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Gastrointestinal polyposis syndromes are rare familial syndromes all sharing an autosomal dominant inheritance.

Familial Adenomatous Polyposis (FAP) Genetic defect on the APC gene (5q21)
500-2500 colonic adenomas with a minimum of 100 needed for diagnosis
Gardner Syndrome
(Familial Polyposis Coli)
Variant of FAP
Colonic adenomas, osteomas of the bone, epidermal cysts, thyroid cancer, and fibromatosis
Turcot Syndrome Adenomatous colon polyps and tumors of the central nervous system (usually gliomas)
Polyps arise from 10-20 yrs, cancer follows after 10-15 yrs


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Familial Adenomatous Polyposis Associated With Multiple Endocrine Neoplasia Type 1-Related Tumors and Thyroid Carcinoma A Case Report With Clinicopathologic and Molecular Analyses

Yuzo Sakai, M.D. ; Koich Koizumi, M.D. ; Iwao Sugitani, M.D. ; Ken Nakagawa, M.D. ; Masami Arai, M.D. ; Joji Utsunomiya, M.D. ; Tetsuichiro Muto, M.D. ; Rikiya Fujita, M.D. ; Yo Kato, M.D.

From the Departments of Medicine, Endoscopy, Head and Neck, Surgery, Familial Cancer Center, and Pathology, Cancer Institute Hospital, Tokyo, Japan.

Am J Surg Pathol 2002;26:103-110 Abstract quote

We describe a sporadic case with familial adenomatous polyposis, multiple endocrine neoplasia type 1 (MEN1)-related tumors (an endocrine cell tumor of the pancreas and bilateral parathyroid tumors), and a papillary thyroid carcinoma.

To clarify how mutations of the adenomatous polyposis coli ( APC ) gene and the MEN1 gene, responsible for familial adenomatous polyposis and MEN1, respectively, might have contributed to tumorigenesis in this case, we studied germline mutations in both genes and loss of heterozygosity at their genetic loci in multiple lesions. In addition, we performed immunohistochemistry for -catenin, associated with the function of the APC gene. A germline mutation was found in the APC gene but not in the MEN1 gene. Normal allelic loss at the APC gene locus was observed in bilateral parathyroid tumors.

Immunohistochemical staining of -catenin demonstrated accumulation in the cytoplasm in addition to membrane staining in all analyzed tumors and a strong nuclear reaction in the endocrine cell tumor of the pancreas.

The presence of normal allelic deletions of the APC gene in bilateral parathyroid tumors and nuclear staining of -catenin in the pancreatic tumor in addition to the germline mutations suggests that functional loss of the APC gene played an important role not only in familial adenomatous polyposis but also in the MEN1-related tumors in this case.


Somatic Mutations in Familial Adenomatous Polyps Nuclear Translocation of b-Catenin Requires More Than Biallelic APC Inactivation

Hendrik Bläker, MD, Martin Scholten, Christian Sutter, PhD, Herwart F. Otto, MD, and Roland Penzel, PhD
Am J Clin Pathol 2003;120:418-423 Abstract quote

Germline mutations of the APC gene cause familial adenomatous polyposis coli (FAP). APC inactivation results in dysregulation of wnt/wingless signaling and contributes to chromosomal instability in vitro.

To investigate somatic alterations that follow a known germline mutation and contribute to the transition from normal to neoplastic mucosa, we studied 10 adenomatous polyps from a 27-year-old patient with an APC germline mutation at codon 554. Chromosomal imbalances were analyzed by comparative genomic hybridization; APC and K- ras were screened for somatic mutations. Before DNA analysis, the polyps were bisected to compare the genetic alterations with the corresponding immunohistologic phenotype of b -catenin, a proto-oncogene product degraded by the APC tumor suppressor. Gains at chromosome 20 were the most frequent chromosomal alterations (6 polyps). Losses were found predominantly at chromosome 4q (3 polyps). A K- ras mutation was seen in 1 polyp, while all polyps displayed somatic intragenic APC mutations. Comparative immunohistologic analysis revealed strong membranous staining for b -catenin in all adenomatous polyps, but only 1 adenoma showed nuclear accumulation.

Our results suggest chromosomal aberrations contribute early to the progression of adenomatous polyps after biallelic APC inactivation. APC inactivation itself is insufficient for immunohistochemically detectable nuclear translocation of b -catenin.

Somatic mutations of the first 14 exons of APC in hamartomatous polyps of the colon.

Kim JC, Roh SA, Kim HC, Yu CS, Lee DH, Ahn BY, Kim KM, Yang SK, Kang GH, Beck NE, Bodmer WF.

Laboratory of Gastrointestinal Cancer Biology and Genetics, Department of Surgery,University of Ulsan College of Medicine and Asan Institute for Life Sciences, 388-1 Poongnap-Dong, Songpa-Ku, Seoul, Korea.

Hum Mutat 1999 Oct;14(4):351-2 Abstract quote

Although hamartomatous or hyperplastic polyps are rarely accompanied by adenomatous or carcinomatous foci, the role of APC (MIM# 175100) mutations in these polyps is not clear.

The neoplastic potential of these polyps was assessed with regard to somatic mutation of the first 14 exons of APC. DNA from 14 hamartomatous polyps (12 patients with juvenile polyp, JP; two patients with Peutz-Jeghers syndrome, PJS) and 27 hyperplastic polyps was used. Exons 1-14 of APC were amplified using verified oligonucleotide primers, and PCR-SSCP analysis was performed. Translation-terminating mutation in exon 15 was also screened using the protein truncation test. All mutations found were transitions or transversions with heterozygous alleles of both wild-type and mutant APC in exons 2, 9, 10, and 11. Four hamartomatous polyps (three from JP and one from PJS) showed seven, new mutations and one common APC variant (codon 486), whereas no hyperplastic polyps demonstrated mutation. APC mutation was not correlated with previous history of colorectal carcinoma or number of polyps.

Since all mutations were missense or silent mutations occurred in exons not previously known to have functionally relevant area, their phenotypic implication appeared to be limited.



Clinical and molecular features of the hereditary mixed polyposis syndrome.

Whitelaw SC, Murday VA, Tomlinson IP, Thomas HJ, Cottrell S, Ginsberg A, Bukofzer S, Hodgson SV, Skudowitz RB, Jass JR, Talbot IC, Northover JM, Bodmer WF, Solomon E.

Colorectal Cancer Unit, St. Mark's Hospital, Harrow, Middlesex, England.

Gastroenterology 1997 Feb;112(2):327-34 Abstract quote

BACKGROUND & AIMS: Various inherited syndromes predispose to the development of colonic juvenile polyps and colorectal cancer, with potential importance for sporadic tumorigenesis. This study describes features of a possibly new syndrome of atypical juvenile polyps and other colonic tumors and compares these features with those of known gastrointestinal tumor syndromes.

METHODS: A large family, St. Mark's family 96, with a tendency to develop colonic polyps of mixed histological types is described. Genetic linkage to known polyposis syndromes has been tested.

RESULTS: Adenomatous and hyperplastic polyps occur in affected members of the family, although the characteristic lesion is an atypical juvenile polyp. Some affected individuals have developed polyps of more than one type, and individual polyps may contain features of more than one histological type. Polyps can undergo malignant change. Typically, fewer than 15 polyps are found at colonoscopy and there is no extracolonic disease associated with the development of polyps. The family's polyps seem to be inherited in an autosomal-dominant fashion, but the disease is probably unlinked to candidate loci with importance in colorectal tumorigenesis, such as APC, hMSH2, and hMLH1.

CONCLUSIONS: We term this family's disease hereditary mixed polyposis syndrome (HMPS). Although mutations in the putative HMPS gene may be responsible for syndromes such as juvenile and Peutz-Jeghers polyposes, HMPS may also be a distinct disease.

Hamartomatous polyposis syndromes: molecular genetics, neoplastic risk, and surveillance recommendations.

Wirtzfeld DA, Petrelli NJ, Rodriguez-Bigas MA.

Division of Surgical Oncology, Roswell Park Cancer Institute, State University of New York at Buffalo, 14263, USA.

Ann Surg Oncol 2001 May;8(4):319-27 Abstract quote

Hamartomatous polyposis syndromes are characterized by an overgrowth of cells or tissues native to the area in which they normally occur.

Juvenile polyposis syndrome (JPS) results from germ-line mutations in the SMAD-4 gene (18q21.1) that encodes for an enzyme involved in transforming growth factor beta(TGF-beta) signal transduction. The increased neoplastic risk may result from SMAD-4 mutations in the stromal component, which stimulate epithelial dysplasia and progression to invasive malignancy. Peutz-Jeghers syndrome (PJS) is associated with germ-line mutations in the LKB1 gene (19p13.3) that encodes a multifunctional serine-threonine kinase. These mutations occur in the epithelial component, suggesting a direct tumor suppressor effect. Patients are at an increased risk of intestinal and extraintestinal malignancies, including breast, pancreatic, ovarian, testicular, and cervical cancer. Cowden's disease is associated with germ-line mutations in the PTEN gene (10q22-23) and an increased risk of breast and thyroid malignancies. Ruvalcaba-Myhre-Smith syndrome is less common; controversy suggests that it may represent a variant of Cowden's disease.

Conclusions: Genetic alterations underlying hamartomatous polyposis syndromes are diverse. Carcinogenesis may result from either germ-line mutations in the stroma (JPS) or as a direct result of functional deletion of tumor suppressor genes (PJS). Diagnosis depends on clinical presentation and patterns of inheritance within families. Suggested surveillance guidelines for the proband and first-degree relatives are outlined.

Gardner-Associated Fibromas (GAF) in Young Patients A Distinct Fibrous Lesion That Identifies Unsuspected Gardner Syndrome and Risk for Fibromatosis

Bret M. Wehrli, etal.

Am J Surg Pathol 2001;25:645-651 Abstract quote

Gardner syndrome (GS), caused by mutations in the adenomatous polyposis coli (APC) gene, is characterized by polyposis coli, osteomas, and various soft-tissue tumors. If undetected or untreated, virtually all patients develop colonic carcinoma at a young age. Early detection, while essential, can be difficult because of attenuated phenotypes or spontaneous mutations.

We present the clinicopathologic features of 11 identical fibromatous lesions that we have termed Gardner-associated fibroma (GAF), which not only appear to be a part of the spectrum of lesions associated with GS but, in some cases, represent the sentinel event leading to its detection. The GAFs occurred in 11 patients (5 boys and 6 girls; age range, 3 months–14 years), were solitary (n = 7) or multiple (n = 4), and occurred in the superficial and deep soft tissues of the paraspinal region (n = 7), back (n = 3), face (n = 2), scalp (n = 2), chest wall (n = 2), thigh (n = 1), neck (n = 1), and flank (n = 1).

Histologically, GAFs resemble nuchal-type fibromas (NFs), consisting of thick, haphazardly arranged collagen bundles between which are found occasional bland fibroblasts, and having margins that frequently engulf surrounding structures including adjacent fat, muscle and nerves. After surgical excision, four patients developed recurrences that were classic desmoid fibromatoses (DFs). In one patient with multiple GAFs, one lesion had the features of GAF and DF in the absence of surgical trauma. A family history of GS or polyposis (n = 6) or DF (n = 1) was known at the time of surgery in seven patients. In three patients, the diagnosis of GAF resulted in the diagnosis of unsuspected APC in older family members, with the detection of an occult colonic adenocarcinoma in one parent. In the family of the remaining patient, no stigmata of GS were present. Genetic analysis of this child was performed to investigate the presence of a spontaneous (new) mutation; however, no abnormalities were detected.

The significance of GAF is that it serves as a sentinel event for identifying GS kindreds, including those with a high risk for the development of DF, and it may potentially identify children with spontaneous mutations of the APC gene. Because NFs and GAFs resemble one another, we suggest that a subset of NF occurring in multiple sites, unusual locations, or children may be GAF.

Familial adenomatous polyposis: more evidence for disease diversity and genetic heterogeneity.

Scott RJ, Meldrum C, Crooks R, Spigelman AD, Kirk J, Tucker K, Koorey D;

Hunter Family Cancer Service. Hunter Area Pathology Service, Locked Bag No 1, Hunter Regional Mail Centre, Newcastle NSW 2310, Australia.

Gut 2001 Apr;48(4):508-14 Abstract quote

Familial adenomatous polyposis (FAP) is characterised by the presence of profuse colonic carpeting of adenomas throughout the entire colon and rectum. The genetic basis of FAP has been shown to be primarily associated with germline mutations in the APC gene. Notwithstanding, several reports have been published indicating that there is genetic heterogeneity in FAP and that the most likely explanation is the existence of another gene.

In this report we further delineate the genotype/phenotype correlation in families that harbour germline mutations in the APC gene and identify some previously unreported changes in the APC gene which predispose to an attenuated disease phenotype. From 53 index patients diagnosed with either FAP or attenuated FAP, 27 harboured changes in the APC gene. The remaining 26 patients were further subgrouped according to their colonic phenotype. There were nine patients with a mixed hyperplastic/adenomatous colonic phenotype and there were 17 patients with an adenomatous colonic phenotype.

Evaluation of the disease characteristics of these patients and their families is presented which may aid in the identification of new genes associated with colonic polyposis.


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

Biasco G, Cenacchi G, Nobili E, Pantaleo Ma M, Calabrese C, Di Febo G, Morselli Labate A, Miglioli M, Brandi G.
Hum Pathol. 2004 May;35(5):622-6. Abstract quote  

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 biopies 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.

Mixed epithelial polyps in association with hereditary non-polyposis colorectal cancer providing an alternative pathway of cancer histogenesis.

Jass JR, Cottier DS, Pokos V, Parry S, Winship IM.

Department of Pathology, University of Queensland Medical School, Australia.

Pathology 1997 Feb;29(1):28-33 Abstract quote

A member of a hereditary non-polyposis colorectal cancer (HNPCC) family developed two colorectal cancers and multiple polyps within four years of a negative colonoscopic examination.

One of the cancers was only 4 mm in diameter and showed the gross and endoscopic appearances of a de novo carcinoma. Microscopic examination of multiple levels revealed a mixed hyperplastic polyp/adenoma (mixed polyp) in contiguity with the cancer. The colon harboured additional polyps of which five were tubular adenomas, seven were hyperplastic polyps and seven were mixed polyps (architecturally compatible with hyperplastic polyps but with atypical cytology). Atypical features of the mixed polyps included tripolar mitoses, bizarre chromatin aggregations and multinucleation. One mixed polyp showed DNA microsatellite instability. Under the influence of the mutator defect, hyperplastic polyps may develop atypical or adenomatous features and show progression to carcinoma.

Such an alternative morphogenetic pathway could explain the differing molecular and pathological profiles of cancers showing DNA microsatellite instability.

Do Sporadic Peutz-Jeghers Polyps Exist? Experience of a Large Teaching Hospital.

*Department of Pathology, The Johns Hopkins Hospital, Baltimore, MD †Dianon Systems, Tampa, FL.


Am J Surg Pathol. 2007 Aug;31(8):1209-1214. Abstract quote

Most types of sporadic gastrointestinal (GI) polyps vastly outnumber their syndromic counterparts. In contrast, the incidence of sporadic Peutz-Jeghers polyps (PJP) is unknown.

We examined all potential PJP seen at our hospital over a 22-year (y) period to assess the incidence of sporadic PJP. The pathology database of a large hospital was searched for "Peutz-Jeghers polyp(s)," yielding 121 polyps from 38 patients. The polyps were reviewed by 3 pathologists to confirm the diagnosis.

Clinical information to confirm or refute a diagnosis of Peutz-Jeghers syndrome (PJS) was collected. Of the 102 polyps included after histologic review, 94 polyps arose in patients meeting the World Health Organization criteria for PJS. These PJS polyps were eliminated from further analysis. Clinical information was obtained for the remaining 8 patients with potential "sporadic" PJP (1 to 50 y; mean=14 y; median=4 y). Of the 8 potential sporadic PJP, only 3 polyps from 3 patients had unequivocal PJP histologic features, all from the small intestine.

All 3 patients had clinical histories suggesting syndromic PJP although they did not meet World Health Organization criteria, that is, 2 developed pancreatic cancer, 1 had bilateral "ovarian cystic masses" and a glomus tympanicum tumor, and 1 had strong family history of GI malignancies. The 5 remaining patients each had a colonic polyp with features suggestive, but not definitely diagnostic of, PJP. In these cases, prolapse lesions could not be excluded. One patient had a history of high-grade dysplasia in a tubulovillous adenoma in the colon at 53 years, but no family cancer history. Another had a family GI cancer history. Another had a history of pituitary adenoma at age 39, and the last had ductal breast carcinoma diagnosed 4 years before the discovery of the polyp.

Our findings suggest that if sporadic PJP exist, they are extremely rare. Moreover, our data suggest that individuals with a single PJP may have a cumulative lifetime risk of cancer similar to those with the syndrome.



Immunolocalization of beta catenin in intestinal polyps of Peutz-Jeghers and juvenile polyposis syndromes.

Back W, Loff S, Jenne D, Bleyl U.

Department of Pathology, Klinikum Mannheim, University of Heidelberg, Germany.

J Clin Pathol 1999 May;52(5):345-9 Abstract quote

AIM: To examine the membranous and nuclear distribution of beta catenin in the epithelial cells of gut polyps from Peutz-Jeghers syndrome and juvenile polyposis in comparison with other types of polyps and tumours.

METHODS: Immunohistochemistry for beta catenin and proliferation markers was performed on conventional paraffin sections. Immunohistological staining was carried out on Peutz-Jeghers syndrome polyps from four different families, on juvenile polyposis polyps from two different families, on solitary juvenile polyps, and on hyperplastic polyps. The immunohistochemistry was evaluated qualitatively in relation to defined areas of the polyps.

RESULTS: All polyps from the hamartomatous polyposis syndromes (Peutz-Jeghers syndrome and juvenile polyposis) showed nuclear localization of beta catenin in some epithelial cell nuclei. In Peutz-Jeghers syndrome polyps beta catenin positive nuclei were seen at the base of the deep crypt infoldings. In juvenile polyposis polyps and in some solitary juvenile polyps they were found in irregularly distributed cryptal epithelial cells corresponding to the proliferative compartments. Normal mucosa of the gut and hyperplastic polyps of the colon do not show nuclear staining for beta catenin.

CONCLUSIONS: The dysregulation of cellular beta catenin distribution is not only a phenomenon of adenoma formation and adenoma progression in the colon--it is at least focally present in polyps of the hamartomatous type and is related to the proliferation zones of these polyps. The nuclear translocation of beta catenin most probably reflects a disturbed beta catenin metabolism. In view of the different functions of beta catenin during development and cell differentiation, the nuclear translocation of beta catenin is likely to be an important factor in enhanced cell proliferation which escapes local control mechanisms.



Polyp guideline: diagnosis, treatment, and surveillance for patients with nonfamilial colorectal polyps. The Practice Parameters Committee of the American College of Gastroenterology.

Bond JH. American College of Gastroenterology, Arlington, VA 22206-1656.

Ann Intern Med 1993 Oct 15;119(8):836-43 Abstract quote

OBJECTIVE: To outline the preferable approach to the management of patients with nonfamilial colorectal polyps.

DATA SOURCES: The human subject English language literature for the past 15 years, searched using MEDLINE and the terms "polyp-," "adenoma-," and "polypectomy-colorectal."

STUDY SELECTION: The titles and abstracts of all pertinent articles were reviewed. All randomized controlled trials and large case-control and cohort studies related to colorectal polyps were reviewed in depth.

DATA SYNTHESIS: Evidence was evaluated along a hierarchy with randomized controlled trials receiving the greatest weight. Conclusions and recommendations were reviewed by a large group of experts in gastroenterology, radiology, and pathology and were circulated for comment to primary care medical societies.

CONCLUSIONS: Most patients with polyps should undergo colonoscopy to excise the polyp and search for synchronous neoplasms. Small polyps (< 0.5 cm) require individualization. A hyperplastic polyp found during proctosigmoidoscopy is not an indication for colonoscopy. Large sessile polyps require careful follow-up to ensure complete resection. The need for further treatment of a resected polyp with invasive carcinoma depends on several well-defined clinical and pathologic criteria. Follow-up surveillance after polypectomy should be tailored to the individual risk assessment for each patient. Initial follow-up should be performed at 3 years for most postpolypectomy patients. After one negative result of a 3-year examination, the interval can be increased to 5 years. Patients with one small tubular adenoma do not have an increased risk for cancer, and therefore follow-up surveillance may not be indicated. Adoption of these recommendations should substantially reduce the cost of postpolypectomy surveillance and of screening for colorectal cancer.

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Last Updated August 7, 2007

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