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In China, it has been well recognized that some female patients with esophageal squamous cell carcinoma (ESCC) have different overall survival (OS) time, even with the same tumor-node-metastasis (TNM) stage, challenging the prognostic value of the TNM system alone. An effective predictive model is needed to accurately evaluate the prognosis of female ESCC patients.To construct a novel prognostic model with clinical and reproductive data for Chinese female patients with ESCC, and to assess the incremental prognostic value of the full model compared with the clinical model and TNM stage.A new prognostic nomogram incorporating clinical and reproductive features was constructed based on univariatie and Cox proportional hazards survival analysis from a training cohort (A clinical-reproductive model including incidence area, age, tumor differentiation, lymph node metastasis (N) stage, estrogen receptor alpha (ESR1) and beta (ESR2) expression, menopausal age, and pregnancy number was constructed to predict OS in female ESCC patients. Compared to the clinical model and TNM stage, the time-dependent ROC and C-index of the clinical-reproductive model showed a good discriminative ability for predicting 1-, 3-, and 5-years OS in the primary training, internal and external validation sets. Based on the optimal cut-off value of total prognostic scores, patients were classified into high- and low-risk groups with significantly different OS. The estrogen response was significantly associated with p53 and apoptosis pathways in esophageal cancer.The clinical-reproductive prognostic nomogram has an incremental prognostic value compared with the clinical model and TNM stage in predicting OS in Chinese female ESCC patients.

BackgroundThe impact of hospital volume on the long-term survival of esophageal squamous cell carcinoma (ESCC) has not been well assessed in China, especially for stage I–III stage ESCC. We performed a large sample size study to assess the relationships between hospital volume and the effectiveness of ESCC treatment and the hospital volume value at the lowest risk of all-cause mortality after esophagectomy in China.AimTo investigate the prognostic value of hospital volume for assessing postoperative long-term survival of ESCC patients in China.MethodsThe date of 158,618 patients with ESCC were collected from a database (1973–2020) established by the State Key Laboratory for Esophageal Cancer Prevention and Treatment, the database includes 500,000 patients with detailed clinical information of pathological diagnosis and staging, treatment approaches and survival follow-up for esophageal and gastric cardia cancers. Intergroup comparisons of patient and treatment characteristics were conducted with the X2 test and analysis of variance. The Kaplan-Meier method with the log-rank test was used to draw the survival curves for the variables tested. A Multivariate Cox proportional hazards regression model was used to analyze the independent prognostic factors for overall survival. The relationship between hospital volume and all-cause mortality was assessed using restricted cubic splines from Cox proportional hazards models. The primary outcome was all-cause mortality.ResultsIn both 1973-1996 and 1997-2020, patients with stage I-III stage ESCC who underwent surgery in high volume hospitals had better survival than those who underwent surgery in low volume hospitals (both PConclusionHospital volume can be used as an indicator to predict the postoperative survival of ESCC patients. Our results suggest that the centralized management of esophageal cancer surgery is meaningful to improve the survival of ESCC patients in China, but the hospital volume should preferably not be higher than 1027 cases/year.Core tipHospital volume is considered to be a prognostic factor for many complex diseases. However, the impact of hospital volume on long-term survival after esophagectomy has not been well evaluated in China. Based on a large sample size of 158,618 ESCC patients in China spanning 47 years (1973-2020), We found that hospital volume can be used as a predictor of postoperative survival in patients with ESCC, and identified hospital volume thresholds with the lowest risk of death from all causes. This may provide an important basis for patients to choose hospitals and have a significant impact on the centralized management of hospital surgery.

Purpose Some studies indicated that gender is associated with prognostic of cancer, However, currently the prognostic value of gender for gastric cardia adenocarcinoma (GCA) survival is unclear. The aim of our study is to reveal the influence of gender on the prognosis of patients with GCA. Patients and methods A total of 42,345 cases Chinese GCA patients were enrolled from our previously established GCA and esophageal cancer databases. The clinicopathological characteristics were retrieved from medical records in hospital. The follow-up was performed through letter, telephone or home interview. Among GCA patients, there were 32,544 (76.9%) male patients with the median age 62 years (range 17–97) and 9,801 (23.1%) female patients with the median age 61 years (range 17–95 years). The Chi-square test and Kaplan–Meier method were used to compare the continuous variables and survival. Cox proportional hazards model was used for competing risk analyses, hazard ratios (HRs) and 95% confidence intervals (CIs) were evaluated. Results Men had shorter GCA-specific survival than women by multivariate analysis (HR 1.114; 95% CI 1.061 to 1.169; P vs. male, P vs. male, P vs. male, P = 0.035). It was worth noting that in patients with stages I, II, III, and IV, female patients survive longer than male patients (P = 0.049; P = 0.011; P P = 0.044, respectively). Conclusion Gender is an independent prognostic factor for patients with GCA. In comparison with men, women have a significantly better outcome. Smoking and drinking may be protective factors for male GCA patients.

BackgroundThis study compared the survival outcomes of different surgical approaches to determine the optimal approach for gastric cardia adenocarcinoma (GCA) and aimed to standardize the surgical treatment guidelines for GCA.MethodsA total of 7103 patients with GCA were enrolled from our previously established gastric cardia and esophageal carcinoma databases. In our database, when the epicenter of the tumor was at or within 2 cm distally from the esophagogastric junction, the adenocarcinoma was considered to originate from the cardia and was considered a Siewert type 2 cancer. The main criteria for the enrolled patients included treatment with radical surgery, no radio- or chemotherapy before the operation, and detailed clinicopathological information. Follow-up was mainly performed by telephone or through home interviews. According to the medical records, the surgical approaches included transthoracic, thoracoabdominal, and transabdominal approaches. Kaplan–Meier and Cox proportional hazards regression models were applied to correlate the surgical approach with survival in patients with GCA.ResultsThere were marked differences in age and tumor stage among the patients who underwent the three surgical approaches (P P P P ConclusionThoracoabdominal approach and transabdominal approach were shown to be poor prognostic factors. Patients with (locally advanced) GCA may benefit from the transthoracic approach. Further prospective randomized clinical trials are necessary.

Objective: There are no comprehensive studies on survival outcomes and optimal treatment protocols for cervical esophageal cancer (CEC), due to its rare clinical prevalence. Our objective was to determine the relationship between pathological characteristics, treatment protocols, and survival outcomes in Chinese CEC patients. Methods: A total of 500 Chinese CEC patients were selected from our 500,000 esophageal and gastric cardia carcinoma database (1973–2018). There were two main groups: patients treated with surgery, and patients receiving non-surgical treatments (radiotherapy, radiochemotherapy, and chemotherapy). The Chi-square test and Kaplan–Meier method were used to compare the continuous variables and survival. Results: Among the 500 CEC patients, 278 (55.6%) were male, and the median age was 60.9 ± 9.4 years. A total of 496 patients (99.2%) were diagnosed with squamous cell carcinoma. In 171 (34.2%) patients who received surgery, 22 (12.9%) had undergone laryngectomy. In 322 (64.4%) patients who received non-surgical treatments, 245 (76.1%) received radiotherapy. Stratified survival analysis showed that only T stage was related with survival outcomes for CEC patients in the surgical group, and the outcomes between laryngectomy and non-laryngectomy patients were similar. It was noteworthy that the 5-year survival rate was similar in CEC patients among the different groups treated with surgery, radiotherapy, chemotherapy, or radiochemotherapy (P = 0.244). Conclusions: The CEC patients had similar survival outcomes after curative esophagectomy and radiotherapy, including those with or without total laryngectomy. These findings suggest that radiotherapy could be the initial choice for treatment of Chinese CEC patients.

Embryo implantation and decidualization are key steps for successful reproduction. Although numerous factors have been identified to be involved in embryo implantation and decidualization, the mechanisms underlying these processes are still unclear. Based on our preliminary data, Prss56, a trypsin-like serine protease, is strongly expressed at implantation site in mouse uterus. However, the expression, regulation and function of Prss56 during early pregnancy are still unknown. In mouse uterus,Prss56is strongly expressed in the subluminal stromal cells at implantation site on day 5 of pregnancy compared to inter-implantation site. Under delayed implantation,Prss56expression is undetected. After delayed implantation is activated by estrogen, Prss56 is obviously induced at implantation site. Under artificial decidualization, Prss56 signal is seen at the primary decidual zone at the initial stage of artificial decidualization. When stromal cells are induced forin vitrodecidualization,Prss56expression is significantly elevated.Dtprpexpression underin vitrodecidualization is suppressed byPrss56siRNA. In cultured stromal cells, HB-EGF markedly stimulatesPrss56expression through EGFR/ERK pathway. Based on promoter analysis, we also showed that Egr2 is involved in Prss56 regulation by HB-EGF. Collectively,Prss56expression at implantation site is modulated by HB-EGF/EGFR/ERK signaling pathway and involved in mouse decidualization.

Based on our initial genome-wide association study (GWAS) on esophageal squamous cell carcinoma (ESCC) in Han Chinese, we conducted a follow-up study to examine the single nucleotide polymorphisms (SNPs) associated with family history (FH) of upper gastrointestinal cancer (UGI) cancer in cases with ESCC. We evaluated the association between SNPs and FH of UGI cancer among ESCC cases in a stage-1 case-only analysis of the National Cancer Institute (NCI, 541 cases with FH and 1399 without FH) and Henan GWAS (493 cases with FH and 869 without FH) data (discovery phase). The top SNPs (or their surrogates) from discovery were advanced to a stage-2 evaluation in additional Henan subjects (2801 cases with FH and 3136 without FH, replication phase). A total of 19 SNPs were associated with FH of UGI cancer in ESCC cases with P −5 in the stage-1 meta-analysis of NCI and Henan GWAS data. In stage-2, the association for rs79747906 (located at 18p11.31, P = 5.79 × 10−6 in discovery) was replicated (P = 0.006), with a pooled-OR of 1.59 (95%CI: 1.11-2.28). We identified potential genetic variants associated with FH of UGI cancer. Our findings may provide important insights into new low-penetrance susceptibility regions involved in the susceptibility of families with multiple UGI cancer cases.

Objective : This study aimed to determine if gastric cardia adenocarcinoma (GCA) risk was associated with the lys (A or *2) allele at the rs671 (glu504lys) polymorphism within the aldehyde dehydrogenase 2 (ALDH2) gene in a Chinese Han population. We also aimed to investigateALDH2 genotypic distributions between subjects from high- and low-incidence areas for both GCA and esophageal squamous cell carcinoma (ESCC). Methods : We designed a case-control study including 2,686 patients with GCA and 3,675 control subjects from high- and low-incidence areas for both GCA and ESCC in China. TaqMan allele discrimination assay was used to genotype the rs671 polymorphism.χ2 test and binary logistic regression analysis were used to estimate the odds ratios for the development of GCA, and multivariate ordinal logistic regression was used to analyzeALDH2 genotypic distributions among different groups. Results : Compared withALDH2*1/*1 homozygotes,ALDH2*1/*2 andALDH2*2/*2 carriers did not increase the risk for GCA in the Chinese Han population (P>0.05). Interestingly, the ratio of homozygous or heterozygousALDH2 *2 carriers in high-incidence areas for both GCA and ESCC was lower than that in low-incidence areas (P

We conducted a joint (pooled) analysis of three genome-wide association studies (GWAS) of esophageal squamous cell carcinoma (ESCC) in individuals of Chinese ancestry (5,337 ESCC cases and 5,787 controls) with 9,654 ESCC cases and 10,058 controls for follow-up. In a logistic regression model adjusted for age, sex, study and two eigenvectors, two new loci achieved genome-wide significance, marked by rs7447927 at 5q31.2 (per-allele odds ratio (OR) = 0.85, 95% confidence interval (CI) = 0.82-0.88; P = 7.72 × 10(-20)) and rs1642764 at 17p13.1 (per-allele OR = 0.88, 95% CI = 0.85-0.91; P = 3.10 × 10(-13)). rs7447927 is a synonymous SNP in TMEM173, and rs1642764 is an intronic SNP in ATP1B2, near TP53. Furthermore, a locus in the HLA class II region at 6p21.32 (rs35597309) achieved genome-wide significance in the two populations at highest risk for ESSC (OR = 1.33, 95% CI = 1.22-1.46; P = 1.99 × 10(-10)). Our joint analysis identifies new ESCC susceptibility loci overall as well as a new locus unique to the population in the Taihang Mountain region at high risk of ESCC.

Background Our previous genome-wide association study (GWAS) identified three independent single nucleotide polymorphisms (SNPs) in human major histocompatibility complex (MHC) region showing association with esophageal squamous cell carcinoma (ESCC). In this study, we increased GWAS sample size on MHC region and performed validation in an independent ESCC cases and normal controls with aim to find additional loci at MHC region showing association with an increased risk to ESCC. Methods The 1,077 ESCC cases and 1,733 controls were genotyped using Illumina Human 610-Quad Bead Chip, and 451 cases and 374 controls were genotyped using Illumina Human 660W-Quad Bead Chip. After quality control, the selected SNPs were replicated by TaqMan genotyping assay on another 2,026 ESCC cases and 2,384 normal controls. Results By excluding low quality SNPs in primary GWAS screening, we selected 2,533 SNPs in MHC region for association analysis, and identified 5 SNPs with p

A single-nucleotide polymorphism (rs2274223: A5780G:His1927Arg) in the phospholipase C epsilon gene (PLCe) was recently identified as a susceptibility locus for esophageal cancer in Chinese subjects. To determine the underlying mechanisms of PLCe and this SNP in esophageal carcinogenesis, we analyzed PLCe genotypes, expression, and their correlation in esophageal cancer cell lines, non-transformed esophageal cells, 58 esophageal squamous cell carcinomas and 10,614 non-cancer subjects from China. We found that the G allele (AG or GG) was associated with increased PLCe mRNA and protein expression in esophageal cancer tissues and in esophageal cancer cell lines. G allele was also associated with higher enzyme activity, which might be associated with increased protein expression. Quantitative analysis of the C2 domain sequences revealed that A:G allelic imbalance was strongly linked to esophageal malignancy. Moreover, the analysis of 10,614 non-cancer subjects demonstrated that the G allele was strongly associated with moderate to severe esophagitis in the subjects from the high-incidence areas of China (OR 6.03, 95% CI 1.59–22.9 in high-incidence area vs. OR 0.74, 95% CI 0.33–1.64 in low-incidence area; P = 0.008). In conclusion, the PLCe gene, particularly the 5780G allele, might play a pivotal role in esophageal carcinogenesis via upregulating PLCe mRNA, protein, and enzyme activity, and augmenting inflammatory process in esophageal epithelium. Thus, 5780G allele may constitute a promising biomarker for esophageal squamous cell carcinoma risk stratification, early detection, and progression prediction.

Yong-Xu Jia,1,2,* Teng-Fei Li,3,* Dan-Dan Zhang,4 Zong-Min Fan,5 Hui-Jie Fan,1,2 Jie Yan,1,2 Li-Juan Chen,6 Hong Tang,6 Yan-Ru Qin,1,2 Xing-Ya Li1 1Department of Oncology, The First Affiliated Hospital of Zhengzhou University, 2Esophageal and Gastric Cancer Center of Henan Province, 3Department of Interventional Radiology, 4Department of Pathology, 5Henan Key Laboratory for Esophageal Cancer Research, The First Affiliated Hospital of Zhengzhou University, 6Department of Oncology, Tumor Hospital of Henan Province, Zhengzhou, Henan, People’s Republic of China *These authors contributed equally to this work Abstract: Molecular-targeted therapy against tyrosine kinase receptors (RTKs) plays an important role in gastric cancer (GC) treatment. Understanding the correlation between RTK coexpression could better guide clinical drug use. In the present study, the coexpression status of c-MET, fibroblast growth factor receptor 2 (FGFR2), and human epidermal growth factor receptor 2 (HER2) in human GC and their clinical significance in clinical therapy were explored. Immunohistochemical (IHC) staining, quantitative real-time polymerase chain reaction and fluorescent in situ hybridization were performed in 143 cases of GC who had undergone gastrectomy without preoperative chemoradiotherapy. Their association with clinicopathological features and clinical prognosis was analyzed. The frequencies of c-MET, FGFR2, and HER2 overexpression were 47.6% (68/143), 34.3% (49/143), and 10.5% (15/143), respectively. In the RTK coexpression study, 30.1% of patients (43/143) were positive for only one RTK, 25.8% (37/143) were positive for two RTKs, 3.5% (5/143) had triple-positive status, and 40.6% (58/143) had triple-negative status. In survival analysis, the overexpression of c-MET, FGFR2, and HER2 were significantly associated with overall survival (OS) (P=0.018, 0.004, and 0.049, respectively). In coexpression analysis, patients with triple-positive GC had the poorest OS (P=0.013). In conclusion, RTK coexpression is significantly associated with poor clinical outcome in GC. Keywords: c-MET, FGFR2, HER2, gastric cancer, coexpression, survival, target therapy

Li Dong Wang and colleagues report a genome wide association study for esophageal squamous cell carcinoma in the Chinese population. They identify two risk loci at PLCE1 and C20orf54.

Decidualization is an essential step in the establishment of pregnancy. However, the functional contributions of long intergenic noncoding RNAs (LincRNAs) to decidualization have not been explored. To explore the regulation and role of LincRNAs during human decidualization, human endometrial stromal cells (HESCs) are induced to undergo in vitro decidualization by treating with estradiol-17β, db-cAMP and medroxyprogesterone acetate. LINC00473 (LINC473) expression is highly induced in HESCs after decidual stimulus. We found that cAMP-PKA pathway regulates the expression of LINC473 through IL-11-mediated STAT3 phosphorylation. RNA interference-mediated down-regulation of LINC473 inhibits in vitro decidualization. These results suggested that LINC473 might be functionally required for human decidualization. This is the first report demonstrating the presence of LincRNA during human decidualization.

It has been well recognized that esophageal squamous cell carcinoma (ESCC) is the major histopathological type of esophageal cancer in China. However, it is not even clear how many histopathological types of esophageal malignant tumor (EMT) exist and if the histopathological patterns have changed over the past decades in China. The present study was thus undertaken to characterize the histopathological patterns over 40 years at a single institute in northern China, the high incidence area for esophageal cancer. All the patient information was from esophageal cancer database in Henan Key Laboratory for Esophageal Cancer Research of the First Affiliated Hospital, Zhengzhou University in Henan, China (1973-2015). A total of 66,216 patients with MET and detailed histopathological records were enrolled in this study, including 39,873 males with a mean age of 60±6 and 26,343 females with a mean age of 60±6 from 1975-2014. All the patients were classified into four period groups based on the diagnosed time, group I (1975-1984, 4,331/6.5 %), group II (1985-1994, 14,577/22%), group III (1995-2004, 20,781/31.4%) and group IV (2005-2014, 26,527/40.1%). The results demonstrated 12 different histopathological types of EMT. The most common type was ESCC (64,800, 97.4%), followed by esophageal adenocarcinoma (EAC, 1268, 1.9%), esophageal small cell carcinoma (201, 0.3%), esophageal adenosquamous carcinomas (EASC, 119, 0.18 %), esophageal spindle cell carcinoma (76, 0.11%), esophageal undifferentiated carcinoma (37, 0.06%), esophageal malignant melanoma (5, 0.008%), esophageal stromal tumor (3, 0.005%), esophageal clear cell carcinoma (2, 0.003%), esophageal malignant schwannoma (1, 0.002%), esophageal lymphatic tumor (1, 0.002%) and esophageal smooth muscle cell sarcoma (1, 0.002%). Time trending analysis showed that, over the past 40 years, ESCC was relatively stable (98.9%, 98.0%, 97.0%, 97.1%, respectively). However, EAC (0.97%, 1.66%, 2.30%, 1.87%, respectively), small cell carcinoma (0.02%, 0.17%, 0.28%, 0.43%, respectively) and spindle cell carcinoma (0.02%, 0.01%, 0.10%, 0.22%, respectively) increased apparently. The present study indicates that ESCC remains the major histopathological type for Chinese esophageal cancer. Interestingly, esophageal adenocarcinoma, small cell carcinoma and spindle cell carcinoma seem to increasing over the past decades. The improved molecular diagnostic biomarkers and the changes of lifestyle including the diet patterns resulted from recent economic development in China, may contribute to the changes of esophageal histopathological types. [Supported by Joint Funds of the National Nature Science Foundation of Chian (U1301227), National Nature Science Foundation of China (81472323), and Correspondence to: Li Dong Wang, Email: ldwang2007@126.com] Note: This abstract was not presented at the meeting. Citation Format: Xue Ke Zhao, Hai Jun Yang, Zong Min Fan, Ji Lin Li, Li Min He, Yun Zhou, Liu Qin Yang, Ying Fa Zhou, Sa Tang, Yang Yang, Lei Ma, Wei Li Han, Li Dong Wang. The changes of esophageal malignant tumors by histopathology over 40 years (1975-2014) at a single institute in northern China [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 258. doi:10.1158/1538-7445.AM2017-258

Background The role of tumor suppressor gene RASSF1A in the esophageal and gastric cardia carcinogenesis is still inconclusive. In this study, the polymorphism, promoter methylation and gene expression of RASSF1A were characterized in esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma (GCA). Methods We firstly analyzed the prevalence of RASSF1A A133S in a total of 228 cancer patients with ESCC (n=112) and GCA (n=116) and 235 normal controls by polymerase chain reaction (PCR) and restriction enzyme-digestion assay. Then, the promoter methylation status of the RASSF1A in ESCC (n=143), GCA (n=92) and corresponding adjacent normal tissues were further investigated using methylation-specific PCR (MSP) approach. Finally, the RASSF1A protein expression were determined in ESCC (n=27), GCA (n=24) and the matched adjacent normal tissues by immunohistochemical method. Results The frequency of 133Ala/Se and Ser/Ser genotype was significantly higher in GCA patients than in normal controls (19.0% vs. 10.2%, P=0.02). Compared with Ala/Ala genotype, Ala/Se and Ser/Ser genotype significantly increased susceptibility to GCA (OR=2.06, 95% CI=1.09–3.97). However, this polymorphism had no association with ESCC (P=0.69). The promoter methylation of RASSF1A gene was significantly increased the risk to both ESCC (OR=5.90, 95% CI=2.78–12.52) and GCA (OR=7.50, 95% CI= 2.78–20.23). Promoter methylation of RASSF1A gene in ESCC was also associated with age and cancer cell differentiation (for age: OR=3.11, 95% CI=1.10–8.73; for differentiation: OR=0.29, 95% CI=0.12–0.69). RASSF1A positive expression was significantly decreased the risk of GCA (OR=0.16, 95% CI=0.03–0.83). In contrast, there was no statistical significance between RASSF1A positive expression and ESCC. The expression of RASSF1A protein trend to be positively related with older GCA patients (OR=16.20, 95% CI=1.57–167.74). Conclusions The present findings suggest that alterations of RASSF1A may play an important role in gastric cardia carcinogenesis in terms of polymorphism, promoter hypermethylation and protein expression. Whereas, RASSF1A hypermethylation may probably also be involved in esophageal squamous cell carcinogenesis.

The etiological role of human papillomavirus (HPV) in cervical cancer has been well established. However, it is inconclusive whether HPV plays the same role in esophageal carcinogenesis. In this study, we detected HPV infection in 145 frozen esophageal tissues, including 30 normal epithelium (ENOR), 37 dysplasia (DYS) and 78 invasive squamous cell carcinoma (ESCC), and in 143 frozen cervical tissues composed of 30 normal epithelium (CNOR), 38 intraepithelial neoplasia (CIN) and 75 invasive squamous cell carcinoma (CSCC). The patients and symptom-free subjects enrolled in this study were from a high-incidence area for both ESCC and CSCC, Linzhou City, Northern China, from 2007 to 2009. The HPV infection analysis was conducted by using an HPV GenoArray Test Kit. We found that the high-risk HPV types accounted for more than 90 % of the HPV-positive lesions of esophagus and cervix tissues. The prevalence of high-risk HPV types increased significantly during the progression of both esophageal and cervical carcinogenesis (positive rate in esophageal tissues: 33 % ENOR, 70 % in DYS and 69 % in ESCC; positive rate in cervical tissues: 27 % in CNOR, 82 % in CIN and 88 % in CSCC; P < 0.001, respectively). Infection with the high-risk HPV types increased the risk for both DYS and ESCC by 4-fold (DYS vs. ENOR: OR = 4.73, 95 %CI = 1.68-13.32; ESCC vs. ENOR: OR = 4.50, 95 %CI = 1.83-11.05) and increased the risk for both CIN and CSCC by 12-fold and 20-fold (CIN vs. CNOR: OR = 12.18, 95 %CI = 3.85-38.55; CSCC vs. CNOR: OR = 20.17, 95 %CI = 6.93-58.65), respectively. The prevalence of high-risk types in ESCC patients was lower than that in CSCC patients (P = 0.005) and was significantly associated with the degree of ESCC tumor infiltration (P = 0.001). HPV 16 was the most prevalent subtype in both esophageal and cervical tissues. Single HPV infection increased significantly along with the progression of ESCC and maintained a high level in cervical tissues, regardless of whether they were CNOR or CSCC tissues. Our results showed that infection with HPV, especially the high-risk types, was positively associated with both esophageal and cervical cancers, suggesting that HPV also plays a role in the etiology of ESCC in the high-incidence area.

AIM: To investigate the relationship between human papillomavirus (HPV) infection and concurrent esophagus and gastric cardia cancer from the same patient (CC) and examine the significance of P16INK4A protein expression. METHODS: Polymerase chain reaction was used to detect the presence of HPV type16 (HPV16). The expression of P16INK4A protein was detected using immunohistochemistry. RESULTS: Among the CC specimens, HPV16-DNA was found in eight cases of esophageal squamous cell carcinoma (ESCC) and five cases of gastric cardia adenocarcinoma (GCA), respectively (47% vs 29%), and two of both ESCC and GCA. P16INK4A was highly expressed in both ESCC and GCA. In the HPV-associated positive CC, higher P16INK4A expression was observed in the GCA than in the ESCC (75% vs 25%, P < 0.05). CONCLUSION: HPV16 as a correlated risk factor may play an important role in the development of ESCC and GCA. P16INK4A may be a screening index in the HPV-associated carcinoma of gastric cardia.

We performed a genome-wide association study of esophageal squamous cell carcinoma (ESCC) by genotyping 1,077 individuals with ESCC and 1,733 control subjects of Chinese Han descent. We selected 18 promising SNPs for replication in an additional 7,673 cases of ESCC and 11,013 control subjects of Chinese Han descent and 303 cases of ESCC and 537 control subjects of Chinese Uygur-Kazakh descent. We identified two previously unknown susceptibility loci for ESCC: PLCE1 at 10q23 (P(Han combined for ESCC) = 7.46 x 10(-56), odds ratio (OR) = 1.43; P(Uygur-Kazakh for ESCC) = 5.70 x 10(-4), OR = 1.53) and C20orf54 at 20p13 (P(Han combined for ESCC) = 1.21 x 10(-11), OR = 0.86; P(Uygur-Kazakh for ESCC) = 7.88 x 10(-3), OR = 0.66). We also confirmed association in 2,766 cases of gastric cardia adenocarcinoma cases and the same 11,013 control subjects (PLCE1, P(Han for GCA) = 1.74 x 10(-39), OR = 1.55 and C20orf54, P(Han for GCA) = 3.02 x 10(-3), OR = 0.91). PLCE1 and C20orf54 have important biological implications for both ESCC and GCA. PLCE1 might regulate cell growth, differentiation, apoptosis and angiogenesis. C20orf54 is responsible for transporting riboflavin, and deficiency of riboflavin has been documented as a risk factor for ESCC and GCA.

To characterize the profile of chromosomal imbalances in esophageal cancer (EC) with or without family history in Linzhou, Henan Province of China.Comparative genomic hybridization (CGH) was used to examine 13 cases with positive family history of EC and 32 cases with negative family history of EC. RESULTS DNA copy number gains on chromosome 10q was observed only in the cases with postivie family history of EC (30%), and none in cases with a negative family history (P0.05). DNA copy number losses on chromosome 15q were significantly higher in cases with postivie family history (38% vs 6%, P0.05). The frequency of DNA copy number gains in 3q, 5p, 7p, 8q and DNA copy number losses in 3p, 19q, 9q were similar in the two groups (both beyond 20%) (P0.05).Frequent DNA copy number gains on chromosome 10q and losses on chromosome 15q in EC casers with postivie family history indicate that these chromosome sites may harbor the genes related to high susceptibility to EC. Such chromosomal sites as 3q, 5p, 7p, 8q, 3p, 19q, and 9q may contain important genes related with the environmental risk factors of esophageal carcinogenesis.

Nutrition deficiencies or poverty traditionally have been recognized to be related with increased risk for esophageal cancer (EC) in rural regions at junction of Henan, Hebei, and Shanxi provinces in northern China--the highest incidence area for esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma (GCA). Since the 1980s, economic and nutrition condition in these areas have been improved greatly. However, the histopathological types, staging pattern, and occurrence of ESCC and GCA, especially for esophageal adenocarcinoma (EAC), which have been rarely examined in the Chinese population during the past decades in these areas have not been well characterized to date.Yearly diagnosed new esophageal cancer (ESCC and EAC) and GCA patients from Beijing Tongren Hospital (in municipal low-risk region) and Cixian People Hospital (in rural high-risk region) during 24-year period (1982-2005) were studied retrospectively. Only local resident patients with surgical resection were included. Age at diagnosis, tumor stage and site, and histopathological pattern were recorded for each patient from the tumor registry database in these hospitals.This study demonstrated that the common ESCC sites were different in municipal (chiefly in lower third of the esophagus) and in rural (chiefly in middle third of the esophagus) regions. The peak age of ESCC, EAC, and GCA patients in rural region was 10 years younger than in municipal region. Eighty-six percent of ESCC and 90% of GCA in municipal region were diagnosed at middle and advanced stage; similarly, more than 95% of ESCC and GCA in rural region were diagnosed at middle and advanced stage during the 24-year study period. An increasing tendency in number of yearly diagnosed new patients with ESCC and GCA was observed in municipal region, but not in rural region. However, an increasing tendency for EAC was observed both in municipal and rural regions during the past 24-year period. The present results demonstrate the difference in municipal and rural regions of ESCC, ECA, and GCA in histopathological types, and suggest that there may be different etiological factors involved in esophageal and gastric cardia carcinogenesis in these different areas.

Aim: To characterize cytogenetic alterations in esophageal squamous cell carcinoma (ESCC) and its metastasis. Methods: A total of 37 cases of primary ESCC and 15 pairs of primary ESCC tumors and their matched metastatic lymph nodes cases were enrolled from Linzhou, the high incidence area for ESCC in Henan, northern China. The comparative genomic hybridization (CGH) was applied to determine the chromosomal aberrations on the DNA extracted from the frozen ESCC and metastatic lymph node samples from these patients. Results: CGH showed chromosomal aberrations in all the cases. In 37 cases of primary ESCC, chromosomal profile of DNA copy number was characterized by frequently detected gains at 8q (29/37, 78%), 3q (24/ 37, 65%), 5p (19/37, 51%); and frequently detected losses at 3p (21/37, 57%), 8p and 9q (14/37, 38%). In 15 pairs of primary ESCC tumors and their matched metastatic lymph node cases, the majority of the chromosomal aberrations in both primary tumor and metastatic lymph node lesions were consistent with the primary ESCC cases, but new candidate regions of interest were also detected. The most significant finding is the gains of chromosome 6p with a minimum high-level amplification region at 6p12-6q12 in 7 metastatic lymph nodes but only in 2 corresponding primary tumors (P = 0.05) and 20p with a minimum high-level amplification region at 20p12 in 11 metastatic lymph nodes but only in 5 corresponding primary tumors (P < 0.05). Another interesting finding is the loss of chromosome 10p and 10q in 8 and 7 metastatic lymph nodes but only in 2 corresponding primary tumors (P < 0.05). Conclusion: Using the CGH technique to detect chromosomal aberrations in both the primary tumor and its metastatic lymph nodes of ESCC, gains of 8q, 3q and 5p and loss of 3p, 8p, 9q and 13q were specifically implicated in ESCC in Linzhou population. Gains of 6p and 20p and loss of 10pq may contribute to the lymph node metastasis of ESCC. These findings suggest that the gains and losses of chromosomal regions may contain ESCC-related oncogenes and tumor suppressor genes and provide important theoretic information for identifying and cloning novel ESCC-related oncogenes and tumor suppressor genes. © 2008 WJG. All rights reserved., published_or_final_version

Some molecular changes occurred in esophageal precancerous and cancerous lesions could be reflected in the serum, but the clinical application is limited because of their low sensitivity and specificity. Serum proteomic profiling is much desirable in identifying the proteins closely related to esophageal carcinogenesis. This study was to characterize the serum protein profiles of the subjects with normal esophagus, esophageal precancerous and cancerous lesions from Linzhou, the area with the highest incidence of esophageal carcinoma (EC) in Henan Province, Northern China.Proteomic spectra were generated with surface-enhanced laser desorption/inionation-time of flight-mass spectra (SELDI-TOF-MS) and weak cation exchange (WCX2) protein chip system, and analyzed by bioinformatics like decision tree classification algorithm on a set of serum from 130 symptom-free subjects [including 63 cases with normal esophageal epithelia, 40 with basal cell hyperplasia (BCH), and 27 with dysplasia (DYS)] and 30 EC patients from Linzhou.One protein in BCH group with a ratio of mass to charge (M/Z) of M9 306.61 u, 1 in DYS group with a M/Z ratio of M13 765.9 u, and 2 in EC group with M/Z ratios of M2 942.15 u and M15 953.4 u were selected to build 3 decision tree classification models to identify the subjects with BCH, DYS, and EC, respectively. With these classification models, the sensitivities of identifying BCH, DYS and EC were 57.5% (23/40), 88.8% (24/27) and 96.6% (29/30), respectively, in the training sets, and 57.5% (23/40), 66.6% (18/27) and 60.0% (18/30), respectively, in the test sets; the specificities of identifying BCH, DYS and EC were 96.8% (61/63), 63.4% (40/63) and 92.0% (58/63), respectively, in the training sets, and 95.2% (60/63), 71.4% (45/63) and 84.1% (53/63), respectively, in the test sets.The protein sets with M/Z ratios of M9 306.61 u, M13 765.9 u, M2 942.15 u, and M15 953.4 u may contain promising serum biomarkers for screening the subjects with high-risk of EC.

To evaluate the serum biomarkers for diagnosis of gastric cardia dysplasia (DYS) and chronic atrophic gastric-carditis (CAG) and to provide a novel screening method for high risk population of gastric-cardia adenocarcinoma (GCA).Proteomic spectra were generated by surface-enhanced laser desorption/ionization-time of flight-mass spectra (SELDI-TOF-MS) and weak cation exchange protein chip system. A set of spectra derived from analysis of serum from 143 symptom-free subjects at high-risk area for GCA, including 63 cases with histologically normal gastric cardia epithelia, 57 of CAG and 23 of DYS, were analyzed by bioinformatics like decision tree classification algorithm. The sensitivity and the specificity for test group were performed by using 10-fold cross validation classification with the decision tree classification model.One protein spot with a ratio of mass to charge (M/Z) of M3894. 0 was selected to build a decision tree classification model to identify the case with DYS or normal. With this classification model, the sensitive rate for DYS identification was 87% (20/23). Two proteins with M/Z of M2942. 15 and M33316. 6 were used to build a decision tree classification model. With this model, the sensitivity for discriminating CAG from normal was 93% (53/57) and the specificity was 92 (58/63).The gastric cardia lesions of DYS and CAG could be identified by SELDI-TOF-MS technique specifically in symptom-free subjects at high incidence area for GCA. The present findings provide a new screening way for high-risk subjects with CGA.

Local lymph node and blood metastasis could occur at early stage of esophageal squamous cell carcinoma (ESCC), which may be the key factors of its recurrence and poor prognosis. However, the mechanism of ESCC metastasis is unclear. This study was to analyze the genetic changes in primary lesion and lymph node metastases of ESCC, to screen for and locate ESCC metastasis-related genes.Genomic alterations in 15 pairs of primary lesions and matched metastatic lymph nodes of ESCC were analyzed by comparative genomic hybridization (CGH).In the 15 pairs of tissues, the most common chromosomal alterations were the gains of 3q, 8q, 6p, 20p, 5p, 18p, 2p, 2q and 1q, and the losses of 10p, 10q, 17p, 18q, 4p and 13q. Of these changes, the most significant finding was the gain of 6p with a frequency of 47% in metastatic lymph nodes and 13% in primary lesions, and the gain of 20p with a frequency of 73% in metastatic lymph nodes and 33% in primary lesions. The second interesting finding was the loss of 10p with a frequency of 53% in metastatic lymph nodes and 13% in primary lesions, and the loss of 10q with a frequency of 47% in metastatic lymph nodes and 13% in primary lesions.The gains of 6p and 20p and the losses of 10p and 10q are common genomic alterations in primary lesion and lymph node metastases of ESCC, which may code ESCC metastasis-related genes.

Anyang County and nearby Linzhou (formerly Linxian) in Henan, Northern China have been well recognized as the highest incidence area for esophageal squamous cell carcinoma (SCC) in the world. SCC remains the leading cause of cancer-related death in these areas and the natural history for esophageal precancerous lesions is not clear.In the present study, to determine the significance of cytological examination and natural history for SCC, esophageal balloon cytological screening and follow-up studies have been performed 2273 symptom-free subjects in Anyang County since 1986. Based on cellular morphological changes, esophageal epithelial cells were classified as normal (NOR), inflammation (IN), hyperplasia (HYP), dysplasia (grades I and II) (DYS I and DYS II), near squamous cell carcinoma (NSCC) and SCC.The prevalence of NOR, IN, HYP, DYS I, DYS II, and NSCC was 22.7, 3.6, 33.6, 21.5, 10.7, and 3.8%, respectively, in males and 25.8, 5.7, 33, 18.9, 10.4, and 3.8%, respectively in females. No difference was observed between the male and female subjects (p0.05). Of the 2273 subjects examined, 2199 subjects entered the final follow-up analysis (97%). During the 15 years' follow-up on these subjects, 94 new cases (4.2%, 94/2199), including 91 with SCC (97%, 91/94, 58 males and 33 females) and 3 with GCA (3%, 3/94, one male and two females) were identified with a mean time of 8 +/- 4.6 years after entry of the follow-up. The incidence for SCC in males was higher than that in females (p0.05). The rate for SCC development increased apparently from the groups of NOR (2.4%) to DYS I (5%), DYS II (8.3%), and NSCC (10.3%) (p0.001). The prevalence of DYS and NSCC increased significantly with age.The present results indicate that esophageal balloon cytology is a reliable approach for early SCC and precancerous lesions screening and that DYS and NSCC are important markers for high-risk subjects with predisposition to SCC. Close follow-up to the subjects with HYP, DYS and NSCC may shed light on the natural history for human esophageal carcinogenesis.

To characterize the profile of chromosomal imbalances of esophageal squamous cell carcinoma (SCC) in Linzhou, the high prevalence area of Henan province.Comparative genomic hybridization (CGH) was used to examine 52 cases of primary SCC of esophagus.Gains in part or in whole of chromosome 3q, 8q, 5p, 1q, 6q, 18p, 20q and losses of 3p, 1p, 9q, 19p, 4p, 8p were detected frequently in SCC (20%). Gain of 3q, 5p, 1q, 11q13-14 and loss of 4pq, 13q were all significantly correlated with pathologic staging (P0.05). Gains of 8q, loss of 4p were linked to nodal metastasis (P0.05). Gains of 2p and loss of 4pq, 11q14-qter were associated with distant organ metastasis (P0.05).These observations suggest that 3q, 8q, 5p, 1q, 6q, 18p, and 20q may contain SCC-related oncogenes; 3p, 1p, 9q, 19p, 4p and 8p may contain SCC-related tumor suppressor genes. It is likely that gain of 3q, 5p, 1q, 11q13-14 and loss of 4pq, 13q are the genetic aberrations critical for the development of esophageal carcinoma, whereas gains of 8q, 2p and loss of 4pq, 11q14-qter are considered later events associated with tumor progression and are thought to confer metastatic potential to esophageal carcinoma. Furthermore, nodal and distant organ metastases involve different genes.

To characterize the profiles of chromosome imbalance in esophageal squamous cell carcinoma (SCC) and gastric cardia adenocarcinoma (GCA) from the high incidence area in Henan.Chromosomal aberrations of 37 samples of SCC and 30 GCA were analyzed by comparative genomic hybridization comparative genomic hybridization (CGH).It was found that the most frequently detected gains were on chromosome arm 8q (78%), and followed by 3q, 5p, 6q and 7p. The most frequent loss was found on 3p (57%), and followed by 8p, 9q and 11q in SCC. For GCA, the most frequent gain was found on chromosome arm 20q (43%), and followed by 6q, 8q and 6p. The most frequent loss was on the chromosome 17p (57%), and followed by 19p, 1p and 4p.The present findings demonstrate that gains of 8q, 3q and 5p, and losses of 3p, 8p, and 9q are characteristic profile of chromosome imbalance in SCC, and the gains of 20q, 6q and losses of 17p, 19p and 1p are characteristic profile of chromosome imbalance in GCA, which provide important theoretic information for identifying and cloning novel SCC/GCA-related genes.

To characterize the protein files in blood from same patients with esophageal squamous cell carcinoma (ESCC) before and after operation at the high-incidence area for ESCC in Henan Province, China.Two-dimensional electrophoresis, silver staining and ImageMaster 2-DE analysis software were applied to the determination of protein files in the blood obtained from normal controls and ESCC patients before and after operation.A total of 655, 662 and 677 protein spots were identified, respectively, from the normal controls and ESCC patients before and after operation. No significant difference in the number of protein spots was observed between the normal group and ESCC patients. A total of seven protein spots were identified with a dramatic difference among the samples before and after operation. Six protein spots were up-regulated and one protein spot was down-regulated in the group after operation compared with those in normal and before operation. Three protein spots were further characterized by matrix-assisted laser desorption/ionization time of flying mass spectrometry (MALDI-TOF-MS). The proteins from these three spots were identified as serum amyloid A (SAA), amyloid related serum protein and haptoglobin.Serum amyloid A, amyloid related serum protein and haptoglobin may be related with ESCC and/or surgery. The significance of these proteins needs to be further characterized. The present study provides informative data for the establishment of serum protein profiles related with ESCC.

To characterize the alteration and significance of p53 and PCNA in cancer and adjacent tissues of concurrent cancers from the esophagus and gastric cardia in the same patient.P53 and PCNA protein accumulation in 25 patients with concurrent cancers from the esophagus and gastric cardia (CC, concurrent carcinomas of esophageal squamous cell carcinoma and gastric cardia adenocarcinoma) were detected by immunohistochemical method (ABC).In CC patients, both esophageal squamous cell carcinoma (SCC) and gastric cardia adenocarcinoma (GCA) tissues showed different positive immunostaining extent of p53 and PCNA protein (P0.05). The positive immunostaining rates for p53 and PCNA were 60 % (15/25) and 92 % (23/25), respectively in SCC; and 40 % (10/25) and 88 % (22/25), respectively in GCA. "Diffuse" immunostaining pattern was frequently observed in both p53 and PCNA. High coincidence rates for p53 and PCNA positive staining were observed in SCC and GCA from the same patients, and accounted for 56 % and 96 %. In SCC patients, with the lesions progressed from normal esophageal epithelium (NOR) to basal cell hyperplasia (BCH) to dysplasia (DYS) to carcinoma in situ (CIS) to SCC, the positive rates for p53 were 27 %, 50 %, 50 %, 29 % and 72 %, and 55 %, 70 %,75 %, 71 % and 93 % for PCNA, respectively. In GCA, with the lesions progressed from normal gastric cardia epithelium to DYS to CIS to GCA, the positive rates of p53 expression were 44 %, 27 %, 22 % and 36 % respectively, the difference was not significant; the positive rates of PCNA protein expression were 67 %, 64 %, 67 % and 86 %, respectively. The chi(2) test, Fisher's Exact Test, Mantel-Haenszel chi(2) Test and Kappa Test were used for the statistics.The high coincident alterations for P53 and PCNA in SCC and GCA from the same patient indicate the possibility of similar molecular basis, which provides important molecular basis and etiological clue for similar geographic distribution and risk factors in SCC and GCA.

Esophageal cancer (EC) remains a leading cause of cancer-related deaths in Linzhou (formerly Linxian) and Huixian of Henan province, northern China, which has been well recognized as the highest incidence area for EC. The lack of useful chemoprevention agents and early detection methods is the key factors for stable EC incidence in these areas. Human esophageal carcinogensis has been considered as a multistep progressive process. The natural history for EC, however is not very clear.Follow-up studies with linear repeated biopsies and histopathological examination were performed on 778 subjects from Linzhou and Huixian. Of these subjects, 578 subjects were followed for 11 years (1989-2000), 400 subjects with different severity of esophageal precancerous lesions were randomly divided into 2 groups for intervention studies with calcium and decaffeinated green tea (DGT). Each group included 200 subjects (100 subjects for treatment, and 100 subjects for placebo). In calcium group, each subject received an oral supplementation of 1,200 mg of calcium daily for 11 months. In DGT group, each subject received 5 mg of DGT daily for 12 months. In placebo group, each subject received placebo pill for 11 months (calcium group) and 12 month (DGT group). At the entry and the end of the trial, esophageal biopsy specimens were taken at the middle and the lower thirds of the esophagus and from macroscopic lesions, if only, of each subject.DGT trail did not show apparent difference between the treatment and placebo group in alleviating the esophageal precancerous lesions and abnormal cell proliferation. For the calcium intervention study, after 11 years' follow-up, 10 subjects had developed into cancers in the calcium group (10%, 8 EC and 2 GCA), and 8 subjects developed into EC in the placebo group (8%). All these patients were diagnosed at very early stage of cancer (symptom-free). Of the 578 subjects, 25 (18 males and 7 females) had developed into EC (n = 23, 4.3%) and gastric cardia cancer (GCA, n = 2, 0.3%), during the 11 years' follow-up. The mean time of cancer development (from entry of the follow-up study to the cancer detection) was 5.0 +/- 2.9 years (males) and 4.7 +/- 3.2 years (females). Of the 25 patients with EC and GCA, 11 were from the 387 followed subjects with "normal" histomorphology of biopsy at the entry of the follow-up study (3%, 11/387), 2 were from the subjects with basal cell hyperplasia, grade I (BCH I, 2%, 2/94), 7 from the subjects with BCH grade II (BCH II, 10%, 7/72), and 5 from BCH III and dysplasia (20%, 5/25).DGT trail was not shown to have beneficial effects in alleviating esophageal precancerous lesions and abnormal cell proliferation patterns. Calcium supplementation did not produce apparent long-term effects on EC. BCH II could be considered as precancerous lesions of EC. The quantitative histopathological analysis in terms of number of proliferating basal cell layers is of importance in determining the high-risk subjects for EC and evaluating the intervention results. Follow-up studies with repeated endoscopic biopsies are the powerful strategy for early detection and mortality control of EC and GAC in the high incidence area.

AIM:To investigate the pathogenesis of gastric cardia and the distal part of stomach cancer and to further characterize the histopathogenesis model for gastric cardia cancer from the high-risk population for esophageal cancer.METHODS:Mass survey with endoscopic mucosa biopsy and histopathological examination were carried out on 226 subjects aged above 30 years. Three biopsies were collected one each from the middle part of the esophagus, the gastric cardia and the pyloric antrum. The biopsy tissue was fixed with 85% alcohol and paraffin-embedded.RESULTS:The incidence of intestinal metaplasia and dysplasia at gastric cardia epithelium was higher than that at the pyloric antrum from the subjects in the same area. And there were high incidences of both esophageal and gastric cardia cancer, but a low incidence of gastric cancer at the distal part of the stomach.CONCLUSION:There might be different etiology and pathogenesis of gastric cardia and pyloric cancer at the distal part of the stomach.

Nat. Genet. 42, 759–763 (2010); published online 22 August 2010; corrected after print 27 August 2014 In contrast to the version of this article initially published, the authors now find no evidence to support association with esophageal squamous cell carcinoma susceptibility for rs13042395[T] at 20p13 in their original data, in two independent sets of cases and controls collected in other Chinese populations or in the joint analysis of these three studies.

AIM: To characterize the histochemical type and pattern of intestinal metaplasia (IM) adjacent to gastric cardia adenocarcinoma (GCA) and distal gastric cancer (GC) in Linzhou, Henan Province, China. METHODS: Alcian-blue-periodic acid Schiff and high iron diamine-Alcian blue histochemical methods were performed on 142 cases of IM, including 49 cases of GCA and 93 cases of GC. All the patients were from Linzhou, Henan Province, China, the highest incidence area for both GCA and squamous cell carcinoma. Radio- or chemotherapy was not applied to these patients before surgery. RESULTS: The detection rate of IM in tissues adjacent to GCA tissues was 44.9%, which was significantly lower than that in GC tissues (80.64%, P < 0.01). The rates of both incomplete small intestinal and colonic IM types identified by histochemistry in GCA tissues (31.82% and 63.64%, respectively) were significantly higher than those in GC (5.33% and 21.33%, respectively, P < 0.01). CONCLUSION: IM in GCA and GC should be considered as a separate entity. Further research is needed to evaluate whether neoplastic progression of IM is related to its mucin profile in GCA.