Cell proliferation and ultrastructural changes of the duodenal mucosa of patients affected by familial adenomatous polyposis

Patients affected by familial adenomatous polyposis (FAP) are at risk of developing duodenal neoplasia. Our objective was to detect early abnormalities of the epithelial cell proliferation and ultrastructure of apparently normal duodenal mucosa of FAP patients. Biopsy specimens were taken from the duodenal mucosa. Cell proliferation was studied by immunohistochemistry with proliferating cell nuclear antigen (PCNA), and ultrastructure, by transmission electron microscopy. We found that the PCNA labeling index for duodenal mucosa of patients with FAP was higher in comparison to the case of hospital controls without cancer risk (P = 0.019). Moreover, ultrastructural changes related to an impairment of cell adhesion function were found in all biopsies of FAP patients but not in the duodenal mucosa of the controls. We conclude that alterations of cell proliferation kinetics and epithelial adherens junction structures were phenotypic characteristics of histologically normal duodenal mucosa of FAP patients. These abnormalities may be considered as intermediate biomarkers of neoplasia and potential surrogate endpoints in chemoprevention studies.     

Ornithine decarboxylase as a biologic marker in familial colonic polyposis

We investigated whether the activity of ornithine decarboxylase might serve as a diagnostic test for detecting the presence of the genotype for familial polyposis. This rate-limiting enzyme in the polyamine biosynthetic pathway is essential for intestinal mucosal proliferation. In colonic mucosa from 16 normal controls, ornithine decarboxylase activity was less than 2.5 nmol per milligram per hour. In contrast, it was higher than 2.5 nmol per milligram per hour in the normal-appearing areas of colonic mucosa from 11 of 13 patients with familial polyposis and in all polyps biopsied from these same subjects (P less than 0.05 for specimens from both sites, as compared with controls). Mucosa from dysplastic polyps showed higher mean ornithine decarboxylase activity than mucosa from polyps that were not dysplastic (P less than 0.05). In colonic mucosa from clinically unaffected, first-degree relatives of patients with familial polyposis, there was a bimodal distribution of ornithine decarboxylase activity, with one peak at the mean for normal controls and the other near the mean for normal-appearing mucosa from affected patients. Our study suggests that ornithine decarboxylase activity in colonic mucosa may reflect the abnormal proliferative state in familial polyposis and identify clinically normal family members who carry the genotype.     

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.     

Mucin expression in the ileoanal reservoir reflects incomplete mucosal adaptation

Restorative proctocolectomy is regarded as a standard surgical procedure for patients who require a proctocolectomy for ulcerative colitis and familial adenomatous polyposis. The ileal mucosa undergoes colonic phenotypic change with time, but the extent and relevance of these changes to the long-term safety of the ileoanal pouch are unclear. The aim of this study was to study the mucin biology of this adaptive process in order to assess its extent and possible impact on pouch safety. Ileoanal pouch biopsies from a cohort of patients and normal ileal and colonic controls were subjected to histological, biochemical, histochemical, and immunohistochemical mucin analysis. Mucin sulphation and sialic acid O-acetylation were studied as parameters of colonic phenotypic change. Fifty-one patients, 16 ileal, and 22 colonic controls were studied. Seventy per cent of biopsies retained villous mucosal architecture, with no cases of dysplasia detected. Ileoanal pouch mucosal sulphation and sialic acid O-acetylation did not reach colonic levels, thus indicating limited evidence for a more colonic phenotype. The data from this study suggest that colonic phenotypic change within the ileoanal reservoir is incomplete, with no cases of dysplasia detected. The degree of phenotypic change is less than in previous studies, which may support, but not prove, our hypothesis that there may be a process of reversion to an ileal type mucosa in the ileoanal reservoir with time.     

Colonic aberrant crypts in children with familial adenomatous polyposis

Aberrant crypt foci of the colonic mucosa have been reported in adults. The alteration may be defined macroscopically or histologically and may or may not be combined with adenomatous changes. Aberrant crypt foci have been regarded as precancerous lesions and are more common in patients with familial adenomatous polyposis. The present report describes the presence of many histologically recognizable aberrant crypt foci without adenomatous changes in the colonic mucosa of 3 children with familial adenomatous polyposis. The openings of the aberrant crypt foci contained inspissated granulofilamentous mucus. Additionally, this report documents the presence of a peculiar serrated appearance of the mucosae surface outline of the nonadenomatous areas. This appears to result from elongation of the crypts and dilated openings/micropapillary arrangement of the uppermost part of the walls of the crypts, with a thin intervening stroma. Neither of these findings has been reported previously to occur in children. They may represent the earliest histologically identifiable changes ever recorded in the colon of patients with familial adenomatous polyposis.     

Nasal mucosal gene expression in patients with allergic rhinitis with and without nasal polyps

BACKGROUND: Nasal polyps are a common problem that is difficult to diagnose and treat, in part because the cause of nasal polyposis is unknown. Although information on the pathogenesis of polyposis is lacking, there are reports suggesting that a genetic predisposition underlies this disorder. OBJECTIVE: We sought to better understand the basis of nasal polyposis associated with allergic rhinitis. We hypothesize that the expression of unique genes is associated with the nasal polyposis phenotype. METHODS: We examined 12000 human genes transcribed in the nasal mucosa of patients with allergic rhinitis with and without nasal polyps. Biopsy specimens of the mucosa of patients with and without polyps were obtained after the patients refrained from the use of topical or systemic steroid therapy for 2 weeks. RESULTS: Thirty-four genes were differentially expressed between the patient groups, including those for inflammatory molecules and putative growth factors. The greatest differential expression identified by the array analysis was for a group of genes associated with neoplasia, including mammaglobin, a gene transcribed 12-fold higher in patients with polyps compared with control patients with rhinitis alone. Quantitative RT-PCR confirmed this differential expression and documented that the number of mammaglobin mRNA copies is actually 64-fold greater in tissues of patients with polyps versus control patients. The specificity of mammaglobin protein expression was evaluated by means of immunohistochemistry, which showed specific staining in nasal polyp mucosal goblet cells only in patients with polyps. CONCLUSION: These data suggest that nasal polyposis involves deregulated cell growth, using gene activation in some ways similar to a neoplasm. In addition, mammaglobin, a gene of unknown function associated with breast neoplasia, might be related to polyp growth.     

Incomplete intestinal metaplasia in the diagnosis of columnar lined esophagus (Barrett's esophagus)

To investigate the distribution and specificity of intestinal metaplasia (IM) in columnar lined esophagus (CLE), the authors reviewed biopsies of the hiatal hernia pouch (HHP) and esophagus from 17 patients with CLE (84 biopsies) and 10 controls (25 biopsies). The proximal margin of the gastric folds was used as an endoscopic landmark, corresponding to the gastroesophageal muscular junction (GEMJ). No biopsies obtained above the GEMJ in control patients showed columnar mucosa. No goblet cell metaplasia was seen in 21 biopsies of the HHP from patients with CLE or in 13 corresponding biopsies from controls. In contrast, alcian blue (AB) stains showed diffuse acid mucins in 3 of 21 biopsies of the HHP from patients with CLE and in 10 of 13 corresponding biopsies from controls, demonstrating that goblet cell metaplasia clearly distinguishes biopsies of CLE from the HHP (P less than 0.01), whereas small amounts of diffuse acid mucin on AB stains do not. IM evidenced by goblet cell metaplasia was frequently seen in biopsies only 2-3 cm above the GEMJ, and CLE was limited to that area in three patients, suggesting that the distal esophagus cannot be dismissed as a site for metaplastic and possibly premalignant mucosa. Adenocarcinoma was diagnosed during the course of the study in one patient with only 5 cm of columnar mucosa above the GEMJ.     

The expression of E-cadherin and catenins in colorectal tumours from familial adenomatous polyposis patients

Familial adenomatous polyposis patients (FAP) harbour a germline mutation of the adenomatous polyposis coli gene (APC), and APC mutations are early events in the development of sporadic colorectal neoplasms. The APC protein interacts with beta-catenin and gamma-catenin and APC mutations are believed to play a role in the altered levels of beta-catenin in colorectal tumours. Immunohistochemical studies have shown changes in the expression and distribution of E-cadherin and catenins in sporadic colorectal neoplasms. This study assessed the expression and distribution of E-cadherin and catenins in colorectal neoplasms and non-neoplastic mucosa from FAP patients. The expression and cellular distribution of E-cadherin and catenins were studied by immunohistochemistry in 61 adenomas, five carcinomas, and non-neoplastic mucosa from 18 FAP patients. mRNA levels in the carcinomas were studied by in situ hybridization. The expression of E-cadherin and catenins was increased in over 80% of the adenomas, with evident cytoplasmic immunoreactivity. There was increased expression of E-cadherin and catenin in the carcinomas, with a notable increase in the levels of mRNA, in comparison with the non-neoplastic mucosa.     

Qualitative assessment and morphometry in the study of the ileal reservoir after restorative proctocolectomy

Little is known about the long-term effects on the reservoir mucosa in patients with ulcerative colitis and familial polyposis coli who undergo proctocolectomy with subsequent construction of ileal reservoir/pouch and ileoanal anastomosis. In these patients, questions regarding adaptation towards a more colon-like mucosa and/or development of (pre)malignant changes are of particular importance. With the aim of designing a method for reliable evaluation of the mucosa in the ileal pouch, biopsies from 10 patients were studied by semiquantitative assessment and morphometry. The findings were compared with those obtained from normal jejunum, ileum, and colon. The following parameters were found to be important: Villous surface density, quantity of goblet cells, number of mitoses, and the presence/absence of predominantly sulphated mucin+ goblet cells. The number of Paneth cells did not show significant changes. The villous surface density was determined by a cycloid test system applied to vertical sections. Semiquantitative assessment was a sufficiently precise method for the evaluation of the quantity of goblet cells. The counting of sulphated mucin+ goblet cells was not reproducible, instead a simple statement about the presence or absence of these cells was judged to be adequate. The number of mitoses and of Paneth cells were counted directly. During the first year of function the ileal pouch showed signs of adaptation towards a colon-like mucosa: Reduction of villous surface density, increased mitotic activity, and appearance of sulphated mucin+ goblet cells. The number of Paneth cells did not show significant changes. The amount of goblet cells was generally not increased, rather reduced in some patients.     

Histologic changes of the gastric mucosa associated with primary gastric lymphoma in endoscopic biopsy specimens

CONTEXT: Recently, we have observed intestinal metaplasia, atrophy, and dysplasia in the mucosa adjacent to primary gastric lymphoma (PGL) in gastrectomy specimens. OBJECTIVE: To determine the frequency and type of epithelial disorders at the histopathologic level in the mucosa adjacent to PGL in endoscopic specimens. DESIGN: We studied 54 endoscopic biopsies from patients harboring PGL. We searched for the following morphologic changes in the gastric mucosa: intestinal metaplasia; atrophy; dysplasia; epithelial erosion; and atypical regeneration of the glandular epithelium. Other nonepithelial findings such as lymphoid follicles, Helicobacter pylori, and lymphoma grade, were also recorded. For comparative purposes, 50 endoscopic biopsies with gastric adenocarcinoma and 50 biopsies with chronic gastritis associated with H pylori infection were also studied. RESULTS: The 54 biopsies included 28 (52%) low-grade and 26 (48%) high-grade PGLs. We found intestinal metaplasia in 32 biopsies (59%), atrophy in 20 biopsies (37%), dysplasia in 2 biopsies (4%), erosion of the epithelium in 33 biopsies (61%), and atypical regenerative changes of the glandular epithelium in 10 biopsies (19%). Lymphoid follicles were found in 21 biopsies (39%), and H pylori was demonstrated in 31 biopsies (57%). When groups were compared, the frequency of epithelial changes in biopsies from patients with PGL and adenocarcinoma was similar. Intestinal metaplasia or atrophy were present in only 10% of biopsies from patients with gastritis, and dysplastic glands were not identified. CONCLUSIONS: Biopsies from patients with PGL showed chronic damage of the gastric mucosa at diagnosis, including precancerous conditions. Intestinal metaplasia and atrophy were among the most frequent disorders, but dysplasia was also occasionally present. Endoscopists and pathologists must be acquainted with such changes and look for them in the initial biopsy, as well in subsequent samples. This practice is particularly important when reviewing biopsies from patients with low-grade mucosa-associated lymphoid tissue (MALT)-lymphomas who are eligible for eradication treatment for H pylori.     

Risk factors for carcinoma of the pelvic ileal pouch/anal canal in ulcerative colitis

Patients with ulcerative colitis who undergo proctocolectomy and an ileal anal anastomosis (IPAA) require surveillance; dysplasia and carcinoma occur in both the small intestinal mucosa of the ileal pouch and the retained rectal mucosa as early as 2 yr after ileostomy closure. This study evaluated risk factors for carcinoma (eg, dysplasia, p53 overexpression, labeling index, and aneuploidy) in the small intestinal and rectal mucosa. Thirty patients (age 14-64 yr) with ulcerative colitis and IPAA were studied. The mean duration of ulcerative colitis prior to IPAA was 3 yr (range 6 mo-21 yr). Patients were followed by annual endoscopy and biopsies of the ileal pouch and rectal mucosa. Sections of small intestine and rectal mucosa were evaluated for inflammation and dysplasia, and by immunohistochemical stains Ki-67 (MIB-1) for a labeling index and for p53. Ploidy determination was performed by flow cytometry. Active inflammation of the small intestinal mucosa and the rectal mucosa was frequent and the labeling index of both the pouch and rectal mucosa was abnormal. Two patients had changes indefinite for dysplasia, one involving the small bowel mucosa of the pouch and the other the retained rectal mucosa. Fifteen of the 30 patients had overexpression of p53, 9 from the pouch, and 6 from the rectal mucosa. Overexpression of p53 was seen in both of the patients with indefinite dysplasia. Aneuploidy was noted in 3 patients: two from the pouch and one from the rectal mucosa. All aneuploidic specimens were p53-positive, but negative for dysplasia. In conclusion, most biopsies of the ileal pouch and rectal mucosa were inflamed. The labeling indexes of the small bowel and rectal mucosa were higher than normal. The risk factors for carcinoma (dysplasia, overexpression of p53, and aneuploidy) occurred in the small intestinal and the rectal mucosa. Overexpression of p53 was noted in 16 patients, dysplasia only in 2. Therefore, p53 overexpression and aneuploidy should be considered in the evaluation of surveillance biopsies of patients with ulcerative colitis with IPAA, whereas dysplasia is an insensitive marker.     

Antralization of the gastric mucosa of the incisura angularis and its gastrin expression

The frequency of antrum-type mucosa and gastrin expression in gastric biopsies from the incisura angularis was assessed in 60 consecutive patients having gastrointestinal symptoms. Following the recommendations from the updated Sydney System for the classification and grading of gastritis, two biopsies were taken from the antrum, one from the incisura and two from the corpus. Sections were stained with H&E, Giemsa and for gastrin. Gastrin-positive cells were semi-quantified as: 0 (none), /=50 gastrin-labelled cells/40x field. Antrum-type mucosa at the incisura (called antralization) occurred in 30% of the biopsies without inflammation, but in 69% of those with H. pylori-induced gastritis, and in 64% of those with autoimmune gastritis. At the incisura, gastrin-labelled cells (>/=10) were found in 62% (18/29) of biopsies showing antralization, but in only 20% (3/15) of those having transitional-type mucosa (p<0.05) and in none of the 16 biopsies having fundic-type mucosa. The similarity in gastrin expression between the mucosa of the gastric antrum and the antral-type mucosa at the incisura substantiates the notion that antralization is a metaplastic transformation. The significantly higher frequency of antral-type mucosa at the incisura in patients with gastritis than in those without gastritis strongly suggests that chronic inflammation per se triggers antralization of the incisura, irrespective of the presence or absence of H. pylori infection.     

Bilateral trephine bone marrow biopsies in Hodgkin's and non-Hodgkin's lymphoma.

This study was undertaken to investigate the usefulness of bilateral rather than unilateral iliac trephine biopsies in demonstrating Hodgkin's disease and non-Hodgkin's lymphoma in the bone marrow. One hundred and seventy adequate bilateral biopsies were obtained from 145 patients. Among 76 bilateral trephine biopsies from 65 patients with Hodgkin's disease, tumour was found bilaterally in 3 cases and on only one side in 2 cases. Among 94 bilateral biopsies from 80 patients with non-Hodgkin's lymphoma, tumour was found bilaterally in 17 cases and on only one side in 12. Considering all of the cases in the series, the performance of bilateral biopsy increased the yield of positive marrows from an estimate of 27 to 34, an increase of 26%. We conclude that bilateral trephine biopsy is superior to unilateral biopsy for the demonstration of bone marrow involvement by Hodgkin's disease or non-Hodgkin's lymphoma and recommend that bilateral trephine biopsies be performed when a knowledge of the state of the bone marrow is important for clinical decision making.     

Abnormal distribution of c-myc oncogene product in familial adenomatous polyposis.

Monoclonal antibodies raised by synthetic peptide immunisation were used to determine the distribution of the protein product of the c-myc gene by immunocytochemical staining of archival wax embedded material from patients with familial adenomatous polyposis. Polyps from 18 cases of familial adenomatous polyposis, 10 of whom had developed malignant change, and 30 normal control colonic biopsy specimens were examined. A consistent staining pattern was observed in normal mucosa; nuclear staining in the basal proliferative zone; mixed nuclear and cytoplasmic staining in the maturation zone; and cytoplasmic localisation in the surface mature zone. In contrast, the polyps and carcinomata showed a mixed pattern of cytoplasmic and nuclear localisation in the basal proliferative zone with nuclear persistence throughout the crypts to the surface mature zone. This abnormal distribution of the c-myc oncogene product may have a role in the evolution of polyps and their subsequent malignant transformation into familial adenomatous polyposis.     

Electron microscopic studies of endocrine hyperplasia in duodenal adenomas in familial adenomatous polyposis

Summary Electron microscopical studies on endocrine cell hyperplasia of duodenal adenomas from five patients with familial adenomatous polyposis were performed. All the endocrine cell types normally found in the duodenal mucosa were identified. A constant feature was proliferation of duodenal-enterochromaffin cells but an increase in the number of all other endocrine cell types apart from pyloricgastrin cells and somatostatin cells, was also observed. Certain types of intestinal endocrine cells (the intestinal enterochromaffin cell and the glicentin cell) are rare cells in the normal duodenal mucosa. The finding of these cells may indicate increased biological aggressivity.     

Diffuse giant inflammatory polyposis: a challenging clinicopathologic diagnosis

Giant inflammatory polyposis of the colon is an uncommon manifestation of inflammatory bowel disease. We report a unique case of localized diffuse giant inflammatory polyposis in a 58-year-old white man, which was characterized by recurrence following initial surgical resection. The patient presented with symptoms of abdominal pain and passing blood per rectum. Colonoscopic examination revealed a near-obstructing, "fungating" mass in the sigmoid colon, which clinically was thought to represent colon carcinoma. Histology of several colon biopsies revealed marked acute inflammation with microabscess formation of the polyps and the adjacent mucosa. There was no evidence of dysplasia or malignancy. Because malignancy was strongly suspected and to relieve the obstructive symptoms, the patient underwent a segmental colectomy. The histologic features of the resected mass showed giant polyps with acute inflammation diagnostic of giant inflammatory polyposis. Again, there was no evidence of malignancy. Seven months later, following an uneventful initial postoperative recovery, the patient developed a recurrence of the mass with obstructive symptoms and required further surgical resection. The gross and histologic features of the lesion were similar to the previous findings. This case highlights the varied presenting symptoms and deceptive gross colonoscopic and radiologic features of localized diffuse giant inflammatory polyposis. Finally, the presence of inflammation at the resection margins appears to predict recurrence or persistence of the disease.     

Restorative proctocolectomy with ileal reservoir: pathological and histochemical study of mucosal biopsy specimens.

Mucosal biopsy specimens from the ileal reservoirs of 92 patients who had undergone restorative proctocolectomy (12 with familial adenomatous polyposis, 78 with ulcerative colitis, and two with functional bowel disease) were studied. Chronic inflammation was found in almost all, as was villous atrophy of varying severity. Other changes included pyloric metaplasia and mucosal prolapse. Acute inflammatory changes and ulceration were less common but, when present, corresponded to the clinical condition of "pouchitis". A grading system was devised to score acute and chronic inflammatory changes. There was a significant increase in acute inflammatory scores in ulcerative colitis compared with those in familial adenomatous polyposis, and pouchitis was present only in patients who had had ulcerative colitis; the morphological features of pouchitis are similar to those seen in the colorectal mucosa in ulcerative colitis. Histochemical studies of mucin in the reservoirs of mucosa showed that there may have been a change from small intestinal mucin to colonic mucin.     

Human gut mucosal mast cells: ultrastructural observations and anatomic variation in mast cell-nerve associations in vivo.

One hundred and seventeen coded intestinal biopsy specimens were examined by electron microscopy. All surgical biopsies were obtained from uninvolved sites of patients with two inflammatory bowel diseases (ulcerative colitis or Crohn's disease) and from patients with preneoplastic and neoplastic diseases (adenocarcinoma, rectal polyp, familial polyposis). Biopsy sites included normal ileum, colon, and rectum as well as conventional ileostomies and continent pouches constructed from the ileum. The data reported here describe the ultrastructural anatomy of human gastrointestinal tract mucosal mast cells in vivo and their anatomic associations with enteric nerves.     

Diffuse colonic ganglioneuromatous polyposis

Ganglioneuromatous polyposis is a very rare intestinal disease which differs from isolated polypoid ganglioneuroma and from diffuse ganglioneuromatosis. Its clinical, endoscopic, microscopic and evolutive features are poorly known. We report three cases of colonic ganglioneuromatous polyposis that illustrated an uncommon diffusion pattern in two men and one woman aged 63-72 who presented with chronic diarrhea. Endoscopic features suggesting the diagnosis were diffuse polyposis predominating in the cecum and right colon, with hyperhemic flat lesions enhanced after indigocarmin instillation. Histological study of the biopsies, and of colectomy specimens, showed a diffuse mucosal ganglioneuromatous proliferation with a few adenomatous polyps. Search for multiple endocrine neoplasia (MEN) type 2b was negative. In conclusion, this polypoid type of diffuse ganglioneuromatosis can be suspected in patients with chronic diarrhea by the special endoscopic aspect of the colonic polyposis. Pathologists should be aware of the distinctive features; diagnosis requires search for adenomas and/or neoplasia by total colopsy in addition to search for MEN 2b.