Lepidic Pattern Research Articles

Diffuse Intrapulmonary Malignant Mesothelioma Masquerading as Interstitial Lung Disease

Malignant mesothelioma typically encases lungs as a thick rind, while relatively sparing lung parenchyma. We describe an unusual presentation of mesothelioma characterized by diffuse intrapulmonary growth, with absent or inconspicuous pleural involvement, clinically simulating interstitial lung disease (ILD). We identified 5 patients (median age 56 y, all men) with diffuse intrapulmonary malignant mesothelioma in our pathology consultation practice from 2009 to 2012. Clinical history, imaging, and pathology materials were reviewed. Symptoms included chronic dyspnea (4 cases), cough (3), and acute dyspnea with bilateral pneumothorax (1). Chest imaging showed irregular opacities (5), reticulation (4), pleural effusions (2), and subpleural nodular densities (1), without radiologic evidence of pleural disease or masses. A clinicoradiologic diagnosis of ILD was made in all cases, and wedge biopsies were performed. Histologic evaluation revealed a neoplastic proliferation of bland epithelioid or spindled cells, showing various growth patterns simulating silicotic nodules, desquamative interstitial pneumonia, organizing pneumonia, and Langerhans cell histiocytosis. Some areas mimicked adenocarcinoma, with lepidic, acinar, micropapillary, and solid patterns. Initial diagnoses by referring pathologists included reactive changes (1), hypersensitivity pneumonitis versus drug reaction (1), desquamative interstitial pneumonia versus neoplasm (1), and mesothelioma (2). Microscopic pleural involvement was identified in 4 cases. Immunohistochemistry confirmed the characteristic immunophenotype of mesothelioma in all cases. Median survival of 3 patients treated with chemotherapy was 28 months. Two patients received no therapy and survived 3 and 4 weeks, respectively. "Diffuse intrapulmonary malignant mesothelioma" is a rare variant with a distinctive presentation that clinically mimics ILD. Recognition is essential to avoid misdiagnosis.

Interobserver Agreement in the Nuclear Grading of Primary Pulmonary Adenocarcinoma

Nuclear grading involves an evaluation of the size and shape of nuclei and the percentage of tumor cells that are in the mitotic phase. To estimate the degree of aggressiveness, this approach has been applied to various types of carcinomas, such as breast carcinoma and pulmonary adenocarcinoma (Nakazato et al.). In the present study, we estimated and evaluated the interobserver variability of nuclear grading in primary pulmonary adenocarcinomas. We selected 122 primary pulmonary adenocarcinomas measuring 2 cm or less in diameter. Eight pathologists independently evaluated the nuclear factors, using the nuclear grading system reported previously by Nakazato et al. The same pathologists also used both the international multidisciplinary classification of pulmonary adenocarcinoma (2011 International Association for the Study of Lung Cancer classification) and Noguchi's classification, and assessed the extent of the lepidic pattern in the largest cut surface of the tumor. Interobserver agreement was evaluated using the κ statistic. The disease-free survival curves of the patients were obtained using the Kaplan-Meier method and analyzed with the log-rank test. The mean (±SD) κ values for the two histological classifications, the extent of the lepidic pattern, and nuclear grading were 0.46 ± 0.09, 0.48 ± 0.09, 0.45 ± 0.16, and 0.58 ± 0.09, respectively. The cases judged as negative on the basis of nuclear grading showed a significantly better prognosis (5-year disease-free survival rate; 91.8% ± 2.7) than the positive cases did (68.6% ± 3.1). : Nuclear grading is practical for prognostic evaluation of pulmonary adenocarcinoma. The interobserver agreement for nuclear grading is significantly higher than for histological classifications and the extent of the lepidic pattern. Nuclear grading is a reliable prognostic indicator for small adenocarcinomas.

Diagnosis of lung adenocarcinoma in resected specimens: implications of the 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification.

A new lung adenocarcinoma classification has been published by the International Association for the Study of Lung Cancer, the American Thoracic Society, and the European Respiratory Society. This new classification is needed to provide uniform terminology and diagnostic criteria, most especially for bronchioloalveolar carcinoma. It was developed by an international core panel of experts representing all 3 societies with oncologists/pulmonologists, pathologists, radiologists, molecular biologists, and thoracic surgeons.This summary focuses on the aspects of this classification that address resection specimens. The terms bronchioloalveolar carcinoma and mixed subtype adenocarcinoma are no longer used. For resection specimens, new concepts are introduced, such as adenocarcinoma in situ and minimally invasive adenocarcinoma for small solitary adenocarcinomas with either pure lepidic growth (adenocarcinoma in situ) and predominant lepidic growth with invasion of 5 mm or less (minimally invasive adenocarcinoma), to define the condition of patients who will have 100% or near 100% disease-specific survival, respectively, if they undergo complete lesion resection. Adenocarcinoma in situ and minimally invasive adenocarcinoma are usually nonmucinous, but rarely may be mucinous. Invasive adenocarcinomas are now classified by predominant pattern after using comprehensive histologic subtyping with lepidic (formerly most mixed subtype tumors with nonmucinous bronchioloalveolar carcinoma), acinar, papillary, and solid patterns; micropapillary is added as a new histologic subtype. Variants include invasive mucinous adenocarcinoma (formerly mucinous bronchioloalveolar carcinoma), colloid, fetal, and enteric adenocarcinoma.It is possible that this classification may impact the next revision of the TNM staging classification, with adjustment of the size T factor according to only the invasive component pathologically in adenocarcinomas with lepidic areas.

Biopsy-site Changes in Lung Adenocarcinoma With Prior Core Needle Biopsy

Although biopsy-site changes are known to cause diagnostic difficulties in thyroid and breast specimens, especially when assessing invasion, such changes have not been described in the lung. Assessment of invasion is important in lung cancers to distinguish bronchioloalveolar carcinoma [adenocarcinoma in situ (AIS)] from invasive adenocarcinoma. The aim of this study was to determine whether biopsy-site changes occur in the lung and whether they may impact this differential diagnosis. Lobectomy specimens were examined from patients whose previous core needle biopsies showed well-differentiated adenocarcinoma with a lepidic pattern. There were 26 adenocarcinomas, including 14 minimally invasive adenocarcinomas, 2 invasive well-differentiated adenocarcinomas, and 10 AISs. Biopsy-site changes were identified in 9 of 26 (35%), including 4 minimally invasive adenocarcinomas, 3 AISs, and 2 well-differentiated adenocarcinomas. The interval between biopsy and resection ranged from 12 to 45 days (mean, 26.1 d). The biopsy sites consisted of a linear scar composed of collagen and plump fibroblasts, ranging from 2.0 to 13.1 mm in length and 0.5 to 1.6 mm in width. Scattered lymphocytes and plasma cells were present in 8 cases, pigment-laden macrophages in 4, and foreign body giant cells in 3. Benign entrapped lung epithelium was present within the scar in all 9 and entrapped malignant epithelium in 4. Biopsy-site changes can be identified in a significant proportion of lung tumors after core needle biopsy. They need to be distinguished from tumor-related stromal reactions that are considered an indication of invasion and are important in the differentiation of AIS and invasive adenocarcinoma.

New Pathologic Classification of Lung Cancer: Relevance for Clinical Practice and Clinical Trials

We summarize significant changes in pathologic classification of lung cancer resulting from the 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) lung adenocarcinoma classification. The classification was developed by an international core panel of experts representing IASLC, ATS, and ERS with oncologists/pulmonologists, pathologists, radiologists, molecular biologists, and thoracic surgeons. Because 70% of patients with lung cancer present with advanced stages, a new approach to small biopsies and cytology with specific terminology and criteria focused on the need for distinguishing squamous cell carcinoma from adenocarcinoma and on molecular testing for EGFR mutations and ALK rearrangement. Tumors previously classified as non-small-cell carcinoma, not otherwise specified, because of the lack of clear squamous or adenocarcinoma morphology should be classified further by using a limited immunohistochemical workup to preserve tissue for molecular testing. The terms "bronchioloalveolar carcinoma" and "mixed subtype adenocarcinoma" have been discontinued. For resected adenocarcinomas, new concepts of adenocarcinoma in situ and minimally invasive adenocarcinoma define patients who, if they undergo complete resection, will have 100% disease-free survival. Invasive adenocarcinomas are now classified by predominant pattern after using comprehensive histologic subtyping with lepidic, acinar, papillary, and solid patterns; micropapillary is added as a new histologic subtype with poor prognosis. Former mucinous bronchioloalveolar carcinomas are now called "invasive mucinous adenocarcinoma." Because the lung cancer field is now rapidly evolving with new advances occurring on a frequent basis, particularly in the molecular arena, this classification provides a much needed standard for pathologic diagnosis not only for patient care but also for clinical trials and TNM classification.

Editorial Comment: Clinical relevance and TNM implications of the new concept of minimally-invasive adenocarcinomas in situ with a lepidic pattern

The most significant recent change in the pathological classification of lung cancer occurred with the 2011 classification of lung adenocarcinoma sponsored by the International Association of the Study of Lung Cancer (IASLC), the American Thoracic Society (ATS), and the European Respiration Society (ERS). This classification outlines many paradigm shifts that affect clinical practice and patient management and opens new avenues for research [1]. This new classification was a multidisciplinary effort at emphasizing the correlations in tumour pathology among clinical, radiological and molecular characteristics. With this classification, a new concept of adenocarcinoma in situ (AIS) was added to the group of pre-invasive lesions along with atypical adenomatous hyperplasia, both presenting at HRCT (high resolution CT-scan) as circumscribed by ground glass opacities (GGO). AIS is defined as a localized, small (≤3 cm) adenocarcinoma consisting of pure lepidic growth characterized by neoplastic pneumocytes growing along pre-existing alveolar walls and lacking stromal, vascular and pleural invasion. This new concept of AIS (former pure bronchioloalveolar carcinoma [BAC]) correlates with 100% disease-free survival if completely resected. A new concept of minimally invasive adenocarcinoma (MIA) is created for small solitary adenocarcinoma (≤3 cm) with a predominant lepidic pattern and ≤5 mm invasion. By CT, this typically presents as a ground glass nodule with a solid component measuring 5 mm or less. Measurement of the invasive component of MIA includes the size of the invasive subtypes other than the lepidic pattern including tumour cells infiltrating myofibroblastic stroma. MIA is restricted to tumours showing neither lymph node blood vessel or pleural invasion nor necrosis. Moreover, MIA defines a population of patients with near 100% 5-year survival. Because the previous taxonomy of bronchioloalveolar carcinoma included a wide variety of different clinico-pathological entities, it was discarded. The current article [2] can be regarded as a validation of the concept that the pure lepidic pattern is biologically and clinically in situ. Correlation of the pathology with CT-findings is helpful in the evaluation of AIS, MIA and lepidic predominant adenocarcinomas since it can be difficult to appreciate tumour size by gross evaluation of a lepidic predominant tumour. It may be easier to identify the size of the lesion on HRCT, particularly in lepidic predominant tumours to distinguish the part solid nodule on a background of a mostly Ground Glass Opacity (GGO). In this article by Murakawa et al., 241 patients with stage I (T1-2N0M0) lung adenocarcinoma (3–5 cm) who were surgically resected were included and histologically reviewed according to the new classification, of which 68 cases with AIS and MIA exhibited 100% recurrence-free survival. Importantly, even in T2 cases, a multivariate analysis revealed that the maximum tumour diameter (solid part measured in mediastinal window), was a better predictor of survival than the diameter measured in the lung window (including solid part and ground glass opacity). The authors show the predictive performance of TDR ( tumour shadow disappearance rate) for recurrence, of which the 2-diameter and area size of the solid part of the mediastinal tumour were the only predictive factors of prognosis, even in the GGO-predominant groups. They conclude from the multivariate analysis that the T factor measured by size of the solid component may be a more accurate prognostic parameter and ab etter assessment of the Ts ize of the staging system, which includes the total tumour size including both the solid (invasive) and ground glass (lepidic) components of the tumour. This confirms previous hypotheses [3–5]. Briefly, GGO-component exclusion from the T size revealed an improved prognostic performance for recurrence-risk assessment and pathological vessel invasion. All together, in addition to the confirmed prognostic power of the predominant pattern (5–6), the Murakawa study provides a validation of the proposed implications of the IASLC/ATS/ERS classification for TNM classification of adenocarcinomas with a lepidic pattern: (1) AIS may be regarded as Tis (adenocarcinoma) in addition to Tis (squamous); (2) consideration of MIA as Tmi; and (3) use of the size of the solid or invasive tumour component both by CT or pathological assessment, respectively, for determining the T factor of size rather than total tumour size including the ground glass or lepidic component.

Tumor islands in resected early-stage lung adenocarcinomas are associated with unique clinicopathologic and molecular characteristics and worse prognosis.

Tumor islands-large collections of tumor cells isolated within alveolar spaces-can be seen in lung adenocarcinomas. Recently we observed by 3-dimensional reconstruction that these structures were connected with each other and with the main tumor in different tissue planes, raising the possibility of tumor islands being a means of extension. However, the clinical and prognostic significance of tumor islands remains unknown. In this study, we compared clinicopathologic and molecular characteristics and prognosis of stages I to II lung adenocarcinomas with tumor islands (n=58) and those without (n=203). Lung adenocarcinomas with tumor islands were more likely to occur in smokers, exhibit higher nuclear grade and a solid or micropapillary pattern of growth, and harbor KRAS mutations. In contrast, lung adenocarcinomas without tumor islands were more likely to present as minimally invasive adenocarcinoma, show a lepidic pattern of growth, and harbor EGFR mutations. Although there was no difference in stage, the prognosis of lung adenocarcinomas with tumor islands was significantly worse than those without. The 5-year recurrence-free survival for patients with tumor islands and those without was 44.6% and 74.4%, respectively (log rank P=0.010). The survival difference remained significant (P <0.020) by multivariate analysis, and the presence of tumor islands was associated with almost 2-fold increase in the risk of recurrence. Even in the stage IA cohort, more than half of the patients with tumor islands experienced recurrence within 5 years. Thus, aggressive surveillance and/or further intervention may be indicated for patients whose tumors exhibit tumor islands.

Reproducibility of histopathological subtypes and invasion in pulmonary adenocarcinoma. An international interobserver study

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

Ethnic difference of driver mutation frequencies and correlations between driver mutations and histologic subtypes in lung adenocarcinoma.

1552 Background: The frequencies of known driver mutation in lung adenocarcinoma from patients in the United States have been reported by the NCI’s Lung Cancer Mutation Consortium (LCMC), indicating driver mutations were detected in 54% (280/516) of tumors. In this report, mutations found: EGFR 17%, KRAS 22%, HER2 0.6%, PIK3CA 1.2%, BRAF 2%, MET amplification 0.6%, MAP2K1 0.4%, NRAS 0.4%, AKT 0%, ALK rearrangements 7%. However little is known about ethnic difference of driver mutation frequencies and correlations between driver mutations and histological subtypes in lung adenocarcinoma. Methods: Known driver mutations in tumors from 97 Japanese patients with lung adenocarcinoma who underwent surgical resection between 1999 and 2003 in National Cancer Center Hospital East were analyzed by next-generation sequencing and confirmed by Sanger sequencing. Correlations between driver mutations and histological subtypes were also assessed. Results: Driver mutations were detected in 72% of tumors. Mutations found: EGFR 57%, KRAS9%, HER2 2%, PIK3CA 2%, BRAF 1%, MET amplification 1%, MAP2K1 0%, NRAS 0%, AKT 0%. Due to the limitation of rearrangement detection by exon-sequencing, ALK rearrangements were not analyzed. Compared with the report by LCMC, the frequency of EGFR mutations was high and that of KRAS mutations was low in the present study. All mutations were mutually exclusive. The number of predominant histological subtypes of tumors harbored EGFR mutations were papillary 28, acinar 3, solid 5, lepidic 19. That with KRAS mutations showed papillary 2, acinar 2, solid 2, lepidic 3, and HER2 mutations showed papillary 1 and acinar 1. Two tumors harbored PIK3CA mutations showed both histological acinar pattern. Each of BRAF mutation and MET amplification showed lepidic and papillary pattern, respectively. Conclusions: It was suggested that there should be ethnic difference of driver mutation frequencies in lung adenocarcinoma between Asian and non-Asian patients, although the details of ethnic distribution included in LCMC study has not been opened. In addition, each driver mutations did not correspond to specific histological subtypes of lung adenocarcinoma.

Abstract 1723: Can histologic patterns of pulmonary adenocarcinoma reflect histologic grade, one of the most important factors of cancer prognosis?

Abstract Background: Pulmonary adenocarcinoma shows highly heterogeneous histologic pattern. Histologic pattern is suggested to be an important prognostic factor, therefore predominant histologic pattern is emphasized in 2010 IASLC/ATS/ERS classification of pulmonary adenocarcinoma. However, there are a few papers on the prognosis of pulmonary adenocarcinoma according to histologic patterns, especially in various stages. The aim of this study is to evaluate prognosis according to histologic patterns in pulmonary adenocarcinoma with various stages. Methods: We examined 125 cases of surgically resected pulmonary adenocarcinomas with various stages from January 1998 to December 2007. Invasive adenocarcinomas were classified into histologic subtypes which are lepidic, papillary, acinar, solid and micropapillary patterns by 2010 IASLC/ATS/ERS classification. Invasive adenocarcinoma was divided into 2010 classification (I), predominant and second predominant pattern (II), predominant and the worst pattern (III), and modified predominant pattern (IV). Results: Proportions of predominant lepidic, papillary, acinar, solid and micropapillary patterns were 11 (9.3%), 8 (6.8%), 54 (45.8%), 38 (32.2%) and 7 (5.9%), respectively. All histologic classification systems were not correlated with clinical manifestations including age, tumor size, T stage, N stage or recurrence. However, all histologic classification systems were significantly correlated with overall survival rates (p=0.010, 0.044, 0.001, and 0.013) by Kaplan-Meier survival test. In Cox proportional hazard model, histologic pattern was independent factor of prognosis on classification according to I, III, IV (p=0.017, 0.006 and 0.023). Conclusion: Histologic pattern is an independent prognostic factor in pulmonary adenocarcinoma with various stages and histologic patterns of pulmonary adenocarcinoma reflect the degree of histologic differentiation, one of the most important prognostic factor. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1723. doi:1538-7445.AM2012-1723

Abstract A13: Lung Adenocarcinoma Subtypes Based on the Expression of Airway Basal Cell Genes

Abstract Purpose: Lung adenocarcinoma, the most common subtype of lung cancer, is a heterogeneous disease. Biologic heterogeneity of cancer is determined, at least in part, by specific cell populations of the original tissue that contribute to the development of the particular tumor subtypes. Airway epithelium, the primary site of molecular changes leading to the development of lung cancer, is composed of various cell types, including ciliated, intermediate, secretory (mucus-producing and Clara), neuroendocrine, and basal cells (BC). The specific contribution of individual cell types of the airway epithelium to lung cancer heterogeneity to lung adenoCa is unclear. Based on the knowledge that airway BC are the stem/progenitor cells of the human airway epithelium and that molecular features of local stem/progenitor cells contribute to a distinct molecular subtype of various tumors, we hypothesized that a subset of lung adenoCa is characterized by activation of unique molecular features of airway BC linked to a distinct phenotype of lung adenoCa. Methods: The normal human BC transcriptome was used to define an airway “BC signature” (Hackett et al., PLoS ONE 2011; 6:e18378). The primary data set included the transcriptomes of 182 lung adenoCa (Chitale et al, Oncogene 2009;28:2773). Two independent lung adenoCa transcriptome validation sets included 58 (Bild et al, Nature 2006;439:353) and 327 (Shedden et al, Nat Med 2008;14:822) subjects. Squamous cell carcinoma transcriptomes (n=53) were from Bild et al (Nature 2006). Survival analyses were performed using the Kaplan-Meier method (univariate) and Cox proportional hazard model (multivariate). Differential expression of selected genes between tumor subtypes was validated by immunohistochemistry. Results: Gene expression analysis identified a subset of lung adenoCa that expressed high levels of airway BC signature genes (“BC-high adenoCa”). Compared to “BC-low adenoCa” (lung adenoCa expressing low levels of the airway BC signature genes), this subset of lung adenoCa exhibited more aggressive features with poorer tumor grade (p&amp;lt;0.001), more advanced pathological tumor stage (p&amp;lt;0.05), larger tumor size (p&amp;lt;0.05), higher frequency of vascular invasion (p&amp;lt;0.004), lymph node metastasis (p&amp;lt;0.04) and a 43 month shorter median survival (log rank p&amp;lt;0.001). Multivariate analysis, in which age, gender, smoking status, pathological stage, adenoCa with lepidic pattern (formerly BAC), and adjuvant therapy were included, demonstrated that high expression of the airway BC signature was an independent prognostic factor associated with shorter survival in lung adenoCa (hazard ratio; 1.59, 95% confidence interval; 1.14–2.22, p&amp;lt;0.008). The strikingly shorter survival of BC-high vs BC-low adenoCa was verified in the 2 independent validation data sets. At the molecular level, BC-high adenoCa displayed higher frequency of KRAS mutations (p&amp;lt;0.04), lower frequency of EGFR mutations (p&amp;lt;0.03) and a distinct differentiation pattern characterized by a suppression of genes related to ciliated and Clara cells, accompanied by a broad activation of genes related to the epithelial-mesenchymal transition program (SNAIL, SLUG, TWIST1, CDH2). Compared to the lung SqCa characterized by overexpression of classical BC genes related to squamous differentiation (TP63, keratin KRT5, KRT6B), BC-high adenoCa exhibited up-regulation of novel BC genes including KRT7, members of the EGFR pathway (amphiregulin, ERBB receptor feedback inhibitor 1), and tissue factor pathway inhibitor 2. In total, 24% of the airway BC signature genes were expressed differentially between these 2 subtypes of lung cancer. Conclusion: Activation of a unique airway BC program contributes to a distinct, more aggressive, BC-high subtype of human lung adenoCa, a novel subtype of lung adenoCa, which may originate from airway BC.

The Role of KRAS Mutational Analysis to Determine the Site of Origin of Metastatic Carcinoma to the Lung: A Case Report

Metastatic carcinomas involving the lung are a common specimen encountered in surgical pathology. These metastases may have different morphologic, and architectural patterns and may mimic primary pulmonary adenocarcinoma, especially the intra-alveolar (lepidic) pattern of spread which may simulate a primary pulmonary bronchioloalveolar carcinoma (adenocarcinoma in situ). We present the case of a metastatic pancreatic adenocarcinoma that morphologically mimicked bronchioloalveolar carcinoma of the lung in that the tumor had an exclusive intra-alveolar pattern of spread and had an immunophenotype that was noninformative as to the site of origin (cytokeratin 7+, cytokeratin 20−, TTF-1−). In this case, we used KRAS gene mutation analysis to support that the lung carcinoma represented a metastatic pancreatic carcinoma as they both possessed identical codon 12 KRAS mutations. We show that this method may be a useful way to prove site of origin of metastatic carcinoma—particularly if standard morphologic or immunohistochemical analysis is not definitive.

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

The American Thoracic Society is a cosponsor of a newly published lung adenocarcinoma classification. An international multidisciplinary panel of experts was formed. A systematic review was performed and recommendations were graded by strength and quality of the evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. The classification addresses both resection specimens and small biopsies/cytology. The terms bronchioloalveolar carcinoma and mixed subtype adenocarcinoma are no longer used. For resection specimens, new concepts are introduced such as adenocarcinoma in situ and minimally invasive adenocarcinoma for small solitary adenocarcinomas with pure lepidic growth and predominant lepidic growth with ≤ 5 mm invasion, respectively. Invasive adenocarcinomas are classified by predominant pattern after using comprehensive histologic subtyping with lepidic, acinar, papillary, and solid patterns; micropapillary is added. In the new aspect of this classification that provides guidance for small biopsies and cytology specimens, non-small cell lung carcinomas (NSCLC), in patients with advanced stage disease, are to be classified into more specific types, such as adenocarcinoma or squamous cell carcinoma, whenever possible, for several reasons: (1) adenocarcinoma or NSCLC not otherwise specified should be tested for EGFR mutations, because the presence of these mutations is predictive of responsiveness to EGFR tyrosine kinase inhibitors, (2) adenocarcinoma histology is a strong predictor for improved outcome with pemetrexed therapy, and (3) squamous histology is a risk factor for life-threatening hemorrhage with bevacizumab therapy. NSCLC- not otherwise specified by light microscopy alone should be studied with immunohistochemistry and/or mucin stains. This classification is intended to support clinical practice as well as research investigation and clinical trials.

Lung Cancer and the Future of Pathology

Molecular diagnostics and molecular therapy have an escalating role in patient management and the implications for pathologists have not always been clear. 1–4 Of course, pathologists, with their command of laboratory methods, test standardization and validation, quality assurance, and laboratory regulations are the obvious choice to direct molecular diagnostic laboratories. Nevertheless, for the foreseeable future, there will be many more pathologists practicing conventional surgical pathology than supervising molecular diagnostic laboratories. And most residents and fellows in pathology continue to emphasize traditional diagnostic skills in their training. 4 At first glance, these observations might appear to suggest that most pathologists will be less valuable in the world of personalized health care. However, if pathologists are willing to adapt, the role of the surgical pathologist has not been diminished by personalized health care, but rather, it has been enhanced, and it is important that other medical specialties, government agencies, third-party payers, and pathologists themselves recognize this. No current field of personalized health care better illustrates the value of the surgical pathologist’s traditional training and expertise than molecular-targeted therapy of lung cancer. Histologic classification by the surgical pathologist using familiar tools is uniquely intertwined with the new molecular diagnosis and targeted therapy of lung cancer. The pathologist’s active discourse with oncologists and other specialists about a patient’s case is more essential than ever. For decades, care of patients with lung cancer was mired in limited treatment options, generally with dismal outcome. The contribution of the surgical pathologist to patient care was largely restricted to differentiating small cell carcinoma from non–small cell carcinoma on small biopsies and cytology specimens and to staging of non– small cell carcinoma resections. 5 In the early 1990s, there were predictions that molecular classification of lung cancers would one day be essential, but without successful molecular-targeted therapies to provide impetus, that idea had no substantive meaning in clinical practice. 6,7 Molecular-targeted therapies involve drugs that ‘‘target’’ specific cell receptors and signaling pathways in lung cancers. So far, most of the drugs for lung cancer that have been approved, are pending approval, or are under investigation target tyrosine kinase receptors or their ligands. 8–13 These include epidermal growth factor receptor (EGFR) 1; anaplastic lymphoma kinase receptor (ALK), primarily as the echinoderm microtubule-associated proteinlike 4-ALK fusion gene (EML4-ALK); vascular endothelial growth factor (VEGF) and the VEGF receptor (VEGFR); and epidermal growth factor receptor 2 (HER2/ ERBB2). Drugs are also under investigation for targets in signaling pathways downstream of the tyrosine kinase receptors, including BRAF, KRAS, MEK, PI3K, and mTOR. The presence of EGFR mutations are the best predictor of response to EGFR tyrosine kinase inhibitors. EGFR mutations occur in lung cancers with adenocarcinoma histology. Indeed, there is an association with specific subtypes of adenocarcinoma, such as lepidic (bronchioloalveolar), papillary, and micropapillary patterns. The EML4-ALK fusion gene is also reported to be associated with adenocarcinoma histology, in particular the signetring pattern and solid subtype. To date, most targeted therapies for lung cancer are effective in adenocarcinoma compared with other cell types, and the corresponding mutations are often more frequently associated with specific subtypes of adenocarcinoma. 14–19

Lung cancer and the future of pathology.

Molecular diagnostics and molecular therapy have an escalating role in patient management and the implications for pathologists have not always been clear. 1–4 Of course, pathologists, with their command of laboratory methods, test standardization and validation, quality assurance, and laboratory regulations are the obvious choice to direct molecular diagnostic laboratories. Nevertheless, for the foreseeable future, there will be many more pathologists practicing conventional surgical pathology than supervising molecular diagnostic laboratories. And most residents and fellows in pathology continue to emphasize traditional diagnostic skills in their training. 4 At first glance, these observations might appear to suggest that most pathologists will be less valuable in the world of personalized health care. However, if pathologists are willing to adapt, the role of the surgical pathologist has not been diminished by personalized health care, but rather, it has been enhanced, and it is important that other medical specialties, government agencies, third-party payers, and pathologists themselves recognize this. No current field of personalized health care better illustrates the value of the surgical pathologist’s traditional training and expertise than molecular-targeted therapy of lung cancer. Histologic classification by the surgical pathologist using familiar tools is uniquely intertwined with the new molecular diagnosis and targeted therapy of lung cancer. The pathologist’s active discourse with oncologists and other specialists about a patient’s case is more essential than ever. For decades, care of patients with lung cancer was mired in limited treatment options, generally with dismal outcome. The contribution of the surgical pathologist to patient care was largely restricted to differentiating small cell carcinoma from non–small cell carcinoma on small biopsies and cytology specimens and to staging of non– small cell carcinoma resections. 5 In the early 1990s, there were predictions that molecular classification of lung cancers would one day be essential, but without successful molecular-targeted therapies to provide impetus, that idea had no substantive meaning in clinical practice. 6,7 Molecular-targeted therapies involve drugs that ‘‘target’’ specific cell receptors and signaling pathways in lung cancers. So far, most of the drugs for lung cancer that have been approved, are pending approval, or are under investigation target tyrosine kinase receptors or their ligands. 8–13 These include epidermal growth factor receptor (EGFR) 1; anaplastic lymphoma kinase receptor (ALK), primarily as the echinoderm microtubule-associated proteinlike 4-ALK fusion gene (EML4-ALK); vascular endothelial growth factor (VEGF) and the VEGF receptor (VEGFR); and epidermal growth factor receptor 2 (HER2/ ERBB2). Drugs are also under investigation for targets in signaling pathways downstream of the tyrosine kinase receptors, including BRAF, KRAS, MEK, PI3K, and mTOR. The presence of EGFR mutations are the best predictor of response to EGFR tyrosine kinase inhibitors. EGFR mutations occur in lung cancers with adenocarcinoma histology. Indeed, there is an association with specific subtypes of adenocarcinoma, such as lepidic (bronchioloalveolar), papillary, and micropapillary patterns. The EML4-ALK fusion gene is also reported to be associated with adenocarcinoma histology, in particular the signetring pattern and solid subtype. To date, most targeted therapies for lung cancer are effective in adenocarcinoma compared with other cell types, and the corresponding mutations are often more frequently associated with specific subtypes of adenocarcinoma. 14–19

International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma.

Adenocarcinoma is the most common histologic type of lung cancer. To address advances in oncology, molecular biology, pathology, radiology, and surgery of lung adenocarcinoma, an international multidisciplinary classification was sponsored by the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society. This new adenocarcinoma classification is needed to provide uniform terminology and diagnostic criteria, especially for bronchioloalveolar carcinoma (BAC), the overall approach to small nonresection cancer specimens, and for multidisciplinary strategic management of tissue for molecular and immunohistochemical studies. An international core panel of experts representing all three societies was formed with oncologists/pulmonologists, pathologists, radiologists, molecular biologists, and thoracic surgeons. A systematic review was performed under the guidance of the American Thoracic Society Documents Development and Implementation Committee. The search strategy identified 11,368 citations of which 312 articles met specified eligibility criteria and were retrieved for full text review. A series of meetings were held to discuss the development of the new classification, to develop the recommendations, and to write the current document. Recommendations for key questions were graded by strength and quality of the evidence according to the Grades of Recommendation, Assessment, Development, and Evaluation approach. The classification addresses both resection specimens, and small biopsies and cytology. The terms BAC and mixed subtype adenocarcinoma are no longer used. For resection specimens, new concepts are introduced such as adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) for small solitary adenocarcinomas with either pure lepidic growth (AIS) or predominant lepidic growth with ≤ 5 mm invasion (MIA) to define patients who, if they undergo complete resection, will have 100% or near 100% disease-specific survival, respectively. AIS and MIA are usually nonmucinous but rarely may be mucinous. Invasive adenocarcinomas are classified by predominant pattern after using comprehensive histologic subtyping with lepidic (formerly most mixed subtype tumors with nonmucinous BAC), acinar, papillary, and solid patterns; micropapillary is added as a new histologic subtype. Variants include invasive mucinous adenocarcinoma (formerly mucinous BAC), colloid, fetal, and enteric adenocarcinoma. This classification provides guidance for small biopsies and cytology specimens, as approximately 70% of lung cancers are diagnosed in such samples. Non-small cell lung carcinomas (NSCLCs), in patients with advanced-stage disease, are to be classified into more specific types such as adenocarcinoma or squamous cell carcinoma, whenever possible for several reasons: (1) adenocarcinoma or NSCLC not otherwise specified should be tested for epidermal growth factor receptor (EGFR) mutations as the presence of these mutations is predictive of responsiveness to EGFR tyrosine kinase inhibitors, (2) adenocarcinoma histology is a strong predictor for improved outcome with pemetrexed therapy compared with squamous cell carcinoma, and (3) potential life-threatening hemorrhage may occur in patients with squamous cell carcinoma who receive bevacizumab. If the tumor cannot be classified based on light microscopy alone, special studies such as immunohistochemistry and/or mucin stains should be applied to classify the tumor further. Use of the term NSCLC not otherwise specified should be minimized. This new classification strategy is based on a multidisciplinary approach to diagnosis of lung adenocarcinoma that incorporates clinical, molecular, radiologic, and surgical issues, but it is primarily based on histology. This classification is intended to support clinical practice, and research investigation and clinical trials. As EGFR mutation is a validated predictive marker for response and progression-free survival with EGFR tyrosine kinase inhibitors in advanced lung adenocarcinoma, we recommend that patients with advanced adenocarcinomas be tested for EGFR mutation. This has implications for strategic management of tissue, particularly for small biopsies and cytology samples, to maximize high-quality tissue available for molecular studies. Potential impact for tumor, node, and metastasis staging include adjustment of the size T factor according to only the invasive component (1) pathologically in invasive tumors with lepidic areas or (2) radiologically by measuring the solid component of part-solid nodules.

Small peripheral lung adenocarcinoma: Clinicopathological features and surgical treatment

The clinical use of high-resolution computed tomography (CT) has greatly advanced diagnosis of small peripheral lesions of the lung. In CT images, these lesions often exhibit ground-glass opacity (GGO). Ground-glass opacity is typical of noninvasive bronchioloalveolar carcinoma (BAC), which is characterized by a lepidic pattern of cells that line the alveoli but do not invade neighboring structures. Bronchioloalveolar carcinoma is classified as a subset of lung adenocarcinoma, but has distinct clinical and pathological features and a favorable prognosis. Most small peripheral lung lesions, including BAC, probably originate in the epithelium of the peripheral airway. As with other subsets of non-small cell lung cancer, surgical resection is a potentially curative treatment. However, it is questionable whether a lobectomy is necessary for small lesions that exhibit GGO, particularly when they are <1 cm in diameter. Although several Japanese investigators have suggested that a limited resection, including a wedge resection and a segmentectomy without nodal dissection, is an appropriate treatment for small lung adenocarcinomas, this approach should be validated by clinical trials.

Bronchioloalveolar Lung Cancer: ACCP Evidence-Based Clinical Practice Guidelines (2nd Edition)

To review the current evidence on special issues relating to the diagnosis, imaging, prognosis, and treatment of bronchioloalveolar carcinoma (BAC). This guideline focuses on aspects of BAC that are unique and ways in which BAC differs importantly from other forms of non-small cell lung cancer (NSCLC). The author reviewed published literature reporting on BAC using key words "histology," "CT scans," "fluorodeoxyglucose positron emission tomography scan," "sensitivity," "specificity," "surgical resection," "sublobar resection," and "epidermal growth factor receptor tyrosine kinase inhibitor" and selected references from published review articles. Also included was a review of the 1999 World Health Organization (WHO) revised classification system for lung tumors, which established a more restrictive definition of BAC to tumors with a pure lepidic spreading pattern and no evidence of stromal, vascular, or pleural invasion. With the notable exception of a lower likelihood of a positive positron emission tomography finding in the presence of BAC, staging, diagnosis, and treatment are the same as for other histologic subtypes of NSCLC, but additional treatment options that may prove to be equivalent, if not more effective, for more patients exist (eg, epidermal growth factor receptor tyrosine kinase inhibitor therapy, sublobar resection). BAC is a form of adenocarcinoma with unique clinical, radiologic, and epidemiologic features. The diagnosis of BAC should be reserved for tumors that meet the WHO criteria. Additional clinical trials are needed on this population of patients, using strict definitions and enrollment criteria to allow the results to be applied to appropriate patient populations.

Reduced expression of CD44 v3 and v6 is related to invasion in lung adenocarcinoma

We have previously reported that the histological pattern of invasion is correlated with the prognosis of surgically treated patients of lung adenocarcinoma. On the other hand, several clinicopathologic studies have shown that CD44 variant isoforms are associated with invasion and metastasis in human malignant tumors. The expression of CD44 variant isoforms v3 and v6 was analyzed in 93 Japanese lung adenocarcinoma patients by immunostaining to study the relationship between their expression and the invasion in lung adenocarcinoma. The specimens were histologically categorized into three groups. Both the invasive lesion and the noninvasive lesion were observed in 49 out of 93 cases (group I). Twenty cases were noninvasive carcinoma growing mainly in a lepidic pattern (group II). Twenty-three cases were invasive carcinoma which showed no frankly noninvasive lesion growing in a lepidic pattern (group III). The significant reduced expression of CD44 v3 and v6 was observed in the invasive lesion compared with the noninvasive lesion in adenocarcinoma of group I ( P<0.05). Although reduced expression of CD44 v3 and v6 was observed in the invasive carcinoma of group III compared with the noninvasive carcinoma of group II, it was not significant ( P=0.0693 for v3, P=0.0827 for v6). The pattern of expression of CD44 v3 was significantly concordant with that of CD44 v6 ( P<0.0001). Our results suggest that reduced expression of CD44 v3 and v6 is associated with the invasion in the lung adenocarcinoma.

CD44v6 expression in primary bronchioloalveolar carcinoma and conventional pulmonary adenocarcinoma: Ohori NP, Coppola D, Landreneau RJ. Montefiore-Pathology, University of Pittsburgh, Medical Center, 200 Lothrop Street, Pittsburgh, PA 15213-2582. Mod Pathol 1996;9:507–512

CD44 is a family of transmembrane glycoproteins involved in cell-to-cell and cell-to-matrix interactions. Of the CD44 isoforms characterized, the v6 variant has been shown to confer metastatic potential in animal models and its expression has been correlated with aggressive behavior in some human malignancies. In an attempt to provide further insight into the heterogeneous appearance and behavior of bronchioloalveolar carcinomas (BACs), the pattern of CD44v6 staining in five mucinous, five nonmucinous, and eight sclerosing stage I BACs were compared with 12 comparably staged conventional pulmonary adenocarcinomas (CPAs). Formalin-fixed, paraffin-embedded sections were stained with monoclonal antibodies to CD44v6 (clone VFF-7). Neoplastic goblet cells, whether growing in a lepidic pattern in mucinous BACs or in an invasive pattern in CPAs, consistently demonstrated low level expression of CD44v6. In contrast, lepidic growth by neoplastic cells of type 2 pneumocyte or Clara cell differentiation demonstrated high levels in five of five cases of nonmucinous BACs, seven of eight cases of sclerosing BACs, and six of nine cases of CPAs. Similar cells of type 2 pneumocyte or Clara cell differentiation within the scarred area of sclerosing BAC demonstrated an intermediate degree of staining with four of eight cases marking with high levels, whereas none of the nine cases of CPAs with invasion by these cells showed high levels in the desmoplastic areas. From these results, two patterns of CD44v6 expression were recognized in BACs and CPAs. First, the expression appeared to be partly dependent on differentiation as cells demonstrating mucinous differentiation, whether in BACs or CPAs, consistently lacked CD44v6 staining. Second, in cells of type pneumocyte or Clara cell differentiation the expression was dependent on the growth pattern and their relationship to the stroma. High level expression was noted in neoplastic cells growing in a lepidic pattern, whereas those demonstrating invasion gradually lost the expression with increasing degrees of stromal reaction. Thus, the expression of CD44v6 in pulmonary BACs and similarly staged CPAs appears to be different from other human malignancies that have a positive correlation with aggressive behavior.