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Peutz-Jeghers syndrome: its natural course and management.

Two hundred and twenty-two patients with Peutz-Jeghers syndrome were ascertained in Japan between 1961 and 1974 through two nationwide surveys, medical literature, and personal examinations. Genetic analysis was made of this group as well as 102 follow-up cases. The average age at diagnosis was 23 in males and 26 in females, with male to female ratio of 1:1.13. Presenting complaints of 170 patients included obstruction (42.8 per cent of patients), abdominal pain (23.4 per cent), rectal bleeding (13.5 per cent), extrusion of polyp (7.2 percent). Diagnosis of 52 patients was based on melanin pigmentation. Intussusception occurred in 46.9 per cent of the patients, most often in the small intestine. Polyps occurred in the stomach in 108 patients (48.6 per cent), small intestine, 142 patients (64 per cent), colon, 118 patients (53.2 per cent) and rectum, 71 patients (32 per cent). Among the 222 patients, cancer was histologically verified in 28. Fifteen early cancers occurred (3 gastric, 8 small intestine, 4 colon), and 11 advanced cancers (3 gastric, 1 small intestine, 6 colon, and 1 both colon and small intestine). Mortality was lower than in patients with familial polyposis coli but higher than in the general population. Conservative surgical management, planned medical follow-up, and the need for a national registration system are stressed.

Adolescent↗

Combined effects of prostaglandin E receptor subtype EP1 and subtype EP4 antagonists on intestinal tumorigenesis in adenomatous polyposis coli gene knockout mice.

Previous studies have shown that prostaglandin E(2) (PGE(2)) is involved in intestinal carcinogenesis through its binding to the PGE(2) receptor subtypes EP(1) and EP(4) and activation of downstream pathways. ONO-8711 and ONO-AE2-227, prostaglandin E receptor subtype EP(1)- and EP(4)-selective antagonists, respectively, are known to suppress formation of intestinal polyps in adenomatous polyposis coli gene-deficient mice. The present study was designed to investigate the combined effects of EP(1) and EP(4) antagonists on spontaneous polyp formation in APC1309 mice in order to determine the contribution of each receptor to intestinal tumorigenesis. APC1309 mice were treated with 400 ppm of ONO-8711 alone, 400 ppm of ONO-AE2-227 alone or both in combination in the diet for 6 weeks. The mean area of polyps found in the intestine, calculated as the longer diameter x the shorter diameter x pi, was reduced by 12%, 43% (P < 0.01) and 56% (P < 0.01) of the mean control value (8.8 mm(2)) in the ONO-8711 alone, ONO-AE2-227 alone and combination treatment groups, respectively, suggesting clear additive effects of the combination. The same additive tendency for suppression was also observed with respect to the numbers of polyps in the intestine. Polyp size reduction was more remarkable with the EP(4) antagonist, while the number reduction was more pronounced with the EP(1) antagonist. Our results indicate that EP(1) and EP(4) may have separate intrinsic roles and, to some extent, contribute to polyp formation independently. Thus, combination treatment has potential for the chemoprevention of colon carcinogenesis.

Animals↗

[Polyps of the large intestine in children].

Polyps in the large intestine is a frequent disease in children. It is more often observed in boys than in girls aged 4 to 9. In most cases solitary polyps are observed (in 73,35%). Two-three polyps are met in 21,62% of cases. Polyposis is a rare disease--0,91%. The main symptom of polyps in children is hemorrhage from the anal orifice. The method of treatment is dependent on the amount, size, height of the situs and spread of the polyps. Dissection of polyps through the rectal speculum is used more frequently, rectoromanoscope is used in rarer cases (electroexcision and coagulation). Resection of the large intestine or colotomy and ablation of polyps can be successfully used in polyposis and high situs of polyps.

Adolescent↗

The epidemiology of colorectal polyps: prevalence in New Orleans and international comparisons.

Based on a study of the prevalence of intestinal polyps in New Orleans and on international comparisons, the following conclusions are reached. 1) There is a close parallelism in the epidemiology of colon cancer and adenomatous polyps. Both conditions are statistically associated with respect to geography, anatomic localization, socioeconomic class, migration experience and time trends. 2) The strength of the association favors the notion of a direct, positive correlation between multiplicity, size and atypia of polyps, and cancer risk, equivalent to "dose-effect". 3) The epidemiologic findings are coherent with other biologic facts derived from clinical, morphological and experimental studies. 4) Adenomatous polyps are a good epidemiologic indicator of colon cancer risk and their presence should be helpful in advancing from studies of the epidemiology of colon cancer to the epidemiology of precursor lesions.

Adult↗

Negative energy balance induced by voluntary wheel running inhibits polyp development in APCMin mice.

Treadmill running of approximately 0.9 km/day has had inconsistent effects on spontaneous intestinal polyp development in C57BL/6J-Apc(Min)/J (Min) mice; the amount of energy expenditure and/or a lack of hormonal changes could account for this variability. The purpose of this study was to examine the effects of a negative energy balance induced by voluntary wheel running on polyps, insulin-like growth factor-1 (IGF-1) and corticosterone in Min mice. Seven-week-old male Min mice were randomly assigned to control (CON, n = 23) or wheel running (EX, n = 24) conditions for a 10-week study period. All mice had water and AIN-76A diet ad libitum for the first approximately 3 weeks on study, after which the EX group was pair-fed to the CON group to maintain a negative energy balance due to the exercise. EX mice voluntarily ran 3.8 km/day (2.7-6.0 km/day) (median, interquartile range) and weighed less than CON mice throughout the study. More CON mice died before the end of the study versus EX mice (26 versus 0%, P < 0.01). CON mice had significantly more polyps versus EX mice (21.6 +/- 1.5 versus 16.9 +/- 2.0, P < 0.01; mean +/- SE), and daily running distance in EX was inversely correlated with total polyp number (r = -0.70, P < 0.01). Urinary corticosterone output (P < 0.01) and serum IGF-1 were significantly higher in EX than CON (P < 0.001); however, total polyp number was unrelated to corticosterone (r = 0.05, P = 0.84) and IGF-1 (r = -0.01, P = 0.93). In this study, a negative energy balance produced by wheel running exercise and restricted feeding decreased polyp burden in male Min mice and appeared to have a dose-response effect on polyp number. Although EX affected IGF-1 and corticosterone, neither marker was related to total polyp number.

Animals↗

Long-term results of polyp clearance by intraoperative enteroscopy in the Peutz-Jeghers syndrome.

PURPOSE: Enteroscopy during laparotomy for Peutz-Jeghers syndrome was introduced in our unit in 1987. Its aim is to achieve more complete polyp clearance and thereby reduce the number of subsequent laparotomies for small intestinal polyps. METHODS: All patients with Peutz-Jeghers syndrome who had undergone intraoperative enteroscopy since its introduction into our unit in 1987 were identified. The numbers of polyps identified by palpation and transillumination and by enteroscopy were recorded. The timing of, indications for, and findings of all subsequent laparotomies were analyzed and compared with data from our unit before the introduction of intraoperative enteroscopy. RESULTS: Twenty-five patients (14 females) were studied. Enteroscopy identified 350 (median 12, range 0-35) polyps not detected by palpation and transillumination. All impalpable polyps were removed endoscopically by snare or biopsy. The median follow-up was 53 (interquartile range, 13-133) months. Six patients have had an additional laparotomy (1 urgent relaparotomy for small-bowel perforation after endoscopic polypectomy, 4 polypectomies, and 1 adhesion obstruction). No patient has required operative polypectomy within 4 years of polyp clearance by intraoperative enteroscopy, compared with registry data of 4 (17 percent) of 23 patients who had more than 1 laparotomy within 1 year. CONCLUSION: Intraoperative enteroscopy for Peutz-Jeghers syndrome improves polyp clearance without the need for additional enterotomies and may help to reduce the frequency of laparotomies.

Child↗

beta-Catenin-accumulated crypts in the colonic mucosa of juvenile ApcMin/+ mice.

Although Apc(Min/+) mice are widely used for an animal model of human familial adenomatous polyposis (FAP), a majority of intestinal polyps locate in the small intestine. We recently reported that numerous beta-catenin-accumulated crypts (BCAC), which are reliable precursor lesions for colonic adenocarcinoma, develop in the large bowel of aged Apc(Min/+) mice. In this study, we determined the presence and location of BCAC in the large intestine of juvenile Apc(Min/+) mice (3 and 5 weeks of age). Surprisingly, BCAC were noted in the colon of even Apc(Min/+) mice of both ages, and mainly located in the distal and middle segments of the colon. Also, a few microadenomas were detected in Apc(Min/+) mice of 5-week old. Our results may indicate need of further investigation of the colorectal mucosa of Apc(Min/+) mice for examining colorectal carcinogenesis using Apc(Min/+) mice.

Adenoma↗

Cyclooxygenases and colon cancer.

There is considerable interest in the involvement of cyclooxygenase-2 (COX-2) in colon carcinogenesis and its progression, because nonsteroidal anti-inflammatory drugs (NSAIDs) reduce mortality from colon cancer and COX-2 is one of the known targets of NSAIDs. COX-2 mRNA and protein levels are increased in colon cancer tissues from patients and in some colon cancer cell lines. The relationship between COX-2 and colon cancer is further confirmed by studies using the murine models of adenomatous polyposis coli, in which NSAIDs and gene knockouts reduce the number of spontaneously developing intestinal polyps. COX-2 expression in intestinal epithelial cells increases resistance to apoptosis, promotes tumor angiogenesis, and enhances invasion and metastasis. COX-2 expression in stromal cells appears to have a role in tumor angiogenesis because tumor growth is attenuated when colon cancer cells are implanted in COX-2 knockout mice due to a decreased vascular supply to the tumors. Although NSAIDs act via COX-2 to inhibit colon cancer growth, there also appear to be COX-2 independent actions for NSAIDs. COX-2 selective inhibitors can be the core drugs for the prevention and the treatment of colon cancer.

Animals↗

[Intussusception in adults].

Intestinal intussusception in adults is a very rare entity whose etiology differs greatly from its pediatric counterparts. Three adult patients with intestinal intussusception presented with intestinal obstruction and required surgery for its resolution. In each case a pathologic cause was found. They had intestinal polyps, two benign (lipoma and hamartomatous polyps) and one malignant (metastasis). Intestinal intussusception in adults usually has a pathologic cause. About half have a malignant etiology. Intestinal resection without reduction of the intussusception is the preferred surgical procedure.

Adult↗

Possible involvement of hyperlipidemia in increasing risk of colorectal tumor development in human familial adenomatous polyposis.

BACKGROUND: Familial adenomatous polyposis (FAP) results from germline adenomatous polyposis coli (APC) gene mutations and many affected patients die from colorectal cancers which arise from colorectal polyps. We previously reported that two strains of Apc gene-deficient mice developing multiple intestinal polyps exhibit a hyperlipidemic state. The triglyceride (TG) levels were approximately 10-fold higher than the levels observed in wild-type mice. METHODS: To examine whether a positive relationship might exist between hyperlipidemia and colorectal tumor development in FAP patients, as with Apc gene-deficient mice, a pilot experiment was performed using readily available clinical data such as ages, serum lipid levels, number of colorectal polyps and cancer development in 28 FAP patients from the National Cancer Center Hospital, Japan. RESULTS: The overall prevalence of hyperlipidemia in FAP cases was 58%. Average TG levels in the 40-60 year age groups of FAP patients were > or =150 mg/dl (the defined threshold level of hyperlipidemia). Moreover, there was a tendency for higher serum TG levels in patients who developed colorectal cancer, as compared with those without colorectal cancer. CONCLUSIONS: These results show that a hyperlipidemic state occurs in FAP patients. Although it is weaker than that in Apc gene-deficient mice, it may be linked to colon tumor development. These data warrant further studies for wider populations of FAP patients.

Adenomatous Polyposis Coli↗

Activation of nuclear hormone receptor peroxisome proliferator-activated receptor-delta accelerates intestinal adenoma growth.

We treated Apc(min) mice, which are predisposed to intestinal polyposis, with a selective synthetic agonist of peroxisome proliferator-activated receptor-delta (PPAR-delta). Exposure of Apc(min) mice to the PPAR-delta ligand GW501516 resulted in a significant increase in the number and size of intestinal polyps. The most prominent effect was on polyp size; mice treated with the PPAR-delta activator had a fivefold increase in the number of polyps larger than 2 mm. Our results implicate PPAR-delta in the regulation of intestinal adenoma growth.

Adenoma↗

Epithelial misplacement in Peutz-Jeghers polyps. A diagnostic pitfall.

Early difficulties with the interpretation of the histopathology caused overdiagnosis of cancer in the Peutz-Jeghers syndrome; and there is still controversy about the magnitude of risk of gastrointestinal carcinoma. Most workers now believe that there is a small but definite increase in the incidence of gastrointestinal carcinoma in Peutz-Jeghers polyps and most of these cancers occur in the upper gastrointestinal tract. In a review of 491 Peutz-Jeghers polyps in the records of St. Mark's Hospital Pathology department, misplacement of epithelium was found in approximately 10% of small intestinal polyps and closely mimicked adenocarcinoma. This "pseudoinvasion" was not observed in polyps of the stomach or colon. The epithelial misplacement may involve all layers of the bowel wall; and the most helpful histological discriminators include a lack of cytological atypia, the presence of the normal epithelial cell subtypes and a brush border, hemosiderin deposition, and intramural mucinous cysts. Epithelial misplacement may account for the overdiagnosis of carcinoma arising in Peutz-Jeghers polyps as reported in the literature.

Adenoma↗

Solitary hamartomatous duodenal polyp; a different entity: report of a case and review of the literature.

Solitary hamartomatous duodenal polyps are a clinical entity considered until now to express an incomplete or initial form of Peutz-Jeghers syndrome (PJ syndrome). Following our experience of 1 case, we analyzed the clinical characteristics of the 12 previously reported cases of solitary hamartomatous duodenal polyps. In none of these cases did we find any documentation of mucocutaneous pigmentation, a family or personal history of intestinal polyps, or local neoplastic degeneration of the disease, and all cases presented during the fifth or sixth decade of life. Thus, we conclude that solitary hamartomatous duodenal polyps constitute a different entity to PJ syndrome, the most appropriate elective treatment for which is endoscopic electrosurgical polypectomy.

Adult↗

Epithelioid leiomyosarcoma originating in a hamartomatous polyp from a patient with Peutz-Jeghers syndrome.

A case of Peutz-Jeghers syndrome with long history and multiple resections is presented. Despite the large number of intestinal polyps in these patients, malignant transformations are rare. In this case, an epithelioid leiomyosarcoma developed within a single polyp. At the time of resection this tumor had already metastasized to the liver. The histology and ultrastructure of this tumor is presented. Reviews of the clinical syndrome and leiomyosarcoma are given, with discussion of the possible interaction of these two processes as presented in this patient.

Adult↗

Three secretory phospholipase A(2) genes that map to human chromosome 1P35-36 are not mutated in individuals with attenuated adenomatous polyposis coli.

Mutation of Pla2g2a, a secretory phospholipase A(2) gene, dramatically increases the number of intestinal polyps that develop in the multiple intestinal neoplasia (Min) mouse, a murine model for adenomatous polyposis coli in humans. We tested the hypothesis that mutation of the human homologue(s) of this gene might be responsible for the more severe phenotype (hundreds of polyps) seen in a subset of individuals with attenuated adenomatous polyposis coli (AAPC). DNA sequence analysis demonstrated that alterations of PLA2G2A, as well as related genes PLA2G2C and PLA2G5, were evenly distributed between three classes of AAPC subjects: those with small, intermediate, and large numbers of adenomatous colonic polyps. Among 67 additional unrelated AAPC subjects, a stop mutation in PLA2G2C did not correlate with an increased burden of adenomatous polyps. Therefore, mutation of the human homologue(s) of murine Pla2g2a does not appear to be responsible for phenotypic variation among subjects with AAPC.

Adenomatous Polyposis Coli↗

Pathology neoplastic and non-neoplastic.

Polyps of the gastrointestinal tract are common and often hard to diagnose by endoscopic or gross examination. Biopsy or polypectomy enables diagnosis and prognostication. This article is by no means encyclopedic, but attempts to discuss the pathology of the more common intestinal polyps.

Adenoma↗