AIM: To identify prognostic factors and to correlate APC mutations with clinical features, including extracolic manifestations.

METHODS: One hundred thirty-five patients who underwent surgical procedures for familial adenomatous polyposis (FAP) were included. FAP was diagnosed when the number of adenomatous polyps was > 100. Data related to patient, extracoloic manifestations, cancer characteristics, operative procedure, follow up and surveillance were collected. APC mutation testing was performed in the 30 most recent patients. DNA was extracted from peripheral blood and polymerase chain reaction products using 31 primer pairs on APC gene were sequenced. A retrospective study was performed to investigate a causal relationship between prognosis and feature of patient.

RESULTS: The mean age of the 51 patients with colorectal cancer (CRC) was older than that of those without CRC (30.5 vs 36.9, P = 0.002). Older individuals were more likely to have colon cancer at the time of FAP diagnosis [odds ratio, 4.75 (95%CI: 1.71-13.89) and 5.91(1.76-22.12) for 40-49 years and age > 50 vs age < 30). The number of confirmed deaths was 13 and the median age at death was 40 years (range, 27 to 85 years). Ten of the deaths (76.9%) were from CRC. Another cause of two cases of death were desmoid tumors (15.4%). Development of cancer on remnant rectal or ileal mucosa after surgery was not observed. The APC mutation testing revealed 23 pathogenic mutations and one likely pathogenic mutation, among which were four novel mutations. The correlation between mutational status and clinical manifestations was investigated. Mutations that could prodict poor prognosis were at codon 1309 which located on mutation cluster region, codon 1465 and codon 1507.

CONCLUSION: Identification of APC mutations should aid in the diagnosis and counseling of family members in terms of early diagnosis and management of FAP.

Familial adenomatous polyposis (FAP) is an autosomal dominantly inherited cancer syndrome caused by germ-line mutation of the adenomatous polyposis coli gene (APC) and characterized by the development of 100 to 1000 colorectal adenomatous polyps in its classic form[1]. Subjects with FAP have a risk of almost 100% of developing colorectal cancer by 40-50 years of age[2]. The extracolic phenotype is characterized by the development of adenomatous polyps in the upper gastrointerstinal tract, gastric fundic polyps, desmoid tumors, osteomas, fibrous bone dysplasia, skin fibromas, pineal blastomas, brain cysts, papillary thyroid cancers (PTCs) and congenital retinal pigment epithelial hypertrophy (CHRPE). Colorectal cancer is the most common cause of death in FAP patients and desmoid tumors are the second[3]. To prevent the development of colon cancer, prophylactic removal of the entire colorectal mucosa is recommended for FAP patients.

The FAP registry was performed to improve the prognosis of FAP through early diagnosis and surgery before the development of colorectal cancer[4]. In addition, a recent molecular genetic test for APC mutations makes it possible to detect asymptomatic or not developing polyposis patients. APC mutations can be detected in 80%-90% of patients who have a valid indication for the test[5]. Since most families are managed through hospital-based registries and not by the nation wide registry, there are few investigations of integrative and continuous follow-up to provide treatment guidelines for Korean families. Patients’ indifference and diagnostic delay appear to make adequate management harder, resulting in advanced colorectal cancers and accompanying morbidities.

The purpose of this study was to describe the clinicopathological features of the disease and the expression of extracolic manifestations, and to evaluate whether APC mutations have prognostic value in Korean patients. Finally, we propose management options for high-risk patients to improve outcome.

While CRC is the inescapable fate of untreated FAP patients, few studies provide information on the age distribution at the time of diagnosis of CRC in FAP since most cases are diagnosed in a premalignant stage. In this study, CRC occurred in more than one-third of FAP patients. The prevalence of CRC in de novo patients was significantly higher than that of patients with a family history of FAP or CRC, but there was no significant difference in the mean age of development of CRC between the two groups. The mean age at diagnosis of FAP was significantly different between patients with CRC and those without CRC. In the present study, the prevalence of CRC in patients with a family history was more frequent than that of a previous study for call up patients who diagnosed FAP through family screening[6] since most patients underwent a colonoscopy after developing intestinal symptoms despite having a family history of CRC or FAP. This means that development of CRC in FAP patients depends more on the age at diagnosis than on family history and that we have the opportunity to reduce the frequency of CRC, especially in patients with a family history. We found that diagnosis of colorectal cancer exceeded 10% at the age of 26 and 50% at the age of 43 and that this age distribution was similar to that described in a previous Western report[7]. We also found that there were no cancer-specific deaths in early cancer cases (carcinoma in situ and cancer restricted to the submucosa). Even though some cases of CRC before 20 years of age were observed in this study, all were diagnosed earlier than stage I and survived without recurrence. To improve survival, a reduction in the incidence of CRC at diagnosis should be achieved. These results suggest that a diagnosis of FAP should be obtained before the early twenties.

The standard prophylactic procedure for the majority of patients with FAP is TPC with IPAA. In selected patients, rectum-preserving surgery might be indicated. We performed TC with IRA in six patients who presented with a few rectal polyps. All of them developed adenomas on remnant rectal mucosa but did not develop any carcinomas. The cumulative risk of rectal cancer after IRA was reported to be about one-fourth of patients after 15-25 years despite surveillance[8]. Therefore continuing endoscopic surveillance is necessary for these patients. The incidence of developing adenomatous polyps after TPC in the anorectal transient zone was reported as 10%-15%[9]. There are several reports of adenomatous polyps and cancers arising from the ileal pouch mucosa as opposed to the anastomotic site[10]. We found nine cases of adenomatous polyps arising from the ileal pouch mucosa but did not observe cancer or dysplasia. Development of cancer on remnant rectal mucosa was also not observed, but one patient among 18 cases of adenomatous polyps arising from remnant mucosa was diagnosed with villotubular adenoma with high-grade dysplasia and underwent trans-anal excision. The incidence of tubular adenoma in remnant mucosa and ileal pouch increased over time, so periodical follow-up was necessary.

In the present study, gastric polyps were a common manifestation of FAP. The histological types of gastric polyps were mostly fundic gland polyps and secondary tubular adenomas biopsied from the antrum of the stomach. This is consistent with previous reports documenting that fundic gland polyps are the most common gastric polyps and that adenoma is the second most prevalent gastric lesion in individuals with FAP[11]. We observed that three patients had asymptomatic gastric carcinoma at their first gastroduodenal endoscopy while one developed carcinoma during the surveillance study 18 years after surgery and one developed TA with high-grade dysplasia (HGD) 10 years after surgery, which was treated with endoscopic submucosal dissection. All of these cancers and HGD developed in the antrum. The overall incidence of 3% for gastric carcinoma in this study is similar to the high prevalence of gastric cancer reported in previous study[12]. Nonetheless, the prevalence of gastric cancer in FAP was not reported to be higher than that in the general population in Western countries and the most common gastric cancer site in Western reports was the fundus of the stomach (fundic gland polyps)[11,13]. The high incidence of gastric cancer and the different sites may indicate inter-ethnic differences in the presentation of FAP. In contrast to Western reports of a relatively high incidence of duodenal cancer, we did not observe any malignant neoplasms on the duodenum[14]; however, it is important to consider the possibility of malignancy on the duodenum, since duodenal adenomatous polyps occurred in one-third of patients and since one case of HGD was detected on the ampulla of vater in our study.

We found that desmoid tumor was the only cause of death associated with FAP except caused by CRC in this study. The incidence of 14.8% and location of intra-abdominal site, particularly small bowel mesentery, in the present study is consistent with previous studies[15]. In particular, mutation on codons 1445-1580 is associated with postoperative development of desmoid tumors and recommended to postpone elective colectomy[16], but this correlation does not always appear to be consistent. In our study, four of 20 desmoid tumors developed without any history of surgical trauma. Desmoid tumors unrelated to surgical trauma are a relatively poor prognostic factor[17]. In two of four synchronous desmoid tumors, the same APC mutation (codon 1465; c.4393-4394delAG), reported as a desmoid tumor-associated mutation[18], was detected in unrelated patients. The mutation at codon 1465 located in exon 15 may implicate progression, so patients having this mutation and desmoid tumors should be considered for permanent stoma at the time of primary surgery. Other mutations associated with desmoid tumors in our study were at codons 461 (c.1381G>T) and 1309 (c.3925-3928delGAAA). The incidence of desmoid tumors increased over time, so periodic follow-up is necessary.

Another feature of FAP is the variation in clinical course between patients, so prediction of the severity of the disease is important in the interest of effective cancer prevention. Correlation between mutation and the age at onset of intestinal symptoms and development of CRC was reported[19], but the manifestation may be variable even in patients with identical germ-line mutations. Tumors with mutations localized in exon 15 between codons 1250 and 1464 (mutation cluster region or MCR) have generally a worse prognosis with early onset of the disease and may be candidates for IPAA due to the high incidence of secondary protectomy after primary colectomy[19,20]. In the present study, two kinds of mutations at codon 1309 within the MCR were detected: c.3925-3928delGAAA and c.3927-3931delAAAGA. Deletion of 5 base pairs at codon 1309 (c.3927-3931delAAAGA), the most common mutation, was detected in a patient who presented with CRC at age 17. This finding corresponds with previous results showing that mutation at codon 1309 (c.3927-3931delAAAGA) is associated with early development of intestinal symptoms and death from colorectal cancer[19]. The incidence of this mutation was 4% in our study and 29% in a previous study[16] and its frequency varied. No other MCR mutation was observed in the present study (Table 4). These findings implicate the possibility of ethnic differences in APC mutations. We also observed one interesting novel mutation at codon 1507 within exon 15, c.4519-4520insTGAGCTCA, which was not located in the MCR but presented in a patient with early onset and poor prognosis of CRC. This information may help support surgical decisions of method and timing. In the present study, two-thirds of APC mutations were localized to exon 15. Two of the most common mutations were also identified in this study: at codon 1061 (c.3183-3187delACAAA) and codon 1465 (c.4393-4394delAG). Mutation at codon 1061 has not been reported in Korean patients even though it is one of the most frequently reported mutations.

Extracolic manifestations showed correlations with APC mutations. The expression of CHRPE is associated with a clearly distinct region of mutations located between codons 311 and 1445 of APC[20,21]. All mutations detected with CHPRE in this study were located on reported distinct region but one mutation was not located within this region (codon1507; c.4519-4520insTGAGCTCA). It is necessary to observe carefully the clinical manifestation of this novel mutation. PTC affects 1%-2% of patients with FAP. PTC is associated with a mutation located between codons 140 and 1309 of APC, and a strong association with CHRPE also exists[21]. In the present study, three mutations on codons 935, 1199 and 1309 were detected and all of them presented CHRPE, which is consistent with previous reports. The mutation detection rate in our study is consistent with previous reports[5]. None of the cases can be explained by large allelic deletions, promoter deletions, deep intronic base changes and chromothripsis in germline[22], reduced or absent expression from one allele of APC or bi-allelic germ-line mutation of MYH[23].

A major limitation of this study was the relatively small number of patients and the fact that the study was based on one medical center, so the result may not be generalizable. A multicenter or nationwide registry investigation is needed. Secondly, the retrospective nature of the study and use of medical records for data collection prevented knowledge about affected family members because of unclear medical records and low rates of hospital utilization in the previous two generations in Korea. A prospective cohort study using the FAP registry is required. Finally, the APC mutation test has been used only recently in suspected patients in the clinical setting since gene analysis only became available in 2008 at our institute. Mutation testing should be conducted in patients who do not know their family history of FAP to identify affected members.

In conclusion, we reported clinicopathologic features and prognosis of FAP in Korean patients. The data suggest the necessity for early diagnosis and management of high-risk patients. APC mutations can inform on the severity of the disease and on prognosis and identify family members having the same mutation. The identification of APC gene mutations and the understanding of genotype-phenotype correlations should aid in the diagnosis and counseling of patients.