanced lung cancer based on small biopsies and cytology: a paradigm shift.
      Unlike previous WHO classifications where the primary diagnostic criteria for as many tumor types as possible were based on hematoxylin and eosin (H&E) examination, this classification emphasizes the use and integration of immunohistochemical (i.e., thyroid transcription factor [TTF-1]/p63 staining), histochemical (i.e., mucin staining), and molecular studies, as specific therapies are driven histologic subtyping. Although these techniques should be used whenever possible, it is recognized that this may not always be possible, and thus, a simpler approach is also provided when only H&E-stained slides are available, so this classification may be applicable even in a low resource setting.

      METHODOLOGY

      Objectives

      This international multidisciplinary classification has been produced as a collaborative effort by the International Association for the Study of Lung Cancer (IASLC), the American Thoracic Society (ATS), and the European Respiratory Society. The purpose is to provide an integrated clinical, radiologic, molecular, and pathologic approach to classification of the various types of lung adenocarcinoma that will help to define categories that have distinct clinical, radiologic, molecular, and pathologic characteristics. The goal is to identify prognostic and predictive factors and therapeutic targets.

      Participants

      Panel members included thoracic medical oncologists, pulmonologists, radiologists, molecular biologists, thoracic surgeons, and pathologists. The supporting associations nominated panel members. The cochairs were selected by the IASLC. Panel members were selected because of special interest and expertise in lung adenocarcinoma and to provide an international and multidisciplinary representation. The panel consisted of a core group (author list) and a reviewer group (Appendix 1, see Supplemental Digital Content 1 available at http://links.lww.com/JTO/A59, affiliations for coauthors are listed in appendix).

      Evidence

      The panel performed a systematic review with guidance by members of the ATS Documents Development and Implementation Committee. Key questions for this project were generated by each specialty group, and a search strategy was developed (Appendix 2, see Supplemental Digital Content 2 available at http://links.lww.com/JTO/A60). Searches were performed in June 2008 with an update in June 2009 resulting in 11,368 citations. These were reviewed to exclude articles that did not have any relevance to the topic of lung adenocarcinoma classification. The remaining articles were evaluated by two observers who rated them by a predetermined set of eligibility criteria using an electronic web-based survey program (www.surveymonkey.com) to collect responses. This process narrowed the total number of articles to 312 that were reviewed in detail for a total of 141 specific features, including 17 study characteristics, 35 clinical, 48 pathologic, 16 radiologic, 16 molecular, and nine surgical (Appendix 2). These 141 features were summarized in an electronic database that was distributed to members of the core panel, including the writing committee. Articles chosen for specific data summaries were reviewed, and based on analysis of tables from this systematic review, recommendations were made according to the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE).
      • Schunemann HJ
      • Jaeschke R
      • Cook DJ
      • et al.
      An official ATS statement: grading the quality of evidence and strength of recommendations in ATS guidelines and recommendations.
      • Schunemann HJ
      • Oxman AD
      • Brozek J
      • et al.
      GRADE: assessing the quality of evidence for diagnostic recommendations. ACP J.
      • Schunemann HJ
      • Oxman AD
      • Brozek J
      • et al.
      Grading quality of evidence and strength of recommendations for diagnostic tests and strategies.
      • Guyatt GH
      • Oxman AD
      • Kunz R
      • et al.
      Going from evidence to recommendations.
      • Guyatt GH
      • Oxman AD
      • Kunz R
      • et al.
      What is “quality of evidence” and why is it important to clinicians?.
      • Guyatt GH
      • Oxman AD
      • Vist GE
      • et al.
      GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.
      Throughout the rest of the document, the term GRADE (spelled in capital letters) must be distinguished from histologic grade, which is a measure of pathologic tumor differentiation. The GRADE system has two major components: (1) grading the strength of the recommendation and (2) evaluating the quality of the evidence.
      • Schunemann HJ
      • Jaeschke R
      • Cook DJ
      • et al.
      An official ATS statement: grading the quality of evidence and strength of recommendations in ATS guidelines and recommendations.
      The strength of recommendations is based on weighing estimates of benefits versus downsides. Evidence was rated as high, moderate, or low or very low.
      • Schunemann HJ
      • Jaeschke R
      • Cook DJ
      • et al.
      An official ATS statement: grading the quality of evidence and strength of recommendations in ATS guidelines and recommendations.
      The quality of the evidence expresses the confidence in an estimate of effect or an association and whether it is adequate to support a recommendation. After review of all articles, a writing committee met to develop the recommendations with each specialty group proposing the recommendations, votes for or against the recommendation, and modifications were conducted after multidisciplinary discussion. If randomized trials were available, we started by assuming high quality but down-graded the quality when there were serious methodological limitations, indirectness in population, inconsistency in results, imprecision in estimates, or a strong suspicion of publication bias. If well-done observational studies were available, low-quality evidence was assumed, but the quality was upgraded when there was a large treatment effect or a large association, all plausible residual confounders would diminish the effects, or if there was a dose-response gradient.
      • Guyatt GH
      • Oxman AD
      • Kunz R
      • et al.
      What is “quality of evidence” and why is it important to clinicians?.
      We developed considerations for good practice related to interventions that usually represent necessary and standard procedures of health care system—such as history taking and physical examination helping patients to make informed decisions, obtaining written consent, or the importance of good communication—when we considered them helpful. In that case, we did not perform a grading of the quality of evidence or strength of the recommendations.
      • Guyatt G
      • Oxman AD
      • Kunz R
      • et al.
      GRADE guidelines: 1. Introduction—GRADE evidence profiles and summary of findings tables.

      Meetings

      Between March 2008 and December 2009, a series of meetings were held, mostly at Memorial Sloan Kettering Cancer Center, in New York, NY, to discuss issues related to lung adenocarcinoma classification and to formulate this document. The core group established a uniform and consistent approach to the proposed types of lung adenocarcinoma.

      Validation

      Separate projects were initiated by individuals involved with this classification effort in an attempt to develop data to test the proposed system. These included projects on small biopsies,
      • Loo PS
      • Thomas SC
      • Nicolson MC
      • et al.
      Subtyping of undifferentiated non-small cell carcinomas in bronchial biopsy specimens.
      • Nicholson AG
      • Gonzalez D
      • Shah P
      • et al.
      Refining the diagnosis and EGFR status of non-small cell lung carcinoma in biopsy and cytologic material, using a panel of mucin staining, TTF-1, cytokeratin 5/6, and P63, and EGFR mutation analysis.
      histologic grading,
      • Barletta JA
      • Perner S
      • Iafrate AJ
      • et al.
      Clinical significance of TTF-1 protein expression and TTF-1 gene amplification in lung adenocarcinoma.
      • Deshpande CG
      • Geisinger K
      • Petersen I
      • et al.
      Grading of lung adenocarcinoma: architectural versus nuclear approach.
      • Sica 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.
      stage I adenocarcinomas,
      • Yoshizawa 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.
      small adenocarcinomas from Japan, international multiple pathologist project on reproducibility of recognizing major histologic patterns of lung adenocarcinoma,
      • Thunnissen FB
      • Beasley MB
      • Borczuk A
      • et al.
      Reproducibility of histopathological subtypes in pulmonary adenocarcinoma.
      molecular-histologic correlations, and radiologic-pathologic correlation focused on adenocarcinoma in situ (AIS), and minimally invasive adenocarcinoma (MIA).
      The new proposals in this classification are based on the best available evidence at the time of writing this document. Nevertheless, because of the lack of universal diagnostic criteria in the literature, there is a need for future validation studies based on these standardized pathologic criteria with clinical, molecular, radiologic, and surgical correlations.

      PATHOLOGIC CLASSIFICATION

      Histopathology is the backbone of this classification, but lung cancer diagnosis is a multidisciplinary process requiring correlation with clinical, radiologic, molecular, and surgical information. Because of the multidisciplinary approach in developing this classification, we are recommending significant changes that should improve the diagnosis and classification of lung adenocarcinoma, resulting in therapeutic benefits.
      Even after publication of the 1999 and 2004 WHO classifications,
      • Travis WD
      • Brambilla E
      • Muller-Hermelink HK
      • et al.
      • Travis WD
      • Colby TV
      • Corrin B
      • et al.
      the former term BAC continues to be used for a broad spectrum of tumors including (1) solitary small noninvasive peripheral lung tumors with a 100% 5-year survival,
      • Noguchi M
      • Morikawa A
      • Kawasaki M
      • et al.
      Small adenocarcinoma of the lung. Histologic characteristics and prognosis.
      (2) invasive adenocarcinomas with minimal invasion that have approximately 100% 5-year survival,
      • Borczuk AC
      • Qian F
      • Kazeros A
      • et al.
      Invasive size is an independent predictor of survival in pulmonary adenocarcinoma.
      • Yim J
      • Zhu LC
      • Chiriboga L
      • et al.
      Histologic features are important prognostic indicators in early stages lung adenocarcinomas.
      (3) mixed subtype invasive adenocarcinomas,
      • Goldstein NS
      • Mani A
      • Chmielewski G
      • et al.
      Prognostic factors in T1 NO MO adenocarcinomas and bronchioloalveolar carcinomas of the lung.
      • Clayton F
      Bronchioloalveolar carcinomas. Cell types, patterns of growth, and prognostic correlates.
      • Daly RC
      • Trastek VF
      • Pairolero PC
      • et al.
      Bronchoalveolar carcinoma: factors affecting survival.
      • Manning Jr, JT
      • Spjut HJ
      • Tschen JA
      Bronchioloalveolar carcinoma: the significance of two histopathologic types.
      • Riquet M
      • Foucault C
      • Berna P
      • et al.
      Prognostic value of histology in resected lung cancer with emphasis on the relevance of the adenocarcinoma subtyping.
      (4) mucinous and nonmucinous subtypes of tumors formerly known as BAC,
      • Clayton F
      Bronchioloalveolar carcinomas. Cell types, patterns of growth, and prognostic correlates.
      • Daly RC
      • Trastek VF
      • Pairolero PC
      • et al.
      Bronchoalveolar carcinoma: factors affecting survival.
      • Manning Jr, JT
      • Spjut HJ
      • Tschen JA
      Bronchioloalveolar carcinoma: the significance of two histopathologic types.
      • Goldstein NS
      • Thomas M
      Mucinous and nonmucinous bronchioloalveolar adenocarcinomas have distinct staining patterns with thyroid transcription factor and cytokeratin 20 antibodies.
      • Garfield DH
      • Cadranel J
      • West HL
      Bronchioloalveolar carcinoma: the case for two diseases.
      and (5) widespread advanced disease with a very low survival rate.
      • Travis WD
      • Brambilla E
      • Muller-Hermelink HK
      • et al.
      • Travis WD
      • Colby TV
      • Corrin B
      • et al.
      The consequences of confusion from the multiple uses of the former BAC term in the clinical and research arenas have been the subject of many reviews and editorials and are addressed throughout this document.
      • Garfield DH
      • Cadranel J
      • West HL
      Bronchioloalveolar carcinoma: the case for two diseases.
      • Garfield DH
      • Cadranel J
      The importance of distinguishing mucinous and nonmucinous bronchioloalveolar carcinomas.
      • Garfield DH
      • Franklin WA
      A comparison of survival and disease-specific survival in surgically resected, lymph node-positive bronchioloalveolar carcinoma versus nonsmall cell lung cancer: implications for adjuvant therapy.
      • Travis WD
      • Garg K
      • Franklin WA
      • et al.
      Evolving concepts in the pathology and computed tomography imaging of lung adenocarcinoma and bronchioloalveolar carcinoma.
      • West HL
      • Garfield DH
      Bronchioloalveolar carcinoma: not as easy as “BAC.”.
      • Raz DJ
      • He B
      • Rosell R
      • et al.
      Bronchioloalveolar carcinoma: a review.
      • Gandara DR
      Bronchioloalveolar carcinoma: the “changing face of lung cancer.”.

      Pathology Recommendation 1

      We recommend discontinuing the use of the term “BAC.” Strong recommendation, low-quality evidence.
      Throughout this article, the term BAC (applicable to multiple places in the new classification, Table 3), will be referred to as “former BAC.” We understand this will be a major adjustment and suggest initially that when the new proposed terms are used, it will be accompanied in parentheses by “(formerly BAC).” This transition will impact not only clinical practice and research but also cancer registries future analyses of registry data.
      TABLE 3Categories of New Adenocarcinoma Classification Where Former BAC Concept was Used
       1. Adenocarcinoma in situ (AIS), which can be nonmucinous and rarely mucinous
       2. Minimally invasive adenocarcinoma (MIA), which can be nonmucinous and rarely mucinous
       3. Lepidic predominant adenocarcinoma (nonmucinous)
       4. Adenocarcinoma, predominantly invasive with some nonmucinous lepidic component (includes some resected tumors, formerly classified as mixed subtype, and some clinically advanced adenocarcinomas formerly classified as nonmucinous BAC)
       5. Invasive mucinous adenocarcinoma (formerly mucinous BAC)
      BAC, bronchioloalveolar carcinoma.

      CLASSIFICATION FOR RESECTION SPECIMENS

      Multiple studies have shown that patients with small solitary peripheral adenocarcinomas with pure lepidic growth may have 100% 5-year disease-free survival.
      • Noguchi M
      • Morikawa A
      • Kawasaki M
      • et al.
      Small adenocarcinoma of the lung. Histologic characteristics and prognosis.
      • Watanabe S
      • Watanabe T
      • Arai K
      • et al.
      Results of wedge resection for focal bronchioloalveolar carcinoma showing pure ground-glass attenuation on computed tomography.
      • Sakurai H
      • Dobashi Y
      • Mizutani E
      • et al.
      Bronchioloalveolar carcinoma of the lung 3 centimeters or less in diameter: a prognostic assessment.
      • Vazquez M
      • Carter D
      • Brambilla E
      • et al.
      Solitary and multiple resected adenocarcinomas after CT screening for lung cancer: histopathologic features and their prognostic implications.
      • Yamato Y
      • Tsuchida M
      • Watanabe T
      • et al.
      Early results of a prospective study of limited resection for bronchioloalveolar adenocarcinoma of the lung.
      • Yamada S
      • Kohno T
      Video-assisted thoracic surgery for pure ground-glass opacities 2 cm or less in diameter.
      • Yoshida J
      • Nagai K
      • Yokose T
      • et al.
      Limited resection trial for pulmonary ground-glass opacity nodules: fifty-case experience.
      • Koike T
      • Togashi K
      • Shirato T
      • et al.
      Limited resection for noninvasive bronchioloalveolar carcinoma diagnosed by intraoperative pathologic examination.
      In addition, a growing number of articles suggest that patients with lepidic predominant adenocarcinomas (LPAs) with minimal invasion may also have excellent survival.
      • Borczuk AC
      • Qian F
      • Kazeros A
      • et al.
      Invasive size is an independent predictor of survival in pulmonary adenocarcinoma.
      • Yim J
      • Zhu LC
      • Chiriboga L
      • et al.
      Histologic features are important prognostic indicators in early stages lung adenocarcinomas.
      Recent work has demonstrated that more than 90% of lung adenocarcinomas fall into the mixed subtype according to the 2004 WHO classification, so it has been proposed to use comprehensive histologic subtyping to make a semiquantitative assessment of the percentages of the various histologic components: acinar, papillary, micropapillary, lepidic, and solid and to classify tumors according to the predominant histologic subtype.
      • Motoi 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.
      This has demonstrated an improved ability to address the complex histologic heterogeneity of lung adenocarcinomas and to improve molecular and prognostic correlations.
      • Motoi 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.
      The new proposed lung adenocarcinoma classification for resected tumors is summarized in Table 1.

      Preinvasive Lesions

      In the 1999 and 2004 WHO classifications, atypical adenomatous hyperplasia (AAH) was recognized as a preinvasive lesion for lung adenocarcinoma. This is based on multiple studies documenting these lesions as incidental findings in the adjacent lung parenchyma in 5 to 23% of resected lung adenocarcinomas
      • Carey FA
      • Wallace WA
      • Fergusson RJ
      • et al.
      Alveolar atypical hyperplasia in association with primary pulmonary adenocarcinoma: a clinicopathological study of 10 cases.
      • Weng S
      • Tsuchiya E
      • Satoh Y
      • et al.
      Multiple atypical adenomatous hyperplasia of type II pneumonocytes and bronchio-alveolar carcinoma.
      • Nakanishi K
      Alveolar epithelial hyperplasia and adenocarcinoma of the lung.
      • Nakahara R
      • Yokose T
      • Nagai K
      • et al.
      Atypical adenomatous hyperplasia of the lung: a clinicopathological study of 118 cases including cases with multiple atypical adenomatous hyperplasia.
      • Miller RR
      Bronchioloalveolar cell adenomas.
      and a variety of molecular findings that demonstrate a relationship to lung adenocarcinoma including clonality,
      • Nakayama H
      • Noguchi M
      • Tsuchiya R
      • et al.
      Clonal growth of atypical adenomatous hyperplasia of the lung: cytofluorometric analysis of nuclear DNA content.
      • Niho S
      • Yokose T
      • Suzuki K
      • et al.
      Monoclonality of atypical adenomatous hyperplasia of the lung.
      KRAS mutation,
      • Sakamoto H
      • Shimizu J
      • Horio Y
      • et al.
      Disproportionate representation of KRAS gene mutation in atypical adenomatous hyperplasia, but even distribution of EGFR gene mutation from preinvasive to invasive adenocarcinomas.
      • Westra WH
      • Baas IO
      • Hruban RH
      • et al.
      K-ras oncogene activation in atypical alveolar hyperplasias of the human lung.
      KRAS polymorphism,
      • Kohno T
      • Kunitoh H
      • Suzuki K
      • et al.
      Association of KRAS polymorphisms with risk for lung adenocarcinoma accompanied by atypical adenomatous hyperplasias.
      EGFR mutation,
      • Yoshida Y
      • Shibata T
      • Kokubu A
      • et al.
      Mutations of the epidermal growth factor receptor gene in atypical adenomatous hyperplasia and bronchioloalveolar carcinoma of the lung.
      p53 expression,
      • Kitamura H
      • Kameda Y
      • Nakamura N
      • et al.
      Atypical adenomatous hyperplasia and bronchoalveolar lung carcinoma. Analysis by morphometry and the expressions of p53 and carcinoembryonic antigen.
      loss of heterozygosity,
      • Takamochi K
      • Ogura T
      • Suzuki K
      • et al.
      Loss of heterozygosity on chromosomes 9q and 16p in atypical adenomatous hyperplasia concomitant with adenocarcinoma of the lung.
      methylation,
      • Licchesi JD
      • Westra WH
      • Hooker CM
      • et al.
      Promoter hypermethylation of hallmark cancer genes in atypical adenomatous hyperplasia of the lung.
      telomerase overexpression,
      • Nakanishi K
      • Kawai T
      • Kumaki F
      • et al.
      Expression of human telomerase RNA component and telomerase reverse transcriptase mRNA in atypical adenomatous hyperplasia of the lung.
      eukaryotic initiation factor 4E expression,
      • Seki N
      • Takasu T
      • Mandai K
      • et al.
      Expression of eukaryotic initiation factor 4E in atypical adenomatous hyperplasia and adenocarcinoma of the human peripheral lung.
      epigenetic alterations in the Wnt pathway,
      • Licchesi JD
      • Westra WH
      • Hooker CM
      • et al.
      Epigenetic alteration of Wnt pathway antagonists in progressive glandular neoplasia of the lung.
      and FHIT expression.
      • Kerr KM
      • MacKenzie SJ
      • Ramasami S
      • et al.
      Expression of Fhit, cell adhesion molecules and matrix metalloproteinases in atypical adenomatous hyperplasia and pulmonary adenocarcinoma.
      Depending on the extensiveness of the search, AAH may be multiple in up to 7% of resected lung adenocarcinomas.
      • Weng S
      • Tsuchiya E
      • Satoh Y
      • et al.
      Multiple atypical adenomatous hyperplasia of type II pneumonocytes and bronchio-alveolar carcinoma.
      • Maeshima AM
      • Tochigi N
      • Yoshida A
      • et al.
      Clinicopathologic analysis of multiple (five or more) atypical adenomatous hyperplasias (AAHs) of the lung: evidence for the AAH-adenocarcinoma sequence.
      A major change in this classification is the official recognition of AIS, as a second preinvasive lesion for lung adenocarcinoma in addition to AAH. In the category of preinvasive lesions, AAH is the counterpart to squamous dysplasia and AIS the counterpart to squamous cell carcinoma in situ.

      Atypical Adenomatous Hyperplasia

      AAH is a localized, small (usually 0.5 cm or less) proliferation of mildly to moderately atypical type II pneumocytes and/or Clara cells lining alveolar walls and sometimes, respiratory bronchioles (Figures 1A, B).
      • Travis WD
      • Brambilla E
      • Muller-Hermelink HK
      • et al.
      • Mori M
      • Rao SK
      • Popper HH
      • et al.
      Atypical adenomatous hyperplasia of the lung: a probable forerunner in the development of adenocarcinoma of the lung.
      • Kitamura H
      • Kameda Y
      • Ito T
      • et al.
      Atypical adenomatous hyperplasia of the lung. Implications for the pathogenesis of peripheral lung adenocarcinoma.
      Gaps are usually seen between the cells, which consist of rounded, cuboidal, low columnar, or “peg” cells with round to oval nuclei (Figure 1B). Intranuclear inclusions are frequent. There is a continuum of morphologic changes between AAH and AIS.
      • Travis WD
      • Brambilla E
      • Muller-Hermelink HK
      • et al.
      • Mori M
      • Rao SK
      • Popper HH
      • et al.
      Atypical adenomatous hyperplasia of the lung: a probable forerunner in the development of adenocarcinoma of the lung.
      • Kitamura H
      • Kameda Y
      • Ito T
      • et al.
      Atypical adenomatous hyperplasia of the lung. Implications for the pathogenesis of peripheral lung adenocarcinoma.
      A spectrum of cellularity and atypia occurs in AAH. Although some have classified AAH into low- and high-grade types,
      • Nakanishi K
      • Kawai T
      • Kumaki F
      • et al.
      Expression of human telomerase RNA component and telomerase reverse transcriptase mRNA in atypical adenomatous hyperplasia of the lung.
      • Koga T
      • Hashimoto S
      • Sugio K
      • et al.
      Lung adenocarcinoma with bronchioloalveolar carcinoma component is frequently associated with foci of high-grade atypical adenomatous hyperplasia.
      grading is not recommended.
      • Travis WD
      • Brambilla E
      • Muller-Hermelink HK
      • et al.
      Distinction between more cellular and atypical AAH and AIS can be difficult histologically and impossible cytologically.
      Figure thumbnail gr1
      FIGURE 1Atypical adenomatous hyperplasia. A, This 3-mm nodular lesion consists of atypical pneumocytes proliferating along preexisting alveolar walls. There is no invasive component. B, The slightly atypical pneumocytes are cuboidal and show gaps between the cells. Nuclei are hyperchromatic, and a few show nuclear enlargement and multinucleation.

      AIS, Nonmucinous, and/or Mucinous

      AIS (one of the lesions formerly known as BAC) is a localized small (≤3 cm) adenocarcinoma with growth restricted to neoplastic cells along preexisting alveolar structures (lepidic growth), lacking stromal, vascular, or pleural invasion. Papillary or micropapillary patterns and intraalveolar tumor cells are absent. AIS is subdivided into nonmucinous and mucinous variants. Virtually, all cases of AIS are nonmucinous, consisting of type II pneumocytes and/or Clara cells (Figures 2A, B). There is no recognized clinical significance to the distinction between type II or Clara cells, so this morphologic separation is not recommended. The rare cases of mucinous AIS consist of tall columnar cells with basal nuclei and abundant cytoplasmic mucin; sometimes they resemble goblet cells (Figures 3A, B). Nuclear atypia is absent or inconspicuous in both nonmucinous and mucinous AIS (Figures 2B and 3B). Septal widening with sclerosis is common in AIS, particularly the nonmucinous variant.
      Figure thumbnail gr2
      FIGURE 2Nonmucinous adenocarcinoma in situ. A, This circumscribed nonmucinous tumor grows purely with a lepidic pattern. No foci of invasion or scarring are seen. B, The tumor shows atypical pneumocytes proliferating along the slightly thickened, but preserved, alveolar walls.
      Figure thumbnail gr3
      FIGURE 3Mucinous adenocarcinoma in situ. A, This mucinous AIS consists of a nodular proliferation of mucinous columnar cells growing in a purely lepidic pattern. Although there is a small central scar, no stromal or vascular invasion is seen. B, The tumor cells consist of cuboidal to columnar cells with abundant apical mucin and small basally oriented nuclei. AIS, adenocarcinoma in situ.
      Tumors that meet criteria for AIS have formerly been classified as BAC according to the strict definition of the 1999 and 2004 WHO classifications and type A and type B adenocarcinoma according to the 1995 Noguchi classification.
      • Travis WD
      • Brambilla E
      • Muller-Hermelink HK
      • et al.
      • Noguchi M
      • Morikawa A
      • Kawasaki M
      • et al.
      Small adenocarcinoma of the lung. Histologic characteristics and prognosis.
      Multiple observational studies on solitary lung adenocarcinomas with pure lepidic growth, smaller than either 2 or 3 cm have documented 100% disease-free survival.
      • Noguchi M
      • Morikawa A
      • Kawasaki M
      • et al.
      Small adenocarcinoma of the lung. Histologic characteristics and prognosis.
      • Watanabe S
      • Watanabe T
      • Arai K
      • et al.
      Results of wedge resection for focal bronchioloalveolar carcinoma showing pure ground-glass attenuation on computed tomography.
      • Sakurai H
      • Dobashi Y
      • Mizutani E
      • et al.
      Bronchioloalveolar carcinoma of the lung 3 centimeters or less in diameter: a prognostic assessment.
      • Vazquez M
      • Carter D
      • Brambilla E
      • et al.
      Solitary and multiple resected adenocarcinomas after CT screening for lung cancer: histopathologic features and their prognostic implications.
      • Yamato Y
      • Tsuchida M
      • Watanabe T
      • et al.
      Early results of a prospective study of limited resection for bronchioloalveolar adenocarcinoma of the lung.
      • Yamada S
      • Kohno T
      Video-assisted thoracic surgery for pure ground-glass opacities 2 cm or less in diameter.
      • Yoshida J
      • Nagai K
      • Yokose T
      • et al.
      Limited resection trial for pulmonary ground-glass opacity nodules: fifty-case experience.
      • Koike T
      • Togashi K
      • Shirato T
      • et al.
      Limited resection for noninvasive bronchioloalveolar carcinoma diagnosed by intraoperative pathologic examination.
      Although most of these tumors are nonmucinous, 2 of the 28 tumors reported by Noguchi as types A and B in the 1995 study were mucinous.
      • Noguchi M
      • Morikawa A
      • Kawasaki M
      • et al.
      Small adenocarcinoma of the lung. Histologic characteristics and prognosis.
      Small size (≤3 cm) and a discrete circumscribed border are important to exclude cases with miliary spread into adjacent lung parenchyma and/or lobar consolidation, particularly for mucinous AIS.

      Pathology Recommendation 2

      For small (≤3 cm), solitary adenocarcinomas with pure lepidic growth, we recommend the term “Adenocarcinoma in situ” that 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.

      MIA, Nonmucinous, and/or Mucinous

      MIA is a small, solitary adenocarcinoma (≤3 cm), with a predominantly lepidic pattern and ≤5 mm invasion in greatest dimension in any one focus.
      • Borczuk AC
      • Qian F
      • Kazeros A
      • et al.
      Invasive size is an independent predictor of survival in pulmonary adenocarcinoma.
      • Yim J
      • Zhu LC
      • Chiriboga L
      • et al.
      Histologic features are important prognostic indicators in early stages lung adenocarcinomas.
      • Maeshima AM
      • Tochigi N
      • Yoshida A
      • et al.
      Histological scoring for small lung adenocarcinomas 2 cm or less in diameter: a reliable prognostic indicator.
      MIA is usually nonmucinous (Figures 4AC) but rarely may be mucinous (Figures 5A, B).
      • Yoshizawa 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.
      MIA is, by definition, solitary and discrete. The criteria for MIA can be applied in the setting of multiple tumors only if the other tumors are regarded as synchronous primaries rather than intrapulmonary metastases.
      Figure thumbnail gr4
      FIGURE 4Nonmucinous minimally invasive adenocarcinoma. A, This subpleural adenocarcinoma tumor consists primarily of lepidic growth with a small (<0.5 cm) central area of invasion. B, To the left is the lepidic pattern and on the right is an area of acinar invasion. C, These acinar glands are invading in the fibrous stroma.
      Figure thumbnail gr5
      FIGURE 5Mucinous minimally invasive adenocarcinoma. A, This mucinous MIA consists of a tumor showing lepidic growth and a small (<0.5 cm) area of invasion. B, The tumor cells consist of mucinous columnar cells growing mostly in a lepidic pattern along the surface of alveolar walls. The tumor invades the areas of stromal fibrosis in an acinar pattern. MIA, minimally invasive adenocarcinoma.
      The invasive component to be measured in MIA is defined as follows: (1) histological subtypes other than a lepidic pattern (i.e., acinar, papillary, micropapillary, and/or solid) or (2) tumor cells infiltrating myofibroblastic stroma. MIA is excluded if the tumor (1) invades lymphatics, blood vessels, or pleura or (2) contains tumor necrosis. If multiple microinvasive areas are found in one tumor, the size of the largest invasive area should be measured in the largest dimension, and it should be ≤5 mm in size. The size of invasion is not the summation of all such foci, if more than one occurs. If the manner of histologic sectioning of the tumor makes it impossible to measure the size of invasion, an estimate of invasive size can be made by multiplying the total percentage of the invasive (nonlepidic) components times the total tumor size.
      Evidence for a category of MIA with 100% disease-free survival can be found in the 1995 article by Noguchi et al., where vascular or pleural invasion was found in 10% of the small solitary lung adenocarcinomas that otherwise met the former definition of pure BAC. Even these focally invasive tumors also showed 100% disease-free survival.
      • Noguchi M
      • Morikawa A
      • Kawasaki M
      • et al.
      Small adenocarcinoma of the lung. Histologic characteristics and prognosis.
      Subsequent articles by Suzuki et al. and Sakurai et al.
      • Suzuki K
      • Asamura H
      • Kusumoto M
      • et al.
      “Early” peripheral lung cancer: prognostic significance of ground glass opacity on thin-section computed tomographic scan.
      • Sakurai H
      • Maeshima A
      • Watanabe S
      • et al.
      Grade of stromal invasion in small adenocarcinoma of the lung: histopathological minimal invasion and prognosis.
      defined subsets of small lung adenocarcinomas with 100% disease-free survival using scar size less than 5 mm and stromal invasion in the area of bronchioloalveolar growth, respectively. More recently, articles by Yim et al., Borczuk et al., and Maeshima et al.
      • Borczuk AC
      • Qian F
      • Kazeros A
      • et al.
      Invasive size is an independent predictor of survival in pulmonary adenocarcinoma.
      • Yim J
      • Zhu LC
      • Chiriboga L
      • et al.
      Histologic features are important prognostic indicators in early stages lung adenocarcinomas.
      • Maeshima AM
      • Tochigi N
      • Yoshida A
      • et al.
      Histological scoring for small lung adenocarcinomas 2 cm or less in diameter: a reliable prognostic indicator.
      have described patients with MIA defined similar to the above criteria, and these have demonstrated near 100% disease specific or very favorable overall survival. There is very limited data regarding mucinous MIA; however, this seems to exist. A mucinous MIA with a minor mixture of a nonmucinous component is being reported.
      • Yoshizawa 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.
      The recent report by Sawada et al.
      • Sawada E
      • Nambu A
      • Motosugi U
      • et al.
      Localized mucinous bronchioloalveolar carcinoma of the lung: thin-section computed tomography and fluorodeoxyglucose positron emission tomography findings.
      of localized mucinous BAC may have included a few cases of mucinous AIS or MIA, but details of the pathology are not specific enough to be certain. A recent series of surgically resected solitary mucinous BAC did not document histologically whether focal invasion was present or not, so AIS versus MIA status cannot be determined, but all eight patients with tumors measuring ≤3 cm had 100% overall 5-year survival rates.
      • Oka S
      • Hanagiri T
      • Uramoto H
      • et al.
      Surgical resection for patients with mucinous bronchioloalveolar carcinoma.
      Presentation as a solitary mass, small size, and a discrete circumscribed border is important to exclude cases of miliary involvement of adjacent lung parenchyma and/or lobar consolidation, particularly for mucinous AIS.

      Pathology Recommendation 3

      For small (≤3 cm), solitary, adenocarcinomas with predominant lepidic growth and small foci of invasion measuring ≤0.5 cm, we recommend a new concept of “Minimally invasive adenocarcinoma” to define patients who have near 100%, disease-specific survival, if completely resected (strong recommendation, low-quality evidence).
      Remark: Most MIA are nonmucinous, rarely are they mucinous.

      Tumor Size and Specimen Processing Issues for AIS and MIA

      The diagnosis of AIS or MIA cannot be firmly established without entire histologic sampling of the tumor. If tumor procurement is performed, it should be done strategically as discussed in the molecular section.
      Because most of the literature on the topic of AIS and MIA deal with tumors 2.0 or 3.0 cm or less, there is insufficient evidence to support that 100% disease-free survival can occur in completely resected, solitary tumors suspected to be AIS or MIA that are larger than 3.0 cm. Until data validate 100% disease-free survival for completely resected, solitary, adenocarcinomas larger than 3.0 cm suspected to be AIS or MIA after complete sampling, the term “lepidic predominant adenocarcinoma, suspect AIS or MIA” is suggested. In such a tumor larger than 3.0 cm, particularly if it has not been completely sampled, the term “lepidic predominant adenocarcinoma” is best applied with a comment that the clinical behavior is uncertain and/or that an invasive component cannot be excluded.

      Invasive Adenocarcinoma

      As invasive adenocarcinomas represent more than 70 to 90% of surgically resected lung cases, one of the most important aspects of this classification is to present a practical way to address these tumors that are composed of a complex heterogeneous mixture of histologic subtypes. This complex mixture of histologic subtypes has presented one of the greatest challenges to classification of invasive lung adenocarcinomas. In recent years, multiple independent research groups have begun to classify lung adenocarcinomas according to the most predominant subtype.
      • Sica 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.
      • Yoshizawa 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.
      • Motoi 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.
      • De Oliveira Duarte Achcar R
      • Nikiforova MN
      • Yousem SA
      Micropapillary lung adenocarcinoma: EGFR, K-ras, and BRAF mutational profile.
      • Nakamura Y
      • Niki T
      • Goto A
      • et al.
      c-Met activation in lung adenocarcinoma tissues: an immunohistochemical analysis.
      • Kim YH
      • Ishii G
      • Goto K
      • et al.
      Dominant papillary subtype is a significant predictor of the response to gefitinib in adenocarcinoma of the lung.
      • Ding L
      • Getz G
      • Wheeler DA
      • et al.
      Somatic mutations affect key pathways in lung adenocarcinoma.
      • Shedden K
      • Taylor JM
      • Enkemann SA
      • et al.
      Gene expression-based survival prediction in lung adenocarcinoma: a multi-site, blinded validation study.
      • Sholl LM
      • Yeap BY
      • Iafrate AJ
      • et al.
      Lung adenocarcinoma with EGFR amplification has distinct clinicopathologic and molecular features in never-smokers.
      • Dacic S
      • Shuai Y
      • Yousem S
      • et al.
      Clinicopathological predictors of EGFR/KRAS mutational status in primary lung adenocarcinomas.
      • Girard N
      • Deshpande C
      • Lau C
      • et al.
      Comprehensive histologic assessment helps to differentiate multiple lung primary nonsmall cell carcinomas from metastases.
      This approach provides better stratification of the “mixed subtype” lung adenocarcinomas according to the 1999/2004 WHO Classifications and has allowed for novel correlations between histologic subtypes and both molecular and clinical features.
      • Sica 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.
      • Yoshizawa 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.
      • Motoi 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.
      • De Oliveira Duarte Achcar R
      • Nikiforova MN
      • Yousem SA
      Micropapillary lung adenocarcinoma: EGFR, K-ras, and BRAF mutational profile.
      • Nakamura Y
      • Niki T
      • Goto A
      • et al.
      c-Met activation in lung adenocarcinoma tissues: an immunohistochemical analysis.
      • Kim YH
      • Ishii G
      • Goto K
      • et al.
      Dominant papillary subtype is a significant predictor of the response to gefitinib in adenocarcinoma of the lung.
      • Ding L
      • Getz G
      • Wheeler DA
      • et al.
      Somatic mutations affect key pathways in lung adenocarcinoma.
      • Shedden K
      • Taylor JM
      • Enkemann SA
      • et al.
      Gene expression-based survival prediction in lung adenocarcinoma: a multi-site, blinded validation study.
      • Sholl LM
      • Yeap BY
      • Iafrate AJ
      • et al.
      Lung adenocarcinoma with EGFR amplification has distinct clinicopathologic and molecular features in never-smokers.
      • Dacic S
      • Shuai Y
      • Yousem S
      • et al.
      Clinicopathological predictors of EGFR/KRAS mutational status in primary lung adenocarcinomas.
      • Girard N
      • Deshpande C
      • Lau C
      • et al.
      Comprehensive histologic assessment helps to differentiate multiple lung primary nonsmall cell carcinomas from metastases.
      In the revised classification, the term “predominant” is appended to all categories of invasive adenocarcinoma, as most of these tumors consist of mixtures of the histologic subtypes (Figures 6AC). This replaces the use of the term adenocarcinoma, mixed subtype. Semiquantitative recording of the patterns in 5% increments encourages the observer to identify all patterns that may be present, rather than focusing on a single pattern (i.e., lepidic growth). This method provides a basis for choosing the predominant pattern. Although most previous studies on this topic used 10% increments, using 5% allows for greater flexibility in choosing a predominant subtype when tumors have two patterns with relatively similar percentages; it also avoids the need to use 10% for small amounts of components that may be prognostically important such as micropapillary or solid patterns. Recording of these percentages also makes it clear to the reader of a report when a tumor has relatively even mixtures of several patterns versus a single dominant pattern. In addition, it provides a way to compare the histology of multiple adenocarcinomas (see later).
      • Girard N
      • Deshpande C
      • Lau C
      • et al.
      Comprehensive histologic assessment helps to differentiate multiple lung primary nonsmall cell carcinomas from metastases.
      This approach may also provide a basis for architectural grading of lung adenocarcinomas.
      • Sica 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.
      A recent reproducibility study of classical and difficult selected images of the major lung adenocarcinoma subtypes circulated among a panel of 26 expert lung cancer pathologists documented kappa values of 0.77 ± 0.07 and 0.38 ± 0.14, respectively.
      • Thunnissen FB
      • Beasley MB
      • Borczuk A
      • et al.
      Reproducibility of histopathological subtypes in pulmonary adenocarcinoma.
      This study did not test recognition of predominant subtype.
      Figure thumbnail gr6
      FIGURE 6Major histologic patterns of invasive adenocarcinoma. A, Lepidic predominant pattern with mostly lepidic growth (right) and a smaller area of invasive acinar adenocarcinoma (left). B, Lepidic pattern consists of a proliferation type II pneumocytes and Clara cells along the surface alveolar walls. C, Area of invasive acinar adenocarcinoma (same tumor as in A and B). D, Acinar adenocarcinoma consists of round to oval-shaped malignant glands invading a fibrous stroma. E, Papillary adenocarcinoma consists of malignant cuboidal to columnar tumor cells growing on the surface of fibrovascular cores. F, Micropapillary adenocarcinoma consists of small papillary clusters of glandular cells growing within this airspace, most of which do not show fibrovascular cores. G, Solid adenocarcinoma with mucin consisting of sheets of tumor cells with abundant cytoplasm and mostly vesicular nuclei with several conspicuous nucleoli. No acinar, papillary, or lepidic patterns are seen, but multiple cells have intracytoplasmic basophilic globules that suggest intracytoplasmic mucin. H, Solid adenocarcinoma with mucin. Numerous intracytoplasmic droplets of mucin are highlighted with this DPAS stain. DPAS, diastase-periodic acid Schiff.

      Pathology Recommendation 4

      For invasive adenocarcinomas, we suggest comprehensive histologic subtyping be used to assess histologic patterns semiquantitatively in 5% increments, choosing a single predominant pattern. Individual tumors are then classified according to the predominant pattern and the percentages of the subtypes are also reported (weak recommendation, low-quality evidence).

      Histologic Comparison of Multiple Adenocarcinomas and Impact on Staging

      Comprehensive histologic subtyping can be useful in comparing multiple lung adenocarcinomas to distinguish multiple primary tumors from intrapulmonary metastases. This has a great impact on staging for patients with multiple lung adenocarcinomas. Recording the percentages of the various histologic types in 5% increments, not just the most predominant type, allows these data to be used to compare multiple adenocarcinomas, particularly if the slides of a previous tumor are not available at the time of review of the additional lung tumors.
      • Girard N
      • Deshpande C
      • Lau C
      • et al.
      Comprehensive histologic assessment helps to differentiate multiple lung primary nonsmall cell carcinomas from metastases.
      In addition to comprehensive histologic subtyping, other histologic features of the tumors such as cytologic (clear cell or signet ring features) or stromal (desmoplasia or inflammation) characteristics may be helpful to compare multiple tumors.
      • Girard N
      • Deshpande C
      • Lau C
      • et al.
      Comprehensive histologic assessment helps to differentiate multiple lung primary nonsmall cell carcinomas from metastases.

      Pathology Recommendation 5

      In patients with multiple lung adenocarcinomas, we suggest comprehensive histologic subtyping may facilitate in the comparison of the complex, heterogeneous mixtures of histologic patterns to determine whether the tumors are metastases or separate synchronous or metachronous primaries (weak recommendation, low-quality evidence).
      LPA typically consists of bland pneumocytic cells (type II pneumocytes or Clara cells) growing along the surface of alveolar walls similar to the morphology defined in the above section on AIS and MIA (Figures 6A, B). Invasive adenocarcinoma is present in at least one focus measuring more than 5 mm in greatest dimension. Invasion is defined as (1) histological subtypes other than a lepidic pattern (i.e., acinar, papillary, micropapillary, and/or solid) or (2) myofibroblastic stroma associated with invasive tumor cells (Figure 6C). The diagnosis of LPA rather than MIA is made if the tumor (1) invades lymphatics, blood vessels, or pleura or (2) contains tumor necrosis. It is understood that lepidic growth can occur in metastatic tumors and invasive mucinous adenocarcinomas. Nevertheless, the specific term “Lepidic predominant adenocarcinoma (LPA)” in this classification defines a nonmucinous adenocarcinoma that has lepidic growth as its predominant component, and these tumors are now separated from invasive mucinous adenocarcinoma. The term LPA should not be used in the context of invasive mucinous adenocarcinoma with predominant lepidic growth.
      In the categories of mixed subtype in the 1999/2004 WHO classifications and type C in the Noguchi classification,
      • Travis WD
      • Brambilla E
      • Muller-Hermelink HK
      • et al.
      • Noguchi M
      • Morikawa A
      • Kawasaki M
      • et al.
      Small adenocarcinoma of the lung. Histologic characteristics and prognosis.
      there was no assessment of the percentage of lepidic growth (former BAC pattern), so in series diagnosed according to these classification systems, most of the LPAs are buried among a heterogeneous group of tumors that include predominantly invasive adenocarcinomas. Nevertheless, several studies have shown lepidic growth to be associated with more favorable survival in small solitary resected lung adenocarcinomas with an invasive component.
      • Borczuk AC
      • Qian F
      • Kazeros A
      • et al.
      Invasive size is an independent predictor of survival in pulmonary adenocarcinoma.
      • Vazquez M
      • Carter D
      • Brambilla E
      • et al.
      Solitary and multiple resected adenocarcinomas after CT screening for lung cancer: histopathologic features and their prognostic implications.
      • Lee HY
      • Han J
      • Lee KS
      • et al.
      Lung adenocarcinoma as a solitary pulmonary nodule: prognostic determinants of CT, PET, and histopathologic findings.
      • Yokose T
      • Suzuki K
      • Nagai K
      • et al.
      Favorable and unfavorable morphological prognostic factors in peripheral adenocarcinoma of the lung 3 cm or less in diameter.
      • Lin DM
      • Ma Y
      • Zheng S
      • et al.
      Prognostic value of bronchioloalveolar carcinoma component in lung adenocarcinoma.
      One recent study of stage I adenocarcinomas using this approach demonstrated 90% 5-year recurrence free survival.
      • Yoshizawa 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.

      Pathology Recommendation 6

      For nonmucinous adenocarcinomas previously classified as mixed subtype where the predominant subtype consists of the former nonmucinous BAC, we recommend use of the term LPA and discontinuing the term “mixed subtype” (strong recommendation, low-quality evidence).
      Acinar predominant adenocarcinoma shows a majority component of glands, which are round to oval shaped with a central luminal space surrounded by tumor cells (Figure 6D).
      • Travis WD
      • Brambilla E
      • Muller-Hermelink HK
      • et al.
      The neoplastic cells and glandular spaces may contain mucin. Acinar structures also may consist of rounded aggregates of tumor cells with peripheral nuclear polarization with central cytoplasm without a clear lumen. AIS with collapse may be difficult to distinguish from the acinar pattern. Nevertheless, when the alveolar architecture is lost and/or myofibroblastic stroma is present, invasive acinar adenocarcinoma is considered present. Cribriform arrangements are regarded as a pattern of acinar adenocarcinoma.
      • Okudela K
      • Woo T
      • Mitsui H
      • et al.
      Proposal of an improved histological sub-typing system for lung adenocarcinoma—significant prognostic values for stage I disease.
      Papillary predominant adenocarcinoma shows a major component of a growth of glandular cells along central fibrovascular cores (Figure 6E).
      • Travis WD
      • Brambilla E
      • Muller-Hermelink HK
      • et al.
      This should be distinguished from tangential sectioning of alveolar walls in AIS. If a tumor has lepidic growth, but the alveolar spaces are filled with papillary structures, the tumor is classified as papillary ade-nocarcinoma. Myofibroblastic stroma is not needed to diagnose this pattern.
      Micropapillary predominant adenocarcinoma has tumor cells growing in papillary tufts, which lack fibrovascular cores (Figure 6F).
      • Travis WD
      • Brambilla E
      • Muller-Hermelink HK
      • et al.
      These may appear detached and/or connected to alveolar walls. The tumor cells are usually small and cuboidal with minimal nuclear atypia. Ring-like glandular structures may “float” within alveolar spaces. Vascular invasion and stromal invasion are frequent. Psammoma bodies may be seen.
      The micropapillary pattern of lung adenocarcinoma was cited in the 2004 WHO classification in the discussion,
      • Travis WD
      • Brambilla E
      • Muller-Hermelink HK
      • et al.
      but there were too few publications on this topic to introduce it as a formal histologic subtype.
      • Silver SA
      • Askin FB
      True papillary carcinoma of the lung: a distinct clinicopathologic entity.
      • Amin MB
      • Tamboli P
      • Merchant SH
      • et al.
      Micropapillary component in lung adenocarcinoma: a distinctive histologic feature with possible prognostic significance.
      • Miyoshi T
      • Satoh Y
      • Okumura S
      • et al.
      Early-stage lung adenocarcinomas with a micropapillary pattern, a distinct pathologic marker for a significantly poor prognosis.
      Although most of the studies have used a very low threshold for classification of adenocarcinomas as micropapillary, including as low as 1 to 5%,
      • Amin MB
      • Tamboli P
      • Merchant SH
      • et al.
      Micropapillary component in lung adenocarcinoma: a distinctive histologic feature with possible prognostic significance.
      • Miyoshi T
      • Satoh Y
      • Okumura S
      • et al.
      Early-stage lung adenocarcinomas with a micropapillary pattern, a distinct pathologic marker for a significantly poor prognosis.
      it has recently been demonstrated that tumors classified as micropapillary according to the predominant subtype also have a poor prognosis similar to adenocarcinomas with a predominant solid subtype.
      • Yoshizawa 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.
      All articles on the topic of micropapillary lung adenocarcinoma in early-stage patients have reported data indicating that this is a poor prognostic subtype.
      • De Oliveira Duarte Achcar R
      • Nikiforova MN
      • Yousem SA
      Micropapillary lung adenocarcinoma: EGFR, K-ras, and BRAF mutational profile.
      • Amin MB
      • Tamboli P
      • Merchant SH
      • et al.
      Micropapillary component in lung adenocarcinoma: a distinctive histologic feature with possible prognostic significance.
      • Miyoshi T
      • Satoh Y
      • Okumura S
      • et al.
      Early-stage lung adenocarcinomas with a micropapillary pattern, a distinct pathologic marker for a significantly poor prognosis.
      • Kamiya K
      • Hayashi Y
      • Douguchi J
      • et al.
      Histopathological features and prognostic significance of the micropapillary pattern in lung adenocarcinoma.
      • Kawakami T
      • Nabeshima K
      • Makimoto Y
      • et al.
      Micropapillary pattern and grade of stromal invasion in pT1 adenocarcinoma of the lung: usefulness as prognostic factors.
      • Kuroda N
      • Hamaguchi N
      • Takeuchi E
      • et al.
      Lung adenocarcinoma with a micropapillary pattern: a clinicopathological study of 25 cases.
      • Kuroda N
      • Hamauzu T
      • Toi M
      • et al.
      Pulmonary adenocarcinoma with micropapillary component: an immunohistochemical study. Case report.
      • Maeda R
      • Isowa N
      • Onuma H
      • et al.
      Lung adenocarcinomas with micropapillary components.
      • Makimoto Y
      • Nabeshima K
      • Iwasaki H
      • et al.
      Micropapillary pattern: a distinct pathological marker to subclassify tumours with a significantly poor prognosis within small peripheral lung adenocarcinoma (</=20 mm) with mixed bronchioloalveolar and invasive subtypes (Noguchi's type C tumours).
      • Miyoshi T
      • Shirakusa T
      • Ishikawa Y
      • et al.
      Possible mechanism of metastasis in lung adenocarcinomas with a micropapillary pattern.
      • Roh MS
      • Lee JI
      • Choi PJ
      • et al.
      Relationship between micropapillary component and micrometastasis in the regional lymph nodes of patients with stage I lung adenocarcinoma.
      • Sanchez-Mora N
      • Presmanes MC
      • Monroy V
      • et al.
      Micropapillary lung adenocarcinoma: a distinctive histologic subtype with prognostic significance. Case series.
      • Tsutsumida H
      • Nomoto M
      • Goto M
      • et al.
      A micropapillary pattern is predictive of a poor prognosis in lung adenocarcinoma, and reduced surfactant apoprotein A expression in the micropapillary pattern is an excellent indicator of a poor prognosis.
      Additional evidence for the aggressive behavior of this histologic pattern is the overrepresentation of the micropapillary pattern in metastases compared with the primary tumors, where it sometimes comprises only a small percentage of the overall tumor.
      • Sica 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.

      Pathology Recommendation 7

      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).
      Solid predominant adenocarcinoma with mucin production shows a major component of polygonal tumor cells forming sheets, which lack recognizable patterns of adenocarcinoma, i.e., acinar, papillary, micropapillary, or lepidic growth (Figure 6G).
      • Travis WD
      • Brambilla E
      • Muller-Hermelink HK
      • et al.
      If the tumor is 100% solid, intracellular mucin should be present in at least five tumor cells in each of two high-power fields, confirmed with histochemical stains for mucin (Figure 6H).
      • Travis WD
      • Brambilla E
      • Muller-Hermelink HK
      • et al.
      Solid adenocarcinoma must be distinguished from squamous cell carcinomas and large cell carcinomas both of which may show rare cells with intracellular mucin.

      Variants

      Rationale for Changes in Adenocarcinoma Histologic Variants

      Rationale for separation of invasive mucinous adenocarcinoma (formerly mucinous BAC) from nonmucinous adenocarcinomas.

      Multiple studies indicate that tumors formerly classified as mucinous BAC have major clinical, radiologic, pathologic, and genetic differences from the tumors formerly classified as nonmucinous BAC (Table 4).
      • Garfield DH
      • Cadranel J
      • West HL
      Bronchioloalveolar carcinoma: the case for two diseases.
      • Sakamoto H
      • Shimizu J
      • Horio Y
      • et al.
      Disproportionate representation of KRAS gene mutation in atypical adenomatous hyperplasia, but even distribution of EGFR gene mutation from preinvasive to invasive adenocarcinomas.
      • Wislez M
      • Antoine M
      • Baudrin L
      • et al.
      Non-mucinous and mucinous subtypes of adenocarcinoma with bronchioloalveolar carcinoma features differ by biomarker expression and in the response to gefitinib.
      • Hata A
      • Katakami N
      • Fujita S
      • et al.
      Frequency of EGFR and KRAS mutations in Japanese patients with lung adenocarcinoma with features of the mucinous subtype of bronchioloalveolar carcinoma.
      • Lee HY
      • Lee KS
      • Han J
      • et al.
      Mucinous versus nonmucinous solitary pulmonary nodular bronchioloalveolar carcinoma: CT and FDG PET findings and pathologic comparisons.
      • Miyake H
      • Matsumoto A
      • Terada A
      • et al.
      Mucin-producing tumor of the lung: CT findings.
      • Casali C
      • Rossi G
      • Marchioni A
      • et al.
      A single institution-based retrospective study of surgically treated bronchioloalveolar adenocarcinoma of the lung: clinicopathologic analysis, molecular features, and possible pitfalls in routine practice.
      • Shah RN
      • Badve S
      • Papreddy K
      • et al.
      Expression of cytokeratin 20 in mucinous bronchioloalveolar carcinoma.
      • Copin MC
      • Buisine MP
      • Leteurtre E
      • et al.
      Mucinous bronchioloalveolar carcinomas display a specific pattern of mucin gene expression among primary lung adenocarcinomas.
      • Awaya H
      • Takeshima Y
      • Yamasaki M
      • et al.
      Expression of MUC1, MUC2, MUC5AC, and MUC6 in atypical adenomatous hyperplasia, bronchioloalveolar carcinoma, adenocarcinoma with mixed subtypes, and mucinous bronchioloalveolar carcinoma of the lung.
      • Sato K
      • Ueda Y
      • Shikata H
      • et al.
      Bronchioloalveolar carcinoma of mixed mucinous and nonmucinous type: immunohistochemical studies and mutation analysis of the p53 gene.
      • Tsuta K
      • Ishii G
      • Nitadori J
      • et al.
      Comparison of the immunophenotypes of signet-ring cell carcinoma, solid adenocarcinoma with mucin production, and mucinous bronchioloalveolar carcinoma of the lung characterized by the presence of cytoplasmic mucin.
      In particular, these tumors show a very strong correlation with KRAS mutation, whereas nonmucinous adenocarcinomas are more likely to show EGFR mutation and only occasionally KRAS mutation (Table 4). Therefore, in the new classification, these tumors are now separated into different categories (Table 1). The neoplasms formerly termed mucinous BAC, now recognized to have invasive components in the majority of cases, are classified as invasive mucinous adenocarcinoma (formerly mucinous BAC).
      • Sica GL
      • Yoshizawa AK
      • Downey RJ
      • et al.
      Reassessment of the histologic spectrum of mucinous bronchioloalveolar carcinoma (mBAC).
      TABLE 4Difference between Invasive Mucinous Adenocarcinoma and Nonmucinous Adenocarcinoma In Situ/Minimally Invasive Adenocarcinoma/Lepidic Predominant Adenocarcinoma
      Invasive Mucinous Adenocarcinoma (Formerly Mucinous BAC)Nonmucinous AIS/MIA/LPA (Formerly Nonmucinous BAC)
       Female49/84 (58%)52,120–123101/140 (72%)52,120–123
       Smoker39/87 (45%)52,120–122,12475/164 (46%)52,120–122,124
       Radiographic appearanceMajority consolidation; air bronchogram125Majority ground-glass attenuation23,56,58,103,129–134
       Cell typeFrequent multifocal and multilobar presentation56,125–128 Mucin-filled, columnar, and/or goblet50–52,125,135Type II pneumocyte and/or Clara cell50–52,125,135
       Phenotype
       CK7Mostly positive (∼88%)a54,55,136–139Positive (∼98%)a54,55,136–139
       CK20Positive (∼54%)a54,55,136–139Negative (∼5%)a54,55,136–139
       TTF-1Mostly negative (∼17%)1a54,55,120,137–139Positive (∼67%)a54,55,120,137–139
       Genotype
      KRAS mutationFrequent (∼76%)a55,94,121,127,140–144Some (∼13%)a55,121,127,140–144
      EGFR mutationAlmost none (∼3)a55,121,127,140–142Frequent (∼45%)a55,121,127,140–142
      BAC, bronchioloalveolar carcinoma; AIS, adenocarcinoma in situ; MIA, minimally invasive adenocarcinoma; LPA, lepidic predominant adenocarcinoma; EGFR, epidermal growth factor receptor; TTF, thyroid transcription factor.
      Numbers represent the percentage of cases that are reported to be positive.

      Rationale for including mucinous cystadenocarcinoma in colloid adenocarcinoma.

      Tumors formerly classified as “Mucinous cystadenocarcinoma” are very rare, and they probably represent a spectrum of colloid adenocarcinoma. Therefore, we suggest that these adenocarcinomas that consist of uni- or oligolocular cystic structures by imaging and/or gross examination be included in the category of colloid adenocarcinoma.
      • Gaeta M
      • Blandino A
      • Scribano E
      • et al.
      Mucinous cystadenocarcinoma of the lung: CT-pathologic correlation in three cases.
      For such tumors, a comment could be made that the tumor resembles that formerly classified as mucinous cystadenocarcinoma.

      Rationale for removing clear cell and signet ring carcinoma as adenocarcinoma subtypes.

      Clear cell and signet ring cell features are now regarded as cytologic changes that may occur in association with multiple histologic patterns.
      • Deshpande CG
      • Yoshizawa A
      • Motoi N
      • et al.
      Clear cell change in lung adenocarcinoma: a cytologic change rather than a histologic variant.
      • Cohen PR
      • Yoshizawa A
      • Motoi N
      • et al.
      Signet ring cell features (SRCF) in lung adenocarcinoma: a cytologic feature or a histologic subtype?.
      Thus, their presence and extent should be recorded, but data are not available that show a clinical significance beyond a strong association with the solid subtype. They are not considered to be specific histologic subtypes, although associations with molecular features are possible such as the recent observation of a solid pattern with more than 10% signet ring cell features in up to 56% of tumors from patients with echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK) gene fusions (EML4-ALK).
      • Rodig SJ
      • Mino-Kenudson M
      • Dacic S
      • et al.
      Unique clinicopathologic features characterize ALK-rearranged lung adenocarcinoma in the western population.

      Rationale for adding enteric adenocarcinoma.

      Enteric adenocarcinoma is added to the classification to draw attention to this rare histologic type of primary lung adenocarcinoma that can share some morphologic and immunohistochemical features with colorectal adenocarcinoma.
      • Inamura K
      • Satoh Y
      • Okumura S
      • et al.
      Pulmonary adenocarcinomas with enteric differentiation: histologic and immunohistochemical characteristics compared with metastatic colorectal cancers and usual pulmonary adenocarcinomas.
      Because of these similarities, clinical evaluation is needed to exclude a gastrointestinal primary. It is not known whether there are any distinctive clinical or molecular features.

      Histologic Features

      Invasive mucinous adenocarcinoma (formerly mucinous BAC) has a distinctive histologic appearance with tumor cells having a goblet or columnar cell morphology with abundant intracytoplasmic mucin (Figures 7A, B). Cytologic atypia is usually inconspicuous or absent. Alveolar spaces often contain mucin. These tumors may show the same heterogeneous mixture of lepidic, acinar, papillary, micropapillary, and solid growth as in nonmucinous tumors. The clinical significance of reporting semiquantitative estimates of subtype percentages and the predominant histologic subtype similar to nonmucinous adenocarcinomas is not certain. When stromal invasion is seen, the malignant cells may show less cytoplasmic mucin and more atypia. These tumors differ from mucinous AIS and MIA by one or more of the following criteria: size (>3 cm), amount of invasion (>0.5 cm), multiple nodules, or lack of a circumscribed border with miliary spread into adjacent lung parenchyma.
      Figure thumbnail gr7
      FIGURE 7Invasive mucinous adenocarcinoma. A, This area of invasive mucinous adenocarcinoma demonstrates a pure lepidic growth. The tumor consists of columnar cells filled with abundant mucin in the apical cytoplasm and shows small basal oriented nuclei. B, Nevertheless, elsewhere this tumor demonstrated invasion associated with desmoplastic stroma and an acinar pattern.
      There is a strong tendency for multicentric, multilobar, and bilateral lung involvement, which may reflect aerogenous spread. Mixtures of mucinous and nonmucinous tumors may rarely occur; then the percentage of invasive mucinous adenocarcinoma should be recorded in a comment. If there is at least 10% of each component, it should be classified as “Mixed mucinous and nonmucinous adenocarcinoma.” Invasive mucinous adenocarcinomas (formerly mucinous BAC) need to be distinguished from adenocarcinomas that produce mucin but lack the characteristic goblet cell or columnar cell morphology of the tumors that have historically been classified as mucinous BAC. When mucin is identified by light microscopy or mucin stains in adenocarcinomas that do not meet the above criteria, this feature should be reported in a comment after classifying the tumor according to the appropriate terminology and criteria proposed in this classification. This can be done by adding a descriptive phrase such as “with mucin production” or “with mucinous features” rather than the term “invasive mucinous adenocarcinoma.”

      Pathology Recommendation 8

      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).
      Colloid adenocarcinoma shows extracellular mucin in abundant pools, which distend alveolar spaces with destruction of their walls (Figure 8A). The mucin pools contain clusters of mucin-secreting tumor cells, which may comprise only a small percentage of the total tumor and, thus, be inconspicuous (Figure 8A).
      • Moran CA
      • Hochholzer L
      • Fishback N
      • et al.
      Mucinous (so-called colloid) carcinomas of lung.
      • Rossi G
      • Murer B
      • Cavazza A
      • et al.
      Primary mucinous (so-called colloid) carcinomas of the lung: a clinicopathologic and immunohistochemical study with special reference to CDX-2 homeobox gene and MUC2 expression.
      The tumor cells may consist of goblet cells or other mucin secreting cells. Colloid adenocarcinoma is found more often as a mixture with other adenocarcinoma histologic subtypes rather than as a pure pattern. A tumor is classified as a colloid adenocarcinoma when it is the predominant component; the percentages of other components should be recorded.
      • Gaeta M
      • Blandino A
      • Scribano E
      • et al.
      Mucinous cystadenocarcinoma of the lung: CT-pathologic correlation in three cases.
      Cystic gross and histologic features are included in the spectrum of colloid adenocarcinoma, but in most cases, this is a focal feature. Cases previously reported as mucinous cystadenocarcinoma are extremely rare, and now these should be classified as colloid adenocarcinoma with cystic changes. The cysts are filled with mucin and lined by goblet or other mucin secreting cells (Figure 8B). The lining epithelium may be discontinuous and replaced with inflammation including a granulomatous reaction or granulation tissue. Cytologic atypia of the neoplastic epithelium is usually minimal.
      • Gao ZH
      • Urbanski SJ
      The spectrum of pulmonary mucinous cystic neoplasia: a clinicopathologic and immunohistochemical study of ten cases and review of literature.
      Figure thumbnail gr8
      FIGURE 8Adenocarcinoma, variants. A, Colloid adenocarcinoma consists of abundant pools of mucin growing within and distending airspaces. Focally well-differentiated mucinous glandular epithelium grows along the surface of fibrous septa and within the pools of mucin. Tumor cells may be very inconspicuous. B, This colloid adenocarcinoma contains a cystic component surrounded by a fibrous wall that is filled with pools of mucin; such a pattern was previously called mucinous cystadenocarcinoma. The surface of the fibrous wall is lined by well-differentiated cuboidal or columnar mucinous epithelium. C, Fetal adenocarcinoma consists of malignant glandular cells growing in tubules and papillary structures. These tumor cells have prominent clear cytoplasm, and squamoid morules are present. D, Enteric adenocarcinoma consists of an adenocarcinoma that morphologically resembles colonic adenocarcinoma with back-to-back angulated acinar structures. The tumor cells are cuboidal to columnar with nuclear pseudostratification.
      Fetal adenocarcinoma consists of glandular elements with tubules composed of glycogen-rich, nonciliated cells that resemble fetal lung tubules (Figure 8C).
      • Travis WD
      • Brambilla E
      • Muller-Hermelink HK
      • et al.
      Subnuclear vacuoles are common and characteristic. Squamoid morules may be seen within lumens. Most are low grade with a favorable outcome. High-grade tumors occur. When mixtures occur with other histologic subtypes, the tumor should be classified according to the predominant component.
      • Nakatani Y
      • Kitamura H
      • Inayama Y
      • et al.
      Pulmonary adenocarcinomas of the fetal lung type: a clinicopathologic study indicating differences in histology, epidemiology, and natural history of low-grade and high-grade forms.
      This tumor typically occurs in younger patients than other adenocarcinomas. Uniquely, these tumors appear driven by mutations in the beta-catenin gene, and the epithelial cells express aberrant nuclear and cytoplasmic staining with this antibody by immunohistochemistry.
      • Nakatani Y
      • Masudo K
      • Miyagi Y
      • et al.
      Aberrant nuclear localization and gene mutation of beta-catenin in low-grade adenocarcinoma of fetal lung type: up-regulation of the Wnt signaling pathway may be a common denominator for the development of tumors that form morules.
      • Sekine S
      • Shibata T
      • Matsuno Y
      • et al.
      Beta-catenin mutations in pulmonary blastomas: association with morule formation.
      Nakatani et al. and Sekine et al.
      • Nakatani Y
      • Masudo K
      • Miyagi Y
      • et al.
      Aberrant nuclear localization and gene mutation of beta-catenin in low-grade adenocarcinoma of fetal lung type: up-regulation of the Wnt signaling pathway may be a common denominator for the development of tumors that form morules.
      • Sekine S
      • Shibata T
      • Matsuno Y
      • et al.
      Beta-catenin mutations in pulmonary blastomas: association with morule formation.
      have suggested that up-regulation of components in the Wnt signaling pathway such as β-catenin is important in low-grade fetal adenocarcinomas and in biphasic pulmonary blastomas in contrast to high-grade fetal adenocarcinomas.
      Enteric differentiation can occur in lung adenocarcinoma, and when this component exceeds 50%, the tumor is classified as pulmonary adenocarcinoma with enteric differentiation. The enteric pattern shares morphologic and immunohistochemical features with colorectal adenocarcinoma.
      • Inamura K
      • Satoh Y
      • Okumura S
      • et al.
      Pulmonary adenocarcinomas with enteric differentiation: histologic and immunohistochemical characteristics compared with metastatic colorectal cancers and usual pulmonary adenocarcinomas.
      In contrast to metastatic colorectal adenocarcinoma, these tumors are histologically heterogeneous with some component that resembles primary lung adenocarcinoma such as lepidic growth. Recording of the percentages of these other components may be useful. The enteric pattern consists of glandular and/or papillary structures sometimes with a cribriform pattern, lined by tumor cells that are mostly tall-columnar with nuclear pseudostratification, luminal necrosis, and prominent nuclear debris (Figure 8D).
      • Inamura K
      • Satoh Y
      • Okumura S
      • et al.
      Pulmonary adenocarcinomas with enteric differentiation: histologic and immunohistochemical characteristics compared with metastatic colorectal cancers and usual pulmonary adenocarcinomas.
      Poorly differentiated tumors may have a more solid pattern. These tumors show at least one immunohistologic marker of enteric differentiation (CDX-2, CK20, or MUC2). Consistent positivity for CK7 and expression of TTF-1 in approximately half the cases helps in the distinction from metastatic colorectal adenocarcinoma.
      • Inamura K
      • Satoh Y
      • Okumura S
      • et al.
      Pulmonary adenocarcinomas with enteric differentiation: histologic and immunohistochemical characteristics compared with metastatic colorectal cancers and usual pulmonary adenocarcinomas.
      • Li HC
      • Schmidt L
      • Greenson JK
      • et al.
      Primary pulmonary adenocarcinoma with intestinal differentiation mimicking metastatic colorectal carcinoma: case report and review of literature.
      CK7-negative cases may occur.

      Hatanaka K, Tsuta K, Watanabe K, et al. Primary pulmonary adenocarcinoma with enteric differentiation resembling metastatic colorectal carcinoma: a report of the second case negative for cytokeratin 7. Pathol Res Pract. In press.

      Primary lung adenocarcinomas that histologically resemble colorectal adenocarcinoma but lack immunohistochemical markers of enteric differentiation are probably better regarded as lung adenocarcinomas with enteric morphology rather than pulmonary adenocarcinoma with enteric differentiation.
      • Yousem SA
      Pulmonary intestinal-type adenocarcinoma does not show enteric differentiation by immunohistochemical study.

      CLASSIFICATION FOR SMALL BIOPSIES AND CYTOLOGY

      Clinical Relevance of Histologic Diagnosis Drives Need to Classify NSCLC Further

      This section applies to pathologic diagnosis of the majority of patients with lung cancer due to presentation with locally advanced or metastatic disease. Because of the need for improved separation of squamous cell carcinoma from adenocarcinoma, as it determines eligibility for molecular testing and impacts on specific therapies, there is now greater clinical interest in application of additional pathology tools to refine further the diagnosis in small biopsies (bronchoscopic, needle, or core biopsies) and cytology specimens from patients with advanced lung cancer, when morphologic features are not clear.
      • Travis WD
      • Rekhtman N
      • Riley GJ
      • et al.
      Pathologic diagnosis of advanced lung cancer based on small biopsies and cytology: a paradigm shift.
      • Loo PS
      • Thomas SC
      • Nicolson MC
      • et al.
      Subtyping of undifferentiated non-small cell carcinomas in bronchial biopsy specimens.
      • Nicholson AG
      • Gonzalez D
      • Shah P
      • et al.
      Refining the diagnosis and EGFR status of non-small cell lung carcinoma in biopsy and cytologic material, using a panel of mucin staining, TTF-1, cytokeratin 5/6, and P63, and EGFR mutation analysis.
      • Rossi G
      • Pelosi G
      • Graziano P
      • et al.
      A reevaluation of the clinical significance of histological subtyping of non–small-cell lung carcinoma: diagnostic algorithms in the era of personalized treatments.
      • Rossi G
      • Papotti M
      • Barbareschi M
      • et al.
      Morphology and a limited number of immunohistochemical markers may efficiently subtype non-small-cell lung cancer.
      Patients with adenocarcinoma should be tested for EGFR mutations (see evidence in Clinical Recommendation section) because patients with EGFR mutation-positive tumors may be eligible for first-line TKI therapy.
      • Mok TS
      • Wu YL
      • Thongprasert S
      • et al.
      Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma.
      • Mitsudomi T
      • Morita S
      • Yatabe Y
      • et al.
      Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial.
      • Maemondo M
      • Inoue A
      • Kobayashi K
      • et al.
      Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR.
      • Zhou C
      • Wu Y-L
      • Chen G
      • et al.
      Efficacy results from the randomized phase III OPTIMAL (CTONG 0802) study comparing first-line erlotinib versus carboplatin (CBDCA) plus gemcitabine (GEM) in Chinese advanced non-small cell lung cancer (NSCLC) patients (PTS) with EGFR activating mutations.
      Adenocarcinoma patients are also eligible for pemetrexed
      • Scagliotti GV
      • Park K
      • Patil S
      • et al.
      Survival without toxicity for cisplatin plus pemetrexed versus cisplatin plus gemcitabine in chemonaive patients with advanced non-small cell lung cancer: a risk-benefit analysis of a large phase III study.
      • Scagliotti GV
      • Parikh P
      • von Pawel J
      • et al.
      Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer.
      • Ciuleanu T
      • Brodowicz T
      • Zielinski C
      • et al.
      Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study.
      • Scagliotti G
      • Hanna N
      • Fossella F
      • et al.
      The differential efficacy of pemetrexed according to NSCLC histology: a review of two phase III studies.
      or bevacizumab-based chemotherapy regimens (see Clinical Recommendation section).
      • Johnson DH
      • Fehrenbacher L
      • Novotny WF
      • et al.
      Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin.
      • Cohen MH
      • Gootenberg J
      • Keegan P
      • et al.
      FDA drug approval summary: bevacizumab (Avastin) plus Carboplatin and Paclitaxel as first-line treatment of advanced/metastatic recurrent nonsquamous non-small cell lung cancer.

      Pathology Recommendation 9

      For small biopsies and cytology, we recommend that NSCLC be further classified into a more specific histologic type, such as adenocarcinoma or squamous cell carcinoma, whenever possible (strong recommendation, moderate quality evidence).

      Data Driving Need to Classify NSCLC Further are Based Only on Light Microscopy

      All current data that justify the importance of the distinction between histologic types of NSCLC in patients with advanced lung cancer are based on light microscopy alone.
      • Mok TS
      • Wu YL
      • Thongprasert S
      • et al.
      Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma.
      • Mitsudomi T
      • Morita S
      • Yatabe Y
      • et al.
      Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial.
      • Maemondo M
      • Inoue A
      • Kobayashi K
      • et al.
      Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR.
      • Zhou C
      • Wu Y-L
      • Chen G
      • et al.
      Efficacy results from the randomized phase III OPTIMAL (CTONG 0802) study comparing first-line erlotinib versus carboplatin (CBDCA) plus gemcitabine (GEM) in Chinese advanced non-small cell lung cancer (NSCLC) patients (PTS) with EGFR activating mutations.
      • Scagliotti GV
      • Park K
      • Patil S
      • et al.
      Survival without toxicity for cisplatin plus pemetrexed versus cisplatin plus gemcitabine in chemonaive patients with advanced non-small cell lung cancer: a risk-benefit analysis of a large phase III study.