Enhanced Cyclooxygenase-2 Expression in Sporadic and Familial Adenomatous Polyposis of the Human Colon

Background: The cyclooxygenase (COX) enzymes exist in two related but unique isoforms (COX-1 and COX-2) and catalyze the formation of prostaglandins (PGs). COX-1 is constitutively expressed, and is responsible for the synthesis of PGs necessary for gastroprotection and normal renal function. The COX-2 isoform is important in a variety of pathophysiological conditions such as inflammation and tumorigenesis. Numerous studies report that regular use of non-steroidal anti-inflammatory drugs (NSAIDs) can decrease the incidence of some tumor types, including gastrointestinal polyposis. Methods: In this study, we evaluated COX-1 and COX-2 expression in 30 polyps collected from 10 patients with familial adenomatous polyposis (FAP) and in 18 polyps collected from 18 patients with sporadic adenomatous polyposis (SAP) using COX-1 or COX-2 isoform-specific antibodies. All tissues were formalin-fixed and paraffin-embedded. Immunoreactivity was detected using tyramide signal amplification and evaluated utilizing an immunohistochemical scoring system. Results: COX-2 was minimally detected in the distant non-neoplastic epithelium, which also served as an internal negative control. In comparison, all polyps collected from SAP or FAP patients overexpressed COX-2 in the neoplastic epithelial cells (P     

Nine-year follow-up of a patient with attenuated familial adenomatous polyposis treated with cyclo-oxygenase-2 inhibitors

Familial adenomatous polyposis (FAP) is caused by germline mutations in the adenomatous polyposis coli (APC) gene with onset of florid polyposis in childhood and development of colorectal cancer by age 30. Colectomy is advised because of the high risk of developing colorectal cancer. Attenuated FAP (AFAP) is a variant of this condition with a later age of onset and milder clinical phenotype; however, colectomy is advised once polyposis develops and polyps cannot be managed endoscopically. We report a case of a patient with AFAP and previously resected colonic carcinoma that was treated with chemoprophylaxis with long-term cyclooxygenase-2 (COX-2) inhibitors after declining colectomy. Colonoscopic examination demonstrated regression of polyps by 18 months. After 9 years of follow-up, there was no evidence of colorectal cancer development or progression of polyposis. This is the first case report on long-term treatment with COX-2 inhibition in a patient with AFAP and previous colonic carcinoma.     

Nine-year follow-up of a patient with attenuated familial adenomatous polyposis treated with cyclo-oxygenase-2 inhibitors

Familial adenomatous polyposis (FAP) is caused by germline mutations in the adenomatous polyposis coli (APC) gene with onset of florid polyposis in childhood and development of colorectal cancer by age 30. Colectomy is advised because of the high risk of developing colorectal cancer. Attenuated FAP (AFAP) is a variant of this condition with a later age of onset and milder clinical phenotype; however, colectomy is advised once polyposis develops and polyps cannot be managed endoscopically. We report a case of a patient with AFAP and previously resected colonic carcinoma that was treated with chemoprophylaxis with long-term cyclooxygenase-2 (COX-2) inhibitors after declining colectomy. Colonoscopic examination demonstrated regression of polyps by 18 months. After 9 years of follow-up, there was no evidence of colorectal cancer development or progression of polyposis. This is the first case report on long-term treatment with COX-2 inhibition in a patient with AFAP and previous colonic carcinoma.     

Molecular and phenotypic markers of hamartomatous polyposis syndromes in the gastrointestinal tract.

Hamartomatous gastrointestinal polyposis syndromes have always been considered as non-neoplastic. Nevertheless, an increased cancer risk both within and outside the gastrointestinal tract may exist in these syndromes. The hamartomatous polyps may sometimes harbor dysplasia, but their neoplastic potential is unknown. The genetic defects causing the hamartomatous syndromes are less well established than, for example, familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer (HNPCC). The genetic studies on the Mendelian inherited syndromes FAP and HNPCC have made a major contribution to the identification of genes involved in colorectal tumorigenesis. The genes involved in colorectal cancer development may also contribute to cancer development in the hamartomatous polyposis syndromes, and are currently under investigation. Furthermore, new insights into the development of various cancers may be obtained by the isolation and characterization of genes involved in Mendelian inherited hamartomatous polyposis syndromes. This report summarizes the available literature on this subject, and describes the pheno- and genotypic features of the hamartomatous syndromes of juvenile polyposis, Peutz-Jeghers syndrome, and Cowden's disease.     

Gastric adenocarcinoma associated with fundic gland polyps in a patient with attenuated familial adenomatous polyposis

Familial adenomatous polyposis (FAP) is a rare autosomal dominant precancerous condition of the colon caused by mutations in the adenomatous polyposis coli (APC) tumor suppressor gene. FAP is characterized by the appearance of innumerable adenomatous polyps throughout the large bowel. Fundic gland polyps are the most common gastric lesion in FAP. It is generally believed that fundic gland polyps have little or no potential for malignant transformation in the population at large, and only a few case reports describe the development of high grade dysplasia or gastric adenocarcinoma associated with diffuse fundic gland polyposis in patients with FAP. We report the second case of gastric adenocarcinoma intimately associated with fundic gland polyposis in a family with an attenuated form of FAP. The patient had undergone routine screening per current guidelines because of his known mutation in the APC gene. This suggests that malignant transformation of fundic gland polyps in patients with FAP occur more frequently than previously believed. Current screening recommendations may not be sufficient for patients with FAP or its attenuated forms.     

Cyclooxygenase-2 Expression in the Hereditary Mixed Polyposis Syndrome

Hereditary mixed polyposis syndrome (HMPS), characterized by hyperplastic, juvenile, admixed, serrated adenomas and eventually colorectal cancer, is managed by repeated polypectomy and surgery. We determined if HMPS polyps express cyclooxygenase-2 (COX-2). Nineteen recent HMPS polyps, from five family members, were stained for COX-2. Polyps' epithelium and stroma and comparison tissues (normal colonic mucosa [9], sporadic juvenile polyps [18], colorectal cancers [3]) were quantified for COX-2 by: area of staining (0-3) x intensity (0-3). Epithelial, stromal, and total scores were evaluated in relationship to histology and dysplasia. HMPS polyps COX-2 mean epithelial (5.0+/-3.0), stromal (6.9+/-1.9), and total (11.8+/-4.6) scores were significantly higher (P < 0.01) than sporadic juvenile polyps (0.6+/-0.7, 3.1+/-2.2, and 3.6+/- 2.2 respectively), while colorectal cancer scored 9, 9, and 18. There was a positive association (P < 0.01) among histology, degree of dysplasia, and COX-2 expression. COX-2 expression in HMPS polyps and its association with dysplasia suggest that chemoprevention might be a useful adjunct therapy.     

Reduced expression of cyclooxygenase 2 proteins in hereditary nonpolyposis colorectal cancers relative to sporadic cancers.

BACKGROUND & AIMS: Cyclooxygenase (COX) enzymes catalyze the conversion of arachidonic acid to prostaglandins. Evidence suggests that nonsteroidal anti-inflammatory drugs reduce the risk of colorectal cancer (CRC) and that this effect is mediated through COX inhibition. We analyzed and compared expression of the inducible COX-2 isoform in colorectal neoplasms from patients with hereditary nonpolyposis colorectal cancer (HNPCC), familial adenomatous polyposis (FAP), and sporadic CRC. Given that COX-2 is induced by transforming growth factor (TGF)-beta and that TGF-beta type II receptor (RII) mutations are found in HNPCCs, we determined the relationship between RII status and COX-2 expression. METHODS: COX-2 protein expression was determined in colorectal epithelia using immunohistochemistry and Western blotting. Patients with HNPCC had known mutations in hMLH1 or hMSH2 genes and/or met the Amsterdam criteria. In CRCs from HNPCC cases, mutations were sought in the coding region of the RII gene using the polymerase chain reaction. RESULTS: COX-2 was detected in adenomas from 2 of 3 HNPCC, 6 of 7 FAP, and 5 of 8 sporadic cases. In CRCs, COX-2 staining was found in 16 of 24 (67%) HNPCC vs. 24 of 26 (92%) sporadic cases (P = 0.035) and in 2 of 2 FAP cases. Staining intensity was reduced in HNPCCs compared with sporadic CRCs (P = 0.035). Staining localized to the cytoplasm of neoplastic cells; normal epithelial cells were negative for COX-2. Overexpression of COX-2 in CRCs relative to normal mucosa was confirmed by Western blotting. TGF-beta RII mutations were detected in 12 of 14 HNPCCs examined, including 3 of 4 COX-2-negative and 9 of 10 COX-2-positive cancers. CONCLUSIONS: The frequency and intensity of COX-2 expression was significantly reduced in HNPCCs relative to sporadic CRCs, and was not a consequence of RII mutations. Given that many HNPCCs express COX-2, inhibition of this enzyme may be an important strategy to prevent CRC in these patients.     

结肠癌及癌前病变组织中COX-2及VEGF的表达

目的: 探讨结肠癌及癌前病变中COX-2和血管内皮生长因子(VEGF)的表达意义.方法:应用免疫组织化学ABC法检测COX-2及VEGF在40例癌旁正常结肠黏膜和结肠癌、27例结肠腺瘤组织中COX-2和VEGF的表达.结果: 结肠腺瘤和结肠癌组COX-2阳性表达率明显高于癌旁正常结肠黏膜组(63.0%, 77.5% vs 0.0%, 0.0%;P<0.05). 结肠腺瘤和结肠癌组VEGF阳性表达率明显高于癌旁正常结肠黏膜组(70.4%, 80.0% vs 25.0%, 25.0%;P<0.05), 且二者表达有相关性(r = 0.411, P<0.01). 结论:COX-2和VEGF在结肠腺瘤及结肠癌中表达异常增高.     

Singapore familial adenomatous polyposis (FAP) patients with classical adenomatous polyposis but undetectable APC mutations have accelerated cancer progression

OBJECTIVES: Germline mutation in adenomatous polyposis coli (APC) is detected in up to 80% of familial adenomatous polyposis (FAP) patients worldwide. In this study, we evaluated clinical features and APC mutations of Singapore FAP patients and contrasted genotype-phenotype correlation with Caucasians from other regions of the world and between FAP patients with and without detectable APC mutations. METHODS: We screened 242 members from 57 unrelated FAP families using a combination of cDNA protein truncation test, multiplex ligation-dependent probe amplification, and differential expression techniques. RESULTS: APC germline mutations were detected in 50 families. In contrast to Caucasians, fundic gland polyposis in Singapore patients was associated with APC mutations throughout the coding region and osteomas were also not confined to codon 767-1573. There was also no FAP-associated hepatoblastoma or medullablastoma. APC mutation-negative patients from four families with mixed (adenomatous/hyperplastic/atypical juvenile) polyps were subsequently reclassified as hereditary mixed polyposis syndrome (HMPS) patients. APC mutation-negative patients with classical adenomatous polyposis were negative for MYH, beta-catenin, and Axin 1 mutations. These patients had a significantly older age at diagnosis (P < 0.001) and more colorectal cancers (P= 0.017) than patients with APC mutations. CONCLUSIONS: We achieved a 94% (50/53) APC mutation detection rate via a combination of techniques, suggesting that the current detection rate is probably not exhaustive. Singapore patients have some features similar to and other features distinct from Caucasians. Furthermore, APC mutation-negative patients have accelerated cancer progression that merits closer surveillance.     

Characteristics of familial juvenile polyps expressing cyclooxygenase-2

OBJECTIVES: Familial juvenile polyposis (FJP) is a dominant genetic disorder characterized by colorectal, gastric, and small bowel juvenile polyps, and high risk for gastrointestinal cancer. Patients are treated by repeated endoscopic polypectomies and elective surgery. We determined the characteristics of FJP polyps expressing cyclooxygenase-2 (COX-2). METHODS: A total of 115 colorectal and 6 gastric polyps were available from 17 FJP patients. Comparison tissues were 18 sporadic juvenile colorectal polyps, 6 gastric hyperplastic polyps, 9 normal colons, and 3 colorectal cancers (CRCs). Histology sections were classified and stained for COX-2. The polyps' epithelium and stroma and comparison tissues were quantified for COX-2 by: area of staining (0-3) x intensity (0-3). Epithelial and stromal scores (0-9) and total scores (0-18) were evaluated in relationship to patient's age, polyp site, size, dysplasia, and stromal cellularity. RESULTS: Colonic FJP polyps mean total COX-2 score was 10.3 +/- 6.0, and that of sporadic juvenile polyps 3.6 +/- 2.2 (p < 0.01), and in contrast to the latter, FJP COX-2 scores increased significantly (p < 0.01) with polyp size. Linear regression analysis showed significant associations of COX-2 in FJP polyps with dysplasia (p < 0.01), stromal cellularity (p < 0.01), size (> or =1.5 cm) (p= 0.02), and site (right colon) (p= 0.01), and not with age. COX-2 total scores of gastric FJP polyps and hyperplastic polyps were similar. CONCLUSIONS: Expression of COX-2 in FJP polyps and its association with size and dysplasia suggest that, in these patients, chemoprevention with selective COX-2 inhibitors might be a useful adjunct therapy to colonoscopic polypectomy.     

Multiple desmoid tumors in a patient with familial adenomatous polyposis caused by the novel W421X mutation

Familial adenomatous polyposis (FAP) is a rare syndrome characterized by the presence of hundreds to thousands of colorectal adenomas and is responsible for less than 1% of all colorectal cancers. The syndrome is also characterized by extra-colorectal features including amongst others upper gastrointestinal tract polyps and desmoid tumors. The syndrome is inherited by an autosomal dominant gene, the adenomatous polyposis coli (APC) gene. We present the physical history, clinical presentation, diagnosis and treatment of a patient with a novel germline APC mutation, the W421X mutation, which resulted in FAP presenting with about a hundred colorectal polyps, gastric hyperplastic polyps and multiple aggressive intra-abdominal and extra-abdominal desmoid tumors.     

Expression of cyclooxygenase-1 and -2 in the baboon endometrium during the menstrual cycle and pregnancy.

Cyclooxygenase (COX) is the rate-limiting enzyme in the biosynthesis of PGs. PGs together with ovarian steroids play important regulatory roles in the establishment and maintenance of pregnancy in a number of different species. In the primate, little is known about the role of PGs in these processes. In this study, the uterine expression of COX-1 and COX-2 throughout the menstrual cycle [late follicular, day 5 postovulation (PO), day 10 PO, and day 14 PO] and pregnancy (days 12-18, day 39, day 51, and near term) was analyzed using semiquantitative RT-PCR, in situ hybridization, and immunocytochemistry. During the menstrual cycle, the highest expression of COX-1 occurred in luteal phase endometrium and was localized to the surface and glandular epithelium. The stromal cells did not express detectable levels of COX-1 at any time. COX-2 messenger RNA (mRNA) expression, as measured by RT-PCR, was evident at all stages of the menstrual cycle, and in situ hybridization showed specific localization for this mRNA in the epithelial cells during the cycle. Treatment of animals with the antiprogestin (ZK 137.316) for 9 days (beginning on the day of the LH surge) inhibited COX-1 expression in the epithelium when the tissue was analyzed on day 10 PO, whereas COX-2 expression disappeared in the epithelium and increased in the stroma. With the onset of pregnancy, COX-1 expression in epithelial cells decreased dramatically. In contrast, COX-2 continued to be detected on the surface epithelium and was also strongly expressed specifically in the stromal cells at the site of implantation. Immunocytochemical staining for COX-2 showed the same pattern of expression for the protein as the message. Finally, near-term decidua expressed very little COX-1 or COX-2 mRNA. These studies suggest that in the baboon endometrium, COX-1 expression is regulated primarily by progesterone, whereas regulation of COX-2 expression may involve additional mediators of embryonic origin at the site of implantation.     

Familial adenomatous polyposis complicated by chronic myelogenous leukemia: response to imatinib mesylate

Familial adenomatous polyposis (FAP) is an autosomal dominant disorder characterized by colonic polyposis and a predisposition for developing colorectal cancer. FAP is frequently complicated by extracolonic disease, but complications of leukemia are rare. We present the first case of FAP complicated by chronic myelogenous leukemia (CML) in a 38-year-old man. The patient had numerous adenomas in the colorectum and a family history compatible with FAP. He was diagnosed as having FAP in February 2000. Two years after the diagnosis, he developed leukocytosis with the Philadelphia chromosome abnormality, indicating complication with CML. Imatinib mesylate was administered for the treatment of CML, and hematologic and cytogenetic remission of CML was achieved in 6 months. Numerous polyps, 2 to 3 mm in diameter, observed in the rectum prior to the administration of imatinib, regressed in size, but not in number, after 1 year of treatment with imatinib. Eighteen months later, however, the polyps were enlarged. In this patient, imatinib administration led to the remission of CML and might also have been responsible for the temporary regression of adenomatous polyps of FAP.     

Synchronous primary carcinomas of the ampulla of Vater and ascending colon in a patient with multiple flat adenomas

Multiple primary cancers occurring in the same patients have been reported to represent 1.8–3.9% of all cancers. The majority of all patients reported to have had a combination of simultaneous neoplastic changes in the ampulla of Vater and the colon showed familial adenomatous polyposis (FAP) syndrome. Variants of familial adenomatous polyposis coli are: attenuated adenomatous polyposis coli (AAPC, previously also known as flat adenoma syndrome) and multiple adenoma coli. AAPC is characterized clinically by many, but usually fewer than 100, colonic lesions that are characteristically slightly elevated and plaque-like, with a reddish surface and sometimes central depression. Genetically it represents an extremely rare variant of FAP. Another group of individuals, so-called multiple adenoma patients, have a phenotype similar to AAPC, but most have no demonstrable germ-line adenomatous polyposis coli mutation, as do patients with FAP or AAPC. However, there have been only a few reports that discussed concurrent neoplastic changes in the ampulla of Vater and colon in patients with multiple colonic flat adenomas, but without the florid phenotype of classical FAP. We present rare clinical course of a patient with multiple (more than 60) flat adenomas in the proximal colon and two primary cancers: of the ampulla of Vater and of the ascending colon. This patient and his family history did not show polyposis compatible with FAP or hereditary nonpolyposis colorectal cancer (HNPCC) syndrome.     

Familial adenomatous polyposis

Familial adenomatous polyposis (FAP) is an autosomal-dominant colorectal cancer syndrome, caused by a germline mutation in the adenomatous polyposis coli (APC) gene, on chromosome 5q21. It is characterized by hundreds of adenomatous colorectal polyps, with an almost inevitable progression to colorectal cancer at an average age of 35 to 40 yr. Associated features include upper gastrointestinal tract polyps, congenital hypertrophy of the retinal pigment epithelium, desmoid tumors, and other extracolonic malignancies. Gardner syndrome is more of a historical subdivision of FAP, characterized by osteomas, dental anomalies, epidermal cysts, and soft tissue tumors. Other specified variants include Turcot syndrome (associated with central nervous system malignancies) and hereditary desmoid disease. Several genotype-phenotype correlations have been observed. Attenuated FAP is a phenotypically distinct entity, presenting with fewer than 100 adenomas. Multiple colorectal adenomas can also be caused by mutations in the human MutY homologue (MYH) gene, in an autosomal recessive condition referred to as MYH associated polyposis (MAP). Endoscopic screening of FAP probands and relatives is advocated as early as the ages of 10-12 yr, with the objective of reducing the occurrence of colorectal cancer. Colectomy remains the optimal prophylactic treatment, while the choice of procedure (subtotal vs proctocolectomy) is still controversial. Along with identifying better chemopreventive agents, optimizing screening of extracolonic cancers and applying new radiological and endoscopic technology to the diagnosis and management of extracolonic features are the major challenges for the future.     

Familial adenomatous polyposis: what is new for the clinician?]

Familial adenomatous polyposis (FAP) is a rare autosomal-dominant disease characterized by the development of more than 100 colorectal adenomatous polyps in young adults. In the absence of surgical intervention, colorectal cancer ineluctably develops in all affected patients. Recent progress in the isolation of the gene responsible for the disease allows to detect gene carriers before they present with symptoms attributable to polyps. Moreover, the presence of four or more lesions of congenital hypertrophy of the retinal pigment epithelium is an extracolonic manifestation of FAP allowing presymptomatic screening of this disease. An effective screening programme combined with the elaboration of a registry for FAP and prophylactic colectomy should reduce mortality related to colorectal cancer. Two other extracolonic manifestations of FAP remain major causes of death: abdominal desmoid tumors and duodenal adenocarcinoma. At this time, no effective medical or surgical therapy has been found to cure these lesions. Restorative proctocolectomy with ileal reservoir is another major advance. This procedure is now regarded as the treatment of choice for patients with FAP because radical removal of all premalignant colorectal mucosa eliminates the risk of subsequent development of a colorectal adenocarcinoma.     

Capsule endoscopy in small-bowel surveillance of patients with hereditary polyposis syndromes

Purpose  

Familial adenomatous polyposis (FAP) and Peutz–Jeghers syndrome (PJS) are hereditary polyposis syndromes with a high risk for benign small-bowel polyps and cancer. The aim of this study was to assess the prevalence of small-bowel polyps beyond the duodenum in patients with FAP and PJS and to examine the clinical value and the optimal interval of capsule endoscopy (CE) for the surveillance of small-bowel polyps in patients with FAP.     

The patient with multiple intestinal polyps

The management of patients with multiple intestinal polyps may be difficult and greatly depends on the correct classification. Polyposis syndromes account for less than 1% of newly diagnosed colorectal cancers. In addition the risk for extracolonic cancer is increased in most syndromes. Here we report the case of a difficult patient with severe gastric polyposis and we present a review of polyposis syndromes such as classical and attenuated familial adenomatous polyposis (FAP), MYH-associated polyposis, Peutz-Jeghers syndrome, juvenile polyposis as well as rare polyposis syndromes. The most practical approach for the diagnostic workup in patients with newly diagnosed gastrointestinal polyposis is based on the histological typing of polyps. In addition, a detailed family history regarding cancer, polyps and congenital abnormalities should be obtained from every polyposis patient. Patients with multiple adenomas are most likely to suffer from FAP, AFAP or MAP. Of these, younger age and higher polyp count are most likely a diagnosis of typical FAP. Older age and fewer polyps favour a diagnosis of AFAP or MAP. Germline testing of the APC gene is suggested, and if negative, MYH gene testing should be done. In patients with hamartomas, extraintestinal features should be evaluated and reference histology should be initiated. In addition panintestinal imaging should be performed with EGD, colonoscopy and small bowel imaging (PE, CE, and MR) enteroclysis. For diagnostic and therapeutic problems a familial colorectal cancer center should be consulted. Using this algorithm, correct classification and adequate treatment should be possible for every polyposis patient.     

The utility of capsule endoscopy small bowel surveillance in patients with polyposis

BACKGROUND: Small intestinal (SI) surveillance is recommended for polyposis patients. The utility and safety of capsule endoscopy (CE) for surveillance of SI neoplasia in patients with familial adenomatous polyposis (FAP) and Peutz-Jeghers syndrome (PJS) is unknown. METHODS: CE was offered to consecutive FAP and PJS patients due for routine upper endoscopic surveillance. The prevalence, location (jejunum, ileum), size (1-5 mm, 6-10 mm, >10 mm) and number (1-5, 6-12, >20) of polyps detected by CE was assessed. RESULTS: 19 subjects (15 FAP/4 PJS) with a mean age of 43 were included. All subjects had previous intestinal surgery. No complications occurred with CE. CE in FAP: 9/15 (60%) of subjects with FAP had SI polyps. The prevalence of SI polyps was related to the duodenal polyposis stage and subject age. The location, size and number of polyps progressed as duodenal polyposis stage advanced. CE in PJS: 3/4 (75%) of subjects with PJS had SI polyps. The polyps were diffuse in 2/4 and only in the ileum in one subject. CE findings led to laparotomy with intra-operative endoscopic polypectomy in two PJS patients. CONCLUSION: SI polyps are common in FAP but their importance is unknown. CE should be performed in FAP patients with stage III and IV duodenal disease. Clinically significant polyps are commonly detected by CE in PJS and lead to change in management in 50% of PJS subjects. CE should replace radiographic SI surveillance for PJS patients. CE is safe in polyposis patients who have undergone major intestinal surgery.