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Laryngeal squamous cell carcinoma (LSCC) recurrences are very difficult to manage in elderly patients (age ≥65 years), because treatment carries significant morbidity and mortality. The aim of this study was to develop a panel of parameters (clinicopathological variables or biomarkers) to improve our ability to detect elderly patients at higher risk of LSCC recurrence. Maspin, nm23-H1, and CD105 were investigated using immunohistochemistry on surgical specimens from 46 elderly patients treated for LSCC. After univariate analysis identified parameters associated with LSCC recurrence, a multivariate prognostic model was constructed. At univariate analysis, a higher recurrence rate was significantly associated with nm23-H1 nuclear expression in carcinoma cells ≤2.0% (p = 0.01), CD105 expression in intratumoral vascular endothelial cells ≥5.28% (p = 0.04), and pN+ status (p = 0.04). Multivariate modeling confirmed that nuclear nm23-H1 ≤2.0% (p = 0.009) and CD105 ≥5.28% (p = 0.013) had a negative prognostic significance in terms of disease recurrence, while pN+ status showed a trend toward significance (p = 0.05). We thus obtained a panel comprising two biomarkers and neck lymph node status that revealed an excellent discriminatory power [AUC (ROC) of 0.81] in terms of the risk of LSCC recurrence. The panel achieved a specificity of 96% and a positive predictive value of 93%. We identified a panel with an excellent discriminatory power in identifying elderly patients at higher risk of recurrence after treatment for LSCC. These patients would benefit from a more aggressive primary treatment.

Purpose: Reported outcomes of postoperative radiotherapy (PORT) for laryngeal squamous cell carcinoma (LSCC) have varied and sometimes been disappointing. The aim of the present preliminary study was to investigate whether a given immunohistochemical pattern of Maspin expression in laryngeal carcinoma cells could be prognostically associated with response to PORT., Materials and Methods: Thirty-two consecutive patients treated for LSCC with primary surgery and PORT. The subcellular (nuclear vs non-nuclear) pattern of Maspin expression was assessed immunohistochemically on LSCC surgical specimens and analyzed in relation to recurrence rate (RR) and disease-free survival (DFS)., Results: A non-nuclear Maspin expression was found in 23 of 32 cases (72%), and all recurrences (17 cases) occurred in this subgroup of patients. A non-nuclear Maspin expression was strongly associated with recurrence [p = 0.0002, hazard ratio (HR) 5.58] and a shorter DFS (p = 0.0004) after PORT for LSCC. Even in N0 patients, a non-nuclear Maspin expression was associated with a significantly higher RR (p = 0.04, HR 1.42) and a shorter DFS (p = 0.02). Among the common clinic-pathological parameters considered, only N stage showed a trend toward an association with prognosis in terms of DFS (p = 0.08)., Conclusion: Assessing subcellular patterns of Maspin expression in LSCC specimens could identify patients less likely to respond to PORT, who might benefit from combined chemo-radiotherapy to improve the efficacy of adjuvant protocols., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Epidermal growth factor receptor (EGFR) is a trans-membrane tyrosine kinase taking part in cell transformation and tumor progression. One of the downstream pathways controlled by EGFR involves the mammalian target of rapamycin (mTOR), a proto-oncogene activated in several cell functions. Recent evidence seems to confirm that both EGFR and mTOR regulate angiogenesis. The aim of this study was to investigate the expression of EGFR and mTOR in laryngeal squamous cell carcinoma (LSCC) cells in a retrospective clinical setting and their correlation with tumor neo-angiogenesis, judged on the grounds of CD105-assessed microvascular density (MVD), and prognosis. We considered 76 consecutive patients with LSCC treated with surgery alone. Immunohistochemical expressions of EGFR, mTOR, and CD105 were measured using image analysis and findings underwent statistical analysis using univariate and multivariate models. We found that nodal status correlated significantly with patient prognosis in terms of disease-free survival (DFS) (p = 0.01). There was a strong direct correlation between mTOR and EGFR expression (p = 0.0003), and between mTOR and CD105-assessed MVD (p = 0.0025). Patients with a CD105-assessed MVD >5.28 % had a significantly higher recurrence rate (RR) (p = 0.026), and a significantly shorter DFS (p = 0.025). On multivariate analysis, only N stage [hazard ratio (HR) 3.54, p = 0.009] and CD105-assessed MVD (HR 2.87, p = 0.027) maintained their independent prognostic significance in terms of DFS. Judging from our promising findings, the EGFR-mTOR pathway should be investigated further to understand its role in LSCC neo-angiogenesis.

Background: Clinicopathological research has focused on identifying molecular and biological prognostic factors for laryngeal carcinoma (LSCC) treated with post-operative radiotherapy (RT). The aim of this study was to assess the prognostic importance of anti-apoptotic proteins survivin and B-cell lymphoma-2 (Bcl-2) in a series of patients with LSCC who had primary surgery followed by RT., Methods: Thirty-three consecutive patients who underwent primary surgery followed by RT were considered. Survivin nuclear and cytoplasmic expressions and Bcl-2 expression were determined immunohistochemically., Results: The loco-regional recurrence rate was significantly higher among LSCC patients with a nuclear survivin expression >10.0% (P = 0.029), and their disease-free survival (DFS) was shorter than in cases whose nuclear survivin expression was ≤10.0% (P = 0.002). DFS was significantly shorter in cases with a Bcl-2 expression >2.0% than in those whose Bcl-2 expression was ≤2.0% (P = 0.035)., Conclusions: Nuclear survivin expression and Bcl-2 expression warrant further investigation as potential predictive biomarkers to enable individualized treatments (e.g. post-operative chemo-radiotherapy instead of RT alone for patients whose LSCCs strongly express nuclear survivin or/and Bcl-2). This preliminary evidence justifies the design of new studies on the association of agents targeting survivin and Bcl-2 with conventional chemotherapeutic agents and RT for advanced LSCC., (© 2012 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.)

Aims: To use image analysis and multivariate analysis to investigate the prognostic significance of Nm23-H1 subcellular localization in a large cohort of laryngeal squamous cell carcinomas (LSCCs)., Methods and Results: Nm23-H1 total and nuclear levels were immunohistochemically determined and calculated with an image analysis system in 104 consecutively operated LSCCs. The mean follow-up was 58.3 ± 35.1 months (median 45 months). Total Nm23-H1 levels correlated only with patient stratification by pT (P=0.01). Mean nuclear Nm23-H1 levels were lower in patients with recurrent disease (P=0.01), and disease-free survival (DFS) was longer in patients whose nuclear levels of Nm23-H1 were >2.0% than in those with levels ≤ 2.0% (P=0.019). On multivariate analysis, Nm23-H1 nuclear expression [hazard ratio (HR) 2.59, P=0.005] and N stage (HR 3.60, P=0.0001) were prognostically significant in relation to DFS., Conclusions: In LSCC, Nm23-H1 nuclear expression may be useful for identifying patients at higher risk of recurrence after treatment and who might be considered for more aggressive therapy. Further investigations are needed before Nm23-H1 can be considered for use in targeted treatments for LSCC., (© 2012 Blackwell Publishing Limited.)

Conclusions: A large series confirmation may suggest elective neck dissection in cN0 MASPIN-negative oral squamous cell carcinomas (SCCs). Re-activated nuclear MASPIN in association with anti-angiogenic or cytotoxic drugs may be extremely effective in the treatment of laryngeal SCC., Objectives: MASPIN is a serpin showing a unique tumour-suppressing activity. Despite the significant incidence of head and neck SCC (HNSCC), a limited number of studies has considered MASPIN's role in these malignancies. This review focuses on the attempts to translate MASPIN's HNSCC suppressive properties toward a diagnostic/prognostic tool and a novel carcinoma therapy., Methods: A systematic literature review was performed to investigate available evidence about MASPIN subcellular localization and biological role in HNSCC., Results: Five studies have investigated MASPIN's expression in oral SCC. Most of them concluded that low or absent MASPIN cytoplasmic expression was more frequent in oral carcinomas with lymph node metastases. Only our group evaluated MASPIN's role in laryngeal SCC. Higher nuclear MASPIN expression was found in patients without SCC recurrence and was significantly associated with longer disease-free survival. Micro-vascular density was lower in laryngeal carcinomas with MASPIN nuclear staining. The relation between MASPIN and M30-assessed apoptosis in laryngeal SCC supports the hypothesis of an important apoptosis-sensitizing effect of nuclear MASPIN.

It is known that 15-20% of oropharyngeal carcinomas develop distant metastases that involve most commonly lung, liver and bone. Clival metastasis from oropharyngeal squamous cell carcinoma has not been previously reported in the English literature. We describe the rare occurrence of clival metastasis from tonsillar carcinoma presenting with abducent paralysis and discuss diagnostic and therapeutic rational approaches. Despite neoadjuvant chemotherapy (cisplatinum/etoposide/epirubicin followed by taxotere), extended left tonsillectomy and ipsilateral radical neck dissection and external radiotherapy (60 Gy) for tonsillar carcinoma, the patient developed clival metastasis and died of disease. The overall prognosis of patients with clival metastases is extremely poor, with an overall median survival of about 2.5 years. Cranial nerve palsy occurrence is associated with a poorer prognosis with an average survival of only 5 months.

Aims: Angiogenesis is essential for malignancies growth. CD105 is a proliferation-associated protein abundantly expressed in angiogenic endothelial cells. The aim of this study has been to determine the expression of CD105 in laryngeal squamous cell carcinoma (SCC) and to investigate the role of CD105-assessed mean vascular density (MVD) in predicting patients' prognosis., Methods: The sections of 43 consecutive cases of laryngeal SCC were stained with mouse monoclonal antibody CD105. All the measures were performed by a computer-based image analysis system. The percentage of the fields occupied by CD105-assessed micro-vessels was determined., Results: The mean CD105-assessed MVD were 11% and 6% in laryngeal SCC with and without malignancy recurrence, respectively. Multivariate logistic regression stated that CD105-assessed MVD was significantly related to disease recurrence (p=0.030)., Conclusions: Our preliminary results suggest that CD105-assessed MVD may be a valuable parameter for predicting patients having an increased risk of developing laryngeal carcinoma loco-regional recurrence.

Conclusions: The present preliminary results suggest that endoglin (CD105)-assessed micro-vessel density (MVD) in primary oral and oropharyngeal squamous cell carcinomas (SCCs) may identify patients at risk of disease recurrence or poor oncological outcome after treatment., Objectives: MVD is an independent prognostic indicator in several human malignancies. Endoglin antibodies have shown a greater specificity for tumour vasculature in comparison with pan-endothelial markers. The present explorative study evaluated endoglin expression and its prognostic role in oral and oropharyngeal SCCs., Patients and Methods: The study considered 13 consecutive cases of oral and oropharyngeal SCC with lymph node metastases (pN+) and 13 consecutive pN0 cases. CD105-assessed MVD was calculated at 400x magnification., Results: The mean MVDs were 3.6 and 3.1 in pN+ and pN0 groups, respectively (p>0.05). The mean CD105-assessed MVDs were 4.7 in the group with locoregional recurrence and 2.9 in the group without locoregional recurrence or post-treatment diagnosis of distant metastasis (p=0.01). The mean CD105-assessed MVD in primary oral and oropharyngeal SCCs with poor oncological outcome (recurrence of disease or occurrence of distant metastasis) was 4.3. The mean MVD in primary oral and oropharyngeal SCCs with good outcome was 2.9. Statistical analysis showed a significant difference between CD105-assessed MVD in poor and good outcome groups (p=0.02).

Conclusions: This comparison of neo-angiogenesis performed by analysing CD105 expression seems to suggest that the biological behaviour of head and neck BSCCs is similar to that of site- and stage-matched conventional SCCs., Objective: Basaloid squamous cell carcinoma (BSCC) is an uncommon, high-grade biomorphic variant of SCC with a predilection for the head and neck region. It is a matter of controversy whether the biological and clinical behaviour of BSCC is more aggressive than that of SCC. Angiogenesis is essential for tumour growth. It has been established that endothelial cells of tumour-associated neovasculature proliferate more rapidly than endothelial cells of normal tissue. Endoglin (CD105) has been shown to be a useful marker for identifying proliferating endothelium involved in tumour angiogenesis. The aim of this study was to investigate the expression of CD105 in head and neck BSCCs and to compare it with that in SCCs., Material and Methods: Nine head and neck BSCCs (five cases in the larynx, three in the tongue and one in the tonsil) were considered. A group of nine site- and stage-matched SCCs was examined simultaneously. For each sample, CD105 reactivity was evaluated immunohistochemically. The mean area fraction (percentage of fields occupied by vessels), the percentage of vessel-presenting fields and the vessel density were considered., Results: The median values of the mean area fraction were 1.01% and 0.9% in BSCCs and SCCs, respectively. The median values of the percentage of vessel-presenting fields were 57.5% and 46.67% in BSCCs and SCCs, respectively. The median values of vessel density were 2.07% and 1.58% in BSCCs and SCCs, respectively. Statistical analysis did not disclose any significant differences between BSCCs and SCCs for any of the above-mentioned parameters.

The frequency of non-lymphatic distant metastases from primary head and neck squamous cell carcinoma (SCC) appears to be higher than previously presumed. The general conditions of the affected patients, who usually also present with locoregional recurrences, are so impaired as to limit the use of available methods for diagnosing the distant spread of head and neck SCC. The incidence reported in autopsy studies is approximately three to four times higher than that in clinical studies. Lung metastases from head and neck SCC are most common, followed by metastases to bone and liver. Metastases to the skin are unusual. Secondary ocular localizations of head and neck SCC are exceedingly rare. We report the first case of synchronous intraocular (involving the choroid and vitreous body) and cutaneous metastases from a recurrent tongue base SCC in a 64-year-old woman who had undergone radiotherapy, bilateral neck dissection and chemotherapy. Cytological evaluation of vitreous aspirate and histological diagnosis of the skin lesion were performed < 1 month before the patient's death. Skin metastases occur in 1-4% of patients with diagnosed head and neck SCC and are usually associated with advanced or recurrent disease. To the best of our knowledge, fewer than 10 cases of ocular metastases from head and neck SCC have been reported. The average survival time after diagnosis of ocular or skin metastases from head and neck SCC is 7 months. Treatment for eye and skin metastases is palliative and rarely alters patient outcome.