Squamous Dysplasia Research Articles

Genetic Alterations in Esophageal Tissues From Squamous Dysplasia to Carcinoma

Esophageal squamous cell carcinoma (ESCC) is the most common subtype of esophageal cancer. Little is known about the genetic changes that occur in esophageal cells during the development of ESCC. We performed next-generation sequence analyses of esophageal nontumor, intraepithelial neoplasia (IEN), and ESCC tissues from the same patients to track genetic changes during tumor development. We performed whole-genome, whole-exome, or targeted sequence analyses of 227 esophageal tissue samples from 70 patients with ESCC undergoing resection at Shantou University Medical College in China from 2012 through 2015 (no patients had received chemotherapy or radiation therapy); we analyzed normal tissues, tissues with simple hyperplasia, dysplastic tissues (IEN), and ESCC tissues collected from different regions of the esophagus at the same time. We also obtained 1191 nontumor esophageal biopsy specimens from the Chaoshan region (a high-risk region for ESCC) of China (a high-risk region for ESCC) and performed immunohistochemical and histologic analyses to detect inflammation. IEN and ESCC tissues had similar mutations and copy number alterations, at similar frequencies; these differed from mutations detected in tissues with simple hyperplasia. IEN tissues had mutations associated with apolipoprotein B messenger RNA editing enzyme, catalytic polypeptide-like-mediated mutagenesis (a DNA damage mutational signature). Genetic analyses indicated that most ESCCs were formed from early stage IEN clones. Trunk mutations (mutations shared by >10% of paired IEN and ESCC tissues) were in genes that regulate DNA repair and cell apoptosis, proliferation and adhesion. Mutations in TP53 and CDKN2A and copy number alterations in 11q (contains CCND1), 3q (contains SOX2), 2q (contains NFE2L2), and 9p (contains CDKN2A) were considered to be trunk variants; these were dominant mutations detected at high frequencies in clones of paired IEN and ESCC samples. In the esophageal biopsy samples from high-risk individuals (residing in the Chaoshan region), 68.9% had an evidence of chronic inflammation; the level of inflammation was correlated with atypical cell structures and markers of DNA damage. We analyzed mutations and gene copy number changes in nontumor, IEN, and ESCC samples, collected from 70 patients. IEN and ESCCs each had similar mutations and markers of genomic instability, including apolipoprotein B messenger RNA editing enzyme, catalytic polypeptide-like. Genomic changes observed in precancerous lesions might be used to identify patients at risk for ESCC.

A Model To Identify Individuals at High Risk for Esophageal Squamous Cell Carcinoma and Precancerous Lesions in Regions of High Prevalence in China

We aimed to develop a population-based model to identify individuals at high risk for esophageal squamous cell carcinoma (ESCC) in regions of China with a high prevalence of this cancer. We collected findings from 15,073 permanent residents (45-69 years old) of 334 randomly selected villages in Hua County, Henan Province, China who underwent endoscopic screening (with iodine staining) for ESCC from January 2012 through September 2015. The entire esophagus and stomach were examined; biopsies were collected from all focal lesions (or from standard sites in the esophagus if no abnormalities were found) and analyzed histologically. Squamous dysplasia, carcinoma in situ, and ESCC were independently confirmed by 2 pathologists. Before endoscopy, subjects completed a questionnaire on ESCC risk factors. Variables were evaluated with unconditional univariate logistic regression analysis; variables found to be significantly associated with ESCC were then analyzed by multivariate logistic regression modeling. We used the Akaike information criterion to develop our final model structure and the coding form of variables with multiple measures. We developed 2 groups of models, separately defining severe dysplasia and above (SDA) (lesions including severe dysplasia and higher-grade lesions) and moderate dysplasia and above (lesions including moderate dysplasia and higher-grade lesions) as outcome events. Age-stratified and whole-age models were developed; their discriminative ability in the full multivariate model and the simple age model was compared. We performed area under the receiver operating characteristic curve (AUC) and the DeLong test to evaluate model performance. Our age-stratified prediction models identified individuals 60 years of age or younger with SDA with an AUC value of 0.795 (95% confidence interval, 0.736-0.854) and individuals older than 60 years with SDA with an AUC value of 0.681 (95% confidence interval, 0.618-0.743). Factors associated with SDA in individuals 60 years or younger included age closer to 60 years, use of coal or wood as a main source of cooking fuel, body mass index of 22 kg/m2 or less, unexplained epigastric pain, and rapid ingestion of meals. In subjects older than 60 years, SDA associated with age, family history of ESCC, cigarette smoking, body mass index of 22 kg/m2 or less, pesticide exposure, irregular eating habits, intake of high temperature foods, rapid ingestion of meals, and ingestion of leftover food in summer months. Use of our model in screening could have allowed 27% of subjects 60 years or younger and 9% of subjects older than 60 years to avoid endoscopy without missing SDAs. This means that approximately 2500 of endoscopies in total (16.6%) could have been avoided. We developed a low-cost, easy-to-use model to identify individuals at risk for severe dysplasia or cancer of the esophagus living in a region of China with a high risk of ESCC. This model might be used to select individuals and groups of persons who should undergo endoscopy analysis for esophageal cancer.

Pathology of esophageal cancer and Barrett's esophagus.

Esophageal cancer is a serious malignancy with high mortality. The two common distinctive pathologic subtypes of esophageal cancer are squamous cell carcinoma and adenocarcinoma. These differ with regards to etiology, ethnic distribution, pathogenesis, and location in the esophagus. The precursor lesions are also unique to each subtype. Squamous cell carcinoma is more common in East Asia, is linked to smoking and tobacco use, more commonly involves the middle esophagus, and the precursor lesion is squamous dysplasia. Adenocarcinoma is more common in the United States and certain European countries, associated with obesity and gastroesophageal reflux disease (GERD), more commonly involves the distal esophagus, and the precursor lesion is Barrett's esophagus. Endoscopic surveillance with biopsy evaluation is the standard of care in high-risk groups. Endoscopic ablative therapies for early cancers have lower morbidity than surgery. Despite increased awareness, identification of high-risk groups and endoscopic surveillance, a large proportion of patients present with advanced cancers. Surgery and chemoradiation, either in neo-adjuvant or adjuvant setting, is the usual treatment for patients with advanced but resectable esophageal cancers. The prognosis and further management largely depends upon the pathologic tumor-node-metastasis (TNM) staging provided by the American Joint Committee on Cancer (AJCC) and the International Union against Cancer. Currently, the 7th edition of TNM staging system is being applied for prognostication and this is more focused on pathologic evaluation. Eighth edition of AJCC/UICC TNM staging has been introduced and will be implemented for clinical use in 2018.

The role of immunosuppression in squamous cell carcinomas arising in seborrheic keratosis

Seborrheic keratoses (SK) are common skin neoplasms considered to be benign. Reports of associated squamous cell carcinoma arising within seborrheic keratosis (SCC-SK) have been described. To describe the histopathologic characteristics of SCC-SK and identify predisposing factors in formation of these rare lesions. There were 162 cases of SCC-SK in a span of a decade (2003-2014). All of the histopathologic specimens and medical records were reviewed. Data from these patients were compared to a control group with seborrheic keratosis who were matched by age, sex, and location of lesion from the same time period (n=162). SCC-SK has the classic histopathologic features of SK, such as hyperkeratosis, parakeratosis, papillomatosis, and pseudohorn cysts. The areas of squamous cell carcinoma were characterized by areas of squamous dysplasia (100%), hypogranulosis (79.6%), squamous eddies (79.6%), solar elastosis (80.9%), and brown pigmentation (59.9%). Patients with a history of immunosuppression had an increased risk for developing SCC-SK (19% vs 3%; P<.01), particularly when inhibition was transplant-associated (10% vs 0%; P<.01). This was a single center, retrospective study. SCC-SK occurs more often in elderly men with a history of immunosuppression associated with organ transplants.

Development of Urinary Bladder Pre-Neoplasia by Schistosoma haematobium Eggs and Chemical Carcinogen in Mice

Schistosoma haematobium is a biocarcinogen of human urinary bladder (UB). The present study investigated developing UB cancer mouse model by injecting S. haematobium eggs into the bladder wall and introduction of chemical carcinogens. Histopathological findings showed mild hyperplasia to epithelial vacuolar change, and high grade dysplasia. Squamous metaplasia was observed in the S. haematobium eggs+NDMA group at week 12 but not in other groups. Immunohistochemistry revealed significantly high expression of Ki-67 in urothelial epithelial cells of the S. haematobium eggs+BBN group at week 20. The qRT-PCR showed high expression of p53 gene in S. haematobium eggs group at week 4 and S. haematobium eggs+BBN group at week 20. E-cadherin and vimentin showed contrasting expression in S. haematobium eggs+BBN group. Such inverse expression of E-cadherin and vimentin may indicate epithelial mesenchymal transition in the UB tissue. In conclusion, S. haematobium eggs and nitrosamines may transform UB cells into squamous metaplasia and dysplasia in correlation with increased expression of Ki-67. Marked decrease in E-cadherin and increase in p53 and vimentin expressions may support the transformation. The present study introduces a promising modified animal model for UB cancer study using S. haematobium eggs.

Bizarre cell dysplasia of the cervix.

The aim of this study was the characterization of a new subtype of high-grade cervical squamous intraepithelial lesion (HSIL) with enlarged cells containing bizarre nuclei: so-called bizarre cell dysplasia (BCD). A total of 29 cervical cone biopsy samples of this type of dysplasia were studied. Multi-target polymerase chain reaction and in situ hybridization human papillomavirus (HPV) detection was performed in all cases. BCD was defined as a subtype of HSIL characterized by the presence of large dysplastic cells with abnormal, large pleomorphic nuclei or multinucleation causing nucleomegaly. This results in bizarre nuclear shapes. Bizarre cells are scattered throughout the whole thickness of the dysplastic squamous epithelium. The BCD lesions arise within the conventional/classic high grade or "bland" type squamous dysplasia HSIL. Statistically they were significantly associated with HVP type 16. A significant association with other studied viruses (Herpes simplex virus [HSV]1, HSV2, Varicella zoster virus, Epstein-Barr virus, cytomegalovirus, human herpesvirus 6, and human polyomaviruses BK and JC) was not confirmed. BCD involves cytologically characteristic morphologic changes that are recognizable, but which may pose some risk of misdiagnosis as low-grade squamous intraepithelial lesion due to the enlargement of dysplastic cells and multinucleation. Based on the unique histological, cytological and biological features of BCD including strong association with HPV 16 infection, we believe that this is a specific, and so far unrecognized variant of HSIL.

Mitochondrial-Related Gene Expression and Macrophage Signatures in Non-Small Cell Lung Cancer, Including Patients with Emphysema as Co-Morbidity

Objective: Our aim is to determine whether mitochondrial dysfunction is a contributing factor to the increased risk of non-small cell lung carcinoma (NSCLC) in COPD patients.Methods: The clinical relevance of mitochondrial-related gene expression in lung cancer was determined using transcriptomic data from more than 1000 human NSCLC samples. Immunohistochemistry was then used to study cell type specific expression of the relevant mitochondrial-related protein in normal and cancerous lung tissue. Gene set variation analysis (GSVA) was applied in NSCLC datasets to determine the relative expression of specific macrophage transcriptomic signatures.Results: The expression of 33 mitochondrial-related genes was correlated with NSCLC patient survival. We studied further the expression of PGAM5 and FUNDC1, which are regulators of mitochondrial degradation (mitophagy). In background lung tissue, PGAM5 and FUNDC1 were only expressed in alveolar macrophages, with highest expression in smokers with emphysema compared to healthy smokers and non-smokers. In cancerous tissue, only the malignant epithelial cells and associated macrophages at the periphery of the cancer, expressed PGAM5 and FUNDC1. PGAM5 was also expressed in pre-neoplastic epithelium (squamous dysplasia and carcinoma in situ). There was no difference in expression in cancer tissue between the emphysema, healthy smokers and non-smokers group. Macrophages at the edge of the cancer from emphysema patients had a trend towards higher expression of PGAM5 and FUNDC1 compared to those from the other groups. There was a significant correlation between PGAM5 expression in cancer tissue and 9 out of 49 previously defined macrophage transcriptomic signatures with one (module 22) associated with patient survival (p<0.05).Conclusion: PGAM5 is expressed in pre-neoplastic tissue and NSCLC, but not in normal epithelium. The association between PGAM5 expression and lung cancer outcome may be mediated by the induction of specific macrophage phenotypes.

MA12.04 Mitochondrial-Related Proteins, PGAM5 and FUNDC1, in COPD-Associated Non-Small Cell Lung Carcinoma

Patients with COPD and/or emphysema have an increased risk of non-small cell lung cancer (NSCLC). COPD and lung cancer are both characterized by increased oxidative stress associated with mitochondrial dysfunction. We hypothesize that mitochondrial dysfunction is a driving mechanism for the increased risk of NSCLC in COPD. We determined whether there is dysregulated expression of mitochondrial-related proteins in NSCLC arising in COPD, and if so, their clinical significance. To determine the clinical relevance of mitochondrial related gene expression, we examined a database containing transcriptomic data of more than 1, 000 human NSCLC samples and with survival outcomes (https://precog.Stanford.edu/). Immunohistochemistry for PGAM5 and FUNDC1 was performed on cancer and background (‘normal’) tissue from lung cancer resections from non-smokers, healthy smokers (without COPD) and COPD/ emphysema patients. Protein expression was assessed using a semi-quantitative immunohistochemical scoring system (H score). Specific gene expression was further correlated with outcome in dataset GSE 72194, containing transcriptomic data of NSCLC cases and patient survival. 25 mitochondrial-related genes were linked to survival in NSCLC. Of those 25, we chose to study further the expression of PGAM5 and FUNDC1, which are regulators of mitochondrial degradation (mitophagy). In background lung tissue, PGAM5 and FUNDC1, only expressed in alveolar macrophages, were most highly expressed in COPD (H score: 180 ± 58 and 23 ± 9, respectively) compared to healthy smokers (146 ± 58 and 20 ± 8) and non-smokers (68 ± 48 and 3.3 ± 1.4) (p<0.05). In cancerous tissue, only the malignant epithelial cells and associated macrophages, at the periphery of the cancer, expressed PGAM5 and FUNDC1. PGAM5 was also expressed in pre-neoplastic epithelium (squamous dysplasia and carcinoma in situ). There was no difference in expression across the 3 groups, although the macrophages, at the edge of cancer, from COPD patients tended to show higher expression of PGAM5 and FUNDC1, compared to those from the other groups. When the expression of PGAM5 was compared with that of 50 known macrophage transcriptomic signatures within NSCLC samples, there was a positive correlation between PGAM5 and 9 macrophage signatures (r= 0.27 - 0.44, p<0.05), with one a determinant of patient survival. PGAM5 expression in pre-neoplastic tissue and NSCLC, but not in normal epithelium, suggests it plays a role in the transformation of malignant epithelial cells. PGAM5 and FUNDC1 may contribute to the pathogenesis of both COPD and NSCLC, possibly through mitophagic processes.

Expression of Podoplanin in Laryngeal Squamous Cell Carcinoma and Dysplasia.

In human cancers, podoplanin expression and its correlation with tumour invasive potential raise its possible role as a diagnostic and prognostic marker for cancer. To investigate the immunohistochemical expression of podoplanin in laryngeal Squamous Cell Carcinoma (SCC) and dysplasia. This study included a total of 60 archived, formalin fixed, paraffin embedded tissue blocks of 40 cases of laryngeal SCC and 20 cases of dysplastic lesions. The samples were immunohistochemically analysed for podoplanin expression. Podoplanin expression was significantly higher in laryngeal SCC (90%) than laryngeal dysplastic lesions (55%) (p-value=0.002). The expression of podoplanin was significantly increased with the higher grades of dysplasia (p-value=0.016). A significant positive correlation was detected between podoplanin expression in laryngeal SCC and depth of tumour invasion (p-value=0.035), and stage (p-value=0.026). The high expression of podoplanin in laryngeal SCC and its significant correlation with poor prognostic parameters recommends podoplanin as a prognostic marker in laryngeal SCC. In addition, increased podoplanin expression with higher grades of dysplasia, supports its role in malignant transformation and allows us to recommend its evaluation in premalignant lesions.

Hydroxyurea and nonmelanoma skin cancers: Report of three cases and review of the literature

Introduction. Hydroxyurea (HU) is a cytostatic agent, frequently used for the treatment of myeloproliferative disorders, sickle cell anemia and severe forms of psoriasis. Cutaneous side effects occur in up to one third of patients taking hydroxyurea, with the most serious side effect being susceptibility to develop non-melanoma skin cancers. Case report. We report 3 patients using HU that have developed multiple skin malignancies on the head and neck region and dorsa of the hands, arranged according to the level of the overall squamous dysplasia expressed. Conclusion. A cumulative dose of hydroxyurea affects skin cancer promotion in concordance with other risk factors determining cumulative ultraviolet exposure (age of the patients, skin phototype, sun habits), but the exact influence of each of them and enrollment of other possible cofactors remains to be elucidated. We point out the importance of adequate skin cancer preventive and therapeutic approach to the patients treated with hydroxyurea.

Expression of p16INK4α in cervical squamous epithelium infected by high-risk HPV and its significance

Objective To investigate p16INK4α protein expression in cervical squamous epithelium infected by high-risk HPV, and to explore the role and significance of p16INK4α in carcinogenesis. Methods High-risk HPV DNA were detected by HC2 methods. 31 cases of chronic cervicitis, 48 cases of cervical intraepithelial neoplasia (CIN) (including 16 cases of CINⅠ, 14 cases of CINⅡ, 18 cases of CINⅢ) and 48 cases squamous cell carcinoma (SCC) cervical tissues with high-risk HPV-positive were collected. p16INK4α protein was detected by immunohistochemistry. Results The positive rates of p16INK4α were 0 (0/31), 25% (4/16), 100% (14/14), 100% (18/18) and 100% (48/48) in chronic cervicitis, CINⅠ, CINⅡ, CINⅢ and SCC group, respectively. The positive rates of CINⅡ, CINⅢ and SCC groups were significantly higher than those of chronic cervicitis and CINⅠ groups (P<0.05). Conclusion The positive expression of p16INK4α protein indicates cervical squamous epithelium dysplasia, which is the important reference in accurate diagnosis of cervical squamous intraepithelial lesions infected by high-risk HPV. Key words: Human papillomavirus; Cervical intraepithelial neoplasia; Uterine cervical neoplasms; Protein, p16INK4α

Risk of persistent and recurrent cervical neoplasia following incidentally detected adenocarcinoma in situ

Adenocarcinoma in situ of the uterine cervix is a precursor to cervical adenocarcinoma and may coexist with both adenocarcinoma and high-grade squamous dysplasia (cervical intraepithelial neoplasia 2 and 3). Up to 60% of adenocarcinoma in situ lesions are detected incidentally following excisional biopsies performed for the treatment of cervical intraepithelial neoplasia 2/3. To date there are no data regarding risk factors for persisting or progressive cervical neoplasia in these patients. We sought to investigate patient outcomes following incidentally detected cervical adenocarcinoma in situ after loop electrosurgical excision procedure or cold knife cone biopsy performed for the treatment of high-grade cervical intraepithelial neoplasia. We conducted a retrospective, population-based cohort study of Western Australian patients with an incidental diagnosis of adenocarcinoma in situ from 2001 through 2012. Primary outcomes were persistent or recurrent cervical intraepithelial neoplasia 2/3 and or adenocarcinoma in situ, and invasive adenocarcinoma during follow-up (<12 months) and surveillance (≥12 months) periods. The cohort comprised 298 patients, with 228 (76.5%) treated initially by loop electrosurgical excision procedure and 70 (23.5%) treated by cold knife cone biopsy. The mean age was 31.2 (range 18-68) years and the median length of follow-up was 2.4 (range 0.3-12.2) years. Overall, 11 (3.7%) patients had cervical intraepithelial neoplasia 2/3, 23 (7.7%) had adenocarcinoma in situ, and 3 (1.0%) had adenocarcinoma diagnosed during the follow-up and surveillance periods. Age >30 years, pure adenocarcinoma in situ lesions, and larger lesions (>8 mm) were associated with a greater risk of disease persistence or recurrence. Following the incidental detection of adenocarcinoma in situ, age >30 years, pure adenocarcinoma in situ lesions, and lesions >8 mm were significantly associated with disease persistence/recurrence.In younger women, incidentally detected adenocarcinoma in situ that coexists with cervical intraepithelial neoplasia 2/3 and is <8 mm extent with clear margins may not require reexcision.

Role of endoscopy in early oesophageal cancer.

Incidence of oesophageal adenocarcinoma has increased exponentially in the West over the past few decades. Following detection of advanced cancers, 5-year survival rates remain bleak, making identification of early neoplasia, which has a better outcome, important. Detection of subtle oesophageal lesions during endoscopy can be challenging, and advanced imaging techniques might improve their detection. High-definition endoscopy has become a standard in most endoscopy centres, and this technology probably provides better delineation of mucosal features than standard-definition endoscopy. Various image enhancement techniques are now available with the development of new electronics and software systems. Image enhancement with chromoendoscopy using dyes has been a cost-effective option for many years, yet these techniques have been replaced in some contexts by electronic chromoendoscopy, which can be used with the press of a button. However, Lugol's chromoendoscopy remains the gold standard to identify squamous dysplasia. Identification and characterization of subtle neoplastic lesions could help to target biopsies and perform endoscopic resection for better local staging and definitive therapy. In vivo histology with techniques such as confocal endomicroscopy could make endotherapy feasible within a shorter timescale than when relying on histology on tissue samples. Once early neoplasia is identified, treatments include endoscopic resection, endoscopic submucosal dissection or various ablative techniques. Endotherapy has the advantage of being a less invasive technique than oesophagectomy, and is associated with lower mortality and morbidity. Endoscopic ablation therapies have evolved over the past few years, with radiofrequency ablation showing the best results in terms of success rates and complications in Barrett dysplasia.

Detection of Angiogenic Squamous Dysplasia Using High Magnification Bronchovideoscopy Combined With Narrow Band Imaging

Detection of Angiogenic Squamous Dysplasia Using High Magnification Bronchovideoscopy Combined With Narrow Band Imaging

4-2 拡大気管支ビデオスコープを用いたsquamous dysplasiaにおけるangiogenesis解析( 第28回日本呼吸器内視鏡学会総会)

4-2 拡大気管支ビデオスコープを用いたsquamous dysplasiaにおけるangiogenesis解析( 第28回日本呼吸器内視鏡学会総会)

Changes in mitochondrial stability during the progression of the Barrett's esophagus disease sequence.

BackgroundBarrett’s esophagus follows the classic step-wise progression of metaplasia-dysplasia-adenocarcinoma. While Barrett’s esophagus is a leading known risk factor for esophageal adenocarcinoma, the pathogenesis of this disease sequence is poorly understood. Mitochondria are highly susceptible to mutations due to high levels of reactive oxygen species (ROS) coupled with low levels of DNA repair. The timing and levels of mitochondria instability and dysfunction across the Barrett’s disease progression is under studied.MethodsUsing an in-vitro model representing the Barrett’s esophagus disease sequence of normal squamous epithelium (HET1A), metaplasia (QH), dysplasia (Go), and esophageal adenocarcinoma (OE33), random mitochondrial mutations, deletions and surrogate markers of mitochondrial function were assessed. In-vivo and ex-vivo tissues were also assessed for instability profiles.ResultsBarrett’s metaplastic cells demonstrated increased levels of ROS (p < 0.005) and increased levels of random mitochondrial mutations (p < 0.05) compared with all other stages of the Barrett’s disease sequence in-vitro. Using patient in-vivo samples, Barrett’s metaplasia tissue demonstrated significantly increased levels of random mitochondrial deletions (p = 0.043) compared with esophageal adenocarcinoma tissue, along with increased expression of cytoglobin (CYGB) (p < 0.05), a gene linked to oxidative stress, compared with all other points across the disease sequence. Using ex-vivo Barrett’s metaplastic and matched normal patient tissue explants, higher levels of cytochrome c (p = 0.003), SMAC/Diablo (p = 0.008) and four inflammatory cytokines (all p values <0.05) were secreted from Barrett’s metaplastic tissue compared with matched normal squamous epithelium.ConclusionsWe have demonstrated that increased mitochondrial instability and markers of cellular and mitochondrial stress are early events in the Barrett’s disease sequence.

The Discovery and Validation of Biomarkers for the Diagnosis of Esophageal Squamous Dysplasia and Squamous Cell Carcinoma.

The 5-year survival rate of esophageal cancer is less than 10% in developing countries, where more than 90% of these cancers are esophageal squamous cell carcinomas (ESCC). Endoscopic screening is undertaken in high incidence areas. Biomarker analysis could reduce the subjectivity associated with histologic assessment of dysplasia and thus improve diagnostic accuracy. The aims of this study were therefore to identify biomarkers for esophageal squamous dysplasia and carcinoma. A publicly available dataset was used to identify genes with differential expression in ESCC compared with normal esophagus. Each gene was ranked by a support vector machine separation score. Expression profiles were examined, before validation by qPCR and IHC. We found that 800 genes were overexpressed in ESCC compared with normal esophagus (P < 10(-5)). Of the top 50 genes, 33 were expressed in ESCC epithelium and not in normal esophagus epithelium or stroma using the Protein Atlas website. These were taken to qPCR validation, and 20 genes were significantly overexpressed in ESCC compared with normal esophagus (P < 0.05). TNFAIP3 and CHN1 showed differential expression with IHC. TNFAIP3 expression increased gradually through normal esophagus, mild, moderate and severe dysplasia, and SCC (P < 0.0001). CHN1 staining was rarely present in the top third of normal esophagus epithelium and extended progressively towards the surface in mild, moderate, and severe dysplasia, and SCC (P < 0.0001). Two novel promising biomarkers for ESCC were identified, TNFAIP3 and CHN1. CHN1 and TNFAIP3 may improve diagnostic accuracy of screening methods for ESCC. Cancer Prev Res; 9(7); 558-66. ©2016 AACR.

Cervical polyps: Is histologic evaluation necessary?

ObjectiveThe aim of this study was to examine a series of clinically identified cervical polyps and determine the incidence of significant histologic and concurrent cytologic findings. MethodsConsecutive cervical polyps from January 2000 through September 2012 were retrieved from the hospital laboratory information system. Histologic evaluation of these polyps was performed, followed by a chart review of clinical findings and correlation with the immediately prior or concurrently collected cervical Papanicolaou (Pap) test results, when available. ResultsA total of 369 cervical polyps were identified and reviewed. The patient ages ranged from 18 to 87 years (mean 46.5years). Eight polyps demonstrated squamous dysplasia (6 Cervical Intraepithelial Neoplasia/CIN I, and 2 CIN II/III), while 6 had malignant or atypical/potentially malignant features (2 adenosarcoma, 2 atypical polyps concerning for Mullerian adenosarcoma, 1 endometrioid endometrial adenocarcinoma and 1 adenocarcinoma in-situ). An increased incidence of atypical squamous cells of undetermined significance (ASCUS) and atypical glandular cells not otherwise specified (AGC NOS) Pap diagnoses (12.7% and 6.1%, respectively) was found in women with benign polyps on biopsy. DiscussionWe demonstrated a higher rate of clinically significant histologic findings in cervical polyps (14 of 369 cases, 3.7%) compared to previously reported studies. The increase in ASCUS and AGC Pap results was most likely related to reactive and inflammatory changes present in benign polyps. Our results suggest that removal of all cervical polyps with subsequent histologic review is warranted.

Higher Serum Selenium Concentration is Associated with a Higher Prevalence of Esophageal Squamous Dysplasia in Bomet, Kenya

Abstract 15 Background: East Africa is a region of high esophageal squamous cell carcinoma (ESCC) incidence, and is known to have low soil selenium levels. Low selenium status measured in blood has been associated with ESCC risk. We measured serum selenium in a cross-sectional study of subjects from Bomet, Kenya, a region with a high incidence of ESCC and esophageal squamous dysplasia (ESD), its precursor lesion. Methods: An age and sex-stratified sample of 294 asymptomatic adult residents completed questionnaires and underwent endoscopy with Lugol's iodine and biopsy for detection of ESD in this community-based study. Serum selenium concentrations were measured using 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, adjusting for multiple potential confounders. Ethical approval was obtained from the National Cancer Institute, Tenwek Hospital, and Kenyatta National Hospital. Results: Higher serum selenium (quartile 4) was associated with prevalence of ESD (OR: 3.03; 95% CI:1.05, 8.74) relative to lower serum selenium (quartile 1). This association remained significant after adjusting for potential confounders (Q4 vs Q1: OR: 4.24; 95% CI: 1.16, 15.46). Serum selenium concentration did differ significantly by geographic location (p=0.001); however, this did not explain the association between selenium and ESD. Conclusions: We found a significant adverse association between higher serum selenium levels and risk of ESD. These results are in contrast to our hypothesis derived from previous observations of an inverse association between selenium and ESCC. The discrepancy may be due to the difference in endpoint of ESD rather than ESCC. Further work is needed to better understand the potential role of selenium in esophageal cancer prevention and control strategies. Funding: This work was supported by the Intramural Research Program, Division of Cancer Epidemiology &amp; Genetics, National Cancer Institute, NIH. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST: Natalie R. Pritchett No relationship to disclose Michael M. Mwachiro No relationship to disclose Stephen L. Burgert Employment: Centers for Gastroenterology, Fort Collins, Colorado, USA Research Funding: Covidien Gwen Murphy No relationship to disclose John D. Brockman No relationship to disclose Christian C. Abnet No relationship to disclose Sanford M. Dawsey No relationship to disclose

Markers of Vitamin D Exposure and Esophageal Cancer Risk: A Systematic Review and Meta-analysis.

Vitamin D has been associated with reduced risk of many cancers, but evidence for esophageal cancer is mixed. To clarify the role of vitamin D, we performed a systematic review and meta-analysis to evaluate the association of vitamin D exposures and esophageal neoplasia, including adenocarcinoma, squamous cell carcinoma (SCC), Barrett's esophagus, and squamous dysplasia. Ovid MEDLINE, EMBASE, and Web of Science were searched from inception to September 2015. Fifteen publications in relation to circulating 25-hydroxyvitamin D [25(OH)D; n = 3], vitamin D intake (n = 4), UVB exposure (n = 1), and genetic factors (n = 7) were retrieved. Higher [25(OH)D] was associated with increased risk of cancer [adenocarcinoma or SCC, OR = 1.39; 95% confidence interval (CI), 1.04-1.74], with the majority of participants coming from China. No association was observed between vitamin D intake and risk of cancer overall (OR, 1.03; 0.65-1.42); however, a nonsignificantly increased risk for adenocarcinoma (OR, 1.45; 0.65-2.24) and nonsignificantly decreased risk for SCC (OR, 0.80; 0.48-1.12) were observed. One study reported a decreased risk of adenocarcinoma with higher UVB exposure. A decreased risk was found for VDR haplotype rs2238135(G)/rs1989969(T) carriers (OR, 0.45; 0.00-0.91), and a suggestive association was observed for rs2107301. In conclusion, no consistent associations were observed between vitamin D exposures and occurrence of esophageal lesions. Further adequately powered, well-designed studies are needed before conclusions can be made. Cancer Epidemiol Biomarkers Prev; 25(6); 877-86. ©2016 AACR.