Immunohistochemical evaluation of adenomatous polyposis coli, β-catenin, c-Myc, cyclin D1, p53, and retinoblastoma protein expression in syndromic and sporadic fundic gland polyps

doi:10.1016/j.humpath.2003.10.010

Human Pathology

Volume 35, Issue 3, March 2004, Pages 328-334

Presented in part in abstract form at the 91st annual meeting of the United States and Canadian Academy of Pathology, held in Chicago, IL, February 23-March 1, 2002.

https://doi.org/10.1016/j.humpath.2003.10.010 Get rights and content

Abstract

Syndromic and sporadic fundic gland polyps are morphologically indistinguishable but may arise via different pathogenetic mechanisms involving mutations of the adenomatous polyposis coli (APC) and its downstream target β-catenin genes. Although a higher frequency of dysplasia has been reported in syndromic forms, the risk of developing invasive carcinoma is exceedingly low. The current study was designed to investigate whether syndromic and sporadic fundic gland polyps differ in protein expression of a number of genes that are thought to be important in the control of neoplastic transformation. A total of 262 fundic gland polyps, including 155 syndromic polyps obtained from 35 patients with familial adenomatous polyposis or Gardner’s syndrome and 107 sporadic polyps randomly selected from 45 patients with gastroesophageal reflux disease or Barrett’s esophagus, were included in this study. Immunohistochemical evaluation showed that loss of immunoreactivity to the antibody against the carboxyl terminus of the APC protein, presumably resulting from APC gene mutations, was more frequent in syndromic than in sporadic cases (40% versus 6.7%, P < 0.001). However, immunostaining failed to show aberrant nuclear localization of β-catenin, a protein regulated by APC, in any of the polyps, irrespective of syndromic or sporadic types. Instead, positive membranous staining for β-catenin was observed in all the cases. In addition, the expression characteristics of 2 other proteins, c-Myc and cyclin D1, whose genes have been reported to be transcriptionally regulated by the APC/β-catenin pathway, were similar in these two types of polyps. Furthermore, all cases, including those harboring dysplasia, showed negative nuclear staining for p53 and positive nuclear staining for retinoblastoma (RB). Taken together, these data show a lack of dysregulation in the APC/β-catenin signaling pathway and in the expression of p53 and RB in fundic gland polyps despite a high frequency of somatic mutations of the APC and β-catenin genes reported in these polyps. These findings may explain at least in part why fundic gland polyps show a negligible malignant potential even in the presence of dysplasia.

Section snippets

Materials and methods

A total of 262 fundic gland polyps were included in this study. These included 155 syndromic polyps biopsied from 35 patients with FAP (27 cases) or Gardner’s syndrome (8 cases) retrieved from the 1988–2001 pathology archives at Washington University Medical Center, the 1990–2000 pathology archives at the University of Chicago Hospitals, and the University of Texas Medical Branch at Galveston. Also included in the study were 107 sporadic polyps that were randomly selected from 45 patients who

Clinicopathologic features of syndromic and sporadic FGPs

The mean ages of the patients with syndromic and sporadic FGPs were 32 years (range, 14 to 70) and 55 years (range, 12 to 85), with male-female ratios of 1.4:1 and 1:2.5, respectively. In sporadic cases, 14 patients (31%) had a documented clinical history of proton pump inhibitor use. Histologically, syndromic and sporadic FGPs were indistinguishable, characterized by the presence of cystically dilated fundic glands lined by an attenuated layer of parietal and chief cells (Fig 1A).

Discussion

Recent studies have shown that FGPs are clonal lesions and thus neoplastic in nature.6, 7, 8, 9, 10, 15 In these elegant studies, a high frequency of somatic mutations in the APC gene was detected in syndromic FGPs, whereas a high frequency of activating mutations in the β-catenin gene was found in sporadic cases. These findings are intriguing because mutations in the APC or β-catenin genes detected in other anatomic locations are always associated with a morphologically overt neoplastic

Acknowledgements

The authors thank Ms. Prosperidad Amargo for her excellent technical assistance.

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Fundic Gland Polyps Lack DNA Content Abnormality Characteristic of Other Adenomatous Precursor Lesions in the Gastrointestinal Tract
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Fundic gland polyps (FGPs) develop sporadically (frequently after proton pump inhibitor therapy) or in the setting of a hereditary polyposis syndrome, such as familial adenomatous polyposis (FAP). FAP-related FGPs often demonstrate low-grade dysplasia (LGD) and are frequently associated with APC mutations, even in the absence of dysplasia. Sporadic FGPs with dysplasia are molecularly similar to FAP-related FGPs and demonstrate frequent mutations in APC gene. Despite having similar molecular alterations with colorectal and other adenomatous precursor lesions in the gastrointestinal (GI) tract, FGPs rarely progress to advanced gastric neoplasia (high-grade dysplasia [HGD] or adenocarcinoma), and their role in gastric tumorigenesis remains unclear but likely limited. The clinicopathologic features of 192 patients diagnosed with FGPs, including 86 with FAP-related FGPs (33 with dysplastic FGPs and 53 with nondysplastic FGPs) and 106 with sporadic FGPs (12 with dysplastic FGPs and 94 with nondysplastic FGPs), were analyzed. DNA flow cytometry was performed on 111 FAP-related FGP biopsies, including 32 FGPs with LGD and 79 nondysplastic FGPs, to assess the presence of abnormal DNA content (ie, aneuploidy or elevated 4N fraction). Moreover, 40 sporadic FGP biopsies, including 14 dysplastic (13 LGD and 1 HGD) and 26 nondysplastic FGPs, were examined for DNA content abnormality. Patients with FAP and nondysplastic FGPs were more likely to be younger (mean age, 32 years) and present with multiple FGPs (92%, defined as having ≥2 FGPs) than those with sporadic nondysplastic FGPs (61 years and 65%, respectively; P < .001). They also recorded higher rates of previous or concurrent gastric epithelial dysplasia not occurring in a FGP (8%, P = .016), nongastric GI dysplasia (96%, P < .001), and nongastric GI malignancy (17%, P = .001) compared with those with sporadic nondysplastic FGPs (0%, 52%, and 2%, respectively). The sporadic group was more frequently associated with proton pump inhibitor therapy (78%, P < .001), gastric intestinal metaplasia (24%, P = .004), and a family history of gastric cancer (10%, P = .027) than the FAP group (19%, 6%, and 0%, respectively). Almost all FAP-related FGPs had a polypoid endoscopic appearance (98% vs 84% for sporadic FGPs; P = .009). The mean size of the largest FAP-related FGPs (0.5 cm) was similar to that of sporadic FGPs (0.7 cm) (P = .069). None of the 147 patients with FAP-related or sporadic nondysplastic FGPs were associated with subsequent detection of advanced gastric neoplasia within a mean follow-up time of 54 months (range, <1 to 277 months). However, 2 (4%) of the 45 patients with FAP-related or sporadic dysplastic FGPs developed advanced gastric neoplasia within a mean follow-up time of 59 months (range, <1 to 236 months). One (3%) of the 33 patients with FAP and dysplastic FGPs developed signet ring cell adenocarcinoma, whereas 1 (8%) of the 12 patients with sporadic dysplastic FGPs developed HGD (P = .445). However, none of the FAP-related and sporadic FGP biopsies, regardless of the presence or absence of dysplasia, demonstrated DNA content abnormality. In conclusion, FGPs lack large-scale chromosomal changes that are characteristic of the typical adenoma-carcinoma sequence involved in the development of other GI malignancies. Progression to advanced gastric neoplasia is rare in FGPs, which may be partly explained by the apparent lack of the chromosomal instability phenotype in these lesions.
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Original contributionImmunohistochemical evaluation of adenomatous polyposis coli, β-catenin, c-Myc, cyclin D1, p53, and retinoblastoma protein expression in syndromic and sporadic fundic gland polyps

Abstract

Section snippets

Materials and methods

Clinicopathologic features of syndromic and sporadic FGPs

Discussion

Acknowledgements

Hum Pathol

Am J Pathol

Am J Pathol

Mod Pathol

Gastroenterology

Am J Gastroenterol

Am J Pathol

Hum Pathol

Gastroenterology

Am J Gastroenterol

Hum Pathol

Trends Genet

Am J Pathol

Gene

Hum Pathol

Am J Gastroenterol

Fundic gland polypsA still elusive entity on the eve of the year 2000

Pol J Pathol

Proton pump inhibitor-associated gastric polypsA retrospective analysis of their frequency, and endoscopic, histologic, and ultrastructural characteristics

Am J Clin Pathol

Fundic gland polyps are not induced by proton pump inhibitor therapy

Am J Clin Pathol

Sporadic, syndromic, and Zollinger-Ellison syndrome associated fundic gland polyps consistently express cytokeratin 7

Virchows Arch

Somatic mutations of the adenomatous polyposis coli gene in gastroduodenal tumors from patients with familial adenomatous polyposis

Cancer Res

β-Catenin mutations in sporadic fundic gland polyps

Virchows Arch

Original contribution
Immunohistochemical evaluation of adenomatous polyposis coli, β-catenin, c-Myc, cyclin D1, p53, and retinoblastoma protein expression in syndromic and sporadic fundic gland polyps