Desmoplastic fibroma of the mandible in a 5-year-old child as an early oral manifestation of familial adenomatous polyposis.

Desmoplastic fibroma (DF) is a benign yet locally aggressive intraosseous tumour rarely encountered in the mandible. It often mimics other oral lesions. Familial adenomatous polyposis (FAP) is a condition in which individuals tend to develop multiple colorectal polyps, which may convert to colorectal cancer unless treated. FAP has various colonic and extra-colonic manifestations, including oral manifestations. A case of DF of the mandible in a 5-year-old child is presented here. The patient remained free of recurrence 4 years after segmental resection and immediate reconstruction with a fibula free flap. Subsequent genetic testing revealed FAP, implicating DF as an early oral manifestation. A review of the existing literature emphasizes the challenges in diagnosing DF and its association with FAP, stressing the importance of comprehensive assessment and genetic screening in suspected cases.

Adrenal tumours in patients with pathogenic APC mutations: a retrospective study.

BACKGROUND: Adrenal tumours are associated with familial adenomatous polyposis (FAP). In the literature, most studies use the clinical definition of FAP (more than 100 adenomatous polyps found in endoscopic studies). However, not all patients that meet clinical criteria for FAP carry pathogenic mutations in the adenomatous polyposis coli (APC) gene, as there is genetic heterogeneity responsible for FAP with the polyposis sometimes explained by genetic and environmental factors other than pathogenic APC mutations. Reciprocally, not all the patients with pathogenic APC variants will fulfil the classic criteria of FAP. OBJECTIVE: This study aims to investigate the characteristics of adrenal tumours in patients with pathogenic or likely pathogenic APC variants and explore the hormonal function of these patients. METHOD: This is a retrospective cohort study. Patients with pathogenic or likely pathogenic APC variants were recruited and their radiological assessments were reviewed. Patient demographic data, APC variants, adrenal mass characteristics and hormonal testing results were collected. RESULT: The prevalence of adrenal mass was 26.7% (24/90) among patients with pathogenic or likely pathogenic APC variants. Using the classic definition, the prevalence was 32.4% (22/68). Four patients had adrenal hormone testing, two of which had Conn's syndrome and two had nonspecific subclinical results. CONCLUSION: In our cohort, the prevalence of adrenal tumours among patients with pathogenic and likely pathogenic APC mutations is at least twice to three times higher than the general population prevalence reported from international population-based studies. The hormonal functions of patients with pathogenic APC variants and adrenal tumours can be investigated with routine testing in further research.

Familial adenomatous polyposis: a case report.

BACKGROUND: Familial adenomatous polyposis is characterized by the presence of multiple colorectal adenomatous polyps and caused by germline mutations in the tumor suppressor gene and adenomatous polyposis coli, located on chromosome 5q21-q22. Familial adenomatous polyposis occurs in approximately 1/10,000 to 1/30,000 live births, and accounts for less than 1% of all colorectal cancers in the USA. It affects both sexes equally and has a worldwide distribution. The incidence of colon cancer in low- and middle-income countries is rising. In addition to the increasing incidence, lack of early detection and impeded access to optimal multidisciplinary treatment may worsen survival outcomes. Developing quality diagnostic services in the proper health context is crucial for early diagnosis and successful therapy of patients with colorectal cancer, and applying a resource-sensitive approach to prioritize essential treatments on the basis of effectiveness and cost-effectiveness is key to overcoming barriers in low- and middle-income countries. We report a case of familial adenomatous polyposis presenting as adenocarcinoma with multiple colorectal adenomatous polyps. The diagnosis of familial adenomatous polyposis was made by the presence of numerous colorectal adenomatous polyps and family history of colonic adenocarcinoma. Due to its rarity, we decided to report it. CASE PRESENTATION: A 22-year-old Ethiopian female patient presented to Addis Ababa University College of Health science, Addis Ababa, Ethiopia with rectal bleeding. Abdominopelvic computed tomography scan was done and showed distal rectal asymmetric anterior wall thickening in keeping with rectal tumor. Colonoscopy was done and she was diagnosed to have familial adenomatous polyposis with severe dysplasia. In the meantime, colonoscopy guided biopsy was taken and the diagnosis of adenocarcinoma with familial adenomatous polyposis was rendered. For this, total proctocolectomy was carried out. On laparotomy there was also incidental finding of left ovarian deposition for which left salpingo-oophorectomy was done, and 4 weeks after surgical resection, the patient was started on oxaliplatin, leucovorin, fluorouracil chemotherapy regimen. CONCLUSION: In the clinical evaluation of a patient with rectal bleeding, familial adenomatous polyposis must be considered as a differential diagnosis in subjects having family history of colonic adenocarcinoma for early diagnostic workup, management, family genetic counseling, and testing.

Exploring Familial Adenomatous Polyposis Through Radiology: A Case Series and Literature Review.

Familial adenomatous polyposis (FAP) is a dominantly inherited, autosomal form of hereditary condition caused by a germline mutation in the adenomatous polyposis coli (APC) gene. The early development of adenomatous polyps in the colon and rectum predisposes to rampant proliferation, which usually leads to colorectal cancer. Hence, this condition demands intensive surveillance and aggressive intervention. This case report epitomizes the convergence of advanced imaging with genetic diagnosis and, in essence, points toward a complete multidisciplinary approach as critical for proper management of FAP. The detailed evaluation of two siblings presenting with similar gut symptoms from this article focused on the individualization that this condition needs when managed, although underpinning the critical role coordinated care plays in changing disease outcomes.

Differential Regulation of Wingless-Wnt/c-Jun N-Terminal Kinase Crosstalk via Oxidative Eustress in Primary and Metastatic Colorectal Cancer Cells.

In the tumor microenvironment (TME), ROS production affects survival, progression, and therapy resistance in colorectal cancer (CRC). H2O2-mediated oxidative stress can modulate Wnt/ß-catenin signaling and metabolic reprogramming of the TME. Currently, it is unclear how mild/moderate oxidative stress (eustress) modulates Wnt/ß-catenin/APC and JNK signaling relationships in primary and metastatic CRC cells. In this study, we determined the effects of the H2O2 concentration inducing eustress on isogenic SW480 and SW620 cells, also in combination with JNK inhibition. We assessed cell viability, mitochondrial respiration, glycolysis, and Wnt/ß-catenin/APC/JNK gene and protein expression. Primary CRC cells were more sensitive to H2O2 eustress combined with JNK inhibition, showing a reduction in viability compared to metastatic cells. JNK inhibition under eustress reduced both glycolytic and respiratory capacity in SW620 cells, indicating a greater capacity to adapt to TME. In primary CRC cells, H2O2 alone significantly increased APC, LEF1, LRP6, cMYC and IL8 gene expression, whereas in metastatic CRC cells, this effect occurred after JNK inhibition. In metastatic but not in primary tumor cells, eustress and inhibition of JNK reduced APC, ß-catenin, and pJNK protein. The results showed differential cross-regulation of Wnt/JNK in primary and metastatic tumor cells under environmental eustress conditions. Further studies would be useful to validate these findings and explore their therapeutic potential.

Endoscopic Surveillance after (Procto)Colectomy with Gastrointestinal Reconstruction in Patients with Familial Adenomatous Polyposis (FAP)-Principles, Goals and Practical Aspects Based on 12 Years of Observation.

(1) Background: Familial adenomatous polyposis (FAP) is a hereditary condition characterized by the development of numerous adenomas in the large intestine, often necessitating colectomy due to an elevated risk of colorectal cancer. Despite surgical intervention, adenomas frequently recur, underscoring the importance of ongoing surveillance. This study evaluates the outcomes of a 12-year endoscopic follow-up after colectomy and gastrointestinal reconstruction for FAP. (2) Methods: A retrospective analysis was conducted on 41 FAP patients who underwent at least one postoperative endoscopic examination. Assessments of the pouch or rectum were performed every 12-18 months following ileorectal anastomosis and every 18-24 months after ileal pouch-anal anastomosis. Follow-up biopsies were assessed using the adopted Spigelman classification. (3) Results: Postoperative pathology revealed invasive colorectal cancer in three patients. Abdominoperineal resection was performed in two cases due to secondary invasive carcinoma, and one T1 tumor was radically removed with ESD. One patient underwent radical pouch excision following a nodal pelvic recurrence of rectal cancer. Over a 12-year observation period, the mean Spigelman score increased by 2 points, and the proportion of patients with low-grade polypoid lesions decreased. The quantity or size of polyps increased in 24 patients, decreased in 8 patients, and remained stable in 9 patients. In four patients, granular, laterally spreading tumors were discovered in the rectal stump. (4) Conclusions: Regular endoscopic surveillance in FAP patients facilitates early identification of neoplastic and inflammatory changes. The downstaging potential highlights the effectiveness of early interventions. While the Spigelman classification assessed polyps well, it did not predict cancer occurrence. A notable number of patients had invasive cancer at the time of surgery, underscoring the importance of early surgical qualification, which is particularly crucial for identifying upstaging or secondary cancer.

Classification of fundic gland polyps for predicting gastric neoplasms in Helicobacter pylori-negative patients with familial adenomatous polyposis.

BACKGROUND: In familial adenomatous polyposis (FAP) patients, fundic gland polyps (FGPs) have been considered a risk factor for gastric neoplasms. We speculated that FGPs in FAP patients spread directionally from the greater to the lesser curvature of the gastric body and investigated the relationship between the distribution of FGPs and gastric neoplasm development. METHODS: We extracted 195 FAP patients from two institutions and reviewed their medical records. Gastric polyposis was classified based on the FGP distribution (P0, no FGPs; P1, localized in the fundus or greater curvature of the gastric body; P2, spreading to the anterior or posterior wall; P3, involving the proximal half of the lesser curvature; and P4, spreading from P3 to the anal side of the lesser curvature). RESULTS: The 195 eligible patients were divided into the neoplasm group (n = 54, 28%) and the non-neoplasm group (n = 141, 72%). Overall, 24% of the patients were Helicobacter pylori (H. pylori)-positive. In the FGP distribution, the rate of patients with gastric neoplasm tended to increase significantly with each step towards an increasingly wide distribution from P0 to P4 in H. pylori-negative patients, but not in H. pylori-positive ones. In addition, in H. pylori-negative patients, the likelihood of neoplasm increased consistently from P0 to P4, with the highest odds ratio (95% confidence interval) at P4 of 14.1 (2.5-154.4). Furthermore, multivariate analysis showed P4 and Spigelman stage ≥III were significantly associated with gastric neoplasm development. CONCLUSION: FGP distribution was correlated with gastric neoplasm development in FAP patients.

GASTRIC POLYPOSIS AND RISK OF GASTRIC CANCER IN PATIENTS WITH FAMILIAL ADENOMATOUS POLYPOSIS (FAP).

BACKGROUND: Gastric polyposis is common in familial adenomatous polyposis. However, the incidence and risk factors for gastric cancer are unclear. We aimed to evaluate the incidence of gastric cancer and associated risk factors in a large familial adenomatous polyposis population. METHODS: Retrospective review of patients with familial adenomatous polyposis undergoing upper endoscopy at Mayo Clinic from 1989 to 2023. Cumulative incidence of gastric cancer(95% confidence intervals) were calculated using Kaplan-Meier survival approaches. Associations of clinical characteristics with development of gastric cancer were examined using Cox proportional hazards regression. RESULTS: 337 patients underwent 2,502 endoscopies with a median of 10.4 (IQR 3.9-17.2) years of endoscopic surveillance. At any time during surveillance, 294 (87%) patients had gastric polyps, 200 (59%), fundic gland polyps; 116 (34%), low-grade dysplasia; and 11 (3.3%), high-grade dysplasia. Amongst these, only 6 (2%) patients developed gastric cancer; 5 with high-grade dysplasia (3 (50%) on prior endoscopy, 2 (33%) at time of cancer diagnosis; and 1 (16%) had low-grade dysplasia on prior endoscopy. The 10-year cumulative incidence of gastric cancer is 0% with no polyps, 1% with polyps, 6% with low-grade dysplasia, 11% with polyps >2cm, and 20% with high-grade dysplasia. Both high-grade dysplasia and polyps >2cm had a strong association with the development of gastric cancer (p<0.001). CONCLUSION: While the overall risk of gastric cancer in familial adenomatous polyposis is low, outcomes remain poor. Gastric cancer can be predicted by endoscopic findings and specific GC surveillance guidelines are imperative to improve detection rates and guide timely intervention.

Effect of genetic profiling on surgical decisions at hereditary colorectal cancer syndromes.

Hereditary colorectal cancer syndromes, such as Lynch syndrome and familial adenomatous polyposis (FAP), present significant clinical challenges due to the heightened cancer risks associated with these genetic conditions. This review explores genetic profiling impact on surgical decisions for hereditary colorectal cancer (HCRC), assessing options, timing, and outcomes. Genotypes of different HCRCs are discussed, revealing a connection between genetic profiles, disease severity, and outcomes. For Lynch syndrome, mutations in the MLH1, MSH2, MSH6, and PMS2 genes guide the choice of surgery. Subtotal colectomy is recommended for patients with mutations in MLH1 and MSH2, while segmental colectomy is preferred for those with MSH6 and PMS2 mutations. In cases of metachronous colon cancer after segmental colectomy, subtotal colectomy with ileorectal anastomosis is advised for all mutations. Surgical strategies for primary rectal cancer include anterior resection or abdominoperineal resection (APR), irrespective of the specific mutation. For rectal cancer occurring after a previous segmental colectomy, proctocolectomy with ileal pouch-anal anastomosis (IPAA) or APR with a permanent ileostomy is recommended. In FAP, surgical decisions are based on genotype-phenotype correlations. The risk of desmoid tumors post-surgery supports a single-stage approach, particularly for certain APC gene variants. Juvenile Polyposis Syndrome (JPS) surgical decisions involve genetic testing, polyp characteristics with attention to vascular lesions in SMAD4 mutation carriers. However, genetic profiling does not directly dictate the specific surgical approach for JPS. In conclusion this review highlights the critical role of personalized surgical plans based on genetic profiles to optimize patient outcomes and reduce cancer risk. Further research is needed to refine these strategies and enhance clinical guidelines.

Dual primary gastric and colorectal cancer: The known hereditary causes and underlying mechanisms.

In this editorial, I commented on the paper by Lin et al, published in this issue of the World Journal of Gastrointestinal Oncology. The work aimed at analysing the clinicopathologic characteristics and prognosis of synchronous and metachronous cancers in patients with dual primary gastric and colorectal cancer (CRC). The authors concluded the necessity for regular surveillance for metachronous cancer during postoperative follow-up and reported the prognosis is influenced by the gastric cancer (GC) stage rather than the CRC stage. Although surveillance was recommended in the conclusion, the authors did not explore this area in their study and did not include tests used for such surveillance. This editorial focuses on the most characterized gastrointestinal cancer susceptibility syndromes concerning dual gastric and CRCs. These include hereditary diffuse GC, familial adenomatous polyposis, hereditary nonpolyposis colon cancer, Lynch syndrome, and three major hamartomatous polyposis syndromes associated with CRC and GC, namely Peutz-Jeghers syndrome, juvenile polyposis syndrome, and PTEN hamartoma syndrome. Careful assessment of these syndromes/conditions, including inheritance, risk of gastric and colorectal or other cancer development, genetic mutations and recommended genetic investigations, is crucial for optimum management of these patients.

Predictive modeling for the germline pathogenic variant of the APC gene in patients with adenomatous polyposis: proposing a new APC score.

BACKGROUND: The precise diagnosis and medical management of patients with suspected familial adenomatous polyposis should be based on genetic testing, which may not always be available. Therefore, establishing a new model for predicting the likelihood of a germline pathogenic variant (GPV) of APC based on its clinical manifestations could prove to be useful in clinical practice. METHODS: The presence of GPVs of APC gene was investigated in 162 patients with adenomatous polyposis (≥ 10 polyps) using a multigene panel or single-gene testing. To generate a predictive model for GPV of the APC gene, a logistic regression analysis was performed using the clinicopathological variables available at the time of the diagnosis of adenomatous polyposis. RESULTS: Ninety (55.6%) patients had GPV of the APC gene. According to a multivariate logistic regression analysis, age < 40 years, polyps ≥ 100, fundic gland polyposis, and a family history of colorectal polyposis were found to be independent predictors of the GPV of APC and were used to establish a formula for predicting the GPV of APC using the four predictors. The prediction model had an area under the curve of 0.91 (0.86-0.96) according to a receiver operating characteristic analysis. CONCLUSION: The model for predicting the GPV of APC will help patients with adenomatous polyposis and physicians make decisions about genetic testing.

Two Cases of Increased Gastrointestinal Polyps in Familial Adenomatous Polyposis following Antiacid Agent Intake.

Introduction: Familial adenomatous polyposis (FAP), a hereditary disorder of the gastrointestinal tract, is an autosomal dominant inherited condition caused by germline mutations in the adenomatous polyposis coli (APC) gene. It is characterized by the development of hundreds to thousands of colorectal adenomatous polyps, which, if left untreated, can eventually develop into colorectal carcinomas. Representative extracolonic tumors in FAP include multiple duodenal adenomas and desmoid tumors. Moreover, multiple fundic gland polyps are frequently identified in the stomachs of patients with FAP. Case Presentation: Herein, we report the two cases. A 52-year-old woman who underwent total colectomy for FAP, and pancreatoduodenectomy was initiated on esomeprazole for the treatment of anastomotic erosion. Esophagogastroduodenoscopy performed 42 months later showed an increased number and size of gastric fundic gland polyps, which subsequently decreased after replacing esomeprazole with ranitidine. Similarly, a 39-year-old woman with FAP was initiated on vonoprazan for the treatment of reflux symptoms. Esophagogastroduodenoscopy and colonoscopy performed 14 months later indicated an increase in the number of gastric fundic gland polyps and colorectal polyps, which subsequently decreased after vonoprazan discontinuation. In these two cases, the increase and decrease in the number and size of fundic gland polyps and colon adenoma were associated with serum gastrin levels. Conclusion: Gastric fundic gland polyps and colon polyps may rapidly increase in number and size due to increased gastrin levels induced by proton pump inhibitor/potassium-competitive acid blocker use. Hence, these drugs should be prescribed with caution.

Interplay between WNT/PI3K-mTOR axis and the microbiota in APC-driven colorectal carcinogenesis: data from a pilot study and possible implications for CRC prevention.

BACKGROUND: Wnt/ß-catenin signalling impairment accounts for 85% of colorectal cancers (CRCs), including sporadic and familial adenomatous polyposis (FAP) settings. An altered PI3K/mTOR pathway and gut microbiota also contribute to CRC carcinogenesis. We studied the interplay between the two pathways and the microbiota composition within each step of CRC carcinogenesis. METHODS: Proteins and target genes of both pathways were analysed by RT-qPCR and IHC in tissues from healthy faecal immunochemical test positive (FIT+, n = 17), FAP (n = 17) and CRC (n = 15) subjects. CRC-related mutations were analysed through NGS and Sanger. Oral, faecal and mucosal microbiota was profiled by 16 S rRNA-sequencing. RESULTS: We found simultaneous hyperactivation of Wnt/ß-catenin and PI3K/mTOR pathways in FAP-lesions compared to CRCs. Wnt/ß-catenin molecular markers positively correlated with Clostridium_sensu_stricto_1 and negatively with Bacteroides in FAP faecal microbiota. Alistipes, Lachnospiraceae, and Ruminococcaceae were enriched in FAP stools and adenomas, the latter also showing an overabundance of Lachnoclostridium, which positively correlated with cMYC. In impaired-mTOR-mutated CRC tissues, p-S6R correlated with Fusobacterium and Dialister, the latter also confirmed in the faecal-ecosystem. CONCLUSIONS: Our study reveals an interplay between Wnt/ß-catenin and PI3K/mTOR, whose derangement correlates with specific microbiota signatures in FAP and CRC patients, and identifies new potential biomarkers and targets to improve CRC prevention, early adenoma detection and treatment.

Development of Desmoid Tumors After Ileorectal Anastomosis Versus Ileal Pouch-Anal Anastomosis in Familial Adenomatous Polyposis.

BACKGROUND & AIMS: Desmoid tumors (DT) are an important cause of morbidity and mortality in patients with familial adenomatous polyposis (FAP). DT development might be related to the type and approach of colectomy. We aimed to compare DT development after colectomy with ileorectal anastomosis (IRA) and proctocolectomy with ileal pouch-anal anastomosis (IPAA). METHODS: We performed an international historical cohort study in patients with FAP who underwent IRA or IPAA between 1961 and 2020. The primary outcome was the incidence of abdominal DT (either mesenteric, retroperitoneal, or abdominal wall). Patients with a DT diagnosis before or at colectomy were excluded. Time to DT was considered censored at an eventual secondary proctectomy after IRA. We used multivariable Cox regression modelling to adjust for potential confounders. RESULTS: We analyzed data from 852 patients: 514 after IRA and 338 after IPAA (median follow-up, 21 and 16 years, respectively). DTs were diagnosed in 64 IRA patients (12%) and 66 IPAA patients (20%). The cumulative DT incidence at 5 and 10 years was 7.5% and 9.3% after open IRA and 4.7% and 10.9% after laparoscopic IRA. These estimates were 13.6% and 15.4% after open IPAA and 8.4% and 10.0% after laparoscopic IPAA. The postoperative risk was significantly higher after IPAA (P < .01) in multivariable analysis, whereas approach did not significantly influence the risk. CONCLUSIONS: The risk of developing an abdominal DT was found to be significantly higher after IPAA than after IRA. Postoperative DT risk should be taken into account when choosing between IRA and IPAA in FAP.

Cribriform morular thyroid carcinoma: Clinicopathological and molecular basis for both a preventive and therapeutic approach for a rare tumor (Review).

Cribriform morular thyroid carcinoma (CMTC) has been included within the group of thyroid tumors of uncertain histogenesis in the recent World Health Organization classification of endocrine tumors. Most CMTCs occur in young euthyroid women with multiple (and bilateral) thyroid nodules in cases associated with familial adenomatous polyposis (FAP) or as single nodules in sporadic cases. CMTC generally behaves indolently, while aggressiveness and mortality are associated with high­grade CMTC. This tumor histologically displays a distinctive combination of growth patterns with morular structures. Strong diffuse nuclear and cytoplasmic immunostaining for ß­catenin is the hallmark of CMTC. Tumor cells are also positive for thyroid transcription factor­1 and for estrogen and progesterone receptors, but negative for thyroglobulin and calcitonin. It is possible that the CMTC phenotype could result from blockage in the terminal/follicular differentiation of follicular cells (or their precursor cells) secondary to the permanent activation of the Wnt/ß­catenin pathway. In CMTC, the activation of the Wnt/ß­catenin pathway is the central pathogenetic event, which in FAP­associated cases results from germline mutations of the APC regulator of WNT signaling pathway (APC) gene, and in sporadic cases from somatic inactivating mutations in the APC, AXIN1 and CTNNB1 genes. Estrogens appear to play a tumor­promoting role by stimulating both the PI3K/AKT/mTOR and the RAS/RAF/MAPK signaling pathways. Additional somatic mutations (i.e. RET rearrangements, or KRAS, phosphatidylinositol­4,5­bisphosphate 3­kinase catalytic subunit α, telomerase reverse transcriptase or tumor protein 53 mutations) may further potentiate the development and progression of CMTC. While hemithyroidectomy would be the treatment of choice for sporadic cases without high­risk data, total thyroidectomy would be indicated in FAP­associated cases. There is insufficient clinical data to propose therapies targeting the Wnt/ß­catenin pathway, but multikinase or selective inhibitors could be used in a manner analogous to that of conventional thyroid tumors. It is also unknown whether adjuvant antiestrogenic therapy could be useful in the subgroup of women undergoing surgery with high­risk CMTC, as well as when there is tumor recurrence and/or metastasis.

Evolutionary history of adenomas to colorectal cancer in FAP families.

Objective: Familial adenomatous polyposis (FAP) is a genetic syndrome characterized by multiple polyps at various evolutionary stages, which, if left untreated, inevitably progress to colorectal cancer (CRC). In this study, we present a comprehensive analysis of the evolutionary history of FAP-CRC from precancerous adenoma to carcinoma. Design: Tissues were collected from gastrointestinal endoscopy or surgical resection. Exome sequencing was performed on multiple regions of adenocarcinoma (n = 8), villous adenoma (n = 10), tubular adenoma (n = 9) and blood samples were obtained from 9 patients belonging to 7 Chinese FAP families. Phylogenetic trees were reconstructed, and evolutionary analysis was conducted to reveal the temporal sequence of events leading to CRC. Results: Inherited germline mutation sites in APC gene were identified in FAP01 (p.S1281*, COSM19212), FAP03 (p.S384Tfs*19), FAP04 (p.E1538*, COSM6041693), FAP05 (p.Q1062*, COSM3696862), and FAP07-FAP09 (p.V677Sfs*3). Notably, p.V677Sfs*3 mutation was recognized as a novel germline mutation in APC, supported by evidence of genotype-phenotype correlation in pedigree analysis. Adenomas exhibited lower mutational rates than FAP-CRC and displayed recurrent alterations in well-known chromosomal instability (CIN) genes (APC, RAS, SMAD4 and TP53) and DNA damage repair genes (SUZ12, KMT2C, BCLAF1, RUNX1, and ARID1B), suggesting the presence of genomic instability. Furthermore, a progressive increase in the HRD score (a measure of "genomic scars") was observed from tubular adenomas to villous adenomas and ultimately to carcinomas. TP53 emerged as the primary driver gene for adenoma-carcinoma transition, with driver mutations consistently appearing simultaneously rather than sequentially acquired from adenomas to carcinomas. Clonal evolution demonstrated that liver metastases can originate from the same cancer-primed cell present in a primary cancerous lesion. Conclusion: We identified a novel pathogenic variant in APC, namely, p.V677Sfs*3. The process of carcinogenesis in FAP-CRC supports the classical cancerization model, where an initial APC mutation leads to the activation of the WNT signaling pathway and CIN. Subsequently, additional mutations occur in other putative CIN genes (e.g., DNA repair, chromatin remodeling), ultimately leading to the development of microsatellite stable (MSS) tumors. Our study provides a comprehensive understanding of the genomic landscapes that underlie the transition from adenoma to carcinoma.

Endoscopic indicators in patients with familial adenomatous polyposis undergoing duodenal resections - a nationwide Danish cohort study with long-term follow-up.

BACKGROUND: Familial adenomatous polyposis (FAP) predisposes individuals to duodenal adenomas. This study describes the histopathological features of endoscopic and surgical specimens from the duodenum, as well as genotype-phenotype associations. METHODS: All known FAP patients were included from the Danish Polyposis Register. FAP patients were defined as having more than 100 cumulative colorectal adenomas and/or having a known germline pathogenic variant in the APC gene. Endoscopic procedures, histopathology, and genetics were evaluated. RESULTS: Of 500 FAP patients, 70.6% underwent esophagogastroduodenoscopy (EGD) at least once. Of these, 59.2% presented with detectable duodenal adenomas. The most severe morphology was tubular in 62.7% patients, tubulovillous in 25.4%, and villous in 12.0%, while the most severe dysplasia was low-grade in 67.5% patients, high-grade in 25.4%, and 6.7% had adenocarcinoma. In 6.2% of FAP patients, duodenal resection was recommended, including 29% with duodenal adenocarcinoma. The risk of duodenal surgery was 1.31 per 1,000 person-years (median age: 53 years). The predominant reason for surgery was extensive polyposis (67.7%). Of the patients who underwent duodenal resection, a median of six (IQR: 4-8) EGDs were performed within five years prior to surgery, but 67.6% and 83.9% never underwent a duodenal polypectomy or endoscopic mucosa resection, respectively. Of note, seventeen of 500 patients (3.4%) developed duodenal adenocarcinoma, of which 47% were advanced at diagnosis. Genetic evaluations revealed various pathogenic variants in the APC gene, with no strong genotype-phenotype association. CONCLUSIONS: The prevalence of duodenal adenomas and cancer in FAP warrants vigilant endoscopic surveillance. Nevertheless, the need for duodenal surgery persists and should together with endoscopic practice be monitored in national registers.

Endoscopic management of patients with familial adenomatous polyposis after prophylactic colectomy or restorative proctocolectomy - systematic review of the literature.

BACKGROUND: Patients with familial adenomatous polyposis (FAP) develop early colorectal adenomas and if left untreated, progression to cancer is an inevitable event. Prophylactic surgery does not prevent further development of cancer in the rectal remnant, rectal cuff in patients with ileal pouch anal anastomosis (IPAA) and even on the ileal mucosa of the pouch body. The aim of this review is to assess long-term rates of cancer and adenoma development in patients with FAP after prophylactic surgery and to summarise current recommendations for endoscopic management and surveillance of these patients. MATERIALS AND METHODS: A systematic literature search of studies from January 1946 through to June 2023 was conducted using the PRISMA checklist. The electronic database PubMed was searched. RESULTS: Fifty-four papers involving 5010 patients were reviewed. Cancer rate in the rectal remnant was 8.8-16.7% in the western population and 37% in the eastern population. The cumulative risk of cancer 30 years after surgery was 24%. Mortality due to cancer in the rectal remnant is 1.1-11.1% with a 5-year survival rate of 55%. The adenoma rate after primary IPAA was 9.4-85% with a cumulative risk of 85% 20 years after surgery and a cumulative risk of 12% for advanced adenomas 10 years after surgery. Cumulative risk for adenomas after ileorectal anastomosis (IRA) was 85% after 5 and 100% after 10 years. Adenomas developed more frequently after stapled (33.9-57%) compared to hand-sewn (0-33%) anastomosis. We identified reports of 45 cancers in patients after IPAA of which 30 were in the pouch body and 15 in the rectal cuff or at the anastomosis. CONCLUSIONS: There was a significant incidence of cancer and adenomas in the rectal remnant and ileal pouch of FAP patients during the long-term follow-up. Regular endoscopic surveillance is recommended, not only in IRA patients, but also in pouch patients after proctocolectomy.

The Duodenal Accessory Ampulloma and the Role of Endoscopic Retrograde Cholangiopancreatography (ERCP) in Familial Adenomatous Polyposis Coli Inheritance.

The adenomatous lesions, which could be benign or malignant, have been described in the duodenum and along the duodenal ampulla in individuals with familial adenomatous polyposis (FAP) post-colectomy, along with other extracolonic manifestations. To our best knowledge, we present a unique case of the involvement of the accessory duodenal ampulla in a patient who had undergone colectomy with ileorectal anastomosis with an established diagnosis of FAP. During the endoscopic examination, the patient was found to have adenomatous growth in the accessory duodenal ampulla, which was successfully removed via endoscopic retrograde cholangiopancreatography (ERCP). To prevent pancreatitis, a temporary plastic stent was inserted and successfully removed three weeks later.