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AIMS In chronic rhinosinusitis with nasal polyps (CRSwNP), tools based on objective evidence, such as histopathology, are needed to assist clinical decision-making. The main aim of this exploratory investigation was to determine whether structured histopathology could be used to classify CRSwNP in homogeneous histological clusters. METHODS AND RESULTS A cohort of 135 CRSwNP patients was assessed, on the basis of clinicopathological features: allergic fungal rhinosinusitis (17 patients); non-steroidal anti-inflammatory drug-exacerbated respiratory disease (19 patients); intrinsic asthma (18 patients); extrinsic asthma (21 patients); allergy (21 patients); histologically eosinophilic (22 patients); and histologically non-eosinophilic (17 patients). For structured histopathology, we considered: the degree of inflammation; eosinophil count; eosinophil aggregates; neutrophil infiltration; goblet cell hyperplasia; basement membrane thickening; fibrosis; hyperplastic/papillary changes; squamous metaplasia; mucosal ulceration; and subepithelial oedema. Cluster analysis identified four distinct sets of cases. On discriminant analysis, the global error rate was 1.48%, and the stratified error rates were 4.34%, 0%, 0%, and 0% for clusters 1, 2, 3 and 4, respectively. Cluster 1 was characterised by infrequent fibrosis (

Marioni G, Ottaviano G, Lionello M, Lora L, Lovato A, Staffieri C, Favaretto N, Giacomelli L, Stellini E, Staffieri A & Blandamura S (2012) Histopathology Nm23-H1 nuclear expression is associated with a more favourable prognosis in laryngeal carcinoma: univariate and multivariate analysis 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.

Marioni G, Agostini M, Bedin C, Blandamura S, Stellini E, Favero G, Lionello M, Giacomelli L, Burti S, D’Angelo E, Nitti D, Staffieri A & De Filippis C (2012) Histopathology 61, 247–256 Survivin and laryngeal carcinoma prognosis: nuclear localization and expression of splice variants Aims: Aberrant survivin expression in cancer cells has been associated with tumour progression, radiation/drug resistance and shorter patient survival. The aim of the present study was to investigate survivin expression in laryngeal carcinoma (LSCC) tissue and – for the first time at this site – the expression of survivin splice variants. P53 was also studied. Methods and results: Survivin and p53 expression was determined immunohistochemically in 86 consecutive patients operated for LSCC. Survivin mRNA expression was assessed by quantitative real-time polymerase chain reaction (PCR). Hot-spot mutations in exons 5, 6, 7 and 8 of the TP53 gene were studied by sequencing analysis. A nuclear localization for survivin predominated. There was a significant association between a higher nuclear survivin expression and LSCC recurrence (P = 0.046). Disease-free survival (DFS) for LSCC patients with a nuclear survivin expression >7.0% was shorter than in cases whose expression was ≤7.0% (P = 0.05). Wild-type survivin correlated significantly with nuclear survivin expression (P = 0.02). p53 expression was associated with the co-expression of wild-type survivin and survivin-2B (P = 0.01). Conclusions: Nuclear expression of survivin appears to influence LSCC aggressiveness, a higher nuclear survivin expression correlating with a higher recurrence rate and a shorter DFS. Wild-type survivin was the most frequently detected splice variant in LSCC tissues.

Marioni G, Staffieri A, Giacomelli L, Lionello M, Guzzardo V, Busnardo A & Blandamura S (2011) Histopathology 58, 1148–1156 Mammalian target of rapamycin expression and laryngeal squamous cell carcinoma prognosis: novel preliminary evidence Aims: The mammalian target of rapamycin (mTOR) has a key role in regulating cancer cell proliferation, apoptosis, cell migration, and angiogenesis. The aim of this study was to assess the relationships between mTOR and clinicopathological and prognostic parameters in laryngeal squamous cell carcinoma (SCC). Methods and results: Mammalian target of rapamycin expression was determined in 103 consecutive operable laryngeal SCCs. Among the mTOR-positive cases, the locoregional recurrence rate was higher (P = 0.048) and the disease-free survival (DFS) rate was shorter (P = 0.031) in patients with mTOR expression >50.7%. In the N0 subgroup, the disease recurrence rate was higher (P = 0.034) and the DFS was shorter (P = 0.009) in patients with mTOR expression >50.7%. In mTOR-positive patients, multivariate analysis showed that N stage (P = 0.0001) and mTOR status (P = 0.042) were independent indicators of a poor prognosis. Conclusions: mTOR appeared to be a significant predictor of DFS in univariate and multivariate models. mTOR expression in laryngeal SCC may be useful for the detection of patients at higher risk for recurrence, and N0 patients at higher risk for early locoregional recurrence who might benefit from more aggressive therapy. The role of mTOR inhibitors in multimodality or multitarget strategies against laryngeal SCC warrants investigation.

Marioni G, Marino F, Blandamura S, D’Alessandro E, Giacomelli L, Guzzardo V, Lionello M, de Filippis C & Staffieri A (2010) Histopathology57, 535–543 Neoangiogenesis in laryngeal carcinoma: angiogenin and CD105 expression is related to carcinoma recurrence rate and disease-free survival Aims: Angiogenin regulates angiogenesis supporting primary and metastatic tumour growth. CD105 is a proliferation-associated protein expressed in angiogenic endothelial cells. The aim of this study was to investigate for the first time angiogenin expression in laryngeal squamous cell carcinoma (LSCC) and to evaluate the relationship between angiogenin and CD105 expression, clinicopathological and prognostic parameters. Methods and results: A total of 108 consecutive operable LSCCs were studied. Angiogenin expression was determined immunohistochemically in both carcinoma cells and intratumoral vessels. CD105 expression was evaluated in endothelial cells of LSCC and calculated by a computer-based image analysis system. The percentage of the fields occupied by CD105-assessed microvessels was determined. Angiogenin expression in carcinoma cells was higher in LSCC patients who experienced loco-regional recurrence of disease (P = 0.032). Disease-free survival (DFS) was shorter in cases with carcinoma cells showing angiogenin expression >21.0% (P = 0.035). Angiogenin expression in carcinoma cells was correlated strongly with the angiogenin score in endothelial cells of intratumoral vessels (P = 0.0000). Higher loco-regional carcinoma recurrence rate and shorter DFS in patients with high CD105 expression were found (P = 0.0004, P = 0.0001). Conclusions: Angiogenin expression in laryngeal carcinoma cells and CD105 expression can be considered as potentially useful to detect LSCC patients with higher risk of disease recurrence who might benefit from more aggressive therapy.

Aims Laryngeal squamous cell carcinoma (LSCC) prognosis is definitely related to lymph node metastasis. Epithelial–mesenchymal transition (EMT) allows neoplastic cells to gain the plasticity and motility required for tumour progression and metastasis. The aim of this study was to investigate the role of EMT in the prognosis of LSCC. Methods and results Immunohistochemical analysis of E-cadherin, N-cadherin, Snail, Slug, ZEB1, and ZEB2 was performed in 37 consecutive LSCC cases. Low E-cadherin levels and high Slug levels correlated with both disease recurrence (P = 0.02 and P =0.01, respectively) and shorter disease-free survival (DFS) (P = 0.04 and P = 0.02, respectively). Relative expression levels of CDH1, SNAI2, miR-1 and the miR-200 family were also evaluated. CDH1, miR-200a and miR-200c down-regulation and SNAI2 overexpression were significantly associated with disease recurrence (P = 0.03, P = 0.02, P = 0.04, and P = 0.04, respectively). Conclusions EMT increases tumour recurrence risk and shortens DFS in LSCC. E-cadherin and Slug immunohistochemical analysis could be useful for identifying patients requiring more aggressive treatment after surgery.