To test the fujinon intelligent color enhancement (FICE) in identifying dysplastic or adenomatous polyps in familial adenomatous polyposis (FAP) patients.

Seventy-six consecutive FAP patients, already treated by colectomy and members of sixty-five families, were enrolled. A FICE system for the upper gastro-intestinal tract with an electronic endoscope system and a standard duodenoscope (for side-viewing examination) were used by two expert examiners. Endoscopic resection was performed with diathermic loop for polyps ≥ 6 mm and with forceps for polyps < 6 mm. Formalin-fixed biopsy specimens were analyzed by two expert gastrointestinal pathologists blinded to size, location and number of FAP-associated fundic gland polyps.

Sixty-nine (90.8%) patients had gastric polyps (34 only in the corpus-fundus, 7 only in the antrum and 28 in the whole stomach) and 52 (68.4%) in duodenum (7 in the bulb, 35 in second/third duodenal portion, 10 both in the bulb and the second portion of duodenum). In the stomach fundus after FICE evaluation, 10 more polyps were removed from 10 patients for suspicious features of dysplasia or adenomas, but they were classified as cystic fundic gland after histology. In the antrum FICE identified more polyps than traditional endoscopy, showing a better tendency to identify adenomas and displastic areas. In the duodenum FICE added a significant advantage in identifying adenomas in the bulb and identified more polyps in the II/III portion.

FICE significantly increases adenoma detection rate in FAP patients but does not change any Spigelman stage and thus does not modify patient’s prognosis and treatment strategies.

Familial adenomatous polyposis (FAP) is an autosomal dominant inherited syndrome characterized by the development of colorectal cancer by the age of 40 years in nearly 100% of individuals[1]. Colon Endoscopic surveillance and prophylactic colectomy have strongly reduced mortality due to colorectal carcinoma and have improved survival of FAP patients with minimal consequences[2,3], leading to the introduction of surveillance strategies for the prevention of other extracolonic malignancies[4].

The duodenum is the second most common site of polyps development after colon, with a life-time risk of duodenal adenomas that approaches 100% in FAP affected individuals[5,6]. The cumulative risk of duodenal cancer or high grade of dysplasia by the age of 60 years is 4%-10%[6-8].

Endoscopic surveillance and removal of neoplastic tissue is useful in the prevention of duodenal cancer[8]. However, the choice of treatment and the optimal timing of surveillance based on endoscopic and histopathology examination for each patient is currently a great challenge. Currently the surveillance of duodenum is based on the Spigelman classification of duodenal adenomatosis (Table 1); however, this staging system has low predictive values and has never been validated[6,8].

Gastric polyps are also a common finding in patients with FAP: they mostly consist of FAP-associated fundic gland polyps (FGPs) reported to occur at variable rates, up to 88%[9,10], against a strongly smaller rate (0.8%-5.0%)[11,12] in non-FAP subjects who undergo an esophagogastroduodenoscopy (EGD).

FGPs have historically been considered non-neoplastic lesions without malignant potential[13]; however recent studies have questioned this assumption reporting high rates of low and high grade dysplasia (up to 54%)[9,14,15]. In particular, European and Asian registries of FAP patients proved the presence of gastric carcinoma arising from FGPs in FAP patients and an incidence of gastric adenocarcinoma between 0.6% and 4.0%[16-19].

Other common types of gastric polyps are represented by adenomas (gastric foveolar or intestinal type-gastric adenomas and pyloric gland adenomas) which are reported in approximately 10% of gastric polyps in FAP patients[10,20,21] and which can arise in the gastric antrum, in the gastric body-fundus or in the context of FGP[22]. So, identification of dysplastic lesions or adenomatous tissue in these patients is often made difficult by the great number of polyps (up to hundreds) and by the patchy distribution of dysplasia.

By now, dysplasia finding in this subgroup of subjects is made on the basis of random biopsies[9] which lead to a time consuming, laborious and poorly performing procedure, that can result in a high rate of missed lesions. According to that, it would be useful identifying FGPs at risk of malignant degeneration.

A better characterization of patients, an optimized program of surveillance and a good survival are possible with a selective and complete asportation and with a careful histological evaluation.

It is well known that is possible to predict the histology of a mucosal lesion by observing the crypt orifices (the so called pit pattern) of mucosal glands[23] and the capillary pattern of the mucosa[24]. Several endoscopic imaging techniques have been proposed to enhance the details of these patterns[25]. Among these, chromoendoscopy is a widely applied staining method that uses biocompatible dye agents which accumulate within crypt orifices during endoscopy[26]. Although chromoendoscopy is effective for many applications, it still has some problems, such as difficulty in achieving complete and even coating of the mucosal surface with the dye, the extra cost of the equipment needed for dye spraying and the extra time required to perform the procedure. Moreover, traditional chromoendoscopy isn’t able to enhance the capillary pattern, whose evaluation is essential in early diagnoses of malignant lesions[24]. In attempt to resolve these problems, other endoscopic technologies have been developed. Fujinon intelligent color enhancement (FICE™, Fujinon Corp, Saitama, Japan) represents a spectral estimation technique based on arithmetically processing of a white-light image captured by a video endoscope and sent to the spectral-estimation matrix-processing circuit. The image of the white-light endoscopic observation is resolved in each color image of the red, green and blue signal. Next, each resolved image is converted into various presumed wavelength images by a pixel unit. The images of an arbitrary single wavelength are then extracted and reconstructed. Due to its variable setting functions (up to 10) it is possible to select flexibly the most suitable wavelengths required for examination. Preliminary studies suggested that FICE successfully achieved enhancements of real-time observations of mucosal and microvascular patterns[27,28].

The light penetration into the mucosa varies according to the wavelengths: Those in the 400-500 nm range are ideal for analyzing surface structures whereas, because of the absorption properties of hemoglobin, longer wavelengths of about 550 nm are more effective for the visualization of blood vessels.

FICE seems able to discriminate between adenomatous and non-adenomatous polyps and to identify the presence of dysplasia[29-32]. Few studies have been conducted to determine the efficacy of chromoendoscopy, both traditional and virtual, in the evaluation of duodenal and peri-ampullary adenomatous polyps in FAP patients[33-35]. Interestingly, FICE application in the discrimination between neoplastic and non-neoplastic gastric lesions has not been throughly investigated[36-39], and no data are available about FICE in evaluating FGPs dysplasia or application of FICE for the screening of FAP patients.

In FAP cohort, the specific identification of who is at a greater risk of cancer development could be of paramount importance to assure a personalized program of surveillance or a therapeutic intervention.

The primary aim of this study was to assess the capability of FICE in identifying gastric polyps with dysplastic or adenomatous tissue in comparison to traditional endoscopy and in identifying a greater number of duodenal adenomas with advanced histological features.

Secondary aim was to assess the capability of FICE in identifying adenomas not seen on white light evaluation.

Seventy-six consecutive FAP patients (41 male and 35 female; mean age 40.3 years old, range 24-64) underwent EGD. Among all patients, 69 (90.8%) had gastric polyps (34 only in the corpus-fundus, 7 only in the antrum and 28 in the whole stomach) and 52 (68.4%) in duodenum (7 in the bulb, 35 in second/third duodenal portion, 10 both in the bulb and the second portion of duodenum) (Table 2).

Duodenal adenomatous polyps are common manifestations of FAP found in 30% to 90% of patients, with a life time risk approaching 100%[5,6,43]. While rare in the general population (0.01%-0.04% of incidence at an average age of 65 years)[43], the risk of duodenal or periampullary cancer is increased several hundreds fold in FAP patients (estimated cumulative risk of 4.5% by age 57 and a median age at presentation of 52 years)[6,8]. Duodenal cancer is the second most common cause of disease-related mortality in patients with FAP, only the second to advanced and metastatic colorectal cancer. A regular and careful program of endoscopic surveillance is worthwhile in identifying early pre-malignant lesions.

Gastric polyps, particularly fundic polyps, are considered always non-neoplastic lesions, also in FAP and non-FAP patients; nonetheless high rate of their prevalence (20%-88%)[6,9-11] and several cases of dysplasia in FGPs in FAP have been recently reported, with rate of incidence up to 54%[9-11,18].

Chromoendoscopy, both traditional and virtual, has been proven to be a good tool to increase polyps identification rate and to predict their histology[29-32]. Only one study was published on the use of FICE in the evaluation of duodenal lesions[44]. This study was conducted using a double balloon enteroscopy on patients with duodenal lesions. In this study only two FAP patients were included and FICE enhanced mucosal pattern of these polyps, and it correlated with the increase of detection of more lesions.

However, neither previous studies using traditional chromoendoscopy nor FICE, were conducted in evaluation of gastric polyps in FAP patients. To the best of our knowledge, our study is the first that has assessed the role of FICE in FGPs dysplasia identification and in the gastroduodenal polyps characterization in FAP subjects.

In agreement with the literature’s data, the prevalence of gastric polyps was relatively elevated (90.8%), while duodenal polyps were diagnosed in 68.4% of patients, slightly lower than the reported literature value.

In the majority of FAP subjects (62/76; 83.3%), gastric polyps were so numerous that they carpeted the fundic mucosa, making difficult identifying dysplasia by random biopsies on the basis of the total number of polyps, as indicated in a recent study conducted by Bianchi et al[9]. Consequently, having an endoscopic technique able to target fundic biopsies is important to overcome this issue. Moreover, Bianchi et al[9] reported a prevalence of dysplasia in fundic polyps of 42%, while we have found only fundic gland polyps without displastic or adenomatous areas, although we have followed their sampling method. A possible explanation to this marked mismatch, could lie in the size of the polyps removed: we did found only subcentimetric polyps, while Bianchi et al[9] have demonstrated that the risk of dysplasia correlated with polyp size. No polyps removed had suspected superficial features according to Kudo classification, while Bianchi et al[9] did not adopted any classification to describe mucosal and vascular pattern; consequently we don’t know if their removed polyps had or not a suspected pattern.

FICE pointed our attention on 10 fundic polyps, that seemed suspected for harboring adenomatous tissue; however histological results did not confirmed this suspect and all of polyps resulted fundic gland polyps. In this case, FICE has not increased the identification rate of dysplasia or adenomatous tissue in fundic polyps.

Prevalence of patients with antral adenomas was about 21.1% (16/76), more than reported in the Western World data, but consistent with Japanese findings. The use of FICE could explain our result, since it has increased the identification rate of antral adenomas compared to white light, with a difference near to statistical significance (P = 0.0857).

The very low specificity of the method (12.0%) could be explained by the presence of phlogosis (in fact almost all false positive harbored flogistic areas) able to distort the mucosal and vascular pattern, specifically enhanced by virtual chromoendoscopy.

Therefore, FICE allows to identify a greater number of adenomas to the detriment of a greater number of biopsies. Anyway this approach didn’t determine a different timing in the surveillance program, but changed the attention on the antral evaluation during the following endoscopies. In duodenal bulb FICE was able to identify more adenomas than traditional endoscopy (P = 0.03). Furthermore, all patients with FICE-identified adenomas had polyps in the duodenum too, thus the identification of bulbar adenomas didn’t modify surveillance timing.

Taking into account also bulbar polyps, duodenal adenomas prevalence in FAP patients was 68.4%, with low Spigelman stages (9.2% stage III e 0% stage IV). In duodenum, FICE has allowed to see a greater number of adenomas than white light (P < 0.001), without no modifications of Spigelman stage neither identification of high grade dysplasia.

Among FICE identified polyps, 4 lesions were suspected for high grade dysplasia, but three were inflammatory polyps at histopathological examination and one was a tubular adenoma with low grade of dysplasia. Other 7 polyps (Kudo IV) had an increased capillary density but they were tubular adenomas with low grade of dysplasia.

Finally, in duodenum, FICE increased the polyps detection rate but didn’t change any Spigelman stage determined with conventional endoscopy. These data are in agreement with the little size and the absence of high grade dysplasia. Moreover this method wasn’t able to modify FAP patients’ prognosis, polyps’ surveillance program and their therapeutic management. We did not find any relationship between the presence of gastric polyps, duodenal polyposis and high Spigelman stage (P = 1).

Adenomas were 435 and 81 of them were diagnosed only by FICE that was able to identify a significative higher number of adenomas (P = 0.0062). Overall, FICE has specificity, sensitivity,positive and negative predictive values higher than traditional endoscopy referring to adenomas (96.0% vs 7.1%; 98.8% vs 80.2%; 90.3% vs 44.9%; 98.8% vs 27.6%, respectively; P < 0.0001). Conversely, it wasn’t possible to correlate for high grade dysplasia due the absence of dysplastic lesions according to the histopathological examination.

The FICE identified lesions (106/468; 22.6%) were mostly flat (67.9%; P = 0.029) and small (all below 1 cm). According to already published data, FICE was particularly able to identify polyps with these features. It isn’t clear if this ability might have clinical and procedural consequences.

In summary, in our study, FICE, like traditional endoscopy, could not identify any adenoma at risk of malignant transformation probably as a consequence of patients features (e.g., favorable genotype, recent EGD).

Nonetheless FICE significantly increases adenoma detection rate (P = 0.0062) but does not change any Spigelman stage and thus does not modify patient’s prognosis, surveillance program and treatment strategies. Probably a careful patient selection, an accurate histological examination, a concomitant use of lateral viewing endoscope, could make FICE gain that role who everybody expects in FAP patient.