Tumor budding to investigate local invasion, metastasis and prognosis in temporal bone squamous cell carcinoma.

BACKGROUND: Few studies have tried to go beyond the conventional clinic-pathological prognostic factors investigating the molecular markers involved in the biology of temporal bone squamous cell carcinoma (TBSSC). Tumor budding represents a very aggressive subpopulation of cancer cells and demonstrates the heterogeneity of cancer cells residing in different locations within tumors. The main aim of this exploratory study was to investigate the role of tumor budding in primary TBSCC prognosis. We also analyzed the association between TBSCC tumor budding and: (i) loco-regional aggressiveness evaluated according to the revised Pittsburgh staging system, (ii) tumor infiltrating lymphocytes, lymphovascular invasion (LVSI), perineural invasion, pattern of invasion, and type of stroma. METHODS: Thirty-two TBSCCs treated surgically were considered. The three-tier grading system recommended by the International Tumor Budding Consensus Conference was used first on TBSCC. RESULTS: Advanced (T3-4) TBSCC was related with high risk intra-tumoral budding (ITB) at two-tier risk grading (p = 0.0361). N + status was associated with intermediate/high budding (Bd2-3) at three-tier risk grading for peri-tumoral budding (PTB) (p = 0.0382). Disease-free survival (DFS) was related with T-stage (p = 0.0406), N-status (p < 0.0001), PTB two-tier risk grading (p = 0.0463), LVSI (p < 0.0001). Overall survival (OS) was associated with N-status (p = 0.0167), PTB absolute count (p = 0.0341), PTB three-tier risk grading (p = 0.0359), PTB two-tier risk grading (p = 0.0132), and LVSI (p = 0.0004). At the multivariate analysis, DFS was related with N-status (p = 0.0147) and LVSI (p < 0.0001), while OS resulted associated only with LVSI (p = 0.0144). CONCLUSIONS: Our preliminary findings suggest that tumor budding in TBSCC, regardless of its localization (the main tumor body [ITB] or invasive front [PTB]) may be a reliable predictor of neck lymph node metastasis and poor prognosis. Tumor budding and LVI could be predictive markers for precise treatment in TBSCC. Further investigations on larger prospective series should be designed to confirm this evidence both in post-operative specimens and in preoperative biopsies.

Epithelial-to-Mesenchymal Transition and Neoangiogenesis in Laryngeal Squamous Cell Carcinoma.

The mechanism of epithelial-mesenchymal transition (EMT) is fundamental for carcinogenesis, tumor progression, cancer cell invasion, metastasis, recurrence, and therapy resistance, comprising important events, such as cellular junction degradation, downregulation of epithelial phenotype markers, overexpression of mesenchymal markers, and increase in cellular motility. The same factors that drive epithelial cells toward a mesenchymal phenotype may also drive endothelial cells toward a proangiogenic phenotype. The aim of this exploratory study was to investigate a potential interplay between EMT and angiogenesis (quantified through CD105 expression) in laryngeal carcinoma (LSCC). CD105-assessed microvessel density (MVD) and EMT markers (E-cadherin, N-cadherin, Snail, Slug, Zeb1, and Zeb2) were assessed on 37 consecutive LSCC cases. The univariate Cox regression model identified pN+ status (p = 0.0343) and Slug expression (p = 0.0268) as predictive of disease-free survival (DFS). A trend toward significance emerged for CD105-assessed MVD (p = 0.0869) and N-cadherin expression (p = 0.0911). In the multivariate Cox model, pN-status, Slug, and N-cadherin expressions retained their significant values in predicting DFS (p = 0.0346, p = 0.0430, and p = 0.0214, respectively). Our data support the hypothesis of a mutual concurrence of EMT and angiogenesis in driving LSCC cells toward an aggressive phenotype. To better characterize the predictive performance of prognostic models based on EMT and angiogenesis, further large-scale prospective studies are required.

The immune cell landscape of metastatic uveal melanoma correlates with overall survival.

BACKGROUND: Uveal melanoma (UM) represents the most common primary intra-ocular malignancy in adults. Up to 50% of the patients develop distant metastases within 10 years from diagnosis, with the liver as the most common site. Upon metastatization, life expectancy strongly reduces and immune checkpoint inhibitors that prove effective in cutaneous melanoma do not modify clinical outcome. To date, few studies have focused on deciphering the immunomodulatory features of metastatic UM microenvironment, and there are no prognostic models for clinical use. This highlights the urgent need to understand the delicate interplay between tumor and immune cells acting at the site of metastasis. METHODS: We collected a patient cohort comprising 21 metastatic UM patients. Hepatic and extra-hepatic UM metastasis samples were studied by multiplex immunofluorescence to assess the tumor immune cell composition. Quantitative analyses were performed to correlate immune cell densities with treatment response, metastasis site and patient survival. RESULTS: Compared to patients with progressive disease, those with controlled disease had a higher intra-tumoral/peritumoral ratio of CD8 + Granzyme B+ cells, higher density of intra-tumoral CD8+ cytotoxic T lymphocytes (CTL) and an increased percentage of UM cells in close proximity to T lymphocytes, reflecting a role of tumor-killing T cells in the disease. In liver metastases (LM), the intra-tumoral densities of CD163+ tumor-associated macrophages (TAM) and of total CD8+ T cells were higher than in extra-hepatic UM metastases, but the percentage of Granzyme B+ CTL was lower. Moreover, LM displayed more UM cells adjacent to both CTL and TAM, and also more T cells in proximity to TAM, all signs of an impaired immune response. The percentage of activated CTL within the tumor represented a prognostic indicator, as patients with a higher intra-tumoral percentage of CD8 + Granzyme B+ cells had the better outcome. A temptative Immunoscore was generated and proved capable to stratify patients with improved survival. Finally, CD4 + FoxP3+ T cells appeared a crucial population for response to immunotherapy. CONCLUSION: The results of this study underly the clinical relevance and functional importance of composition and localization of antitumor effector cells for the progression of UM metastasis.

Prognostic role of programmed death ligand 1 (PD-L1) and the immune microenvironment in laryngeal carcinoma.

OBJECTIVES: The immune system is crucial in the evolution of head and neck cancer. Programmed cell death ligand 1 (PD-L1) seems to rely on close relations between neoplastic cells and immune cells in the tumor microenvironment. The main aim of this study was to apply univariate/multivariate analysis to investigate the prognostic significance of PD-L1, tumor-infiltrating lymphocytes (TILs), and tertiary lymphoid structures (TLS) in laryngeal carcinoma (LSCC). MATERIALS AND METHODS: PD-L1 (in terms of combined positive score [CPS]), TILs and TLS were assessed at pathology on 70 consecutive samples of LSCC. RESULTS: A CPS ≥ 1 coincided with a lower recurrence rate (RR) (p = 0.007) and longer disease-free survival (DFS) than a CPS < 1 (p = 0.0027). Cases with higher TIL counts showed a lower RR (p = 0.036) and longer DFS than those with lower TIL counts (p = 0.0062). Cases revealing TLS had a lower RR (p = 0.004) and longer DFS (p = 0.0034) than those with no TLS. On multivariate analysis, the presence of TLS retained its positive prognostic value (p = 0.024), while CPS remained significant as regards disease recurrence (p = 0.050). CONCLUSIONS: PD-L1 seems to be an indirect marker of effective anti-tumor response in LSCC, possibly being expressed as a result of a greater immune pressure on cancer cells. The presence of TLS emerged as a positive prognostic factor. Further prospective studies are needed to characterize the role of PD-L1 as a marker of anti-tumor immune response and prognostic factor in LSCC, also with regard to the effectiveness of immunotherapeutic protocols.

Biological tumor markers (maspin, CD105, nm23-H1) and disease relapse in laryngeal cancer: cluster analysis.

BACKGROUND: The aim of this investigation was to see if a panel of biomarkers (maspin, CD105, and nm23-H1) could be used to stratify patients with laryngeal squamous cell carcinoma (LSCC) in homogeneous disease recurrence risk clusters. METHODS: Cluster analysis was used to classify 89 patients based on their immunohistochemical expression of nm23-H1, CD105, and maspin. RESULTS: Our analysis identified seven homogeneous clusters: the LSCC recurrence rate was lowest in cluster 6 (non-nuclear maspin pattern, nuclear nm23-H1 expression ≥10%, endothelial CD105 expression <6%; P = .009), and highest in cluster 3 (non-nuclear maspin pattern, nuclear nm23-H1 expression <10%, endothelial CD105 expression ≥6%; P <.001). CONCLUSIONS: Similar panels of biological variables identified by cluster analysis should be tested in prospective clinical trials to establish whether treating patients identified as being at higher risk of LSCC recurrence more aggressively could significantly improve their recurrence rate and/or disease-specific survival.

Maspin expression and anti-apoptotic pathway regulation by bcl2 in laryngeal cancer.

OBJECTIVES: Comprehension of the interplay of pro-apoptotic and anti-apoptotic stimuli in laryngeal squamous cell carcinoma (LSCC) is crucial to understand tumor development, biological behavior and treatment response. Bcl-2 family proteins mainly regulate the apoptotic signal cascade. In some cancers, maspin seems to influence the balance between pro-apoptosis and anti-apoptosis bcl-2 family proteins. The aim of this study was to investigate the potential relationship between bcl-2 anti-apoptotic factor and the tumor suppressor maspin in LSCC. MATERIALS AND METHODS: 31 consecutive patients who underwent primary surgery and post-operative radiotherapy for LSCC were evaluated retrospectively. For each case, immunohistochemistry assays for bcl-2 and maspin were performed. Data were also collected on N-status, pT stage, grading, recurrence and disease-free survival (DFS). RESULTS: Patients with nuclear maspin pattern of expression showed a significantly lower recurrence rate (p = 0.04) and longer DFS (p = 0.0018). The expression of bcl-2 was not associated with recurrence rate or DFS either in the whole cohort or in cases with nuclear maspin pattern, while in patients with non-nuclear maspin pattern, a statistical trend was found toward a shorter DFS for bcl-2 positive cases (p = 0.062). In the multivariate model, only maspin expression pattern retained its independent prognostic significance (p = 0.006). CONCLUSIONS: Nuclear maspin pattern seemed to be an independent positive prognostic factor, while bcl-2 prognostic value was related to maspin expression pattern. Further investigations are needed to support the use of bcl-2 inhibitors in multimodality or multitarget strategies against advanced LSCCs, also considering the role and expression of tumor suppressor genes.

Expression of maspin tumor suppressor and mTOR in laryngeal carcinoma.

PURPOSE: The main aim of this study was to conduct a preliminary investigation into the possible relationship between mTOR and the nuclear tumor suppressor maspin in laryngeal carcinoma (LSCC). MATERIALS AND METHODS: mTOR expression and maspin pattern were ascertained, also with the aid of image analysis in 79 consecutive LSCCs. RESULTS: Considering the whole series, univariate statistical analysis identified significant differences in the distributions by lymph node status (N0 vs N+) between two subgroups of patients with and without loco-regional carcinoma recurrences (p = 0.017). The log-rank test also showed a shorter disease-free survival (DFS) in pN+ patients (p = 0.0008). mTOR expression was significantly higher in patients whose disease recurred (p = 0.009). The DFS rate was also significantly shorter in cases of LSCC with an mTOR expression ≥11.55% (p = 0.049). Multivariate analysis showed that N status (p = 0.002) and mTOR expression (p = 0.037) retained their prognostic significance in relation to cancer recurrence. In a subgroup of LSCCs with a non-nuclear maspin pattern, mTOR expression was significantly higher in patients whose disease recurred. Multivariate analysis disclosed that N stage (p = 0.012) retained its independent prognostic significance for disease recurrence in this setting. mTOR expression showed a trend towards independent significance in terms of carcinoma recurrence (p = 0.083). CONCLUSIONS: mTOR inhibitors seem promising for use in cancer therapies. Further investigations are needed on the prospects of incorporating modern mTOR inhibitors in multimodality or multitarget strategies against advanced LSCCs, also considering the role and expression of tumor suppressor genes.

Endoglin-based assessment of neoangiogenesis in sporadic VIII cranial nerve schwannoma.

Although the diagnosis and treatment of sporadic vestibular schwannoma has improved in recent years, no factors capable of predicting its growth have been identified as yet. Endoglin (CD105) is a proliferation-associated protein expressed in angiogenic endothelial cells, and a potential prognostic indicator for several solid tumors. The aim of the present study was primarily to investigate the expression and role of CD105 in a series of sporadic vestibular nerve schwannomas. In 71 consecutive cases of vestibular schwannoma, vessel cross-sectional area and density were calculated from immunohistochemically assessed CD105 expression using image analysis to correlate them with: (i) tumor dimensions; and (ii) tumor growth rate measured on high-resolution contrast-enhanced MRI (ceMRI). Based on assessments of CD105 expression, a significant positive correlation was identified between vessel cross-sectional area and tumor size at the time of surgery (p = 0.0024), and between vessel density and tumor size (p = 0.013). Vessel cross-sectional area (p = 0.0006) and vessel density (p = 0.003) were significantly greater in tumors measuring ≥10 mm in size than in those <10 mm. Conversely, when tumor growth rate could be calculated from two or more ceMRI (38 cases), there was no significant correlation between tumor growth rate and cross-sectional vessel area or vessel density as assessed with CD105. Further investigations are needed to ascertain the feasibility of: (i) using circulating endoglin assay to monitor tumor growth; and (ii) targeting neoangiogenesis with anti-endoglin antibodies in sporadic vestibular schwannoma.

Adrenal metastasis from endometrial cancer: A case report.

BACKGROUND: Metastases to adrenal glands originate principally from lung, breast, or gastrointestinal cancers, followed by malignant melanoma and thyroid neoplasms. We present an unusual case of uterine cancer metastasizing to the adrenal glands with a review of the English literature on the management of this rare disease. CASE SUMMARY: A 53-year-old Caucasian woman with a history of endometrial cancer (grade 2; International Federation of Gynecology and Obstetrics III A) was hospitalized in November 2017 for a left adrenal mass found on a follow-up computed tomography scan 3 years after her gynecological surgery. Laboratory test results were normal. A laparoscopic left adrenalectomy was performed. The postoperative course was uneventful, and no chemotherapy was administered. The pathological report confirmed an adrenal endometrioid metastasis. At 36 mo of follow-up, the patient is alive and well, with no evidence of recurrent disease. A literature review identified only 11 previously-published cases of adrenal metastases from uterine cancer. CONCLUSION: Adrenal metastasis from uterine cancer is very rare. Laparoscopic adrenalectomy may be an effective treatment in selected cases of localized adrenal metastasis.

Is vitamin D deficiency a risk factor for osteonecrosis of the jaw in patients with cancer? A matched case-control study.

PURPOSE: A previous case-control histomorphometric study showed higher odds of osteomalacia in patients with bisphosphonate-related osteonecrosis of the jaw (BRONJ). Vitamin D deficiency causes osteomalacia and may therefore be involved in the pathogenesis of BRONJ. The present case-control study aimed at testing such hypothesis. MATERIALS AND METHODS: BRONJ+ and BRONJ- patients treated with bisphosphonates were matched by sex (same) and age (within 5 years). Serum 25-hydroxy-vitamin D (25-OH-D), parathyroid hormone, bone alkaline phosphatase, total procollagen type 1 amino-terminal propeptide, carboxy-terminal collagen crosslinks, Dickkopf WNT signaling pathway inhibitor 1 and sclerostin were measured. RESULTS: The main outcome was vitamin D deficiency defined as 25-OH-D < 50 nmol/l. A total of 51 BRONJ+ and 73 BRONJ- patients were studied. The frequency (95% CI) of vitamin D deficiency was 59% (45%-72%) in BRONJ+ and 62% (48%-75%) in BRONJ- patients. This amounts to a difference of -3% (-22%-16%, p = 0.77) for BRONJ+ patients. Serum 25-hydroxy-vitamin D and parathyroid hormone were similar in BRONJ+ and BRONJ- patients. Among the bone metabolism markers, only sclerostin differed between the two groups, being higher in BRONJ+ patients. CONCLUSION: The present matched case-control study suggests that vitamin D deficiency is not a risk factor for BRONJ.

Nuclear expression of onco-suppressors nm23-H1 and maspin are associated with lower recurrence rate in laryngeal carcinoma.

PURPOSE: The main aim of the study was to preliminarily investigate the possibly related role of nuclear onco-suppressors maspin and nm23-H1, a metastasis suppressor, in laryngeal squamous cell carcinoma (LSCC). MATERIALS AND METHODS: Maspin expression pattern and nuclear nm23-H1 expression were ascertained in 62 consecutive LSCCs. RESULTS: Recurrence rate was significantly lower in patients with a nuclear maspin pattern of expression; nuclear nm23-H1 expression was significantly lower in patients who experienced disease recurrence. Disease free survival (DFS) was significantly longer in patients with maspin nuclear pattern or with nuclear nm23-H1 expression ≥10%. A significant association was found between nuclear nm23-H1 expression and maspin pattern of expression in LSCC. KNN discriminant analysis considered N status, maspin sub-cellular localization and nuclear nm23-H1 expression. The selected variables' accuracy in terms of relapse was 82%. Positive predictive accuracy was 100%, and negative predictive accuracy 79%. CONCLUSIONS: Nuclear nm23-H1 expression and maspin pattern, also in association, show promise as recurrence indicators in LSCC. Further studies are needed to shed more light on the nm23-H1 mechanism of action in LSCC and thus find ways to restore nm23-H1 loss. These preliminary findings suggest that re-activating maspin functions might represent an important goal in the treatment of advanced LSCC.

MicroRNA-Based Prophylaxis in a Mouse Model of Cirrhosis and Liver Cancer.

Most hepatocellular carcinomas (HCCs) arise in the context of chronic liver disease and/or cirrhosis. Thus, chemoprevention in individuals at risk represents an important but yet unproven approach. In this study, we investigated the ability of microRNA (miRNA)-based molecules to prevent liver cancer development in a cirrhotic model. To this end, we developed a mouse model able to recapitulate the natural progression from fibrosis to HCC, and then we tested the prophylactic activity of an miRNA-based approach in the model. The experiments were carried out in the TG221 transgenic mouse, characterized by the overexpression of miR-221 in the liver and predisposed to the development of liver tumors. TG221 as well as wild-type mice were exposed to the hepatotoxin carbon tetrachloride (CCl4) to induce chronic liver damage. All mice developed liver cirrhosis, but only TG221 mice developed nodular lesions in 100% of cases within 6 months of age. The spectrum of lesions ranged from dysplastic foci to carcinomas. To investigate miRNA-based prophylactic approaches, anti-miR-221 oligonucleotides or miR-199a-3p mimics were administered to TG221 CCl4-treated mice. Compared to control animals, a significant reduction in number, size, and, most significantly, malignant phenotype of liver nodules was observed, thus demonstrating an important prophylactic action of miRNA-based molecules. In summary, in this article, we not only report a simple model of liver cancer in a cirrhotic background but also provide evidence for a potential miRNA-based approach to reduce the risk of HCC development.

miR-199a-3p Modulates MTOR and PAK4 Pathways and Inhibits Tumor Growth in a Hepatocellular Carcinoma Transgenic Mouse Model.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. Prognosis is poor, and therapeutic options are limited. MicroRNAs (miRNAs) have emerged as potential therapeutic molecules against cancer. Here, we investigated the therapeutic efficacy of miR-199a-3p, an miRNA highly expressed in normal liver and downregulated in virtually all HCCs. The therapeutic value of miR-199a-3p mimic molecules was assayed in the TG221 mouse, a transgenic model highly predisposed to the development of liver cancer. Administration of miR-199a-3p mimics in the TG221 transgenic mouse showing liver cancer led to a significant reduction of number and size of tumor nodules compared to control animals. In vivo delivery confirmed protein downregulation of the miR-199a-3p direct targets, mechanistic target of rapamycin (MTOR) and p21 activated kinase 4 (PAK4), ultimately leading to the repression of FOXM1. Remarkably, the anti-tumor activity of miR-199a-3p mimics was comparable to that obtained with sorafenib. These results suggested that miR-199a-3p may be considered a promising HCC therapeutic option.

Nuclear nonmetastatic protein 23-H1 expression and epithelial-mesenchymal transition in laryngeal carcinoma: A pilot investigation.

BACKGROUND: In epithelial-to-mesenchymal transition, epithelial cells lose their features, acquiring a mesenchymal-like phenotype. Nm23-H1 protein relates to tumor cells' metastatic potential, its low expression in carcinomas often meaning a poor prognosis. This study newly investigated the role of nuclear nm23-H1 in laryngeal squamous cell carcinoma epithelial-to-mesenchymal transition. METHODS: Immunohistochemical analyses of nuclear nm23-H1, E-cadherin, N-cadherin, Snail, Zinc finger E-box binding homeobox (ZEB)1, and ZEB2 were performed in 33 consecutive patients with laryngeal SCC. RESULTS: Mean nuclear nm23-H1 expression was lower in patients whose disease recurred (P = .0046). Disease-free survival (DFS) was longer for patients whose nuclear nm23-H1 expression was ≥10% (P = .0083). Nuclear nm23-H1 and E-cadherin expressions correlated directly (P = .018). Mean E-cadherin expression was lower in patients whose disease recurred (P = .03). The DFS was shorter in patients with ZEB2 expression ≥5% (P = .006). CONCLUSIONS: Nuclear nm23-H1 expression warrants further investigation in laryngeal SCC as a prognostic marker identifying patients at higher risk of recurrence. nm23-H1 targeted treatments may be capable of regulating epithelial-to-mesenchymal transition.

Cortactin and phosphorylated cortactin tyr421 and tyr466 expression in supraglottic laryngeal carcinomas and lymph node metastases.

BACKGROUND: The most important adverse prognostic factor for laryngeal squamous cell carcinoma (LSCC) is the presence of cervical lymph node metastases. The supraglottic area of the larynx is richly supplied with lymphatics, and 25%-75% of supraglottic carcinomas metastasize in neck lymph nodes. Cortactin is a multidomain protein related to actin cytoskeleton regulation, podosome and lamellipodia formation, integrin signaling, axon guidance and extracellular matrix degradation. Cortactin is involved in metastasis formation because of its role in cell mobility. The present study focused mainly on the role of cortactin and phosphorylated cortactin (residues tyr421 and tyr466) expression and subcellular localization in primary supraglottic LSCCs and their cervical lymph node metastases. METHODS: The immunohistochemical expression of cortactin, p-Y466-cortactin and p-Y421-cortactin was assessed in 38 primary supraglottic LSCCs and 10 lymph node metastases. The statistical approach included bootstrapping analysis. RESULTS: Despite a significantly higher expression of cortactin in carcinoma cells than in adjacent normal laryngeal mucosa, no associations emerged between prognosis and the expression of cortactin or its isoforms in supraglottic LSCC. Statistical analysis found cortactin expression higher in less-differentiated LSCCs (p = 0.03). A significant direct correlation was found between cortactin and p-Y466-cortactin levels (p = 0.031), and between p-Y466-cortactin and p-Y421-cortactin levels (p = 0.001). CONCLUSIONS: Cortactin expression in carcinoma cells and its known involvement in the EGFR pathway suggest a role for this protein as a target for LSCC therapy. Further prospective studies are needed to investigate the potential of cortactin, p-Y466-cortactin and p-Y421-cortactin expression as markers of response to treatment (particularly EGFR-directed agents) in LSCC.

Para-aortic node involvement is not an independent predictor of survival after resection for pancreatic cancer.

AIM: To analyze the importance of para-aortic node status in a series of patients who underwent pancreaticoduodenectomy (PD) in a single Institution. METHODS: Between January 2000 and December 2012, 151 patients underwent PD with para-aortic node dissection for pancreatic adenocarcinoma in our Institution. Patients were divided into two groups: patients with negative PALNs (PALNs-), and patients with metastatic PALNs (PALNs+). Pathologic factors, including stage, nodal status, number of positive nodes and lymph node ratio, invasion of para-aortic nodes, tumor's grading, and radicality of resection were studied by univariate and multivariate analysis. Survival curves were constructed with Kaplan-Meier method and compared with Log-rank test: significance was considered as P < 0.05. RESULTS: A total of 107 patients (74%) had nodal metastases. Median number of pathologically assessed lymph nodes was 26 (range 14-63). Twenty-five patients (16.5%) had para-aortic lymph node involvement. Thirty-three patients (23%) underwent R1 pancreatic resection. One-hundred forty-one patients recurred and died for tumor recurrence, one is alive with recurrence, and 9 are alive and free of disease. Overall survival was significantly influenced by grading (P = 0.0001), radicality of resection (P = 0.001), stage (P = 0.03), lymph node status (P = 0.04), para-aortic nodes metastases (P = 0.02). Multivariate analysis showed that grading was an independent prognostic factor for overall survival (P = 0.0001), while grading (P = 0.0001) and radicality of resection (P = 0.01) were prognostic parameters for disease-free survival. Number of metastatic nodes, node ratio, and para-aortic nodes involvement were not independent predictors of disease-free and overall survival. CONCLUSION: In this experience, lymph node status and para-aortic node metastases were associated with poor survival at univariate analysis, but they were not independent prognostic factors.

Collision of ductal adenocarcinoma and neuroendocrine tumor of the pancreas: a case report and review of the literature.

BACKGROUND: Simultaneous occurrence of exocrine and neuroendocrine tumors of the pancreas is very infrequent. We report a patient with an endocrine tumor in the pancreatic-duodenal area and extensive exocrine carcinoma involving the whole pancreas. CASE PRESENTATION: A 69-year-old woman was hospitalized in May 2016 for epigastric pain and weight loss. Her past medical history revealed an undefined main pancreatic duct dilation that was subsequently confirmed at CT scan (23 mm) and endoscopic ultrasound. There was no evidence of pancreatic masses, but the cephalic portion of the main pancreatic duct presented hypoechoic nodules. A diagnosis of the main-duct intraductal papillary mucinous neoplasm was made, and the patient underwent total pancreatectomy. Pathological examination showed a collision tumor constituted by a ductal adenocarcinoma involving the whole pancreas and a neuroendocrine tumor located in the duodenal peripancreatic wall and the head of the pancreas. There was one peripancreatic lymph node metastasis from the ductal adenocarcinoma and eight node metastases from the neuroendocrine tumor. These findings suggested a diagnosis of collision of neuroendocrine and ductal adenocarcinomas of the pancreas. The postoperative course was uneventful. CONCLUSIONS: The coexistence of pancreatic endocrine and exocrine tumors is very uncommon. When present, problems in differential diagnosis may arise between mixed exocrine-endocrine carcinoma or the collision of separate tumors.

Nuclear survivin expression correlates with endoglin-assessed microvascularisation in laryngeal carcinoma.

AIMS: Survivin-a member of the family of inhibitor of apoptosis proteins that control cell division, apoptosis and metastasis-is overexpressed in virtually all human cancers, including laryngeal squamous cell carcinoma (LSCC). Recent findings also correlate survivin expression with the regulation of angiogenesis. The novel main aim of this study was a preliminary investigation into the potential role of survivin expression in LSCC neoangiogenesis, as determined by endoglin-assessed microvascular density (MVD). METHODS: Immunohistochemical expression of nuclear survivin and endoglin-assessed MVD were ascertained by image analysis in 75 consecutive LSCCs. RESULTS: Statistical analysis disclosed a strong direct correlation between nuclear survivin expression and MVD. Patients whose nuclear survivin expression was ≥6.0% had a significantly higher LSCC recurrence rate, and a significantly shorter disease-free survival (DFS) than those with a nuclear survivin expression <6.0%. The LSCC recurrence rate was also higher and the DFS shorter in patients with endoglin-assessed MVD ≥6.89%. The OR for recurrence was 2.79 in patients with LSCC with a nuclear survivin expression ≥6.0%, and 12.31 in those with an MVD≥6.89%. CONCLUSIONS: Survivin-targeting strategies to enhance tumour cell response to apoptosis and inhibit tumour growth should receive more attention with a view to developing agents for use in multimodality advanced LSCC treatment, or combined with conventional chemotherapy. Given the present preliminary evidence in LSCC, survivin targeting should also be further investigated for anti-angiogenic purposes, to reduce tumour blood flow and induce cancer necrosis.

Thymoma metastatic to liver and pancreas: case report and review of the literature.

A 71-year-old man presented with a thymic mass involving the superior vena cava. A mediastinoscopical biopsy initially suggested a diagnosis of type A thymoma. After neoadjuvant chemotherapy, the patient underwent en-bloc thymectomy and vascular resection for a pathology-confirmed type B3 thymoma involving the superior vena cava, the left brachiocephalic vein and the distal part of the right brachiocephalic vein. Adjuvant radiotherapy was administered. Two years after the primary surgery, abdominal computed tomography (CT) and whole body fluorodeoxyglucose (18-FDG) positron emission tomography (PET) scans showed a single hepatic lesion that was treated with wedge liver resection. Pathological examination confirmed metastatic type B3 thymoma. Almost 4 years later, abdominal CT and 18-FDG PET revealed a 2.9-cm solid mass involving the body of the pancreas. Distal pancreatectomy with lymph node dissection was performed. Pathological examination showed a pancreatic metastasis from a type B3 thymoma, without lymph node involvement. The patient is alive and free of disease 6 months after the pancreatectomy (68 months after the initial thymectomy surgery). Intra-abdominal recurrence and pancreatic metastases are very uncommon manifestations of thymoma, but this event should be kept in mind when an abdominal mass is seen during follow-up.

Cortactin and phosphorylated cortactin tyr466 expression in temporal bone carcinoma.

PURPOSE: Cortactin is a multidomain protein engaged in several cellular mechanisms involving actin assembly and cytoskeletal arrangement. Cortactin overexpression in several malignancies has been associated with increased cell migration, invasion, and metastatic potential. Cortactin needs to be activated by tyrosine or serine/threonine phosphorylation. The role of cortactin and phosphorylated cortactin (residue tyr466) was investigated in temporal bone squamous cell carcinoma (TBSCC). MATERIALS AND METHODS: Immunohistochemical expression of cortactin and phosphorylated cortactin (residue tyr466) was assessed in 27 consecutively-operated TBSCCs. RESULTS: Several clinicopathological variables correlated with recurrence (pT stage, dura mater involvement), and disease-free survival (DFS) (cT stage, pT stage, pN status, dura mater involvement). Twenty-three of 24 immunohistochemically evaluable TBSCCs were cortactin-positive. Median cortactin expression was 75.0%. Cortactin reaction in the cytoplasm was more intense in carcinoma cells than in normal adjacent tissue. Recurrence and DFS rates did not correlate with cortactin and phosphorylated cortactin (residue tyr466) expression in TBSCC specimens. CONCLUSIONS: Cortactin upregulation in TBSCC supports the conviction that inhibiting cortactin functions could have selective effects on this malignancy. Multi-institutional studies should further investigate the role of cortactin and phosphorylated cortactin in TBSCC, and their potential clinical application in integrated treatment modalities.