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Introduction: The WHO classification of pulmonary neuroendocrine tumors (PNETs) is also used to classify thymic NETs (TNETs) into typical and atypical carcinoid (TC and AC), large cell neuroendocrine carcinoma (LCNEC), and small cell carcinoma (SCC), but little is known about the usability of alternative classification systems., Methods: One hundred seven TNET (22 TC, 51 AC, 28 LCNEC, and 6 SCC) from 103 patients were classified according to the WHO, the European Neuroendocrine Tumor Society, and a grading-related PNET classification. Low coverage whole-genome sequencing and immunohistochemical studies were performed in 63 cases. A copy number instability (CNI) score was applied to compare tumors. Eleven LCNEC were further analyzed using targeted next-generation sequencing. Morphologic classifications were tested against molecular features., Results: Whole-genome sequencing data fell into three clusters: CNI low , CNI int , and CNI high . CNI low and CNI int comprised not only TC and AC, but also six LCNECs. CNI high contained all SCC and nine LCNEC, but also three AC. No morphologic classification was able to predict the CNI cluster. Cases where primary tumors and metastases were available showed progression from low-grade to higher-grade histologies. Analysis of LCNEC revealed a subgroup of intermediate NET G3 tumors that differed from LCNEC by carcinoid morphology, expression of chromogranin, and negativity for enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2)., Conclusions: TNETs fall into three molecular subgroups that are not reflected by the current WHO classification. Given the large overlap between TC and AC on the one hand, and AC and LCNEC on the other, we propose a morphomolecular grading system, Thy-NET G1-G3, instead of histologic classification for patient stratification and prognostication., (Copyright © 2019 International Association for the Study of Lung Cancer. All rights reserved.)

Since the 2015 WHO classification was introduced into clinical practice, immunohistochemistry (IHC) has figured prominently in lung cancer diagnosis. In addition to distinction of small cell versus non-small cell carcinoma, patients' treatment of choice is directly linked to histologic subtypes of non-small cell carcinoma, which pertains to IHC results, particularly for poorly differentiated tumors. The use of IHC has improved diagnostic accuracy in the classification of lung carcinoma, but the interpretation of IHC results remains challenging in some instances. Also, pathologists must be aware of many interpretation pitfalls, and the use of IHC should be efficient to spare the tissue for molecular testing. The International Association for the Study of Lung Cancer Pathology Committee received questions on practical application and interpretation of IHC in lung cancer diagnosis. After discussions in several International Association for the Study of Lung Cancer Pathology Committee meetings, the issues and caveats were summarized in terms of 11 key questions covering common and important diagnostic situations in a daily clinical practice with some relevant challenging queries. The questions cover topics such as the best IHC markers for distinguishing NSCLC subtypes, differences in thyroid transcription factor 1 clones, and the utility of IHC in diagnosing uncommon subtypes of lung cancer and distinguishing primary from metastatic tumors. This article provides answers and explanations for the key questions about the use of IHC in diagnosis of lung carcinoma, representing viewpoints of experts in thoracic pathology that should assist the community in the appropriate use of IHC in diagnostic pathology., (Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Objectives: The Blueprint (BP) Programmed Death Ligand 1 (PD-L1) Immunohistochemistry Comparability Project is a pivotal academic/professional society and industrial collaboration to assess the feasibility of harmonizing the clinical use of five independently developed commercial PD-L1 immunohistochemistry assays. The goal of BP phase 2 (BP2) was to validate the results obtained in BP phase 1 by using real-world clinical lung cancer samples., Methods: BP2 were conducted using 81 lung cancer specimens of various histological and sample types, stained with all five trial-validated PD-L1 assays (22C3, 28-8, SP142, SP263, and 73-10); the slides were evaluated by an international panel of pathologists. BP2 also assessed the reliability of PD-L1 scoring by using digital images, and samples prepared for cytological examination. PD-L1 expression was assessed for percentage (tumor proportional score) of tumor cell (TC) and immune cell areas showing PD-L1 staining, with TCs scored continuously or categorically with the cutoffs used in checkpoint inhibitor trials., Results: The BP2 results showed highly comparable staining by the 22C3, 28-8 and SP263 assays; less sensitivity with the SP142 assay; and higher sensitivity with the 73-10 assay to detect PD-L1 expression on TCs. Glass slide and digital image scorings were highly concordant (Pearson correlation >0.96). There was very strong reliability among pathologists in TC PD-L1 scoring with all assays (overall intraclass correlation coefficient [ICC] = 0.86-0.93), poor reliability in IC PD-L1 scoring (overall ICC = 0.18-0.19), and good agreement in assessing PD-L1 status on cytological cell block materials (ICC = 0.78-0.85)., Conclusion: BP2 consolidates the analytical evidence for interchangeability of the 22C3, 28-8, and SP263 assays and lower sensitivity of the SP142 assay for determining tumor proportion score on TCs and demonstrates greater sensitivity of the 73-10 assay compared with that of the other assays., (Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: To highlight the role of immunohistochemistry to lung cancer classification on the basis of existing guidelines and future perspectives., Areas Covered: Four orienting key-issues were structured according to an extensive review on the English literature: a) cancer subtyping; b) best biomarkers and rules to follow; c) negative and positive profiling; d) suggestions towards an evidence-based proposal for lung cancer subtyping. A sparing material approach based on a limited number of specific markers is highly desirable. It includes p40 for squamous cell carcinoma ('no p40, no squamous'), TTF1 for adenocarcinoma, synaptophysin for neuroendocrine tumors and vimentin for sarcomatoid carcinoma. A close relationship between genotype and phenotype also supports a diagnostic role for negative profiles. Expert commentary: Highly specific and sensitive IHC markers according to positive and negative diagnostic algorithms seem appropriate for individual patients' lung cancer subtyping.

Introduction: Neuroendocrine neoplasms of the lung (Lung NENs) encompass NE tumors (NETs), which are in turn split into typical and atypical carcinoids, and NE carcinomas (NECs), which group together small-cell carcinoma and large-cell NE carcinoma. This classification is the current basis for orienting the daily practice of these patients, with diagnostic, prognostic, and predictive inferences.Areas Covered: The clinical implications of lung NEN classification are addressed according to three converging perspectives, which were dissected through an extensive literature overview: (1) how to put intratumor heterogeneity into the context of the current classification; (2) how to contextualize immunohistochemistry markers to improve diagnosis, prognosis, and therapy prediction; and (3) how to use immuno-oncology strategies for life-threatening NECs, which still account for 90% or more of lung NENs.Expert Opinion: We provide practical insights to account for intratumor heterogeneity, practice the choice of immunohistochemistry markers, and emphasize once again the added value of immuno-oncology in the setting of personalized medicine of lung NENs. [ABSTRACT FROM AUTHOR]

Aims The association between lung cancer and idiopathic pulmonary fibrosis ( IPF) is well known, but the significance of this association is poorly understood. Bronchiolar honeycomb cysts have been proposed as possible precursors for the development of carcinoma, but limited evidence in support of this hypothesis is available. The aim of this study was to investigate this hypothesis analysing a series of carcinomas arising in IPF by immunohistochemistry. Methods and results Thirty-three lung carcinomas arising in patients with IPF were analysed with a panel of immunohistochemical markers. The antibodies included those against pneumocyte markers [thyroid transcription factor 1 ( TTF1), napsin-A, and surfactant protein A], the goblet cell marker mucin 5 AC, markers of basal/squamous cell differentiation [cytokeratin ( CK) 5/6 and ΔN-p63], and markers related to enteric differentiation ( CDX2, mucin 2, CK20, and villin). A series of 100 consecutive lung adenocarcinomas arising in smokers without IPF were investigated as controls. All carcinomas arising in IPF patients were peripherally located on imaging analysis. The diagnoses were: eight squamous cell carcinomas, 20 adenocarcinomas, three small-cell carcinomas (including one composite small-cell carcinoma and adenocarcinoma), and two large-cell carcinomas. Among adenocarcinomas, a 'pneumocyte' profile ( TTF1/napsin-A/ SPA1-triple-positive) was observed in seven of 20 (35% versus 84% in non- IPF controls, P = 0.0001). The remaining 13 adenocarcinomas (65%) showed rare histotypes: four invasive mucinous adenocarcinomas (20% in IPF patients versus 1% in non- IPF controls, P = 0.002), seven tumours (35%) that were characterized by variable expression of markers of enteric differentiation, and two tumours (10%) that showed a peculiar basaloid component. Conclusions The immunohistochemical characterization of carcinomas arising in IPF patients shows striking divergence from that in non- IPF smokers. The prevalence of rare entities showing bronchiole-related markers is in line with the hypothesis that these tumours arise from transformed small airways in honeycomb lung areas where abnormal bronchiolar proliferation takes place. [ABSTRACT FROM AUTHOR]

Little is known about molecular testing on tumor tissue retrieved from stained sections, for which there may be a clinical need. We retrospectively analyzed 112 sections from 56 tumor patients using either fluorescence in situ hybridization (FISH) with different probes (19 sections from 17 patients) or Sanger or targeted next generation sequencing for detection of BRAF, EGFR, KRAS, C-KIT, and TP53 mutations (93 sections from 39 patients). Tumor tissue sections had been stained by hematoxylin and eosin (H&E) (42 sections) or by immunohistochemistry for cytoplasmic or nuclear/nuclear-cytoplasmic markers (70 sections) with a peroxidase (P-IHC, with 3,3'-diaminobenzidine as chromogen) or alkaline phosphatase label (AP-IHC, with Warp Red™ as chromogen). For FISH analysis, the concordance rate between the original diagnosis and that obtained on H&E- or P-IHC-stained tissue sections (AP-IHC was not on record for this set of patients) was 95% (18 out of 19 tumor sections). Only one tumor sample, diffusely positive for MLH1, did not yield any nuclear hybridization signal. For sequencing analysis, the concordance rate was 100% on negative P-IHC and positive AP-IHC-stained sections, regardless of the subcellular localization of the reaction product. Mutations were detected in only 52% of cases expressing nuclear/nuclear-cytoplasmic markers, regardless of the sequencing technology used (p = 0.0002). In conclusion, stained sections may be a valuable resource for FISH or sequencing analysis, but on cases expressing nuclear markers sequencing results need to be interpreted cautiously. [ABSTRACT FROM AUTHOR]

Large cell carcinoma (LCC) is a merely descriptive term indicating a subtype of lung cancer with no specific features of small-cell lung cancer (SCLC), adenocarcinoma (ADC) or squamous cell carcinoma (SQC). This diagnosis is allowed on surgical specimens only, whereas its counterpart in biopsy/cytology samples is non-small-cell lung carcinoma (NSCLC), not otherwise specified (NOS). Although these two terms do not fulfill the same concept, they can be interchangeable synonyms at the clinical level, reflecting, in different ways, the inability to define a specific subtype. Immunohistochemistry (IHC), next generation sequencing (NGS) analysis and, historically, electron microscopy have been unveiling diverse cell differentiation lineages in LCC, resulting in LCC-favor ADC, LCC-favor SQC and LCC-favor large-cell neuroendocrine carcinoma (LCNEC), the latter hopefully to be included into the neuroendocrine tumor (NET) group in the future. Paradoxically, however, the interpretation issues of LCC/NSCLC-NOS are not diminishing, but even increasing albeight an accurate diagnosis is oncologically required and crucial. Also, rare LCC/NSCLC-NOS cases exhibiting null/unclear phenotype, are difficult to classify, and this terminology could be maintained for the sake of classification (basically these tumors are serendipitous ADC, as also confirmed by the lack of p40). In this review article, seven relevant issues to LCC have been addressed by using a question–answer methodology, with final key points discussing major interpretation issues. In conclusion, most LCC/NSCLC-NOS may be eventually re-classified and addressed by exploiting IHC and/or molecular testing to satisfy the criteria of precision medicine (the right drug, to the right patient, at the right time). [ABSTRACT FROM AUTHOR]

Neuroendocrine tumors (NETs) and gastrointestinal stromal tumors (GISTs) are different tumor categories with no pathogenetic, morphologic, clinical, or therapeutic similarities: NETs are epithelial to neural tumors in contrast to GISTs, which show mesenchymal cell lineage. Both tumors, however, arise more frequently from the gastrointestinal tract and may benefit of specific target therapeutic approaches: imatinib/STI-571 for GISTs and m-Tor pathway inhibitors or somatostatin analogs for NETs. The role of pathologist is crucial when dealing with both NETs and GISTs, as morphological, immunohistochemical, and molecular analysis often provide helpful information on the clinical behavior and management. We here propose a general overview on nomenclature of tumors classification and suggestions for histological report of both NETs and GISTs. Moreover, we will approach in finer details the immunohistochemical analysis on origin and differential diagnosis in NETs as well as the prognosis and resistance to therapy in GISTs. This review emphasized recent literature advances regarding similarities and differences in the managerial pathologist's approach to either tumor type. [ABSTRACT FROM AUTHOR]

Pulmonary mucin-producing adenocarcinomas may be indistinguishable on conventional histology from a metastasis, as thyroid transcription factor-1 (TTF-1) expression often is lacking and KRAS mutations are widely present even in extrapulmonary sites. Few data have been reported on the diagnostic role of napsin-A and epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) gene alterations in this challenging differential diagnosis. Seventy-seven surgically resected cases, including 53 primary and 24 metastatic tumors from different sites, were evaluated for napsin-A, TTF-1, and ALK by immunohistochemistry and for EGFR mutations by direct sequencing. Overall, napsin-A expression in primary lung mucin-producing adenocarcinomas was 36% (8% mucinous, 17% colloid, 87.5% solid, and 100% signet ring cell) and TTF-1 expression reached an overall figure of 42% (12.5% mucinous, 33% colloid, 87.5% solid, and 100% signet ring cell). Metastatic mucinous adenocarcinomas did not react with napsin-A or with TTF-1. All primary and metastatic tumors lacked EGFR mutations, while a single case of signet ring cell lung adenocarcinoma showed ALK expression and rearrangement at fluorescent in situ hybridization analysis. Napsin-A has a lower sensitivity compared with TTF-1 in primary mucin-producing adenocarcinomas of the lung. However, both antibodies have an absolute specificity, being always negative in metastatic mucinous adenocarcinomas. EGFR mutations and ALK translocation or expression are exceedingly rare in mucin-producing adenocarcinomas of the lung, resulting unnecessary as diagnostic tool in this setting. [ABSTRACT FROM AUTHOR]