Gastric-type Mucin Research Articles

Gastrointestinal: Multiple metastases of laterally spreading non-ampullary duodenal adenocarcinoma with gastric phenotype.

Non-ampullary duodenal adenocarcinoma could be divided into two major types: gastric and intestinal types with mucin immunohistochemistry. Ushiku et al. reported that the gastric type has a worse prognosis than the intestinal type in patients with duodenal adenocarcinoma. However, few studies have examined the malignant potential of gastric-type duodenal adenocarcinomas. A 76-year-old woman with respiratory symptoms underwent computed tomography, which showed bilateral cavitary pulmonary lesions. Esophagogastroduodenoscopy detected a duodenal tumor spreading from the superior duodenal angle to the prepylorus (Fig. 1a–c). Biopsy showed well-differentiated adenocarcinoma, which was immunohistochemically positive for the MUC5AC (gastric foveolar mucin) and focally positive for the MUC6 (pyloric and Brunner's gland mucin), but negative for MUC2 (major intestinal goblet cell mucin), CDX2 (intestinal transcription factor), and CD10 (intestinal epithelial cells) (Fig. 2a–g). The tumor was soft and flat without any findings suggesting muscle invasion. But positron emission tomography/computed tomography revealed increased uptake in the duodenal bulb, multiple lung lesions, para-aortic lymph nodes, sternum, and ninth thoracic spine (Fig. 1d–f). Histology and immunohistochemistry of lung lesion showed mucinous adenocarcinoma with gastric-type mucin expression, which was similar to the finding of duodenal carcinoma (Fig. 2h–n). Therefore, we diagnosed the patient with multiple metastases from gastric-type duodenal adenocarcinoma. The patient underwent palliative chemotherapy with S-1 plus oxaliplatin, but she died from progressive disease 7 months after diagnosis.

The Origin of Epithelium with Low-Grade Atypia in Early Gastric Cancer

Introduction: Helicobacter pylori (HP) infection causes chronic inflammation and atrophy of the gastric mucosa and thus a high risk of gastric cancer (GC). With the increasing success of HP infection treatment, a larger number of GCs that develop after eradication can be assessed. Several studies have shown that epithelium with low-grade atypia (ELA) is a frequent characteristic of these GCs, but the origin of this condition is unknown. In this study, we compared the mucin phenotype, cellular proliferation, and p53 staining in ELA and cancerous tissues obtained from patients with GC with and without HP eradication. Methods: The study population consisted of 23 patients with GC that developed after successful HP eradication therapy (eradicated group) and 24 patients with GC and HP infection (infected group). The prevalence of ELA was determined by hematoxylin and eosin staining. Tumor tissue and ELA samples were further analyzed by immunohistochemical staining for Muc5AC, Muc2, p53, and Ki-67. Results: The ELA coverage rate was significantly higher in the eradicated group than in the infected group. Gastric-type mucin was frequently expressed by the ELA, and the mucin phenotypes of ELA and cancerous areas differed in 75% of cases. The Ki-67 labeling index was consistently lower in ELA than in the cancerous mucosa. Fourteen of 21 (66.7%) cancerous lesions, but only 3 ELA samples, were p53-positive. Conclusion: In most cases, ELA on the surfaces of GCs seems to have originated from normal gastric cells, not from cancer cells.

Massively parallel sequencing analysis of 68 gastric-type cervical adenocarcinomas reveals mutations in cell cycle-related genes and potentially targetable mutations.

Gastric-type cervical adenocarcinoma (GCA) is an aggressive type of endocervical adenocarcinoma characterized by mucinous morphology, gastric-type mucin, lack of association with human papillomavirus (HPV) and resistance to chemo/radiotherapy. We characterized the landscape of genetic alterations in a large cohort of GCAs, and compared it with that of usual-type HPV-associated endocervical adenocarcinomas (UEAs), pancreatic adenocarcinomas (PAs) and intestinal-type gastric adenocarcinomas (IGAs).GCAs (n=68) were subjected to massively parallel sequencing targeting 410–468 cancer-related genes. Somatic mutations and copy number alterations (CNAs) were determined using validated bioinformatics methods. Mutational data for UEAs (n=21), PAs (n=178) and IGAs (n=148) from The Cancer Genome Atlas (TCGA) were obtained from cBioPortal.GCAs most frequently harbored somatic mutations in TP53 (41%), CDKN2A (18%), KRAS (18%) and STK11 (10%). Potentially targetable mutations were identified in ERBB3 (10%), ERBB2 (8%) and BRAF (4%). GCAs displayed low levels of CNAs with no recurrent amplifications or homozygous deletions. In contrast to UEAs, GCAs harbored more frequent mutations affecting cell cycle related genes including TP53 (41% vs 5%, p<0.01) and CDKN2A (18% vs 0%, p=0.01), and fewer PIK3CA mutations (7% vs 33%, p=0.01). TP53 mutations were less prevalent in GCAs compared to PAs (41% vs 56%, p<0.05) and IGAs (41% vs 57%, p<0.05). GCAs showed a higher frequency of STK11 mutations than PAs (10% vs 2%, p<0.05) and IGAs (10% vs 1%, p<0.05). GCAs harbored more frequent mutations in ERBB2 and ERBB3 (9% vs 1%, and 10% vs 0.5%, both p<0.01) compared to PAs, and in CDKN2A (18% vs 1%, p<0.05) and KRAS (18% vs 6%, p<0.05) compared to IGAs.GCAs harbor recurrent somatic mutations in cell cycle-related genes and in potentially targetable genes, including ERBB2/3. Mutations in genes such as STK11 may be used as supportive evidence to help distinguish GCAs from other adenocarcinomas with similar morphology in metastatic sites.

Gastroprotective Effects of Cudrania tricuspidata Leaf Extracts by Suppressing Gastric cAMP and Increasing Gastric Mucins

Cudrania tricuspidata has been used as an East Asian folk remedy to treat various symptoms. Recently, scientific evidence of the efficacy of C. tricuspidata has emerged. The objective of this study was to elucidate protective role of C. tricuspidata in the gastric mucosa using pylorus-ligated Sprague-Dawley rats and primary parietal cells. C. tricuspidata ethanol extracts attenuated gastric mucosal damage, secretion, and juice acidity in pylorus-ligated rats; however, it did not affect expression of gastric acid-related genes [muscarinic acetylcholine receptor M3 receptor (M3R), histamine H2-receptors (H2R), and cholecystokinin-2/gastrin receptors (CCK2R)] or serum gastrin concentrations. Furthermore, extracts greatly reduced levels of gastric cyclic adenosine monophosphate (cAMP) and significantly increased mRNA levels of gastric-type mucins (MUC5AC and MUC6). To identify the mode of action of C. tricuspidata extract in regulating gastric acid secretion, intracellular cAMP and mRNA for H2R, M3R, and CCK2R were measured in primary parietal cells. mRNA levels of H2R, M3R, and CCK2R did not significantly differ following treatment with C. tricuspidata extract, whereas cAMP induced by the H2R-specific agonist was significantly decreased. C. tricuspidata may therefore reduce gastric acid secretion by inhibiting H2R activity rather than regulating mRNA expression. These finding suggest that ethanol extracts of C. tricuspidata inhibit H2R-related gastric acid secretion and increase gastric mucus to help prevent gastric mucosal damage. Therefore, C. tricuspidata extract has potential to be used in foods and medicines to prevent diseases related to gastric mucosal damage, such as gastritis and functional dyspepsia.

Refined Criteria for Separating Low-grade Dysplasia and Nondysplastic Barrett Esophagus Reduce Equivocal Diagnoses and Improve Prediction of Patient Outcome

The indefinite for dysplasia (IFD) category in Barrett esophagus (BE) is used for biopsies that are neither unequivocally dysplastic nor negative for dysplasia (NFD). In 2012, we refined our criteria so that BE with maintained cell polarity and surface gastric-type mucin vacuoles is considered NFD even with mild to moderate nuclear enlargement. A total of 1549 cases from 1130 patients with BE biopsies were identified from 2007 to 2016. Follow-up on patients with IFD biopsies was obtained to learn if the new thresholds better defined risk of progression. The earlier cases (2007-2011) were less likely than later cases (2012-2016) to be NFD (84.0% vs. 90.4%) and more likely to be IFD (8.4% vs. 4.3%). The proportions of low-grade dysplasia (3.9% vs. 2.5%, high-grade dysplasia (1.4% vs. 1.3%), and intramucosal carcinoma (2.3% vs. 1.6%) were similar between the earlier and later cases, respectively. Later IFD cases were more frequently dysplastic (3/21, 14.3%) on the next biopsy than earlier cases (1/48, 2.1%). The rate of dysplasia on the next biopsy for NFD cases was not higher in the later cases (6/222, 2.7%) than the earlier cases (16/360, 4.4%). Improved diagnostic criteria reduced the proportion of IFD cases by nearly 50% from 2007 to 2016. This change coincided with a higher proportion of IFD cases having dysplasia on the next biopsy. NFD patients had no increase in dysplasia on the next biopsy providing evidence that dysplastic cases are not missed by the refined criteria.

Interpretation of Endocervical Cells With Gastric-Type Mucin on Pap Smears.

Early detection of endocervical adenocarcinoma is especially important for cancers that are human papillomavirus (HPV) negative. We investigated the clinicopathologic significance of yellow gastric-type mucin observed on Papanicolaou smears. We described "atypical endocervical cells with gastric-type mucin" (AEC-GAM) when yellow mucin was observed in endocervical cells. We retrieved AEC-GAM samples from 58,752 cervical smears performed at Yamanashi University Hospital during our study period and reviewed clinical, cytologic, and pathologic features. We detected AEC-GAM in 172 (0.29 %) smears from 65 patients, and 41 of these 65 patients were histologically diagnosed with lobular endocervical glandular hyperplasia (LEGH) (43%) or pyloric gland metaplasia (20%). The prevalence of adenocarcinoma was 25% (7/28) in LEGH cases and 11% (7/65) in AEC-GAM smears. Yellow mucin is a diagnostic clue for endocervical glandular lesions with gastric differentiation. We recommend describing AEC-GAM on cytologic reports to improve cytologic screening for HPV-negative cervical cancers.

Clinicopathological characteristics of duodenal epithelial neoplasms: Focus on tumors with a gastric mucin phenotype (pyloric gland-type tumors).

ObjectiveEpithelial tumors less commonly occur in the duodenum than in the stomach or large intestine. The clinicopathological characteristics of duodenal epithelial tumors remain a matter of debate. We therefore studied resected specimens to investigate the clinicopathological characteristics of duodenal epithelial tumors.Materials and methodsAmong duodenal epithelial tumors resected endoscopically or surgically in our hospital, we studied the clinicopathological characteristics of 110 adenomas or intramucosal carcinomas. The grade of atypia of all tumors was classified into 3 groups according to the World Health Organization (WHO) 2010 classification. The tumors were immunohistochemically evaluated to determine the frequency of differentiation toward fundic glands.ResultsAs for patient characteristics, there were 76 men (75.2%) and 25 women (24.8%), with a median age of 65 years (range, 34 to 84). The tumors most commonly arose in the first to second part of the duodenum. Many lesions were flat, and the median tumor diameter was 8.0 mm. The lesions were classified into 2 types according to mucin phenotype: intestinal-type tumors (98 lesions, 89.1%) and gastric-type tumors (12 lesions, 10.9%). Intestinal-type tumors were subdivided into 2 groups: tubular-type tumors (91 lesions, 82.7%) and tubulovillous-type tumors (7 lesions, 6.4%). Gastric-type tumors were classified into 2 types: foveolar type (3 lesions, 2.7%) and pyloric gland-type (PG) tumors (9 lesions, 8.2%). The grade of atypia was significantly higher in gastric-type tumors (p<0.01). PG tumors were gastric-type tumors characterized by pyloric glands and findings suggesting differentiation toward fundic glands.ConclusionsAbout 10% of the duodenal tumors had a gastric-type mucin phenotype. Gastric-type tumors showed high-grade atypia. In particular, PG tumors showed similarities to PG tumors of the stomach, such as differentiation toward fundic glands.

Usefulness of a management protocol for patients with cervical multicystic lesions: A retrospective analysis of 94 cases and the significance of GNAS mutation.

AimThe proper preoperative diagnosis and management of cervical proliferative disorders presenting with multiple cysts, including minimal deviation adenocarcinoma (MDA), lobular endocervical glandular hyperplasia (LEGH), and nabothian cyst (NC), have not been fully established. We previously proposed a management protocol comprising a diagnostic approach using cytology, magnetic resonance imaging, and gastric‐type mucin and subsequent treatment. We herein evaluate the usefulness of this protocol and implications of GNAS mutations in LEGH.MethodsThe clinical courses of 94 patients with cervical multicystic lesions who visited our hospital between June 1995 and September 2014 were retrospectively analyzed. GNAS mutations were investigated in 10 LEGH, five LEGH with atypia, and two MDA cases.ResultsOf the 94 patients, the conditions of 10, 59, and 25 were clinically diagnosed as suspicious of MDA or carcinoma (S/O MDA‐Ca), suspicious of LEGH (S/O LEGH), and NC, respectively. Ten patients each with S/O MDA‐Ca and S/O LEGH underwent hysterectomy, and the correct ratio for diagnosis was 90% (18/20). Of the 42 S/O LEGH cases followed‐up for more than 12 months, three showed an increase in tumor size. After hysterectomy, two were LEGH with atypia while one was NC. The GNAS mutation was detected in two cases of LEGH with atypia, one of which showed an increase in tumor size during follow‐up.ConclusionThe management protocol we propose herein will be useful. An increase in tumor size is important to detect potentially malignant LEGH. GNAS mutations may be involved in the tumorigenesis of potentially malignant LEGH.

Diagnosis of HPV-negative, gastric-type adenocarcinoma of the endocervix.

Gastric-type adenocarcinoma of the cervix (GAS) is a novel, recently described subtype of endocervical adenocarcinoma. The clinical importance of accurate diagnosis of GAS stems from the observation that it confers worse prognosis than the usual-type endocervical adenocarcinoma. There are two unique characteristics of GAS: the tumor cells contain voluminous amounts of gastric-type mucins, and the tumor pathogenesis is not related to infection with high-risk human papillomavirus types. The histopathologic diagnosis of GAS is difficult; however, it may be confirmed by demonstration of intra-cytoplasmic gastric-type mucins using immunohistochemical staining with monoclonal antibody HIK1083. A protocol for HIK1083 immunostaining is described.

Characteristic epithelium with low-grade atypia appears on the surface of gastric cancer after successful Helicobacter pylori eradication therapy.

The incidence of gastric cancer after successful Helicobacter pylori eradication has been increasing. We previously reported that epithelium with low-grade atypia (ELA) appeared on the surface of gastric cancer after H. pylori eradication. Here, we investigate the clinical and biological characteristics of such ELA. We studied 27 cases of gastric cancer detected after successful H. pylori eradication therapy. We examined the prevalence of ELA among these cases and its significance for endoscopic discovery after H. pylori eradication. We additionally investigated the mucus, p53 and Ki67 expressions in ELA. Epithelium with low-grade atypia that continuous with the gastric tumor was detected in 22 of 27 cases (81%), a significantly greater percentage than that for controls (p < 0.01). We found that gastric-type mucin was frequently expressed in this epithelium. Neither p53- nor Ki67-positive cells were found in ELA, irrespective of their expression in tumor tissue. The presence of ELA was positively correlated with the clinical interval between H. pylori eradication and gastric cancer detection. Epithelium with low-grade atypia on gastric cancer tissue, which may develop from gastric cancer cells, is frequently present after successful eradication therapy. This phenomenon could influence the practice of endoscopic diagnosis of gastric cancers.

Crohn enteritis–associated small bowel adenocarcinomas exhibit gastric differentiation

Primary small bowel adenocarcinoma is rare. Although generally similar to colonic adenocarcinoma, some small bowel adenocarcinomas exhibit unique morphologic features, particularly those arising in association with Crohn disease. In this study, 15 sporadic small bowel adenocarcinomas and 11 Crohn enteritis-associated small bowel adenocarcinomas were examined for histology and immunohistochemical profile including cytokeratins (CK) 7 and 20, intestinal markers CDX2 and MUC2, and gastric epithelial markers MUC5AC and MUC6. We found that Crohn enteritis-associated small bowel adenocarcinomas frequently resemble gastric tubular adenocarcinoma histologically. In addition, when compared to sporadic small bowel adenocarcinoma, the former expressed MUC5AC and MUC6 with much higher frequency (82% vs. 7% and 73% vs. 0%, respectively). Ten of 11 Crohn enteritis-associated small bowel adenocarcinomas (91%) were positive for at least one gastric-type marker (MUC5AC or MUC6). Expression of CK7 was also more frequent in Crohn enteritis-associated small bowel adenocarcinoma (73% versus 27%) while expression of CK20 was less frequent (64% vs. 100%). There was no difference between sporadic and Crohn enteritis-associated small bowel adenocarcinoma in expression of CDX2 (100% vs. 91%) and MUC2 (93% vs. 73%). These observations suggest that there is a difference in the morphologic and immunohistochemical characteristics of sporadic versus Crohn enteritis-associated small bowel adenocarcinoma, particularly in their expression of gastric-type mucin. The findings also suggest that gastric differentiation in Crohn enteritis-associated small bowel adenocarcinoma is related to gastric metaplasia, a common phenomenon in Crohn disease.

Different Roles for Lactococcal Aggregation Factor and Mucin Binding Protein in Adhesion to Gastrointestinal Mucosa

Adhesion of bacteria to mucosal surfaces and epithelial cells is one of the key features for the selection of probiotics. In this study, we assessed the adhesion property of Lactococcus lactis subsp. lactis BGKP1 based on its strong autoaggregation phenotype and the presence of the mucin binding protein (MbpL). Genes involved in aggregation (aggL) and possible interaction with mucin (mbpL), present on the same plasmid pKP1, were previously separately cloned in the plasmid pAZIL. In vivo and in vitro experiments revealed potentially different physiological roles of these two proteins in the process of adherence to the intestine during the passage of the strain through the gastrointestinal tract. We correlated the in vitro and in vivo aggregation of the BGKP1-20 carrying plasmid with aggL to binding to the colonic mucus through nonspecific hydrophobic interactions. The expression of AggL on the bacterial cell surface significantly increased the hydrophobicity of the strain. On the other hand, the presence of AggL in the strain reduced its ability to adhere to the ileum. Moreover, MbpL protein showed an affinity to bind gastric type mucin proteins such as MUC5AC. This protein did not contribute to the binding of the strain to the ileal or colonic part of the intestine. Different potential functions of lactococcal AggL and MbpL proteins in the process of adhesion to the gastrointestinal tract are proposed.

Nuclear atypia grading score is a useful prognostic factor in papillary gastric adenocarcinoma

To investigate nuclear atypical in papillary gastric adenocarcinoma (PGA). Hundred cases of PGA were classified into two groups according to nuclear pleomorphism and nuclear polarity; these groups were designated as high nuclear grade and low nuclear grade. Correlations between nuclear grade and clinicopathological features were evaluated for prognostic value. In order to evaluate which types of biological factors influence nuclear atypia, the expression of gastric-type mucin phenotype, p53, HER2 and Ki-67 detected by immunohistochemistry and DNA ploidy detected by laser scanning cytometry. The high nuclear grade group correlated with deeper wall invasion, the presence of lymphatic and venous invasion and the positivity of lymph node metastasis. High nuclear grade was an independent prognostic factor for disease-free survival. Moreover, significant correlations were observed between high nuclear grade and positivity of gastric-type mucin phenotype, p53 and HER2 and DNA aneuploidy. Nuclear grade could be a new and useful morphological predictor for high malignant potential in PGA.

Intraductal oncocytic papillary neoplasm of the bile duct: clinicopathologic and immunohistochemical characteristics of 6 cases

Intraductal oncocytic papillary neoplasm is known as a distinct subtype of intraductal papillary mucinous neoplasm of the pancreas. Similar neoplasms of the bile duct are rarely reported, and their disease characteristics are not well established. In this study, we examined 6 cases of biliary neoplasms consisting of oncocytic cells with almost exclusively intraductal growth. The patients were 5 women and 1 man of 51 to 68 years. Grossly, 4 appeared to be cystic neoplasms with papillary projections located in the liver and the other two were papillary neoplasms of the dilated hilar bile duct that ranged from 1.5 to 16 cm in size. The most prominent neoplastic cells were cuboidal epithelial cells that showed abundant eosinophilic granular cytoplasm with strongly positive staining for antimitochondrial antibody. Four neoplasms were mixed with minor components of nononcocytic cells. All neoplasms showed arborized papillary and/or cribriform formations except one, which showed a villous architecture. All neoplasms were adenocarcinomas accompanied by a microscopic minimally invasive carcinoma. The oncocytic neoplastic cells, as well as the nononcocytic cells, produced gastric-type mucin (MUC5AC and MUC6) and showed claudin18 and HepPar-1 positivity. Five patients lived disease-free for 10 to 112 months after resection, and 1 died of tumor recurrence at 26 months postoperatively. The present series of biliary tumors are intraductal papillary neoplasms with oncocytic features and can be clinicopathologically regarded as counterparts of pancreatic intraductal oncocytic papillary neoplasm. Our results also suggest that oncocytic changes occur in epithelial cells of biliary tracts that show a predominant gastric phenotype.

S2060 Aberrant Expressions of Gastric Type Mucin and Claudin in Colorectal Serrated Polyps

F ratio of intestinal type cancer was 3.41 at age less than 50, reached a peak of 7.86 at age 50-59, and then showed a progressive decrease with a minimum of 2.29 at age group 80 years and over. In contrast, the crude incidence rate of diffuse-type adenocarcinoma was similar in males and females (5.58 vs. 5.20 /100, 000/ year) yielding M/F of 1.07. Curve modelling of the age-specific rates for diffuse subtypes showed similar equations, y = 0.016 x mean age 2.007 +32.98, R2 = 0.999 and y = 0.016 x mean age 1.954+35.97, R2 = 0.989, for male and females, respectively. For the intestinal histological type, the age-specific incidence rates were different for males and females. Curve modelling indicated the same kinetic equation for rise in incidence with age, in males (y = 0.016 x mean age 2.315+28.75, R2 = 0.990) and in females (y = 0.016 x mean age 2.316+46.07, R2 = 0.998). However, the female curve was displaced to the right indicating a delay in the cancer onset. The estimated cancer onset delay for females was 17.2 years (i.e. +46.07 minus +28.75= 17.22). Conclusion Male predominance in upper GI adenocarcinomas is a reflection of approximately 2 decades delay of development of intestinal subtype adenocarcinoma in females. The mechanism of the marked delay in development of intestinal subtype requires elucidation.

Adenomatous and Foveolar Gastric Dysplasia: Distinct Patterns of Mucin Expression and Background Intestinal Metaplasia

Gastric epithelial dysplasia (GED) can be morphologically categorized into adenomatous (or intestinal) and foveolar (or gastric) types. Although limited genetic differences have been demonstrated between these subtypes, the expression of various mucins has not been systematically evaluated in this context. Endoscopic mucosal resections from 69 cases of GEDs were evaluated for the expression of MUC2, MUC5AC, MUC6, and CD10. The results were correlated with morphologic categorization and clinicopathologic parameters. GED was classified as adenomatous, foveolar, or hybrid (showing features of both types), on the basis of histologic evaluation. The neighboring intestinal metaplasia (IM) was also evaluated. An adenomatous morphology was seen in 45%, hybrid type in 33.3%, and a "pure" foveolar type was seen in 21.7% of the cases. Foveolar GED was often depressed/flat on endoscopy and showed a statistically significant association with high-grade morphology (P = 0.046). Immunohistochemistry confirmed the histologic stratification. The foveolar and hybrid types were more often positive for MUC5AC (P = 0.0001 for both) and negative for CD10 (P = 0.019 and 0.016, respectively) as compared with adenomatous GED. High-grade morphology was associated with MUC5AC expression regardless of the morphologic phenotype (P = 0.026). Foveolar (73.3%) and hybrid (86.9%) GEDs were associated more often with IM showing a retained expression of gastric type mucin than adenomatous GED (29%) (P < 0.01 for both). In contrast, adenomatous type (58.1%) of GED was significantly associated with IM showing a complete intestinal phenotype (CD10+) compared with the foveolar (13.3%) and hybrid types (17.4%) of GED (P = 0.005 for both comparisons). In conclusion, our study indicates that foveolar and adenomatous types of GED have distinct clinicopathologic features, mucin profiles, and association with different types of IM.

The expression of hepatocyte nuclear factor-4α, a developmental regulator of visceral endoderm, correlates with the intestinal phenotype of gastric adenocarcinomas

Hepatocyte nuclear factor (HNF)-4alpha is a developmental regulator of the visceral endoderm, which is expressed in the embryonic gut and later in the adult intestine and colon. However, adult gastric mucosa does not express HNF-4alpha. We investigated the possible involvement of HNF-4alpha in intestinal metaplasia and the intestinalisation of gastric adenocarcinomas. Thirty-five cases of adenocarcinomas and 46 cases of adjacent non-neoplastic mucosa with (22 lesions) or without (24 lesions) intestinal metaplasia were immunostained for HNF-4alpha. The gastric or the intestinal phenotype was also examined using immunohistochemistry for MUC5AC, MUC2, CD10, and gastric-type mucin (GTM). Adenocarcinomas were classified into the gastric type (G-type, 42.9%), the mixed gastric and intestinal type (GI-type, 31.4%), and the intestinal type (I-type, 25.7%). The HNF-4alpha expression was exclusively seen in glandular cells with intestinal metaplasia, which was correlated with MUC2 expression (p<0.05) and inversely correlated with MUC5AC expression (p<0.05). All adenocarcinomas more or less expressed HNF-4alpha, with an intense expression being seen in the I-type (p<0.01) and in well-differentiated adenocarcinomas (p<0.03). HNF-4alpha expression is associated with the intestinal phenotype of non-neoplastic and neoplastic gastric glandular cells, suggesting a possible involvement in the establishment and/or maintenance of the intestinal phenotype of the gastric mucosa and adenocarcinomas.

Cytokeratin 7/20 and mucin core protein expression in ulcerative colitis-associated colorectal neoplasms

Different histogenetic pathways have been suggested between ulcerative colitis (UC)-associated neoplasia and sporadic colorectal neoplasia. Little is known about the cytokeratin (CK) and mucin expression in UC-associated neoplasms. To clarify the characteristics of UC-associated colorectal carcinogenesis, we examined the immunohistochemical expression of CK7, CK20, MUC2, MUC5AC and MUC6 in 90 colorectal neoplasms, including 22 UC-associated adenocarcinomas (colitic cancer; CC), ten high-grade dysplasias (HGD) in UC, nine low-grade dysplasias (LGD) in UC, 24 sporadic tubular adenomas (TA) and 25 adenocarcinomas (AC). CK7 was positive in most of UC-associated neoplasms: 59% of CC cases, 80% of HGD and 89% of LGD, respectively, whereas, in non-UC associated neoplasia, 21% of TA and 12% of AC. The frequency of MUC6 expression in UC-associated neoplasia was 32% in CC, 30% in HGD and 44% in LGD, respectively, whereas, in non-UC associated neoplasia, 4.2% in TA and 0% in AC. MUC5AC expression in UC-associated neoplasia was detectable in 73% of CC, 90% of HGD and 89% of LGD, respectively; in non-UC associated neoplasia 67% in AC and 20% in TA. There were obvious differences in the expression of CK7 and MUC6 between UC-associated neoplasms and sporadic tumors. The incidence of MUC5AC expression in UC-associated neoplasms was also higher than sporadic tumors. These results suggest that gastric-type mucins play an important role in the initial step of CC-tumorigenesis, and CK7 and gastric-type mucins may be useful in the differential diagnosis between UC-associated neoplasms and sporadic ones.

Barrett's esophagus is characterized by expression of gastric-type mucins (MUC5AC, MUC6) and TFF peptides (TFF1 and TFF2), but the risk of carcinoma development may be indicated by the intestinal-type mucin, MUC2

Barrett's esophagus (BE) consists of metaplastic epithelium of the esophagus, generally diagnosed by mucin histochemistry. We aimed to determine which mucins were expressed in BE, and to relate their expression to BE pathology. Archival biopsies of 4 patient groups were selected, based on standard histochemistry: BE without inflammation, BE with inflammation, ulcerating BE, and BE with dysplasia. Sections were stained by immunohistochemistry for secretory mucins (MUC2, MUC5AC, MUC5B, and MUC6), the proliferation marker Ki-67, and mucin-associated trefoil factor family (TFF) peptides (TFF1, TFF2, and TFF3). MUC5AC and TFF2 were expressed at similar high levels in each clinical group. Intestinal metaplasia (IM), detected both histochemically and by the intestinal mucin MUC2, was lowest in inflamed BE. The expression of the intestinal-type TFF3 did not differ among the groups. Ulcerating BE was distinguished by very low expression of MUC6 and MUC5B, but very high expression of TFF1. Proliferation was not different among the groups. In the total group of BE patients, H. pylori infection of the stomach correlated with decreased TFF2 expression in the BE epithelium. We conclude that BE is best characterized by the specific expression of the gastric-type markers, MUC5AC, MUC6, TFF1, and TFF2. Ulcerating BE constitutes the most distinguished group with respect to mucin and TFF expression. Of the intestinal markers, MUC2 is very specific for IM in BE, whereas TFF3 is not a marker for IM. The low occurrence of IM in inflamed BE suggests that these patients may have the lowest risk of developing carcinoma. Hum Pathol 33:660-668. Copyright 2002, Elsevier Science (USA). All rights reserved.

Each Barrett's esophagus expresses gastric type mucins and trefoil factors, whereas the risk of carcinoma development may be indicated by the intestinal type MUC2

Each Barrett's esophagus expresses gastric type mucins and trefoil factors, whereas the risk of carcinoma development may be indicated by the intestinal type MUC2