Del(10)(q22.3q24.1) associated with juvenile polyposis

Juvenile polyps are the most frequent gastrointestinal polyps with a malignant potential for which the genetic basis is unknown. Juvenile polyps, with a normal epithelium but hypertrophic lamina propria, are histologically quite distinct from adenomatous polyps which have dysplastic changes in epithelial nuclei. Furthermore, the adenomatous polyposis coli (APC) gene on Chr 5, mutated somatically in adenomatous polyps and mutated in the germline of patients with familial adenomatous polyposis, is not linked to hereditary juvenile polyposis. We provide the first report indicating that a tumor suppressor gene associated with juvenile polyposis may be located at 10q22.3q24.1. Cytogenetic studies of a patient with juvenile polyposis and multiple congenital abnormalities of the head, extremities, and abdomen revealed a de novo interstitial deletion of Chr 10 as the only defect, del(10)(10q22.3q24.1). Am. J. Med. Genet. 70:361–364, 1997. © 1997 Wiley-Liss, Inc.     

Genetic alterations and epithelial dysplasia in juvenile polyposis syndrome and sporadic juvenile polyps.

Juvenile polyps are regarded as hamartomatous polyps and occur in sporadic and familial syndromic settings. There is increased risk of gastrointestinal neoplasia in patients with juvenile polyposis syndrome, but the molecular mechanisms are not known. We therefore studied 78 colorectal juvenile polyposis from 12 patients with juvenile polyps syndrome and 34 sporadic juvenile polyps for epithelial dysplasia and genetic changes associated with colorectal neoplasia. Dysplasia occurred in 31% of syndromic juvenile polyps but not in sporadic juvenile polyps (P < 0.0001). Topographic control of proliferation and expression of the cyclin-dependent kinase inhibitor p21(WAFI/CIP1) seen in native colorectal epithelium was lost in 79% of dysplastic juvenile polyps and in 8% of nondysplastic juvenile polyps (P < 0.000001). Somatic mutations in the adenomatous polyposis coli (APC) gene were demonstrated in 50% of dysplastic juvenile polyps (3 of 6) but not in any of 16 juvenile polyps without dysplasia (P = 0.01). Both sporadic and syndromic juvenile polyps had K-ras mutations (14%) and there was no relationship to dysplasia. p53 gene product overexpression identified by immunohistochemical staining occurred rarely in dysplastic juvenile polyps (2 of 24, 8%). Our results indicate that the multiple genetic alterations involved in usual colorectal neoplasia also play a role in neoplastic transformation of juvenile polyps, predominantly in juvenile polyposis syndrome.     

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.     

Gastric polyps: an update of their pathology and biological significance

Gastric polyps are clinically important lesions that are frequently encountered in routine pathology (2-3% of all gastroscopies). Polyps may occur sporadically or in polyposis syndromes, such as familial adenomatous polyposis coli (FAP), Peutz-Jeghers syndrome, juvenile polyposis, Cowden's disease and Cronkhite-Canada syndrome. In biopsy specimens taken during routine gastroscopic examinations, it is almost always possible to differentiate between neoplastic and non-neoplastic polyps and to type polyps. In this review, we focus on the morphological spectrum of gastric polyps in an attempt to assist the pathologist and the gastroenterologist in recognising the lesion and in treating patients with gastric polyps, respectively. Further, we propose that the World Health Organization (WHO) classification should be modified to include the following categories: non-neoplastic polyps (WHO: tumour-like lesion), hamartomatous polyps/polyps of polyposis syndromes (WHO: tumour-like lesion), heterotopic tissue polyps (WHO: tumour-like lesion), neoplastic polyps (WHO: epithelial, non-epithelial and endocrine tumours) and reactive polypoid lesions.     

Juvenile polyposis–a precancerous condition

Clinical and pathological findings in 87 patients with juvenile polyposis have been reviewed; 1032 polyps were available from 80 of these patients; 840 were typical spherical juvenile polyps whereas 169 differed in being multilobulated or showing a villous configuration; 79 (46.7%) of the latter contained foci of epithelial dysplasia whereas only 76 (9.0%) of the typical juvenile polyps were dysplastic. The series also included 21 adenomas and two hyperplastic (metaplastic) polyps. The demonstration of dysplasia provides a histogenetic mechanism for the evolution of colorectal cancer from hamartomatous polyps; 18 juvenile polyposis patients have developed colorectal cancer at a mean age of 34 years (range 15-59). The clinical outcome was generally poor. No clinical or pathological distinction could be made between polyposis patients with and without colorectal cancer. Thus, the development of cancer in juvenile polyposis appears to be a random event. A working definition of juvenile polyposis is provided: (1) more than five juvenile polyps of the colorectum; and/or (2) juvenile polyps throughout the gastrointestinal tract; and/or (3) any number of juvenile polyps with a family history of juvenile polyposis. It is suggested that the condition should be treated as seriously as familial adenomatous polyposis except that regular colonoscopic surveillance may obviate the need for prophylactic colectomy.     

Colorectal juvenile polyps: an epidemiological and histopathological study of 144 cases in Jordanians

The minimal incidence rate of colorectal juvenile polyps in Jordanians was 1.4 per 100 000 in the general population and 2.8 per 100 000 in children under 10 years of age. Out of 144 cases, nine had two to seven polyps and one juvenile polyposis coli. There was male preponderance and a mean age of 8 years: 96.5% of the polyps were in the rectum. Characteristically, stromal oedema, inflammation, ulceration with granulation tissue cap formation and gland regeneration were present. Epithelial hyperplasia was not uncommon and focal dysplastic change was occasionally noted, being always accompanied by hyperplastic change. Focal severe dysplasia was seen in one solitary juvenile polyp. It is concluded that varying degrees of focal epithelial atypia can occasionally develop in solitary juvenile polyps, rarely reaching severe dysplastic change. Malignant transformation in the commonly seen form of juvenile polyp (solitary type) is probably a rare phenomenon, but its frequency needs further evaluation.     

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.     

Incidence and significance of argentaffin and Paneth cells in some tumours of the large intestine

The incidence of argentaffin and Paneth cells in epithelial tumours of the large intestine was investigated. Argentaffin cells were found in adenomatous polyps, villus adenomas, polyposis coli, Peutz-Jehgers' polyps, juvenile polyposis, and adenocarcinomas. Paneth cells were not found in metaplastic or juvenile polyps.The crypt unit was destroyed in neoplasia and argentaffin and Paneth cells occurred either as a result of sequestration or were taking part in the neoplastic process.The crypt unit was retained in the disorders of epithelial growth. The identification of argentaffin and Paneth cells enabled the crypt to be defined and thus provided a useful, practical aid in the differentiation between neoplasms and disorders of epithelial growth.     

Hypertrophic and polypoid gastropathy associated with juvenile adenomatous polyposis coli

Juvenile Polyposis is a syndrome with gastrointestinal polyps and increased cancer risk. The commonest form of this syndrome is inherited as autosomal dominant trait and presents as Familial Juvenile Polyposis Coli. Another variant involves mainly the stomach and another is generalized throughout the gastrointestinal tract. We present the case of two brothers with polyposis coli complicated by colonic cancer. The polyps were of juvenile, adenomatous and mixed types. The two patients after a decade of colonic endoscopic polypectomies presented gastric involvement by polyps and needed multiple endoscopic gastric resections. One brother underwent total gastrectomy. This stomach showed diffuse polyposis of hyperplastic and fundic gland types within an unexpected background of foveolar and glandular hypertrophic gastropathy. The patients at present are followed up with endoscopic procedures.     

Morphogenesis of polyps in diffuse polyposis of the colon

Sixty operative specimens of the colon or its fragments removed for diffuse juvenile polyposis (the diagnosis was clinical) were evaluated morphologically. A structural study of the polyps ranging in size from the smallest to large lobular formations elicited a significant role of inflammation in polyp morphogenesis. Large polyps often show fragments of typical adenomatous structure. These adenomatous sites mark a higher risk of malignant transformation which develops in polyps of mixed structure in diffuse juvenile colon polyposis. Structurally, there are more reasons for referring juvenile polyps to adenomas than to hamartomas.     

Epithelial and neuroendocrine tumors of the duodenum

This review considers the pathologic features of epithelial tumors and tumor-like lesions of the duodenum and highlights potential pitfalls in their histological diagnosis. The tumor-like lesions include Brunner's gland hamartoma, myoepithelial hamartoma, and the mucosal polyps of the Peutz-Jeghers and juvenile polyposis syndromes. The true neoplasms are of two broad groups. The first includes duodenal adenomas and carcinomas, whose microscopic features, histogenetic relationships, and clinical significance closely mimic their commoner counterparts in the large intestine and which, when multiple, are closely associated with familial adenomatous polyposis coli. The second includes a number of uncommon endocrine cell tumors showing a great diversity of histological pattern, and which may be single or multiple. Among these are typical argyrophil carcinoids, which may secrete gastrin to give rise to the Zollinger-Ellison syndrome, and which may occur as part of the inherited multiple endocrine neoplasia syndrome type 1 (MEN-1); glandular somatostatin-rich, apparently nonargyrophil, carcinoids containing psammoma bodies that can be easily confused histologically with adenocarcinomas, and which are linked to type 1 neurofibromatosis (von Recklinghausen's disease) and phaeochromocytoma; and the gangliocytic paraganglioma, a rare tumor composed of neural elements, ganglion cells, and endocrine cells. Accurate histologic diagnosis of mucosal tumors and tumor-like lesions of the duodenum is important not only for immediate patient management, but also because it may provide the first clue to the existence of an inherited tumor syndrome, with its broader implications for the patient's family and potentially important consequences for genetic counseling.     

The gastrointestinal manifestation of constitutional mismatch repair deficiency syndrome: from a single adenoma to polyposis‐like phenotype and early onset cancer

Data on the clinical presentation of constitutional mismatch repair deficiency syndrome (CMMRD) is accumulating. However, as the extraintestinal manifestations are often fatal and occur at early age, data on the systematic evaluation of the gastrointestinal tract is scarce. Here we describe 11 subjects with verified biallelic carriage and who underwent colonoscopy, upper endoscopy and small bowel evaluation. Five subjects were symptomatic and in six subjects the findings were screen detected. Two subjects had colorectal cancer and few adenomatous polyps (19, 20 years), three subjects had polyposis‐like phenotype (13, 14, 16 years), four subjects had few adenomatous polyps (8, 12–14 years) and two subjects had no polyps (both at age 6). Of the three subjects in the polyposis‐like group, two subjects had already developed high‐grade dysplasia or cancer and one subject had atypical juvenile polyps suggesting juvenile polyposis. Three out of the five subjects that underwent repeated exams had significant findings during short interval. The gastrointestinal manifestations of CMMRD are highly dependent upon age of examination and highly variable. The polyps may also resemble juvenile polyposis. Intensive surveillance according to current guidelines is mandatory.     

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.     

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.     

Adenomas arising in Barrett's esophagus with adenocarcinoma. Report of three cases.

Adenocarcinoma of the esophagus is a well known complication of Barrett's esophagus, and results from a dysplasia-carcinoma sequence. This report describes 3 patients with adenomatous polyps arising in Barrett's esophagus. One patient presented with multiple sessile or pedunculated polyps giving a polyposis appearance; the other two patients had single polyps associated with distinct adenocarcinoma arising in Barrett's esophagus. Polyps consisted of adenomatous proliferation with adenocarcinoma in the 3 patients. Review of the literature identified twelve previously reported cases. These cases show that although rare, adenomas may arise in Barrett's esophagus, and are most likely premalignant lesions such as other adenomas of the gastrointestinal tract.     

Morphological characteristics of gastrointestinal lesions in patients after total colectomy for colon polyposis

11 patients with juvenile polyposis and 4 patients with familial adenomatous polyposis after total colectomy entered the study. Long-term follow-up with endoscopic examination and multiple biopsies in these patients showed high probability of polyps in preserved regions of the gastrointestinal tract. Therefore, regular prophylactic endoscopy, morphological examinations and biopsies of endoscopically normal mucous membrane are justified. Such policy is recommended especially for patients with familial adenomatous polyposis.     

Inverted hyperplastic polyposis of the colon.

AIMS: To describe and evaluate two apparently unique cases of inverted hyperplastic (metaplastic) polyposis of the colon. METHODS: The cases were analysed by standard histopathological, histochemical, and immunohistochemical techniques and the findings compared with those of regular hyperplastic polyps of the colorectum. RESULTS: Both patients were middle-aged men with concurrent adenocarcinoma of the proximal large intestine. The inverted polyps numbered 18 and 12, measured between 0.4 and 2.5 cm in diameter, and all were present in the proximal ascending colon. The polyps had characteristic macroscopic features: they were positioned on the apex of mucosal folds and demonstrated surface pitting and mucus hypersecretion. Histologically, inversion and misplacement of hyperplastic epithelium was related to lymphoglandular complexes. The polyps showed all the histochemical and immunohistochemical features of regular hyperplastic polyps. CONCLUSIONS: Inverted hyperplastic polyps are an unusual but distinctive polyp of the proximal colon, may be multiple, and share the phenotypic changes of regular hyperplastic polyps. The pathogenesis of epithelial inversion probably relates to misplacement of epithelium through anatomical defects in the muscularis mucosae due to mechanical forces. The polyps may mimic both adenomas and carcinomas. The neoplastic potential of inverted hyperplastic polyposis is likely to be very low: one polyp only showed adenomatous change.     

Metaplastic polyps and polyposis of the colorectum

Five hundred and fifty-four colorectal metaplastic polyps have been studied histologically. Whilst most lesions were small and sessile, 16.1% measured greater than 0.5 cm in diameter and 0.9% were greater than 1 cm. The larger polyps were frequently pedunculated and occasionally showed a tubulo-villous or villous pattern. A structural similarity between the larger metaplastic polyps and colorectal adenomas is illustrated and the importance of the distinction of metaplastic from dysplastic epithelium in the differentiation of these lesions is stressed. Other unusual features of metaplastic polyps are described. Evidence is given to suggest that males have a greater propensity to develop metaplastic polyps than females. A search for metaplastic-like areas in other colorectal polyps revealed that they are rare (0.6%) in adenomas, but relatively frequent (20.8%) in juvenile polyps. Finally, seven patients with multiple metaplastic polyps of the colorectum are described, in whom a diagnosis of adenomatous polyposis had been made at some stage in their management. Six of the seven patients were males and the mean age at presentation was 37.4 years. Larger metaplastic polyps were frequent in these cases. The necessity for histological confirmation in all cases of intestinal polyposis is stressed, and the possibility that 'metaplastic polyposis' is a pathological entity is discussed.     

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.     

Ganglioneuromatous proliferation associated with juvenile polyposis coli

A case of nonfamilial juvenile polyposis coli was associated ganglioneuromatous proliferation in the polyps is described. The ganglioneuromatous proliferation was characterized by clusters of mature ganglion cells and nerve fiber bundles in the lamina propria and submucosa of the juvenile polyps. The patient had no history of von Recklinghausen's disease or multiple endocrine neoplasia syndrome, type 2b. The implications of this peculiar finding are discussed and the literature is reviewed.