Claudin expression in pulmonary adenoid cystic carcinoma and mucoepidermoid carcinoma.

Background: Although the expression of tight junction protein claudins (CLDNs) is well known in common histological subtypes of lung cancer, it has not been investigated in rare lung cancers. The aim of our study was to examine the expression of different CLDNs in pulmonary salivary gland tumors. Methods: 35 rare lung cancers including pathologically confirmed 12 adenoid cystic carcinomas (ACCs) and 23 mucoepidermoid carcinomas (MECs) were collected retrospectively. Immunohistochemical (IHC) staining was performed on formalin fixed paraffin embedded (FFPE) tumor tissues, and CLDN1, -2, -3, -4, -5, -7, and -18 protein expressions were analyzed. The levels of immunopositivity were determined with H-score. Certain pathological characteristics of ACC and MEC samples (tumor grade, presence of necrosis, presence of blood vessel infiltration, and degree of lymphoid infiltration) were also analyzed. Results: CLDN overexpression was observed in both tumor types, especially in CLDN2, -7, and -18 IHC. Markedly different patterns of CLDN expression were found for ACC and MEC tumors, especially for CLDN1, -2, -4, and -7, although none of these trends remained significant after correction for multiple testing. Positive correlations between expressions of CLDN2 and -5, CLDN3 and -4, and CLDN5 and -18 were also demonstrated. Tumors of never-smokers presented lower levels of CLDN18 than tumors of current smokers (p-value: 0.003). Conclusion: This is the first study to comprehensively describe the expression of different CLDNs in lung ACC and MEC. Overexpression of certain CLDNs may pave the way for targeted anti-claudin therapy in these rare histological subtypes of lung cancer.

PD-1 and PD-L1 expression in rare lung tumors.

Background: Our knowledge is still limited about the characteristics and treatment of rare lung tumors. The aim of our study was to determine programmed cell death ligand-1 (PD-L1) and programmed cell death-1 (PD-1) expression in rare pulmonary tumors to assess the potential role of immunotherapy. Methods: 66 pathologically confirmed rare lung tumors including 26 mucoepidermoid carcinomas (MECs), 27 adenoid cystic carcinomas (ACCs), and 13 tracheobronchial papillomas (TBPs) were collected retrospectively. Immunohistochemical (IHC) staining was performed on formalin fixed paraffin embedded (FFPE) tumor tissues, and PD-L1 expression on tumor cells (TCs) and immune cells (ICs), and PD-1 expression on ICs were determined. The cut off value for positive immunostaining was set at 1% for all markers. Results: PD-L1 expression on TCs was observed in two cases of MEC (7.7%), one case of ACC (3.7%), and was absent in TBP samples. PD-L1 expression on ICs could be demonstrated in nine cases of MEC (34.6%), four cases of ACC (14.8%), and was absent in TBPs. All PD-L1 TC positive tumors were also PD-L1 IC positive. Higher expression level than 5% of PD-L1 TC and/or IC was observed only in one ACC and in two MEC patients. Among them, strong PD-L1 immunopositivity of >50% on TCs and of >10% on ICs could be demonstrated in one MEC sample. PD-L1 expression of ≥1% on ICs was significantly more common in MEC, than in TBP (p < 0.001). In MEC ≥1% PD-L1 TC or IC expressions were significantly more common in patients aged 55 or older, than in younger patients (p = 0.046, and p = 0.01, respectively). PD-1 expression on ICs was found in five cases of MEC (19.2%), four cases of ACC (14.8%), and in two cases of TBP (15.4%). Only one MEC case showed a higher than 5% expression level of PD-1 on ICs. Conclusion: This retrospective study comprehensively demonstrated the rare expression of PD-L1 and PD-1 in pulmonary MEC, ACC, and TBP. However, we found very strong PD-L1 immunopositivity on both TCs and ICs in one MEC sample, which warrants further investigations in a larger cohort.

Tumor necrosis correlates with PD-L1 and PD-1 expression in lung adenocarcinoma.

Background: Predictive biomarkers for immunotherapy in lung cancer are intensively investigated; however, correlations between PD-L1/PD-1 expressions and clinical features or histopathological tumor characteristics determined on hematoxylin and eosin stained sections have not extensively been studied. Material and methods: We determined PD-L1 expression of tumor cells (TC) and immune cells (IC), and PD-1 expression of IC by immunohistochemistry in 268 lung adenocarcinoma (LADC) patients, and correlated the data with smoking, COPD, tumor grade, necrosis, lepidic growth pattern, vascular invasion, density of stromal IC, and EGFR/KRAS status of the tumors. Results: There was a positive correlation between PD-L1 expression of TC and IC, as well as PD-L1 and PD-1 expression of IC. Tumor necrosis was associated with higher PD-L1 expression of TC and PD-1 expression of IC. A negative correlation was observed between lepidic growth pattern and PD-L1 expression of TC and PD-L1/PD-1 expression of IC. EGFR mutation seemed to negatively correlate with PD-1 expression of IC, but this tendency could not be verified when applying corrections for multiple comparisons. No significant effect of the KRAS mutation on any of the studied variables could be established. Conclusion: Here we first demonstrate that the presence of necrosis correlates with higher PD-L1 expression of TC and PD-1 expression of IC in LADC. Further studies are required to determine the predictive value of this observation in LADC patients receiving immunotherapy.

New insights into the impact of primary lung adenocarcinoma location on metastatic sites and sequence: A multicenter cohort study.

INTRODUCTION: The presence of organ metastases is a major factor for unfavorable prognosis in lung adenocarcinoma (LADC). However, the influence of primary tumor location on metastatic sites and sequence has not been extensively analyzed. METHODS: We performed a multicenter cohort study, evaluating clinicopathological data of 1126 Caucasian LADC patients, focusing on the distinct location of primary tumors and metastatic sites during disease progression. RESULTS: Metastases to the lung (p < 0.001), pleura (p < 0.001) and adrenal glands (p < 0.001) occurred earlier during disease progression and central primary tumors were associated with early metastases (OR 1.43, p = 0.02). In secondary exploratory analysis we found that bone metastases were more frequent in patients with central tumors (OR 1.86, p = 0.017), whereas lung metastases in those with peripheral tumors (OR 1.35, p = 0.015). Central primary LADCs were associated with decreased median overall survival (vs. peripheral tumors, 10.2 vs. 22 months) both in univariate (HR 2.075, p = 0.001) and in multivariate (HR 1.558, p < 0.001) analyses and independent from stage and T factor. By subsequent analysis, we found that bone metastases tend to appear together with adrenal and liver metastases, and adrenal with skin, and pleural with pericardial metastases more frequently than expected if metastatic events occurred independently. CONCLUSION: This comprehensive large cohort analysis demonstrates metastatic site- and sequence-specific variations in patients with LADC. Central LADC is associated with early metastatic disease, bone involvement and, consequently, decreased survival.

Significance of Primary Tumor Location and Histology for Brain Metastasis Development and Peritumoral Brain Edema in Lung Cancer.

BACKGROUND: Brain metastasis of lung cancer adversely affects overall survival (OS) and quality of life, while peritumoral brain edema is responsible for life-threatening complications. METHODS: We retrospectively analyzed the clinicopathological and cerebral radiological data of 575 consecutive lung cancer patients with brain metastases. RESULTS: In adenocarcinoma and squamous cell carcinoma, peritumoral brain edema was more pronounced than in small-cell lung cancer (p < 0.001 and p < 0.001, respectively). There was a positive correlation between the size of metastasis and the thickness of peritumoral brain edema (p < 0.001). It was thicker in supratentorial tumors (p = 0.019), in younger patients (≤50 years) (p = 0.042), and in females (p = 0.016). The time to development of brain metastasis was shorter in central than in peripheral lung cancer (5.3 vs. 9.0 months, p = 0.035). Early brain metastasis was characteristic for adenocarcinomas. A total of 135 patients had brain only metastases (N0 disease) characterized by peripheral lung cancer predominance (p < 0.001) and a longer time to development of brain metastasis (9.2 vs. 4.4 months, p < 0.001). OS was longer in the brain only subgroup than in patients with N1-3 diseases (p < 0.001). CONCLUSIONS: The clinicopathological characteristics of lung cancer are related to the development and radiographic features of brain metastases. Our results might be helpful in selecting patients who might benefit from prophylactic cranial irradiation.

Decreased ERCC1 Expression After Platinum-Based Neoadjuvant Chemotherapy in non-Small Cell Lung Cancer.

We have already demonstrated in a small cohort of 17 non-small cell lung cancer patients that ERCC1 (excision repair cross-complementation group 1) protein expression decreased after platinum-based treatment, however, certain clinicopathological parameters, such as histologic subtypes, ERCC1 expression scores, chemotherapeutic combinations, response rate, gender and smoking history were not analyzed. The aim of our present study was to extend the studied cohort and analyze those parameters. ERCC1 protein expression was examined in 46 patients treated with neoadjuvant chemotherapy. 46 bronchoscopic biopsy samples (27 squamous cell carcinomas /SCC/ and 19 adenocarcinomas /ADC/) together with their corresponding surgical biopsies were studied. ERCC1 immunohistochemistry was performed on formalin-fixed, paraffin-embedded tissues. Staining scores were calculated by multiplying the percentage of positive tumor cells (0-100) by the staining intensity (0-3). 24/27 bronchoscopic SCC tissues expressed ERCC1. Thirteen of these cases became negative after neoadjuvant therapy and the expression differences between pre- and postchemotherapy samples were highly significant (p < 0.001). 11/19 bronchoscopic ADC tissues expressed ERCC1. Six of these cases became negative after neoadjuvant therapy and the expression differences were significant (p < 0.010). There was no newly expressed ERCC1 postoperatively. Comparison of staining score changes revealed more pronounced decrease in SCC (p = 0.032). We observed no correlation between initial ERCC1 level or ERCC1 decrease and overall survival, but we demonstrated correlations between decrease in ERCC1 expression and histologic subtypes of tumors and gender. We could confirm our previous data in a larger cohort that platinum-based chemotherapy affects the ERCC1 expression probably referring to an induction of tumor cell selection.

Subtype-specific KRAS mutations in advanced lung adenocarcinoma: a retrospective study of patients treated with platinum-based chemotherapy.

BACKGROUND: Platinum-based chemotherapy is the most common treatment in advanced-stage lung adenocarcinoma. Because the clinical significance of KRAS mutational status in this setting has not yet been clearly determined, a mutation subtype-specific analysis was performed in the so far largest cohort of Caucasian patients with KRAS mutant advanced-stage lung adenocarcinoma treated with platinum-based chemotherapy. METHODS: 505 Caucasian stage III-IV lung adenocarcinoma patients with known amino acid substitution-specific KRAS mutational status and treated with platinum-based chemotherapy were included. The correlations of subtype-specific KRAS mutations with smoking status, progression-free and overall survival (PFS and OS, respectively) and therapeutic response were analysed. RESULTS: Among 338 KRAS wild-type, 147 codon 12 mutant and 20 codon 13 mutant patients, there were no mutation-related significant differences in PFS or OS (P values were 0.534 and 0.917, respectively). Eastern Cooperative Oncology Group (ECOG) status and clinical stage were significant independent prognostic factors. KRAS mutation showed a significant correlation with smoking status (P=0.018). Importantly, however, G12V KRAS mutant patients were significantly more frequent among never-smokers than all other codon 12 KRAS mutant (G12x) subtypes (P=0.016). Furthermore, this subgroup tended to have a higher response rate (66% versus 47%; P=0.077). A modestly longer median PFS was also found in the G12V mutant cohort (233days; versus 175days in the G12x group; P=0.145). CONCLUSIONS: While KRAS mutation status per se is neither prognostic nor predictive in stage III-IV lung adenocarcinoma, subtype-specific analysis may indeed identify clinically relevant subgroups of patients that may ultimately influence treatment decisions.

Platinum-based chemotherapy in lung cancer affects the expression of certain biomarkers including ERCC1.

Chemotherapies are widely used in the treatment of lung cancer. However, little is known about their effect in the expression of different tissue markers. Seventeen lung cancer tissue blocks obtained by bronchoscopic biopsies together with their corresponding surgical biopsies after neoadjuvant chemotherapy were studied. They included 9 adenocarcinomas (ADC) and 8 squamous cell carcinomas (SCC). Immunohistochemistry was performed on formalin-fixed, paraffin-embedded tissues to study the expression of Ki-67, p53, Bcl-2, Bax, Fas-ligand and ERCC1 (excision repair cross-complementation group 1). Out of 17 NSCLC 6 expressed proapoptotic markers and 4 expressed antiapoptotic markers, while in 7 cases the apoptotic markers did not show detectable changes after neoadjuvant chemotherapy. Six of 17 bronchoscopic NSCLC cases expressed increased level of Ki-67 after neoadjuvant treatment. Eight bronchoscopic NSCLC tissues (6 SCC, 2 ADC) expressed ERCC1. All but one ADC became ERCC1 negative after neoadjuvant therapy. There was no newly expressed ERCC1 positive case in the surgical biopsy group. Platinum-based neoadjuvant chemotherapy had no effect on the apoptotic activity of 17 patients' tumor specimen, however, 6 of 17 bronchoscopic NSCLC cases expressed increased level of Ki-67 after neoadjuvant treatment, in 3 cases the level of Ki-67 became decreased, while 8 cases had no detectable change of proliferation activity. The results of the present study suggest that platinum-based chemotherapy probably induces a selection of tumor cells with more aggressive phenotype, and also affects the expression of tissue marker (ERCC1) that could have predictive value.

[Management of malignant and benign airway stenosis by stent implantation]. / Malignus és benignus légúti szukületek megoldása légúti protézis (stent) beültetésével.

INTRODUCTION: In the last few decades the different bronchoscopic procedures have gained an important role in the treatment of airway stenosis, and the number of implanted airway stents has also greatly increased. PATIENTS: Between 1998 and 2004 the authors implanted altogether 108 airway prosthesis in 90 patients at the Institute of Pulmonology of Pest County. 58% of the patients were males, 42% females, the average age was 57.5 years, the average follow-up time was 7 months. RESULTS: On the basis of different etiology the patients were separated into two main groups. In 57% the airway stenosis was caused by malignant illnesses, in these cases stents can be used only with palliative purpose. However, in case of benign lesions they can offer a long-term solution and require an adequate follow-up of the patients. The authors' main aim was to get an overall picture of the interventions they had done by processing the data, with the help of the measurable characteristics that make possible to follow the airways' permeability and its changes. Analysing the results of the respiratory function and blood gas examinations they didn't find a significant difference inspite of the subjective improvement.