Periampullary adenomas and adenocarcinomas in familial adenomatous polyposis: Cumulative risks and APC gene mutations

doi:10.1053/gast.2001.28707

Gastroenterology

Volume 121, Issue 5, November 2001, Pages 1127-1135

https://doi.org/10.1053/gast.2001.28707 Get rights and content

Abstract

Background & Aims: Patients with familial adenomatous polyposis (FAP) have a high prevalence of duodenal adenomas, and the region of the ampulla of Vater is the predilection site for duodenal adenocarcinomas. This study assessed the risk of stage IV periampullary adenomas according to the Spigelman classification and periampullary adenocarcinomas in Swedish FAP patients screened by esophagogastroduodenoscopy (EGD). The genotype of patients with stage IV periampullary adenomas and periampullary adenocarcinomas was also investigated. Methods: A retrospective study of 180 patients screened by EGD in 1982-1999 was undertaken. Kaplan-Meier analysis was performed to evaluate cumulative risk. Mutation analysis was carried out in patients with periampullary adenocarcinomas diagnosed outside the screening program, in addition to patients in the screening group with stage IV periampullary adenomas and adenocarcinomas. Results: Periampullary adenoma stage IV was diagnosed in 14 patients (7.8%), with a cumulative risk of 20% at age 60 years. Periampullary adenocarcinoma was diagnosed in 5 patients (2.8%), with a cumulative risk of 10% at age 60. Three of the adenocarcinomas occurred in patients with stage IV periampullary adenomas compared with 2 in patients with less severe periampullary adenomatosis at screening (odds ratio, 31; 95% confidence interval, 4.6-215). Fifteen (88%) of the APC gene mutations were detected; 12 of these were located downstream from codon 1051 in exon 15. Conclusions: The life time risk of severe periampullary lesions in FAP patients is high, and an association between stage IV periampullary adenomas and a malignant course of the periampullary adenomatosis is strongly suggestive. Mutations downstream from codon 1051 seem to be associated with severe periampullary lesions.

GASTROENTEROLOGY 2001;121:1127-1135

Section snippets

Patients

The Swedish Polyposis Registry includes data on 467 patients with verified FAP from 154 Swedish FAP-families registered since the late 1950s.⁵ One hundred ten of the patients were dead before introduction of EGD surveillance, and another 62 were not screened because at the end of the study period they were younger than 30 years old, the recommended starting age for screening in Sweden. Thus, 265 patients remained, and the registry had EGD surveillance information for 180 (68%) of these patients

Duodenal adenomas

Duodenal adenomas were found in 134 (74%) of the FAP patients. As shown in Figure 1, the cumulative age-dependent risks of duodenal adenomatosis were 80% (95% CI, 72.9-87.1) and 98% (95% CI, 95-100) at ages 60 and 75 years, respectively.

. The cumulative risk of developing duodenal adenomas, Spigelman stage IV periampullary adenomas (PA stage IV), and periampullary adenocarcinomas (PC) in 180 Swedish FAP patients screened by EGD from 1982 through the end of 1999.

Stage IV periampullary adenomas

As shown in Table 1, stage IV

Discussion

We found that 74% of the FAP patients screened by upper endoscopy had duodenal adenomas, compared with the 33%-92% reported in previous studies of 100 or more patients.8, 16, 17, 18, 19 However, the cumulative risk in our material was almost 100% at the age of 75 years, indicating that all FAP patients eventually develop duodenal adenomas. The malignant potential of the most common lesions of the duodenum, the sessile adenomatous polyps predominantly located at the mucosal folds, seems to be

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All known patients with FAP up until April 2021 were identified in the nationwide Danish Polyposis Register and paired with 4 unique controls matched by birth year, sex, and postal code. The risk of overall cancers, specific cancer types, and risk of a second primary cancer was assessed and compared with controls.
The analysis included 565 patients with FAP and 1890 controls. The overall risk of cancer was significantly higher for patients with FAP than for controls (hazard ratio [HR], 4.12; 95% confidence interval [CI], 3.28–5.17; P < .001). The increased risk was mainly due to CRC (HR, 4.61; 95% CI, 2.58–8.22; P < .001), pancreatic cancer (HR, 6.45; 95% CI, 2.02–20.64; P = .002), and duodenal/small-bowel cancer (HR, 14.49; 95% CI, 1.76–119.47; P = .013), whereas no significant difference was observed for gastric cancer (HR, 3.29; 95% CI, 0.53–20.23; P = .20). Furthermore, the risk of a second primary cancer was significantly higher for patients with FAP (HR, 1.89; 95% CI, 1.02–3.50; P = .042). Between 1980 and 2020, the risk of cancer among patients with FAP decreased by ∼50%.
Despite an absolute reduction in the risk of developing cancer among patients with FAP, the risk remained significantly higher than for the background population due to colorectal, pancreatic, and duodenal/small-bowel cancers.
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Genotype–phenotype correlation of small-intestinal polyps on small-bowel capsule endoscopy in familial adenomatous polyposis
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In familial adenomatous polyposis (FAP), neoplastic lesions outside the colon have become increasingly important. The genotype–phenotype correlation has been established for duodenal polyps, and regular screening is recommended. However, this correlation remains unclear for small-intestinal lesions, except for reports on the relationship between their occurrence and Spigelman stage. Here, we used small-bowel capsule endoscopy (SBCE) to investigate the genotype–phenotype correlation of small-intestinal polyps in FAP.
The genotype–phenotype correlation of small-intestinal polyps was investigated in patients with FAP who underwent SBCE, Esophagogastroduodenoscopy (EGD), and adenomatous polyposis coli (APC) gene analysis. Of 64 patients with FAP who underwent SBCE, 41 were included in the final analysis, 4 did not undergo a complete small intestine examination, and 19 did not undergo genetic analysis.
The prevalence (median number) of small-intestinal polyps by Spigelman stage was 26% (1.5), 0% (0), 44% (5), 60% (4), and 73% (25.5) for stages 0 to IV, respectively. Significantly more small-intestinal polyps were found in Spigelman stage III and IV groups than in the stage 0 group (P < .05). The APC variant was negative for 6 patients (15%), and the sites associated with more than 5 small-intestinal polyps were codons 278, 1062, 1114, 1281, 1307, 1314, and 1504.
In FAP patients, SBCE surveillance is potentially recommended for patients with pathogenic variants in the APC gene at codons 278 and 1062 to 1504 or with Spigelman stage III or higher.
Pancreas-preserving total duodenectomy for advanced duodenal polyposis in patients with familial adenomatous polyposis: short and long-term outcomes
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In patients with familial adenomatous polyposis (FAP), extensive nonmalignant duodenal polyposis not amenable to endoscopic management demands surgical resection for which pancreas-preserving total duodenectomy (PPTD) offers a pancreatic parenchyma sparing approach.
This is a retrospective cohort study including consecutive patients who underwent PPTD for FAP. Reconstruction involved a Billroth II anastomosis with a short isolated jejunal limb to facilitate future endoscopic surveillance. Short and long-term outcomes were evaluated.
Overall, 30 patients underwent PPTD for Spigelman stage III (n = 6) or IV (n = 24). Sixteen patients experienced a severe complication (Clavien–Dindo grade III/IV) including postoperative pancreatic fistula (ISGPS grade B/C) in twelve. There was no all cause in-hospital and 90-day mortality. During follow-up (median 125 months), five patients developed acute pancreatitis, one new-onset diabetes and one exocrine pancreatic insufficiency. During endoscopic surveillance in 27 patients, jejunal adenomas were detected in 22 and advanced adenomas in 11. An additional surgical resection was required in four patients with extensive jejunal polyposis. None developed jejunal cancer. The 10-year overall survival rate was 93.3%.
Postoperative morbidity after PPTD is substantial but on the long-term, rates of pancreatic insufficiencies are low. Most patients develop jejunal adenomas at follow-up, highlighting the need for endoscopic surveillance.
Management of familial adenomatous polyposis and MUTYH-associated polyposis; new insights
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Familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP) are rare inherited polyposis syndromes with a high colorectal cancer (CRC) risk. Therefore, frequent endoscopic surveillance including polypectomy of relevant premalignant lesions from a young age is warranted in patients. In FAP and less often in MAP, prophylactic colectomy is indicated followed by lifelong endoscopic surveillance of the retained rectum after (sub)total colectomy and ileal pouch after proctocolectomy to prevent CRC. No consensus is reached on the right type and timing of colectomy. As patients with FAP and MAP nowadays have an almost normal life-expectancy due to adequate treatment of colorectal polyposis, challenges in the management of FAP and MAP have shifted towards the treatment of duodenal and gastric adenomas as well as desmoid treatment in FAP. Whereas up until recently upper gastrointestinal surveillance was mostly diagnostic and patients were referred for surgery once duodenal or gastric polyposis was advanced, nowadays endoscopic treatment of premalignant lesions is widely performed. Aiming to reduce polyp burden in the colorectum as well as in the upper gastrointestinal tract, several chemopreventive agents are currently being studied.
Natural history of ampullary adenomas in familial adenomatous polyposis: a long-term follow-up study
2022, Gastrointestinal Endoscopy
Ampullary adenomas (AAs), common in familial adenomatous polyposis (FAP), are precursors to ampullary carcinoma. We assessed the natural history of AAs and factors associated with clinically significant progression (CSP).
Consecutive FAP patients with AAs and at least 2 EGDs were identified from a hereditary GI cancer registry. We assessed the incidence of CSP (increase in size to ≥10 mm and/or development of advanced histology) of AAs. Clinical, endoscopic, and pathologic features between patients with CSP and nonprogressors were compared.
One hundred forty-three patients with AAs were included. Over a median follow-up of 7.8 years (interquartile range, 4.3-11.1), 41 patients (28.6%) developed CSP for an incidence of 35 per 1000 patient-years. Of 143 patients, 22 (15.6%) progressed to AAs ≥10 mm, 12 (8.5%) progressed to advanced histology, and 7 (4.9%) progressed both in size and histology. Two patients (1.4%) developed ampullary cancer. Male gender, abnormal appearance of the papilla at initial AA detection, prior cholecystectomy, and personal history of extracolonic malignancy were associated with CSP. Neither Spigelman stage nor the adenomatous polyposis coli gene pathogenic variants were associated with CSP. An intervention specifically for AA and not duodenal polyposis was performed in 24% of patients with AAs, including endoscopic papillectomy in 23 patients and duodenectomy in 3 patients at a median observation of 8.2 years.
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^☆: Address requests for reprints to: Jan Björk, M.D., Ph.D., The Swedish Polyposis Registry, Department of Gastroenterology and Hepatology, Karolinska Hospital, S-171 76 Stockholm, Sweden. e-mail: [email protected]; fax: (46) 8-51775768.

^☆☆: Supported by grants from the Cancer Society in Stockholm and the Karolinska Institute and the King Gustav V Jubilee Clinic Cancer Research Foundation.

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Clinical ResearchPeriampullary adenomas and adenocarcinomas in familial adenomatous polyposis: Cumulative risks and APC gene mutations☆,☆☆

Abstract

Section snippets

Patients

Duodenal adenomas

Stage IV periampullary adenomas

Discussion

Localization of the gene for familial adenomatous polyposis on chromosome 5

Nature

Identification and characterization of the adenomatous polyposis coli gene

Cell

Identification of a FAP locus gene from chromosome 5q21

Science

Centralized registration, prophylactic examination, and treatment results in improved prognosis in familial adenomatous polyposis. Results from the Danish polyposis register

Scand J Gastroenterol

Epidemiology of familial adenomatous polyposis in Sweden: changes over time and differences in phenotype between males and females

Scand J Gastroenterol

Extracolonic manifestations of familial adenomatous polyposis: desmoid tumours, and upper gastrointestinal adenomas and carcinomas

Scand J Gastroenterol

Upper gastrointestinal cancer in familial adenomatous polyposis

Lancet

Upper gastrointestinal cancer in patients with familial adenomatous polyposis

Lancet

The risk of upper gastrointestinal cancer in familial adenomatous polyposis

Gastroenterology

Phenotypic expression of disease in families that have mutations in the 59 region of the adenomatous polyposis coli gene

Ann Intern Med

Familial segregation in the occurrence and severity of periampullary neoplasms in familial adenomatous polyposis

Am J Surg

Molecular analysis of the APC gene in 205 families: extended genotype-pheno-type correlations in FAP and evidence for a role of APC amino acid changes in colorectal cancer predisposition

J Med Genet

APC mutation analysis by chemical cleavage of mismatch and a protein truncation assay in familial adenomatous polyposis

Br J Cancer

Rapid detection of translation-terminating mutations at the adenomatous polyposis coli gene by direct protein truncation test

Genomics

Germ-line mutations of the APC gene in 53 familial adenomatous polyposis patients

Proc Natl Acad Sci U S A

Duodenal adenomatosis in familial adenomatous polyposis. DAF Project Group

Int J Colorect Dis

Gastric and duodenal polyps in familial adenomatous polyposis: a prospective study of the nature and prevalence of upper gastrointestinal polyps

Gut

Gastroduodenal polyps in patients with familial adenomatous polyposis

Dis Colon Rectum

Clinical Research
Periampullary adenomas and adenocarcinomas in familial adenomatous polyposis: Cumulative risks and APC gene mutations☆,☆☆