Caracterización clínica y genética de las poliposis intestinales hereditarias / Clinics and genetic characteristics in hereditary colon polyposis

Se denomina pólipo intestinal a una lesión visible elevada o tumor que se proyecta desde la superficie epitelial al lumen visceral. En relación al número, presencia de antecedentes familiares, manifestaciones extraintestinales y estudios genéticos es que se constituyen diversas poliposis intestinales. Si bien, las poliposis intestinales se manifiestan en general en la edad adulta, existen manifestaciones que pueden hacer sospechar la presencia de un síndrome poliposico hereditario en la infancia. Además en una proporción considerable estas poliposis presentan manifestaciones extraintestinales, tanto benignas como tumores en otros órganos. Es por esto, que una alta tasa de sospecha, en particular frente a pacientes con antecedentes familiares, puede conducir a un diagnóstico y tratamiento oportuno, además de considerar a la familia como potenciales pacientes e ingresar al grupo familiar a un registro de tumores hereditarios. Diversas técnicas de biología molecular han permitido la identificación de las mutaciones que son heredadas en estas enfermedades, permitiendo realizar conductas preventivas al saber el riesgo de cada persona en una familia afectada. El objetivo de esta revisión, es caracterizar las distintas poliposis intestinales, en cuanto a sus manifestaciones clínicas, clasificaciones, estudio genético y enfrentamiento multidisciplinario.

Polyps are solid or tumoral elevated lesions that arise from the intestinal epithelium so that they become visible in the intestinal epithelium so that they become visible in the intestinal lumen. Information regarding familial history, number, extraintestinal manifestations and genetic studies of polyps, assemble different types of intestinal polyposis. Generally, clinical manifestations occur in adult patients, although in children there are several signs that should make the physician suspect a hereditary polyposis syndrome. In addition it is important to know extraintestinal manifestations which are mostly benign but tumors may be present in other organs too. Bearing in mind that high clínical suspicion of hereditary polyposis syndrome especially if familial history is present, provides early diagnosis and appropriate treatment for the patient and eventually for the family members that could be affected, entering that family in a registry of hereditary tumors. Molecular biology has created different techniques to identify the presence of hereditary mutations that are specific for intestinal polyposis. Acknowledgment of these mutations establishes risks groups allowing adequate prevention strategies. The objective of this revision is to characterize and different types of intestinal polyposis, according to clinical manifestations, classification, genetic study and multidisciplinary approach.

Colorectal polyposes: from phenotype to diagnosis.

The colorectal polyposes are uncommon and frequently present diagnostic difficulties. Although the final diagnostic arbiter is the demonstration of a germline mutation, this may not always be demonstrable, and some forms of colorectal polyposis have no known genetic basis. Therefore, an accurate description of the phenotype by the pathologist is central to the establishment of a working diagnosis. This can direct the search for the underlying genetic cause (if any) and is also essential for establishing the magnitude of risk of colorectal malignancy for the patient and the patient's relatives. The pathologist may be provided with only a small and selected sample of endoscopically resected polyps or with prodigious numbers of polyps (too many to sample) when receiving a surgical specimen. Each type of polyposis presents its own particular diagnostic problems that may relate to polyp numbers, gross recognition of small or flat polyps, incomplete development of the full phenotype at the stage of investigation, and the histological classification of unusual or mixed polyps. The aim of this review is to highlight the principles and pitfalls in achieving a comprehensive description of the various types of colorectal polyposis, including classical FAP, attenuated FAP, MUTYH- (formerly MYH-) associated polyposis (MAP), other presentations of multiple adenomas, Peutz-Jeghers syndrome (P-JS), juvenile polyposis syndrome (JPS), Cowden syndrome (CS), hereditary mixed polyposis syndrome (HMPS), and hyperplastic polyposis syndrome (HPS).

Molecular classification of patients with unexplained hamartomatous and hyperplastic polyposis.

CONTEXT: Significant proportions of patients with hamartomatous polyposis or with hyperplastic/mixed polyposis remain without specific clinical and molecular diagnosis or present atypically. Assigning a syndromic diagnosis is important because it guides management, especially surveillance and prophylactic surgery. OBJECTIVE: To systematically classify patients with unexplained hamartomatous or hyperplastic/mixed polyposis by extensive molecular analysis in the context of central rereview of histopathology results. DESIGN, SETTING, AND PATIENTS: Prospective, referral-based study of 49 unrelated patients from outside institutions (n = 28) and at a comprehensive cancer center (n = 21), conducted from May 2, 2002, until December 15, 2004. Germline analysis of PTEN, BMPR1A, STK11 (sequence, deletion), SMAD4, and ENG (sequence), specific exon screening of BRAF, MYH, and BHD, and rereview of polyp histology results were performed. MAIN OUTCOME MEASURES: Molecular, clinical, and histopathological findings in patients with unexplained polyposis. RESULTS: Of the 49 patients, 11 (22%) had germline mutations. Of 14 patients with juvenile polyposis, 2 with early-onset disease had mutations in ENG, encoding endoglin, previously only associated with hereditary hemorrhagic telangiectasia; 1 had hemizygous deletion encompassing PTEN and BMPR1A; and 1 had an SMAD4 mutation. One individual previously classified with Peutz-Jeghers syndrome had a PTEN deletion. Among 9 individuals with an unknown hamartomatous polyposis, 4 had mutations in STK11 (1), BMPR1A (2), and SMAD4 (1). Of the 23 patients with hyperplastic/mixed polyposis, 2 had PTEN mutations. Substantial discrepancies in histopathology results were seen. CONCLUSIONS: Systematic molecular classification of 49 patients with unexplained hamartomatous or hyperplastic polyposis uncovered a potential novel susceptibility gene, ENG, for juvenile polyposis. Importantly, given the substantial proportion of patients found to have germline mutations, more extensive analysis of the known susceptibility genes is indicated. Rereview of histology results by a dedicated gastrointestinal pathologist should be considered routinely, as organ-specific surveillance rests on defining syndromic diagnosis.