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Gastric and duodenal polyps in familial adenomatous polyposis patients: Conventional endoscopy vs virtual chromoendoscopy (fujinon intelligent color enhancement) in dysplasia evaluation

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


INTRODUCTION
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 sur veillance strategies for the prevention of other extra colonic malignancies [4] . The duodenum is the second most common site of polyps development after colon, with a lifetime 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% [68] . 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 FAPassociated 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 nonFAP subjects who undergo an esophagogastroduodenoscopy (EGD). FGPs have historically been considered nonneoplastic 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% [1619] .
Other common types of gastric polyps are repre sented 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 bodyfundus 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 le sions. 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 spectralestimation matrixprocessing circuit. The image of the whitelight 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 realtime observations of mucosal and microvascular patterns [27,28] . The light penetration into the mucosa varies acc ording to the wavelengths: Those in the 400500 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 nonadenomatous polyps and to identify the presence of dysplasia [2932] . Few studies have been conducted to determine the efficacy of chromoendoscopy, both traditional and virtual, in the evaluation of duodenal and periampullary adenomatous polyps in FAP patients [3335] . Interestingly, FICE application in the discrimination between neoplastic and nonneoplastic gastric lesions has not been throughly investigated [3639] , 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.

Patients
Seventysix consecutive FAP patients, already treated by colectomy and members of sixty-five families, were enrolled. Exclusion criteria were: Uncorrectable coa gulopathy, inability to give informed consent, age < 18 years, prior gastroduodenal surgery or a personal history of gastroduodenal cancer. All patients underwent a surveillance esophagogastroduodenoscopy (EGD) in deep sedation at the Gastroenterology U.O. of the Azienda Ospedaliero Universitaria di Careggi, Firenze, Italy. Written informed consent were obtained before EGD and sedation.

Endoscopy
A FICE system (EG590ZW; Fujinon Corp, Saitama, Lami G et al . Dysplasia evaluation by FICE Japan) for the upper gastrointestinal tract with an electronic endoscope system (EPX4400; Fujinon Corp, Saitama, Japan) was used for this study. In this system, ten channels with different predefined combinations of absorption wavelengths are available. We used channel 5, corresponding to R 500 nm, G 480 nm, B 420 nm, on the basis of previous studies. A standard duodenoscope was used for sideviewing examination. Because this model of duodenoscope does not support FICE system, ampullary and periampullary evaluations were not included in the analysis. All of the endoscopic procedures were performed by two experts examiners.
"A" operator performed the exam on white light, while "B" operator used only FICE system for gastroduodenal visualization. Each EGD was divided into three phases.
During the first phase, "A" operator observed stomach and duodenum by white light recording photographic images of suspected polyps and pointing them. We intended suspected polyps on white light those larger than 1 cm and those with irregular shape or surface features.
During the second phase, "B" operator performed the exam using FICE and, like "A" operator, recorded photographic images of suspected polyps on the basis of Kudo classification [23] and capillary pattern, and pointed them.
Kudo classification classifies mucosal crypt patterns into five types, with type Ⅰ and Ⅱ predicting nonadenomatous lesions and type ⅢⅤ predicting adenomatous lesions.
Hyperplastic polyps were suspected when the surface showed pale color with only minute thin superficial (couperoselike) vessels and round or asteroid pattern (type Ⅰ and Ⅱ). Adenomas were suspected in the pre sence of increased vascular density (darkening of the mucosal pattern or a fine meshwork of brownish/bluish vessels) and a typical tubular or gyruslike pattern (type ⅢⅣ). Finally, type V have a non structural pattern which identifies high dysplastic or yet carcinomatous lesions.
During this phase we intended suspected those lesions with a pit pattern type ⅢⅤ and those with an increased capillary density.
During the third phase, after the two endoscopists' crossevaluation, lesions which seemed suspected only by FICE, only by white light or by both methods were resected or biopsied according to Kudo class.
Endoscopic resection was performed with diatermic loop for polyps ≥ 6 mm and with forceps for polyps < 6 mm. The size was estimated using on open biopsy forceps (8 mm) for comparison and recorded as smaller than 6 mm, 6 to 10 mm, 11 to 20 mm and greater than 20 mm. The total number of FGPs was documented as below: 0 to 2 polyps, 3 to 20, 21 to 30 and more than 30 polyps. On the basis of location we identified: Funduscorpus, antrum, duodenal bulb, Ⅱ°/Ⅲ° duodenal portion.
For fundic polyps seen on white light, the number of FGPs from which a biopsy specimen was taken was based on the total number of FGPs present: 3 biopsies if 320 polyps, 5 biopsies if 2130 polyps, 7 biopsies if > 30 polyps [9] . On FICE, only suspected polyps (Kudo ⅢⅤ, high capillary density) were removed.
For antral and bulbar polyps, all of them were re moved or biopsied both on withe light than on FICE.
In the second and third duodenal portion, on white light only suspected polyps were resected or biopsied, while on FICE were biopsied those with Kudo Ⅴ and those with Kudo Ⅳ and high capillary density.
Macroscopic classification of lesions followed the Paris classification [40] as polyp, superficially flat or depressed lesion, and lateral spreading tumor.

Histology
All biopsy specimens, fixed in 10% neutral buffered formalin, were analyzed by two expert gastrointestinal pathologists blinded to size, location and number of FGPs.
In the case of multiple lesions in the same patient, each lesion was identified and placed in different flasks. Lesions were histological classified in adenomatous, hyperplastic or inflammatory polyps, fundic gland polyps, and metaplastic areas.
Adenomatous polyps were classified according to OMS classification: Tubular if holding more than 75% of tubular glands, villus if holding more than 75% of villus glands, tubulovillus if not prevailing none of the two patterns.
Dysplasia was classified according to Vienna criteria [41] in low grade if holding nuclear enlargement, stratification and hyperchromasia with overall preservation of nuclear polarity; high grade as above but with nuclear polarity loss and glandular crowding; indefinite for dysplasia if present mild nuclear enlargment and insufficient hypercromasia to be classified as dysplasia or if present a significant obscuring background inflammation. The stage of duodenal polyposis was graded according to Spigelman classification modified sec. Saurin [42] , which take into account duodenal polyp number, size, histological type and grade of dysplasia. It was noted before and after FICE evaluation.

Statistical analysis
The diagnostic performances (sensitivities, specificities, positive and negative predictive values) of FICE and WL were determined by comparing the endoscopic diagnoses with the histo-pathological findings. To identify associations of demographic, clinical and endoscopic features with the presence of FGP dysplasia or with adenomas, the Fisher exact test was used to study univariable associations of categoric demographic and endoscopic factors with the presence of dysplasia or adenomatous tissue. The Student t test was used for continuous factors. A P value "two tailed" < 0.05 was considered statistical significant. The strength of association was calculated by odds ratio (OR). The statistical methods of this study were reviewed by S. Milani, University of Florence.  Table 2).
After FICE evaluation, 10 polyps were removed from 10 patients on the basis of suspicious features of dysplasia or adenomatous tissue. All of them were cystic fundic gland polyps, none of them harboring dysplasia or adenomatous foci (specificity 97%; sensitivity NV; positive predictive value 0%; negative predictive value 100%) ( Table 4).
Antrum: A total of 56 polyps were identified and removed in the antrum of 35 patients (average 1.6 polyps per patient). Twentyfour polyps were identified in 35 patients by white light endoscopy (0.7 polyps per patient); 21 of them were tubular adenomas with low grade dysplasia while 3 were inflammatory polyps (specificity 88.0%; sensitivity 67.7%; positive predictive value 87.5%; negative predictive value 68.7%) ( Table 5).
FICE identified a higher number of polyps than traditional endoscopy (56 vs 24; P < 0.0001), showing a better, but not statistically significant, tendency to identify adenomas and displastic areas (31 vs 21; P = 0.0857). All but 4 polyps missed out by white light, were flat.
Eighteen of patients with antral lesions (51.4%) had polyps also in the duodenum. There is no relationship between presence of dysplasia in antral stomach and Spigelman advanced stages (P = 1; OR = NV).
During FICE evaluation, beside polyps seen with conventional endoscopy, 7 more polyps in 7 patients, five    Lami G et al . Dysplasia evaluation by FICE Table 7 Features of bulbal polyps identified by white light endoscopy of them new, were discovered. All of them were tubular adenomas with low grade dysplasia (specificity 62.5%; sensitivity 100%; positive predictive value 81.3%; negative predictive value 100%) ( Table 8). FICE was able to see further 7 polyps than traditional endoscopy, and it was able to identify a quite significant higher number of polyp in the duodenal bulb (21 vs 14; P = 0.069). FICE added a statistical significant advantage in identifying adenomas (13 vs 6; P = 0.03). All FICE identified polyps were flat lesions. All patients with bulbal polyps had also lesions in the gastric fundus and no adenoma in the antrum.
All patients with bulbal adenomas had polyps in the second/third portion of duodenum, while patients with inflammatory polyps had a Spigelman's stage 0.
( Table 9). FICE identified further 67 polyps in 35 patients and 11 were removed or biopsied in 11 subjects. All of them were tubular adenomas with low grade dysplasia. No case of high grade dysplasia (Table 10). FICE was able to identify a higher number of polyps than traditional endoscopy (8.7 vs 7.2; P < 0.001). All polyps not seen on white light were flat lesions.
Thirtyfive of patients with duodenal polyposis had also polyps in the fundus, 4 had adenomas and 2 dysplastic areas in the antrum, thus FICE didn't change any Spigelman stage just defined with conventional endoscopy.

DISCUSSION
Duodenal adenomatous polyps are common mani festations 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 diseaserelated mortality in patients with FAP, only the  Lami G et al . Dysplasia evaluation by FICE second to advanced and metastatic colorectal cancer. A regular and careful program of endoscopic surveillance is worthwhile in identifying early premalignant lesions. Gastric polyps, particularly fundic polyps, are con sidered always nonneoplastic lesions, also in FAP and nonFAP patients; nonetheless high rate of their prevalence (20%88%) [6,911] and several cases of dysplasia in FGPs in FAP have been recently reported, with rate of incidence up to 54% [911,18] . Chromoendoscopy, both traditional and virtual, has been proven to be a good tool to increase polyps identification rate and to predict their histology [2932] .
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 pre valence 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;  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.
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.

COMMENTS Background
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. The use of colon endoscopic surveillance and prophylactic colectomy have strongly reduced mortality in FAP patients leading to the introduction of surveillance strategies for the prevention of other extracolonic malignancies (e.g., in the duodenum and in the stomach). Duodenal adenomatous polyps are common manifestations of FAP found in 30% to 90% of patients. 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. 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%) and several cases of dysplasia in FGPs in FAP have been recently reported, with rate of incidence up to 54%.

Research frontiers
The observation of the pit and capillary patterns of the mucosal glands and the mucosa, respectively, by chromoendoscopy might predict the histology of mucosal lesions.

Innovations and breakthroughs
Chromoendoscopy is a staining method that uses biocompatible dye agents which accumulate within crypt orifices during endoscopy. Chromoendoscopy has difficulty in achieving complete and even coating of the mucosal surface with the dye, requires the extra cost for the of the dye spraying equipments and extra time to perform the procedure. Fujinon Intelligent Color Enhancement (FICE™, Fujinon Corp, Saitama, Japan) is 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. Preliminary studies suggested that FICE successfully achieves enhancements of real-time observations of mucosal and microvascular patterns and may discriminate between adenomatous and non-adenomatous polyps and it may identify the presence of dysplasia. In the study, FICE, like traditional endoscopy, could not identify any adenoma at risk of malignant transformation probably as a consequence of patients features. However FICE significantly increases adenoma detection without changing 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.

COMMENTS
Lami G et al . Dysplasia evaluation by FICE