The impact of growth pattern on the distribution of connective tissue and on the vascularization of brain metastases (40 colon, lung and breast carcinoma samples) was analyzed. Most of the cases showed either a "pushing-type" (18/40, mostly colon and lung carcinomas) or a "papillary-type" (19/40, mostly breast carcinomas) growth pattern. There was a striking difference in the growth pattern and vascularization of colon/lung versus breast carcinoma metastases. Pushing-type brain metastases incorporated fewer vessels and accumulated more collagen in the adjacent brain parenchyma, whereas papillary-type brain metastases incorporated more vessels and accumulated collagen in the center of the tumor. We observed duplication of the PDGFRβ-positive pericyte layer accompanied by an increase in the amount of collagen within the vessel walls. The outer layer of pericytes and the collagen was removed from the vessel by invasive activity of the tumors, which occurred either peri- or intratumorally, depending on the growth pattern of the metastasis. Our findings suggest that pericytes are the main source of the connective tissue in brain metastases. Vascularization and connective tissue accumulation of the brain metastases largely depend on the growth pattern of the tumors.
Management of lung cancer patients who suffer from brain metastases represents a major challenge. Considering the promising results with immune checkpoint inhibitor treatment, evaluating the status of immune cell (IC) infiltrates in the prognosis of brain metastasis may lead to better therapeutic strategies with these agents. The aim of this study was to characterize the distribution of ICs and determine the expression of the checkpoint molecules programmed death protein 1 (PD-1) and its ligand, PD-L1, in brain metastasis of lung adenocarcinoma (LUAD) patients and to analyze their clinicopathological correlations. We determined the presence of peritumoral mononuclear cells (mononuclear ring) and the density of intratumoral stromal mononuclear cells on brain metastasis tissue sections of 208 LUAD patients. PD-L1/PD-1 expressions were analyzed by immunohistochemistry. Mononuclear rings were significantly associated with better survival after brain metastasis surgery. Cases with massive stromal IC infiltration also showed a tendency for better overall survival. Lower expression of PD-1 and PD-L1 was associated with better survival in patients who underwent surgery for the primary tumor and had multiple brain metastases. Steroid administration and chemotherapy appear not to influence the density of IC in brain metastasis. This is the first study demonstrating the independent prognostic value of mononuclear rings in LUAD cases with brain metastasis. Our results also suggest that the density of tumor-associated ICs in addition to PD-L1 expression of tumor cells and ICs as well as PD-1 expression of ICs may hold relevant information for the appropriate selection of patients who might benefit from anti–PD-L1 or anti–PD-1 therapy.
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.
BRAF is a critical member of proliferation pathways in cancer, and a mutation is present in only 2-4% of lung adenocarcinomas (LADC). There is no data available on the expression pattern of BRAF RNA that might result in enhanced signalling and drug resistance.LADC tissue samples (n=64) were fixed and processed into paraffin blocks. Tissue microarrays (TMA) were constructed, and RNAScope®in situ hybridization (ISH) assay was performed for wild-type (WT) BRAF RNA. Apart from pathological assessment of tumor samples (grade, necrosis, vascular involvement and peritumoral infiltration), anti-programmed death ligand 1 (PD-L1) and anti-programmed death 1 (PD-1) immunohistochemistry and validation in public databases [The Cancer Genome Atlas (TCGA), Human Protein Atlas (HPA)] were carried out.WT BRAF RNA is expressed in LADC, with no significant expressional difference between early-stage (I-II) and advanced-stage (III-IV) patients (P=0.317). Never smokers exhibited significantly increased BRAF expression (compared to current and ex-smokers, P<0.01) and tumor necrosis correlated significantly with BRAF expression (P=0.014). PD-L1 expression was assessed on tumor cells and immune cells, PD-1 expression was evaluated on immune cells. There was no significant difference in BRAF RNA expression between tumor cell PD-L1-high vs. low patients (P=0.124), but it was decreased in immune cell PD-L1-high patients (P=0.03). Kaplan-Meier survival analysis showed that high BRAF expression was associated with significantly decreased OS (P<0.01) and was an independent negative prognostic factor according to multivariate Cox hazard regression (P=0.024). TCGA validation cohort confirmed our findings regarding OS in early-stage patients (P=0.034).We found an increased expression of BRAF RNA in all stages in LADC. High BRAF expression was associated with tumor necrosis, distinct immune checkpoint biology and outcomes. We recommend further evaluating the potential of targeting overexpressed BRAF pathways in LADC.
Background Metastatic lung cancer is a debilitating disease, but with the advances in immunotherapy, therapeutic options have vastly increased. Numerous complete blood count parameters (CBC) have been described as easily accessible biomarkers that might predict response to immunotherapy. However, to date, no comprehensive study has been performed on the longitudinal changes of these parameters during cancer progression. Methods The clinicopathological variables and CBC parameters of 986 advanced stage lung cancer patients were retrospectively analyzed. Blood tests were performed as part of the routine checkup and the results were recorded at the time of the diagnosis of the primary tumor, the diagnosis of brain or bone metastases, and also during the last available follow‐up. Results In the experimental subcohort, 352 and 466 patients were diagnosed with brain and bone metastases, respectively. The control group consisted of 168 patients without clinically detectable or other distant organ metastases. In our longitudinal analyses, we found significantly decreasing absolute lymphocyte count (ALC: P < 0.001), and significantly increasing absolute neutrophil count (ANC: P < 0.001) levels in all patient subgroups, irrespective of histopathological type and metastatic site. Interestingly, patients with brain metastases had significantly descending‐ascending platelet count (PLT) trendlines ( P < 0.001), while the bone metastatic subgroup exhibited significantly ascending‐descending trendlines ( P = 0.043). Conclusions Significantly decreasing ALC, significantly increasing ANC and fluctuating PLT levels may be found in brain and bone metastatic lung cancer patients during disease progression. Our findings might contribute to improve personalized healthcare in this devastating malignancy. Key points Significant findings of the study Significantly decreasing ALC, and significantly increasing ANC levels can be found in advanced‐stage lung cancer patients during disease progression Patients with brain metastases have descending‐ascending PLT trendlines, while patients with bone metastases exhibit ascending‐descending trendlines during disease progression What this study adds The descending values for ALC, and the ascending mean values for PLT and ANC, might be suggestive of poor response to second‐ or third‐line immunotherapy in advanced‐stage lung cancer patients. The current study might help to improve patient selection and treatment strategies for brain and/or bone metastatic lung cancer patients.
Glioblastomas and brain metastases (BM) of solid tumours are the most common central nervous system neoplasms associated with very unfavourable prognosis. In this study, we report the association of prostate-specific membrane antigen (PSMA) with various clinical parameters in a large cohort of primary and secondary brain tumours. A tissue microarray containing 371 cases of ascending grades of gliomas pertaining to astrocytic origin and samples of 52 cases of primary lung carcinomas with matching BM with follow-up time accounting to 10.4 years was evaluated for PSMA expression using immunohistochemistry. In addition, PSMA expression was studied in BM arising from melanomas and breast carcinomas. Neovascular expression of PSMA was evident alongside with high expression in the proliferating microvasculature of glioblastomas when compared to the tumour cell expression. This result correlated with the results obtained from the in silico (cancer genome databases) analyses. In gliomas, only the vascular expression of PSMA associated with poor overall survival but not the tumour cell expression. In the matched primary lung cancers and their BM (n = 52), vascular PSMA expression in primary tumours associated with significantly accelerated metastatic dissemination to the brain with a tendency towards poor overall survival. Taken together, we report that the vascular expression of PSMA in the primary and secondary brain tumours globally associates with the malignant progression and poor outcome of the patients.
Abstract Glioblastomas and brain metastases (BM) of solid tumors are the most common central nervous system neoplasms associated with very unfavorable prognosis. In this study, we report the association of Prostate Specific Membrane Antigen with various clinical parameters in a large cohort of primary and secondary brain tumors. A tissue micro array containing 371 cases of ascending grade gliomas pertaining to astrocytic origin, samples of 52 cases of primary lung carcinomas with matching brain metastases with follow-up time accounting to 10.4 years was evaluated for PSMA expression using immunohistochemistry. In addition, PSMA expression was studied in brain metastases arising from melanomas and breast carcinomas. Neovascular expression of PSMA was evident alongside with high expression in the proliferating microvasculature of glioblastomas when compared to the tumor cell expression. This result corroborated with the results obtained from the in silico (cancer genome databases) analyses. In the matched primary lung cancers and their brain metastases (n = 52), vascular PSMA expression in primary tumors led to significantly accelerated metastatic dissemination to the brain with a tendency towards poor overall survival. Taken together, we report the vascular expression of PSMA in the primary and secondary brain tumors that globally associates with the malignant progression and poor outcome of the patients.
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