Search

• Spread through air spaces is suggested to be invasion way of lung parenchyma. • Spread through air spaces has been described around lung neuroendocrine neoplasms. • Spread through air spaces may be made up by hyperplastic neuroendocrine cells. • Spread through air spaces is likely to be an ex vivo artifact due to tissue manipulation. Spread through air spaces (STAS) is a recently proposed invasion way of lung cancer, including neuroendocrine (NE) neoplasms. However, if this phenomenon is a real one or an artifact while manipulating lung specimens, it is still matter of debate. Three consecutive patients with newly diagnosed diffuse idiopathic pulmonary NE cell hyperplasia (DIPNECH) were reviewed for STAS. In well-fixed lung specimens, DIPNECH was seen to coexist with atypical carcinoid, bifocal typical carcinoid and adenocarcinoma in the three patients, respectively. While STAS was not observed at the growing edges of tumors, a few freely-floating aggregates of hyperplastic NE cells within air spaces were noticed to emanate from foci of NE hyperplasia and tumorlets and in intimate association with normal bronchiolar cells and erythrocytes to denote artifactual derivation upon tissue manipulation. Traveling of hyperplastic NE cells through air spaces is likely to artifactually occur via knife, surgeon or other way, thus challenging invasion by STAS. [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]

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]

Abstract: Background: Genetic alterations for targeting therapy are largely unexplored issues in pulmonary sarcomatoid carcinoma (PSC), a life-threatening tumor subset. Methods: EGFR, HER2, KRAS, p53, CTNNB1, BRAF and PIK3CA mutations were assessed by direct sequencing, ALK, EGFR and HER2 gene status by fluorescence in situ hybridization (FISH), and ALK protein expression by immunohistochemistry (IHC) in 20 pleomorphic carcinomas (PLC), two pulmonary blastomas (PB) and one carcinosarcoma (CS). Surgical specimens and, in case of positivity, the corresponding preoperative biopsies were analyzed. Furthermore, 51 consecutive metastatic lung adenocarcinomas (MELAD) were used as controls for FISH and IHC assays of ALK gene. Results: While no rearrangements of ALK were detected in PSC, relevant amplification was identified 5/23 (22%) surgical specimens and paired biopsies (four PLC and one PB, two females and three males, four current and one never smoker, aged 30–83 years). Considering tumor heterogeneity, the percentage of ALK amplified tumor cells ranged from 11% to 43%, with a mean gene copy gain (GCG±SD) of 6.9±0.8 and no signal differences between the epithelial (6.5±0.9) and the sarcoma-like components (6.8±0.9) of tumors. In the remaining 18 non-amplified PSC, the relevant value was 2.9±0.5 in 1–80% tumor cells (p <0.001). ALK amplification was closely associated with chromosome 7 (EGFR) or 17 (HER2) polysomy (p <0.001). Out of 51 MELAD, 10 were ALK-rearranged (p =0.026) and only one amplified (p =0.009). No amplified tumors, either PSC or MELAD, expressed the relevant protein by IHC, while the 10 ALK-rearranged MELAD were strongly positive. TP53, KRAS and CTNNB1 mutations accounted for 30%, 22%, and 4% of cases, respectively, with no significant relationship with ALK amplification. No mutations for EGFR, HER2, BRAF or PIK3CA gene were observed. Conclusion: ALK gene amplification is a nonrandom and clonally related event in a subset of PSC, but its biologic rationale deserves further investigation. KRAS mutation could represent a novel tool for therapy of such so deadly tumors with MEK inhibitors. [Copyright &y& Elsevier]

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]

Summary: Detailed studies on the pathologic and molecular features of low-dose computed tomography (LDCT)-detected carcinomas and comparison with unscreened tumors are still lacking. We evaluated the histopathologic features of 89 LDCT-detected lung cancers resected between 2004 and 2006. These tumors occurred within a cohort of 5202 volunteers undergoing annual LDCT, aged ≥50 years, and with a minimum 20 pack-year index. In adenocarcinomas, central scar diameter, invasion foci size and K-ras mutations were also assessed. The results were compared with those of 89 consecutive lung carcinomas matched for confounding factors (sex, smoking habit), selected from group of 363 consecutive clinically worked-up lung cancer, surgically resected in the same period and at the same Institution. The tumors were diagnosed in 63 males and 26 females (range 50–79 years), 55 of which diagnosed at the baseline (1.05%) and 34 (including 10 repeat cancers) operated after work-up during the second year (0.72%). LDCT-detected tumors showed high resectability rate (89%), earlier stage (63%) and prevalence of adenocarcinoma nodules (72%), most often of the mixed subtype, in comparison with unscreened tumors. A similar prevalence of K-ras mutations was found in both screened and unscreened adenocarcinomas. Repeat cancers were found in 10 screened patients, and were predominantly stage I adenocarcinomas of mixed subtype exhibiting smaller dimension but greater central scar diameter and stromal invasion size in comparison with the other second-year, slower-growing adenocarcinomas. Multiple tumor nodules were identified in 10 patients exclusively at the baseline, were mostly mixed adenocarcinomas and differed in their K-ras mutation profile. Screening-detected lung cancers shared most of the histologic features of fully malignant tumors, in addition to a similar prevalence of K-ras mutations, despite their earlier detection and less advanced clinical stage. Repeat cancers are potentially aggressive tumors. K-ras mutation analysis supports the impression that multifocal tumors at baseline are separate synchronous primaries. [Copyright &y& Elsevier]

Summary: High levels of serum carcinoembryonic antigen (S-CEA) are considered a negative prognostic factor in non-small-cell lung cancer (NSCLC), while the prognostic value of tumour CEA (T-CEA) is unknown. We investigated the prognostic role of T-CEA in radically resected early stage NSCLC. We measured preoperative S-CEA levels and T-CEA in 146 patients with stage 1–2 NSCLC, and analysed their influence on survival. In patients positive for T-CEA, 3-year survival was 80%, compared to 65% in T-CEA-negative patients (p =0.03). After stratification by histology, T-CEA positivity was prognostic of better survival in squamous cell carcinoma (SCC) (p =0.024) but not in adenocarcinomas (ADK) (p =0.87). Multiple Cox regression analysis showed that T-CEA positivity was an independent predictor of better survival in patients with early stage NSCLC (p =0.02). In SCC patients, the magnitude of the hazard ratio was confirmed even if the precision of the estimate is decreased (p =0.06). In conclusion, T-CEA expression appears to be an important prognostic factor in early stage SSC of the lung. [Copyright &y& Elsevier]

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]

Large cell carcinomas (LCCs) of the lung are heterogeneous and may be of different cell lineages. We analyzed 56 surgically resected lung tumors classified as LCC on the basis of pure morphologic grounds, using a panel of immunophenotypic markers (adenocarcinoma [ADC]-specific, thyroid transcription factor-1, cytokeratin 7, and napsin A; squamous cell carcinoma [SQCC]-specific, p63, cytokeratin 5, desmocollin 3, and Δnp63) and the quantitative analysis of microRNA-205 (microRNA sample score [mRSS]). Based on immunoprofiles 19 (34%) of the cases were reclassified as ADC and 14 (25%) as SQCC; 23 (41%) of the cases were unclassifiable. Of these 23 cases, 18 were classified as ADC and 5 as SQCC according to the mRSS. Our data show that an extended panel of immunohistochemical markers can reclassify around 60% of LCCs as ADC or SQCC. However, a relevant percentage of LCCs may escape convincing immunohistochemical classification, and mRSS could be used for further typing, but its clinical relevance needs further confirmation. [ABSTRACT FROM AUTHOR]

BACKGROUND: [ABSTRACT FROM AUTHOR]

Summary: Background: Indeterminate non-calcified lung nodules are frequent when low-dose spiral computed tomography (LD-CT) is used for lung cancer screening. We assessed the diagnostic utility of a non-invasive work-up protocol for nodules detected at baseline in volunteers enrolled in our single-centre screening trial, and followed for at least 1 year. Methods: 5201 high-risk volunteers, recruited over 1 year from October 2004, underwent baseline LD-CT; 4821 (93%) returned for the first repeat LD-CT. Nodules ≤5mm underwent repeat LD-CT at 1 year; nodules 5.1–8mm underwent LD-CT 3 months later; lesions >8mm received combined CT-positron emission tomography (CT-PET). A subset of nodules >8mm was studied by CT with contrast. Protocol failures were delayed diagnosis with disease progression beyond stage I, and negative surgical biopsy. Results: 2754 (53%) volunteers presented one or more non-calcified nodules. Ninety-two lung cancers were diagnosed: 55 at baseline and 37 at annual screening (66% stage I). Among the 37 incident cancers, 17 had a baseline nodule that remained stage I, 7 had a baseline nodule that progressed beyond stage I, and 13 presented a new malignant nodule. Baseline and annual cancers were 79 (1.5%) and 13 (0.2%), respectively. In 15 of 104 (14%) invasive diagnostic procedures, the lesion was benign. Sensitivity, and specificity were 91 and 99.7%, respectively, for the entire protocol; 88 and 93% for CT-PET; and 100 and 59% for CT with contrast. Conclusions: The protocol limits invasive diagnostic procedures while few patients have diagnosis delay, supporting the feasibility of lung cancer screening in high-risk subjects by LD-CT. Nevertheless further optimization of the clinical management of screening-detected nodules is necessary. [Copyright &y& Elsevier]

Summary: Objective: Large cell neuroendocrine carcinoma of the lung are considered aggressive. However, reported prognoses are heterogeneous and the optimum treatment remains undefined. We retrospectively evaluated outcomes in a series of patients with a pathological diagnosis of large cell neuroendocrine lung carcinoma, who underwent lung resection. We also assessed the utility of chemotherapy in a small subgroup. Patients and methods: The clinical records of 144 consecutive patients were reviewed in a multicenter study. Survival times, assessed from the day of surgery until death or most recent follow-up, were estimated by the Kaplan–Meier method, and compared by the log rank test. Results: There were 117 men and 27 women of median age 63 years. Twelve wedge resections, 3 segmentectomies, 95 lobectomies, 7 bilobectomies and 24 pneumonectomies were performed. Induction chemotherapy was given in 21 and postoperative chemotherapy in 24. Pathologically, 73 (50%) were stage I, 29 (20%) stage II, 40 (28%) stage III and 2 stage IV. Postoperative mortality was 2.8% and morbidity 26%. Overall 5-year survival was 42.5%: 52% for stage I, 59% for stage II and 20% for stage III (p =0.001 log-rank test on Kaplan–Meier curves). A trend to better outcome was associated with preoperative or postoperative chemotherapy in stage I disease (p =0.077) compared to no chemotherapy. The response rate to induction chemotherapy was 80% in the 15 patients with data available. Conclusion: large cell neuroendocrine carcinoma of the lung are confirmed as aggressive but are also chemosensitive. Our experience suggests that chemotherapy may improve prognosis in stage I disease. [Copyright &y& Elsevier]

Presents a letter to the editor concerning Akt phosphor and gefitinib efficacy in patients with advanced non-small-cell lung cancer.