Pulmonary malignant peripheral nerve sheath tumour

Malignant peripheral nerve sheath tumours (MPNSTs) may occur in any peripheral nerve. They are often found in the chest wall and the posterior mediastinum. On the other hand, primary pulmonary MPNST is extremely rare, and surgically treated cases have been reported. Here, we present 3 cases of primary MPNST originating from the pulmonary parenchyma who underwent surgery in our institution. We discuss the possible clinical and pathological associations in the view of the literatur

Primary Sclerosing Epithelioid Fibrosarcoma of the Lung in a Patient with Lynch Syndrome

Sclerosing epithelioid fibrosarcoma (SEF) is a rare neoplasm arising mostly in limbs and limb girdles, with a high rate of recurrence and a strong tendency to metastasize. This case study is of a 54-year-old woman with an asymptomatic mass in the upper lobe of the left lung detected by PET-CT when staging for Lynch syndrome-associated colon carcinoma. Histology of the resected tumor showed epithelioid cells arranged in nests, partly restiform within a zone of sclerosing fibrosis. Immunohistochemistry was positive for vimentin, epithelial membrane antigen, and S100-protein. Eight months after lung resection, the patient was diagnosed for basal cell carcinoma on her back. At the end of a twoyear follow-up period, she developed metastases to the mediastinum, vertebrae, ribs, femurs, pelvic bones, kidneys, and one lung, histologically all related to SEF. Here we report the first case of a SEF primarily arising from the lung and discuss it in the context of the current literatur

Metastasis of a pleural mesothelioma to a hyperplastic stomach polyp: an increase of vimentin expression is seen during a gain in deciduoid morphology

Deciduoid mesothelioma is a rare variant of the epithelioid histotype spectrum, resembling decidua of gravid uterus. It is found in the peritoneum of young women, but also in the pleura of elderly people. Histotype plasticity from epithelioid to sarcomatoid mesothelioma may be considered as epithelial-mesenchymal transition (EMT). A full autopsy was performed and mesothelioma infiltrates were analysed by immunohistochemistry. The metastasis of an epithelioid pleural mesothelioma to a hyperplastic polyp of the stomach is presented in this autopsy case. Deciduoid morphology increased during tumour progression and metastasis. The increase in eosinophilic cytoplasm correlated with the upregulation of the intermediate filament vimentin. High expression of vimentin was found in both central and superficial periglandular regions of the polyp. High vimentin expression also can occur in epithelioid rather than sarcomatoid differentiation. Thus, although vimentin is considered to be the major EMT marker, additional pathways must regulate its expression

PTEN expression is a strong predictor of survival in mesothelioma patients

Background: Malignant pleural mesothelioma (MPM) is a highly aggressive tumour with poor prognosis and limited response to therapy. MPM is characterised by complex chromosomal aberrations, including chromosome 10 losses. The tumour suppressor gene phosphatase and tensin homologue deleted from chromosome 10 (PTEN) located on chromosome 10q23 plays an important role in different cancer, but its relevance for MPM is unclear. Patients and methods: In the present tissue microarray-based study, 341 MPM were studied for PTEN expression by immunohistochemistry using a monoclonal mouse PTEN antibody. Expression levels were semiquantitatively scored (negative, weak, moderate, strong). Expression of PTEN was correlated to overall survival. Results: Clinical data from 206 patients were available. One hundred and five patients were stage T4 and 92 patients presented with regional and mediastinal lymph node metastasis. Loss of PTEN expression was observed in 62% of the cases. The survival time was correlated to PTEN expression in 126 cases with complete follow-up data. Comparing any PTEN expression versus no expression, median survival time was significantly longer (log rank test p=0.0001) in patients with PTEN expression (15.5 months; 95% CI: 3.8; 27.2 vs 9.7 months; 95% CI: 7.9; 11.7). Cox regression analysis revealed an association between PTEN expression and survival (p=0.003) independently from the histological subtype (p=0.7). Conclusion: PTEN is an independent prognostic biomarker in mesothelioma patients. The frequent loss of expression of the tumour suppressor gene PTEN suggests involvement of the PI3K-AKT/protein kinase B (PKB) pathway in MPMs, which may be relevant for future mesothelioma treatmen

Transbronchial Cryobiopsy Compared to Forceps Biopsy for Diagnosis of Acute Cellular Rejection in Lung Transplants: Analysis of 63 Consecutive Procedures

BACKGROUND Acute cellular rejection (ACR) is a complication after lung transplantation (LTx). The diagnosis of ACR is based on histologic findings using transbronchial forceps biopsy (FB). However, its diagnostic accuracy is limited because of the small biopsy size and crush artifacts. Transbronchial cryobiopsy (CB) provides a larger tissue size compared with FB. METHODS FB and CB were obtained consecutively during the same bronchoscopy (February 2020-April 2021). All biopsies were scored according to the ISHLT criteria by three pathologists. Interobserver agreement was scored by the kappa index. We assessed the severity of bleeding and the presence of pneumothorax. RESULTS In total, 35 lung transplant recipients were included, and 126 CBs and 315 FBs were performed in 63 consecutive bronchoscopies. ACR (A1-A3, minimal-moderate) was detected in 18 cases (28.6%) by CB, whereas ACR was detected in 3 cases (4.8%) by FB. Moderate and severe bleeding complicated FB and CB procedures in 23 cases (36.5%) and 1 case (1.6%), respectively. Pneumothorax occurred in 6.3% of patients. The interobserver agreement was comparable for both CB and FB. CONCLUSIONS CB provided an improved diagnostic yield for ACR diagnosis, leading to reclassification and changes in treatment strategies in 28.6% of cases. Prospective studies should better define the role of CB after LTx

Caveolin-1 Expression and Hemodynamics in COPD Patients

Caveolin-1 is a regulator of both intracellular calcium homeostasis and endothelial nitric oxide synthase and may play a pathogenetic role in pulmonary hypertension. In the present study, we aimed to investigate the correlations between pulmonary hemodynamics and vessel morphology including the expression of Caveolin-1 in pulmonary arterioles from patients with chronic obstructive pulmonary disease (COPD) who underwent lung-volume reduction surgery. Staining and subsequent analysis was performed on paraffin-embedded lung tissue from COPD patients (n = 12). Pulmonary arteries with an external diameter of 100-500µm were analysed. Immunhistochemistry with antibodies against caveolin-1 was performed and intensity was assessed. Morphometric data were obtained by using computer-assisted imaging software. The findings were quantified and correlated to hemodynamic data obtained by right-heart catheterization. In COPD patients with pulmonary hypertension (n = 5), the expression of caveolin-1 within the medial smooth muscle cell layer was found to be increased, whereas the intimal caveolin-1 was more prominently expressed in COPD patients with normal pulmonary pressures (n = 7). The ratio between these expression patterns was positively correlated to the mean pulmonary artery pressure. Similar findings were observed for the ratio between intimal and medial thickness as well as for the expression of smooth muscle actin (SMA)

Immuno-chemotherapy reduces recurrence of malignant pleural mesothelioma: an experimental setting

Objective: To assess the effect of immuno-chemotherapy on the extent of local tumour recurrence in an established rat model of malignant pleural mesothelioma (MPM). Methods: Six days after subpleural inoculation of a syngeneic MPM cell line Interleukin-45 (IL-45), left-sided pneumonectomy and resection of the tumour nodule was performed. Animals were randomised into four treatment groups for intrapleural therapy: control (n=6), 500μg cytosine phosphate guanosine oligodeoxynucleotide (CpG-ODN) (n=6), cisplatin-fibrin (n=6), cisplatin-fibrin+500μg CpG (n=6). Six days later the volume of tumour recurrence was assessed, which was the primary endpoint. Secondary endpoints were quantification of the ratio host/tumour cells in the local recurrence and cytokine expression profile in the tumour tissue by real time quantitative PCR (qPCR). T lymphocyte subpopulations in the tumour recurrence tissue were evaluated by immunohistochemistry. Treatment-related toxicity was monitored by measuring blood chemistry and complete blood count. Results: The volume of tumour recurrence was significantly reduced from 610mm3 in the control group to 11.7mm3 in the cisplatin-fibrin group (p=0.004) and to 21.8mm3 in the cisplatin-fibrin+CpG group (p=0.004). Pro-inflammatory cytokines (Interferon-γ (IFN-γ), Interleukin-6 (IL-6), Interleukin-12 (IL-12)) were increased after treatment with cisplatin-fibrin+CpG in comparison to cisplatin-fibrin alone but differences were not statistically significant. We found a higher ratio of host/tumour cells in the cisplatin-fibrin+CpG group (45/55%) compared to the cisplatin-fibrin group (27/73%). In comparison to the control group, animals treated with cisplatin-fibrin+CpG showed a higher number of CD8+ T-cells in the tumour tissue. No significant treatment-related toxicity was observed. Conclusions: Adjuvant treatment with chemotherapy or immuno-chemotherapy leads to significant reduction of mesothelioma recurrence after surgery in this rat MPM model. Immuno-chemotherapy resulted in an increased recruitment of inflammatory cells to the site of tumourigenesis and elicited higher level of tumour growth inhibiting cytokine

Pleural mesothelioma side populations have a precursor phenotype

DyeCycleViolet was used to set up the side population (SP) functional assay aimed at identifying subpopulations of malignant pleural mesothelioma (MPM) tumor cells with chemoresistance phenotype associated with ABCG2 transporter activity. Self-renewal, chemoresistance and tumorigenicity were tested for SP and non-side population (NSP) cells. Tumors were characterized by mesothelin, calretinin, N-cadherin, D2-40 and Wilms tumor 1 (WT1) immunohistochemistry. Surface expression of mesenchymal stem cell markers CD90, CD73 and CD105 was investigated in SP and NSP cells. We identified SP cells with self-renewal properties and increased chemoresistance in MPM cell lines and tumor-derived primary cell cultures. Compared with the non-SP fraction (NSP), the SP fraction led to the development of tumors including cells with mesothelium precursor phenotype characterized by mesenchymal morphology, being WT1 negative but cytoplasmic D2-40 positive and having a tendency of increased tumorigenicity. The same phenotypic shift was observed in patients with relapsing tumors after chemotherapy. Furthermore, the SP cells were enriched in CD105−/low expressing cells, which were small sized and had increased tumorigenicity compared with CD105high cells. Taken together, our results support the hypothesis that MPM CD105−/low, chemoresistant small sized SP cells may constitute the cellular pool out of which recurrence develops. Further characterization of mechanisms of chemoresistance and self-renewal should lead to targets specific for this subpopulation in MPM patient

L1CAM protein expression is associated with poor prognosis in non-small cell lung cancer

Background: The L1 cell adhesion molecule (L1CAM) is potentially involved in epithelial-mesenchymal transition (EMT). EMT marker expression is of prognostic significance in non-small cell lung cancer (NSCLC). The relevance of L1CAM for NSCLC is unclear. We investigated the protein expression of L1CAM in a cohort of NSCLC patients. L1CAM protein expression was correlated with clinico-pathological parameters including survival and markers of epithelial-mesenchymal transition. Results: L1CAM protein expression was found in 25% of squamous cell carcinomas and 24% of adenocarcinomas and correlated with blood vessel invasion and metastasis (p < 0.05). L1CAM was an independent predictor of survival in a multivariate analysis including pT, pN, and pM category, and tumor differentiation grade. L1CAM expression positively correlated with vimentin, beta-catenin, and slug, but inversely with E-cadherin (all p-values < 0.05). E-cadherin expression was higher in the tumor center than in the tumor periphery, whereas L1CAM and vimentin were expressed at the tumor-stroma interface. In L1CAM-negative A549 cells the L1CAM expression was upregulated and matrigel invasion was increased after stimulation with TGF-beta1. In L1CAM-positive SK-LU-1 and SK-LC-LL cells matrigel invasion was decreased after L1CAM siRNA knockdown. Conclusions: A subset of NSCLCs with vessel tropism and increased metastasis aberrantly expresses L1CAM. L1CAM is a novel prognostic marker for NSCLCs that is upregulated by EMT induction and appears to be instrumental for enhanced cell invasion

Comparison of PI3K Pathway in HPV-Associated Oropharyngeal Cancer With and Without Tobacco Exposure

Objectives The aim of the study was to evaluate whether HPV associated OPSCC with tobacco exposure follows a different carcinogenic pathway compared to HPV associated OPSCC without tobacco exposure and to investigate its prognostic significance. The question was addressed with focus on components of the PI3K pathway. Methods 184 patients with newly diagnosed OPSCC treated with curative intent were consecutively enrolled. The expression level of p16, p53, PI3K, mTOR, and PTEN was assessed by immunohistochemistry and analyzed in relation to the risk factors HPV status and tobacco exposure. Results 94 of 184 (51%) patients were p16 positive, p53 overexpression was detected in 48 of 184 (26%) cases. PI3K overexpression with 70 of 184 (38%) cases was significantly higher in p16 positive tumors. mTOR overexpression was present in 90 of 184 (49%) cases and significantly higher in p16 negative tumors. PTEN loss was found in 42 of 184 (23%) cases without association to p16 expression. p16 positive OPSCC showed lower rates of p53 expression and mTOR expression as well as higher rates of PI3K expression irrespective of tobacco exposure. Survival analysis showed a distinct intermediate survival rate of p16 positive smokers. The markers PI3K, mTOR, and PTEN did not have a significant impact on survival. Conclusion HPV associated OPSCC with tobacco exposure follows the same expression level of the PI3K pathway as HPV associated OPSCC without tobacco exposure. The impaired survival rate of the intermediate risk group cannot be explained by different expression patterns of PI3K, mTOR, and PTEN. Level of Evidence 2b