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Pathology of Lung Cancer

      Keywords

      Classification

      Worldwide, lung cancer is the most common cause of major cancer incidence and mortality in men, whereas in women it is the third most common cause of cancer incidence and the second most common cause of cancer mortality.
      • Jemal A.
      • Bray F.
      • Center M.M.
      • et al.
      Global cancer statistics.
      In 2010 the American Cancer Society estimated that lung cancer would account for more than 222,520 new cases in the United States during 2010 and 157,300 cancer deaths.
      • Jemal A.
      • Siegel R.
      • Xu J.
      • et al.
      Cancer statistics, 2010.
      Although lung cancer incidence in the United States began to decline in men in the early 1980s,
      • Travis W.D.
      • Lubin J.
      • Ries L.
      • et al.
      United States lung carcinoma incidence trends: declining for most histologic types among males, increasing among females.
      it seems to have plateaued in women.
      • Jemal A.
      • Siegel R.
      • Xu J.
      • et al.
      Cancer statistics, 2010.
      Lung cancer can be diagnosed pathologically either by a histologic or cytologic approach.
      • Rekhtman N.
      • Brandt S.M.
      • Sigel C.S.
      • et al.
      Suitability of thoracic cytology for new therapeutic paradigms in non-small cell lung carcinoma: high accuracy of tumor subtyping and feasibility of EGFR and KRAS molecular testing.
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The new IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.
      • Travis W.D.
      • Brambilla E.
      • Müller-Hermelink H.K.
      • et al.
      Pathology and genetics: tumours of the lung, pleura, thymus and heart.
      • Travis W.D.
      • Rekhtman N.
      Pathological diagnosis and classification of lung cancer in small biopsies and cytology: strategic management of tissue for molecular testing.
      • Nizzoli R.
      • Tiseo M.
      • Gelsomino F.
      • et al.
      Accuracy of fine needle aspiration cytology in the pathological typing of non-small cell lung cancer.
      The new International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) Lung Adenocarcinoma Classification has made major changes in how lung adenocarcinoma is diagnosed.
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The new IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.
      • Travis W.D.
      • Rekhtman N.
      Pathological diagnosis and classification of lung cancer in small biopsies and cytology: strategic management of tissue for molecular testing.
      • Travis W.D.
      • Brambilla E.
      • Van Schil P.
      • et al.
      Paradigm shifts in lung cancer as defined in the new IASLC/ATS/ERS lung adenocarcinoma classification.
      It will significantly alter the structure of the previous 2004 World Health Organization (WHO) classification of lung tumors (Box 1). Not only does it address classification in resection specimens (see Box 1), but it also makes recommendations applicable to small biopsies and cytology specimens, for diagnostic terms and criteria for other major histologic subtypes in addition to adenocarcinoma (Table 1). The 4 major histologic types of lung cancer are squamous cell carcinoma, adenocarcinoma, small cell carcinoma, and large cell carcinoma.
      • Travis W.D.
      • Brambilla E.
      • Müller-Hermelink H.K.
      • et al.
      Pathology and genetics: tumours of the lung, pleura, thymus and heart.
      These major types can be subclassified into more specific subtypes such as lepidic predominant subtype of adenocarcinoma or the basaloid variant of large cell carcinoma.
      • Travis W.D.
      • Brambilla E.
      • Müller-Hermelink H.K.
      • et al.
      Pathology and genetics: tumours of the lung, pleura, thymus and heart.
      More detailed reviews of the pathology, cytology, and molecular biology of lung cancer can be found elsewhere.
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The new IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.
      • Travis W.D.
      • Brambilla E.
      • Müller-Hermelink H.K.
      • et al.
      Pathology and genetics: tumours of the lung, pleura, thymus and heart.
      • Travis W.D.
      • Rekhtman N.
      Pathological diagnosis and classification of lung cancer in small biopsies and cytology: strategic management of tissue for molecular testing.
      • Brambilla E.
      • Gazdar A.
      Pathogenesis of lung cancer signalling pathways: roadmap for therapies.
      • Dacic S.
      Molecular diagnostics of lung carcinomas.
      • Gomperts B.N.
      • Spira A.
      • Massion P.P.
      • et al.
      Evolving concepts in lung carcinogenesis.
      • Dowell J.
      • Minna J.D.
      Small-cell lung cancer: translational research enroute to therapeutic advances.
      • Travis W.D.
      Classification of lung cancer.
      • Wallace W.A.
      The challenge of classifying poorly differentiated tumours in the lung.
      • Idowu M.O.
      • Powers C.N.
      Lung cancer cytology: potential pitfalls and mimics–a review.
      • Saad R.S.
      • Silverman J.F.
      Respiratory cytology: differential diagnosis and pitfalls.
      • Siddiqui M.T.
      Pulmonary neuroendocrine neoplasms: a review of clinicopathologic and cytologic features.
      Histologic classification of lung cancera
      • Preinvasive lesions
        • Squamous dysplasia/carcinoma in situ (CIS)
        • Atypical adenomatous hyperplasia (AAH)
        • Adenocarcinoma in situ (AIS) (nonmucinous, mucinous, or mixed nonmucinous/mucinous)
        • Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH)
      • Squamous cell carcinoma
        • Variants
          • Papillary
          • Clear cell
          • Small cell (probably should be discontinued)
          • Basaloid
      • Small cell carcinoma
        • Combined small cell carcinoma
      • Adenocarcinoma
        • Minimally invasive adenocarcinoma (MIA) (≤3 cm lepidic predominant tumor with ≤5 mm invasion)
          • nonmucinous, mucinous, mixed mucinous/nonmucinous
        • Invasive adenocarcinoma
          • Lepidic predominant (formerly nonmucinous bronchioloalveolar carcinoma (BAC) pattern, with >5 mm invasion)
          • Acinar predominant
          • Papillary predominant
          • Micropapillary predominant
          • Solid predominant with mucin
        • Variants of invasive adenocarcinoma
          • Invasive mucinous adenocarcinoma (formerly mucinous BAC)
          • Colloid
          • Fetal (low and high grade)
          • Enteric
      • Large cell carcinoma
        • Variants
        • Large cell neuroendocrine carcinoma (LCNEC)
          • Combined LCNEC
        • Basaloid carcinoma
        • Lymphoepithelioma-like carcinoma
        • Clear cell carcinoma
        • Large cell carcinoma with rhabdoid phenotype
      • Adenosquamous carcinoma
      • Sarcomatoid carcinomas
        • Pleomorphic carcinoma
        • Spindle cell carcinoma
        • Giant cell carcinoma
        • Carcinosarcoma
        • Pulmonary blastoma
        • Other
      • Carcinoid tumor
        • Typical carcinoid (TC)
        • Atypical carcinoid (AC)
      • Carcinomas of salivary gland type
        • Mucoepidermoid carcinoma
        • Adenoid cystic carcinoma
        • Epimyoepithelial carcinoma
      a Modified from the 2004 WHO Classification
      • Travis W.D.
      • Brambilla E.
      • Müller-Hermelink H.K.
      • et al.
      Pathology and genetics: tumours of the lung, pleura, thymus and heart.
      and the 2011 IASLC/ATS/ERS Classification of Lung Adenocarcinoma.
      • Brambilla E.
      • Gazdar A.
      Pathogenesis of lung cancer signalling pathways: roadmap for therapies.
      This classification primarily addresses histology in resected specimens.
      Table 1Proposed IASLC/ATS/ERS classification for small biopsies/cytology
      From Travis WD, Brambilla E, Noguchi M, et al. The new IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification. J Thorac Oncol 2011;6:247.
      2004 WHO ClassificationSmall Biopsy/Cytology: IASLC/ATS/ERS
      • Adenocarcinoma
        • Mixed subtype
        • Acinar
        • Papillary
        • Solid
      Morphologic adenocarcinoma patterns clearly present:

      Adenocarcinoma, describe identifiable patterns present (including micropapillary pattern not included in 2004 WHO classification)

      If pure lepidic growth: mention an invasive component cannot be excluded in this small specimen
      No 2004 WHO counterpart: most are solid adenocarcinomasMorphologic adenocarcinoma patterns not present (supported by special stains):

      Non–small cell carcinoma, favor adenocarcinoma
       BAC (nonmucinous)Adenocarcinoma with lepidic pattern (if pure, add note: an invasive component cannot be excluded)
       BAC (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
      • Squamous Cell Carcinoma
        • Papillary
        • Clear cell
        • Small cell
        • Basaloid
      Morphologic 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)
      LCNECNon–small cell carcinoma with NE morphology (positive NE markers), possible LCNEC
       Large cell carcinoma with NE morphologyNon–small cell carcinoma with NE morphology (negative NE markers): see comment

      Comment: This is a non–small cell carcinoma in which LCNEC is suspected, but stains failed to show NE differentiation
      Adenosquamous carcinomaMorphologic squamous cell and adenocarcinoma patterns present:

      Non–small cell carcinoma, NOS (comment that glandular and squamous components are present)

      Comment: this could represent adenosquamous carcinoma
      No counterpart in 2004 WHO classificationMorphologic squamous cell or adenocarcinoma patterns not present but immunostains favor separate favor glandular and adenocarcinoma component

      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 or giant cell carcinoma (mention if adenocarcinoma or squamous carcinoma are present)
      Although lung cancer can be divided into many subtypes, historically the most important distinction was between small cell lung carcinoma (SCLC) and non–small cell lung carcinoma (NSCLC).
      • Travis W.D.
      • Brambilla E.
      • Müller-Hermelink H.K.
      • et al.
      Pathology and genetics: tumours of the lung, pleura, thymus and heart.
      This situation is because of the major clinical differences in presentation, metastatic spread, and response to therapy. However, in the past decade, there has been a major transformation in the approach to diagnosis of NSCLC, so now more attention is given to its precise classification in small biopsies and cytology.
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The new IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.
      • Travis W.D.
      • Rekhtman N.
      Pathological diagnosis and classification of lung cancer in small biopsies and cytology: strategic management of tissue for molecular testing.
      • Travis W.D.
      • Brambilla E.
      • Van Schil P.
      • et al.
      Paradigm shifts in lung cancer as defined in the new IASLC/ATS/ERS lung adenocarcinoma classification.
      • Travis W.D.
      • Rekhtman N.
      • Riley G.J.
      • et al.
      Pathologic diagnosis of advanced lung cancer based on small biopsies and cytology: a paradigm shift.
      Because 70% of lung cancers present in advanced stages, most patients are unresectable and the diagnosis is based on small biopsies and cytology. The main reason for this new importance to classify NSCLC further is because the choice of therapies now is dependent on histology. For example, patients with adenocarcinomas and NSCLC not otherwise specified (NSCLC-NOS) are eligible for EGFR tyrosine kinase inhibitors (TKIs) if an EGFR mutation is present
      • Mok T.S.
      • Wu Y.L.
      • 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.
      • Rosell R.
      • Gervais R.
      • Vergnenegre A.
      • et al.
      Erlotinib versus chemotherapy (CT) in advanced non-small cell lung cancer (NSCLC) patients (p) with epidermal growth factor receptor (EGFR) mutations: interim results of the European Erlotinib Versus Chemotherapy (EURTAC) phase III randomized trial.
      ; they are also eligible for either pemetrexed-based
      • 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.
      • Scagliotti G.V.
      • Parikh P.
      • von P.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.
      • Scagliotti G.
      • Brodowicz T.
      • Shepherd F.A.
      • et al.
      Treatment-by-histology interaction analyses in three phase III trials show superiority of pemetrexed in nonsquamous non-small cell lung cancer.
      or bevacizumab-based regimens.
      • Johnson D.H.
      • Fehrenbacher L.
      • Novotny W.F.
      • 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.
      In contrast, if the diagnosis is squamous cell carcinoma, patients are not eligible for these therapies. The implications of these new therapeutic paradigms for lung cancer classification are profound and are outlined in this review.

      Preinvasive lesions

      The pathology of preinvasive lesions for lung cancer has attracted increasing interest in recent years because of the growing importance of early detection of lung cancer using screening of high-risk patients by fluorescence bronchoscopy
      • Ishizumi T.
      • McWilliams A.
      • MacAulay C.
      • et al.
      Natural history of bronchial preinvasive lesions.
      • Edell E.
      • Lam S.
      • Pass H.
      • et al.
      Detection and localization of intraepithelial neoplasia and invasive carcinoma using fluorescence-reflectance bronchoscopy: an international, multicenter clinical trial.
      and by spiral or helical computed tomography (CT).
      • Aberle D.R.
      • Berg C.D.
      • Black W.C.
      • et al.
      The National Lung Screening Trial: overview and study design.
      • Aberle D.R.
      • Adams A.M.
      • Berg C.D.
      • et al.
      Baseline characteristics of participants in the Randomized National Lung Screening Trial.
      In addition, the concepts of preinvasive lesions have evolved over the past several decades, with none mentioned in the 1967 WHO classification of lung tumors
      • Travis W.D.
      Lung.
      and only bronchial squamous dysplasia and CIS in the 1981 WHO histologic classification of lung tumors.
      • World Health Organization
      Histological typing of lung tumors.
      In the 1999 WHO classification 2 new lesions were described: AAH and DIPNECH, and these were maintained in the 2004 WHO classification.
      • Travis W.D.
      • Brambilla E.
      • Müller-Hermelink H.K.
      • et al.
      Pathology and genetics: tumours of the lung, pleura, thymus and heart.
      • Travis W.D.
      • Colby T.V.
      • Corrin B.
      • et al.
      In collaboration with L.H. Sobin and pathologists from 14 countries
      Histological Typing of Lung and Pleural Tumors.
      So in the 1999 and 2004 WHO classification, there were only 3 preinvasive lesions. Now, in the 2011 IASLC/ATS/ERS Classification of Lung Adenocarcinoma, AIS was added as a new preinvasive lesion for adenocarcinoma (see Box 1).
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The new IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.

      Squamous Dysplasia and CIS

      Bronchial carcinogenesis is conceptualized as a multistep process involving transformation of the normal bronchial mucosa through a continuous spectrum of lesions, including basal cell hyperplasia, squamous metaplasia, dysplasia, and CIS.
      • Travis W.D.
      • Brambilla E.
      • Müller-Hermelink H.K.
      • et al.
      Pathology and genetics: tumours of the lung, pleura, thymus and heart.
      • Travis W.D.
      • Colby T.V.
      • Corrin B.
      • et al.
      In collaboration with L.H. Sobin and pathologists from 14 countries
      Histological Typing of Lung and Pleural Tumors.
      • Travis W.D.
      • Brambilla E.
      Pathology of lung preneoplasia.
      • Lantuejoul S.
      • Salameire D.
      • Salon C.
      • et al.
      Pulmonary preneoplasia–sequential molecular carcinogenetic events.
      Associated with the morphologic changes are a series of molecular events that accumulate as the squamous lesions progress through increasing dysplasia to CIS and invasive squamous cell carcinoma. Such changes include allelic loss at the 3p region, which is an early event found in 78% of preinvasive bronchial lesions.
      • Lantuejoul S.
      • Salameire D.
      • Salon C.
      • et al.
      Pulmonary preneoplasia–sequential molecular carcinogenetic events.
      Followed by a series of other molecular events such as loss of heterozygosity at 9p21 (p16), 17p loss (hyperplasia), telomere activation, telomerase reactivation, retinoic acid receptor (RAR) β loss (mild dysplasia), p53 mutation, vascular endothelial growth factor overexpression (moderate dysplasia), p16 inactivation, Bcl-2 overexpression, and cyclin D1 and E overexpression (CIS).
      • Lantuejoul S.
      • Salameire D.
      • Salon C.
      • et al.
      Pulmonary preneoplasia–sequential molecular carcinogenetic events.
      Squamous dysplasia may be mild, moderate, or severe depending on the severity of cytologic atypia and the thickness of the abnormality within the bronchial epithelium.
      • Travis W.D.
      • Brambilla E.
      • Müller-Hermelink H.K.
      • et al.
      Pathology and genetics: tumours of the lung, pleura, thymus and heart.
      • Travis W.D.
      • Colby T.V.
      • Corrin B.
      • et al.
      In collaboration with L.H. Sobin and pathologists from 14 countries
      Histological Typing of Lung and Pleural Tumors.
      • Travis W.D.
      • Brambilla E.
      Pathology of lung preneoplasia.
      CIS shows full thickness involvement of the epithelium by marked cytologic atypia. There is a continuum of morphologic changes, but these categories can be separated with good reproducibility.
      • Nicholson A.G.
      • Perry L.J.
      • Cury P.M.
      • et al.
      Reproducibility of the WHO/IASLC grading system for pre-invasive squamous lesions of the bronchus: a study of inter-observer and intra-observer variation.
      Care must be taken not to confuse dysplasia with reactive atypia associated with inflammation or granulation tissue. CIS with involvement of submucosal glands must also be separated from microinvasive squamous cell carcinoma.
      • Travis W.D.
      • Brambilla E.
      • Müller-Hermelink H.K.
      • et al.
      Pathology and genetics: tumours of the lung, pleura, thymus and heart.
      • Travis W.D.
      • Colby T.V.
      • Corrin B.
      • et al.
      In collaboration with L.H. Sobin and pathologists from 14 countries
      Histological Typing of Lung and Pleural Tumors.
      • Travis W.D.
      • Brambilla E.
      Pathology of lung preneoplasia.

      AAH and AIS

      AIS is now added to AAH as a new preinvasive lesion for lung adenocarcinoma.

      AAH

      AAH is a bronchioloalveolar proliferation that resembles but falls short of criteria for BAC, nonmucinous type (Fig. 1).
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The new IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.
      • Travis W.D.
      • Brambilla E.
      • Müller-Hermelink H.K.
      • et al.
      Pathology and genetics: tumours of the lung, pleura, thymus and heart.
      • Travis W.D.
      • Brambilla E.
      Pathology of lung preneoplasia.
      • Lantuejoul S.
      • Salameire D.
      • Salon C.
      • et al.
      Pulmonary preneoplasia–sequential molecular carcinogenetic events.
      • Noguchi M.
      Stepwise progression of pulmonary adenocarcinoma–clinical and molecular implications.
      • Yoo S.B.
      • Chung J.H.
      • Lee H.J.
      • et al.
      Epidermal growth factor receptor mutation and p53 overexpression during the multistage progression of small adenocarcinoma of the lung.
      • Ruffini E.
      • Bongiovanni M.
      • Cavallo A.
      • et al.
      The significance of associated pre-invasive lesions in patients resected for primary lung neoplasms.
      AAH is most commonly encountered as an incidental histologic finding in a lung cancer resection specimen.
      • Travis W.D.
      • Colby T.V.
      • Corrin B.
      • et al.
      In collaboration with L.H. Sobin and pathologists from 14 countries
      Histological Typing of Lung and Pleural Tumors.
      • Kitamura H.
      • Kameda Y.
      • Ito T.
      • et al.
      Atypical adenomatous hyperplasia of the lung. Implications for the pathogenesis of peripheral lung adenocarcinoma.
      • Miller R.R.
      Bronchioloalveolar cell adenomas.
      Figure thumbnail gr1
      Fig. 1AAH. (A) This millimeter-sized bronchioloalveolar proliferation is ill defined, with mild thickening of the alveolar walls (hematoxylin-eosin, original magnification ×20). (B) The alveolar walls show mild fibrous thickening and the hyperplastic pneumocytes show minimal atypia and there are gaps between the cells (hematoxylin-eosin, original magnification ×400).
      The incidence of AAH varies from 5.7% to 21.4% depending on extent of the search and the criteria used for the diagnosis.
      • Miller R.R.
      Bronchioloalveolar cell adenomas.
      • Weng S.Y.
      • Tsuchiya E.
      • Kasuga T.
      • et al.
      Incidence of atypical bronchioloalveolar cell hyperplasia of the lung: relation to histological subtypes of lung cancer.
      • Carey F.A.
      • Wallace W.A.
      • Fergusson R.J.
      • et al.
      Alveolar atypical hyperplasia in association with primary pulmonary adenocarcinoma: a clinicopathological study of 10 cases.
      • Nakanishi K.
      Alveolar epithelial hyperplasia and adenocarcinoma of the lung.
      Most lesions of AAH are less than 5 mm in diameter and frequently they are multiple.
      • Miller R.R.
      Bronchioloalveolar cell adenomas.
      • Weng S.Y.
      • Tsuchiya E.
      • Kasuga T.
      • et al.
      Incidence of atypical bronchioloalveolar cell hyperplasia of the lung: relation to histological subtypes of lung cancer.
      Histologically AAH consists of a focal proliferation of slightly atypical cuboidal to low columnar epithelial cells along alveoli and respiratory bronchioles (see Fig. 1). Slight thickening of alveolar septa may be present.
      AAH must be separated from a variety of lesions, the most important of which is the nonmucinous AIS, MIA, or lepidic predominant adenocarcinoma (LPA).
      • Mori M.
      • Chiba R.
      • Tezuka F.
      • et al.
      Papillary adenoma of type II pneumocytes might have malignant potential.
      This distinction can be difficult because there is considerable overlap in the morphologic features between AAH and the lepidic pattern of adenocarcinoma.
      • Travis W.D.
      • Colby T.V.
      • Corrin B.
      • et al.
      In collaboration with L.H. Sobin and pathologists from 14 countries
      Histological Typing of Lung and Pleural Tumors.
      • Kitamura H.
      • Kameda Y.
      • Ito T.
      • et al.
      Atypical adenomatous hyperplasia of the lung. Implications for the pathogenesis of peripheral lung adenocarcinoma.
      • Mori M.
      • Chiba R.
      • Takahashi T.
      Atypical adenomatous hyperplasia of the lung and its differentiation from adenocarcinoma. Characterization of atypical cells by morphometry and multivariate cluster analysis.
      • Ritter J.H.
      Pulmonary atypical adenomatous hyperplasia. A histologic lesion in search of usable criteria and clinical significance.
      There are currently no data to show that patients with lung cancer and AAH have any different prognosis from those without AAH.
      • Suzuki K.
      • Nagai K.
      • Yoshida J.
      • et al.
      The prognosis of resected lung carcinoma associated with atypical adenomatous hyperplasia: a comparison of the prognosis of well-differentiated adenocarcinoma associated with atypical adenomatous hyperplasia and intrapulmonary metastasis.

      AIS

      In the new IASLC/ATS/ERS adenocarcinoma classification AIS is defined as a glandular proliferation measuring 3 cm or less that has pure lepidic growth lacking invasion (Fig. 2).
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The new IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.
      In most cases the tumor cells are nonmucinous, with a proliferation of type II pneumocytes or Clara cells, but rarely are they mucinous consisting of tall columnar goblet cells having abundant apical mucin. If these lesions are completely resected, patients have been reported to have 100% 5-year disease-free survival (DFS).
      • 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.
      • 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.
      • Noguchi M.
      • Morikawa A.
      • Kawasaki M.
      • et al.
      Small adenocarcinoma of the lung. Histologic characteristics and prognosis.
      • Yim J.
      • Zhu L.C.
      • Chiriboga L.
      • et al.
      Histologic features are important prognostic indicators in early stages lung adenocarcinomas.
      By CT these lesions typically consist of a ground-glass nodule if nonmucinous and a solid nodule if mucinous AIS.
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The new IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.
      Figure thumbnail gr2
      Fig. 2Nonmucinous AIS. This circumscribed nonmucinous tumor grows purely with a lepidic pattern. No foci of invasion or scarring are seen.

      DIPNECH

      DIPNECH is a rare condition in which the peripheral airways are diffusely involved by neuroendocrine (NE) cell hyperplasia and tumorlets (Box 2, Fig. 3).
      • Aguayo S.M.
      • Miller Y.E.
      • Waldron Jr., J.A.
      • et al.
      Brief report: idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells and airways disease.
      • Davies S.J.
      • Gosney J.R.
      • Hansell D.M.
      • et al.
      Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: an under-recognised spectrum of disease.
      The clinical presentation resembles interstitial lung disease manifest by airway obstruction caused by bronchiolar fibrosis in approximately half of the patients.
      • Aguayo S.M.
      • Miller Y.E.
      • Waldron Jr., J.A.
      • et al.
      Brief report: idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells and airways disease.
      • Davies S.J.
      • Gosney J.R.
      • Hansell D.M.
      • et al.
      Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: an under-recognised spectrum of disease.
      The remaining patients typically present with multiple incidentally discovered pulmonary nodules, often found during follow-up for an extrathoracic malignancy. Because carcinoid tumors are frequently found in patients with DIPNECH and the tumors are often multiple, this is believed to represent a preinvasive lesion for carcinoid tumors.
      • Travis W.D.
      • Brambilla E.
      • Müller-Hermelink H.K.
      • et al.
      Pathology and genetics: tumours of the lung, pleura, thymus and heart.
      • Davies S.J.
      • Gosney J.R.
      • Hansell D.M.
      • et al.
      Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: an under-recognised spectrum of disease.
      There is a distinctive CT appearance consisting of centrilobular nodules and pulmonary nodules, which correspond to the tumorlets and carcinoid tumors, respectively. Furthermore, in patients who present with clinical manifestations of interstitial lung disease, the CT can be normal or it can show mosaic perfusion from air trapping, bronchial wall thickening, and bronchiectasis.
      • Davies S.J.
      • Gosney J.R.
      • Hansell D.M.
      • et al.
      Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: an under-recognised spectrum of disease.
      • Koo C.W.
      • Baliff J.P.
      • Torigian D.A.
      • et al.
      Spectrum of pulmonary neuroendocrine cell proliferation: diffuse idiopathic pulmonary neuroendocrine cell hyperplasia, tumorlet, and carcinoids.
      The spectrum of NE lung proliferations and tumors
      • 1.
        NE cell hyperplasia and tumorlets
        • a.
          NE cell hyperplasia
          • i.
            NE cell hyperplasia associated with fibrosis or inflammation
          • ii.
            NE cell hyperplasia adjacent to carcinoid tumors
          • iii.
            Diffuse idiopathic NE cell hyperplasia with or without airway fibrosis/obstruction
        • b.
          Tumorlets (less than 0.5 cm)
      • 2.
        Tumors with NE morphology
        • a.
          TC (0.5 cm or larger)
        • b.
          AC
        • c.
          LCNEC
          • Combined large cell NE carcinomaa
        • d.
          Small cell carcinoma
          • Combined small cell carcinomaa
      • 3.
        Non–small cell carcinomas with NE differentiation (NED)
      • 4.
        Other tumors with NE properties
        • a.
          Pulmonary blastoma
        • b.
          Primitive neuroectodermal tumor
        • c.
          Desmoplastic round cell tumor
        • d.
          Carcinomas with rhabdoid phenotype
        • e.
          Paraganglioma
      a The histologic type of the other component of non–small cell carcinoma should be specified.
      Figure thumbnail gr3
      Fig. 3DIPNECH. (A) This bronchiole shows mild fibrotic thickening of the wall and increased numbers of NE cells in the mucosa (hematoxylin-eosin, original magnification ×200). (B) At the base of the mucosa are numerous round to oval NE cells with small nuclei and clear cytoplasm (hematoxylin-eosin, original magnification ×400).

      Squamous cell carcinoma

      Squamous cell carcinoma accounts for approximately 20% of all lung cancers in the United States.
      • Travis W.D.
      • Travis L.B.
      • Devesa S.S.
      Lung cancer.
      Historically, two-thirds of squamous cell carcinomas presented as central lung tumors, whereas many among the remaining third are peripheral.
      • Tomashefski Jr., J.F.
      • Connors Jr., A.F.
      • Rosenthal E.S.
      • et al.
      Peripheral vs central squamous cell carcinoma of the lung. A comparison of clinical features, histopathology, and survival.
      • Colby T.V.
      • Koss M.N.
      • Travis W.D.
      Tumors of the lower respiratory tract; Armed Forces Institute of Pathology fascicle, third series.
      However, recent reports document that an increasing percentage of squamous cell carcinomas are found in the periphery, exceeding 50% in some studies.
      • Funai K.
      • Yokose T.
      • Ishii G.
      • et al.
      Clinicopathologic characteristics of peripheral squamous cell carcinoma of the lung.
      The morphologic features that suggest squamous differentiation include intercellular bridging, squamous pearl formation, and individual cell keratinization (Fig. 4). In well-differentiated tumors these features are readily apparent; however, in poorly differentiated tumors they are difficult to find.
      • Carlile A.
      • Edwards C.
      Poorly differentiated squamous carcinoma of the bronchus: a light and electron microscopic study.
      Squamous cell carcinoma arises most often in segmental bronchi and involvement of lobar and mainstem bronchus occurs by extension.
      • Melamed M.R.
      • Zaman M.B.
      • Flehinger B.J.
      • et al.
      Radiologically occult in situ and incipient invasive epidermoid lung cancer: detection by sputum cytology in a survey of asymptomatic cigarette smokers.
      Squamous cell carcinoma can have papillary, clear cell, small cell,
      • Churg A.
      • Johnston W.H.
      • Stulbarg M.
      Small cell squamous and mixed small cell squamous–small cell anaplastic carcinomas of the lung.
      and basaloid subtypes.
      • Travis W.D.
      • Colby T.V.
      • Corrin B.
      • et al.
      In collaboration with L.H. Sobin and pathologists from 14 countries
      Histological Typing of Lung and Pleural Tumors.
      However, this subtyping needs updating because it does not address well the morphologic spectrum of appearances of lung squamous cell carcinoma and it does not allow for meaningful correlations with clinical, prognostic, or molecular features. For example, the small cell variant probably should be discarded, because most of these cases would better be classified as basaloid variants and the term small cell creates confusion with true small cell carcinoma. Papillary squamous cell carcinomas often show a pattern of exophytic endobronchial growth.
      • Dulmet-Brender E.
      • Jaubert F.
      • Huchon G.
      Exophytic endobronchial epidermoid carcinoma.
      • Sherwin R.P.
      • Laforet E.G.
      • Strieder J.W.
      Exophytic endobronchial carcinoma.
      Figure thumbnail gr4
      Fig. 4Squamous cell carcinoma. These tumor cells have abundant eosinophilic keratinized cytoplasm and form nests and keratin pearls characteristic of squamous differentiation (hematoxylin-eosin, original magnification ×200).
      Several articles have proposed alternative approaches to subclassifying pulmonary squamous cell carcinomas.
      • Funai K.
      • Yokose T.
      • Ishii G.
      • et al.
      Clinicopathologic characteristics of peripheral squamous cell carcinoma of the lung.
      • Maeshima A.M.
      • Maeshima A.
      • Asamura H.
      • et al.
      Histologic prognostic factors for small-sized squamous cell carcinomas of the peripheral lung.
      • Watanabe Y.
      • Yokose T.
      • Sakuma Y.
      • et al.
      Alveolar space filling ratio as a favorable prognostic factor in small peripheral squamous cell carcinoma of the lung.
      These approaches include recognition of an alveolar space-filling variant, which corresponds to favorable prognosis.
      • Funai K.
      • Yokose T.
      • Ishii G.
      • et al.
      Clinicopathologic characteristics of peripheral squamous cell carcinoma of the lung.
      • Watanabe Y.
      • Yokose T.
      • Sakuma Y.
      • et al.
      Alveolar space filling ratio as a favorable prognostic factor in small peripheral squamous cell carcinoma of the lung.
      Funai and colleagues
      • Funai K.
      • Yokose T.
      • Ishii G.
      • et al.
      Clinicopathologic characteristics of peripheral squamous cell carcinoma of the lung.
      reported 5 cases with 100% disease-free survival, and Watanabe and colleagues
      • Watanabe Y.
      • Yokose T.
      • Sakuma Y.
      • et al.
      Alveolar space filling ratio as a favorable prognostic factor in small peripheral squamous cell carcinoma of the lung.
      found that an alveolar space-filling ratio of 70% or more also had a 100% disease-free survival. However, this pattern occurs in only a few cases and is more often seen only focally; in a study from North America prognostic significance could not be shown.
      • Yousem S.A.
      Peripheral squamous cell carcinoma of lung: patterns of growth with particular focus on airspace filling.
      Maeshima and colleagues
      • Maeshima A.M.
      • Maeshima A.
      • Asamura H.
      • et al.
      Histologic prognostic factors for small-sized squamous cell carcinomas of the peripheral lung.
      defined minimal tumor cell nests as large (>6 tumor cells), small (2–5 cells), and single cell. In this study the single-cell infiltrating tumors had the worst prognosis. Also tumors associated with a background of usual interstitial pneumonia and lymph node metastases had a poor prognosis. Further work is needed to develop a more practical approach to subclassification of squamous cell carcinoma and to identify better histologic predictors of prognosis.

      Adenocarcinoma

      Adenocarcinomas represent 38% of all lung cancers in the United States.
      • Travis W.D.
      • Travis L.B.
      • Devesa S.S.
      Lung cancer.
      • Altekruse S.F.
      • Kosary C.L.
      • Krapcho M.
      • et al.
      SEER cancer statistics review, 1975-2007.
      The 2011 IASLC/ATS/ERS lung adenocarcinoma classification recommends multiple major changes (see Box 1).
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The new IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.
      • Travis W.D.
      • Rekhtman N.
      Pathological diagnosis and classification of lung cancer in small biopsies and cytology: strategic management of tissue for molecular testing.
      • Travis W.D.
      • Brambilla E.
      • Van Schil P.
      • et al.
      Paradigm shifts in lung cancer as defined in the new IASLC/ATS/ERS lung adenocarcinoma classification.
      • Travis W.D.
      • Rekhtman N.
      • Riley G.J.
      • et al.
      Pathologic diagnosis of advanced lung cancer based on small biopsies and cytology: a paradigm shift.
      First, it is recommended to no longer use the term BAC because the tumors formerly classified under this term are now classified into 5 different tumors. Second, there are new concepts of AIS (see preinvasive lesions) and MIA. Third, it is recommended to no longer use the term mixed subtype, but rather to use comprehensive histologic subtyping to estimate the percentage of histologic patterns in 5% increments within a tumor with final classification according to the predominant subtype. Fourth, tumors with a predominant component formerly called nonmucinous BAC should be classified as LPA. Fifth, micropapillary adenocarcinoma is recognized as a new subtype with a poor prognosis. Sixth, invasive mucinous adenocarcinoma is the term recommended for those tumors formerly classified as mucinous BAC. Sixth, specific terminology and diagnostic criteria are proposed for tumors in small biopsies and cytology specimens along with recommendations for strategic management of tissue and EGFR mutation testing in patients with advanced adenocarcinoma.
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The new IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.
      • Travis W.D.
      • Rekhtman N.
      Pathological diagnosis and classification of lung cancer in small biopsies and cytology: strategic management of tissue for molecular testing.
      • Travis W.D.
      • Brambilla E.
      • Van Schil P.
      • et al.
      Paradigm shifts in lung cancer as defined in the new IASLC/ATS/ERS lung adenocarcinoma classification.
      • Travis W.D.
      • Rekhtman N.
      • Riley G.J.
      • et al.
      Pathologic diagnosis of advanced lung cancer based on small biopsies and cytology: a paradigm shift.

      Adenocarcinoma classification in resected specimens

      MIA

      MIA was introduced as a lepidic predominant tumor measuring 3 cm or less that has 5 mm or less of an invasive component (Fig. 5).
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The new IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.
      Limited data suggest patients with MIA have a near 100% 5-year disease-free survival.
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The new IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.
      • Yim J.
      • Zhu L.C.
      • Chiriboga L.
      • et al.
      Histologic features are important prognostic indicators in early stages lung adenocarcinomas.
      Although few articles use the same criteria,
      • Yim J.
      • Zhu L.C.
      • Chiriboga L.
      • et al.
      Histologic features are important prognostic indicators in early stages lung adenocarcinomas.
      • Yoshizawa A.
      • Motoi N.
      • Riely G.J.
      • et al.
      Impact of proposed IASLC/ATS/ERS classification of lung adenocarcinoma: prognostic subgroups and implications for further revision of staging based on analysis of 514 stage I cases.
      multiple studies support this concept
      • Borczuk A.C.
      • Qian F.
      • Kazeros A.
      • et al.
      Invasive size is an independent predictor of survival in pulmonary adenocarcinoma.
      • Suzuki K.
      • Yokose T.
      • Yoshida J.
      • et al.
      Prognostic significance of the size of central fibrosis in peripheral adenocarcinoma of the lung.
      Most of these cases are nonmucinous, but rarely mucinous cases may occur.
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The new IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.
      By CT nonmucinous MIA typically shows a ground-glass nodule with a solid component measuring 5 mm or less. However, mucinous MIA presents as a solid nodule on CT.
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The new IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.
      Figure thumbnail gr5
      Fig. 5Nonmucinous MIA. (A) This adenocarcinoma tumor consists primarily of lepidic growth with a small (<0.5 cm) area of invasion (bottom left) (hematoxylin-eosin, original magnification ×1). (B) From the area of invasion, these acinar glands are invading in the fibrous stroma (hematoxylin-eosin, original magnification ×200).

      Invasive Adenocarcinoma

      Classification of overtly invasive adenocarcinomas is now made according to the predominant subtype. This classification is best determined after using comprehensive histologic subtyping to estimate the percentages of the various histologic subtypes within a tumor in a semiquantitative fashion in 5% to 10% increments. LPA consists of tumors formerly classified as mixed subtype tumors containing a predominant lepidic growth pattern of type II pneumocytes or Clara cells (formerly known as nonmucinous BAC) that have an invasive component greater than 5 mm (Fig. 6A–C). The other major subtypes include acinar (see Fig. 6D), papillary (see Fig. 6E), micropapillary (see Fig. 6F), and solid with mucin-predominant adenocarcinomas (see Fig. 6G, H). The micropapillary predominant subtype is a new addition as a result of the observation in multiple studies that it is associated with poor prognosis in early-stage adenocarcinomas (see Fig. 3).
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The new IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.
      • Yoshizawa A.
      • Motoi N.
      • Riely G.J.
      • et al.
      Impact of proposed IASLC/ATS/ERS classification of lung adenocarcinoma: prognostic subgroups and implications for further revision of staging based on analysis of 514 stage I cases.
      • 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.
      • 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.
      Signet ring and clear cell carcinoma subtypes are no longer regarded as histologic subtypes, but they are now documented as cytologic features whenever present with a comment about the percentage identified. Although clear and signet ring cell cytologic changes are seen mostly in the solid subtype, they can also be seen in acinar or papillary patterns as well.
      • Cohen P.R.
      • Yoshizawa A.
      • Motoi N.
      • et al.
      Signet ring cell features (SRCF) in lung adenocarcinoma: a cytologic feature or a histologic subtype?.
      • Deshpande C.G.
      • Yoshizawa A.
      • Motoi N.
      • et al.
      Clear cell change in lung adenocarcinoma: a cytologic change rather than a histologic variant.
      Figure thumbnail gr6
      Fig. 6Major histologic patterns of invasive adenocarcinoma. (A) Lepidic predominant pattern with mostly lepidic growth (left) and an area of invasive acinar adenocarcinoma (right) (hematoxylin-eosin, original magnification ×100). (B) Lepidic pattern consists of a proliferation type II pneumocytes and Clara cells along the surface alveolar walls (hematoxylin-eosin, original magnification ×200). (C) Area of invasive acinar adenocarcinoma (same tumor as in 6A, B) (hematoxylin-eosin, original magnification ×400). (D) Acinar adenocarcinoma composed of round to oval malignant glands invading a fibrous stroma (hematoxylin-eosin, original magnification ×200). (E) Papillary adenocarcinoma consists of malignant cuboidal to columnar tumor cells growing on the surface of fibrovascular cores (hematoxylin-eosin, original magnification ×100). (F) Micropapillary adenocarcinoma consists of small papillary clusters of glandular cells growing within this airspace, most of which do not show fibrovascular cores (hematoxylin-eosin, original magnification ×200). (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 (hematoxylin-eosin, original magnification ×400). (H) Solid adenocarcinoma with mucin. Numerous intracytoplasmic droplets of mucin are highlighted with this mucicarmine stain (original magnification ×400).
      By CT there is a good correlation between amount of the ground-glass component and lepidic growth on biopsy versus the solid component on CT and the invasive components by biopsy.
      • Yoshizawa A.
      • Motoi N.
      • Riely G.J.
      • et al.
      Impact of proposed IASLC/ATS/ERS classification of lung adenocarcinoma: prognostic subgroups and implications for further revision of staging based on analysis of 514 stage I cases.
      However, few studies have addressed this issue according to the new classification.

      Adenocarcinoma Variants

      The variants of lung adenocarcinoma consist of invasive mucinous adenocarcinoma (formerly mucinous BAC), colloid adenocarcinoma, fetal adenocarcinoma, and enteric adenocarcinoma.
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The new IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.
      Invasive mucinous adenocarcinomas (formerly mucinous BAC) are separated from the nonmucinous invasive adenocarcinomas because of the frequent association with KRAS mutation, lack of thyroid transcription factor 1 (TTF-1), and frequent multicentric lung lesions. Histologically these tumors show varying amounts of lepidic, acinar, papillary, or micropapillary growth consisting of columnar cells with abundant apical mucin and small basally oriented nuclei (Fig. 7).
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The new IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.
      CT findings frequently show localized or multifocal consolidation with air bronchograms forming nodules and lobar consolidation.
      Figure thumbnail gr7
      Fig. 7Invasive mucinous adenocarcinoma. This area of invasive mucinous adenocarcinoma shows a pure lepidic growth. The tumor consists of columnar cells filled with abundant mucin in the apical cytoplasm and small basal oriented nuclei (hematoxylin-eosin, original magnification ×200).

      Prognosis of Adenocarcinoma Subtypes in Resected Specimens

      Few studies have evaluated prognosis of the adenocarcinoma subtypes according to the precise criteria and terminology of the new classification. However, multiple studies have reported 100% 5-year DFS for tumors that would be classified as AIS in the new classification.
      • 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.
      • 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.
      • Noguchi M.
      • Morikawa A.
      • Kawasaki M.
      • et al.
      Small adenocarcinoma of the lung. Histologic characteristics and prognosis.
      • Yim J.
      • Zhu L.C.
      • Chiriboga L.
      • et al.
      Histologic features are important prognostic indicators in early stages lung adenocarcinomas.
      Although the specific criteria for MIA proposed in the new classification were not used in previous studies, data from multiple studies suggest that these tumors also have a 100% or near 100% 5-year DFS.
      • Noguchi M.
      • Morikawa A.
      • Kawasaki M.
      • et al.
      Small adenocarcinoma of the lung. Histologic characteristics and prognosis.
      • Yim J.
      • Zhu L.C.
      • Chiriboga L.
      • et al.
      Histologic features are important prognostic indicators in early stages lung adenocarcinomas.
      • Suzuki K.
      • Yokose T.
      • Yoshida J.
      • et al.
      Prognostic significance of the size of central fibrosis in peripheral adenocarcinoma of the lung.
      • Sakurai H.
      • Maeshima A.
      • Watanabe S.
      • et al.
      Grade of stromal invasion in small adenocarcinoma of the lung: histopathological minimal invasion and prognosis.
      In a study of 514 stage I adenocarcinomas reported by Yoshizawa and colleagues,
      • Yoshizawa A.
      • Motoi N.
      • Riely G.J.
      • et al.
      Impact of proposed IASLC/ATS/ERS classification of lung adenocarcinoma: prognostic subgroups and implications for further revision of staging based on analysis of 514 stage I cases.
      3 groups of tumors were identified according to grades of clinical behavior: (1) low-grade AIS and MIA with 100% 5-year DFS; (2) intermediate-grade nonmucinous lepidic predominant, papillary predominant, and acinar predominant with 90%, 83%, and 84% 5-year DFS, respectively; and (3) high-grade invasive mucinous adenocarcinoma, colloid predominant, solid predominant, and micropapillary predominant with 75%, 71%, 70%, and 67% 5-year DFS, respectively. Similar results were found in 2 independent datasets.

      Kadota K, Suzuki K, D’Angelo SP, et al. Validation of the proposed IASLC/American Thoracic Society (ATS)/European Respiratory Society (ERS) international multidisciplinary classification of lung adenocarcinoma (ADC). J Thorac Oncol 2011;6:244–85.

      • Yoshizawa A.
      • Sumiyoshi S.
      • Moreira A.L.
      • et al.
      Validation of the IASLC/ATS/ERS lung adenocarcinoma (ADC) classification and use of comprehensive histologic subtyping (CHS) for architectural grading in 432 Japanese patients.
      This finding was confirmed by Kadota and colleagues

      Kadota K, Suzuki K, D’Angelo SP, et al. Validation of the proposed IASLC/American Thoracic Society (ATS)/European Respiratory Society (ERS) international multidisciplinary classification of lung adenocarcinoma (ADC). J Thorac Oncol 2011;6:244–85.

      in a separate dataset of 540 stage I lung adenocarcinomas in which there was 100% DFS for AIS and MIA, 97% for lepidic predominant, 87% for acinar, 80% for papillary, 59% for micropapillary, and 69% for solid with a 62% 3-year DFS for invasive mucinous and colloid adenocarcinoma. In a Japanese cohort of 432 patients that included some higher stage patients (250 Stage IA, 88 1B, 30 IIA, 13 IIB, 26 IIIA, 4 IIIB, and 15 IV), 5-year DFS was 100% for AIS and MIA, 89% for lepidic predominant, 67% for papillary, 59% for acinar, 61% for solid predominant, and 17% for micropapillary, with 80% for invasive mucinous adenocarcinoma.
      • Yoshizawa A.
      • Sumiyoshi S.
      • Moreira A.L.
      • et al.
      Validation of the IASLC/ATS/ERS lung adenocarcinoma (ADC) classification and use of comprehensive histologic subtyping (CHS) for architectural grading in 432 Japanese patients.

      Potential Impact of Classification on TNM Staging

      There are 2 major ways the new lung adenocarcinoma classification affects TNM staging. First, comprehensive histologic subtyping provides a useful way to compare multiple lung adenocarcinomas by providing a detailed way to assess whether the 2 tumors represent metastasis versus synchronous or metachronous primaries. The distribution of percentages of the histologic components is one of multiple morphologic features in addition to cytologic and stromal characteristics that have been shown to correlate highly with molecular and clinical approaches to making this distinction.
      • Girard N.
      • Deshpande C.
      • Azzoli C.G.
      • et al.
      Use of epidermal growth factor receptor/Kirsten rat sarcoma 2 viral oncogene homolog mutation testing to define clonal relationships among multiple lung adenocarcinomas: comparison with clinical guidelines.
      • Girard N.
      • Deshpande C.
      • Lau C.
      • et al.
      Comprehensive histologic assessment helps to differentiate multiple lung primary nonsmall cell carcinomas from metastases.
      • Girard N.
      • Ostrovnaya I.
      • Lau C.
      • et al.
      Genomic and mutational profiling to assess clonal relationships between multiple non-small cell lung cancers.
      Whether or not a second tumor is classified as a separate primary or an intrapulmonary metastasis can significantly alter TNM staging and patient management, particularly for separate lobe or contralateral tumors.
      Second, it is possible that in invasive lung adenocarcinomas with a prominent lepidic component comprehensive histologic subtyping may help to determine the size of the invasive component, and this may be more predictive of survival than total tumor size as suggested in several studies reporting that the invasive size is an independent prognostic factor.
      • Yoshizawa A.
      • Motoi N.
      • Riely G.J.
      • et al.
      Impact of proposed IASLC/ATS/ERS classification of lung adenocarcinoma: prognostic subgroups and implications for further revision of staging based on analysis of 514 stage I cases.
      • Borczuk A.C.
      • Qian F.
      • Kazeros A.
      • et al.
      Invasive size is an independent predictor of survival in pulmonary adenocarcinoma.
      The invasive tumor size can be estimated by subtracting the percentage of the lepidic component from the total gross size. These data suggest that, similar to breast cancer, the size T factor for early lung adenocarcinomas may be best determined by the size of the invasive component rather than the total tumor size. This finding also needs to be studied by CT to determine if prognosis is best predicted according to the size of the solid component rather than total tumor size including the ground-glass component.
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The new IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.
      It is hoped that sufficient data can be accumulated before the next TNM revision to address this issue.

      Adenocarcinoma classification in small biopsies and cytology

      For the first time in lung cancer classification formal criteria for diagnosis of lung cancer in small biopsies and cytology were proposed by the new IASLC/ATS/ERS lung adenocarcinoma classification (see Table 1).
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The new IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.
      Because 70% of lung cancers present in advanced stages and are unresectable, they are diagnosed in these small specimens. These new criteria were driven by the need to separate adenocarcinoma from squamous cell carcinoma because of the therapeutic implications based on histology. Patients who have either adenocarcinoma, NSCLC, favor adenocarcinoma, or NSCLC-NOS rather than squamous cell carcinoma are eligible at the moment for 3 therapeutic options. Patients with advanced stage lung adenocarcinoma with 1 of these histologic diagnoses should be tested for EGFR mutation, and if the result is positive, EGFR TKI therapy has predictive benefit for response rate and progression-free survival.
      • Mok T.S.
      • Wu Y.L.
      • 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.
      Furthermore, it has been shown that in patients with adenocarcinoma or NSCLC-NOS, histology is a strong predictor of response to pemetrexed in patients who have advanced 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.
      • Scagliotti G.V.
      • Parikh P.
      • von P.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.
      • Scagliotti G.
      • Brodowicz T.
      • Shepherd F.A.
      • et al.
      Treatment-by-histology interaction analyses in three phase III trials show superiority of pemetrexed in nonsquamous non-small cell lung cancer.
      In addition patients with squamous cell carcinoma are at risk for life-threatening hemorrhage in contrast to those with adenocarcinoma.
      • Johnson D.H.
      • Fehrenbacher L.
      • Novotny W.F.
      • 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.
      For tumors that show clear morphologic features of adenocarcinoma or squamous cell carcinoma, these standard terms are used. However, if the tumor shows only a carcinoma with no clear squamous or glandular features (NSCLC-NOS), a minimal immunohistochemical workup is recommended using a single adenocarcinoma marker and squamous marker, which should allow for classification of most tumors. The best markers for adenocarcinoma and squamous cell carcinoma are TTF-1 and p63, respectively.
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The new IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.
      In a tumor that shows no clear squamous or glandular morphology, but the staining results favor adenocarcinoma (ie, TTF-1 positive, p63 negative), the tumor should be classified as NSCLC, favor adenocarcinoma (Fig. 8). Likewise, the stains in such a tumor favor squamous cell carcinoma, the diagnosis would be NSCLC, favor squamous cell carcinoma (Fig. 9). Then for tumors for which there is clear differentiation by light microscopy or special stains, or if the results are conflicting, the diagnosis remains NSCLC-NOS. Cytology is another powerful tool in subclassifying poorly differentiated NSCLC. In some cases, it may be easier to classify the tumor based on cytology than biopsy.
      • Rekhtman N.
      • Brandt S.M.
      • Sigel C.S.
      • et al.
      Suitability of thoracic cytology for new therapeutic paradigms in non-small cell lung carcinoma: high accuracy of tumor subtyping and feasibility of EGFR and KRAS molecular testing.
      • Travis W.D.
      • Rekhtman N.
      Pathological diagnosis and classification of lung cancer in small biopsies and cytology: strategic management of tissue for molecular testing.
      It is recommended to avoid use of the term nonsquamous carcinoma and state the specific diagnosis in precise terms as outlined earlier.
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The new IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.
      Also use of the term NSCLC should be minimized and instead the specific diagnosis of adenocarcinoma or squamous cell carcinoma should be used whenever possible.
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The new IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.
      Figure thumbnail gr8
      Fig. 8Non–small cell carcinoma, favor adenocarcinoma. (A) This carcinoma shows no clear squamous or glandular differentiation (hematoxylin-eosin, original magnification ×200). (B) The diffuse positive TTF-1 staining allows for the diagnosis of non–small cell carcinoma, favor adenocarcinoma (hematoxylin-eosin, original magnification ×200).
      Figure thumbnail gr9
      Fig. 9Non–small cell carcinoma, favor squamous cell carcinoma. (A) This carcinoma shows no clear squamous or glandular differentiation (hematoxylin-eosin, original magnification ×200). (B) The diffuse positive p63 staining and negative TTF-1 staining (not shown) allows for the diagnosis of non–small cell carcinoma, favor squamous cell carcinoma (immunohistochemistry for p63, original magnification ×200).
      The approach to interpretation of small biopsies and cytology must include considerations of diagnoses other than NSCLC, such as NE tumors (carcinoid, small cell carcinoma, or large cell NE carcinoma) as well as metastatic tumors including metastatic malignant melanoma, breast cancer, or prostate cancer.
      • Travis W.D.
      • Rekhtman N.
      Pathological diagnosis and classification of lung cancer in small biopsies and cytology: strategic management of tissue for molecular testing.
      Therefore if the initial evaluation does not clearly point to adenocarcinoma or squamous cell carcinoma, some of these other diagnoses may need to be considered.
      Because the diagnosis of NSCLC-NOS was encouraged by previous WHO classifications, because of the lack of any clinical reason to be more precise, in studies of advanced NSCLC, this diagnosis has been made in 20% to 40% of cases, and some data suggest its use has been increasing.
      • Scagliotti G.V.
      • Parikh P.
      • von P.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.
      • Ou S.H.
      • Zell J.A.
      Carcinoma NOS is a common histologic diagnosis and is increasing in proportion among non-small cell lung cancer histologies.
      However, with the new IASLC/ATS/ERS criteria and use of immunohistochemistry as well as cytology correlation, the percentage of NSCLC diagnosed as NSCLC-NOS should be less than 5% of cases.
      • Rekhtman N.
      • Brandt S.M.
      • Sigel C.S.
      • et al.
      Suitability of thoracic cytology for new therapeutic paradigms in non-small cell lung carcinoma: high accuracy of tumor subtyping and feasibility of EGFR and KRAS molecular testing.
      • Travis W.D.
      • Rekhtman N.
      Pathological diagnosis and classification of lung cancer in small biopsies and cytology: strategic management of tissue for molecular testing.

      EGFR Mutation Testing

      In the new IASLC/ATS/ERS lung adenocarcinoma classification, there is a clinical recommendation that EGFR mutation testing be performed in advanced lung adenocarcinomas because of the predictive benefit of EGFR mutation with treatment by EGFR TKIs as described earlier.
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The new IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.
      EGFR mutation testing should be performed for all patients with a pathologic diagnosis of: (1) adenocarcinoma, (2) NSCLC, favor adenocarcinoma, and (3) NSCLC-NOS. This recommendation has major implications for tissue management and pathologic diagnosis.

      Multidisciplinary Strategy Needed to Obtain and Process Small Biopsies and Cytology

      Each institution needs to develop a multidisciplinary strategy to manage these small pieces of tissue from (1) obtaining the specimen, (2) processing it in the pathology laboratory, (3) providing material to the molecular diagnostic laboratory, and (4) getting the results back into a pathology report and into the medical record.
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The new IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.
      • Travis W.D.
      • Rekhtman N.
      Pathological diagnosis and classification of lung cancer in small biopsies and cytology: strategic management of tissue for molecular testing.
      This process requires ongoing communication between specialists to ensure optimal management of tissues and efficient reporting of results. One of the central aspects of this process that affects radiologists, pulmonologists, or surgeons is the need to obtain sufficient tissue not only for diagnosis but also for molecular studies. To achieve this goal, biopsy procedures should be designed to result either in a core biopsy or a cell block from tissue samples obtained for cytology.
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The new IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.
      • Solomon S.B.
      • Zakowski M.F.
      • Pao W.
      • et al.
      Core needle lung biopsy specimens: adequacy for EGFR and KRAS mutational analysis.
      Cytology specimens such as pleural fluids should also be processed to generate cell blocks so immunostaining and molecular studies can be performed.

      Use Minimal Stains to Maximize Tissue for Molecular Testing

      Pathologists should minimize the amount of tissue used for making the diagnosis, including use of as few special stains as possible.
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The new IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.
      • Travis W.D.
      • Rekhtman N.
      Pathological diagnosis and classification of lung cancer in small biopsies and cytology: strategic management of tissue for molecular testing.
      This strategy is necessary to preserve as much tissue as possible for molecular testing. One helpful approach is to cut multiple unstained slides from the block after initial review in cases that are potential candidates for molecular testing, so the block is cut only once and valuable tissue is not lost during the process of facing the block multiple times.
      • Travis W.D.
      • Rekhtman N.
      Pathological diagnosis and classification of lung cancer in small biopsies and cytology: strategic management of tissue for molecular testing.
      This strategy includes tumors that are either clearly adenocarcinoma or those with NSCLC-NOS patterns on hematoxylin and eosin stain that require special stains. If adenocarcinoma is suspected, by performing only a TTF-1 stain, if the result is positive, it would confirm not only the adenocarcinoma diagnosis but also a pulmonary origin. If by morphology the tumor could be either adenocarcinoma or squamous cell carcinoma, it may be best to perform 1 adenocarcinoma (ie, TTF-1) and 1 squamous (ie, p63) marker as recommended in the new classification.
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The new IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.
      Limited additional stains may be considered for the small percentage of cases that cannot be classified after this initial panel.
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The new IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.
      • Travis W.D.
      • Rekhtman N.
      Pathological diagnosis and classification of lung cancer in small biopsies and cytology: strategic management of tissue for molecular testing.

      Small cell carcinoma

      SCLC comprises 14% of all lung cancers, and more than 30,000 new cases are diagnosed per year in the United States.
      • Travis W.D.
      • Travis L.B.
      • Devesa S.S.
      Lung cancer.
      • Altekruse S.F.
      • Kosary C.L.
      • Krapcho M.
      • et al.
      SEER cancer statistics review, 1975-2007.
      Approximately two-thirds of SCLC present as a perihilar mass. SCLC typically are situated in a peribronchial location with infiltration of the bronchial submucosa and peribronchial tissue. Bronchial obstruction is usually caused by circumferential compression, although rarely endobronchial lesions can occur. Because the diagnosis is usually established on transbronchial biopsy or cytology, is it unusual to encounter SCLC as a surgical specimen. Extensive lymph node metastases are common. The tumor is white-tan, soft, and friable and frequently shows extensive necrosis. With advanced disease, the bronchial lumen may be obstructed by extrinsic compression. SCLC may present as a solitary coin lesion in up to 5% of cases.
      • Kreisman H.
      • Wolkove N.
      • Quoix E.
      Small cell lung cancer presenting as a solitary pulmonary nodule.
      • Gephardt G.N.
      • Grady K.J.
      • Ahmad M.
      • et al.
      Peripheral small cell undifferentiated carcinoma of the lung. Clinicopathologic features of 17 cases.
      Three subtypes of SCLC were proposed in the 1981 WHO classification: (1) oat cell carcinoma, (2) intermediate cell type, and (3) combined oat cell carcinoma.
      • World Health Organization
      Histological typing of lung tumors.
      However, in 1988 the IASLC recommended dropping the category of intermediate cell type because expert lung cancer pathologists could not reproduce this subclassification and significant differences in survival could not be shown. They also recommended adding the category of mixed small cell/large cell carcinoma because these patients seemed to have a worse prognosis than other patients with SCLC.
      • Hirsch F.R.
      • Matthews M.J.
      • Aisner S.
      • et al.
      Histopathologic classification of small cell lung cancer. Changing concepts and terminology.
      The category of combined SCLC was retained for SCLC with a mixture of adenocarcinoma or squamous cell carcinoma.
      • Hirsch F.R.
      • Matthews M.J.
      • Aisner S.
      • et al.
      Histopathologic classification of small cell lung cancer. Changing concepts and terminology.
      The 1999 WHO classification discarded the category of mixed small cell/large cell carcinoma because there were data indicating problems in reproducibility for this subtype and lack of confirmation that these patients had a worse prognosis.
      • Travis W.D.
      • Colby T.V.
      • Corrin B.
      • et al.
      In collaboration with L.H. Sobin and pathologists from 14 countries
      Histological Typing of Lung and Pleural Tumors.
      • Fraire A.E.
      • Johnson E.H.
      • Yesner R.
      • et al.
      Prognostic significance of histopathologic subtype and stage in small cell lung cancer.
      Therefore in the 2004 WHO classifications there are only 2 types of SCLC: SCLC (with pure SCLC histology) and combined SCLC (with a mixture of any non–small cell type) (see Box 2).
      • Travis W.D.
      • Brambilla E.
      • Müller-Hermelink H.K.
      • et al.
      Pathology and genetics: tumours of the lung, pleura, thymus and heart.
      SCLC has a distinctive histologic appearance. The tumor cells are small and have a round to fusiform shape, scant cytoplasm, finely granular nuclear chromatin, and absent or inconspicuous nucleoli (Fig. 10).
      • Travis W.D.
      • Brambilla E.
      • Müller-Hermelink H.K.
      • et al.
      Pathology and genetics: tumours of the lung, pleura, thymus and heart.
      Nuclear molding and smearing of nuclear chromatin as a result of crush artifact may be conspicuous. There is usually extensive necrosis and mitotic rates are high, with an average of 80 mitoses per 2 mm2 area.
      • Travis W.D.
      • Brambilla E.
      • Müller-Hermelink H.K.
      • et al.
      Pathology and genetics: tumours of the lung, pleura, thymus and heart.
      • Nicholson S.A.
      • Beasley M.B.
      • Brambilla E.
      • et al.
      Small cell lung carcinoma (SCLC): a clinicopathologic study of 100 cases with surgical specimens.
      • Travis W.D.
      Advances in neuroendocrine lung tumors.
      The growth pattern usually consists of diffuse sheets, but rosettes, peripheral palisading, organoid nesting, streams, ribbons, and rarely, tubules or ductules may be present.
      • Azzopardi J.G.
      Oat-cell carcinoma of the bronchus.
      Basophilic encrustation of vessel walls, also known as the Azzopardi effect, is often seen in necrotic areas.
      • Azzopardi J.G.
      Oat-cell carcinoma of the bronchus.
      SCLC is reliably diagnosed in small biopsies and cytology specimens.
      Figure thumbnail gr10
      Fig. 10Small cell carcinoma. This tumor is composed of small cells with scant cytoplasm, finely granular chromatin, and frequent mitoses. Nucleoli are absent (hematoxylin-eosin, original magnification ×400).
      After chemotherapy, mixtures of large cell, squamous, giant cell, or adenocarcinoma may be seen in 15% to 45% of SCLC.
      • Bégin P.
      • Sahai S.
      • Wang N.S.
      Giant cell formation in small cell carcinoma of the lung.
      • Sehested M.
      • Hirsch F.R.
      • Osterlind K.
      • et al.
      Morphologic variations of small cell lung cancer. A histopathologic study of pretreatment and posttreatment specimens in 104 patients.
      • Bepler G.
      • Neumann K.
      • Holle R.
      • et al.
      Clinical relevance of histologic subtyping in small cell lung cancer.

      Combined SCLC

      The frequency of combined SCLC depends on the extent of histologic sampling but most studies report this occurs in less than 10% of cases. A combination of SCLC and large cell carcinoma (see Fig. 8) is found in about 4% to 6% of cases.
      • Hirsch F.R.
      • Matthews M.J.
      • Aisner S.
      • et al.
      Histopathologic classification of small cell lung cancer. Changing concepts and terminology.
      Approximately 1% to 3% of SCLC may be combined with adenocarcinoma or squamous cell carcinoma.
      • Hirsch F.R.
      • Matthews M.J.
      • Aisner S.
      • et al.
      Histopathologic classification of small cell lung cancer. Changing concepts and terminology.
      • Fraire A.E.
      • Johnson E.H.
      • Yesner R.
      • et al.
      Prognostic significance of histopathologic subtype and stage in small cell lung cancer.
      • Sehested M.
      • Hirsch F.R.
      • Osterlind K.
      • et al.
      Morphologic variations of small cell lung cancer. A histopathologic study of pretreatment and posttreatment specimens in 104 patients.
      • Mangum M.D.
      • Greco F.A.
      • Hainsworth J.D.
      • et al.
      Combined small-cell and non-small-cell lung cancer.
      The amount of the non–small cell component is not important for adenocarcinoma or squamous cell carcinoma so long as the histology is clear. However, for combined small cell and large cell carcinoma at least 10% of large cells is required to make the diagnosis.
      • Travis W.D.
      • Brambilla E.
      • Müller-Hermelink H.K.
      • et al.
      Pathology and genetics: tumours of the lung, pleura, thymus and heart.
      • Nicholson S.A.
      • Beasley M.B.
      • Brambilla E.
      • et al.
      Small cell lung carcinoma (SCLC): a clinicopathologic study of 100 cases with surgical specimens.
      • Travis W.D.
      Advances in neuroendocrine lung tumors.
      SCLC can also be associated with spindle cell carcinoma,
      • Tsubota Y.T.
      • Kawaguchi T.
      • Hoso T.
      • et al.
      A combined small cell and spindle cell carcinoma of the lung. Report of a unique case with immunohistochemical and ultrastructural studies.
      • Fishback N.F.
      • Travis W.D.
      • Moran C.A.
      • et al.
      Pleomorphic (spindle/giant cell) carcinoma of the lung. A clinicopathologic correlation of 78 cases.
      giant cell carcinoma,
      • Fishback N.F.
      • Travis W.D.
      • Moran C.A.
      • et al.
      Pleomorphic (spindle/giant cell) carcinoma of the lung. A clinicopathologic correlation of 78 cases.
      and carcinosarcoma.
      • Sümmermann E.
      • Huwer H.
      • Seitz G.
      Carcinosarcoma of the lung, a tumour which has a poor prognosis and is extremely rarely diagnosed preoperatively.
      However, there are no consistent data to suggest that there is any significant difference in clinical features, prognosis, and response to therapy compared with patients with pure SCLC.
      • Fraire A.E.
      • Johnson E.H.
      • Yesner R.
      • et al.
      Prognostic significance of histopathologic subtype and stage in small cell lung cancer.
      • Mangum M.D.
      • Greco F.A.
      • Hainsworth J.D.
      • et al.
      Combined small-cell and non-small-cell lung cancer.
      Although immunohistochemistry is useful in the diagnosis of SCLC, the most important stain is a good-quality hematoxylin and eosin stain that is not too thick or overstained. The diagnosis can be established without immunostains in most cases and it is needed only in problematic cases. A pancytokeratin antibody such as AE1/AE3 is useful to confirm that the tumor is a carcinoma rather than a lymphoid lesion and the most useful NE markers include CD56, chromogranin and synaptophysin, which are best used as a panel. TTF-1 expression is found in 70% to 80% of SCLC.
      • Travis W.D.
      • Brambilla E.
      • Müller-Hermelink H.K.
      • et al.
      Pathology and genetics: tumours of the lung, pleura, thymus and heart.
      • Travis W.D.
      Advances in neuroendocrine lung tumors.
      • Folpe A.L.
      • Gown A.M.
      • Lamps L.W.
      • et al.
      Thyroid transcription factor-1: immunohistochemical evaluation in pulmonary neuroendocrine tumors.
      • Sturm N.
      • Rossi G.
      • Lantuejoul S.
      • et al.
      Expression of thyroid transcription factor-1 in the spectrum of neuroendocrine cell lung proliferations with special interest in carcinoids.
      • Sturm N.
      • Lantuejoul S.
      • Laverriere M.H.
      • et al.
      Thyroid transcription factor 1 and cytokeratins 1, 5, 10, 14 (34betaE12) expression in basaloid and large-cell neuroendocrine carcinomas of the lung.
      • Travis W.D.
      Neuroendocrine lung tumors.
      • Travis W.D.
      Lung tumours with neuroendocrine differentiation.
      However, because extrapulmonary small cell carcinomas can express TTF-1, this stain should not be used to determine the primary site of small cell carcinomas.
      • Agoff S.N.
      • Lamps L.W.
      • Philip A.T.
      • et al.
      Thyroid transcription factor-1 is expressed in extrapulmonary small cell carcinomas but not in other extrapulmonary neuroendocrine tumors.
      The proliferation rate by Ki-67 staining is high, averaging 70% to 90%.
      • Pelosi G.
      • Rodriguez J.
      • Viale G.
      • et al.
      Typical and atypical pulmonary carcinoid tumor overdiagnosed as small-cell carcinoma on biopsy specimens: a major pitfall in the management of lung cancer patients.

      Clinical features and prognosis

      SCLC has distinctive clinical properties, with an aggressive clinical course, frequent widespread metastases at presentation, common paraneoplastic syndromes, and responsiveness to chemotherapy.
      • Krug L.M.
      • Pietanza M.C.
      • Kris M.G.
      • et al.
      Small cell and other neuroendocrine tumors of the lung.
      With combination chemotherapy (etoposide/cisplatin) and chest radiotherapy, for patients with limited-stage disease, the median survival is 15 months and 5-year survival is 10%.
      • Krug L.M.
      • Pietanza M.C.
      • Kris M.G.
      • et al.
      Small cell and other neuroendocrine tumors of the lung.

      Differential diagnosis

      Separation of SCLC from large cell carcinoma or LCNEC requires the application of a constellation of criteria including cell size, nucleoli, nuclear/cytoplasmic (N/C) ratio, nuclear chromatin, nucleoli, nuclear molding, cell shape (fusiform vs polygonal), and hematoxylin vascular staining (Table 2).
      • Travis W.D.
      Neuroendocrine lung tumors.
      • Vollmer R.T.
      The effect of cell size on the pathologic diagnosis of small and large cell carcinomas of the lung.
      There is a continuum of cell size between SCLC and large cell carcinoma,
      • Vollmer R.T.
      The effect of cell size on the pathologic diagnosis of small and large cell carcinomas of the lung.
      but the cells of SCLC usually are about the diameter of 2 to 3 small resting lymphocytes.
      • Travis W.D.
      • Brambilla E.
      • Müller-Hermelink H.K.
      • et al.
      Pathology and genetics: tumours of the lung, pleura, thymus and heart.
      Vollmer
      • Vollmer R.T.
      The effect of cell size on the pathologic diagnosis of small and large cell carcinomas of the lung.
      showed that the size of cells of SCLC also seems greater in larger biopsy specimens. This finding explains why the tumor cells of SCLC seem larger in well-fixed open biopsies than in transbronchial biopsy specimens.
      Table 2Light microscopic features for distinguishing small cell carcinoma and large cell NE carcinoma
      Data from Travis WD. Neuroendocrine lung tumors. Path Case Rev 2006;11:235–42; and Vollmer RT. The effect of cell size on the pathologic diagnosis of small and large cell carcinomas of the lung. Cancer 1982;50:1380–3.
      Histologic FeatureSmall Cell CarcinomaLCNEC
      Cell sizeSmaller (less than diameter of 3 lymphocytes)Larger
      N/C ratioHigherLower
      Nuclear chromatinFinely granular, uniformCoarsely granular or vesicular

      Less uniform
      NucleoliAbsent or faintOften (not always) present

      May be prominent or faint
      Nuclear moldingCharacteristicLess prominent
      FusiformCommonUncommon
      Polygonal with ample pink cytoplasmUncharacteristicCharacteristic
      Nuclear smearFrequentUncommon
      Basophilic staining of vessels and stromaOccasionalRare
      Disagreement among expert lung cancer pathologists over the distinction between SCLC and NSCLC may occur in up to 5% to 7% of cases.
      • Vollmer R.T.
      • Ogden L.
      • Crissman J.D.
      Separation of small-cell from non-small-cell lung cancer. The Southeastern Cancer Study Group pathologists’ experience.
      • Roggli V.L.
      • Vollmer R.T.
      • Greenberg S.D.
      • et al.
      Lung cancer heterogeneity: a blinded and randomized study of 100 consecutive cases.
      • Travis W.D.
      • Gal A.A.
      • Colby T.V.
      • et al.
      Reproducibility of neuroendocrine lung tumor classification.
      In the study by Roggli and colleagues,
      • Roggli V.L.
      • Vollmer R.T.
      • Greenberg S.D.
      • et al.
      Lung cancer heterogeneity: a blinded and randomized study of 100 consecutive cases.
      agreement for the diagnosis of SCLCs for all 5 observers was 93% and for at least 4 of 5 observers it was 98%. In problem cases it can be helpful to try to achieve a consensus approach among other pathology colleagues. If a consensus diagnosis cannot be reached locally, it may be appropriate to refer the case for extramural consultation. For problematic cases in small biopsy specimens, it can be helpful to evaluate any cytology specimens that may have been taken at the time of bronchoscopy because the morphology by cytology may be more diagnostic than in the biopsy specimen.
      Crush artifact is common in small biopsy specimens and this can complicate evaluation for diagnosis. Whereas most tumors showing dense sheets of small blue cells turn out to be SCLC, this artifact can also be seen in carcinoid tumors, lymphocytic infiltrates, or poorly differentiated NSCLC. However, even in crushed specimens, some preserved tumor cells with morphology compatible with SCLC should be seen to confirm the diagnosis. Immunohistochemical markers can be of assistance in crushed specimens, because SCLC may show positive staining for cytokeratin, chromogranin, CD56, synaptophysin, TTF-1, and a high proliferation index with Ki-67.
      • Marchevsky A.M.
      • Chuang M.T.
      • Teirstein A.S.
      • et al.
      Problems in the diagnosis of small cell carcinoma of the lungs by fiberoptic bronchoscopy.
      • Travis W.D.
      • Garg K.
      • Franklin W.A.
      • et al.
      Bronchioloalveolar carcinoma and lung adenocarcinoma: the clinical importance and research relevance of the 2004 World Health Organization pathologic criteria.
      Up to 10% of SCLC may be negative for a panel of NE markers if the workup includes CD56. So if all other morphologic features are present the diagnosis of SCLC can be rendered even with negative NE markers.
      • Hiroshima K.
      • Iyoda A.
      • Shida T.
      • et al.
      Distinction of pulmonary large cell neuroendocrine carcinoma from small cell lung carcinoma: a morphological, immunohistochemical, and molecular analysis.
      If keratin staining is negative in a suspected SCLC, one should be careful to exclude other possibilities such as chronic inflammation, lymphoma, primitive neuroectodermal tumor, or small round cell sarcoma.
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The new IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.
      • Travis W.D.
      • Rekhtman N.
      Pathological diagnosis and classification of lung cancer in small biopsies and cytology: strategic management of tissue for molecular testing.
      There is no immunohistochemical or molecular marker that reliably distinguishes SCLC from non-SCLC.
      • Souhami R.L.
      • Beverley P.C.
      • Bobrow L.G.
      Antigens of small-cell lung cancer. First International Workshop.
      • Tome Y.
      • Hirohashi S.
      • Noguchi M.
      • et al.
      Preservation of cluster 1 small cell lung cancer antigen in zinc-formalin fixative and its application to immunohistological diagnosis.
      However, in a poorly differentiated tumor that is TTF-1–negative and NE-marker– negative but diffusely positive for p63, the diagnosis of basaloid carcinoma or basaloid variant of squamous cell carcinoma is favored.
      • Maleki Z.
      Diagnostic issues with cytopathologic interpretation of lung neoplasms displaying high-grade basaloid or neuroendocrine morphology.
      Nevertheless, the primary criteria for separating SCLC from NSCLC are based on light microscopy (see Box 2).
      • Travis W.D.
      • Brambilla E.
      • Müller-Hermelink H.K.
      • et al.
      Pathology and genetics: tumours of the lung, pleura, thymus and heart.

      Large cell carcinoma

      Large cell carcinoma comprised 3% of all lung carcinomas in a recent report of the US National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) data.
      • Altekruse S.F.
      • Kosary C.L.
      • Krapcho M.
      • et al.
      SEER cancer statistics review, 1975-2007.
      This finding is a decrease from 9% reported in the SEER monograph for 1983 to 1987.
      • Travis W.D.
      • Travis L.B.
      • Devesa S.S.
      Lung cancer.
      The SEER data include unresectable tumors that would have been diagnosed on small biopsies or cytology as well as resected tumors; other recent surgical series also report a frequency of approximately 3%.
      • Sun Z.
      • Aubry M.C.
      • Deschamps C.
      • et al.
      Histologic grade is an independent prognostic factor for survival in non-small cell lung cancer: an analysis of 5018 hospital- and 712 population-based cases.
      • Sawabata N.
      • Asamura H.
      • Goya T.
      • et al.
      Japanese Lung Cancer Registry Study: first prospective enrollment of a large number of surgical and nonsurgical cases in 2002.
      These tumors are mostly found in the lung periphery, although they may be centrally located. By gross examination they frequently appear as large necrotic tumors. Large cell carcinoma is a diagnosis of exclusion, where the presence of squamous cell or glandular differentiation needs to be excluded by light microscopy. Histologically the tumors usually consist of sheets and nests of large polygonal cells with vesicular nuclei and prominent nucleoli (Fig. 11).
      • Travis W.D.
      • Brambilla E.
      • Müller-Hermelink H.K.
      • et al.
      Pathology and genetics: tumours of the lung, pleura, thymus and heart.
      In the separation from solid adenocarcinoma with mucin, there should be less than 5 mucin positive cells in at least 2 high power fields.
      • Travis W.D.
      • Brambilla E.
      • Müller-Hermelink H.K.
      • et al.
      Pathology and genetics: tumours of the lung, pleura, thymus and heart.
      Figure thumbnail gr11
      Fig. 11Large cell carcinoma. This tumor consists of sheets and nests of large cells with abundant cytoplasm and vesicular nuclei with prominent nucleoli (hematoxylin-eosin, original magnification ×400).
      The diagnosis of large cell carcinoma cannot be made without a resection specimen.
      • Travis W.D.
      • Brambilla E.
      • Müller-Hermelink H.K.
      • et al.
      Pathology and genetics: tumours of the lung, pleura, thymus and heart.
      This situation is because in small biopsies and cytology, the presence of an adenocarcinoma or squamous cell carcinoma component cannot be excluded. There is considerable confusion in the literature on this topic, because tumors have been classified as large cell carcinoma in both pathology as well as clinical publications in which the data were based on small biopsy specimens rather than resections.
      • Scagliotti G.V.
      • Parikh P.
      • von P.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.
      • Rossi G.
      • Marchioni A.
      • Milani M.
      • et al.
      TTF-1, cytokeratin 7, 34betaE12, and CD56/NCAM immunostaining in the subclassification of large cell carcinomas of the lung.
      According to the 2011 IASLC/ATS/ERS lung adenocarcinoma classification, in small biopsy specimens, these tumors would now be classified as NSCLC-NOS if evaluated by light microscopy alone.
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The new IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.
      • Travis W.D.
      • Brambilla E.
      • Müller-Hermelink H.K.
      • et al.
      Pathology and genetics: tumours of the lung, pleura, thymus and heart.
      If immunostains are performed, some of these tumors might be reclassified as NSCLC favor adenocarcinoma or NSCLC favor squamous cell carcinoma and a small percentage would remain as NSCLC-NOS.
      • Travis W.D.
      • Brambilla E.
      • Noguchi M.
      • et al.
      The new IASLC/ATS/ERS international multidisciplinary lung adenocarcinoma classification.
      • Travis W.D.
      • Brambilla E.
      • Müller-Hermelink H.K.
      • et al.
      Pathology and genetics: tumours of the lung, pleura, thymus and heart.
      It has been known for decades that electron microscopy (EM) of large cell carcinoma frequently reveals features of adenocarcinoma or squamous differentiation.
      • Churg A.
      The fine structure of large cell undifferentiated carcinoma of the lung. Evidence for its relation to squamous cell carcinomas and adenocarcinomas.
      • Horie A.
      • Ohta M.
      Ultrastructural features of large cell carcinoma of the lung with reference to the prognosis of patients.
      • Kodama T.
      • Shimosato Y.
      • Koide T.
      • et al.
      Large cell carcinoma of the lung–ultrastructural and immunohistochemical studies.
      Similar observations are being made using immunohistochemistry, in which studies of large cell carcinomas express adenocarcinoma (TTF-1) or squamous (p63) markers and some have suggested these tumors should now be reclassified.
      • Rossi G.
      • Marchioni A.
      • Milani M.
      • et al.
      TTF-1, cytokeratin 7, 34betaE12, and CD56/NCAM immunostaining in the subclassification of large cell carcinomas of the lung.
      • Carvalho L.
      Reclassifying bronchial-pulmonary carcinoma: differentiating histological type in biopsies by immunohistochemistry.
      A small percentage of these tumors may also harbor mutations such as KRAS that are associated with adenocarcinoma. However, this information by immunohistochemistry or mutation testing does not add any new information beyond what we have known for decades with EM: (1) tumors classified as large cell carcinoma by light microscopy consist of a heterogeneous group of poorly differentiated tumors most of which share properties (EM, immunohistochemistry, or molecular) of adenocarcinoma, some have squamous features, a smaller percentage have both, and a small subset remains a null phenotype or truly undifferentiated large cell carcinoma. How to resolve this issue needs to be addressed in the upcoming revision of the WHO classification. Regardless of whether the decision is to lump (keep large cell carcinoma close to the current definition) or to split (reclassify most large cell carcinomas according to immunohistochemistry), this decision is arbitrary in the absence of any clinical trial data to compare clinical properties, such as different outcomes or response to therapy, relative to the other major lung cancer histologic subtypes. One option may be to retain the diagnosis of large cell carcinoma based on traditional criteria, but add a comment about the immunophenotype that may reflect adenocarcinoma or squamous cell carcinoma differentiation.
      Several variants of large cell carcinoma are recognized in the 2004 WHO histologic classification of lung cancer (see Box 1). These variants include LCNEC,
      • Travis W.D.
      • Brambilla E.
      • Müller-Hermelink H.K.
      • et al.
      Pathology and genetics: tumours of the lung, pleura, thymus and heart.
      • Travis W.D.
      • Rush W.
      • Flieder D.B.
      • et al.
      Survival analysis of 200 pulmonary neuroendocrine tumors with clarification of criteria for atypical carcinoid and its separation from typical carcinoid.
      • Travis W.D.
      • Linnoila R.I.
      • Tsokos M.G.
      • et al.
      Neuroendocrine tumors of the lung with proposed criteria for large-cell neuroendocrine carcinoma. An ultrastructural, immunohistochemical, and flow cytometric study of 35 cases.
      basaloid carcinoma,
      • Moro-Sibilot D.
      • Lantuejoul S.
      • Diab S.
      • et al.
      Lung carcinomas with a basaloid pattern: a study of 90 cases focusing on their poor prognosis.
      lymphoepithelial-like carcinoma,
      • Chang Y.L.
      • Wu C.T.
      • Shih J.Y.
      • et al.
      Unique p53 and epidermal growth factor receptor gene mutation status in 46 pulmonary lymphoepithelioma-like carcinomas.
      • Chang Y.L.
      • Wu C.T.
      • Shih J.Y.
      • et al.
      New aspects in clinicopathologic and oncogene studies of 23 pulmonary lymphoepithelioma-like carcinomas.
      clear cell carcinoma,
      • Katzenstein A.L.
      • Prioleau P.G.
      • Askin F.B.
      The histologic spectrum and significance of clear-cell change in lung carcinoma.
      and large cell carcinoma with rhabdoid phenotype.
      • Cavazza A.
      • Colby T.V.
      • Tsokos M.
      • et al.
      Lung tumors with a rhabdoid phenotype.
      • Izquierdo-Garcia F.M.
      • Moreno-Mata N.
      • Herranz-Aladro M.L.
      • et al.
      Lung carcinoma with rhabdoid component. A series of seven cases associated with uncommon types of non-small cell lung carcinomas and alveolar entrapment.
      LCNEC is discussed below.

      LCNEC

      LCNEC comprises approximately 3% of resected lung cancers.
      • Travis W.D.
      Lung tumours with neuroendocrine differentiation.
      LCNEC is a high-grade non–small cell NE carcinoma that differs from AC and small cell carcinoma (see Table 2). Histologic criteria include: (1) NE morphology: organoid, palisading, trabecular, or rosette-like growth patterns (Fig. 12); (2) non–small cell cytologic features: large size, polygonal shape, low N/C ratio, coarse or vesicular nuclear chromatin, and frequent nucleoli; (3) high mitotic rate (11 or more per 2 mm2) with a mean of 60 mitoses per 2 mm2; (4) frequent necrosis; and (5) at least 1 positive NE immunohistochemical marker or NE granules by EM (see Fig. 12B).
      • Travis W.D.
      • Brambilla E.
      • Müller-Hermelink H.K.
      • et al.
      Pathology and genetics: tumours of the lung, pleura, thymus and heart.
      • Travis W.D.
      • Linnoila R.I.
      • Tsokos M.G.
      • et al.
      Neuroendocrine tumors of the lung with proposed criteria for large-cell neuroendocrine carcinoma. An ultrastructural, immunohistochemical, and flow cytometric study of 35 cases.
      It is difficult to diagnose LCNEC based on small biopsy specimens such as needle or bronchoscopic biopsy specimens because it is usually difficult to be certain of the NE morphology without a substantial sampling of the tumor. However, recently criteria were proposed to diagnose LCNEC based on cytology.
      • Wiatrowska B.A.
      • Krol J.
      • Zakowski M.F.
      Large-cell neuroendocrine carcinoma of the lung: proposed criteria for cytologic diagnosis.
      The term large cell carcinoma, with NE morphology, can be used for tumors resembling LCNEC by light microscopy but lacking proof of NED by EM or immunohistochemistry.
      • Travis W.D.
      • Brambilla E.
      • Müller-Hermelink H.K.
      • et al.
      Pathology and genetics: tumours of the lung, pleura, thymus and heart.
      The term combined LCNEC is used for those tumors associated with other histologic types of NSCLC such as adenocarcinoma or squamous cell carcinoma (see Box 1).
      • Travis W.D.
      • Brambilla E.
      • Müller-Hermelink H.K.
      • et al.
      Pathology and genetics: tumours of the lung, pleura, thymus and heart.
      A variety of criteria must be used to separate SCLC from LCNEC (see Table 2).
      Figure thumbnail gr12
      Fig. 12LCNEC. (A) Peripheral palisading and rosette-like structures give this tumor an NE morphologic appearance. The tumor cells have abundant cytoplasm with large hyperchromatic nuclei. Some of the nuclei show vesicular chromatin or prominent nucleoli. Mitoses are frequent (hematoxylin-eosin, original magnification ×400). (B) The tumor cells are diffusely positive for synaptophysin (immunohistochemistry for synaptophysin, original magnification ×200).

      Clinical features

      Patients with LCNEC have a median age of 62 years (range 33–87 years) and they are typically heavy cigarette smokers.
      • Travis W.D.
      • Linnoila R.I.
      • Tsokos M.G.
      • et al.
      Neuroendocrine tumors of the lung with proposed criteria for large-cell neuroendocrine carcinoma. An ultrastructural, immunohistochemical, and flow cytometric study of 35 cases.
      Patients with LCNEC have a poor prognosis. Travis and colleagues
      • Travis W.D.
      • Rush W.
      • Flieder D.B.
      • et al.
      Survival analysis of 200 pulmonary neuroendocrine tumors with clarification of criteria for atypical carcinoid and its separation from typical carcinoid.
      found the 5-year and 10-year survival for LCNEC is 27% and 11%, respectively, with a significantly worse prognosis than patients with AC. Iyoda and colleagues
      • Iyoda A.
      • Hiroshima K.
      • Toyozaki T.
      • et al.
      Clinical characterization of pulmonary large cell neuroendocrine carcinoma and large cell carcinoma with neuroendocrine morphology.
      found a 35.3% and 31.7% 5-year and 10-year survival, respectively, for LCNEC. Iyoda and colleagues
      • Iyoda A.
      • Hiroshima K.
      • Toyozaki T.
      • et al.
      Clinical characterization of pulmonary large cell neuroendocrine carcinoma and large cell carcinoma with neuroendocrine morphology.
      also found a worse survival for LCNEC compared with classic large cell carcinoma (P = .031), whereas Jiang and colleagues
      • Jiang S.X.
      • Kameya T.
      • Shoji M.
      • et al.
      Large cell neuroendocrine carcinoma of the lung: a histologic and immunohistochemical study of 22 cases.
      found a worse survival for LCNEC compared with non–small cell carcinomas (P = .046). However, it has not been possible to show a difference in survival between LCNEC and SCLC.
      • Travis W.D.
      • Rush W.
      • Flieder D.B.
      • et al.
      Survival analysis of 200 pulmonary neuroendocrine tumors with clarification of criteria for atypical carcinoid and its separation from typical carcinoid.
      • Beasley M.B.
      • Thunnissen F.B.
      • Brambilla E.
      • et al.
      Pulmonary atypical carcinoid: predictors of survival in 106 cases.
      Surgical resection should be performed if possible; however, it remains to be proved whether adjunctive radiation or chemotherapy is effective. Iyoda and colleagues
      • Iyoda A.
      • Hiroshima K.
      • Toyozaki T.
      • et al.
      Clinical characterization of pulmonary large cell neuroendocrine carcinoma and large cell carcinoma with neuroendocrine morphology.
      found no significant difference between the age, sex, smoking history, tumor size, and survival for patients with large cell carcinoma with NE morphology compared with those with LCNEC, although the mitotic rate was higher (P = .0071). A recent analysis of the NCI SEER data suggested overall survival and lung cancer specific survival rates for patients with LCNEC after surgical resection without radiation therapy were similar to those for patients who had other large cell carcinoma and better than for those patients with SCLC, although the differences were not significant on multivariate analysis.
      • Varlotto J.M.
      • Medford-Davis L.N.
      • Recht A.
      • et al.
      Should large cell neuroendocrine lung carcinoma be classified and treated as a small cell lung cancer or with other large cell carcinomas?.
      If immunohistochemistry is performed on non–small cell carcinomas lacking NE morphology, positive staining can be found in 10% to 20% of cases. Similarly NE granules can be found in up to 10% of cases by EM. Such tumors are called non–small cell carcinomas (adenocarcinoma, squamous cell carcinoma, or large cell carcinoma) with neuroendocrine differentiation (NSCLC-NED).
      • Travis W.D.
      • Colby T.V.
      • Corrin B.
      • et al.
      In collaboration with L.H. Sobin and pathologists from 14 countries
      Histological Typing of Lung and Pleural Tumors.
      • Travis W.D.
      • Linnoila R.I.
      • Tsokos M.G.
      • et al.
      Neuroendocrine tumors of the lung with proposed criteria for large-cell neuroendocrine carcinoma. An ultrastructural, immunohistochemical, and flow cytometric study of 35 cases.
      The clinical significance of the diagnosis of NSCLC-NED is not known. Iyoda and colleagues
      • Iyoda A.
      • Hiroshima K.
      • Toyozaki T.
      • et al.
      Clinical characterization of pulmonary large cell neuroendocrine carcinoma and large cell carcinoma with neuroendocrine morphology.
      found that the tumor size of large cell carcinoma with NED (LCC-ND) was larger than that for LCNEC (P = .0033), but the survival was not different from patients with LCNEC. Whether these tumors are responsive to SCLC chemotherapy regimens
      • Graziano S.L.
      • Mazid R.
      • Newman N.
      • et al.
      The use of neuroendocrine immunoperoxidase markers to predict chemotherapy response in patients with non-small-cell lung cancer.
      • Gazdar A.F.
      • Kadoyama C.
      • Venzon D.
      • et al.
      Association between histological type and neuroendocrine differentiation on drug sensitivity of lung cancer cell lines.
      or whether expression of NE markers may be an unfavorable prognostic factor
      • Berendsen H.H.
      • de Leij L.
      • Poppema S.
      • et al.
      Clinical characterization of non-small-cell lung cancer tumors showing neuroendocrine differentiation features.
      • Kibbelaar R.E.
      • Moolenaar K.E.
      • Michalides R.J.
      • et al.
      Neural cell adhesion molecule expression, neuroendocrine differentiation and prognosis in lung carcinoma.
      • Schleusener J.T.
      • Tazelaar H.D.
      • Jung S.H.
      • et al.
      Neuroendocrine differentiation is an independent prognostic factor in chemotherapy-treated nonsmall cell lung carcinoma.
      • Addis B.J.
      Neuroendocrine differentiation in lung carcinoma.
      • Kiriakogiani-Psaropoulou P.
      • Malamou-Mitsi V.
      • Martinopoulou U.
      • et al.
      The value of neuroendocrine markers in non-small cell lung cancer: a comparative immunohistopathologic study.
      • Linnoila R.I.
      • Piantadosi S.
      • Ruckdeschel J.C.
      Impact of neuroendocrine differentiation in non-small cell lung cancer. The LCSG experience.
      • Carles J.
      • Rosell R.
      • Ariza A.
      • et al.
      Neuroendocrine differentiation as a prognostic factor in non-small cell lung cancer.
      • Skov B.G.
      • Sorensen J.B.
      • Hirsch F.R.
      • et al.
      Prognostic impact of histologic demonstration of chromogranin A and neuron specific enolase in pulmonary adenocarcinoma.
      remains to be determined.

      Adenosquamous carcinoma

      Adenosquamous carcinoma accounts for 0.6% to 2.3% of all lung cancers
      • Fitzgibbons P.L.
      • Kern W.H.
      Adenosquamous carcinoma of the lung: a clinical and pathologic study of seven cases.
      • Ishida T.
      • Kaneko S.
      • Yokoyama H.
      • et al.
      Adenosquamous carcinoma of the lung. Clinicopathologic and immunohistochemical features.
      • Naunheim K.S.
      • Taylor J.R.
      • Skosey C.
      • et al.
      Adenosquamous lung carcinoma: clinical characteristics, treatment, and prognosis.
      • Sridhar K.S.
      • Raub Jr., W.A.
      • Duncan R.C.
      • et al.
      The increasing recognition of adenosquamous lung carcinoma (1977-1986).
      • Takamori S.
      • Noguchi M.
      • Morinaga S.
      • et al.
      Clinicopathologic characteristics of adenosquamous carcinoma of the lung.
      and it is defined as a lung carcinoma having at least 10% squamous cell and adenocarcinoma by light microscopy.
      • Travis W.D.
      • Colby T.V.
      • Corrin B.
      • et al.
      In collaboration with L.H. Sobin and pathologists from 14 countries
      Histological Typing of Lung and Pleural Tumors.
      Similar to large cell carcinoma enormous confusion has been introduced by use of immunostains. The current WHO definition recognizes this tumor if the 10% of squamous and adenocarcinoma components are diagnosable by light microscopy. This diagnosis should be made only if the adenocarcinoma and squamous components are both recognizable by light microscopy and not purely by immunohistochemistry. This diagnosis may be suspected, but cannot be made by small biopsy or cytology, because a resection specimen is needed.

      Carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements

      Sarcomatoid carcinomas comprise 0.3% of all invasive lung malignancies.
      • Travis W.D.
      • Travis L.B.
      • Devesa S.S.
      Lung cancer.
      This group of lung carcinomas is poorly differentiated and expresses a spectrum of pleomorphic, sarcomatoid, and sarcomatous elements.
      • Travis W.D.
      Sarcomatoid neoplasms of the lung and pleura.
      Pleomorphic carcinomas tend to be large, peripheral tumors that often invade the chest wall and are associated with a poor prognosis.
      • Travis W.D.
      Sarcomatoid neoplasms of the lung and pleura.
      Because of the prominent histologic heterogeneity of this tumor, adequate sampling is important and should consist of at least 1 section per centimeter of the tumor diameter. Pleomorphic carcinomas should have at least a 10% component of a spindle cell or giant cell component, and frequently other histologic types such as adenocarcinoma or squamous cell carcinoma (Fig. 13) are present.
      • Travis W.D.
      • Brambilla E.
      • Müller-Hermelink H.K.
      • et al.
      Pathology and genetics: tumours of the lung, pleura, thymus and heart.
      • Travis W.D.
      Sarcomatoid neoplasms of the lung and pleura.
      Figure thumbnail gr13
      Fig. 13Pleomorphic carcinoma. This tumor is composed of squamous cell carcinoma (left) and an malignant spindle cell proliferation (right) (hematoxylin-eosin, original magnification ×200).
      If the tumor has a pure giant cell or spindle cell pattern the term giant cell or spindle cell carcinoma, respectively, can be used. Giant cell carcinoma consists of huge bizarre pleomorphic and multinucleated tumor giant cells.
      • Travis W.D.
      • Brambilla E.
      • Müller-Hermelink H.K.
      • et al.
      Pathology and genetics: tumours of the lung, pleura, thymus and heart.
      • Travis W.D.
      Sarcomatoid neoplasms of the lung and pleura.
      The cells are often dyscohesive and infiltrated by inflammatory cells, particularly neutrophils. This tumor is defined by light microscopy, but immunohistochemistry, particularly for epithelial markers such as keratin, can be helpful in confirming epithelial differentiation.
      • Travis W.D.
      • Brambilla E.
      • Müller-Hermelink H.K.
      • et al.
      Pathology and genetics: tumours of the lung, pleura, thymus and heart.
      • Travis W.D.
      Sarcomatoid neoplasms of the lung and pleura.
      The diagnosis of pleomorphic carcinoma cannot be made based on small biopsies or cytology; a resection specimen is required to identify the criteria outlined earlier.

      Carcinosarcoma and Pulmonary Blastoma

      Carcinosarcoma is a tumor composed of a mixture of carcinoma and sarcoma that should show heterologous elements such as malignant cartilage, bone, or skeletal muscle according to the 2004 WHO classification.
      • Travis W.D.
      • Brambilla E.
      • Müller-Hermelink H.K.
      • et al.
      Pathology and genetics: tumours of the lung, pleura, thymus and heart.
      • Travis W.D.
      Sarcomatoid neoplasms of the lung and pleura.
      Pulmonary blastomas are composed of a glandular component that resembles well-differentiated fetal adenocarcinoma and a primitive sarcomatous component. Fetal adenocarcinoma is no longer regarded as the epithelial pattern of pulmonary blastoma, but rather as a variant of adenocarcinoma.
      • Travis W.D.
      • Brambilla E.
      • Müller-Hermelink H.K.
      • et al.
      Pathology and genetics: tumours of the lung, pleura, thymus and heart.
      • Travis W.D.
      Sarcomatoid neoplasms of the lung and pleura.

      Typical and atypical carcinoid

      Carcinoid tumors account for 1% to 2% of all invasive lung malignancies.
      • Travis W.D.
      • Travis L.B.
      • Devesa S.S.
      Lung cancer.
      Approximately 50% of patients are asymptomatic at presentation.
      • Travis W.D.
      Advances in neuroendocrine lung tumors.
      • Krug L.M.
      • Pietanza M.C.
      • Kris M.G.
      • et al.
      Small cell and other neuroendocrine tumors of the lung.
      • Asamura H.
      • Kameya T.
      • Matsuno Y.
      • et al.
      Neuroendocrine neoplasms of the lung: a prognostic spectrum.
      Typical carcinoid (TC) and atypical carcinoid (AC) occur at any age, with an average of 45 to 55 years, and there is no sex predilection. They are the most common lung tumor in childhood.
      • Lack E.E.
      • Harris G.B.
      • Eraklis A.J.
      • et al.
      Primary bronchial tumors in childhood. A clinicopathologic study of six cases.
      Symptoms include hemoptysis in 18%, postobstructive pneumonitis in 17%, and dyspnea in 2% of patients. Paraneoplastic syndromes include the carcinoid syndrome, Cushing syndrome.
      • Travis W.D.
      Advances in neuroendocrine lung tumors.
      • Krug L.M.
      • Pietanza M.C.
      • Kris M.G.
      • et al.
      Small cell and other neuroendocrine tumors of the lung.
      The primary approach to treatment of pulmonary carcinoids is surgical resection.
      • Naalsund A.
      • Rostad H.
      • Strom E.H.
      • et al.
      Carcinoid lung tumors–incidence, treatment and outcomes: a population-based study.
      • Rea F.
      • Rizzardi G.
      • Zuin A.
      • et al.
      Outcome and surgical strategy in bronchial carcinoid tumors: single institution experience with 252 patients.
      Patients with TC have an excellent prognosis and rarely die of tumor.
      • Travis W.D.
      Advances in neuroendocrine lung tumors.
      • Krug L.M.
      • Pietanza M.C.
      • Kris M.G.
      • et al.
      Small cell and other neuroendocrine tumors of the lung.
      The finding of metastases should not be used as a criterion for distinguishing TC from AC because 5% to 20% of TCs have regional lymph node involvement.
      • Naalsund A.
      • Rostad H.
      • Strom E.H.
      • et al.
      Carcinoid lung tumors–incidence, treatment and outcomes: a population-based study.
      • Rea F.
      • Rizzardi G.
      • Zuin A.
      • et al.
      Outcome and surgical strategy in bronchial carcinoid tumors: single institution experience with 252 patients.
      Compared with TCs, ACs have a larger tumor size, a higher rate of metastases, and the survival is significantly reduced. The mortality reported in most series is approximately 30%, ranging from 27% to 47%.
      • Travis W.D.
      Advances in neuroendocrine lung tumors.
      • Krug L.M.
      • Pietanza M.C.
      • Kris M.G.
      • et al.
      Small cell and other neuroendocrine tumors of the lung.
      Carcinoid tumors may be central, with a frequent polypoid endobronchial component. Peripheral carcinoids are usually found in the subpleural parenchyma. Both TCs and ACs are characterized histologically by an organoid growth pattern and uniform cytologic features consisting of moderate eosinophilic, finely granular cytoplasm with nuclei possessing a finely granular chromatin pattern (Fig. 14, Table 3). Nucleoli are inconspicuous in most TCs, but they may be more prominent in ACs. A variety of histologic patterns may occur in both ACs and TCs, including spindle cell, trabecular, palisading, rosette-like, papillary, sclerosing papillary, glandular, and follicular patterns.
      • Travis W.D.
      • Linnoila R.I.
      • Tsokos M.G.
      • et al.
      Neuroendocrine tumors of the lung with proposed criteria for large-cell neuroendocrine carcinoma. An ultrastructural, immunohistochemical, and flow cytometric study of 35 cases.
      The tumor cells of pulmonary carcinoid tumors may have oncocytic, acinic cell–like, signet ring, mucin-producing, or melanocytic features.
      • Travis W.D.
      • Linnoila R.I.
      • Tsokos M.G.
      • et al.
      Neuroendocrine tumors of the lung with proposed criteria for large-cell neuroendocrine carcinoma. An ultrastructural, immunohistochemical, and flow cytometric study of 35 cases.
      Figure thumbnail gr14
      Fig. 14Typical carcinoid. This tumor is growing in organoid nests and consists of uniform medium-sized cells with a moderate amount of eosinophilic cytoplasm (hematoxylin-eosin, original magnification ×200).
      Table 3Typical and atypical carcinoid: distinguishing features
      Data from Colby TV, Koss MN, Travis WD. Tumors of the lower respiratory tract; Armed Forces Institute of Pathology fascicle, third series. Washington, DC: Armed Forces Institute of Pathology, 1995 . p. 295; and Travis WD. Pathology of lung cancer. Clin Chest Med 2002;23:77.
      Histologic or Clinical FeatureTypical CarcinoidAtypical Carcinoid
      Histologic patterns: organoid, trabecular, palisading and spindle cellCharacteristicCharacteristic
      MitosesAbsent or <2 per 2 mm2 area of viable tumor (10 high power fields on some microscopes)2–10 per 2 mm2 or area of viable tumor (10 high power fields on some microscopes)
      NecrosisAbsentCharacteristic, usually focal or punctate
      Nuclear pleomorphism, hyperchromatismUsually absent, not sufficient by itself for diagnosis of ACOften present
      Regional lymph node metastases at presentation (%)5–1540–48
      Distant metastases at presentation (%)Rare20
      Survival at 5 years (%)90–9550–60
      Survival at 10 years (%)90–9535
      ACs are defined as carcinoid tumors with mitoses between 2 and 10 per 2 mm2 area of viable tumor (10 high power fields in certain microscopes) or the presence of necrosis (Fig. 15).
      • Travis W.D.
      • Rush W.
      • Flieder D.B.
      • et al.
      Survival analysis of 200 pulmonary neuroendocrine tumors with clarification of criteria for atypical carcinoid and its separation from typical carcinoid.
      The presence of features such as pleomorphism, vascular invasion, and increased cellularity is not so helpful in separating TC from AC. In TC necrosis is absent and mitotic figures are rare (<2 per 2 mm2) (see Table 3).
      • Travis W.D.
      • Rush W.
      • Flieder D.B.
      • et al.
      Survival analysis of 200 pulmonary neuroendocrine tumors with clarification of criteria for atypical carcinoid and its separation from typical carcinoid.
      • Travis W.D.
      • Linnoila R.I.
      • Tsokos M.G.
      • et al.
      Neuroendocrine tumors of the lung with proposed criteria for large-cell neuroendocrine carcinoma. An ultrastructural, immunohistochemical, and flow cytometric study of 35 cases.
      The necrosis in AC usually consists of small foci centrally located within organoid nests of tumor cells; uncommonly the necrosis may form larger confluent zones.
      Figure thumbnail gr15
      Fig. 15Atypical carcinoid. (A) Punctate foci of necrosis are present in the center of several organoid nests of uniform tumor cells. This feature is characteristic of atypical carcinoids (hematoxylin-eosin, original magnification ×200). (B) The tumor cells are uniform, with moderate spindle-shaped cytoplasm, and the nuclear chromatin is finely granular. A single mitosis is present (center) (hematoxylin-eosin, original magnification ×800).
      Carcinoid tumors stain for NE markers such as chromogranin, synaptophysin, and CD56. A low proliferation rate (≤5%) is seen in TC by Ki-67 staining compared with AC, in which it is usually between 5% and 20%.
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      Typical and atypical pulmonary carcinoid tumor overdiagnosed as small-cell carcinoma on biopsy specimens: a major pitfall in the management of lung cancer patients.