Pulmonary LCNEC represents an aggressive tumor requiring multimodal treatment even for resectable stage I disease, and LCNEC seems to respond to adjuvant platinum-etoposide-based chemotherapy. Patients who received this therapy had the best survival rate. Despite our failure in finding mutational events in the tested RTKs, the strong expression of KIT, PDGFRalpha, PDGFRbeta, and Met in tumor cells suggests an important role of these RTKs in LCNEC, and these RTKs seem to be attractive therapeutic targets.

Pleuro-pulmonary solitary fibrous tumor (SFT) is a relatively uncommon mesenchymal neoplasm of uncertain histogenesis, unknown molecular features, and unpredictable clinical behavior. Although complete resection is universally accepted as the most important single prognostic factor, some clinicopathologic characteristics (gross appearance, tumor size, mitotic index, tumor necrosis, hypercellularity, and pleomorphism) are related to patient outcome, and a staging system based on these parameters with practical therapeutical implications has been recently proposed by de Perrot et al. Here, 88 pleuro-pulmonary SFTs were collected and clinicopathologic characteristics including de Perrot classification, patients' follow-up, p53 expression, and several "targetable" kinases [c-kit, v-raf murine sarcoma viral oncogene homolog B1, platelet-derived growth factor receptor (PDGFR)-alpha/beta, c-met, epidermal growth factor receptor (EGFR)] were retrospectively analyzed. Fifty-two cases (59%) had at least 1 clinicopathologic feature related to malignancy, whereas mortality and recurrences occurred in 10.2% and 18.2% of the cases, respectively. de Perrot staging and high p53 expression were significantly related to the conventional clinicopathologic prognostic features as well as to overall survival (OS) and disease-free survival (DFS) (P<0.001). At multivariate analysis, high p53 expression and tumor necrosis were the only parameters significantly associated with OS and DFS (P=0.017 and P=0.012, respectively). Immunohistochemical expression was frequently detected for PDGFR-alpha (97.7%), PDGFR-beta (86.5%), and hepatocyte growth factor receptor (96.6%), whereas missense mutations were only identified in 2 cases both involving PDGFR-beta (exons 18 and 20). We conclude that de Perrot stratification of SFT is a reliable prognostic indicator and merits consideration in view of its suggestions for the management of these tumors in daily practice. p53 expression may represent a valid and easy-to-test prognostic factor significantly related to OS and DFS. Although mutations of the corresponding genes are rare events in SFT, PDGFR-alpha/beta, and hepatocyte growth factor receptor tyrosine kinases should be further investigated given the availability of specific inhibitory molecules which might provide useful and novel therapeutical approaches for SFT patients.

Accurate fetal autopsy and placental examination related to meticulous clinical collecting data are requisites in the valuation of stillbirth and could play an important role in reduction of unexplained stillbirth rate.

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BACKGROUND: Tumor infiltrating lymphocytes (TILs) are widely considered a key sign of the immune interaction between host and tumor, and potentially prognostic biomarkers of good or bad outcome in many cancers, included invasive breast cancer (BC). However, results about the association between TIL typology, location and BC prognosis, are controversial. The aim of the study was to evaluated the prognostic significance of TIL subtypes (CD4+, CD8+, FOXP3+ T cells) and their location (stromal “s” and intratumoral “i” CD4+ and CD8+) in BC patients, focusing on the association between these markers and immunocheckpoint molecules such as cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed cell death ligand 1 (PD-L1) and its receptor (PD-1). METHODS: CD4+, CD8+, FOXP3+, CTLA4+, PD-L1+ and PD-1+ expression was examined by immunohistochemistry on tissue microarrays (TMAs) from 180 BC patients. Univariate and Kaplan–Meier analyses of disease free survival (DFS) were performed to evaluate the prognostic significance of marker expression. RESULTS: Total CD8+ T cells were not significantly associated with DFS. Differently, patients with iCD8+ and sCD8+ overexpression showed a trend toward respectively a worse (P = .050) and a better 5-years DFS (P = .064). Interestingly, TIL expression of both PD-1+ and PD-L1+, was significantly associated with iCD8+ (P = .0004; P < .0001 respectively), while only TIL expression of PD-1 was associated with sCD8+ (P = .001). CONCLUSION: Our data show that iCD8+ T cells, but no sCD8+ T cells identify a subgroup of patients with poor DFS and this could be due to the overexpression of PD-L1/PD-1 pathway.

BackgroundIn clinical practice the gold standard method to assess BRAF status in patients with metastatic melanoma is based on molecular assays. Recently, a mutation-specific monoclonal antibody (VE1), which detects the BRAF V600E mutated protein, has been developed. With this study we aimed to confirm the clinical value of the VE1 Ventana® antibody, as today a univocal validated and accredited immunohistochemical procedure does not exist, to preliminary detect BRAF status in our routine diagnostic procedures. Moreover, we explored the biological meaning of BRAF immunohistochemical labeling both as a predictor marker of response to target therapy and, for the first time, as a player of acquired tumor drug resistance.MethodsWe analyzed a retrospective series of 64 metastatic melanoma samples, previously investigated for molecular BRAF status, using a fully automatized immunohistochemical method. We correlated the data to the clinicopathologic characteristics of patients and their clinical outcome.ResultsThe sensitivity and the specificity of the Ventana® VE1 antibody were 89.2 and 96.2% respectively, while the positive predictive value and negative predictive value were 97.1 and 86.2%, respectively. For six mutated patients the histological sample before treatment and when disease progressed was available. The immunohistochemical BRAF V600E expression in the specimens when disease progressed was less intense and more heterogeneous compared to the basal expression. Multivariate analysis revealed that a less intense grade of positive expression is an independent predictor of a less aggressive stage at diagnosis (p = 0.0413).ConclusionsOur findings encourage the introduction of immunohistochemistry as a rapid screening tool for the assessment of BRAF status in melanoma patients in routine diagnostic procedures and prepare the ground for other studies to highlight the role of immunohistochemical BRAF V600E expression in patients at the time of progression.

It has been recognized that Na+/H+ Exchanger Regulatory Factor 1 (NHERF1) in breast cancer (BC) acts as a tumor suppressor or as an oncogenic protein, depending on its subcellular localization. This study aims to correlate NHERF1 expression to BRCA1 and PARP1 proteins, to investigate their relationship, and their biological and clinical significance. Using immunohistochemistry on tissue microarrays, we evaluated subcellular NHERF1, BRCA1 and PARP1 expression in 308 BCs including a subgroup (n=80) of triple negative BCs (TNBCs). Herein, we show that nuclear NHERF1 (nNHERF1) expression was significantly associated with nuclear BRCA1 (nBRCA1) expression (p=0.0008), and an association was also found between nuclear PARP1 (nPARP1) and nBRCA1 (p<0.0001). Cytoplasmic NHERF1 (cNHERF1) was correlated to nPARP1 (p<0.0001). Survival analyses showed that the patients with positive nPARP1 and nNHERF1 tended toward a shorter 5-year overall survival (OS) (p=0.057). In TNBCs, the association between nBRCA1 and nPARP1 was maintained (p<0.0001), and an association between nNHERF1 and nPARP1 was observed (p=0.010). Univariate analysis revealed that TNBCs with positive cNHERF1 and nPARP1 had a shorter 5-year OS (p=0.048).Our data suggest that NHERF1 could be a new potential biomarker in combination with PARP1 and BRCA1 expression to stratify BC patients. In particular, in TNBCs, cNHERF1 associated with nPARP1 expression identified a patient subgroup with a shorter survival, for whom it may be useful to develop novel therapeutic strategies.

The expression of cytokeratins in gastrointestinal stromal tumours (GISTs) is rare and may lead to diagnostic confusion when it occurs. This report describes a metastatic GIST that stained strongly for cytokeratins, CD117, and CD34 in a patient who was previously diagnosed with gastric epithelioid angiosarcoma. A review of both tumours showed the same histological and immunohistochemical profiles, and c-kit molecular analysis revealed an insertional mutation at codon 558 of exon 11 in both tumours. Thus, pathologists should be aware that GISTs can occasionally express cytokeratins, and that c-kit mutational investigations may have a key diagnostic role and may prevent diagnostic mistakes that could have important clinical implications.