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Esophageal cancer (EC) is a pressing global health concern, ranking as the eighth most common cancer and the sixth leading cause for cancer-related deaths worldwide. Esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC) are the two major histological types of esophageal cancer associated with distinct risk factors and geographical distributions. Unfortunately, the outcomes for both types of EC remain discouraging, with a five-year survival rate of less than 20% when diagnosed at advanced stages. Advanced endoscopic techniques have the potential to vastly enhance patient outcomes and impede the progression of pre-malignant lesions to cancer. However, low screening rates with endoscopy due to its invasive nature and high cost hinder its effectiveness. Despite extensive research on risk predictors, a significant number of cases still go undiagnosed, highlighting the need for improved screening techniques that can be implemented at the population level. To increase uptake, a shift towards minimally invasive, well-tolerated and cost-effective non-endoscopic technologies is crucial. The implementation of such devices in primary care settings, specifically targeting high-risk populations, can be a promising strategy. With early detection and enrollment in surveillance programs, there is hope for substantial improvement in morbidity and mortality rates through modern minimally invasive endoscopic and surgical techniques. [ABSTRACT FROM AUTHOR]

Cancer-associated fibroblasts (CAFs), a heterogenous population, can promote cancer cell proliferation, migration, invasion, immunosuppression, and therapeutic resistance in solid tumors. These effects are mediated through secretion of cytokines and growth factors, remodeling of the extracellular matrix, and providing metabolic support for cancer cells. The presence of CAFs in esophageal carcinoma are associated with reduced overall survival and increased resistance to chemotherapy and radiotherapy; thus, identifying therapeutic vulnerabilities of CAFs is a necessity. In esophageal cancer, the mechanisms for CAF recruitment, CAF-mediated promotion of tumorigenesis, metastatic dissemination, and therapeutic resistance have yet to be fully evaluated. Here, we provide an overview of the current understanding of CAFs in esophageal cancer, namely in esophageal squamous cell carcinoma and esophageal adenocarcinoma, as well as in the preneoplastic conditions that predispose to these cancers. Interestingly, there is a discrepancy in our knowledge of CAF biology between esophageal cancer subtypes, with very few studies in esophageal adenocarcinoma, and its precursor lesion Barrett’s esophagus, compared with esophageal squamous cell carcinoma. We propose that although great strides have been made, certain questions remain to which answers hopefully will emerge to have an impact on biomarker diagnostics and translational therapeutics.

Endoscopy is the gold standard for the diagnosis of cancers and cancer precursors in the oesophagus and stomach. Early detection of upper GI cancers requires high-quality endoscopy and awareness of the subtle features these lesions carry. Endoscopists performing surveillance of high-risk patients including those with Barrett's oesophagus, previous squamous neoplasia or chronic atrophic gastritis should be familiar with endoscopic features, classification systems and sampling techniques to maximise the detection of early cancer. In this article, we review the current approach to diagnosis of these conditions and the latest advanced imaging and diagnostic techniques. [ABSTRACT FROM AUTHOR]

Squamous dysplasia is the histological precursor of esophageal squamous cell carcinoma (ESCC). The optimal management for distinct squamous dysplasia grades remains unclear because the corresponding risk of developing ESCC is unknown. We aimed to assess the ESCC risk in patients with esophageal squamous dysplasia in a Western country. This nationwide cohort study included all patients with esophageal squamous dysplasia, diagnosed between 1991 and 2020 in the Dutch nationwide pathology databank (Palga). Squamous dysplasia was divided in mild-to-moderate dysplasia (mild, low-grade, and moderate dysplasia) and higher-grade dysplasia (high-grade dysplasia, severe dysplasia, carcinoma in situ). ESCC were identified in Palga and the Netherlands Cancer Registry. The primary endpoint was diagnosis of prevalent (≤6 months) and incident (>6 months after squamous dysplasia) ESCC. In total, 873 patients (55% male, aged 68 years SD ± 13.2) were diagnosed with esophageal squamous dysplasia, comprising mild-to-moderate dysplasia (n  = 456), higher-grade dysplasia (n  = 393), and dysplasia not otherwise specified (n  = 24). ESCC was diagnosed in 77 (17%) patients with mild-to-moderate dysplasia (49 prevalent , 28 incident ESCC) and in 162 (41%) patients with higher-grade dysplasia (128 prevalent , 34 incident ESCC). After excluding prevalent ESCC, the annual risk of ESCC was 4.0% (95% CI: 2.7–5.7%) in patients with mild-to-moderate dysplasia and 8.5% (95% CI: 5.9–11.7%) in patients with higher-grade dysplasia. All patients with squamous dysplasia, including those with mild-to-moderate dysplasia, have a substantial risk of developing ESCC. Consequently, endoscopic surveillance of the esophageal mucosa or endoscopic resection of dysplasia should be considered for patients with mild-to-moderate dysplasia in Western countries. KEY MESSAGES What is already known on this topic? Squamous dysplasia is the histological precursor of ESCC and is divided in distinct grades, based on the proportion of the squamous epithelium with histopathological abnormalities. In Western countries, the optimal management for distinct squamous dysplasia grades remains unclear because the corresponding risk of developing ESCC is unknown. What this study adds The ESCC risk of patients with squamous dysplasia was increased for all patients with squamous dysplasia in a Western country; 2.1% for patients with mild dysplasia, 5.1% for low-grade dysplasia, and 5.2% for moderate dysplasia. Increasing grades of squamous dysplasia were associated with an increased ESCC risk. How this study might affect research, practice, or policy We recommend that endoscopic follow-up or treatment should be considered in all patients with esophageal squamous dysplasia in Western countries: 1) for patients with mild, low-grade, and moderate dysplasia, endoscopic surveillance with careful inspection with narrow band imaging or dye-based chromoendoscopy of the esophageal mucosa is indicated; and 2) for patients with high-grade dysplasia, severe dysplasia and carcinoma in situ adequate endoscopic staging and in case of suspected neoplasia endoscopic treatment should be performed. [ABSTRACT FROM AUTHOR]

Endoscopy is the gold standard for the diagnosis of cancers and cancer precursors in the oesophagus and stomach. Early detection of upper GI cancers requires high-quality endoscopy and awareness of the subtle features these lesions carry. Endoscopists performing surveillance of high-risk patients including those with Barrett’s oesophagus, previous squamous neoplasia or chronic atrophic gastritis should be familiar with endoscopic features, classification systems and sampling techniques to maximise the detection of early cancer. In this article, we review the current approach to diagnosis of these conditions and the latest advanced imaging and diagnostic techniques.

Purpose of the study. Investigation of morphological characteristics of changes in the epithelium of foregut in experimental animals put under conditions of provoked carcinogenesis.Materials and methods. The method of chronic experiment on animals is applied: 40 female non-linear white rats, which are divided into 4 equal groups (n = 10). The first (I) and second (II) control groups of animals were exposed to mechanical trauma of the oral mucosa with additional application of 0.9 % NaCl solution and 1 % aqueous dimethyl sulfoxide (DMSO) solution with a frequency of 2 times a week. The third group of animals, i.e. the main group (4-NQO), was subjected to mechanical traumatization of the oral mucosa with additional application of 1 % DMSO aqueous solution containing 0.1 mg/ml of 4 nitroquinoline-N-oxide, with a frequency of 2 times a week. The fourth group of animals was intact. On the 1st, 7th, 10th, 14th day from the beginning of the experiment, and then every 14 days, cytological material was taken from the oral mucosa and stained with Papanicolaou stain. To compare the emerging changes, the histological picture of the organs of the foregut was studied.Results. Animals from the main group (4-NQO) showed a lag in body weight gain over the standard variance in the control (I and II) and intact groups. Atypical cells of indeterminate significance appeared in smears starting from 42 days of the experiment. Starting from the 56th day of the experiment, atypical cells (1–2 in the field of view), described in Bethesda terms as low-grade intraepithelial lesions, were detected in smears obtained from the main group of animals (4-NQO). Parabasal cells of the squamous epithelium with atypical large (more than 3 times compared to the reference) nuclei, anisonucleosis, with variable contours of the nuclear membrane within one cell, coarse chromatin were recognized as diagnostically significant.Conclusion. The severity of morphological changes in foregut epithelium in the direction of the precancerous state is significantly higher in the main group with prolonged exposure to carcinogenic factor, compared with the control and intact groups (р < 0.05). Thus, the effectiveness of modeling the conditions of provocation of carcinogenesis of the epithelium of the upper digestive tube in experimental animals was studied and proved by mechanical traumatization of the oral mucosa with additional application of carcinogen (4-NQO). This model of provocation of carcinogenesis will be used in the next study of neoplastic processes of the female reproductive system.

Esophageal squamous cell carcinoma is the seventh most common cancer and the sixth most common cause of cancer death worldwide. Esophageal squamous dysplasia is the only histopathology that predicts the development of esophageal squamous cell carcinoma. It is difficult to identify esophageal squamous dysplasia by conventional endoscopy; however, Lugol chromoendoscopy is useful for the diagnosis of such a lesion. In addition, advance endoscopic detection techniques, such as image-enhanced endoscopy (especially, narrow-band imaging), magnifying endoscopy, and endocytoscopy, are helpful in detecting esophageal squamous dysplasia. Similar to the treatment for early esophageal cancer, endoscopic resection such as endoscopic mucosal resection and endoscopic submucosal dissection is the choice of treatment for esophageal squamous dysplasia. This review discusses esophageal squamous dysplasia in detail, especially in terms of endoscopic diagnosis and clinical management.

Background: Several studies have suggested a possible role of human papillomavirus (HPV) and Epstein-Barr virus in the pathogenesis of oral premalignant lesions. This study aimed to investigate the correlation between squamous dysplasia of the tongue and expression of p16 and Ki67 immunohistochemically as well as HPV genotypes with real-time polymerase chain reaction (PCR). Methods: Twenty-three tongue biopsies were stained immunohistochemically for p16, Epstein-Barr virus and Ki67 and real-time PCR and chromogenic in-situ hybridization for HPV. Results: Dysplasia was diagnosed in 16 of 23 cases without invasive carcinoma and suspicious for dysplasia (n=17) and HPV infection (n=6). These were subjected to chromogenic in-situ hybridization for HPV DNA (HPV-III family 16). There was no immunoreactivity for Epstein-Barr virus. p16 was positive in 4/16 (25%) of dysplastic lesions. One lesion was positive for HPV by chromogenic in-situ hybridization, and one case was positive by real-time PCR for HPV. Conclusion: This evidence suggested that HPV infection but not Epstein-Barr virus infection plays a role in pathogenesis of squamous dysplasia localized tongue. [ABSTRACT FROM AUTHOR]

Demand for anal cancer screening is expected to rise following the recent publication of the Anal Cancer-HSIL Outcomes Research trial, which showed that treatment of high-grade squamous intraepithelial lesions significantly reduces the rate of progression to anal cancer. While screening for human papillomavirus-associated squamous lesions in the cervix is well established and effective, this is less true for other sites in the lower anogenital tract. Current anal cancer screening and prevention rely on high-resolution anoscopy with biopsies. This procedure has a steep learning curve for providers and may cause patient discomfort. Scattering-based light-sheet microscopy (sLSM) is a novel imaging modality with the potential to mitigate these challenges through real-time, microscopic visualization of disease-susceptible tissue. Here, we report a proof-of-principle study that establishes feasibility of dysplasia detection using an sLSM device. We imaged 110 anal biopsy specimens collected prospectively at our institution's dysplasia clinic (including 30 nondysplastic, 40 low-grade squamous intraepithelial lesion, and 40 high-grade squamous intraepithelial lesion specimens) and found that these optical images are highly interpretable and accurately recapitulate histopathologic features traditionally used for the diagnosis of human papillomavirus-associated squamous dysplasia. A reader study to assess diagnostic accuracy suggests that sLSM images are noninferior to hematoxylin and eosin images for the detection of anal dysplasia (sLSM accuracy = 0.87; hematoxylin and eosin accuracy = 0.80; P = .066). Given these results, we believe that sLSM technology holds great potential to enhance the efficacy of anal cancer screening by allowing accurate sampling of diagnostic tissue at the time of anoscopy. While the current imaging study was performed on ex vivo biopsy specimens, we are currently developing a handheld device for in vivo imaging that will provide immediate microscopic guidance to high-resolution anoscopy providers., (Copyright © 2024 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Esophageal sponge cytology is an endoscopy alternative well accepted by patients with extensive data for accuracy in the context of adenocarcinoma. Few studies have assessed its feasibility in asymptomatic community members, and fewer still in East Africa, where esophageal squamous cell carcinoma (ESCC) rates are high. We aimed to assess the feasibility of a capsule‐based diagnosis of esophageal squamous dysplasia (ESD), an ESCC precursor, which may benefit epidemiological and early detection research. We collected Cytosponge collections in 102 asymptomatic adults from Kilimanjaro, Tanzania. Uptake, acceptability and safety were assessed. Participants scored acceptability immediately following the procedure and 7 days later on a scale of 0 (least) to 10 (most acceptable). Slides from paraffin‐embedded cell clots were read by two pathologists for ESD and other pathologies. All participants (52 men, 50 women, aged 30‐77) swallowed the device at first attempt, 100 (98%) of which gave slides of adequate cellularity. Acceptability scores were 10 (53%), 9 (24%), 8 (21%), 7 (2%) and 6 (1%), with no differences by age, sex or time of asking. Cytological findings were esophageal inflammation (4%), atypical squamous cells of uncertain significance (1%), low‐grade dysplasia (1%), gastritis (22%) and suspected intestinal metaplasia (6%). Setting‐specific logistical and ethical considerations of study implementation are discussed. We demonstrate the safety, acceptability and feasibility of Cytosponge sampling in this setting, paving the way for innovative etiology and early‐detection research. Targeted sampling strategies and biomarker development will underpin the success of such initiatives. The study protocol is registered on ClinicalTrials.gov (NCT04090554). What's new? Endoscopy is often the standard method for diagnosing esophageal squamous cell carcinoma (ESCC). However, in resource‐limited regions, lower‐cost alternatives are urgently needed, especially for early‐detection screening programs. Esophageal sponge cytology is one such alternative, but would it be useful for large‐scale screening? In this preliminary study, the authors tested this "pill‐on‐a‐string" approach in a region of Tanzania with high ESCC incidence. They found that the method is acceptable, safe, and feasible for screening asymptomatic community members in a high‐risk region. These results will aid in the design of novel aetiology, biomarker, and early‐detection research studies. [ABSTRACT FROM AUTHOR]

Competing Interests: None disclosed.

Clinicopathological and molecular studies have demonstrated that dysplasia is a precancerous and/or neoplastic lesion with malignant potential. Further, it is subclassified into two grades: high-grade and low-grade dysplasia. High-grade dysplasia is a clinically significant lesion requiring resection or ablation. Low-grade dysplasia has a much lower risk of carcinoma; thus, it should be followed by endoscopic surveillance. Because squamous dysplasia may progress to squamous cell carcinoma, periodic endoscopy is useful to detect the lesion in patients with risk factors. Squamous dysplasia is diagnosed histopathologically by evaluating both cytologic and structural changes., Competing Interests: Disclosure The authors declare that they have no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Abstract Background Low serum selenium status has been associated with increased risk of esophageal squamous cell carcinoma (ESCC). East Africa is a region of high ESCC incidence and is known to have low soil selenium levels, but this association has not previously been evaluated. In this study we assessed the association of serum selenium concentration and the prevalence of esophageal squamous dysplasia (ESD), the precursor lesion of ESCC, in a cross-sectional study of subjects from Bomet, Kenya. Methods 294 asymptomatic adult residents of Bomet, Kenya completed questionnaires and underwent endoscopy with Lugol’s iodine staining and biopsy for detection of ESD. Serum selenium concentrations were measured by instrumental neutron activation analysis. Odds ratios (OR) and confidence intervals (95% CI) for associations between serum selenium and ESD were calculated using unconditional logistic regression. Results The mean serum selenium concentration was 85.5 (±28.3) μg/L. Forty-two ESD cases were identified (14% of those screened), including 5 (12%) in selenium quartile 1 (Q1), 5 (12%) in Q2, 15 (36%) in Q3, and 17 (40%) in Q4. Higher serum selenium was associated with prevalence of ESD (Q4 vs Q1: OR: 3.03; 95% CI: 1.05–8.74) and this association remained after adjusting for potential confounders (Q4 vs Q1: OR: 3.87; 95% CI: 1.06–14.19). Conclusion This is the first study to evaluate the association of serum selenium concentration and esophageal squamous dysplasia in an African population at high risk for ESCC. We found a positive association between higher serum selenium concentration and prevalence of ESD, an association contrary to our original hypothesis. Further work is needed to better understand the role of selenium in the etiology of ESCC in this region, and to develop effective ESCC prevention and control strategies.

Cancer-associated fibroblasts (CAFs), a heterogenous population, can promote cancer cell proliferation, migration, invasion, immunosuppression, and therapeutic resistance in solid tumors. These effects are mediated through secretion of cytokines and growth factors, remodeling of the extracellular matrix, and providing metabolic support for cancer cells. The presence of CAFs in esophageal carcinoma are associated with reduced overall survival and increased resistance to chemotherapy and radiotherapy; thus, identifying therapeutic vulnerabilities of CAFs is a necessity. In esophageal cancer, the mechanisms for CAF recruitment, CAF-mediated promotion of tumorigenesis, metastatic dissemination, and therapeutic resistance have yet to be fully evaluated. Here, we provide an overview of the current understanding of CAFs in esophageal cancer, namely in esophageal squamous cell carcinoma and esophageal adenocarcinoma, as well as in the preneoplastic conditions that predispose to these cancers. Interestingly, there is a discrepancy in our knowledge of CAF biology between esophageal cancer subtypes, with very few studies in esophageal adenocarcinoma, and its precursor lesion Barrett's esophagus, compared with esophageal squamous cell carcinoma. We propose that although great strides have been made, certain questions remain to which answers hopefully will emerge to have an impact on biomarker diagnostics and translational therapeutics., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Eruptive squamous atypia (ESA), which is an idiopathic, sometimes koebnerizing, proliferation of atypical but well-differentiated keratinocytes (also termed eruptive keratoacanthoma), is often misdiagnosed as cancer and managed by excisional surgery, provoking further koebnerization. A clear definition of this phenomenon and treatment outcome data are lacking.Objective: To define ESA and evaluate efficacy of intralesional (IL) 5-fluorouracil (5-FU) treatment.Methods: A retrospective cohort study examined patients with ESA that arose spontaneously or within a recent surgical scar and was treated with IL 5-FU at a tertiary academic center between January 2008 and December 2016. Complete clearance, partial clearance, and number of surgical excisions performed were tabulated.Results: Of 30 patients with 136 ESA lesions, 20 (67%) had resolution of ESA with IL 5-FU monotherapy. In all, 10 patients (33%) required additional therapy (topical 5-FU, steroids, cryotherapy, or acitretin). No IL 5-FU-treated ESA lesions required surgical excision. The number of excisional procedures decreased significantly (P = .006), with 27 patients (90%) needing fewer excisions 12 months after versus 12 months before initiation of IL 5-FU therapy. Dyspigmentation was the only adverse event.Limitations: Limitations include retrospective analysis and use of data from a single institution.Conclusion: With close clinical monitoring, IL 5-FU can be used to successfully treat ESA. [ABSTRACT FROM AUTHOR]

The classification of neoplastic precursor lesions in the urinary tract has evolved slowly with the gradual accumulation of clinicopathological data. Current nomenclature was codified most recently by the 2016 WHO classification, which is based on primary data with clinical outcome, consensus group statements and considerations of practical utility in routine diagnosis. This review discusses precursor lesions of urothelial, squamous and glandular lineage. For urothelial neoplasia, both flat lesions with atypia and early 'difficult‐to‐classify' proliferations are considered. Subtypes of squamous metaplasia, florid non‐invasive squamous proliferations and frank squamous dysplasia are also addressed. Finally, rare glandular precursors of adenocarcinoma are reviewed, to include intestinal metaplasia, glandular dysplasia and villous adenoma. For each category, morphology (including differential diagnostic considerations), immunohistochemistry and any known molecular correlates are detailed. The goal is to provide a concise, practical up‐to‐date overview of this complex topic. [ABSTRACT FROM AUTHOR]

Squamous dysplasia is the histological precursor of esophageal squamous cell carcinoma (ESCC). The optimal management for distinct squamous dysplasia grades remains unclear because the corresponding risk of developing ESCC is unknown. We aimed to assess the ESCC risk in patients with esophageal squamous dysplasia in a Western country. This nationwide cohort study included all patients with esophageal squamous dysplasia, diagnosed between 1991 and 2020 in the Dutch nationwide pathology databank (Palga). Squamous dysplasia was divided in mild-to-moderate dysplasia (mild, low-grade, and moderate dysplasia) and higher-grade dysplasia (high-grade dysplasia, severe dysplasia, carcinoma in situ). ESCC were identified in Palga and the Netherlands Cancer Registry. The primary endpoint was diagnosis of prevalent (≤6 months) and incident (>6 months after squamous dysplasia) ESCC. In total, 873 patients (55% male, aged 68 years SD ± 13.2) were diagnosed with esophageal squamous dysplasia, comprising mild-to-moderate dysplasia (n = 456), higher-grade dysplasia (n = 393), and dysplasia not otherwise specified (n = 24). ESCC was diagnosed in 77 (17%) patients with mild-to-moderate dysplasia (49 prevalent, 28 incident ESCC) and in 162 (41%) patients with higher-grade dysplasia (128 prevalent, 34 incident ESCC). After excluding prevalent ESCC, the annual risk of ESCC was 4.0% (95% CI: 2.7-5.7%) in patients with mild-to-moderate dysplasia and 8.5% (95% CI: 5.9-11.7%) in patients with higher-grade dysplasia. All patients with squamous dysplasia, including those with mild-to-moderate dysplasia, have a substantial risk of developing ESCC. Consequently, endoscopic surveillance of the esophageal mucosa or endoscopic resection of dysplasia should be considered for patients with mild-to-moderate dysplasia in Western countries. KEY MESSAGES What is already known on this topic? Squamous dysplasia is the histological precursor of ESCC and is divided in distinct grades, based on the proportion of the squamous epithelium with histopathological abnormalities. In Western countries, the optimal management for distinct squamous dysplasia grades remains unclear because the corresponding risk of developing ESCC is unknown. What this study adds The ESCC risk of patients with squamous dysplasia was increased for all patients with squamous dysplasia in a Western country; 2.1% for patients with mild dysplasia, 5.1% for low-grade dysplasia, and 5.2% for moderate dysplasia. Increasing grades of squamous dysplasia were associated with an increased ESCC risk. How this study might affect research, practice, or policy We recommend that endoscopic follow-up or treatment should be considered in all patients with esophageal squamous dysplasia in Western countries: 1) for patients with mild, low-grade, and moderate dysplasia, endoscopic surveillance with careful inspection with narrow band imaging or dye-based chromoendoscopy of the esophageal mucosa is indicated; and 2) for patients with high-grade dysplasia, severe dysplasia and carcinoma in situ adequate endoscopic staging and in case of suspected neoplasia endoscopic treatment should be performed., (© The Author(s) 2023. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Worldwide oral squamous cell carcinoma (OSCC) is one of the most frequent malignancies, with a mortality rate of 1.9 deaths per 100,000 per year. Most cases of OSCC are preceded by clinical lesions referred to as oral potentially malignant disorders (OPMDs). The World Health Organization defines OPMDs as “clinical presentations that carry a risk of cancer development in the oral cavity, whether in a clinically definable precursor lesion or in clinically normal oral mucosa”. These disorders include leukoplakia, erythroplakia, erythroleukoplakia, oral submucous fibrosis, palatal lesion of reverse cigar smoking and oral lichen planus. In this review we discuss the clinical, pathologic and molecular features of OPMDs. [ABSTRACT FROM AUTHOR]

Background: Low serum selenium status has been associated with increased risk of esophageal squamous cell carcinoma (ESCC). East Africa is a region of high ESCC incidence and is known to have low soil selenium levels, but this association has not previously been evaluated. In this study we assessed the association of serum selenium concentration and the prevalence of esophageal squamous dysplasia (ESD), the precursor lesion of ESCC, in a cross-sectional study of subjects from Bomet, Kenya.Methods: 294 asymptomatic adult residents of Bomet, Kenya completed questionnaires and underwent endoscopy with Lugol's iodine staining and biopsy for detection of ESD. Serum selenium concentrations were measured by instrumental neutron activation analysis. Odds ratios (OR) and confidence intervals (95% CI) for associations between serum selenium and ESD were calculated using unconditional logistic regression.Results: The mean serum selenium concentration was 85.5 (±28.3) μg/L. Forty-two ESD cases were identified (14% of those screened), including 5 (12%) in selenium quartile 1 (Q1), 5 (12%) in Q2, 15 (36%) in Q3, and 17 (40%) in Q4. Higher serum selenium was associated with prevalence of ESD (Q4 vs Q1: OR: 3.03; 95% CI: 1.05-8.74) and this association remained after adjusting for potential confounders (Q4 vs Q1: OR: 3.87; 95% CI: 1.06-14.19).Conclusion: This is the first study to evaluate the association of serum selenium concentration and esophageal squamous dysplasia in an African population at high risk for ESCC. We found a positive association between higher serum selenium concentration and prevalence of ESD, an association contrary to our original hypothesis. Further work is needed to better understand the role of selenium in the etiology of ESCC in this region, and to develop effective ESCC prevention and control strategies. [ABSTRACT FROM AUTHOR]

Squamous cell carcinoma (SqCC) in ulcerative colitis (UC) is rare. A 38 year-old Japanese woman, who suffered from left-sided UC for 18 years, underwent total colectomy due to SqCCs in the rectum and the sigmoid colon. They were well differentiated SqCC, and metastasis was found in the paracolic lymph nodes. Multiple small foci of squamous dysplasia (SD) were noted in the rectal mucosa. Glandular dysplasia was not found. TP53 was not detected in SD. Approximately 40% of cells were immunostained with TP53 in SqCC, however no mutation was found in TP53 gene. Human papilloma virus and Epstein Barr virus were negative in SD and SqCCs. The patient is free of the disease at one and half years after surgery and chemotherapy. SD may be a precursor of SqCC. It appeared that TP53 does not play a vital role in the development of SqCCs in the current case. Careful attention should be paid to SD in UC patients. Viral infection may need to be examined. The pathogenesis of SqCC in patients of UC needs to be elucidated. [ABSTRACT FROM AUTHOR]

Objectives: To analyze interobserver reproducibility and compare practice patterns between academic and community settings of Lower Anogenital Squamous Terminology (LAST).Methods: In total, 132 anal biopsy slides were revised as well as p16 immunostains.Results: LAST was used in 49% of cases (academic center, 68%; satellite hospitals [community practice setting], 32%). After pathology review and consensus interpretation, 23 (17%) case diagnoses were reclassified: eight (34.8%) cases (benign or low-grade squamous intraepithelial lesion [LSIL]) were upgraded to high-grade squamous intraepithelial lesion (HSIL) (p16 confirmed ordered during review); four (17.4%) cases originally classified as HSIL were downgraded to LSIL (p16 originally ordered in one case). There was no significant difference in discrepancies between original and consensus diagnosis in the community vs academic setting or by subspecialty (gynecological vs gastrointestinal). Overall interobserver agreement among reviewers was substantial (κ = 0.63) and improved with the use of p16 immunostain in challenging cases (κ = 0.71; P < .001).Conclusions: This new terminology is not yet uniformly used by pathologists in anal/perianal biopsy specimens; this two-tier system has a good interobserver agreement and is further improved with p16 use in appropriate cases. [ABSTRACT FROM AUTHOR]

Introduction: Primary small cell carcinoma of the esophagus is a rare and aggressive tumor. Patients present with metastatic disease and have a poor clinical outcome. The objective of the study was to correlate clinical and histopathological features of primary small cell carcinoma of the esophagus diagnosed and treated at our hospital. Materials and Methods: A retrospective study of 11 patients diagnosed with primary small cell carcinoma of the esophagus in Kasturba Hospital, Manipal between 2006 and 2014 was done. The histopathological and immunohistochemical features were correlated with clinical and endoscopic findings. Results: Eleven patients were diagnosed to have small cell carcinoma of esophagus with a male preponderance. Common presenting symptoms were dysphagia and weight loss. Majority of the patients showed mid esophageal ulceroproliferative growth. Biopsy findings were consistent with the characteristic morphology of small cell carcinoma and demonstrated immunoreactivity to neuroendocrine markers. In addition, few cases also showed adjacent squamous dysplasia/carcinoma. Most of the patients presented with metastatic disease, liver being the most common site. These patients were treated by chemotherapy and radiotherapy. Conclusion: Esophageal small cell carcinomas are aggressive tumors with high rates of distant metastasis. Presence of squamous dysplasia /squamous cell carcinoma in the adjacent mucosa supports the hypothesis that this neoplasm arise from pleuripotent stem cells. Presence of the latter is also useful to rule out spread from lung primary.

Aims Oesophageal epidermoid metaplasia is defined by a dense granular layer with overlying hyperorthokeratosis, resembling the epidermis of skin. A possible association between epidermoid metaplasia, squamous dysplasia and squamous cell carcinoma has been proposed. The aim of this study was to compare the prevalence of epidermoid metaplasia in patients with oesophageal squamous neoplasms with that in a control cohort. Methods and results Medical records and slides from 1048 consecutive oesophageal biopsies and resections for any indication and 58 patients with oesophageal squamous neoplasms were reviewed. Two cases (0.19%) of epidermoid metaplasia were identified in the 1048-patient control group. The prevalence of epidermoid metaplasia was significantly higher ( P < 0.05) in the 58 patients with oesophageal squamous neoplasms, two of whom (3.5%) had concurrent epidermoid metaplasia (odds ratio 18.1, 95% confidence interval 2.5-131). One case was associated with a verrucous carcinoma and the other with a well-differentiated, superficial ( pT1), exophytic squamous cell carcinoma. No patients had epidermoid metaplasia in a biopsy prior to the diagnosis of squamous neoplasia. Conclusions The increased prevalence of epidermoid metaplasia observed in patients with squamous neoplasms provides some additional support for the proposed association. The hypothesis that epidermoid metaplasia is a precursor to squamous neoplasms remains unproven. [ABSTRACT FROM AUTHOR]

Squamous dysplasia of the urinary bladder is uncommon and may represent a precursor to invasive squamous cell carcinoma. Though significant focus has been devoted to squamous differentiation in invasive bladder cancer, relatively little attention has been given to squamous dysplasia. We methodically reviewed microscopic slides from a consecutive cystectomy series at our institution (n = 303; 2001-2014), with special attention given to squamous dysplasia and squamous differentiation within association invasive carcinoma. Of these 303 cases, 3% (9 cases) had squamous dysplasia. The majority (89%; 8/9) had a similar morphological appearance to squamous dysplasia of the head and neck (ie, cytological atypia, architectural disturbances, and abnormal keratinization). Invasive carcinoma was present in 230 of the cystectomy cases. Of these 230 cases with invasive carcinoma, 4% (8 cases) also had squamous dysplasia. The invasive carcinoma had evidence of squamous differentiation in all cases with concurrent squamous dysplasia. Concurrent flat urothelial carcinoma in situ was present in 3 of the 8 cases with both invasive carcinoma and squamous dysplasia. Squamous dysplasia was not associated with clinical outcomes data, including death from bladder cancer and bladder cancer recurrence. The data from this study indicate that squamous dysplasia is uncommon in the cystectomy setting, frequently has the morphology of head and neck dysplasia, and is often associated with invasive carcinoma with squamous differentiation. [ABSTRACT FROM AUTHOR]

Rationale: Autofluorescence bronchoscopy (AFB) and computed tomography (CT) enable lung cancer (LC) detection at the early (pre-)invasive stage. However, LC risk in patients with preinvasive endobronchial lesions is unclear.Objectives: To assess LC incidence and identify potential risk determinants in patients with preinvasive lesions.Methods: In our tertiary care referral center, 164 subjects with preinvasive lesions were monitored up to 12.5 years by repeated AFB and CT. Occurrence of LC was monitored. Clinical management depended on histological grade, with cancer patients receiving standard care. Potential risk determinants (smoking status, baseline histology, cancer history, and chronic obstructive pulmonary disease [COPD] status) were evaluated in relation to cancer occurrence, event-free survival (EFS), and overall survival (OS).Measurements and Main Results: During surveillance (median of 30 mo, range 4-152) of 164 subjects with preinvasive lesions (80 high grade and 84 low grade at inclusion), 61 LCs were detected in 55 subjects (median time to event 16.5 mo). Twenty-three LCs (38%) were detected by CT, and 38 (62%) were detected by AFB. More cancers (36 of 61; 59%) developed from separate, rather than initial lesional sites. Subjects with high-grade lesions were more likely to be diagnosed with LC at the same or another site in the lungs than those with low-grade lesions (P = 0.03). Independent risk determinants for OS were previous curatively treated cancer and COPD (P ≤ 0.05).Conclusions: Presence of preinvasive lesions, especially high-grade lesions, may serve as LC risk markers. LCs occur both at preinvasive lesion sites and elsewhere in the bronchial epithelium or lung parenchyma. Prospective validation of biomarkers and randomized intervention studies are needed to determine optimal management strategies. [ABSTRACT FROM AUTHOR]

The majority of conventional leukoplakia remains constant and only a subset progress to high-grade dysplasia or invasive carcinoma. A less recognized form known as proliferative verrucous leukoplakia (PVL) represents a unique progressive and elusive variant. Identifying patients with this form can only be achieved through the keen clinical observation of the temporal gross and histologic progression in individual patients with squamous cell carcinoma. The difficulty in the early diagnosis of PVL stems from the overlapping clinical and pathologic features with conventional multifocal leukoplakia with dysplasia. We present the current view on the clinicopathologic and biological characteristics of PVL and discuss their diagnosis, differential diagnosis, and management. © 2014 Wiley Periodicals, Inc. Head Neck 36: 1662-1668, 2014 [ABSTRACT FROM AUTHOR]

Early detection of squamous dysplasia and esophageal squamous cell carcinoma is of great importance. Adopting computer aided algorithms in predicting cancer risk using its risk factors can serve in limiting the clinical screenings to people with higher risks. In the present study, we show that the application of an advanced classification method, the Minimum Classification Error, could considerably enhance the classification performance in comparison to the logistic regression model and the variable structure fuzzy neural network, as the latest successful methods. The results yield the accuracy of 89.65% for esophageal squamous cell carcinoma, and 88.42% for squamous dysplasia risk prediction. [ABSTRACT FROM AUTHOR]

Aims Oesophageal hyperkeratosis is rarely described. In contrast to hyperkeratosis of orolaryngeal mucosa, where its risk factors and association with squamous neoplasia are well-studied, the prevalence and clinicopathological features of oesophageal hyperkeratosis are unknown. Methods and results We reviewed prospectively 1845 oesophageal biopsies and found hyperkeratosis in 37 (2.0%). Among 98 patients studied, hyperkeratosis occurred in two distinct settings: group 1 [within Barrett's oesophagus ( BO)/adenocarcinoma, n = 61, 62%] and group 2 (outside BO/adenocarcinoma, n = 37, 38%). In contrast to group 1, hyperkeratosis in group 2 was more often multifocal (>3 foci in 51% versus 16%, P = 0.0001), involved mid-oesophagus (51% versus 2%, P < 0.0001), showed endoscopic leucoplakia (24% versus 3%, P = 0.003) and involved current/former alcohol users (51% versus 19%, P = 0.0012). Importantly, invasive squamous carcinoma and squamous dysplasia were seen only in group 2 (47% and 19% versus 0%, P < 0.0001). Further, 42% of group 2, but none of group 1, had benign or malignant squamous lesions of the oral cavity/larynx ( P < 0.0001). Conclusion Hyperkeratosis involves ~2% of oesophageal biopsies and can be divided into cases occurring within BO/adenocarcinoma and those occurring outside BO/adenocarcinoma. The former lack clinical significance, whereas the latter are associated frequently with oesophageal squamous neoplasia and squamous pathology of the head and neck region. [ABSTRACT FROM AUTHOR]

Background: Identifying people at higher risk of having squamous dysplasia, the precursor lesion for esophageal squamous cell carcinoma (ESCC), would allow targeted endoscopic screening. Methods: We used multivariate logistic regression models to predict ESCC and dysplasia as outcomes. The ESCC model was based on data from the Golestan Case-Control Study (total n = 871; cases = 300), and the dysplasia model was based on data from a cohort of subjects from a gastroenterology clinic in Northeast Iran (total n = 724; cases = 26). In each of these analyses, we fit a model including all risk factors known in this region to be associated with ESCC. Individual risks were calculated using the linear combination of estimated regression coefficients and individual-specific values for covariates. We used cross-validation to determine the area under the curve (AUC) and to find the optimal cut points for each of the models. Results: The model had an area under the curve of 0.77 (95% CI: 0.74-0.80) to predict ESCC with 74% sensitivity and 70.4% specificity for the optimum cut point. The area under the curve was 0.71 (95% CI: 0.64-0.79) for dysplasia diagnosis, and the classification table optimized at 61.5% sensitivity and 69.5% specificity. In this population, the positive and negative predictive values for diagnosis of dysplasia were 6.8% and 97.8%, respectively. Conclusion: Our models were able to discriminate between ESCC cases and controls in about 77%, and between individuals with and without squamous dysplasia in about 70% of the cases. Using risk factors to predict individual risk of ESCC or squamous dysplasia still has limited application in clinical practice, but such models may be suitable for selecting high risk individuals in research studies, or increasing the pretest probability for other screening strategies. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: To assess risk of lung cancer (LC) in patients with preinvasive bronchial lesions and to identify factors associated with higher risk. Methods: 124 patients with one or more preinvasive bronchial lesions and normal chest computed tomography (CT) (mean age 66.7 years, 121 males and 3 females), followed-up by white light and autofluorescence bronchoscopy (AFB) every 4–6mo and chest CT every 6–12mo, end points were development of carcinoma in situ (CIS) or LC. Results: Among 124 patients with 240 preinvasive bronchial lesions, 20 CIS or LC lesions were detected during follow-up in 20 (16%) patients, 7 were detected as new endobronchial lesions, 10 as new peripheral lesions and 3 as local progression from severe dysplasia to CIS. Median time to progression from the same site or development of CIS/LC elsewhere was 24 months (range: 6–54mo). The Cumulative risk of development of CIS/LC was 7% at one year, 20% at three years and 44% at 5 years. Among detected lung cancers, 80% were stage 0 or stage I and underwent treatment with curative intent. Diagnosis of new SD during follow-up (p =0.0001), chronic obstructive pulmonary disease (COPD) (p =0.001) or smoking index >52 pack-year (p =0.042) was associated with higher risk. Even after controlling for other risk factors, COPD was associated with risk for lung cancer. Baseline lesion grade was not predictive of patient outcome (p =0.146). Conclusion: Patients with preinvasive bronchial lesions, especially those with new SD during follow-up, COPD or smoking >52 pack-year are at high risk of LC, AFB and CT follow-up facilitated early detection and treatment with curative intent. [Copyright &y& Elsevier]

Abstract: Loss of heterozygosity at the FHIT locus is coincident with activation of DNA damage response checkpoint proteins; thus damage at fragile loci may trigger checkpoint activation. We examined preneoplastic lesions adjacent to non-small cell lung carcinomas for alterations to expression of Fhit and activated checkpoint proteins. Expression scores were analyzed for pair-wise associations and correlations among proteins and type of lesion. Hyperplastic and dysplastic lesions were positive for nuclear γH2AX expression; 12/20 dysplastic lesions were negative for Fhit expression. Fhit positive lesions showed expression of most checkpoint proteins examined, while Fhit negative lesions showed absence of expression of Chk1 and phosphoChk1. The results show that loss of expression of Fhit is significantly directly correlated with absence of activated Chk1 in dysplasia, and suggest a connection between loss of Fhit and modulation of checkpoint activity. [Copyright &y& Elsevier]

Background and Aims: It has not been determined whether low-grade squamous dysplasia (LGD) of the esophagus is a precancerous lesion or not. If LGD progresses to squamous cell carcinoma, early carcinoma lesions that have such a natural history might contain a remaining LGD component. Methods: The lesions in the 68 patients with early invasive squamous cell carcinoma who underwent endoscopic mucosal resection were examined for the presence of an LGD component. If LGD components were observed, the degrees of architectural and cytological abnormalities of LGD components and those of tumor invasive fronts in the same lesions were studied. The degrees of abnormalities of 28 small LGD lesions were also studied. Results: Histological examination of resected specimens confirmed LGD components in 43% of the squamous cell carcinoma lesions. The lesions of lamina propria mucosae (m2) cancer contained a significantly broader area of LGD component than did the lesions of muscularis mucosae (m3) and submucosal layer (sm) cancer ( P = 0.037). Mean score for the degrees of cytological abnormalities of LGD component was similar to that of tumor invasive front ( P = 0.457) and significantly higher than that of small LGD lesions ( P < 0.001). Conclusion: Our results indicate the possibility that the lesion was formed by a combination of small lesions that arose as a multicentric occurrence of squamous cell carcinoma and dysplasia. Our results also suggest that an LGD component would transform to carcinoma along with tumor progression. However, the concept of ‘basal cell layer type carcinoma in situ’ may be suitable for squamous cell lesions with a high degree of cytological abnormalities confined to the lower half of the epithelium. [ABSTRACT FROM AUTHOR]

Aim : Most epithelial malignancies are characterized by multistep progression from preinvasive/intraepithelial neoplasia to invasive malignancy. Detection and grading of early squamous intraepithelial neoplasia may at times be problematic. The aim of this study was to examine the ability of immunomarkers GLUT1, phospho-histone H1 and p63 to detect such early lesions. Methods : Sections of formalin-fixed paraffin-embedded tissue from 27 cases of squamous intraepithelial neoplasia, 26 associated with invasive carcinoma, were immunostained with anti-p63 (4A4; Santa Cruz), anti-GLUT1 (Chemicon) and anti-phospho-histone H1 (monoclonal 12D11) and compared with normal, hyperplastic and immature squamous metaplastic epithelium. Results : Normal epithelium displayed phospho-histone H1 in scattered parabasal cells; p63 in the basal one-quarter to one-half of epithelium; and GLUT1 negativity or weak/equivocal mid-epithelial GLUT1+ foci. In hyperplasia phospho-histone H1+ cells were also limited to the parabasal layer; p63 positivity was essentially identical to that in normal epithelium; GLUT1 characteristically stained basal cells in rete-like areas. p63 staining in squamous intraepithelial neoplasia (grade 1) was indistinguishable from normal epithelial staining; in contrast, squamous intraepithelial neoplasia (grade 3) was readily apparent, with up to full-thickness p63 positivity. Squamous intraepithelial neoplasia (grade 1) was readily distinguishable from normal epithelium with both phospho-histone H1 and GLUT1 immunostaining; both markers were detected in cell layers above the parabasal layer. With both, progressively higher cell layers stained in proportion to the severity of the intraepithelial neoplasia, up to full thickness positivity in grade 3 squamous intraepithelial neoplasia. Squamous metaplasia and grade 3 squamous intraepithelial neoplasia were not distinguishable with p63 (both showed full-thickness staining) but were readily distinguishable with GLUT1 and phospho-histone H1 stains. GLUT1 appeared to be the most sensitive marker for all grades of intraepithelial neoplasia. Conclusion : Altered expression of all three markers was a common finding in squamous intraepithelial neoplasia, hence, dysregulation of cell cycle-promoting cyclin-dependent kinases (phospho-histone H1), altered stem cell regulatory pathways (p63) and enhancement of hypoxia-sensing pathways (GLUT1) are all early alterations in the progression of squamous malignancy of head and neck origin. A panel of all three may be a useful means of detecting squamous intraepithelial neoplasia. [ABSTRACT FROM AUTHOR]

Study design:A case report.Objective:To raise awareness among spinal cord clinicians of the possible carcinogenic effect of phenoxybenzamine and of the rare occurrence of small cell carcinoma in the neuropathic bladder.Setting:Regional Spinal Injuries Centre and District General Hospital, Southport, Merseyside, United Kingdom.Case report:A 28-year-old man sustained a fracture dislocation of L-1 with consequent paraplegia (ASIA impairment scale A). Phenoxybenzamine treatment enabled his indwelling catheter to be discarded in favour of a penile sheath, but it caused unacceptable dizziness and was stopped after 7 years. After 20 years, he developed chronic lymphocytic leukaemia, which was treated with chlorambucil and fludarabine. After 2 years, investigation of bilateral hydronephrosis revealed a primary small cell carcinoma of the bladder with coexistent squamous dysplasia. Uraemia supervened and, declining active treatment, the patient died 3 weeks after diagnosis.Conclusion:Phenoxybenzamine, a known carcinogen in rodents, is likely also to be carcinogenic in humans, and patients with spinal cord injury who have received the drug for any significant period of time, need close follow-up to allow early detection of cancer. Phenoxybenzamine should not be prescribed on a long-term basis, and should instead be replaced with a selective alpha-blocker.Spinal Cord (2006) 44, 188–191. doi:10.1038/sj.sc.3101789; published online 30 August 2005 [ABSTRACT FROM AUTHOR]