Lipomatosis coli,a mimicker of familial polyposis

Multiple intestinal lipomas (lipomatous polyposis) are quite rare, and they can be quite challenging to diagnose because this condition may be clinically confused with familial adenomatous polyposis with a suggestive family history. Herein, we present a case of lipomatous polyposis that was presented with abdominal pain and, in colonoscopy, had more than 100 polyps. The patient was admitted for surgery with diagnosis of familial polyposis. Resected colon specimen had multiple polyps ranging from 0.1 to 1.5 cm. Microscopically, the polyps were composed of mature adipose tissue with normal overlying mucosa. There were also increased fat cells in the submucosa of the colon adjacent to the polyps. Lipomatous polyposis rarely occurs and can be confused with familial polyposis. Polypectomy is a simple and cost-effective procedure to help in diagnosis and prevent a major surgery.     

Frequent CpG island methylation in sporadic and syndromic gastric fundic gland polyps

We studied methylation of 2 tumor suppressor genes (p14, p16) and 4 MINT (methylated in tumor) clones (MINT1, MINT2, MINT25, MINT31) among 51 fundic gland polyps (FGPs) and 27 normal gastric body biopsy samples using bisulfite treatment of genomic DNA followed by methylation-specific polymerase chain reaction. Thirty-two FGPs were syndromic polyps from 14 patients with familial adenomatous polyposis (FAP); 19 were sporadic FGPs from 15 patients without FAP. Significantly higher mean methylation indices were found between FGPs and normal gastric mucosa (P = .012). FGPs arising in a background of proton pump inhibitor (PPI) effect had significantly higher mean methylation indices than those that did not (P = .023). Perhaps because sporadic FGPs were more likely to be associated with PPI effect than were FAP-associated FGPs, they also demonstrated higher mean methylation indices than syndromic polyps (P = .024). Among FAP-associated FGPs, there was no statistical difference in methylation indices between polyps that were dysplastic, indefinite for dysplasia, or nondysplastic (P = .87). Epigenetic alterations involving methylation of CpG islands might have a role in the development of some FGPs, particularly those with a PPI effect. They do not account for the presence or absence of a dysplastic phenotype in FGPs.     

Diffuse filiform polyposis with unique histology mimicking familial adenomatous polyposis in a patient without inflammatory bowel disease

Filiform polyposis is an uncommon entity that is most often encountered in the colon of patients with a history of inflammatory bowel disease (IBD). Filiform polyposis is characterized by a large number of "wormlike" polyps lined by histologically normal colonic mucosa. These polyps can mimic adenomatous polyps. Only rare cases without a history or evidence of IBD have been reported. Neuromuscular and vascular hamartoma of the small bowel is a rare, focal disorder characterized by disorganized smooth muscle fascicles throughout the submucosa accompanied by fibrosis, nerve fibers, ganglion cells, and vessels. To our knowledge, there is only one report of this lesion in the large bowel (cecum), where it presented as a mass. Here we report the case of a 50-year-old man with no known history or symptoms of IBD presenting with filiform polyposis involving the entire colon, clinically mimicking familial adenomatous polyposis, and showing histologic features similar to neuromuscular and vascular hamartoma of the small bowel.     

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.     

Decreased activity of hepatic uroporphyrinogen decarboxylase in sporadic porphyria cutanea tarda

To investigate the role of uroporphyrinogen decarboxylase in the pathogenesis of the sporadic form of porphyria cutanea tarda, we measured this enzyme in liver, erythrocytes and cultured skin fibroblasts, and also measured coproporphyrinogen oxidase and the total iron concentration in liver. The mean uroporphyrinogen decarboxylase activity was lower in liver from seven male patients (9.0 pmol of coproporphyrin per minute per milligram of protein) than in 12 controls, including seven with alcoholic liver disease (22.3 pmol per minute per milligram; P less than 0.05). Coproporphyrinogen oxidase activities were the same in each group. Liver iron concentrations were lower during remission, but uroporphyrinogen decarboxylase activities were not related to clinical activity for uroporphyrin excretion. Erythrocyte and fibroblast enzyme activities were the same as in normal subjects. A hepatic uroporphyrinogen decarboxylase defect is a prerequisite for the development of porphyria cutanea tarda, but other factors, which probably do not alter uroporphyrinogen decarboxylase activity, determine the clinical onset. In sporadic porphyria cutaneous tarda, the enzyme defect appears to be restricted to the liver.     

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.     

Terminal deoxynucleotidyl transferase activity in malignant lymphomas.

To determine the usefulness of terminal deoxynucleotidyl transferase enzyme activity as a biochemical marker in the study of lymphoma, we assayed 50 various malignant lymphomas as well as normal lymphoid tissue for this activity. Neoplastic cells from patients with Hodgkin's disease, Burkitt's tumor, Sézary's syndrome, chronic lymphocytic leukemia, leukemic reticuloendotheliosis and lymphocytic lymphomas (poorly differentiated and intermediate) were all without notable enzyme activity. Large-cell tumors of B-cell type were also negative. One of three large-cell tumors without B-cell or T-cell-surface specificity was positive (1.40 nmol per hour per milligram of DNA). Enzyme activity was consistently present only in lymphoblastic lymphomas (all six cases studied), with a mean activity of 7.80 nmol per hour per milligram of DNA. These six cases had heterogeneous surface immunomarkers. We conclude that terminal deoxynucleotidyl transferase is a biochemical marker that will be useful in the study of lymphoma.     

Fumarase deficiency: a new cause of mitochondrial encephalomyopathy

We observed a deficiency of both the mitochondrial and cytosolic forms of fumarase in a male infant with mitochondrial encephalomyopathy who presented at one month of age with failure to thrive, developmental delay, hypotonia, cerebral atrophy, lactic and pyruvic acidemia, and fumaric aciduria. The patient died at eight months of age. Isolated skeletal-muscle mitochondria showed selective defects in the oxidation of glutamate (31 ng atoms of oxygen consumed per minute per milligram of mitochondrial protein, as compared with 94 +/- 19 [mean +/- SD] in five controls) and of succinate (18 vs. 145 +/- 18 ng atoms of oxygen per minute per milligram of protein), whereas isolated liver mitochondria oxidized these and other substrates normally. Fumarase activity was virtually absent in both liver mitochondria (53 vs. 2878 +/- 248 nmol per minute per milligram of protein [5 controls]) and skeletal-muscle mitochondria (23 vs. 1997 +/- 717 nmol per minute per milligram [12 controls]). Seventeen other mitochondrial enzymes had normal activity in both liver and muscle mitochondrial extracts. Fumarase activity was also significantly reduced in homogenates of liver tissue (less than 1 vs. 90 +/- 25 mumol per minute per gram of wet weight [five controls]) and skeletal muscle (less than 1 vs. 21 +/- 4 mumol per minute per gram [five controls]), indicating a deficiency of both mitochondrial and cytosolic fumarases. Organ differences in intramitochondrial accumulation of fumarate may have accounted for the selective oxidative defects observed in the skeletal-muscle mitochondria but not liver mitochondria. All these findings are consistent with a profound combined fumarase deficiency.     

Genetic analysis of an inherited predisposition to colon cancer in a family with a variable number of adenomatous polyps

We studied a large kindred with a history of colorectal cancer of early onset. Proctosigmoidoscopic examination of 51 family members identified only 2 with familial polyposis coli, which strongly predisposes those who have it to colorectal cancer and which is defined as the presence of more than 100 polyps in the colon. However, eight family members had 2 to 40 colonic polyps. We suspected that in this family, colorectal cancer was the result of a mutation in the gene on chromosome 5 that is responsible for familial polyposis coli. To test our hypothesis, we obtained genotypic information on 81 family members with respect to seven polymorphic DNA markers previously shown to be linked to the locus for familial polyposis coli. Multilocus analysis of the data demonstrated genetic linkage (lod score, 5.58) between these markers and the locus responsible for the defined syndrome of colonic polyps or colorectal cancer in this kindred. These findings constitute evidence that the genetic defect in this family is a mutation in the gene that causes familial polyposis coli. We conclude that mutations at the genetic locus for familial polyposis coli may be the cause of other, more subtle syndromes involving an inherited susceptibility to colonic adenomatous polyps and colorectal cancer.     

Transiently reduced activity of carbamyl phosphate synthetase and ornithine transcarbamylase in liver of children with Reye's syndrome.

Since Reye's syndrome is associated with hyperammonemia, we measured the urea-cycle enzymes in hepatic tissue of 13 patients. Expressed as nanomoles of citrulline per milligram of hepatic protein per minute, mean activity of carbamyl phosphate synthetase (6.27 +/- 2.45 S.D.) and ornithine transcarbamylase (136.19 +/- 41.83) in Reye's syndrome was reduced significantly (P less than 0.005) when compared with that of 25 "normal" controls (11.54 +/- 4.24 and 307.49 +/- 94.15, respectively). Activity was maximally reduced during the first days of clinical symptoms; it returned toward normal during the following week regardless of whether the disease ended in death or recovery. The activity of the two enzymes was normal in patients with salicylate intoxication or heritable argininosuccinic acid synthetase deficiency. The apparent Km of hepatic ornithine transcarbamylase for ornithine was in the normal range in patients with Reye's syndrome (mean 0.24 mM). These observations indicate that Reye's syndrome is associated with acquired and transient dysfunction of hepatic mitochondrial urea-cycle enzymes.     

Ultrastructural features of the colonic epithelium in familial polyposis coli

Colectomy specimens from 6 cases of familial polyposis coli (FPC) were examined. Macroscopically normal mucosa between polyps was taken at intervals along the ascending, transverse and descending colons and studied at EM level. All three regions show the same cell populations varying only in their ratio and height of the epithelium. The same cell types seen in the normal crypt epithelium are present in the mucosa from FPC. As in the normal, 'intermediate' cells are present in FPC but they are less conspicuous than in the mucosa adjacent to colonic carcinoma. However, there are ultrastructural features which distinguish the "normal" mucosa in FPC from the true normal: (a) the presence of "clear columnar" cells; (b) increased vesiculation in the absorptive cells; (c) large number of lysosomes; and (d) the presence of small electron-dense bodies. The ultrastructure of the "clear columnar" cells suggests their being incompletely differentiated cells, thus raising the possibility that their presence in the upper crypt and surface epithelium may represent an early stage in the process of polyp and cancer formation.     

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.     

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.     

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.     

Expression of histocompatibility antigens and characterization of the lymphocyte infiltrate in hyperplastic polyps of the large bowel

HLA-DR expression, lymphocyte subsets, and the distribution of proliferating cells were studied in hyperplastic polyps from the colorectum. The density of T-cells (CD5+) (mean of cells/mm2 of tissue +/- SEM) was higher in the lamina propria of hyperplastic polyps (64.2 +/- 4.2) than in normal colonic mucosa (36.7 +/- 2.6, P less than .001). The CD4/CD8 ratio was higher in hyperplastic polyps (6.3 +/- 0.9, P less than .0001) and in colonic adenomas (5.9 +/- 0.9, P less than .001) compared with normal mucosa (2.3 +/- 0.2). Lymphocytes of the lamina propria were never Ki-67 positive either in normal mucosa or in hyperplastic polyps or adenomas. The epithelial layer of hyperplastic polyps and of normal mucosa did not express the HLA-DR antigen, whereas pericryptal fibroblasts and most of the leukocytes of the lamina propria were strongly positive for this antigen. In the epithelial layer proliferating cells were localized exclusively in the lower part of epithelial crypts, as was the case in normal mucosa, whereas in adenomas Ki-67-positive cells were present throughout the entire height of the mucosa. Thus, in hyperplastic polyps lymphocytes are increased in the lamina propria, with a predominance of the CD4 subset in close contact with HLA-DR positive pericryptal fibroblasts.     

Dominant inheritance of adenomatous colonic polyps and colorectal cancer

Except in the rare polyposis syndromes, the contribution of heritable factors to the genesis of colorectal cancer and adenomatous polyps is not well understood. We examined the inheritance of susceptibility to colonic polyps and cancer in a large Utah pedigree with multiple cases of common colorectal cancer but no recognizable inheritance pattern among them. Inheritance was clarified, however, by systematic screening for colonic polyps in pedigree members and spouse controls, using flexible proctosigmoidoscopy. One or more adenomatous polyps were found in 21 per cent of family members (41 of 191) but in only 9 per cent of controls (12 of 132) (P less than 0.005). Pedigree analysis was performed with likelihood methods that compared random occurrence of cancer and polyps with autosomal recessive and autosomal dominant patterns of inheritance. The analysis suggested that the observed excess of discrete adenomatous polyps and colorectal cancers was the result of an inherited autosomal dominant gene for susceptibility, rather than an inherited recessive gene for susceptibility or a chance occurrence. This type of inheritance of colorectal polyps and cancer may be more common than previously recognized.     

Quantitative biomarkers of colonic dysplasia based on intrinsic second-harmonic generation signal

Most colorectal cancers arise from dysplastic lesions, such as adenomatous polyps, and these lesions are difficult to be detected by the current endoscopic screening approaches. Here, we present the use of an intrinsic second-harmonic generation (SHG) signal as a novel means to differentiate between normal and dysplastic human colonic tissues. We find that the SHG signal can quantitatively identify collagen change associated with colonic dysplasia that is indiscernible by conventional pathologic techniques. By comparing normal with dysplastic mucosa, there were significant differences in collagen density and collagen fiber direction, providing substantial potential to become quantitative intrinsic biomarkers for in vivo clinical diagnosis of colonic dysplasia.     

Abnormal red-cell calcium pump in patients with idiopathic hypercalciuria

Idiopathic hypercalciuria is a common disorder whose inheritance suggests an enzyme abnormality in calcium transport. We measured calcium-magnesium-ATPase activity in erythrocytes from 38 patients (mean age [+/- SEM], 40 +/- 2.1 years) with idiopathic hypercalciuria (24-hour urinary calcium excretion greater than or equal to 0.1 mmol per kilogram of body weight) and a history of multiple calcium oxalate kidney stones. As compared with 41 healthy controls, the patients with hypercalciuria had increased erythrocyte-membrane calcium-magnesium-ATPase activity (64.2 +/- 2.19 vs. 51.6 +/- 1.91 nmol of ATP split per milligram per minute; P less than 0.01) and increased sodium-potassium pump activity (6866 +/- 233 vs. 6096 +/- 228 mumol of sodium per liter of red cells per hour; P less than 0.05). No significant difference between the two groups was found in erythrocyte sodium-potassium cotransport, sodium-lithium countertransport, or potassium content. In 66 patients with kidney stones (38 with hypercalciuria and 28 with normal calcium excretion), 24-hour urinary calcium excretion correlated with calcium-magnesium-ATPase activity (r = 0.46, P less than 0.001). Erythrocyte calcium-magnesium-ATPase activity remained unchanged in eight subjects studied after four months on a low-calcium diet. A study of 30 healthy families found significant correlations between mean values in parents and those in offspring for calcium-magnesium-ATPase (r = 0.68, P less than 0.001) and urinary calcium excretion (r = 0.45, P less than 0.02), with no significant correlations between parents with respect to these measures (r = 0.27 and r = 0.08, respectively). We conclude that abnormalities in erythrocyte calcium-magnesium-ATPase activity may represent an inherited defect in calcium transport related to the cause of idiopathic hypercalciuria.     

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.     

Colonic and duodenal flat adenomas in children with classical familial adenomatous polyposis

Flat adenomas of the colon and duodenum have been described as associating with familial adenomatous polyposis (FAP), its attenuated variant, and the so-called hereditary nonpolyposis colorectal cancer. There seem to be no report on the occurrence of flat adenomas in pediatric patients with family history of FAP. We are reporting 4 children from 2 cancer-prone families in whom colonic and duodenal moderately dysplastic flat adenomas were found. Gastrointestinal endoscopy and biopsies were performed in 3 female siblings (7, 9, and 11 years old) and 1 male (9 years old) when referred for screening owing to familial history of bowel cancer (family 1) or evidence of bilateral congenital hypertrophy of the retinal pigment epithelium (CHRPE), which is known to be associated with FAP (family 2). Endoscopic visualization of the mucosa was improved by use of 0.2% indigo carmine solution spray. Biopsies were routinely processed for H&E and immunohistochemistry staining. Present patients were asymptomatic, with the exception of 2 weeks rectal bleeding in 1 of them. The colonic videoendoscopy showed in 2/3 siblings hundreds of flat or slightly raised plaques less than 1 cm in diameter as well as some classic polyps throughout the colon. The other sibling showed 40 flat-topped lesions with minimal elevation and central umbilication in the cecum. Upper endoscopy demonstrated a few flat lesions in the nonperiampullary area of the duodenum in 2/4 patients. The colonic videoendoscopy performed on the 9-year-old boy revealed multiple small sessile polyps. Microscopic study demonstrated tubular adenomas with a few neoplastic crypts, slight disarray of the overall architecture, and moderate (low-grade) dysplasia of the epithelium. These features were more obvious at the center and superficial areas of the adenomas. The 4 children had multiple flat adenomas of the colon and duodenum (2/4) matching with those described in adult patients. Flat adenomas in the context of FAP probably represent early stages of the adenoma development. Careful endoscopic-histologic correlation may result in increasing recognition of these lesions at the pediatric age.