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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]

Whether non–small cell lung carcinoma (NSCLC) unveiled by immunohistochemistry (IHC) has the same clinical outcome as those typed by morphology is still matter of debate. A total of 145 stage III-IV, consecutive inoperable NSCLC patients treated by chemotherapy (133 cases) or EGFR tyrosine kinase inhibitor (12 cases) and including 100 biopsies, 11 surgical specimens, and 34 cytological samples had originally accounted for 120 adenocarcinomas (ADs), 19 squamous cell carcinomas (SQCs), and 6 adenosquamous carcinomas (ADSQCs) by integrating morphology and thyroid transcription factor-1 (TTF1)/p40 IHC. Thirty-two NSCLC–not otherwise specified (NSCLC-NOS) cases were identified by morphology revision of the original diagnoses, which showed solid growth pattern (P < .001), 22 ADs, 5 SQCs, and 5 ADSQCs by IHC profiling (P < .001), and 10 gene-altered tumors (3 EGFR, 5 KRAS, and 2 ALK). While no significant relationships were observed between response to therapy and original, morphology or IHC diagnoses, driver mutations and tumor differentiation by TTF1 expression, AD run better progression-free survival (PFS) or overall survival (OS) than other tumor types by morphology (P = .010 and P = .047) and IHC (P = .033 and P = .046), respectively. Furthermore, patients with NSCLC-NOS confirmed as AD by IHC tended to have poorer OS (P = .179) and PFS (P = .193) similar to that of ADSQC and SQC (P = .702 and P = .540, respectively). A category of less differentiated AD with poorer prognosis on therapy could be identified by IHC, while there were no differences for SQC or ADSQC. The terminology of “NSCLC-NOS, favor by IHC” is appropriate to alert clinicians toward more aggressive tumors. [ABSTRACT FROM AUTHOR]

Morphology still remains the cornerstone in lung cancer classification and cytology and small biopsy samples should be interpreted by morphology, whenever feasible, according to shared and widely agreed-upon diagnostic schemes. However, as novel therapy strategies are being offered on the basis of the diverse tumor characteristics, pathologists are now challenged by the need to offer clinicians more detailed typing of non–small cell lung cancer, not otherwise specified (NSCLC-NOS), especially when dealing with limited diagnostic material or poorly differentiated tumors. Close integration of morphology, immunohistochemistry, and clinical data is highly warranted according to a multidisciplinary approach to limit the category of NSCLC-NOS as much as possible or exclude unsuspected metastases, so rendering more definite and clinically useful diagnoses. Among the many proposed immunohistochemical markers, which as a whole are more practical and diagnostically useful than cumbersome and expensive molecular assays, a 2-hit model including thyroid transcription factor-1 (TTF-1) and p40 (the latter more specific for squamous differentiation than p63) seems to be the most effective to basically highlight adenocarcinoma (positivity for TTF-1 regardless of p63) and squamous (always strongly and diffusely positive for p40 or p63 and negative for TTF-1) differentiation. This minimalist 2-hit diagnostic approach paves the way to novel perspectives in clinical trials on lung cancer, and it is also in keeping with the need of strategically preserving diagnostic material for molecular assays that are essential for personalizing therapies. [ABSTRACT FROM PUBLISHER]

ΔNp63 (henceforth simply p40) is a squamous/basal-type biomarker corresponding to nontransactivating (non-TA) isoforms of p63 gene. Its prospective relevance as driver biomarker in lung cancer has not yet been thoroughly investigated. In all, 72 adenocarcinomas (ADs), 27 squamous cell carcinomas (SQCs), 13 pleomorphic carcinomas (PLCs), 10 small-cell lung carcinomas (SCLCs), 5 large-cell neuroendocrine carcinomas (LCNECs), 5 adenosquamous carcinomas (ADSQCs), 3 large-cell carcinomas with basaloid features (B-LCC), 2 carcinoids, 2 carcinosarcomas (CS), 2 salivary-gland type tumors (SGTTs) of the lung, and 5 pleural malignant epithelioid mesotheliomas (MEMs) were prospectively diagnosed by morphology and verified by immunohistochemistry for p40, p63, and thyroid transcription factor 1 (TTF1). Histological scores (HS) were devised by multiplying the percentage of immunoreactive cells (0 to 100%) by immunostaining intensity (low = 1 vs strong = 2, according to internal controls). There was a nonrandom distribution of p40 across the diverse tumor groups and cell differentiation lineages, with p40-HS > 100 closely paralleling squamous or myoepithelial carcinomas (SQC, B-LCC, SQC-containing PLC, ADSQC with predominant SQC, SGTT), and p40-HS ≤ 10 pinpointing AD, AD-containing PLC, or CS and neuroendocrine (NE) tumors. At variance, p63-HS was significantly higher than p40 in AD (P < .0001) and NE tumors (P = .0156), with positive predictive value being 83% and 95% and overall accuracy being 95% and 99%, respectively. Also, TTF1 was shared by gland-differentiated and NE tumors. MEM cases were always negative for all biomarkers. The HS-guided assessment of p40 allowed an effective orientation among thoracic malignancies at the level of individual tumor patients thereby contributing to prospectively realize a driver, holistic approach to cancer characterization. [ABSTRACT FROM AUTHOR]

Morphology still remains the cornerstone in lung cancer classification and always has been accompanying pathologists in their daily activity, even though several ancillary techniques have been incorporated over time to improve diagnostic, prognostic, and predictive capabilities in lung cancer. Currently, we are also faced with a global rethinking of lung cancer care, especially once novel therapy strategies have been made available on the basis of the diverse characteristics of tumors. Although morphology still remains a not easily replaceable tool for lung cancer classification, we are now challenged by the need of offering clinicians more detailed subtyping of non-small-cell lung cancer especially in event of limited diagnostic material, poorly differentiated tumors, or unresectable lesions. Close integration of improved morphology, immunohistochemistry, and molecular tests will be able to not only sharpen our diagnostic algorithms and prognostic and predictive potentialities but also get insights into several lung cancer biology issues, such as histogenesis and new classification schemes. [ABSTRACT FROM AUTHOR]

The classification of lung cancer has always been primarily based on the morphologic assessment of routinely stained histological sections, but this approach may be difficult or even unfeasible in cytological preparations or small biopsies. Moreover, the simplistic dichotomization between small-cell carcinoma and non-small cell carcinoma (NSCLC) should be overcome, as new drugs have been discovered that are effective in specific subtypes of lung cancer. A more accurate characterization of NSCLC, however, may be hard in carcinomas lacking clear-cut signs of differentiation. The incorporation into the diagnostic algorithm of poorly differentiated carcinomas of an immunohistochemical panel including markers of squamous (high-molecular-weight cytokeratins, p63) and glandular (TTF-1, cytokeratin 7) cell differentiation seems the most promising approach. The evaluation of lung cancer for gene mutations, gene amplification, tumor-related angiogenesis, expression levels of DNA repair genes and genomic or proteomic profiles represents an exciting challenge for the pathologist in the near future. [ABSTRACT FROM AUTHOR]

Immunoreactivity for fascin, an actin-bundling protein related to cell motility, has been reported in breast, ovary, pancreas, skin, and non-small cell carcinomas, and associated with more advanced disease stage and poorer prognosis. Data on pulmonary neuroendocrine (NE) tumors, however, are lacking. We evaluated the expression of fascin by immunohistochemistry—using two different monoclonal antibodies—in surgical specimens of pulmonary NE tumors of all the diverse histological types from 128 consecutive patients recruited between 1987 and 2001, and investigated its relationship with the presence of lymph node metastases. Overall, fascin immunoreactivity was detected in 5% of 38 typical carcinoids (TC), 35% of 23 atypical carcinoids (AC), 83% of 40 large-cell neuroendocrine carcinomas (LCNEC), and 100% of 27 small-cell lung carcinomas (SCLC) (P<0.001), Normal NE cells or hyperplastic NE tumorlets were consistently unreactive. No statistically significant differences in fascin immunoreactivity were found between the two antibodies. In TC and AC but not high-grade NE tumors, fascin immunoreactivity closely correlated with the occurrence of lymph node metastases, the pN class and the number of involved lymph nodes (P<0.001). It was also significantly associated with an increased proliferative activity (Ki-67 labeling index >5%) (P=0.020), and with either down-regulation or altered subcellular compartmentalization of E-cadherin (P<0.001) and CD99 (P=0.030), two cell adhesion complexes in pulmonary NE tumors. At multivariate analysis, only fascin emerged as an independent predictor of lymph node metastases in this tumor group (HR 30.28; 95% confidence intervals: 1.59–574.49; P=0.023). This study indicates that fascin immunoreactivity may identify subsets of pulmonary carcinoid patients with different metastatic potential to regional lymph nodes. Targeting the fascin pathway could be a novel therapeutic strategy of pulmonary carcinoids. [Copyright &y& Elsevier]

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]

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]

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]

Aims Primary Ewing sarcoma of the ileum has rarely been documented. Little is known about its pathogenesis and clinical implications, and it would be helpful to identify novel molecular markers. EWSR1-FEV translocation is exceedingly rare in Ewing sarcoma, as FEV expression is restricted to prostate, brain and serotonin neuroendocrine cells ( NE) and related tumours. Methods and Results Paraffin sections or snap-frozen material were used in this investigation. Tumours were investigated by means of immunohistochemistry, RT-PCR ( EWSR1- FLI1, EWSR1- ERG and EWSR1- FEV transcripts), FISH analysis ( EWSR1 break-apart and specific EWSR1- FEV translocation) and spectral karyotyping ( SKY). Ten ileal neuroendocrine tumours ( INET) made up the control group for EWSR1- FEV translocation. Among 445 Ewing sarcomas cases spanning a period of 20 years, seven (1.6%) arose in the ileum. All tumours were immunoreactive for synaptophysin, CD99, FLI1 and vimentin. FISH identified EWSR1 rearrangement in all cases, with EWSR1-FLI1 transcripts being detected in all but one tumour showing the uncommon EWSR1- FEV rearrangement, with SKY, RT- PCR and FISH confirmation. The mean survival of EWSR1- FLI1 patients was 14 months, whereas the EWSR1- FEV patient was alive after 15 years despite several recurrences controlled by surgery alone. No INET showed EWSR1 translocation. Conclusions Most primary Ewing sarcomas of the ileum show the common EWSR1- FLI1 translocation, but EWSR1- FEV could be specific for tumours arising in the ileum and showing better prognosis. [ABSTRACT FROM AUTHOR]

Somatostatin receptors (SSTRs) may be used in lung carcinoids (LCs) for diagnosis and therapy, although additional targets are clearly warranted. This study aimed to investigate whether olfactory receptor 51E1 (OR51E1) may be a potential target for LCs. OR51E1 coding sequence was analyzed in LC cell lines, NCI-H727 and NCI-H720. OR51E1 transcript expression was investigated in LC cell lines and frozen specimens by quantitative real-time PCR. OR51E1, SSTR2, SSTR3, and SSTR5 expression was evaluated by immunohistochemistry on paraffin-embedded sections of 73 typical carcinoids (TCs), 14 atypical carcinoids (ACs), and 11 regional/distant metastases and compared with OctreoScan data. Immunohistochemistry results were rendered semiquantitatively on a scale from 0 to 3, taking into account the cellular compartmentalization (membrane vs cytoplasm) and the percentage of tumor cells (!50 vsO50%). Our results showed that WT OR51E1 transcript was expressed in both LC cell lines. OR51E1 mRNA was expressed in 9 out of 12 TCs and 7 out of 9 ACs (PZNS). Immunohistochemically, OR51E1, SSTR2, SSTR3, and SSTR5 were detected in 85, 71, 25, and 39% of TCs and in 86, 79, 43, and 36% of ACs respectively. OR51E1 immunohistochemical scores were higher or equal than those of SSTRs' in79%of TCsand86%of ACs. Furthermore, in the LC caseswhere all SSTR subtypes were lacking,membraneOR51E1 expressionwas detected in 10 out of 17 TCs and 1 out of 2 ACs. Moreover, higher OR51E1 immunohistochemical scores were detected in 5 out of 6 OctreoScan-negative LC lesions. Therefore, the high expression of OR51E1 in LCs makes it a potential novel diagnostic target in SSTR-negative tumors. [ABSTRACT FROM AUTHOR]

Abstract: Immunohistochemical loss of the succinate dehydrogenase subunit B (SDHB) has recently been reported as a surrogate biomarker of malignancy in sporadic and familial pheocromocytomas and paragangliomas through the activation of hypoxia pathways. However, data on the prevalence and the clinical implications of SDHB immunoreactivity in ileal neuroendocrine tumors are still lacking. Thirty-one consecutive, advanced primary midgut neuroendocrine tumors and related lymph node or liver metastases from 24 males and seven females were immunohistochemically assessed for SDHB. All patients were G1 tumors (Ki-67 labeling index ⩽2%). SDHB immunohistochemistry results were expressed as immunostaining intensity and scored as low or strong according to the internal control represented by normal intestinal cells. Strong positivity for SDHB, with granular cytoplasmatic reactivity, was found in 77% of primary tumors (T), whilst low SDHB expression was detected in 90% of metastases (M). The combined analysis (T+M) confirmed the loss of SDHB expression in 82% of metastases compared to 18% of primary tumors. SDHB expression was inversely correlated with Ki-67 labeling index, which accounted for 1.54% in metastastic sites and 0.7% in primary tumors. A correlation between SDHB expression loss, increased Ki-67 labeling index and biological aggressiveness was shown in advanced midgut neuroendocrine tumors, suggesting a role of tumor suppressor gene. [ABSTRACT FROM AUTHOR]

BACKGROUND: [ABSTRACT FROM AUTHOR]