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The landscape of neoplastic pathology of the oesophagus is dominated by malignancies of epithelial origin, in particular by oesophageal adenocarcinoma and oesophageal squamous cell carcinoma. However, several other histopathological variants can be distinguished, some associated with peculiar histopathological profiles and prognostic behaviours and frequently underrecognized in clinical practice. The aim of this review is to provide a comprehensive characterization of the main morphological and clinical features of these rare variants of oesophageal neoplastic lesions., Competing Interests: Conflict-of-interest statement: Matteo Fassan had roles as a consultant or advisor for Tesaro and Astellas. He received research funding from Astellas and QED. The other authors have no competing interests to declare., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Aim: The novel primary end-point of the present study was to ascertain β-arrestin-1 expression in a cohort of consecutive patients with laryngeal squamous cell carcinoma (LSCC) with information available on their cigarette-smoking habits. A secondary end-point was to conduct a preliminary clinical and pathological investigation into the possible role of β-arrestin-1 in the epithelial-to-mesenchymal transition (EMT), identified by testing for E-cadherin, Zeb1, and Zeb2 expression, in the setting of LSCC., Methods: The expression of β-arrestin-1, E-cadherin, zeb1, and zeb2 was ascertained in 20 consecutive LSCCs., Results: Statistical analysis showed no significant associations between β-arrestin-1 and EMT (based on the expression of E-cadherin, Zeb1, and Zeb2). The combined effect of nicotine and β-arrestin-1 was significantly associated with a shorter disease-free survival ( P=0.01) in our series of LSCC. This latter result was also confirmed in an independent, publicly available LSCC cohort ( P=0.047)., Conclusions: Further investigations on larger series (ideally in prospective settings) are needed before we can consider closer follow-up protocols and/or more aggressive treatments for patients with LSCC and a combination of nicotine exposure and β-arrestin-1 positivity in tumor cells at the time of their diagnosis. Further studies on how β-arrestin functions in cancer via different signaling pathways might reveal potential targets for the treatment of even advanced laryngeal malignancies.

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., (© 2018 Wiley Periodicals, Inc.)

Dysregulation of host microRNA expression has been involved in the development and progression of human papillomavirus (HPV)-related tumors. Analysis of miR-146a expression in a series of 59 penile squamous cell carcinomas (PSCCs) showed that its levels were lower in high-risk HPV-positive than in HPV-negative PSCCs and inversely correlated with expression of epidermal growth factor receptor (EGFR), a known target for miR-146a. Analysis of genotype distribution for rs2910164, a common functional polymorphism of miR-146a, did not identify correlations with miR-146a levels and EGFR expression in PSCCs. In vitro experiments demonstrated that E6 of HPV type 16, but not low-risk HPV-6, down-regulated miR-146a in human foreskin keratinocytes and up-regulated EGFR. Ectopic expression of miR-146a decreased expression of EGFR and inhibited proliferation of keratinocytes and cervical carcinoma cells. EGFR is commonly overexpressed in penile cancer and in other squamous cell carcinomas. Molecular mechanisms leading to EGFR overexpression and activation are known for HPV-negative cancers and include amplification or mutations of the EGFR gene. The results of this study indicate that down-regulation of miR-146a may represent another mechanism of EGFR overexpression in PSCCs, which can be mediated by high-risk HPV E6 in HPV-related tumors., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Temporal bone squamous cell carcinoma (TBSCC) is an uncommon, aggressive malignancy with a poor prognosis in advanced cases. The dismal outcome is partially related to: the lack of reliable clinical or pathological prognostic factors and the largely unstandardized surgical and integrated treatments adopted. There is an undeniable need for novel diagnostic/therapeutic strategies to improve the prognosis. The purpose of this critical review was to explore the level of available knowledge concerning the molecular markers involved in the biology of TBSCC that have a prognostic potential. The Pub-Med and Scopus electronic databases were searched without publication date limits for studies investigating molecular markers in cohorts of patients with primary TBSCC. The search terms used were: "temporal bone cancer", "temporal bone carcinoma", "temporal bone malignancy", "ear cancer", "ear carcinoma", and "ear malignancy". We decided preliminarily not to consider series with less than five cases. Nine retrospective case series of TBSCC were found in which different analytical techniques had been used to study the role of several biomarkers (HPV, vimentin, transforming growth factor β, CD105, RECK, matrix metalloproteinase-9, MASPIN, EBV, p16, TP53 mutation, pSTAT3, relaxin-2). CD105 expression (in tumor vessel endothelial cells) and MASPIN cytoplasmic expression (in carcinoma cells) were, respectively, found directly and inversely related with the neoplasm's recurrence rate. CD105 expression was also inversely related with disease-free survival in TBSCC. A future goal of such analyses should be to ascertain the radio- and chemo-sensitivity profiles of individual TBSCCs, enabling truly personalized therapies. A further, more ambitious goal will be to find targets for therapeutic agents that might prove crucial in improving the disease-specific survival for patients with advanced TBSCC.

Background: When advanced, oral squamous cell carcinoma (OSCC) may involve adjacent non-epithelial structures, and the prognosis is worse for bone invasion. Human relaxin-2 is a peptide hormone that has recently been associated with cancer. It can induce human osteoclast differentiation and activation, suggesting a role in tumor-driven osteolysis. This study was a preliminary assessment of the prognostic role of relaxin-2 in surgical specimens of OSCC tissue and adjacent but uninvolved mandibular/maxillary bone., Methods: Relaxin-2 immunohistochemical expression and reaction intensity were assessed in tumor and uninvolved adjacent mandibular/maxillary bone specimens from 23 operated OSCC patients., Results: All OSCC specimens were positive for relaxin-2. The intensity of its reaction in OSCC correlated significantly with the pattern of the tumor's invasion front (p = 0.02), being higher with the infiltrative pattern. Mean relaxin-2 immunohistochemical expression was higher in patients whose OSCC recurred after treatment than those experiencing no recurrence (81.3% ± 22.6% vs. 59.5% ± 29.7%, respectively). A significant direct association emerged between relaxin-2 expression in OSCC specimens and recurrence rate (p = 0.049)., Conclusions: Relaxin-2 expression in OSCC should be further investigated as a potentially useful marker for identifying patients at higher risk of recurrence, who might benefit from closer follow-up and more aggressive adjuvant therapy. In other oncological settings, increasing evidence of relaxin being produced by cancer cells is prompting efforts to synthesize human relaxin-2 analogs capable of acting as antagonists and limiting tumor growth.

Background: Laryngeal verrucous squamous cell carcinoma (VSCC) is a highly differentiated squamous cell carcinoma (SCC), the diagnosis of which can meet with many pitfalls: benign hyperplastic lesions and conventional SCC are the most important differential diagnoses. The microRNA miR-19a is overexpressed in many solid tumours and regulates the suppressor of cytokine signalling-1 (SOCS-1) expression., Aims: The main endpoints were to assess miR-19a and SOCS-1 expression in glottic VSCC, and the former's potential role in differentiating between glottic VSCC, conventional SCC and hyperplastic lesions., Methods: The expression of MiR-19a (by reverse transcription and quantitative real-time PCR) and SOCS-1 (by immunohistochemistry, rabbit polyclonal anti-SOCS-1 antibody) was assessed in 11 consecutive cases of glottic VSCC, 20 of papillary hyperplasia and 42 cases of conventional SCC., Results: Mean miR-19a expression was significantly higher (p = 0.000) in malignant glottic lesions (conventional SCC/VSCC) than in benign conditions. Significant differences in mean miR-19a expression also emerged between conventional SCC and papillary hyperplasia (p = 0.000), and between conventional SCC and VSCC (p = 0.03). miR-19a expression was not statistically associated with SOCS-1 immunoreactivity or immunostaining intensity in VSCC, conventional SCC or papillary hyperplasia., Conclusions: Our preliminary outcomes suggest the utility of miR-19a in the challenging differential diagnosis of laryngeal VSCC. Although miR-19a has been found to regulate SOCS-1 expression, this evidence was not confirmed by this investigation., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

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., (© 2015 John Wiley & Sons Ltd.)

Background: Development of novel therapeutic drugs and regimens for cancer treatment has led to improvements in patient long-term survival. This success has, however, been accompanied by the increased occurrence of second primary cancers. Indeed, patients who received regional radiotherapy for Hodgkin's Lymphoma (HL) or breast cancer may develop, many years later, a solid metachronous tumor in the irradiated field. Despite extensive epidemiological studies, little information is available on the genetic changes involved in the pathogenesis of these solid therapy-related neoplasms., Methods: Using microsatellite markers located in 7 chromosomal regions frequently deleted in sporadic esophageal cancer, we investigated loss of heterozygosity (LOH) and microsatellite instability (MSI) in 46 paired (normal and tumor) samples. Twenty samples were of esophageal carcinoma developed in HL or breast cancer long-term survivors: 14 squamous cell carcinomas (ESCC) and 6 adenocarcinomas (EADC), while 26 samples, used as control, were of sporadic esophageal cancer (15 ESCC and 11 EADC)., Results: We found that, though the overall LOH frequency at the studied chromosomal regions was similar among metachronous and sporadic tumors, the latter exhibited a statistically different higher LOH frequency at 17q21.31 (p = 0.018). By stratifying for tumor histotype we observed that LOH at 3p24.1, 5q11.2 and 9p21.3 were more frequent in ESCC than in EADC suggesting a different role of the genetic determinants located nearby these regions in the development of the two esophageal cancer histotypes., Conclusions: Altogether, our results strengthen the genetic diversity among ESCC and EADC whether they occurred spontaneously or after therapeutic treatments. The presence of histotype-specific alterations in esophageal carcinoma arisen in HL or breast cancer long-term survivors suggests that their transformation process, though the putative different etiological origin, may retrace sporadic ESCC and EADC carcinogenesis.

Penile squamous cell carcinoma (PSCC) is a rare tumor associated with high-risk human papillomavirus (HR-HPV) infection in 30% to 60% of cases. Altered expression of miRNAs has been reported in HPV-related cervical and head and neck cancers, but such data have not been available for PSCC. We analyzed a series of 59 PSCCs and 8 condylomata for presence of HPV infection, for p16(INK4a), Ki-67, and p53 immunohistochemical expression, and for expression of a panel of cellular miRNAs (let-7c, miR-23b, miR-34a, miR-145, miR-146a, miR-196a, and miR-218) involved in HPV-related cancer. HR-HPV DNA (HPV16 in most cases) was detected in 17/59 (29%) PSCCs; all penile condylomata (8/8) were positive for low-risk HPV6 or HPV11. HR-HPV(+) PSCCs overexpressed p16(INK4a) in 88% cases and p53 in 35% of cases, whereas HR-HPV(-) PSCCs were positive for p16(INK4a) and p53 immunostaining in 9% and 44% of cases, respectively. Among the miRNAs investigated, expression of miR-218 was lower in PSCCs with HR-HPV infection and in p53(-) cancers. Hypermethylation of the promoter of the SLIT2 gene, which contains miR-218-1 in its intronic region, was frequently observed in PSCCs, mainly in those with low miR-218 expression. Epigenetic silencing of miR-218 is a common feature in HR-HPV(+) PSCCs and in HR-HPV(-) PSCCs without immunohistochemical detection of p53., (Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Objective: Temporal bone squamous cell carcinoma (SCC) accounts for less than 0.2% of all head and neck tumors. Although some progress has been made in treating this aggressive tumor, the prognosis in advanced cases remains poor. More effective therapeutic strategies need to be considered, including receptor-mediated carcinoma-targeted therapy. Phosphorylated STAT3 (pSTAT3) regulates many genes that are necessarily expressed in cancer initiation, development, and progression, being involved in proliferation, anti-apoptosis, invasion, angiogenesis, and immune surveillance evasion. The aim of the present study was to preliminarily investigate the potential prognostic role of pSTAT3 expression in temporal bone SCC., Study Design: Retrospective clinicopathologic investigation., Setting: Tertiary referral centers., Patients: Twenty-five consecutively operated patients with primary temporal bone SCC., Intervention: pSTAT3 immunohistochemical expression in primary temporal bone SCCs was assessed with the aid of computer-based image analysis., Main Outcome Measures: Conventional clinicopathologic parameters and pSTAT3 expression were correlated with SCC prognosis., Results: pT, stage, and surgical margin status were significantly related with recurrence rate (p = 0.002, p = 0.01, and p = 0.047, respectively) and disease-free survival (DFS) (p = 0.0049, p = 0.031, and p = 0.035, respectively). pT classification was also related with disease-specific survival (DSS) (p = 0.035). The SCC recurrence rate did not correlate with pSTAT3 expression. Statistical analyses ruled out any significant difference in DFS or DSS when patients were stratified by pSTAT3 expression (>80.0% or ≤80.0%)., Conclusion: Despite our preliminary results, the role of pSTAT3 in temporal bone SCC warrants further investigation in larger series because there is increasing evidence in preclinical models to indicate that inhibiting STAT3 phosphorylation can be a useful addition to different anticancer strategies.

AThe emerging treatment revolution determined by the advent of new targeted therapies requires accurate tumour subtyping as a mandatory step in the clinical workup of patients with non-small cell lung carcinoma (NSCLC). As a result of advanced and inoperable disease or poor performance status, in many patients, minimally invasive procedures must be employed to obtain diagnostic material. Fine needle aspiration (FNA) is a valid and widely employed alternative to either tru-cut or open-sky biopsy. Indeed, cytological specimens are suitable for techniques such as immunocytochemistry, mutation and microRNA analysis, and may present advantages over small biopsies especially if cell blocks are prepared and attention is paid to cytomorphology and pre-analytic management of specimens at the time they are collected. These will allow the adequate stratification of patients into different diagnostic and prognostic classes., (© 2012 Blackwell Publishing Ltd.)

Background: Emerging targeted lung cancer therapies require the accurate morphologic subclassification of non-small cell lung cancer (NSCLC), even in scant and distorted specimens obtained by transthoracic needle aspiration (TTNA). MicroRNAs (miRNAs) are small noncoding genes recently reported as useful in differentiating squamous cell carcinoma (SCC) from adenocarcinoma (AD) in resected tumor specimens. We investigated their ability to do so in TTNA specimens., Methods: Smears, immunocytochemistry slides, and corresponding cell blocks of 31 NSCLC TTNA specimens were retrieved and classified as AD or SCC based on their cytologic features and immunocytochemical profiles. Data on EGFR and K-RAS mutational status were available for all cases of AD. We quantified the hsa-let-7 family and hsa-miR-205 by quantitative reverse transcription-polymerase chain reaction and compared the miRNA expression levels in AD and SCC using Student t test., Results: Eighteen cases were classified as AD and 13 as SCC by light microscopy and immunocytochemistry. miRNA expression profiles demonstrated considerable, statistically significant differences between AD and SCC, showing an upregulation of hsa-let-7a, hsa-let-7b, hsa-let-7c,hsa-let-7f, hsa-let-7g, hsa-let-7i, and hsa-miR-98 and a downregulation of hsa-miR-205 in AD specimens (all P < .05; t test)., Conclusions: Profiling the hsa-let-7 family and hsa-miR-205 is a promising method for differentiating AD from SCC, even in such small specimens as transthoracic aspirates. Subject to the validation of these findings in further, larger studies, this could prove to be a reliable, standardizable tool for the subclassification of NSCLC.