Kolorektale Polyposen

Biopsies and resection specimens of the gastrointestinal tract are a major part of the routine workload in many histopathology departments, whereby polypoid lesions are generally the main focus. In addition to distinguishing non-neoplastic from neoplastic polyps and evaluating the grade of dysplasia of the latter, the pathologist should always consider the possibility of an underlying polyposis syndrome. Not only have additional hereditary polyposis syndromes been identified in recent years due to a better understanding of their genetic and epigenetic alterations but also knowledge on well known polyposes has improved, leading to subtyping of various forms according to their different genotype. It is essential for the histopathologist to understand that the conventional histomorphology of individual polyps combined with information on the number and distribution of these lesions and clinical data can provide clues regarding a possible hereditary background. Therefore, the correct histological assessment of polyps is not just about getting the diagnosis right, it might also lead to genetic screening of family members and spouses.     

Gastric polyps

Frequently encountered in pathology practice, gastric polyps are defined as luminal projections above the plane of the adjacent mucosa. These can be non-neoplastic, neoplastic or hamartomatous and syndromic. The classification of gastric polyps has important clinical implications and provides targeted clues towards discovering abnormalities in the remaining gastric mucosa or even elsewhere in the body in syndromic cases. The primary goal in the classification of gastric polyps is to exclude dysplasia and malignancy. Due to the tendency of some gastric polyps to arise in a background of inflammatory or atrophic gastritis or in association with polyposis syndromes, the second major diagnostic goal is to evaluate the surrounding flat mucosa. Numerous types of gastric polyps have been extensively described in the literature. The aim of this article is to review the most commonly encountered polyps in routine practice as well as a few special types of polyps and to describe their histologic features and their clinical implications.     

High-grade dysplasia associated with fundic gland polyposis in a familial adenomatous polyposis patient, with special reference to APC mutation profiles.

We report a patient with familial adenomatous polyposis who developed high-grade dysplasia against a background of fundic gland polyposis. Two large high-grade dysplasia lesions were found in the gastric body, where numerous fundic gland polyps were present. In both lesions, the dysplastic epithelium covered non-neoplastic oxyntic glands that occasionally exhibit cystic changes. A genetic analysis for APC (adenomatous polyposis coli) revealed a somatic 50-bp deletion involving codons 1502-1517 and 2-bp deletion at codon 1465 in each lesion of high-grade dysplasia. In contrast, six of the 18 fundic gland polyps were found to harbor an identical mutation: 1-bp insertion at codon 1556. Both lesions of high-grade dysplasia and the fundic gland polyps were similarly located in the fundic gland area and were caused by the inactivation of APC; however, their mutation profiles of APC were different. These results imply that fundic gland polyps and high-grade dysplasia of the stomach have distinct preferences for APC genotypes in their development.     

The pathology of gastric and duodenal polyps: current concepts

The liberal use of upper endoscopy has led to an increased detection of gastric and duodenal polyps, which are identified in as many as 6 and 4.6% of patient examinations, respectively. Gastroduodenal polyps are a heterogeneous group of lesions that can be neoplastic or non‐neoplastic (e.g. hyperplastic or heterotopical). Most polyps present characteristic topographical features, as well as endoscopic appearance and size. Evaluation of the surrounding mucosa is essential in assessing the underlying pathology (e.g. Helicobacter pylori, autoimmune gastritis or inherited polyposis syndromes). Phylogenetically, gastric and duodenal polyps can be classified according to the epithelial compartment from which they derive. Polyps that arise from the surface epithelium can either be of foveolar or intestinal type, and they can develop from either the native mucosa or the metaplastic epithelium (gastric intestinal metaplasia or duodenal foveolar metaplasia). Other polyps develop from the deeper glandular component, such as pyloric/oxyntic gland derived subtypes. In this review we focus upon epithelial polyps, with an emphasis on the most common and clinically relevant lesions, and present recently described entities.     

Comparative molecular pathology of sporadic hyperplastic polyps and neoplastic lesions from the same individual

AIM: The biology of colorectal hyperplastic polyps is of considerable relevance, because recent evidence suggests that under certain circumstances hyperplastic polyps may be precursors of neoplasms. The aim of this study was to assess and compare the clinical and molecular characteristics of hyperplastic polyps and neoplastic lesions removed from patients without the hyperplastic polyposis syndrome. METHODS: One hundred and twenty six patients were identified through a series of genetic epidemiological studies. Each patient had at least one neoplastic lesion and one hyperplastic polyp; there was a total of 147 hyperplastic polyps. All lesions were evaluated for K-ras mutations, loss of heterozygosity (LOH) of the adenomatous polyposis coli (APC) gene, and microsatellite instability. RESULTS: K-ras mutation was detected in 15 (10%) hyperplastic polyps, all from the rectosigmoid colon. No hyperplastic polyp had APC LOH or microsatellite instability. Patients with adenomas or carcinomas showing K-ras mutations were not more likely to have hyperplastic polyps with K-ras mutations. The average number of adenomas did not differ between those patients with hyperplastic polyps with K-ras mutations and those without K-ras mutations. There was no association between the hyperplastic polyp and the adenoma regarding the colon segments from which the two lesions were removed. CONCLUSIONS: The sporadic hyperplastic polyp is a lesion with limited molecular change and no relation to patients' neoplastic lesions.     

Gastric polyps and polyposis syndromes

Gastric polyps show significant morphologic overlap, and some polyps defy classification altogether. Nevertheless, gastric polyps, particularly when profuse, should prompt further clinical and endoscopic investigation, as it may lead to the diagnosis of a polyposis syndrome. This review summarizes the common gastric polyps that are found in familial and non-inherited polyposis syndromes of the gastrointestinal tract. Examples of the gastric polyps are illustrated, and a discussion of polyp morphology and distribution is paired with a discussion of relevant clinical features and diagnostic criteria of polyposis syndromes. This information provides pathologists guidance for further patient workup, genetic testing, and cancer surveillance.     

What is a juvenile polyp? An analysis based on 21 patients with solitary and multiple polyps

BACKGROUND: Juvenile polyps, the most common pediatric gastrointestinal polyp, have been typically characterized as either hamartomatous overgrowths or reactive inflammatory proliferations. Recent observations of excessive colonic and gastric carcinoma and dysplasia in juvenile polyposis have prompted reclassification of this entity as a premalignant condition. The relationship between solitary or multiple juvenile polyps and malignancy is less clear. PATIENTS AND METHODS: To further investigate the frequency and significance of dysplasia in juvenile polyps, we analyzed 28 polyps from 21 patients histologically and immunohistochemically for substances previously associated with neoplastic transformation in the colorectal adenomacarcinoma sequence. RESULTS: Fifteen patients had a solitary polyp, two had 2 to 9 polyps, and four had polyposis with 10 or more polyps. Most polyps exhibited inflammatory or regenerative atypia. Foci of dysplasia were noted in polyps from 11 patients, and immunoreactivity for p53 and human chorionic gonadotropin was present in 12 of the 28 polyps each. These findings were all more frequent in the polyposis specimens than in solitary polyps. CONCLUSIONS: These observations, in combination with reports of an increased risk of carcinoma in juvenile polyposis, suggest that juvenile polyps are lesions with a potential for neoplastic and malignant transformation, although they share features of an inflammatory reactive process. The implications for clinical management of patients and pathologic evaluation of juvenile polyps warrant further investigation.     

Recent advances in the pathology of heritable gastric cancer syndromes

Despite the relative rarity of hereditary gastric cancer syndromes, the prompt recognition of their specific clinical features and histopathological characteristics is pivotal in offering patients the most appropriate treatment. In this article, we address the three major inherited syndromes that primarily affect the stomach: hereditary diffuse gastric cancer (HDGC), caused by germline variants in CDH1 and CTNNA1; gastric adenocarcinoma and proximal polyposis of the stomach, caused by germline mutations in promoter 1B of APC; and familial intestinal gastric cancer, which has a poorly defined genetic cause. The main focus will be on HDGC, in light of the recent publication of updated clinical practice guidelines and emerging concepts regarding HDGC histopathology. In particular, we describe the broad morphological spectrum of HDGC lesions, stressing the importance of recognising indolent and aggressive phenotypes. Moreover, we discuss the increased risk of gastric (pre)malignancies developing in patients with other well‐defined hereditary cancer syndromes, such as familial adenomatous polyposis, Lynch syndrome, Peutz–Jeghers syndrome, juvenile polyposis, Li–Fraumeni syndrome, and hereditary breast and ovarian cancer syndrome.     

HISTOLOGICAL CLASSIFICATION OF EPITHELIAL POLYPOID LESIONS OF THE GALLBLADDER

Thirty epithelial polypoid lesions in 24 surgically resected gallbladders were examined histologically and immunohistochemically and then classified into two types according to the characterstics of the epithelium. One type consisted of proliferation of ordinary gallbladder epithelium without any metaplastic change while the other type was characterized by proliferation of metaplastic epithelium, such as mucous glands, endocrine cells and lysozyme-immuno-reactive cells. Moreover, each lesion was subdivided into non-neoplastic epithelial polyp or neoplastic adenoma. We therefore classified the non-neoplastic epithelial polyps into hyperplastic polyps and metaplastic polyps, and the adenomas into ordinary type and metaplastic type. Moreover, we found that atypical glands within metaplastic-type adenoma were not infrequently observed, and that these lesions also presented metaplastic changes. From these results, the possibility of an adenoma-carcinoma sequence was discussed. ACTA PATHOL JPN 38: 181–192, 1988.     

Non-neoplastic colorectal polyps

With the explosion in the number of screening colonoscopic procedures, pathologists have learned to recognize a host of non-neoplastic polyps that can be loosely categorized as those stemming from mucosal prolapse, hamartomatous lesions, incidental benign stromal polyps and polyps associated with systemic diseases. We briefly review solitary rectal ulcer syndrome, inflammatory cloacogenic polyps, diverticular disease-associated prolapse polyps, cap polyps, juvenile polyps, Peutz–Jeghers polyps, Cronkhite–Canada polyposis, elastosis, benign fibroblastic polyps, inflammatory fibroid polyps, pneumatosis, vascular lesions, filiform polyps, lymphoid polyps, malakoplakia, amyloidosis and endometriosis.     

Fundic gland polyps in familial adenomatous polyposis: neoplasms with frequent somatic adenomatous polyposis coli gene alterations

Fundic gland polyps (FGPs) are the most common gastric polyps in patients with familial adenomatous polyposis (FAP). FGPs have traditionally been regarded as nonneoplastic, possibly hamartomatous lesions, but the pathogenesis of FGPs in both FAP and sporadic patients remains unclear. FGPs in FAP can show foveolar dysplasia, and rarely invasive gastric adenocarcinoma has been reported in patients with FAP and fundic gland polyposis. Using direct gene sequencing and allelic loss assays at 5q, we analyzed somatic adenomatous polyposis coli (APC) gene alterations in 41 FAP-associated FGPs (20 with foveolar dysplasia, six indefinite for dysplasia, and 15 nondysplastic) and 13 sporadic FGPs. The foveolar epithelium and dilated fundic glands of the polyps were separately microdissected and analyzed in 25 of 41 FAP-associated FGPs and 13 of 13 sporadic FGPs. Somatic APC gene alterations were identified frequently (21 of 41 cases, 51%) in FAP-associated FGPs. Both the foveolar epithelium and the dilated fundic gland epithelium comprising the FGPs were shown to carry the same somatic APC gene alteration in 24 (96%) of 25 cases. Furthermore, there was no difference in the frequency of somatic APC gene alterations between FGPs with foveolar dysplasia (10 of 20, 50%), indefinite for dysplasia (four of six, 67%), and nondysplastic (seven of 15, 47%) in FAP patients (P: = 0.697). In contrast, FGPs from non-FAP patients showed infrequent (one of 13, 8%) APC gene alterations (P: = 0.008). These results show that FGPs in FAP patients are pathogenetically distinct from sporadic FGPs. Somatic, second-hit APC gene alterations, which precede morphological dysplasia in many FAP-associated FGPs, indicate that FGPs arising in the setting of FAP are neoplastic lesions.     

Genetic conditions associated with intestinal juvenile polyps

Juvenile polyps are hamartomatous polyps found primarily in infants and children, and in association with juvenile polyposis (JP; OMIM #174900), Cowden syndrome (CS; OMIM #158350), and Bannayan-Riley-Ruvalcaba syndrome (BRRS; OMIM# 153480). Although solitary juvenile polyps are benign lesions, when present in JP patients they may lead to gastrointestinal cancers. Germline mutations in MADH4 and BMPR1A predispose to JP, and both genes are involved in TGF-beta superfamily signaling pathways. In CS and BRRS, juvenile polyps are a less consistent feature, and CS patients are at risk for breast and thyroid cancers. Mutations of the tumor suppressor gene PTEN have been found in the germline of both CS and BRRS patients. Despite different underlying genetic mechanisms, these and other syndromes share the same phenotypic feature of juvenile polyps.     

Histological classification of epithelial polypoid lesions of the gallbladder

Thirty epithelial polypoid lesions in 24 surgically resected gallbladders were examined histologically and immunohistochemically and then classified into two types according to the characteristics of the epithelium. One type consisted of proliferation of ordinary gallbladder epithelium without any metaplastic change while the other type was characterized by proliferation of metaplastic epithelium, such as mucous glands, endocrine cells and lysozyme-immunoreactive cells. Moreover, each lesion was subdivided into non-neoplastic epithelial polyp or neoplastic adenoma. We therefore classified the non-neoplastic epithelial polyps into hyperplastic polyps and metaplastic polyps, and the adenomas into ordinary type and metaplastic type. Moreover, we found that atypical glands within metaplastic-type adenoma were not infrequently observed, and that these lesions also presented metaplastic changes. From these results, the possibility of an adenoma-carcinoma sequence was discussed.     

Polyps of the small intestine

Polyps of the small bowel are rare compared to those of the colorectum. A correct histopathological diagnosis is crucial for the choice of subsequent treatment. This article reviews the most frequently found and some rare but distinct polyps and polyp-like lesions in the small intestine. Adenomas are the most commonly found polyps in the small intestine. Other polypoid lesions include Brunner gland hyperplasia, Brunner gland hamartoma, periampullary myoepithelial hamartoma and pyogenic granuloma. Adenomas are usually found in the distal portion of the duodenum, whereas, Brunner gland hamartoma and inflammatory polyps are noted in the proximal portion of the duodenum. The rare but distinct Peutz–Jeghers polyp and juvenile polyp are reviewed, including the associated hereditary autosomal dominant syndromes (i.e. Peutz–Jeghers and juvenile polyposis syndrome) of which these lesions are the phenotypic hallmarks. Finally, an extremely rare polyposis syndrome with unknown aetiology, i.e. Cronkhite–Canada syndrome, is described with documentation.     

Sporadic fundic gland polyps: common gastric polyps arising through activating mutations in the beta-catenin gene

Fundic gland polyps (FGPs) are the most common gastric polyps. FGPs traditionally have been regarded as nondysplastic hamartomatous or hyperplastic lesions, but their pathogenesis remains unclear. We have recently shown that somatic adenomatous polyposis coli (APC) gene alterations are frequently present in FGPs associated with familial adenomatous polyposis (FAP), raising the possibility that mutations of the beta-catenin gene affecting the APC/beta-catenin pathway might be involved in the pathogenesis of sporadic FGPs. We analyzed somatic beta-catenin gene mutations in 57 sporadic FGPs from 40 patients without FAP and in 19 FGPs from 13 FAP patients. Direct DNA sequencing of exon 3 encompassing the glycogen synthase kinase-3beta phosphorylation region for beta-catenin was used with confirmation by HIN:fI restriction endonuclease digestion. The foveolar epithelium and dilated fundic glands of the polyps were separately microdissected and analyzed in 22 of 57 sporadic FGPs. Activating beta-catenin gene mutations were present in 91% (52 of 57) of sporadic FGPs. Both the foveolar epithelium and the dilated fundic gland epithelium comprising the polyps were shown to have the same somatic beta-catenin mutation in 21 of 22 (95%) sporadic FGPs. In contrast, beta-catenin gene mutations were not present in any of the 19 FAP-associated FGPs (P: < 0.000001). The high frequency of beta-catenin mutations in sporadic FGPs indicates that these lesions arise through activating mutations of the beta-catenin gene. Beta-catenin mutations in gastrointestinal tract polyps have previously only been demonstrated in a subset of adenomatous (dysplastic) or neoplastic polyps. Sporadic FGPs are therefore the only lesions of the gastrointestinal tract to demonstrate beta-catenin mutations while lacking dysplastic morphology.     

Atypical juvenile polyposis

Two cases of atypical juvenile polyposis are described in males of 9 months and 25 years-of-age. The first was associated with congenital megacolon and presented as juvenile polyps with features suggesting mild dysplasia. In the second case six histological lesions are found: 1 hyperplastic polyps; 2 juvenile polyps; 3 hyperplastic polyps with adenomatous areas; 4 juvenile polyps with areas of dysplastic epithelium; 5 adenomas; and 6 adenocarcinomas. On the basis of the morphological features we propose a pathogenetic sequence of focal mucosal hyperplasia to adenoma and carcinoma through stages of non-neoplastic and non premalignant polyps. Finally, the possibility that hyperplastic epithelium can in some circumstances have a greater dysplastic potential than normal colorectal mucosa is raised.     

A survey of phenotypic features in juvenile polyposis.

Solitary juvenile polyps are quite frequent in children, but juvenile polyposis (JP) is a rare autosomal dominant trait characterised by the occurrence of numerous polyps in the gastrointestinal tract. Extracolonic phenotypic abnormalities are well documented in patients with familial adenomatous polyposis and Peutz-Jeghers syndrome and can allow a clinical diagnosis to be made before the bowel pathology becomes available. Though described, characteristic extracolonic abnormalities have not been clearly defined in juvenile polyposis. We sought to determine whether there are consistent extracolonic phenotypic abnormalities in JP patients and how frequently this would allow diagnosis of one of the genetic syndromes known to be associated with juvenile polyposis. Twenty-two JP patients underwent clinical examination and data from one patient were obtained from case notes. Those consenting to further investigations had x rays of the skull, chest, and hands and an echocardiogram if clinically indicated. Significant extracolonic phenotypic abnormalities were present in 18 patients (14 male and four female), and included dermatological (13), skeletal (16), neurological (5), cardiopulmonary (4), gastrointestinal (3), genitourinary (4), and ocular (1) features. In five patients the diagnosis of a genetic syndrome was possible: two had Bannayan-Riley-Ruvalcaba syndrome, two had Gorlin syndrome, and one had hereditary haemorrhagic telangiectasia (HHT, also known as Osler-Rendu-Weber syndrome). Other patients had some features of these conditions and of Cowden and Simpson-Golabi-Behmel syndromes, but these were not sufficient to allow a definitive diagnosis.     

Immunolocalization of beta catenin in intestinal polyps of Peutz-Jeghers and juvenile polyposis syndromes

AIM: To examine the membranous and nuclear distribution of beta catenin in the epithelial cells of gut polyps from Peutz-Jeghers syndrome and juvenile polyposis in comparison with other types of polyps and tumours. METHODS: Immunohistochemistry for beta catenin and proliferation markers was performed on conventional paraffin sections. Immunohistological staining was carried out on Peutz-Jeghers syndrome polyps from four different families, on juvenile polyposis polyps from two different families, on solitary juvenile polyps, and on hyperplastic polyps. The immunohistochemistry was evaluated qualitatively in relation to defined areas of the polyps. RESULTS: All polyps from the hamartomatous polyposis syndromes (Peutz-Jeghers syndrome and juvenile polyposis) showed nuclear localization of beta catenin in some epithelial cell nuclei. In Peutz-Jeghers syndrome polyps beta catenin positive nuclei were seen at the base of the deep crypt infoldings. In juvenile polyposis polyps and in some solitary juvenile polyps they were found in irregularly distributed cryptal epithelial cells corresponding to the proliferative compartments. Normal mucosa of the gut and hyperplastic polyps of the colon do not show nuclear staining for beta catenin. CONCLUSIONS: The dysregulation of cellular beta catenin distribution is not only a phenomenon of adenoma formation and adenoma progression in the colon--it is at least focally present in polyps of the hamartomatous type and is related to the proliferation zones of these polyps. The nuclear translocation of beta catenin most probably reflects a disturbed beta catenin metabolism. In view of the different functions of beta catenin during development and cell differentiation, the nuclear translocation of beta catenin is likely to be an important factor in enhanced cell proliferation which escapes local control mechanisms.     

Familial gastric carcinoma

Most cases of gastric cancer are sporadic and familial clustering is observed in about 10% of cases. Hereditary gastric cancer accounts for a very low percentage of cases (1–3%), encompassing: hereditary diffuse gastric cancer (HDGC) and gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS). Furthermore, gastric cancer can develop in the setting of other hereditary cancer syndromes such as Li–Fraumeni syndrome, Familial Adenomatous Polyposis, Peutz–Jeghers syndrome, Lynch syndrome, MUTYH-associated adenomatous polyposis, Juvenile Polyposis syndrome, and Cowden syndrome. HDGC is caused by alterations of the CDH1 gene that encodes for e-cadherin and the model of development encompasses non-atrophic gastritis, in situ signet ring cell carcinoma, pagetoid spread of signet ring cells and invasive carcinoma. GAPPS is characterized by proximal fundic gland polyposis, with areas of dysplasia or intestinal-type gastric cancer, without evidence of colorectal polyposis or other heritable gastrointestinal cancer syndromes. The genetic cause of GAPPS has not been identified yet.