Extracolonic Manifestations Of Familial Adenomatous Polyposis Research Articles

A Multi-Institutional Cohort of Therapy-Associated Polyposis in Childhood and Young Adulthood Cancer Survivors.

Prior small reports have postulated a link between gastrointestinal polyposis and childhood and young adulthood cancer (CYAC) treatment (therapy-associated polyposis; TAP), but this remains a poorly understood phenomenon. The aim of this study was to describe the phenotypic spectrum of TAP in a multi-institutional cohort. TAP cases were identified from eight high-risk cancer centers. Cases were defined as patients with ≥10 gastrointestinal polyps without known causative germline alteration or hereditary colorectal cancer predisposition syndrome who had a history of prior treatment with chemotherapy and/or radiotherapy for CYAC. A total of 34 TAP cases were included (original CYAC: 27 Hodgkin lymphoma, three neuroblastoma, one acute myeloid leukemia, one medulloblastoma, one nephroblastoma, and one non-Hodgkin lymphoma). Gastrointestinal polyposis was first detected at a median of 27 years (interquartile range, 20-33) after CYAC treatment. A total of 12 of 34 (35%) TAP cases had ≥50 colorectal polyps. A total of 32 of 34 (94%) had >1 histologic polyp type. A total of 25 of 34 (74%) had clinical features suggestive of ≥1 colorectal cancer predisposition syndrome [e.g., attenuated familial adenomatous polyposis (FAP), serrated polyposis syndrome, extracolonic manifestations of FAP, mismatch repair-deficient colorectal cancer, or hamartomatous polyposis] including 8 of 34 (24%) with features of multiple such syndromes. TAP is an apparently acquired phenomenon that should be considered in patients who develop significant polyposis without known causative germline alteration but who have had prior treatment for a CYAC. Patients with TAP have features that may mimic various hereditary colorectal cancer syndromes, suggesting multiple concurrent biologic mechanisms, and recognition of this diagnosis may have implications for cancer risk and screening.

Diagnosis and Management of Familial Adenomatous Polyposis in Adolescence: Case Report and Review of Literature

Introduction: Familial Adenomatous Polyposis (FAP) is characterized by development of numerous polyps (typically more than 100) in the epithelium of colon. Extra colonic manifestations of the disease are also common and 58-90% of FAP patents develop polyps in stomach and duodenum. The disease is most commonly inherited as an autosomal dominant trait caused by a germ line mutation of a tumor suppressor gene called the adenomatous polyposis coli gene in chromosome 5q21 and has a reported incidence of 1 in 5000 to 1 in 17000 live birth annually. If left untreated, the predisposition of malignant transformation is significant and typically occurs in the third to fifth decade of life with 100% disease penetrance by 40 years of age. In the United States, FAP is responsible for approximately 1% of all the colon cancer reported each year. We present four cases of FAP. Methods: Medical records of four patients diagnosed with FAP (defined on colonoscopy findings) at BGA were reviewed. The collected data included demographics, disease presentation, investigation, treatment, hospital charts, endoscopy, and pathology. Results: The median age at presentation was 14 (SD±2) years. Three patients had a strong family history (75%) and one patients who underwent genetic testing was positive for APC mutation. One patient presented in early childhood with failure to thrive and the most common presenting complaint was rectal bleeding (3/4, 75%). After diagnosis, all four patients were referred for surgical intervention. One patient underwent total Procto-colectomy and two patients underwent total Colectomy with rectal preservation and recovered with no major complications. As of now, fourth patient has not had any surgical intervention. All four patients had extra-colonic manifestations with Gastric polyps being the most common (2/4), one patient had Pancreatitis (1/4) and one developed Medullary Thyroid Cancer (1/4). During the follow-up period, nine Flexible Sigmoidoscopy were performed. Both patient with rectal preservation developed polyps in the rectum and the number of polyps ranged from 5-50. Ten follow-up Esophageo-gastroscopies were performed. Two patients had Gastric and duodenal polyps and one developed a single polyp near the Ampulla of Vater. Conclusion: Methods and intervals of surveillance for gastric lesions in patents with FAP are decided by individual patient presentation and further studies appear to be needed to establish guidelines.Figure: Patient profile.Figure: Extra colonic manifestations of FAP.

FAP Associated Papillary Thyroid Carcinoma: A Peculiar Subtype of Familial Nonmedullary Thyroid Cancer.

Familial Nonmedullary Thyroid Carcinoma (FNMTC) makes up to 5–10% of all thyroid cancers, also including those FNMTC occurring as a minor component of familial cancer syndromes, such as Familial Adenomatous Polyposis (FAP). We give evidence that this extracolonic manifestation of FAP is determined by the same germline mutation of the APC gene responsible for colonic polyps and cancer but also shows some unusual features (F : M ratio = 80 : 1, absence of LOH for APC in the thyroid tumoral tissue, and indolent biological behaviour, despite frequent multicentricity and lymph nodal involvement), suggesting that the APC gene confers only a generic susceptibility to thyroid cancer, but perhaps other factors, namely, modifier genes, sex-related factors, or environmental factors, are also required for its phenotypic expression. This great variability is against the possibility of classifying all FNMTC as a single entity, not only with a unique or prevalent causative genetic factor, but also with a unique or common biological behavior and a commonly dismal prognosis. A new paradigm is also suggested that could be useful (1) for a proper classification of FAP associated PTC within the larger group of FNMTC and (2) for making inferences to sporadic carcinogenesis, based on the lesson from FAP.

Familial adenomatous polyposis: natural history and care of the patient

Familial adenomatous polyposis (FAP) is a rare, autosomal dominantly inherited condition. It is characterised by the development of hundreds to thousands of colorectal adenomas, which usually develop during adolescence (Bussey, 1975). The diagnosis of FAP is based clinically upon the identification of the colorectal adenomas, and may be confirmed by genetic testing. In many cases, a family history will reveal an autosomal dominant inheritance pattern. This article will review the natural history of FAP and discuss the care of this patient group. It will include the recommended screening and surgical options for the lower gastrointestinal tract and discuss suggestions for screening the upper gastrointestinal tract. The associated extra-colonic manifestations of FAP will be explained and the importance of a multidisciplinary approach for the care of these patients will be highlighted.

Necrotizing Pancreatitis in a Patient with Gardnerʼs Variant Familial Adenomatous Polyposis

Purpose: To evaluate the etiology of necrotizing pancreatitis in a patient with Gardner's variant familial adenomatous polyposis (FAP). Review of patient records and literature review with OVID and PubMED. Patient was a 62-year-old male with Gardner's syndrome status-post colectomy and subsequent secondary proctectomy with ileostomy secondary to anastomatic tumor. Patient had high-grade dysplasia of papilla on prior EGD and was undergoing scheduled EGD as part of surveillance. After the endoscopy, the patient was discharged but within 10 minutes of discharge complained of severe pain and a stat CT showed no perforation but some stranding of pancreas. He was hemodynamically stable but labs were significant for WBC 21.04 (16.4 neutrophils, 0.13 bands), amylase 2,312, and lipase 4,477. Other labs were normal. Patient was admitted with pancreatitis and resuscitated aggressively. He was started on empiric antibiotic therapy and re-imaging revealed necrotizing pancreatitis. He continued to deteriorate with development of ARDS and sepsis. Patient was taken for ex-lap 29 days after the EGD with removal of 1.8 L of necrotic fluid. He succumbed to the complications and died 31 days after EGD. Review of literature revealed one other case of iatrogenic necrotizing pancreatitis in a patient with FAP.1 In a case similar to this, patient developed necrotizing pancreatitis after surveillance EGD. Even though the exact incidence of pancreatitis after biopsy is unknown, there appears to be an increased risk of pancreatitis in patients with FAP, even without endoscopic intervention. Classically, this has been attributed to development of obstructive ampullary adenomas (though the incidence of this is also rare). One retrospective review studied eight patients with Gardner's variant FAP who developed pancreatitis.2 Five of eight patients had obstructing focal or diffuse adenomatous disease involving the ampulla and the others had no identifiable cause. Finally, one case series suggests that patients with FAP are at increased risk of pancreatitis regardless of obstruction of ampulla.3 This series reviewed seven patients with FAP who experienced one or more episodes of pancreatitis. None of these patients had obstruction of the ampulla. Two of the seven patients developed pancreatitis after endoscopic treatment of ampullary adenoma, while the etiology of pancreatitis in the other five could not be determined. This suggests that pancreatitis may be a extra-colonic manifestation of FAP through an unknown mechanism. However, despite the risks of iatrogenic pancreatitis (with biopsy or with ampullary lesion) the risk of malignancy supports continued surveillance both ethically and clinically. This is the second case FAP in the literature to have fatal outcome after biopsy of papilla.

P-0234 Surgical Approach to the Familial Adenomatous Polyposis According to the Genetic Basis

ABSTRACT Introduction Familial adenomatous polyposis (FAP) is an autosomic dominant syndrome defined by the presence of more than a hundred colonic adenomatous polyps. It results from germline mutations in APC gene. In FAP, the risk of malignant transformation is 100%, thus the need for prophylactic surgery is beyond question. Debate exists about which surgical technique should be carried out. Although, proctocolectomy with ileal pouch-anal anastomosis has been practiced more often, because of its postoperative complications and the impact on quality of life, other less extensive resections have been accomplished in some particular cases. Nowadays, there is a preference for individualized treatment, based upon genotype-phenotype correlations. Methods We present two cases showing different surgical treatment based on the location of the mutation within APC gene. Results CASE 1: A 28-year-old female with a family history of FAP was evaluated at the High Risk CRC Unit of our institution. A diagnostic colonoscopy was carried out in which more than 100 polyps were found along the whole length of the large bowel, including more than 20 in the rectum. Biopsies from some of them were reported as adenomatous polyps without dysplasia in any of them. A genetic analysis was carried out on her. A mutation in the APC gene was detected (exon 7, c.268 G>T). Due to these clinical and molecular findings, she underwent prophylactic surgery, in which a proctocolectomy with ileal pouch-anal anastomosis was carried out. CASE 2: A 45- year-old male, with a medical history of only hypertension, osteochondrosis and gastroesophageal reflux disease, without any familial predisposition to cancer. He was examined in our institution because of nonspecific abdominal symptoms. A colonoscopy was carried out, which showed many polyps along the large bowel. In the rectum, only one lesion was found with same characteristics. Biopsies from some of them were reported as adenomatous polyps with several dysplasias. A mutation in the APC gene was detected (exon 1. c70c>T). The patient underwent total colectomy with ileorectal anastomosis, exceeding the rectal polyp. Conclusion Nowadays, it is recognised that a correlation might exist between the site of mutations in APC gene and clinical phenotype of FAP. Whilst, some mutations have been associated with the severity of colonic polyposis (case 1), others lead to attenuated forms of the disease (case 2). In the same way, the extracolonic manifestations of FAP, as upper intestinal tumors and desmoids, have also been correlated with the site of APC mutation. Therefore, the debate continuous about which operation should be carried out. Up to now, proctocolectomy was considered when >1000 polyps develop, a large number in the rectum, when rectal adenomas >3 cm are found, or when advanced histology appears. However, we support the idea that these recommendations should be completed with the consideration of the site of the mutations in the gene APC. This work was funded by the Spanish Fondo de Investigaciones Sanitarias (grant number FIS-PI10/0683).

Ovarian steroid cell tumor with biallelic adenomatous polyposis coli inactivation in a patient with familial adenomatous polyposis

Familial adenomatous polyposis (FAP) is an autosomal dominant cancer predisposition syndrome that accounts for approximately 0.5-1% of all colorectal cancer cases. It is caused by germline mutations in the gene encoding the adenomatous polyposis coli (APC) tumor suppressor. Somatic APC inactivation due to mutation or loss of heterozygosity (LOH) promotes the development of adenomatous polyps by stabilizing the transcriptional coactivator β-catenin. Although colorectal cancer is by far the most common malignancy seen in FAP patients, the widespread use of prophylactic colectomy in these patients has increased the clinical importance of extracolonic tumors that are part of the neoplastic spectrum in FAP. Many of these tumors exhibit LOH or somatic APC mutation, strongly supporting a causative role of APC inactivation in their pathogenesis. Here we describe a 47-year-old female FAP patient with clinical manifestations of virilization who was found to have an ovarian steroid cell tumor, a rare neoplasm not known to be associated with FAP. Immunohistochemical analysis of the ovarian tumor demonstrated strong nuclear β-catenin staining consistent with somatic APC inactivation, and molecular analysis confirmed biallelic APC inactivation in the tumor. Our findings provide the first evidence that ovarian steroid cell tumors may be an extracolonic manifestation of FAP and implicate β-catenin activation as an oncogenic mechanism in ovarian steroid cell tumorigenesis.

Hepatoblastoma: when to screen?

Hepatoblastoma is a rare hepatic malignancy that is seen in Familial Adenomatous Polyposis (FAP). The occurrence is four hundred fold higher than the general population [1]. Hepatoblastoma is generally treatable with surgery; in addition it is highly responsive to chemotherapy. While the literature reports on this extracolonic manifestation of FAP, no screening recommendations exist, this may be due to the rarity of the condition and paucity of published literature. Our aim was to examine and assess the number of hepatoblastoma patients, their associated demographics and the outcome of disease.

Inherited multitumoral syndromes including colorectal carcinoma

Inherited multitumoral syndromes including colorectal carcinoma are the followings: familial adenomatous polyposis (FAP), hereditary non-polyposis colon cancer (HNPCC) and Peutz-Jeghers syndrome (PJS). The studies of genotype-phenotype correlation have shown that various types of colonic polyposis are related with germline mutation of adenomatous polyposis coli (APC) gene, that is also responsible for a wide number of extracolonic manifestations. Concerning severity of polyposis, it has been suggested to perform ileorectal anastomosis in patients with intermediate FAP, whereas it has been suggested to remove the rectum from the beginning and to perform ileopouch anastomosis in patients with severe FAP (germline APC mutations between codons 1250 and 1464, i.e. mutation cluster region-MCR). Concerning extracolonic manifestations, original studies from our laboratory have shown that three peculiar, even if unusual extracolonic manifestations of FAP, were in the 5' portion of the gene, but almost always outside of MCR. In particular, in some patients or in some kindreds all these manifestations may be present together. It is suggested, from one hand, because of the wide variety of genotype-phenotype correlation word of caution before selecting surgical treatment simply on the basis of the germline mutations, on the other hand co-segregation of some extracolonic manifestations could facilitate intensive screening, early diagnosis and optimal time for treatment.

Preclinical studies of gene transfer for the treatment of desmoid disease in familial adenomatous polyposis.

Familial adenomatous polyposis (FAP) arises following mutation or loss of the adenomatous polyposis coli (APC) gene. Desmoid tumours are proliferations of fibroblasts and occur as an extracolonic manifestation of FAP. They are a leading cause of death after colectomy. The aim of this study was to assess the potential for APC gene transfer into fibroblasts in vitro and in vivo as a basis for consideration of gene therapy in the prevention or treatment of desmoid tumours. The APC gene was transferred by lipofection into fibroblasts in tissue culture and into peritoneum and small bowel mesentery in vivo. Reverse transcriptase-polymerase chain reaction was used to determine whether or not transfection was successful. Transgene expression was recorded in vitro to 7 days after transfection. High levels of transgene expression were also seen in samples of peritoneum (all eight mice), small bowel mesentery (seven of eight), liver (seven of eight) and intestinal tissues (five to six of eight) following intraperitoneal treatment. Interestingly, transgene expression in gonadal tissues was occasionally noted. Liposomal transfection of APC gave prolonged high-level expression of the transgene, an important basis for gene therapy. No adverse effects were recorded. Further work is needed in animal models of desmoid disease to assess the clinical effects of gene therapy.

Clinical management and genetics of gastrointestinal polyps in children.

Clinical management and genetics of gastrointestinal polyps in children.

AN OPERATIVE CASE OF FAMILIAL ADENOMATOUS POLYPOSIS WITH INTRAABDOMINAL DESMOID

Familial adenomatous polyposis (FAP) is thought to be caused by abnormality of APC gene on 7q chromosome and has the property of autosomal-dominant heritage. We have experienced an operated case of FAP with diverse extracolonic manifestations. A 26-year-old man was referred to the hospital because of anal bleeding. Colonfiberscopy and barium enema study demonstrated colorectal polyposis. On family history, it was outstanding that paternal brothers died at relatively younger age due to rectal cancer, and moreover his younger sister was proved to have colorectal polyposis. Consequently, his family was thought to be FAP family line. In this case, apart from colorectal polyposis, we detected many complications including abnormal dentition, congenital hypertrophy of retinal pigment epithelium, and mesenteric desmoid as extracolonic manifestations of FAP. When prophylactic total colectomy and ileo-rectostomy were performed, desmoid of mesenteric-origin involving terminal ileum, caecum and retroperitoneum was resected concurrently. It is said that the desmoid usually develops after prophylactic colectomy in most cases of FAP, and so preoperative development of desmoid as this case seems to be relatively rare.

Overview of screening and management of familial adenomatous polyposis.

The rarity of familial adenomatous polyposis (FAP) means that many clinicians may be unaware of the major advances that have taken place in screening for the condition over the past five years. This review is not only to document the current scene but also to give details of those involved in establishing registries throughout the country. FAP is a hereditary disorder which carries with it almost a 100% risk of colorectal cancer. The aim of screening is to detect gene carriers before they present with symptoms attributable to colonic polyps. In this way the incidence of colorectal cancer can be greatly reduced. The use of gene probes to identify patients with FAP is in its infancy but in selected pedigrees gene carriers can be identified using a venous blood sample. The recognition that congenital hypertrophy of the retinal pigment epithelium is an extracolonic manifestation of FAP in most pedigrees allows non-invasive ophthalmological screening of relatives at risk. The combination of these new screening methods with an effective regional registry for FAP can increase the number of patients detected by screening rather than by symptoms. This facilitates appropriate prophylactic surgery and reduces mortality related to colorectal cancer.