Expression and localization of Reg IV in human neoplastic and non-neoplastic tissues: Reg IV expression is associated with intestinal and neuroendocrine differentiation in gastric adenocarcinoma

Regenerating islet-derived family, member 4 (Reg IV) is a candidate marker for cancer and inflammatory bowel disease. In the present study, immunohistochemical analysis of Reg IV was performed in various human neoplastic (n = 289) and non-neoplastic tissues. In the stomach, foveolar epithelium was negative for Reg IV, whereas goblet cells of intestinal metaplasia and neuroendocrine cells at the base of intestinal metaplasia expressed Reg IV. Neuroendocrine cells of the small intestine and colon showed strong expression of Reg IV, whereas goblet cells of the small intestine and colon showed weak or no expression of Reg IV. Insulin-producing beta cells of the endocrine pancreas were positive for Reg IV. Among 143 gastric adenocarcinomas, Reg IV expression was detected in 42 (29.4%) and was associated with both the intestinal mucin phenotype and neuroendocrine differentiation. No association was found between Reg IV expression and clinical characteristics such as tumour stage and patient prognosis. Of 36 colorectal adenocarcinomas, 13 (36.1%) were positive for Reg IV, which was associated with tumour stage (p = 0.0379, Fisher's exact test). Expression of Reg IV was detected in 14 (93.3%) of 15 colorectal carcinoid tumours. Reg IV expression was also detected in 5 (21.7%) of 23 ductal adenocarcinomas of the pancreas. In contrast, lung cancers (n = 30) and breast cancers (n = 30) did not express Reg IV. This is the first immunohistochemical analysis of the expression and distribution of Reg IV protein in human tumours. These data suggest that Reg IV is expressed by gastrointestinal and pancreatic tumours, including adenocarcinomas and carcinoid tumours, and that Reg IV is associated with intestinal and neuroendocrine differentiation of the stomach and gastric carcinoma.     

Aberrant maspin expression in gallbladder epithelium is associated with intestinal metaplasia in patients with cholelithiasis

OBJECTIVE: Aberrant expression of maspin protein related to DNA hypomethylation in the promoter region is frequently observed in gallbladder carcinomas, whereas the non-tumorous gallbladder epithelium is maspin negative. We investigated maspin expression in non-tumorous gallbladder epithelium in patients with cholelithiasis. METHODS: An immunohistochemical study of maspin expression was performed in 69 patients with cholelithiasis and 30 patients with gastric cancer without cholelithiasis. RESULTS: Immunoreactivity for maspin was observed in focal and patchy regions of the gallbladder epithelium. Positive immunoreactivity for maspin was significantly associated with the presence of intestinal metaplasia in patients with cholelithiasis (p<0.05). CONCLUSION: The high incidence of aberrant maspin expression in both intestinal metaplasia and carcinoma of the gallbladder supports the assumption that intestinal metaplasia of the gallbladder may predispose to gallbladder carcinoma.     

Expression of MUC2, MUC5AC and MUC6 apomucins in carcinoma, dysplasia and non-dysplastic epithelia of the gallbladder

To date, nine apomucins have been characterized and their expression in malignant and premalignant lesions is under evaluation. The purpose of this study was to characterize immunohistochemically the expression of MUC2 (colonic/ intestinal type), MUC5AC (gastric surface type), and MUC6 (pyloric gland type) apomucins in 55 patients with gallbladder carcinoma (10 with in situ carcinoma, 45 with invasive carcinoma), 20 patients with gallbladder dysplasia, and 15 patients with non-dysplastic gallbladder. MUC2 was expressed mainly in 'goblet type' cells. The frequency was increased in non-dysplastic gallbladder (47%), dysplasia (75%), and in situ carcinoma (100%), and decreased in invasive carcinoma (58%). Carcinoma cells expressing MUC2, which were usually distributed at superficial areas, and well-differentiated carcinoma expressed MUC2 more extensively than moderately and poorly differentiated ones. MUC5AC was frequently expressed in gallbladder irrespective of non-dysplastic epithelia, dysplasia and carcinoma. MUC5AC was expressed also in carcinoma cells at deeply invasive sites. MUC6 was expressed frequently in pseudopyloric gland metaplasia as well as dysplasia and carcinoma. In conclusion, non-dysplastic gallbladder has a similar phenotype to gastric pyloric mucosa. Gallbladder carcinoma exhibits both intestinal and gastric surface phenotypes in the early stage of carcinogenesis, with the gastric surface phenotype dominant in invasive carcinoma.     

Fatty acid synthase is highly expressed in carcinoma, adenoma and in regenerative epithelium and intestinal metaplasia of the stomach

AIMS: To investigate the relation of fatty acid synthase (FAS) expression to the clinicopathological characteristics of gastric cancers and gastric tumorigenesis. METHODS AND RESULTS: FAS expression was examined immunohistochemically in 626 gastric cancers, 51 gastric adenomas, and non-neoplastic epithelium contiguous with cancer tissue including normal foveolae, intestinal metaplasia, regenerative epithelium, and gastric glands. FAS expression was found in more than 70% of gastric cancers. Interestingly, it occurred preferentially in differentiated carcinomas, male cases, and in patients over 51 years old. Although previous reports showed that FAS expression is closely related to cancer progression, in gastric cancers FAS expression had no relationship with prognosis, cancer progression as indicated by depth of invasion, venous and lymphatic permeation, and distant metastasis. Gastric tubular adenoma and intestinal metaplasia, which are thought to be associated with well-differentiated gastric carcinomas, showed a frequency of FAS expression similar to that of differentiated carcinomas; however, normal foveolae and gastric glands showed no or less FAS expression. CONCLUSIONS: FAS expression occurs at the early stage of tumorigenesis and plays important roles in the formation of precancerous foci rather than in the progression of carcinoma of the stomach.     

Reg IV expression is associated with cell growth and prognosis of adenoid cystic carcinoma in the salivary gland

Aims: Regenerating islet‐derived family, member 4 (Reg IV) is associated with the progression of various cancers. The aim was to examine Reg IV expression in adenoid cystic carcinomas (ACCs) in salivary glands. Methods and results: Reg IV expression was detected by immunohistochemistry and compared with clinicopathological parameters. Expression of phosphorylated epidermal growth factor receptor (pEGFR), phosphorylated AKT (pAKT) and MUC2 was examined by immunohistochemistry. Reg IV function was assessed with Reg IV antisense S‐oligodeoxynucleotides (AS) in ACC3 human ACC cells. Reg IV was expressed by salivary duct epithelia and acinus myoepithelia, but not in squamous epithelia. Reg IV expression was found in 41% (17/41) of ACCs, but in none of 40 oral squamous cell carcinomas (OSCCs) and was associated with nodal metastasis (P = 0.047) and poor prognosis (P = 0.012) in ACCs. Reg IV expression was associated with pEGFR (14/17, 82%) in Reg IV + ACCs, but had no relationship with pAKT or MUC2 expression in ACCs. Cell growth was inhibited by AS treatment in Reg IV + ACC3 cells, but not in HSC‐4 OSCC cell s , whereas in vitro invasion of neither cell types was affected by AS treatment. Conclusions: These results suggest that Reg IV might accelerate cell growth and disease progression of ACCs.     

Expression of MUC1 and MUC2 mucin gene products in Barrett's metaplasia, dysplasia and adenocarcinoma: an immunopathological study with clinical correlation

AIMS: Changes in the histochemical characteristics of the surface epithelial mucins is the hallmark of Barrett's metaplasia. The study investigated the pattern of expression of MUC1 and MUC2 mucin gene products in Barrett's metaplasia, dysplasia and adenocarcinoma as possible indicators of increased malignant potential. METHODS AND RESULTS: Tissue sections from 51 patients with Barrett's intestinal metaplasia, nine with dysplasia (three indefinite) and 28 resected adenocarcinomas were stained with monoclonal antibodies to MUC1 and MUC2. The majority of the patients were men (70/88, 80%) who were treated over a period of 3 years. None of the patients with dysplasia or carcinoma were under surveillance at the time of presentation. All 51 biopsies with Barrett's metaplasia expressed MUC2 and MUC1 was consistently absent. Neither MUC1 or MUC2 were expressed in the dysplastic epithelium whether in its pure form (6/6) or when associated with carcinoma (26/28) (P < 0.005). Three biopsies which were initially classified as high-grade dysplasia expressed MUC1 and these turned out to be carcinomas on further investigations. MUC1 was also expressed in 12/28 (43%) of the adenocarcinomas and majority of these were poorly differentiated stage 3 tumours (P < 0.05). MUC2 was only positive in mucin-secreting carcinomas (4/28; 14%) irrespective of the tumour stage. CONCLUSION: Despite the large number of patients with Barrett's metaplasia and carcinoma, very few patients presented with dysplasia, implying that Barrett's oesophagus is a silent disease in the community presenting late as carcinoma. The study has demonstrated aberrant expression of MUC2 (an intestinal mucin) in Barrett's metaplasia and this expression is lost when the cells become dysplastic. The lack of MUC1 in dysplastic epithelium and its expression in carcinoma could be utilized as a marker which could differentiate dysplasia from carcinoma in mucosal biopsies. Furthermore, expression of MUC1 in advanced stage oesophageal cancers (as in breast cancer) suggests an unfavourable prognosis.     

c-met蛋白表达与胃粘膜病变的关系及预后意义

目的 研究ｃ－ｍｅｔ蛋白在胃粘膜病变演进过程中的表达及关系,探讨ｃ－ｍｅｔ表达对胃癌预后的意义。方法 对１６９例经病理证实的不同胃粘膜病变采用免疫组织化学ＳＰ法检测ｃ－ｍｅｔ蛋白表达,用Ｋａｐｌａｎ－Ｍｅｉｅｒ法的Ｌｏｇ－ｒａｎｋ检验胃癌生存率。结果 在浅表性胃炎、萎缩性胃炎、肠化生、异型增生、早期胃癌和进展期胃癌中,ｃ－ｍｅｔ蛋白表达率分别为２３．５％（４／１７）,３６．８％（１４／３８）,５１．５％（１７／３３）,６１．３％（１９／３１）,６６．７％（８／１２）和７３．７％（２８／３８）,而且肠化生、异型增生、胃癌均显著高于浅表性胃炎（Ｐ〈０．０５）。胃粘膜增殖程度与ｃ－ｍｅｔ阳性表达强度密切关系分析,两者有显著关联（Ｐ〈０．０１）。ｃ－ｍｅｔ阳性表达与胃癌组织类型、浆膜浸润和淋巴结转移密切相关,而且Ｂｏｒ     

Reg4在胃肠道肿瘤中的表达及意义

Reg4是再生基因家族（regenerating gene family）中的一员,定位于染色体1p12～13.1,表达一种由158个氨基酸组成的分泌性蛋白。Reg4蛋白主要表达于胃黏膜壁细胞和小肠上皮神经内分泌细胞,与胃肠道细胞的增殖分化有关。Reg4与人类胃肠道肿瘤的发生、演进、浸润、淋巴结转移、腹腔播散、5-氟脲嘧啶（5-FU）抗药性以及临床预后密切相关,为胃肠道肿瘤的临床诊断、用药指导及预后评估奠定了理论基础。     

Das gastral differenzierte Magenadenokarzinom

Gastric carcinomas are classified histogenetically into diffuse and differentiated types. The latter are often referred to as intestinal-type carcinomas and are believed to originate from intestinal metaplasia. However, histogenetic studies on smaller and initial lesions of the differentiated adenocarcinoma do not support this. From phenotypical expressions of neoplastic lesions arising in hyperplastic polyps of the stomach we first proposed an entity of gastric-type adenocarcinomas, which has been widely accepted. Our recent mucin and immunohistochemical investigations reveal that most smaller adenocarcinomas retain gastric-type differentiation and that those of the exclusively intestinal phenotype are rather rare. On the other hand, most adenomas are strongly and extensively positive for intestinal marker, indicating that the adenoma-carcinoma sequence is not a common event in the stomach carcinogenesis. Other studies show that the expression of intestinal mucin or carbohydrate antigen as expressed in intestinal metaplasia is manifested more extensively in carcinoma cells in larger tumors. It is suggested that intestinalization of tumor cells is a time-dependent phenomenon. Differential gene abnormalities between gastric- and intestinal-type carcinomas of the stomach are discussed, regarding their histogenesis and progression.     

Gastric phenotypic expression in human gallbladder cancers revealed by pepsinogen immunohistochemistry and mucin histochemistry

Summary Gastric phenotypic expression indicated by paradoxical concanavalin A (Con A) staining for class III mucins and the immunoperoxidase method for pepsinogen (Pg) I and Pg II was found in pyloric gland metaplasia of gallbladder epithelium. Using the same methods, the features of gallbladder cancers and their relationship to pyloric gland metaplasia in the human gallbladder epithelium were studied. Histologically, 57 gallbladder cancers were classified into 5 papillary adenocarcinomas, 29 tubular adenocarcinomas, 8 poorly differentiated adenocarcinomas, 6 signet-ring cell carcinomas, 4 mucinous adenocarcinomas, and 5 squamous cell carcinomas. In papillary and tubular adenocarcinomas, Pg I and/or Pg II staining was detected in 80% and 75.9% of cancers, respectively. Pg II staining was significantly more frequent than Pg I staining. One signetring cell carcinoma also had Pg II activity. Pyloric gland metaplasias all contained class III mucins and were further classified into complete type and incomplete type on the basis of presence or absence Pg I and/ or Pg II activities. A few cancer cells with class III mucins were negative for Pg staining; conversely, a few cells with Pg I and/or Pg II had no class III mucins. Phenotypic diversity in both class III mucin reactivity and Pg activities was observed in gallbladder cancer cells with the pyloric gland cell type. By comparison, pyloric gland metaplasia varied only in Pg activities. A few Pg-positive cancers were found in the gallbladder with Pg-negative pyloric gland metaplasia. The present results clearly indicate the appearance of gastric phenotypic expression in both gallbladder epithelium and gallbladder cancers and suggest the independent induction of pyloric gland metaplasia and cancer with gastric phenotypic expression.     

Clinicopathological significant and prognostic influence of cadherin-17 expression in gastric cancer

Cadherin-17 (CDH17), also called liver–intestine cadherin, is a structurally unique member of the cadherin superfamily. Our serial analysis of gene expression demonstrated that CDH17 was one of the most up-regulated genes in advanced gastric carcinomas. CDH17 expression is known to be regulated by Cdx2. In the present study, we examined the expression of CDH17 in primary gastric carcinoma tissues by immunohistochemistry, and analyzed the correlation of CDH17 expression with clinicopathological characteristics and patients prognosis. CDH17 expression was detected in 63/94 (67%) of gastric adenocarcinomas in addition to intestinal metaplasia. The expression of CDH17 tended to be associated with intestinal type carcinoma, and carcinomas with CDH17 expression was significantly more frequent in advanced stage cases (80%) than in early stage (53%). The prognosis of patients with positive CDH17 expression was significantly poorer than that of the negative cases (P=0.0314). However, multivariate analysis revealed that CDH17 was not an independent prognostic factor. Six of seven cases that showed positive expression of Cdx2 simultaneously expressed CDH17 protein. These results suggested that the expression of CDH17 was characteristic of the advanced gastric carcinoma that is associated with poor prognosis.     

Loss of E-cadherin expression in gastric intestinal metaplasia and later stage p53 altered expression in gastric carcinogenesis

Gastric cancers are commonly subdivided into intestinal and diffuse subtypes on a morphologic basis, supported by corollary evidence of differences at the pathogenetic and molecular levels. Chronic atrophic gastritis with intestinal metaplasia is a common precursor lesion for the intestinal type of carcinoma. To identify early molecular changes, in this study we have examined 13 surgical specimens both for the expression of E-cadherin, p53 and beta-catenin by immunohistochemistry and for methylation of the CDH1 promoter (E-cadherin) by bisulfite genomic sequencing of laser capture microdissected samples. Each specimen examined contained areas of normal (nonmetaplastic) gastric mucosa, as well as areas of intestinal metaplasia and/or carcinoma. Reduced or absent E-cadherin and partial to complete methylation of one to multiple CpG sites examined in the CDH1 promoter were observed in all of the metaplasia samples. Thus, the methylation status of the CDH1 promoter and expression of E-cadherin together provide strong evidence that loss of E-cadherin is an early event in intestinal type gastric carcinogenesis. In contrast, expression of p53, assumed to be mutant p53, was generally not detected (except for isolated cells) until the carcinoma stage in tissues from these patients. These results suggest that mutation of p53 is a late event in intestinal type gastric cancer. The level of beta-catenin expression did not appear to change between normal, metaplastic and carcinoma cells of intestinal type, and no nuclear staining was visible in any of the tissues. These results suggest that the Wnt signaling pathway is not upregulated in this type of cancer.     

T (Thomsen–Friedenreich) antigen and other simple mucin-type carbohydrate antigens in precursor lesions of gastric carcinoma

In a previous report we suggested that T antigen appeared to be associated with gastric carcinoma. To verify this hypothesis and characterize the pattern of expression of simple-mucin type carbohydrate antigens (Tn. sialyl-Tn and T before and after neuraminidase) in normal gastric mucosa and precursor lesions of gastric carcinoma, we studied the mucosa adjacent to 100 cases of gastric carcinoma, gastric biopsies of 60 dyspeptic patients, eight adenomatous polyps and eight hyperplastic polyps. The expression of the antigens was more related to the cell type and underlying lesions than to the coexistence of carcinoma. The most distinctive findings concerned intestinal metaplasia, dysplasia and hyperplastic lesions. In intestinal metaplasia, Tn was found mostly in columnar cells and sialyl-Tn in goblet cells. T was more prevalent in incomplete intestinal metaplasia than in complete. A high prevalence of sialyl-Tn expression and cell membrane immunoreactivity for T antigen, similar to those previously found in gastric carcinomas, were observed in three adenomatous polyps, one hyperplastic polyp, five cases of adenomatous dysplasia in the neighbourhood of intestinal carcinomas and four cases of marked foveolar hyperplasia, three of which were from the mucosa adjacent to diffuse carcinomas. We conclude that adenomatous and hyperplastic lesions share with gastric carcinomas features of aberrant glycosylation, namely the cell membrane expression of T antigen.     

Endocrine neoplasm of the stomach. Study of thirteen cases

A Thirteen patients with primary endocrine neoplasm of the stomach were studied for 20 years. Six patients were male and 7 female with an age range of 33 to 77, mean age 57 years. Nine cases corresponded to well differentiated carcinoids and four to neuroendocrine carcinomas. Of the former, three were sporadic and six were associated with atrophic gastritis. These two forms of neoplasm showed important differences: those associated with atrophic gastritis had hypergastrinemia, all of the multiple small tumors confined to the corpus and fundus were well differentiated carcinoids associated with intestinal metaplasia and G cell hyperplasia in antrum and ECL cell hyperplasia in corpus and fundus. Tumors were clinically benign, with an excellent prognosis. All patients are currently alive with no evidence of neoplasm. In only one of these cases, antiparietal cell antibodies were documented; in three of them, extensive intestinal metaplasia probably due to Helicobacter pylori infection was found. In contrast, sporadic carcinoids were large isolated tumors originating in the antrum or corpus. Two patients died as a consequence of the neoplasm; all of them were moderately differentiated and in none of the cases we found evidence of endocrine hyperplasia. All were positive for generic endocrine markers and were focally positive to some of the specific hormone markers. Al four neuroendocrine carcinomas had a clinical course similar to that of gastric adenocarcinomas and were poorly differentiated large tumors. We conclude that gastric carcinoids associated with atrophic gastritis have an excellent prognosis. On the other hand, neuroendocrine carcinomas have a very poor prognosis with fatal outcome of patients. Sporadic carcinoids have an intermediate prognosis.     

MUC5B、Villin、P53在胆囊黏膜幽门腺化生、肠上皮化生及胆囊腺癌中的表达及意义

目的：通过观察MUC5B、Villin、P53蛋白在胆囊黏膜幽门腺化生、肠上皮化生及胆囊腺癌的表达,探讨胆囊黏膜两种化生与胆囊腺癌发生的关系。方法：收集2013年1月至2015年1月兰州市第二人民医院病理科诊断的胆囊黏膜幽门腺化生40例、肠上皮化生40例及胆囊腺癌40例,采用免疫组化方法检测MUC5B、Villin、P53在胆囊黏膜幽门腺化生、肠上皮化生及胆囊腺癌的表达。结果：MUC5B在胆囊黏膜幽门腺化生、肠上皮化生、胆囊腺癌的阳性表达率分别为95.00%(38/40)、75.00%(30/40)、27.50%(11/40);Villin在三组中的阳性表达率分别为0.00%(0/40)、87.50%(35/40)、22.50%(9/40);P53在三组中的阳性表达率分别为2.50%(1/40)、7.50%(3/40)、80.00%(32/40)。各组间比较MUC5B在幽门腺及肠上皮化生的阳性表达率明显高于胆囊腺癌,差异有统计学意义(χ2=42.754,P=0.001);Villin在肠上皮化生的阳性表达率明显高于幽门腺化生及胆囊腺癌,差异有统计学意义(χ2=71.124, P=0.001);P53在胆囊腺癌中的阳性表达率明显高于幽门腺及肠上皮化生,差异有统计学意义(χ2=71.667,P=0.001)。MUC5B、Villin在幽门腺化生、肠上皮化生及胆囊腺癌的阳性表达率递减;P53在幽门腺化生、肠上皮化生及胆囊腺癌的阳性表达率递增。结论：幽门腺及肠上皮化生可能参与了胆囊腺癌的发生。     

50例胆囊癌黏液组化与免疫组化观察

目的：探讨黏液分泌变化和肿瘤相关抗原表达对胆囊癌早期诊断及其预后判断的价值。方法：采用黏液组化和免疫组化染色对40例胆囊癌,10例胆囊腺瘤,10例慢性胆囊炎的黏液分泌和CEA,CA50,E－cad及PCNA表达进行检测。结果：胆囊癌与胆囊炎和腺瘤相比,分泌硫酸黏液明显减少,唾酸黏液显著增多（P＜0．05）。胆囊癌CEA,CA50阳性表达率显著高于腺瘤和胆囊炎组（P＜0．05）,而E－cad阳性表达率明显降低,伴有转移者E－cad表达更低,胆囊癌PCNA LI高于胆囊炎和腺瘤组（P＜0．01）,CEA,PCNA过度表达者其3年生存率显著降低（P＜0．01）,E－cad过度表达者其3年生存率较阴性组明显增高（P＜0．05）。结论：黏液组化染色和CEA,CA50以及PCNA检测可能有助于胆囊腺瘤恶变和胆囊癌的早期诊断,且CEA PCNA和E－cad检测可作为胆囊癌预后判断的参考指标。     

p53 gene alteration in atypical epithelial lesions and carcinoma in patients with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is well known to be associated with lung cancer. Several atypical epithelial lesions are frequently observed in the fibrotic area in IPF patients, and they have been suspected to be related to lung carcinogenesis. Several studies have suggested that p53 protein accumulation and mutation occur in the early pathogenesis of squamous cell carcinoma of the lung, suggesting some abnormality of the p53 tumor-suppressor gene in interstitial lung diseases. To examine the cause of the high frequency of lung cancer in IPF, we examined the p53 changes in atypical epithelial lesions and carcinoma in patients with IPF by immunohistochemistry and mutational analysis. We examined 19 lung cancer patients with IPF who underwent surgical resection for lung cancer in our institute. Paraffin-embedded tissues were treated by microwave and stained with an anti-p53 antibody (RSP53) by the avidin-biotin-peroxidase complex method. Mutations in exons 5 through 8 of the p53 gene were also examined by polymerase chain reaction mediated single-strand conformation polymorphism (polymerase chain reaction-single-strand conformation polymorphism) analysis and DNA sequencing. p53 protein was immunohistochemically detected in 13 (62%) of 21 squamous cell carcinomas, 3 (60%) of 5 squamous metaplasia with atypia, 16 (54%) of 30 squamous metaplasia, and 1 (4%) of 26 other hyperplastic lesions. p53 mutation was detected in 12 (57%) of 21 squamous cell carcinomas, 2 (40%) of 5 squamous metaplasia with atypia, 7 (23%) of 30 squamous metaplasia, and 0 (0%) of 26 other hyperplastic lesions. In conclusion, there are frequent p53 gene alterations in squamous metaplasia, which is distributed in the peripheral zone of the fibrotic area in patients with IPF. The present findings might provide a clue to the molecular mechanisms underlying the high incidence of lung cancer, especially peripheral-type squamous cell carcinoma in IPF patients, and suggest that p53 gene alterations play an important role in the early stages of lung carcinogenesis in patients with IPF.     

Are histological alterations observed in the gallbladder precancerous lesions?

INTRODUCTION

Gallbladder cancer, which is characterized by rapid progression and a poor prognosis, is a complex disease to treat. Unfortunately, little is known currently about its etiology or pathogenesis. A better understanding of its carcinogenesis and determining risk factors that lead to its development could help improve the available treatment options.

METHOD

Based on this better understanding, the histological alterations (such as acute cholecystitis, adenomyomatosis, xanthogranulomatous cholecystitis, polyps, pyloric metaplasia, intestinal metaplasia, dysplasia, cancer and others) in gallbladders from 1,689 patients who underwent laparoscopic cholecystectomy for cholecystolithiasis were analyzed. The association of these gallbladder histological alterations with clinical data was studied.

RESULTS

Gender analysis revealed a greater incidence of inflammatory changes in males, while dysplasia and cancer were only found in women. The incidence of cholesterolosis was greater in the patients 60 years of age and under, and the incidence of adenomyomatosis and gangrene was greater in the elderly patients. A progressive increase in the average age was observed as alterations progressed through pyloric metaplasia, intestinal metaplasia, dysplasia and then cancer, suggesting that the metaplasia-dysplasia-carcinoma sequence may occur in gallbladder cancer. Gallbladder histological alterations were also observed in asymptomatic patients.

CONCLUSION

The results of this study suggest that there could be an association between some histological alterations of gallbladder and cancer, and they also suggest that the metaplasia-dysplasia-carcinoma sequence could in fact be true in the case of gallbladder cancer. Nevertheless, further studies directed towards a perfect understanding of gallbladder carcinogenesis are required.