Extracolonic Manifestations Research Articles

Aggressive mutation in a familial adenomatous polyposis syndrome family: when phenotype guides clinical surveillance.

Familial adenomatous polyposis (FAP) is an autosomal dominant genetic condition, caused by mutations in the adenomatous polyposis coli (APC) tumor suppressor gene. Desmoid tumors (DTs) are seen in 15% to 20% of FAP patients. Specific location of mutation serves as a guide to predict colonic and extra colonic manifestations and their aggressiveness. A severe FAP-phenotypic family was registered in a genetic counselling high-risk Uruguayan hereditary cancer clinic. Proband's DNA was analysed by NGS, detecting a pathogenic mutation in APC gene. All willing family members were counselled and encouraged to be tested. Here we report a kindred formed by 16 individuals with a very severe FAP phenotype. A two-base deletion mutation: c.4393_4394delAG in APC gene and a consequent premature stop codon was detected. DTs were diagnosed in 6 individuals, ranging from 2 to 25 years of age. The causes of death were diverse: gastric cancer, rectal cancer and desmoid tumor. The already described genotype-phenotype correlation has proved its worth in this family, as clinical features reflect the mutation location at 3' end of APC gene. The inheritable and lethal nature of the disease needs a tailored follow up approach in order to reduce mortality, optimize local tumor control, and preserve patients' quality of life.

Granulomatous Upper Gastrointestinal Inflammation in Pediatric Ulcerative Colitis.

Differentiating ulcerative colitis (UC) and Crohn disease (CD) can be clinically challenging, especially in children. Granulomatous inflammation has traditionally been attributed to CD. Crypt-associated giant cells and granulomas, however, have been observed in colonic biopsies of patients with UC. This phenomenon has not been described in the upper gastrointestinal (UGI) tract with UC. Seven pediatric patients with UC with granulomatous UGI (gUGI) lesions were identified. Diagnosis of UC was based on symptoms, clinical course, laboratory results, imaging, and endoscopy. We compared the gUGI patients to a large cohort of pediatric patients with UC (n = 149). All fully evaluated cases were associated with bloody diarrhea and moderate to severe pancolitis. Gastric and/or duodenal biopsies demonstrated giant cells or granulomas near gland destruction. Small bowel imaging did not reveal any involvement. The majority of cases responded to standard medical therapies, except for 2 patients (28.6%) who required total colectomy. Acute severe, refractory colitis (ie, colectomy within 1 month of presentation) was significantly more common in the gUGI group than the large pediatric UC group (28.6% vs 1.3%, Fisher exact P = 0.01). This is the first report of pediatric UC-associated granulomatous inflammation in the UGI tract. We speculate that these lesions represent extracolonic manifestations of intense colonic disease. These atypical findings expand the diagnostic considerations that should be incorporated during the differentiation between UC and CD in the pediatric age group.

APC mosaicism in a young woman with desmoid type fibromatosis and familial adenomatous polyposis

Familial adenomatous polyposis (FAP) is usually caused by germline mutations in the adenomatous polyposis coli (APC) gene. The classic form is characterized by hundreds to thousands of adenomas in the colorectum and early onset colorectal cancer (CRC) if left untreated. FAP is also associated with multiple extra-colonic manifestations such as gastroduodenal polyps, osteomas, epidermoid cysts, fibromas and desmoids. Most desmoid tumours in FAP patients occur intra-abdominally. Approximately 15–20% of the APC mutations are de novo mutations. Somatic mosaicism has been reported in some sporadic cases of polyposis but is probably an underestimated cause of the disease. This case report presents the detection of a mosaic APC mutation in a 26-year-old woman who as a child had been diagnosed with desmoid type fibromatosis. FAP was suggested when she presented with extensive extra abdominal fibromatosis. Our findings indicate that APC mutations may be suspected in patients presenting with a desmoid regardless of its location. If there is clinical evidence that the patient has FAP, adenomas and colonic mucosa in addition to leukocyte DNA should be included in the screening, preferably using methods that are more sensitive than Sanger sequencing.

Congenital Hypertrophy of Retinal Pigment Epithelium for Diagnosis of Familial Adenomatous Polyposis - the First FAP registry in Iran

Objective:Familial adenomatous polyposis (FAP), an autosomal dominant inherited disorder is characterized by the presence of multiple adenomatous colorectal polyps, which can develop into cancer during early adulthood. Therefore, early diagnosis is essential. Most FAP patients have several extracolonic manifestations, including congenital hypertrophy of the retinal pigment epithelium (CHRPE). Whereas genetic markers may provide the main route to detection of “at risk” subjects , at present this approach is clearly limited and searches for a noninvasive phenotypic marker continue to be high priority. The aim of this study was to describe the pattern of distribution of CHRPE lesions and evaluate their diagnostic value in FAP patients and their family members in a local population.Methods:A total of 23 FAP patients and 26 relatives belonging to 12 families at high risk of developing FAP were subjected to colonoscopic and ophthalmological examination.Result:Retinal examinations demonstrated prevalences of CHRPE in FAP patents and their siblings of 78% and 38%, respectively. We were able to illustrate a significant correlation between FAP disease and the presence of retinal lesions. Sensitivity and specificity of CHRPE as a screening test to detect the presence of FAP are 78.3% and 61.5%, respectively, with a positive predictive value of 64.3% and a negative predictive value of 76.2 %. A “lesion form” significant difference was found between FAP and normal participants. Spearman nonparametric analysis revealed no correlation between age and number or size of lesions.Conclusion:Multiple CHRPE lesions are a diagnostic feature of FAP patients They are specific and sensitive clinical markers of this disease (specificity 60% and sensitivity 77%).

When Should Patients Undergo Genetic Testing for Hereditary Colon Cancer Syndromes?

When Should Patients Undergo Genetic Testing for Hereditary Colon Cancer Syndromes?

Postoperative outcome and quality of life after surgery for FAP-associated duodenal adenomatosis.

Prophylactic colon surgery has increased life expectancy of familial adenomatous polyposis patients. Extracolonic manifestations are life limiting, above all duodenal adenomas. Severe duodenal adenomatosis or cancer may necessitate pancreas-preserving total duodenectomy or partial pancreatico-duodenectomy, mostly after previous proctocolectomy and often after limited local resections of duodenal adenomas. Scarce information on long-term postoperative outcome and quality of life after surgery for duodenal adenomatosis is available. Aim of the present study was to analyze perioperative and long-term outcome after PD and PPTD for FAP-associated duodenal adenomatosis, including QoL and recurrence of adenomas in the neoduodenum after PPTD. Thirty-eight patients, 27 after pancreas-preserving duodenectomy and 11 after partial pancreaticoduodenectomy, were included. Pancreas-preserving total duodenectomy was associated with shorter operation time and less blood loss than partial pancreatico-duodenectomy. Clinically relevant pancreatic fistula occurred in 31.5%. In-hospital mortality was 5.3%. Long-term follow-up revealed recurrent pancreatitis after pancreas-preserving total duodenectomy in 22% of patients, two (7.4%) required re-operation. Recurrent adenomatosis was detected in 26% of patients. Quality of life was comparable to the German normal population after both surgical procedures. Patients with postoperative complications showed worse results than those without complications. Disease-specific 10-year survival rate with respect to duodenal adenomatosis was 100%. Surgery for FAP-associated duodenal adenomatosis and cancer can be carried out with reasonable morbidity rates despite previous proctocolectomy. Long-term outcome, quality of life, and survival rates are favorable.

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.

Adenomatous Polyposis Syndromes: Familial Adenomatous Polyposis and MutYH-Associated Polyposis

The purpose of this review is to provide an overview of the etiology, diagnosis, and clinical management of the two most common polyposis; change adenomatous to polyposis hereditary colorectal cancer syndromes, familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). The syndromes are caused by inherited genetic variants in the APC and MutYH genes, respectively. Both syndromes carry significant increased risk of colorectal and extracolonic cancers. Intense surveillance is required to reduce this risk, and colectomy or proctocolectomy is frequently the ultimate form of colorectal cancer risk reduction. The colorectal phenotype and extracolonic manifestations continue to evolve as more is learned about the natural history of the diseases, particularly MAP.

Gastric tumours in FAP.

Gastric cancer is not a recognised extra-colonic manifestation of FAP, except in countries with a high prevalence of gastric cancer. Data regarding gastric adenomas in FAP are sparse. The aim of this study was to review the clinical characteristics of gastric tumours occurring within an FAP population from the largest European polyposis registry. All patients that developed a gastric adenoma or carcinoma were identified from a prospectively maintained registry database. The primary outcome measure was the occurrence of gastric adenoma or adenocarcinoma. Secondary outcomes included APC mutation, tumour stage, management and survival. Eight patients developed gastric cancer and 21 an adenoma (median age 52 and 44 years, respectively). Regular oesophagogastroduodenoscopy surveillance was performed in 6/8 patients who developed cancer. Half were advanced T3/4 tumours and 6/8 had nodal or metastatic spread at diagnosis. All cancer cases died within a median of 13.5 months from diagnosis. Gastric adenomas were evenly distributed: 11/21 (52%) in the distal and 10/21 (48%) proximal stomach, whereas 5/8 (63%) cancers were located proximally. An association between gastric tumour and desmoid development was observed; 7/8 (88%) cancer and 11/21 (52%) adenoma cases had a personal or family history of desmoid. It would appear from this small, retrospective study that gastric cancer is not a prominent extra-colonic feature of FAP in the Western world. It seems to present at an advanced stage with a poor prognosis. There may be an association between gastric tumour and desmoid occurrence but a large multicentre cohort is necessary to investigate this further.

Incidence and Clinical Characteristics of Colonic and Extra Colonic Lynch Syndrome Manifestations in Uruguayan Mismatch Repair Carriers

Background: Colon cancer is a frequent diagnosis worldwide affecting both men and women. Lynch syndrome in an autosomal dominant inheritable condition, accountable for 5 to 7% of colon cancer, as well as other malignancies. Methodology: From a Uruguayan high risk cancer clinical setting, adult probands from 115 families, registered between 2015 and 2016, meeting Amsterdam I, II or Bethesda Revised guidelines, were tested for MMR genes and EPCAM. Results: Pathogenic Lynch Syndrome mutations were detected in 23.4% families. A total of 90 mutation carriers were diagnosed, from which information regarding molecular diagnosis, cancer diagnosis, cancer site, tumor staging, age at diagnosis and course of treatment was carefully analyzed. Cancer diagnosis before determination of carrier status was seen in 52.5% individuals; were 46.8% had more than one cancer diagnosis throughout lifetime, mostly colon cancer. The average age for colon cancer was 36.9 years old and 77% were stage II at diagnosis. Consequently, surgical treatment was the most frequent option, and partial colectomies the preferred surgical choice. Conclusions: Young age of onset and metachronous tumors are part of Lynch syndrome hallmark. How effective surveillance strategies are, are reflected on how well and timely we identify these young high risk adults. Treatment options are most frequently surgical ones, because of the stage these malignant tumors are found upon diagnosis. There is no unanimous consensus about the best surgical strategy for colon cancer Lynch syndrome carriers.

Clinicopathological features of a kindred with SCG5-GREM1–associated hereditary mixed polyposis syndrome

Since first characterized in 1997, patients with hereditary mixed polyposis syndrome (HMPS) have been difficult to identify because of lack of well-established diagnostic criteria. Recently, HMPS was found to be caused by a duplication on chromosome 15 spanning the 3' end of the SCG5 gene and a region upstream of the GREM1 locus. Clinical testing for the duplication is available; however, the clinical characteristics of hereditary mixed polyposis to support testing are ill defined. The clinicopathological findings of 10 HMPS patients with confirmed germline SCG5-GREM1 duplication were reviewed. Mean age at presentation was 33.3 years. Fifty-one colonoscopies yielded 207 polyp specimens, all of which were reexamined. Adenomas (n = 80) and a fairly unique polyp composed of a mixture of hyperplastic polyp and inflammatory polyp-type changes (n = 74) were the most common findings; however, other polyps, including hyperplastic (n = 28), mixed inflammatory polyp/adenoma (n = 8), inflammatory polyp (n = 7), prolapse-type polyp (n = 6), and lymphoid aggregates (n = 4), were encountered. None of the patients developed colorectal malignancy during surveillance, demonstrated extracolonic manifestations, or underwent colectomy on follow-up (mean, 26.2 years). SCG5-GREM1 duplication-associated polyposis is characterized by a few polyps per endoscopy with a mixture of phenotypes, most commonly adenoma and nondysplastic mixed hyperplastic/inflammatory polyps. Nine of 10 patients had at least 1 mixed hyperplastic-inflammatory polyp, which is the characteristic lesion of SCG5-GREM1 duplication-associated HMPS.

A role for the vitamin D pathway in non-intestinal lesions in genetic and carcinogen models of colorectal cancer and in familial adenomatous polyposis.

Vitamin D is implicated in the etiology of cancers of the gastrointestinal tract, usually characterized by alteration in the APC/β-catenin/TCF tumor suppressor pathway. The vitamin D receptor (VDR) is also implicated in cardiovascular and skin diseases as well as in immunity. Activated VDR can indirectly alter β-catenin nuclear localization and directly suppress β-catenin/TCF mediated transcriptional activity. We treated VDR null mice with the carcinogen azoxymethane (AOM) and generated mice bearing a mutated APC (hypomorph) on a VDR null background (Apc1638N/+Vdr−/−). VDR null mice do not develop GI or extra-colonic tumors but loss of VDR decreased intestinal tumor latency and increased progression to adenocarcinoma in both models. AOM treatment of VDR null mice also caused squamous cell carcinoma of the anus. Although levels and distribution of total or activated β-catenin in the epithelial component of tumors were unaffected by loss of VDR, β-catenin dependent cyclin D1 expression was affected suggesting a direct VDR effect on β-catenin co-activator activity. Extra-colonic mucosa manifestations in Apc1638N/+Vdr−/− animals included increased nuclear β-catenin in submucosal stromal cells, spleno- and cardiomegaly and large epidermoid cysts characteristic of the FAP variant, Gardner's syndrome. Consistent with this, SNPs in the VDR, vitamin D binding protein and CYP24 as well as mutations in APC distal to codon 850 were strongly associated with Gardners syndrome in a cohort of 457 FAP patients, This work suggests that alterations in the vitamin D/VDR axis are important in Gardner's syndrome, as well as in the etiology of anal cancer.

Differences in neuropsychological and behavioral parameters and brain structure in patients with familial adenomatous polyposis: a sibling-paired study.

BackgroundFamilial adenomatous polyposis (FAP) is an autosomal dominant hereditary colon cancer syndrome caused by mutations in adenomatous polyposis coli (APC) with both colonic and extra-colonic manifestations. Case reports have noted an association with FAP and intellectual disability and animal studies have shown that APC is implicated in neural development and function, but no studies have investigated neuropsychological, behavioral, or structural brain characteristics of patients with FAP.MethodsWe undertook a pilot, sibling-pair study comparing three patients with FAP to their sex-matched siblings without FAP. Each sibling pair underwent neuropsychological testing by a blinded examiner, high resolution brain MRI scans, and the mother of each pair rated her children’s adaptive life skills and behavioral and emotional characteristics. Given the small number of study participants in this pilot study, quantitative comparisons of results were made by subtracting the score of the non-FAP sibling from the FAP patient on the various neuropsychological tests and parent rating questionnaires to calculate a difference, which was then divided by the standard deviation for each individual test to determine the difference, corrected for the standard deviation. Diffusion numbers in multiple regions of the brain as assessed by MRI were calculated for each study participant.ResultsWe found similarity between siblings in all three pairs on a wide range of neuropsychological measures (general intelligence, executive function, and basic academic skills) as tested by the psychologist as well as in descriptions of adaptive life skills as rated by mothers. However, mothers’ ratings of behavioral and emotional characteristics of two of the three pairs showed differences between the siblings, specifically that the patients with FAP were found to have more behavioral and emotional problems compared to their siblings. No differences in brain structure were identified by MRI.ConclusionWe report the first study exploring neuropsychological, behavioral, emotional, and structural brain characteristics of patients with FAP and found subjective differences as assessed by maternal perception in behavioral and emotional characteristics in patients with FAP compared to their siblings. Larger studies are needed to elucidate the relationship, if any, between FAP and brain function.

A Rare Case Report of Gardner Syndrome: A Familial Adenomatous Polyposis Variant

Gardner syndrome is a rare autosomal dominant clinical variant of familial adenomatous polyposis (FAP). It is characterized by the prominence of inherited colonic adenomatosis together with osteomas, epidermoid cysts, desmoid tumors, and dental abnormalities. Along with FAP, Gardner syndrome can be explained by the mutation of the APC gene on chromosome 5q21-q22. In addition, the specific mutation of the MYH gene on chromosome 1p34.3-p32.1 may determine the extra-colonic manifestations found in Gardner syndrome, as well as the number, time frame, and malignant potential of the disorder. Due to its rarity, the exact prevalence of Gardner syndrome is unknown, as its statistical prevalence cannot be separated from FAP when considering reported studies. Estimates for the prevalence of the combined syndromes vary from 1 in 6,850 to 1 in 31,250 individuals.Figure 1Figure 2In this case report, we will present a patient with a prior diagnosis of Gardner syndrome that was seen for screening EGD and colonoscopy and was found to have painful, enlarging bilateral breast masses. The patient was also found to have clinically detectable cranial lesions and soft tissue lesions. A right breast mass needle biopsy was performed and resulted positive for fibrous tissue proliferation consistent with desmoid fibromatosis. EGD resulted in innumerable number of polyps within the cardia, fundus, and proximal aspect of the greater curvature as well as several large polyps in the second portion of the duodenum. Colonoscopy resulted in innumerable number of polyps throughout the colon from the cecum to the rectum. Polyps were biopsied during both exams and were positive for inflammatory, hyperplastic polyps in the stomach and tubular adenomas in the duodenum, cecum, and colon. Patients with Gardner syndrome and any FAP-encompassing disease will require regular screening for numerous neoplastic transformations, as presented in this case. A prophylactic colectomy is recommended and unavoidable. It should be performed early in the disease course in order to decrease the patient's risk of colorectal cancer formation. After surgical prophylaxis has been conducted, patients will continue to require lower gastrointestinal surveillance at the anastomosis site as well as lifetime upper gastrointestinal screening based on Spigelman classification. Strict follow-up and surveillance guidelines remain a vital component to the treatment of these patients in order to reduce overall morbidity and mortality.

Extracolonic Clostridium difficile Infection with Peri-rectal Abscesses: A Rare Occurence

Introduction:Clostridium difficile (C.difficile) is the agent implicated for pseudomembranous colitis. It is responsible for 10% - 25% of cases of antibiotic associated diarrhea. Extracolonic manifestations of clostridium difficile infections are rare and very few reports have been published in the literature. We present a case of recurrent clostridium difficile colitis in a patient with rectal adenocarcinoma treated surgically, presenting with multiple peri-rectal abscesses with polymicrobial clostridium difficile infection. Case: 74 y/o female with past medical history significant of rectal adenocarcinoma s/p neoadjuvant chemotherapy and surgery, hypertension, CVA, seizure disorder and recurrent C.difficile colitis presented to the hospital with intermittent diarrhea for 3 weeks. The diarrhea was associated with intermittent rectal bleeding for 10 days, right lower quadrant abdominal pain, nausea and vomiting. The patient was started on iv metronidazole and PO vancomycin. CT abdomen and pelvis revealed 1.9 x 4.8 x 1.9 cm fluid collection in the left peri-rectal fossa, 2.1 x 3.3 x 2.8 cm fluid collection in the right peri-rectal fossa with air and a 2.3 cm collection of air in the left pelvic wall muscle. MRI of the pelvis revealed heterogenous signal and contrast enhancement in the sacrum consistent with post treatment changes or fibrosis. IR guided bone biopsy was negative for osteomyelitis or metastasis. IR guided drainage of the perirectal abscesses was also performed with placement of a drain. The culture was positive for candida dubliniensis, streptococcus milleri and clostridium difficile. She was hence started on fluconazole, iv vancomycin for streptococcus milleri and oral vancomycin was switched to fidaxomicin along with iv metronidazole for treatment of C.difficile. Patient eventually had resolution of symptoms along with improvement in nutritional status. Discussion: Extracolonic manifestations of clostridium difficile infection include osteomyelitis, bacteremia, visceral abscesses, empyema, pyelonephritis, prosthetic infection, reactive arthritis, skin and soft tissue infections. It is more common in patients with significant comorbidities and relative immunosuppression. Studies have also shown that increased extracolonic infections are seen in patients with intestinal surgery as evident in our patient. Most of the cases are polymicrobial in nature and treatment has been directed towards all organisms as described in our case.Figure 1Figure 2

Prospective Evaluation of Terminal Ileitis in a Surveillance Population of Patients with Ulcerative Colitis.

Ulcerative colitis (UC) is a disease that is normally limited to involvement of the colon. Terminal ileitis in patients with UC with only inactive or mildly active disease has never been investigated. The aim of this prospective study was to determine the prevalence and significance of ileitis among patients with UC enrolled in an endoscopic surveillance program. The study consisted of 72 patients with UC and 90 healthy controls who underwent surveillance and screening colonoscopy, respectively. The endoscopic and histologic features of the terminal ileum (both groups) and colon (UC group only) were evaluated in a standardized fashion. Extensive clinical and endoscopic information was obtained from the subjects, and these data were compared between patients with UC either with or without ileitis. Sixteen of 72 patients with UC (22%) had ileitis compared to only 4 of 90 (4%) of the non-UC controls (P < 0.001). None of the patients had features of backwash. Among patients with UC, the presence of ileitis showed a trend towards correlation with extent of disease, but a significant association with involvement of the colonic side of the ileocecal valve (P = 0.02) was noted. Alcohol use in the week before the colonoscopy was also significant (P = 0.02). There were no other features that were significantly related to ileitis in the patients with UC. Only one UC case with ileitis developed Crohn's disease on follow-up. Ileitis in patients with UC may represent a primary extracolonic manifestation of UC in patients with inactive or mild disease and is not due to backwash.

Gastric Tubular Adenomas Five Years After Total Proctocolectomy in Familial Adenomatous Polyposis

Familial Adenomatous Polyposis (FAP) is an autosomal dominant syndrome caused by mutations in the Adenomatous polyposis c (APC) gene. The prevalence of FAP ranges from 1 in 6, 850 to 1 in 31,250 births.Guidelines suggest FAP patients should start the surveillance process for colorectal cancer around age 10-12.However, endoscopy to look for FAP-like extra-colonic manifestations is recommended to start at age 25-30. Patients with FAP frequently have gastric polyps which could be fundic gland polyps and tubular adenomas, however it is uncommon to have mostly gastric tubular adenomas. A 23-yearold female with a past medical history of FAP presented for gastrointestinal surveillance. The patient's mother had FAP and thus the patient was screened for APC gene mutation which turned out to be positive. She underwent endoscopic surveillance of the gastrointestinal tract at age 18 when she found to have multiple colonic tubulovillous adenomas and subsequently had a total proctocolectomy with a J-pouch ileoanal anastomosis. She also had an abdominal wall desmoid tumor that was removed. The patient's first endoscopy was at age 19. The first three endoscopies (age 19, 20, and 21) showed fundic gland polyps in the stomach and tubular adenomas in the small bowel. The patient's most recent endoscopy showed multiple diminutive fundic gland like gastric polyps (figure 1, A) which turned to be tubular adenomas on histology. She also was noted to have duodenal tubular adenomas, figure 1, B. The prevalence of gastric adenomas is estimated to be about 9.2%- 23% in FAP. The risk for gastric cancer in FAP patients is 0.6% and seems to be more common in attenuated FAP than in FAP. Although we do not have a true estimate for the rate of transformation from gastric adenoma to malignancy, endoscopic surveillance is still recommended. Endoscopic surveillances have better metric measures in small bowel tubular adenomas than in gastric adenomas using the Spigelman staging system. This case had gastric and duodenal polyps at a much earlier age (19) than the recommended age of screening endoscopy (25-30). This case reminds us of the importance of surveillance EGDs in FAP patients and taking multiple biopsies from polyps which may look like fundic gland polyps on endoscopic evaluation but may be tubular adenomas on histology.Figure 1Figure 2

Clinical Characteristics of Multiple Colorectal Adenoma Patients Without Germline APC or MYH Mutations.

Patients with multiple colorectal adenomas (MCRA) without genetic cause are increasingly being diagnosed. The characteristics and natural history of this condition are not well studied. Twenty-seven patients with MCRA, with cumulatively 10 to 99 colorectal adenomas and without deleterious mutations of APC or MYH genes, were investigated. Results of colonoscopies with a mean follow-up of 4.9 years (range, 0 to 27 y) were evaluated. Findings from esophagogastroduodenoscopy and extracolonic manifestations were assessed. The mean age at polyp diagnosis and MCRA diagnosis was 47.8±13.1 years (range, 21 to 72 y) and 50.4±14.6 years (range, 21 to 72 y), respectively. In 22% of patients another family member had MCRA. At first colonoscopy, the mean number of adenomas was 35.0±35.9 (range, 0 to 99). Serrated polyps were rare. Esophagogastroduodenoscopy revealed 47% of patients had upper tract neoplasia. Patients with upper tract findings were diagnosed with MCRA at significantly younger mean age than those without findings, P<0.05. Eighteen patients (67%) underwent colectomy with a mean time from diagnosis of MCRA of 3.1±1.3 years. After surgery, surveyed patients developed recurrent adenomas in retained colorectum. Nine patients (33%) had extracolonic cancers. MCRA patients have a similar clinicopathologic phenotype to known syndromes of attenuated adenomatous polyposis and the majority have need for colectomy. The management of MCRA patients and families should parallel that of attenuated familial adenomatous polyposis and MUTYH-associated polyposis including surveillance of the upper tract.

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.

Germline and somatic mutations of the APC gene in papillary thyroid carcinoma associated with familial adenomatous polyposis: Analysis of three cases and a review of the literature.

Patients with familial adenomatous polyposis (FAP), which is caused by the dysfunction of the adenomatous polyposis coli (APC) protein, have the possibility of developing extracolonic manifestations, including thyroid cancer (TC), congenital hypertrophy of the retinal pigment epithelium, desmoid tumors, and gastric and duodenal adenomas. The pathogenesis of these disorders associated with FAP is considered to be affected by the site of the germline mutation on the APC gene as a genotype-phenotype correlation. Moreover, β-catenin binding sites consist of 20-amino acid repeats (20-AARs) in the APC protein, and they are essential for the development of colorectal adenomas and certain other extracolonic manifestations. The present study retrospectively analyzed the germline and somatic mutations of the APC gene in three papillary TC patients with FAP to analyze the association between the remaining number of 20-AARs and the development of TC. The mutation sites of two TCs did not include 20-AARs in each allele. In one patient, the remaining number of 20-AARs was two in the germline mutation and zero in the somatic mutation. Together with the data on 13 FAP-associated thyroid cancerous lesions in 3 FAP patients reported previously, the majority of the remaining numbers of 20-AARs was zero in the TC patients with FAP (13/16; 81.3%). Consequently, the APC/β-catenin signaling pathway may be strongly involved with the pathogenesis of TC with FAP. Further accumulation of FAP patients with TC will be required to confirm the molecular pathogenesis of TC.