Age and manifestation related symptoms in familial adenomatous polyposis

Background To identify early symptoms of familial adenomatous polyposis with a view to improve early diagnosis and treatment. Diagnosis on the basis of genetic testing is usually limited to where there is a known family history, so FAP is more usually diagnosed on clinical grounds. Except for those identified via FAP registers, the majority of patients are symptomatic at the time of diagnosis. Methods We undertook a retrospective study of 143 FAP patients treated at the Department of Surgery, University of Erlangen between 1971 and 2000. We identified patterns of symptoms, endoscopic findings and extracolonic manifestations in three age groups. Results FAP was diagnosed clinically on the basis of symptoms in 84% (120/143) of these patients. Most presented with intestinal symptoms such as colonic bleeding (68%) and diarrhea (42%). All but one of the patients between 20 and 40 years old had rectal polyps (98.7%, 75/76), whereas in those over 40 years old the prevalence was 76% (35/46). Non-specific symptoms such as abdominal pain, fatigue and bloating were less frequent and were mainly reported by patients older than 40. Conclusion The commonest presenting features of FAP are alteration of bowel habit and rectal bleeding, but both are found in many other conditions. Patients with these findings need immediate endoscopy to allow prompt diagnosis and prophylactic surgery.


Background
Familial adenomatous polyposis (FAP) is an autosomal dominantly inherited disease and is caused by germline mutations in the adenomatous polyposis coli gene (APC) in chromosome 5q21 [1]. Somatic mutations of the APC gene occur in about 80% of sporadic colorectal cancers. APC encodes for a multimodal protein that plays an important role in the wnt-signalling pathway and in intercellular adhesion [2,3]. The APC germline mutation has a penetrance which is close to 100% [4]. Untreated, the disease usually leads to the appearance of hundreds of adenomatous polyps in the colorectum between puberty and age 20 and to cancer by the early forties at the latest which is the most frequent reason for death in patients with FAP [5]. Attenuated forms of FAP (AFAP) are variations in phenotype. AFAP with less than 100 adenomatous polyps is diagnosed at a mean age of 44 years, and cancer is diagnosed at a mean age of 56 years [6]. Congenital hypertrophy of retinal pigment epithelium, upper gastrointestinal polyps, desmoid tumors, adrenal adenomas and osteomas are extracolonic FAP phenotypic features whose expression depends upon the mutated region of the APC gene [7][8][9][10][11].
The incidence of FAP is approximately 1 in 8000 [12]. Early detection, prophylactic surgery and lifelong surveillance are essential to prevent the development of colorectal cancer [13]. When an index patient is newly diagnosed in a center with an established FAP register, screening of family members with molecular diagnostics is carried out as a matter of routine and can detect the condition before the development of symptoms. It is rare for patients outside this system to be diagnosed prior to the development of symptoms. Also in patients with spontaneous new mutations of the APC gene, early clinical diagnosis can increase their descendants' chance of survival. Lack of awareness and the absence of systematic family screening may cause diagnosis to be delayed in patients at risk of inherited colorectal cancer [14]. According to the literature, new mutations occur in 25% of all FAP cases and this predominantly young patient population is burdened with a high risk of colorectal cancer. It is therefore desirable that there are defined clinical algorithms for detecting the characteristic clinical signs of FAP, ideally within a multidisciplinary setting in which patients are entered on an FAP register.
In a retrospective analysis, we evaluated all clinical symptoms of FAP prior to surgery. We categorized these according to patient age and into colorectal and extracolonic manifestations of the disease. Our aim was to detect specific characteristics in each age group which could lead to an early clinical diagnosis and prevent the development of colorectal cancer.

Definition
The diagnosis of FAP was established clinically if more than 100 polyps were detected endoscopically in the colorectum.

Patient population
Between 1971 and 2000, we registered 157 patients (66 women, 85 men, 6 unknown) with an endoscopic diagnosis of FAP. The mean age at primary diagnosis was 34 (± 15 SD) years with a range of 5 to 73 years. In 151 cases, surgery was performed. Sixty-seven patients had colectomy with ileorectal anastomosis, 55 patients underwent restorative proctocolectomy with ileal pouch-anal anasto-mosis, and 10 had proctocolectomy with an end-ileostomy. Nineteen patients underwent various other surgical procedures. Presently, 83 patients remain alive and 28 patients have been lost to follow-up. Forty patients are known to have died: 20 of colorectal cancer, 5 due to desmoid tumors, 10 of other causes and 5 for unknown reasons.
A predominant early symptom could be defined and documented in 143 patients. Family screening revealed that 29 of these patients had affected relatives, while no FAP was detected in the families of the remaining 114 patients.

Evaluation of symptoms
The predominant symptoms of FAP were analyzed and documented retrospectively in all 143 cases. The entire patient population was divided into three age groups according the time of primary diagnosis: less than 20, 20 to 40, and more than 40 years of age. Abdominal pain, pain during defecation, bloating, fatigue and loss of weight were categorized as non-specific symptoms (figure 1). Colonic bleeding, anemia, mucous discharge, diarrhea, paradoxical diarrhea and constipation were categorized as bleeding and stool disorders (figure 2).

Evaluation of colorectal and extracolonic manifestations
The endoscopic reports were obtained and the pattern of polyps in the colorectum was divided into several groups: no rectal polyps, less than 10 rectal polyps, 10-100 polyps, and more than 100 polyps. We recorded the prevalence of carcinoma at the primary FAP diagnosis (table 1). In addition, we documented any extracolonic manifestations of FAP: desmoid tumors (abdominal wall, mesenteric, retroperitoneal), gastric polyps, duodenal polyps and polyps of the small bowel (table 2).

Data presentation
The relative prevalence of symptoms in each age group is shown in figures 1 and 2. Molecular findings are grouped according to the mutations detected in the APC gene (table 3). Colorectal and extracolonic manifestations at primary diagnosis are presented for each of the recorded symptoms. Values in brackets indicate the percentage of affected patients in each subgroup (tables 1 and 2).

Age and symptoms
The diagnosis of FAP was made on the basis of clinical symptoms in 66% of patients (94/143). Diagnosis was incidental in 6% (9/143) and the reasons are unknown in 8% (11/143).

Discussion
Most patients with FAP (80%) will be detected by more or less specific symptoms of colorectal disorders which lead to further diagnostic evaluation. Prior to the mid-nineties, when there was no FAP register, families of patients with FAP underwent no routine molecular screening, nor any further specific clinical surveillance. The diagnosis of FAP was verified in 29% of patients by molecular diagnostics, which became available for routine clinical use in the 1990s. The disperson of APC mutations in our study was similar to evaluations concerning other patient populations [15]. Our study also demonstrates the importance of clinical FAP registers, with systematic family screening to identify presymptomatic carriers with APC gene mutations [16,17]. Recent evaluations of physicians' awareness  of genetic tests for inherited colorectal cancer showed a need for information concerning the availability and appropriate use of these tests [18]. In principle, genetic testing of index patients and their offspring can be carried out without using a register, but the lack of awareness and possibly the financial costs prevent an effective application of existing knowledge and expertise.
Most patients in our hospital were diagnosed between age 20 and 40 (53%). In 75% (57/76) the diagnosis was made clinically. They mainly presented with fecal occult blood (50%), colonic bleeding (68%) and diarrhea (42%). Rectal polyps were present in 98.7% of patients in this age group. For this reason rectoscopy, which is widely available, should be the first-line investigation in symptomatic patients younger than 40 years of age. Complete colonoscopy should be supplemented if symptoms persist without diagnostic findings during rectoscopy. Some patients presented with extracolonic manifestations such as desmoid tumors. They could be detected in 29% of patients between 20 and 40 years old. In two patients with desmoid tumors, FAP was diagnosed incidentally. In these cases especially, rectoscopy should be performed to exclude polyps. Generally, bleeding and stool disorders were found in cases with severe manifestations in the colon and rectum and colorectal carcinoma. There is an ongoing discussion concerning the benefit of colonoscopy vs. sigmoidoscopy for patients less than 40 years of age with non-acute rectal bleeding [19]. In terms of our findings, FAP in patients younger than 40 years old can certainly be diagnosed with rectoscopy or flexible sigmoidoscopy. As no rectal polyps could be detected in 24% of patients older than 40 years of age, and colon carcinoma was found in 50%, we propose colonoscopy in patients of this age who present with bleeding and stool disorders. Although fecal occult blood, colonic bleeding and diarrhea make a colorectal disease highly probable, they are not specific for FAP and are found in other gastrointestinal disorders such as inflammatory bowel disease, irritable bowel syndrome and malabsorption syndromes or infection, which must always be kept in mind [20][21][22].
Non-specific symptoms were less frequent and occurred in only 0.8-16% of our patients. They were associated with pronounced colorectal manifestations and many polyps of the upper gastrointestinal tract. Non-specific symptoms were commonest in patients over 40 years old. The incidence of colonic carcinoma was 42-50% in this age group. We conclude that non-specific symptoms can imply a pronounced manifestation of FAP which usually affects patients beyond 40 years of age [12]. Non-specific symptoms are present in other malignancies, endocrine or neuromuscular disorders as well [23][24][25].
In summary, we found no symptoms specific for FAP in our patient population. Yet it was possible to correlate several symptoms with disease in our age groups. In a few cases, extracolonic manifestations were the first noticeable changes. Due to their young age and mostly moderate symptoms, patients younger than 40 years of age with FAP are not easily identifiable in routine gastrointestinal practice. In all patients who present with the gastrointestinal symptoms we describe, the first diagnostic step should be rectoscopy, followed by complete colonoscopy to exclude FAP. Patients over 40 years old in whom inherited colorectal cancer is suspected, even without rectal manifestations, should generally undergo colonoscopy earlier than recommended for the general population. In patients of all age groups genetic testing should be recommended in order to allow presymptomatic testing in their sibs and offspring. Family members with positive tests and all persons at risk from families where the mutation could not be identified must be examined and monitored by clinical registers.