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Increased prevalence of Barrett’s esophagus in patients with MUTYH-associated polyposis (MAP)

Increased prevalence of Barrett’s esophagus in patients with MUTYH-associated polyposis (MAP) Barrett’s oesophagus (BE) has been associated with an increased risk of both colorectal adenomas and colorectal cancer. A recent investigation reported a high frequency of BE in patients with adenomatous polyposis coli (APC)-associated polyposis (FAP). The aim of the present study is to evaluate the prevalence of BE in a large cohort of patients with MUTYH-associated polyposis (MAP) and APC-associated adenomatous polyposis. Patients with a genetically confirmed diagnosis of familial adenomatous polyposis (FAP) or MAP were selected and upper gastrointestinal (GI) endoscopy reports, pathology reports of upper GI biopsies were reviewed to determine the prevalence of BE in these patients. Histologically confirmed BE was found in 7 (9.7%) of 72 patients with MAP. The mean age of diagnosis was 60.2 years (range 54.1–72.4 years). Two patients initially diagnosed with low grade dysplasia showed fast progression into high grade dysplasia and esophageal cancer, respectively. Only 4 (1.4%) of 365 patients with FAP were found to have pathologically confirmed BE. The prevalence of BE in patients with MAP is much higher than reported in the general population. We recommend that upper GI surveillance of patients with MAP should not only focus on the detection of gastric and duodenal adenomas but also on the presence of BE. Keywords Barrett’s esophagus · MUTYH-associated polyposis · Familial adenomatous polyposis · Esophageal adenocarcinoma Ceranza G. Daans and Zeinab Ghorbanoghli are first authors. Introduction * Jurjen J. Boonstra J.J.Boonstra@lumc.nl The incidence of esophageal adenocarcinoma (EAC) in Western populations has substantially increased over the Department of Infectious Diseases, Public Health Service past several decades. The majority of EACs is thought to of Amsterdam, Amsterdam, The Netherlands derive from a precursor lesion—Barrett esophagus (BE). BE Department of Internal Medicine, Amsterdam UMC, VU is characterized by the presence of columnar epithelium that University Medical Center, Amsterdam, The Netherlands has replaced the normal squamous cell lining of the distal Center of Expertise on Gender Dysphoria, Amsterdam UMC, esophagus. EAC develops through multistep progression VU University Medical Center, Amsterdam, The Netherlands from metaplasia into low grade dysplasia, high grade dys- The Netherlands Foundation for the Detection of Hereditary plasia, early adenocarcinoma, and, finally, invasive cancer. Tumours, Leiden, The Netherlands This metaplastic change is driven by chronic inflammation Department of Gastroenterology & Hepatology, Leiden due to gastro-esophageal reflux disease (GERD), which is University Medical Center, PO BOX 9600, 2300 RC Leiden, The Netherlands aggravated by abdominal obesity and smoking [1, 2]. In addition to environmental factors associated with BE and Department of Genetics, University Medical Center Utrecht (Location WKZ), Lundlaan 6, 3584 EA Utrecht, EAC, also genetic factors are thought to play a role [3, 4]. The Netherlands The prevalence of BE in asymptomatic patients varies Department of Pathology, University Medical Center Utrecht, between 0.5 and 1.8% and in patients with reflux symptoms, PO BOX 855000, 3508 GA Utrecht, The Netherlands between 1.5 and 12.3% ([5–9], Table 1). It has been reported Department of Gastroenterology, Radboud University that BE and EAC are associated with a higher incidence Medical Center, PO BOX 9101, 6500 HB Nijmegen, of (sporadic) colorectal adenomatous polyps [10]. Also, The Netherlands Vol.:(0123456789) 1 3 184 C. G. Daans et al. Table 1 The prevalence of Barrett’s esophagus (BE) reported in the general population (GP) and patients with and without gastro-esophageal reflux disease (GERD) symptoms Study Year Country Total number of Prevalence of BE Prevalence of BE in Prevalence of BE in patients in GP (%) patients with GERD (%) patients without GERD (%) Ronkainen et al. 2005 Sweden 1000 1.6 2.3 1.2 Zagari et al. 2008 Italy 1033 1.3 1.5 1.0 Peng et al. 2009 China 2580 1.0 – 0.5 Lee et al. 2010 South Korea 2048 1.0 12.3 0.5 Zou et al. 2011 China 1030 1.8 2.1 1.8 familial adenomatous polyposis (FAP) caused by germline included patients were collected from the PALGA (Dutch mutations in the adenomatous polyposis coli (APC) gene, acronym for “Pathologisch-Anatomisch Landelijk Geau- has been associated with an increased risk of developing tomatiseerd Archief”) database to confirm the histological BE [11, 12]. It is not known whether adenomatous polypo- diagnosis of BE. The PALGA database is a national auto- sis caused by bi-allelic germline mutations in the MUTYH mated archive where all pathology reports of all performed gene (MUTYH-associated polyposis (MAP)) is also associ- biopsies in the Netherlands are registered. BE was defined ated with BE [13]. The MUTYH gene plays an important as esophageal columnar epithelium in the presence of goblet role in base excision repair. Base excision repair is a cellular cells [18]. The available section slides of the Barrett biop- mechanism that repairs damaged DNA throughout the cell sies were reviewed by an expert GI pathologist (GJHO and cycle. It is responsible primarily for removing small, non- MML). helix-distorting base lesions from the genome [14]. EAC has Only patients from the Department of Clinical Genet- been reported as part of the extracolonic tumor spectrum of ics that have given their informed consent for their medical MAP [15]. records to be reviewed were included. All patients registered Surveillance of the upper gastrointestinal (GI)-tract is at the Dutch Hereditary Cancer Registry have given written recommended for patients with MAP and FAP because of informed consent for registration and use of their anonymous the increased risk of gastric and duodenal adenomas [16]. data for research. In the present study we assessed the prevalence of BE and Descriptive statistical analysis was used. Frequencies are EAC by reviewing the endoscopy reports in a large cohort presented as absolute numbers and percentages. Continuous of patients with FAP and MAP. data are presented as mean [standard deviation (SD)], and in the case of non-normally distributed data as median (range). Last follow-up was calculated as death, diagnosis of BE or Methods end of the study. Initially, the database of the Department of Genetics at the University Medical Centre Utrecht was used to iden- Results tify patients diagnosed with a polyposis syndrome between November 1987 and April 2015. Patients with a genetically Prevalence of BE in patients with MAP confirmed diagnosis of FAP or MAP were eligible for this study if one or more upper GI endoscopy reports and/or A total of 94 patients with genetically proven MAP were pathology reports of upper GI biopsies were available. selected. In 72 of the 94 MAP patients, the upper GI endos- To increase the number of FAP and MAP patients, we copy reports and/or pathology reports of upper GI biopsies also used data from the Dutch Hereditary Cancer Registry. were available, including 28 females and 44 males. The This national registry, established in 1985, collect medical mean age at last follow-up was 60.9 years (range 27.3–87.6, and pathology reports and reports of upper and lower GI SD 11.4) and the mean length of follow-up (in 60 of 72 MAP endoscopy of all registered patients with FAP and MAP. patients where data was available) was 10.1 years (range All available original upper-GI endoscopy reports were 0–26.2). Patients characteristics and endoscopic findings are reviewed. Data on the presence of BE, length of BE and, if shown in Table 2. available, the Prague criteria (endoscopic grading system A total of nine patients had an endoscopical diagno- for BE) were recorded. Also, the presence of a hiatal hernia sis of BE, and in seven out of the nine patients, BE was and GERD (based on the Los Angeles, LA classification confirmed by histology (Table 3). Revision of the section [17]) were obtained. Secondly, the pathology reports of all slides by an expert pathologist was possible in six out of 1 3 Increased prevalence of Barrett’s esophagus in patients with MUTYH-associated polyposis… 185 Table 2 Frequency of MAP patients (%) FAP patients (%) endoscopic findings in the esophagus in MAP and FAP- Total number of patients 72 356 patients Gender  Female 28 (38.9) 179 (50.3)  Male 44 (61.1) 177 (49.7) Age at last follow-up (range) 60.9 (27.3–87.6) 48.9 (30.3–86.0) Endoscopic findings esophagus  Histologically proven Barrett’s mucosa 7 (9.7) 4 (1.4%)  Esophagus adenocarcinoma 1 (1.4) 0 Other findings  Gastro-esophageal reflux esophagitis 18 (25) NA  Hiatal hernia 10 (14) NA MAP MUTYH-associated polyposis, FAP APC-associated polyposis. NA not available Table 3 Clinical, genetic and pathological characteristics of seven MAP patients with Barrett’s esophagus Patient Sex Age at Mutation 1 Mutation 2 Initial PA report Revision diagnosis (years) 1 F 61 c.536A>G p.(Tyr179Cys) c.638C>T p.(Pro213Leu) No dysplasia No dysplasia 2 M 72 c.1147delC, p.(Glu369Argfs*39) c.1214C>T p.(Pro405Leu) High grade dysplasia High grade dysplasia 3 F 54 c.1187G>A p.(Gly396Asp) c.1214C>T p.(Pro405Leu) Low grade dysplasia No dysplasia 4 M 58 c.536A>G p.(Tyr179Cys) c.536A>G p.(Tyr179Cys) Low grade dysplasia Not available 5 M 57 c.536A>G p.(Tyr179Cys) c.1214C>T p.(Pro405Leu) No dysplasia Indefinite for dysplasia 6 M 55 c.536A>G p.(Tyr179Cys) c.933 + 3A >C splice site intron No dysplasia Indefinite for dysplasia 7 M 65 c.536A>G p.(Tyr179Cys) c.1187G>A p.(Gly396Asp) No dysplasia No dysplasia seven patients, and in all six patients the diagnoses of Prevalence of BE in patients with (A)FAP BE was confirmed. Thus, the prevalence of pathologi- cally confirmed BE in the total cohort was 9.7% (7/72). In total, 407 FAP patients were identified from the 2 data- The seven patients with BE included five males and two sets. Upper GI endoscopy reports and/or pathology reports of females. The mean age at diagnosis of BE was 60.2 years upper GI biopsies were available in 356 patients including 177 (range 54.1–72.4 years, SD 6.5). The characteristics of males and 179 females. The mean age at the last follow-up was the seven patients with BE are summarized in Table 3. 48.9 years (range 30.3–86.0, SD 11.8). Information on previous endoscopies was available in In the total cohort, five patients with BE were detected. In six out of the seven patients with BE. In three patients, four of these patients including two males and two females the BE was diagnosed at the first upper-GI endoscopy. In the diagnosis was confirmed by histological examination. In the remaining three patients, the previous endoscopy, per- f fi th patient the diagnosis could not be conr fi med as no goblet formed 1–4 years earlier, did not demonstrate evidence cells were present in the biopsies. The prevalence of histologi- for BE. cally proven BE in this cohort is, therefore, 1.4%. The mean At time of diagnosis, two patients had low-grade dys- age at diagnosis of the four patients with BE was 52.5 years plasia. The first patient developed high grade dyspla- (range 34.0–60.0, SD 12.4). The endoscopic findings are sum- sia after having low grade dysplasia in previous biop- marized in Table 2. sies. The treatment consisted of piecemeal endoscopic mucosal resection. The second patient, initially diagnosed with low grade dysplasia, developed adenocarcinoma after 6 months and underwent a surgical resection of a pT2N2Mx EAC. The follow-up of the patients with BE are shown in Fig. 1. 1 3 186 C. G. Daans et al. Fig. 1 Findings at follow-up Pt 1 upper GI-endoscopies in the seven patients with Barrett’s Pt 2 esophagus. Arrow blocks rep- Duodenoscopy Pt 3 resent screening intervals and No intestinal metaplasia the colors indicate the stage of Pt 4 metaplasia/dysplasia. pt patient. Intestinal Metaplasia Pt 5 (Color figure online) Low Grade Dysplasia Pt 6 High Grade Dysplasia Pt 7 Adenocarcinoma Time of diagnosis 3years 6years 9years Follow-up been reported as part of the tumor spectrum of MAP but Discussion not in FAP supports our findings. The strength of this study is the large number of patients The present study demonstrated a prevalence of BE (9.7%) with MAP and FAP and the long follow-up time. in MAP patients which is > 5 times higher than reported in In addition, all pathology reports were cross linked the general population. In contrast with a previous study, with the National Database (PALGA) and all biopsies of no increased frequency of BE was found in a large series patients with BE were reviewed by an expert pathologist. of FAP-patients. There are also some limitations. At first, it is a retrospec- The prevalence of BE depends on which population is tive analysis which might have led to selection of patients screened. In asymptomatic patients that undergo an upper with BE. Secondly, not all risk-factors for the development GI endoscopy the prevalence varies between 0.5 and 1.8% of BE could be collected, such as smoking, obesity, symp- and in patients with reflux symptoms, it is between 1.5 and toms of GERD or alcohol use. 12.3% (Table 1; [5–9]). The proportion of MAP patients What is the clinical implication of our study? Based on in our series with gastro-esophageal reflux esophagitis our observations, we recommend that upper GI surveil- (25%) is not higher than reported in the general population lance of patients with MAP should not only focus on the which suggests that the frequency of BE is not increased identification of gastric and duodenal adenomas but also by selection of symptomatic patients. on the presence of BE. In view of the observed accel- Another interesting finding was that in this small cohort eration of high-grade dysplasia and EAC development, of BE patients, two of the seven patients with initial low- more intensive follow-up might be considered in patients grade dysplasia showed fast progression to high grade dys- with BE. In conclusion, this study demonstrates that the plasia and EAC, respectively. From a biological point of prevalence of BE with patients with MAP is much higher view our findings seem plausible. Persistent inflammation compared to the general population. This can be explained in esophageal mucosa due to acids and bile acids is associ- by the impaired MUTYH protein function that plays a role ated with DNA impairment caused by increased formation in the repair of DNA damage caused by oxidative stress of reactive oxygen species (ROS) [19–21]. One of the main such as GERD. defensive mechanisms to eliminate ROS induced DNA damage in cells is base-excision repair. Since MUT YH Acknowledgements The Authors wish to thank Dr. C.M.J. Tops for protein is a key player in base-excision repair, loss of the MUTYH mutation analysis. MUTYH-proteins could lead to accumulation of mutations and finally drive oncogenesis. Author contributions Study concept and design (JJB, PDS, MGEMA); Analysis of our cohort of 356 FAP patients revealed acquisition of data (CGD, MEV, ZG, JJB, GJAO, MML, MGEMA); analysis and interpretation of data (JJB, MGEMA, HFAV); drafting of that the prevalence of BE (1.4%) is not higher than in the the manuscript (CGD, MGEMA, JJB, HFAV, ZG); critical revision of general population. This is in contrast with a previous the manuscript for important intellectual content (HFAV, PDS, GJAO, report on 36 (A)FAP patients of whom 6 (16%) had histo- JJB). logically proven BE [11]. We do not have an explanation for the observed differences but in view of the relatively Compliance with ethical standards small number of patients in the previous report, the find- ings might be due to chance. The fact that EAC has only Conflict of interests The authors declare that they have no potential conflicts of interest. 1 3 Increased prevalence of Barrett’s esophagus in patients with MUTYH-associated polyposis… 187 Open Access This article is licensed under a Creative Commons Attri- 10. Kumaravel A, Thota PN, Lee HJ et al (2014) Higher prevalence of bution 4.0 International License, which permits use, sharing, adapta- colon polyps in patients with Barrett’s esophagus: a case–control tion, distribution and reproduction in any medium or format, as long study. Gastroenterol Rep (Oxf) 2:281–287 as you give appropriate credit to the original author(s) and the source, 11. Gatalica Z, Chen M, Snyder C (2014) Barrett’s esophagus in provide a link to the Creative Commons licence, and indicate if changes the patients with familial adenomatous polyposis. Fam Cancer were made. The images or other third party material in this article are 13:213–217 included in the article’s Creative Commons licence, unless indicated 12. Gupta M, Dhavaleshwar D, Gupta V et al (2011) Barrett esopha- otherwise in a credit line to the material. If material is not included in gus with progression to adenocarcinoma in multiple family mem- the article’s Creative Commons licence and your intended use is not bers with attenuated familial polyposis. Gastroenterol Hepatol permitted by statutory regulation or exceeds the permitted use, you will (NY) 7:340–342 need to obtain permission directly from the copyright holder. To view a 13. Al-Tassan N, Chmiel NH, Maynard J et al (2002) Inherited vari- copy of this licence, visit http://creativ ecommons .or g/licenses/b y/4.0/. ants of MYH associated with somatic G: C → T: A mutations in colorectal tumors. Nat Genet 30:227–232 14. Ruggieri V, Pin E, Russo MT et al (2013) Loss of MUTYH func- tion in human cells leads to accumulation of oxidative damage and References genetic instability. Oncogene 32:4500–4508 15. Vogt S, Jones N, Christian D et al (2009) Expanded extracolonic 1. Hvid-Jensen F, Pedersen L, Drewes AM et al (2011) Incidence of tumor spectrum in MUTYH-associated polyposis. Gastroenterol- adenocarcinoma among patients with Barrett’s esophagus. N Engl ogy 137:1976–1985 J Med 365:1375–1383 16. Gallagher M, Phillips R, Bulow S (2006) Surveillance and man- 2. Harrison RF, Perry I, Balkwill F et al (2000) Barrett’s metaplasia. agement of upper gastrointestinal disease in Familial Adenoma- Lancet 356:2079–2085 tous Polyposis. Fam Cancer 5:263–273 3. Levine DM, Ek WE, Zhang R et al (2013) A genome-wide asso- 17. Katz PO, Gerson LB, Vela MF (2013) Diagnosis and manage- ciation study identie fi s new susceptibility loci for esophageal ade - ment of gastroesophageal reflux disease. 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Jimenez P, Piazuelo E, Sanchez MT et al (2005) Free radicals and ageal reflux symptoms, oesophagitis and Barrett’s oesophagus antioxidant systems in reflux esophagitis and Barrett’s esophagus. in the general population: the Loiano-Monghidoro study. Gut World J Gastroenterol 11:2697–2703 57:1354–1359 21. Hardikar S, Onstad L, Song X et al (2014) Inflammation and oxi- 7. Peng S, Cui Y, Xiao YL et  al (2009) Prevalence of erosive dative stress markers and esophageal adenocarcinoma incidence esophagitis and Barrett’s esophagus in the adult Chinese popula- in a Barrett’s esophagus cohort. Cancer Epidemiol Biomark Prev tion. Endoscopy 41:1011–1017 23:2393–2403 8. Lee IS, Choi SC, Shim KN et  al (2010) Prevalence of Bar- rett’s esophagus remains low in the Korean population: nation- Publisher’s Note Springer Nature remains neutral with regard to wide cross-sectional prospective multicenter study. Dig Dis Sci jurisdictional claims in published maps and institutional affiliations. 55:1932–1939 9. Zou D, He J, Ma X et al (2011) Epidemiology of symptom-defined gastroesophageal reflux disease and reflux esophagitis: the sys - tematic investigation of gastrointestinal diseases in China (SILC). Scand J Gastroenterol 46:133–141 1 3 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Familial Cancer Springer Journals

Increased prevalence of Barrett’s esophagus in patients with MUTYH-associated polyposis (MAP)

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Abstract

Barrett’s oesophagus (BE) has been associated with an increased risk of both colorectal adenomas and colorectal cancer. A recent investigation reported a high frequency of BE in patients with adenomatous polyposis coli (APC)-associated polyposis (FAP). The aim of the present study is to evaluate the prevalence of BE in a large cohort of patients with MUTYH-associated polyposis (MAP) and APC-associated adenomatous polyposis. Patients with a genetically confirmed diagnosis of familial adenomatous polyposis (FAP) or MAP were selected and upper gastrointestinal (GI) endoscopy reports, pathology reports of upper GI biopsies were reviewed to determine the prevalence of BE in these patients. Histologically confirmed BE was found in 7 (9.7%) of 72 patients with MAP. The mean age of diagnosis was 60.2 years (range 54.1–72.4 years). Two patients initially diagnosed with low grade dysplasia showed fast progression into high grade dysplasia and esophageal cancer, respectively. Only 4 (1.4%) of 365 patients with FAP were found to have pathologically confirmed BE. The prevalence of BE in patients with MAP is much higher than reported in the general population. We recommend that upper GI surveillance of patients with MAP should not only focus on the detection of gastric and duodenal adenomas but also on the presence of BE. Keywords Barrett’s esophagus · MUTYH-associated polyposis · Familial adenomatous polyposis · Esophageal adenocarcinoma Ceranza G. Daans and Zeinab Ghorbanoghli are first authors. Introduction * Jurjen J. Boonstra J.J.Boonstra@lumc.nl The incidence of esophageal adenocarcinoma (EAC) in Western populations has substantially increased over the Department of Infectious Diseases, Public Health Service past several decades. The majority of EACs is thought to of Amsterdam, Amsterdam, The Netherlands derive from a precursor lesion—Barrett esophagus (BE). BE Department of Internal Medicine, Amsterdam UMC, VU is characterized by the presence of columnar epithelium that University Medical Center, Amsterdam, The Netherlands has replaced the normal squamous cell lining of the distal Center of Expertise on Gender Dysphoria, Amsterdam UMC, esophagus. EAC develops through multistep progression VU University Medical Center, Amsterdam, The Netherlands from metaplasia into low grade dysplasia, high grade dys- The Netherlands Foundation for the Detection of Hereditary plasia, early adenocarcinoma, and, finally, invasive cancer. Tumours, Leiden, The Netherlands This metaplastic change is driven by chronic inflammation Department of Gastroenterology & Hepatology, Leiden due to gastro-esophageal reflux disease (GERD), which is University Medical Center, PO BOX 9600, 2300 RC Leiden, The Netherlands aggravated by abdominal obesity and smoking [1, 2]. In addition to environmental factors associated with BE and Department of Genetics, University Medical Center Utrecht (Location WKZ), Lundlaan 6, 3584 EA Utrecht, EAC, also genetic factors are thought to play a role [3, 4]. The Netherlands The prevalence of BE in asymptomatic patients varies Department of Pathology, University Medical Center Utrecht, between 0.5 and 1.8% and in patients with reflux symptoms, PO BOX 855000, 3508 GA Utrecht, The Netherlands between 1.5 and 12.3% ([5–9], Table 1). It has been reported Department of Gastroenterology, Radboud University that BE and EAC are associated with a higher incidence Medical Center, PO BOX 9101, 6500 HB Nijmegen, of (sporadic) colorectal adenomatous polyps [10]. Also, The Netherlands Vol.:(0123456789) 1 3 184 C. G. Daans et al. Table 1 The prevalence of Barrett’s esophagus (BE) reported in the general population (GP) and patients with and without gastro-esophageal reflux disease (GERD) symptoms Study Year Country Total number of Prevalence of BE Prevalence of BE in Prevalence of BE in patients in GP (%) patients with GERD (%) patients without GERD (%) Ronkainen et al. 2005 Sweden 1000 1.6 2.3 1.2 Zagari et al. 2008 Italy 1033 1.3 1.5 1.0 Peng et al. 2009 China 2580 1.0 – 0.5 Lee et al. 2010 South Korea 2048 1.0 12.3 0.5 Zou et al. 2011 China 1030 1.8 2.1 1.8 familial adenomatous polyposis (FAP) caused by germline included patients were collected from the PALGA (Dutch mutations in the adenomatous polyposis coli (APC) gene, acronym for “Pathologisch-Anatomisch Landelijk Geau- has been associated with an increased risk of developing tomatiseerd Archief”) database to confirm the histological BE [11, 12]. It is not known whether adenomatous polypo- diagnosis of BE. The PALGA database is a national auto- sis caused by bi-allelic germline mutations in the MUTYH mated archive where all pathology reports of all performed gene (MUTYH-associated polyposis (MAP)) is also associ- biopsies in the Netherlands are registered. BE was defined ated with BE [13]. The MUTYH gene plays an important as esophageal columnar epithelium in the presence of goblet role in base excision repair. Base excision repair is a cellular cells [18]. The available section slides of the Barrett biop- mechanism that repairs damaged DNA throughout the cell sies were reviewed by an expert GI pathologist (GJHO and cycle. It is responsible primarily for removing small, non- MML). helix-distorting base lesions from the genome [14]. EAC has Only patients from the Department of Clinical Genet- been reported as part of the extracolonic tumor spectrum of ics that have given their informed consent for their medical MAP [15]. records to be reviewed were included. All patients registered Surveillance of the upper gastrointestinal (GI)-tract is at the Dutch Hereditary Cancer Registry have given written recommended for patients with MAP and FAP because of informed consent for registration and use of their anonymous the increased risk of gastric and duodenal adenomas [16]. data for research. In the present study we assessed the prevalence of BE and Descriptive statistical analysis was used. Frequencies are EAC by reviewing the endoscopy reports in a large cohort presented as absolute numbers and percentages. Continuous of patients with FAP and MAP. data are presented as mean [standard deviation (SD)], and in the case of non-normally distributed data as median (range). Last follow-up was calculated as death, diagnosis of BE or Methods end of the study. Initially, the database of the Department of Genetics at the University Medical Centre Utrecht was used to iden- Results tify patients diagnosed with a polyposis syndrome between November 1987 and April 2015. Patients with a genetically Prevalence of BE in patients with MAP confirmed diagnosis of FAP or MAP were eligible for this study if one or more upper GI endoscopy reports and/or A total of 94 patients with genetically proven MAP were pathology reports of upper GI biopsies were available. selected. In 72 of the 94 MAP patients, the upper GI endos- To increase the number of FAP and MAP patients, we copy reports and/or pathology reports of upper GI biopsies also used data from the Dutch Hereditary Cancer Registry. were available, including 28 females and 44 males. The This national registry, established in 1985, collect medical mean age at last follow-up was 60.9 years (range 27.3–87.6, and pathology reports and reports of upper and lower GI SD 11.4) and the mean length of follow-up (in 60 of 72 MAP endoscopy of all registered patients with FAP and MAP. patients where data was available) was 10.1 years (range All available original upper-GI endoscopy reports were 0–26.2). Patients characteristics and endoscopic findings are reviewed. Data on the presence of BE, length of BE and, if shown in Table 2. available, the Prague criteria (endoscopic grading system A total of nine patients had an endoscopical diagno- for BE) were recorded. Also, the presence of a hiatal hernia sis of BE, and in seven out of the nine patients, BE was and GERD (based on the Los Angeles, LA classification confirmed by histology (Table 3). Revision of the section [17]) were obtained. Secondly, the pathology reports of all slides by an expert pathologist was possible in six out of 1 3 Increased prevalence of Barrett’s esophagus in patients with MUTYH-associated polyposis… 185 Table 2 Frequency of MAP patients (%) FAP patients (%) endoscopic findings in the esophagus in MAP and FAP- Total number of patients 72 356 patients Gender  Female 28 (38.9) 179 (50.3)  Male 44 (61.1) 177 (49.7) Age at last follow-up (range) 60.9 (27.3–87.6) 48.9 (30.3–86.0) Endoscopic findings esophagus  Histologically proven Barrett’s mucosa 7 (9.7) 4 (1.4%)  Esophagus adenocarcinoma 1 (1.4) 0 Other findings  Gastro-esophageal reflux esophagitis 18 (25) NA  Hiatal hernia 10 (14) NA MAP MUTYH-associated polyposis, FAP APC-associated polyposis. NA not available Table 3 Clinical, genetic and pathological characteristics of seven MAP patients with Barrett’s esophagus Patient Sex Age at Mutation 1 Mutation 2 Initial PA report Revision diagnosis (years) 1 F 61 c.536A>G p.(Tyr179Cys) c.638C>T p.(Pro213Leu) No dysplasia No dysplasia 2 M 72 c.1147delC, p.(Glu369Argfs*39) c.1214C>T p.(Pro405Leu) High grade dysplasia High grade dysplasia 3 F 54 c.1187G>A p.(Gly396Asp) c.1214C>T p.(Pro405Leu) Low grade dysplasia No dysplasia 4 M 58 c.536A>G p.(Tyr179Cys) c.536A>G p.(Tyr179Cys) Low grade dysplasia Not available 5 M 57 c.536A>G p.(Tyr179Cys) c.1214C>T p.(Pro405Leu) No dysplasia Indefinite for dysplasia 6 M 55 c.536A>G p.(Tyr179Cys) c.933 + 3A >C splice site intron No dysplasia Indefinite for dysplasia 7 M 65 c.536A>G p.(Tyr179Cys) c.1187G>A p.(Gly396Asp) No dysplasia No dysplasia seven patients, and in all six patients the diagnoses of Prevalence of BE in patients with (A)FAP BE was confirmed. Thus, the prevalence of pathologi- cally confirmed BE in the total cohort was 9.7% (7/72). In total, 407 FAP patients were identified from the 2 data- The seven patients with BE included five males and two sets. Upper GI endoscopy reports and/or pathology reports of females. The mean age at diagnosis of BE was 60.2 years upper GI biopsies were available in 356 patients including 177 (range 54.1–72.4 years, SD 6.5). The characteristics of males and 179 females. The mean age at the last follow-up was the seven patients with BE are summarized in Table 3. 48.9 years (range 30.3–86.0, SD 11.8). Information on previous endoscopies was available in In the total cohort, five patients with BE were detected. In six out of the seven patients with BE. In three patients, four of these patients including two males and two females the BE was diagnosed at the first upper-GI endoscopy. In the diagnosis was confirmed by histological examination. In the remaining three patients, the previous endoscopy, per- f fi th patient the diagnosis could not be conr fi med as no goblet formed 1–4 years earlier, did not demonstrate evidence cells were present in the biopsies. The prevalence of histologi- for BE. cally proven BE in this cohort is, therefore, 1.4%. The mean At time of diagnosis, two patients had low-grade dys- age at diagnosis of the four patients with BE was 52.5 years plasia. The first patient developed high grade dyspla- (range 34.0–60.0, SD 12.4). The endoscopic findings are sum- sia after having low grade dysplasia in previous biop- marized in Table 2. sies. The treatment consisted of piecemeal endoscopic mucosal resection. The second patient, initially diagnosed with low grade dysplasia, developed adenocarcinoma after 6 months and underwent a surgical resection of a pT2N2Mx EAC. The follow-up of the patients with BE are shown in Fig. 1. 1 3 186 C. G. Daans et al. Fig. 1 Findings at follow-up Pt 1 upper GI-endoscopies in the seven patients with Barrett’s Pt 2 esophagus. Arrow blocks rep- Duodenoscopy Pt 3 resent screening intervals and No intestinal metaplasia the colors indicate the stage of Pt 4 metaplasia/dysplasia. pt patient. Intestinal Metaplasia Pt 5 (Color figure online) Low Grade Dysplasia Pt 6 High Grade Dysplasia Pt 7 Adenocarcinoma Time of diagnosis 3years 6years 9years Follow-up been reported as part of the tumor spectrum of MAP but Discussion not in FAP supports our findings. The strength of this study is the large number of patients The present study demonstrated a prevalence of BE (9.7%) with MAP and FAP and the long follow-up time. in MAP patients which is > 5 times higher than reported in In addition, all pathology reports were cross linked the general population. In contrast with a previous study, with the National Database (PALGA) and all biopsies of no increased frequency of BE was found in a large series patients with BE were reviewed by an expert pathologist. of FAP-patients. There are also some limitations. At first, it is a retrospec- The prevalence of BE depends on which population is tive analysis which might have led to selection of patients screened. In asymptomatic patients that undergo an upper with BE. Secondly, not all risk-factors for the development GI endoscopy the prevalence varies between 0.5 and 1.8% of BE could be collected, such as smoking, obesity, symp- and in patients with reflux symptoms, it is between 1.5 and toms of GERD or alcohol use. 12.3% (Table 1; [5–9]). The proportion of MAP patients What is the clinical implication of our study? Based on in our series with gastro-esophageal reflux esophagitis our observations, we recommend that upper GI surveil- (25%) is not higher than reported in the general population lance of patients with MAP should not only focus on the which suggests that the frequency of BE is not increased identification of gastric and duodenal adenomas but also by selection of symptomatic patients. on the presence of BE. In view of the observed accel- Another interesting finding was that in this small cohort eration of high-grade dysplasia and EAC development, of BE patients, two of the seven patients with initial low- more intensive follow-up might be considered in patients grade dysplasia showed fast progression to high grade dys- with BE. In conclusion, this study demonstrates that the plasia and EAC, respectively. From a biological point of prevalence of BE with patients with MAP is much higher view our findings seem plausible. Persistent inflammation compared to the general population. This can be explained in esophageal mucosa due to acids and bile acids is associ- by the impaired MUTYH protein function that plays a role ated with DNA impairment caused by increased formation in the repair of DNA damage caused by oxidative stress of reactive oxygen species (ROS) [19–21]. One of the main such as GERD. defensive mechanisms to eliminate ROS induced DNA damage in cells is base-excision repair. Since MUT YH Acknowledgements The Authors wish to thank Dr. C.M.J. Tops for protein is a key player in base-excision repair, loss of the MUTYH mutation analysis. MUTYH-proteins could lead to accumulation of mutations and finally drive oncogenesis. Author contributions Study concept and design (JJB, PDS, MGEMA); Analysis of our cohort of 356 FAP patients revealed acquisition of data (CGD, MEV, ZG, JJB, GJAO, MML, MGEMA); analysis and interpretation of data (JJB, MGEMA, HFAV); drafting of that the prevalence of BE (1.4%) is not higher than in the the manuscript (CGD, MGEMA, JJB, HFAV, ZG); critical revision of general population. This is in contrast with a previous the manuscript for important intellectual content (HFAV, PDS, GJAO, report on 36 (A)FAP patients of whom 6 (16%) had histo- JJB). logically proven BE [11]. We do not have an explanation for the observed differences but in view of the relatively Compliance with ethical standards small number of patients in the previous report, the find- ings might be due to chance. 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Familial Cancer – Springer Journals

Published: Apr 22, 2020

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