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Cowden syndrome (CS) is an autosomal-dominant disorder characterized by multiple hamartomatous and benign and malignant neoplastic lesions of the skin, mucous membranes, thyroid, breast, endometrium, and brain.1, 2, 3 Germline mutations in the PTEN tumor suppressor gene are found in 80% of classic CS.4, 5 CS is very difficult to ascertain, especially in subtler cases, and recently a clinical scoring system based on a prospective study of 3,042 CS and CS-like individuals has been proposed.6 According to this semiquantitative system, a score of 10, carrying at least a 3% likelihood of finding a PTEN pathogenic mutation, is minimal for considering PTEN testing.6 Classically, although CS patients might harbor ‘polyps’ throughout the gastrointestinal tract, they are mostly believed to be hamartomas without malignant potential. Up to now, the National Comprehensive Cancer Network (NCCN) guidelines state that routine gastrointestinal (GI) surveillance in CS patients is not indicated in the absence of symptoms.7 Prior to our recent report,8 there were scattered reports about the occurrence of GI polyposis9, 10, 11, 12, 13 but few reports documenting age-specific prevalence of gastric and colon cancers in CS patients.14, 15, 16, 17 In our prospective series of 127 unrelated individuals with pathogenic PTEN mutations, 69 (54.3%) underwent at least one endoscopy and most had GI polyps comprising multiple histologies.8 Importantly, nine (13%) mutation carriers in this series had prevalent colorectal cancers, yielding an age- and sex-adjusted standardized incidence ratio of >200. All but one with colorectal carcinomas had existing colonic polyposis. What was surprising was that 16 individuals out of 67 who underwent colonoscopy had colonic adenomatous polyps and 2 individuals out of 39 who underwent esophagogastroduodenoscopy (EGD) had upper GI adenomas. It is important to note, however, that in this series, upper or lower GI endoscopies were performed as part of clinical routine, and were not systematically performed on a regular longitudinal basis. Thus, of the 127 mutation carriers, 67 had one or more colonoscopies, and only 39, an EGD. As an important caveat to this study, therefore, an important follow-up study was to document the GI phenotype of PTEN mutation carriers undergoing systematic GI surveillance performed by one or very few endoscopists on a regular longitudinal basis, and having only one or very few pathologists read the histologies. The High Risk Cancer Clinic (HRCC) at Rabin Medical Center (RMC) is a tertiary referral center of the largest HMO in Israel. All CS patients treated at the HRCC participate in a surveillance program, where they undergo biannual dual upper and lower endoscopy, using narrow-band imaging (NBI) at the advanced endoscopy unit from the age of 25 years old, or earlier, if symptomatic. The technique of NBI allows recognition of flat lesions and helps to recognize adenomatous changes in both the upper and lower digestive tract.18, 19 Here, we sought to document the GI endoscopic and pathologic findings of 10 PTEN mutation–positive CS patients who have been systematically surveillanced annually with dual upper and lower endoscopies at the advanced endoscopy unit by three endoscopists. Immunohistochemistry (IHC) for the mismatch repair proteins, MLH1, MSH2, MSH6, and PMS2, was performed on standard 5-micron thick deparaffinized, formalin-fixed tissue sections. Monoclonal mouse primary antibodies for all four proteins (MLH1, MSH2, MSH6 from Biocare Medical, Concord, CA and PMS2 from BD Pharmingen, San Diego, CA) were used at 1:10, 1:100, and 1:500 dilutions, respectively, for 90 min (MLH1, MSH6, and PMS2) and 30 min (MSH2) incubation times at room temperature. PTEN IHC was performed with the monoclonal antibody 6H2.1 raised against the terminal 100 amino acids of human PTEN as previously described, with minor modifications.17 Utilizing the NCCN-2006/International Cowden Consortium clinical diagnostic criteria, we identified 10 CS patients out of 3,000 patients referred to the HRCC in the last 5 years. All 10 were found to have germline PTEN mutations. These patients belong to six different families. Seven patients (70%) were Jews and the remaining three were Arabs. The current mean age of the patients with CS is 36.4±14.3 years, and seven (70%) are males. The research participants’ demographic characteristics and major phenotypic findings and PTEN genotypes are presented in Table 1. Colorectal polyps were identified in 8 of 10 (80%) research participants. The lower GI polyps were found throughout the colon with increased density of polyps in the rectum. Eight subjects (80%) had hyperplastic polyps, five (50%) had hamartomatous polyps, three (30.0%) had ganglioneuromatous polyps, three had adenomatous polyps (one of them at age 29 years), and two (20.0%) had juvenile polyps. It should be noted, however, that pathology results from cold biopsies are often misleading. In five cases, we used the technique of cold biopsy before snare polypectomy. In three out of those five patients, the superficial biopsy contained “hyperplastic tissue”, while inspection of the whole resected polyp revealed that it contained hamartomatous components. All the adenomatous lesions were detected during the surveillance program (Table 2). Using both WL and NBI, we were able to identify correctly adenomatous polyps in three patients and to resect these lesions. It is impossible to decide whether it is the careful dual inspection or the added value of NBI that lead to the detection of adenomas. One out of the ten PTEN mutation–positive patients (10%) had rectal cancer at an early age (44 years). He was found to have synchronous hyperplastic, hamartomatous, and adenomatous polyps. The cancer was found to be microsatellite stable (MSS), and IHC showed normal nuclear expression of MLH1, MSH2, MSH6, and PMS2 in the carcinoma cells and PTEN expression was null by IHC. All 10 individuals had abnormal upper GI endoscopic findings, which varied from severe esophageal acanthosis and massive gastroduodenal polyposis to only a few diminutive gastric polyps. Eight patients (80%) had glycogenic acanthosis, of which five had severe acanthosis, and in two cases, the presentation was mild. Gastric polyps were detected in all patients (100%), mostly hyperplastic with varying sizes and number. Duodenal polyps were observed in nine patients (90%; Figure 1). Using both WL and NBI, we were able to identify correctly adenomatous polyps in three patients and to resect these lesions (Figure 2). Again, it is impossible to decide whether it is the careful dual inspection or the added value of NBI use that lead to the detection of adenomas. In one patient, a carpeting of polyps in the duodenal bulb proved to contain hyperplastic Brunner glands, and in one case, a 15 mm polyp in the second duodenal part contained Brunner gland hyperplasia and gastric metaplasia. While the increased risk for breast and thyroid cancer is well documented, CS is not considered as a syndrome with an increased colon cancer or upper GI cancer risk, at least in the most studied population, whites of European ancestry. In fact, Online Mendelian Inheritance in Man (OMIM)20 does not report colon or upper GI cancer in CS patients, and currently, the NCCN states that CRC screening in CS patients is not indicated in the absence of symptoms, but rather focuses largely on the increased risks of breast, thyroid, and endometrial cancers.7 A currently updated Gene Reviews21 recommend baseline colonoscopy at age 50 years, unless symptoms arise earlier, and if only hamartomatous polyps are found, the American Cancer Society guidelines for colon cancer screening (i.e., annual fecal occult blood testing and sigmoidoscopy every 5 years or colonoscopy every 10 years) should be followed.21 In late 2010 and this year, we analyzed prospective series of individuals who met classic criteria for the clinical diagnosis of CS (NCCN-2006)7 and relaxed criteria (full criteria minus one) also referred to as CS-like.6, 8 For the first time, upper and lower GI polyps, comprising broad histologies, and even polyposis are an important part of the phenotypic spectrum of individuals with pathogenic germline PTEN mutations (variants of unknown significance were excluded from analysis)8 and a clinical feature signaling the potential of the diagnosis.6 However, the caveat to these analyses is that examination of the upper and/or lower GI tracts was performed as part of clinical care, and not systematically and periodically performed as a routine. The current study directly addresses this caveat because all PTEN mutation–positive individuals here were given active annual upper and lower GI surveillance from the age of 25 years, and starting earlier should there be symptoms. Confirming our previous observation, this current study reveals 8 (80%) with colonic polyps of varying histologies and one male, currently, 61, with rectal carcinoma diagnosed at age 44. As with the Heald et al.8 observations, this cancer was accompanied by prevalent colonic polyposis. Indeed, our patient who was diagnosed with rectal cancer had undergone several endoscopies in the “community” where some of the polyps were biopsied, and were found to be “inflammatory” or hyperplastic, while careful colonoscopy using dual WL and NBI inspection we detected large adenomatous polyps (up to 15 mm) that were removed again with the endoscope. Thus, polyposis may be an indicator of future colorectal cancer risk in individuals with PTEN mutations. The rectal cancer identified here was MSS and showed normal expression of MLH1, MSH2, MSH6, and PMS2 proteins but was PTEN protein null by IHC. The fact that this MSS rectal tumor was completely null for PTEN protein expression strongly suggests that this rectal cancer was facilitated by the existing germline PTEN mutation.22 Up to our recent GI series by Heald et al.,8 there were several reports of gastric cancers in PTEN mutation carriers,14, 15 but no reports about adenomatous polyps in the upper GI tract. In our current study from active GI surveillance, we report that all patients had upper GI polyps and that three patients (30%) had adenomatous polyps, the latter contrasts with only 2 of 39 (5%) research participants found to have upper GI adenomatous polyps when EGD was performed for clinical reasons8 (P=0.05). It should be noted that the mean age of both series are similar (40 and 39 years). Two plausible explanations for the higher prevalence of GI adenomas include the use of NBI, which was used to advantage to detect all three with upper GI adenomatous polyps in this series, and the active yearly surveillance of both the upper and lower GI tracts. Therefore, as individuals with PTEN mutations may routinely develop numerous upper GI polyps and it is impossible to resect every visualized polyp, it seems reasonable to examine the polyps with dual WL and NBI and endoscopically resect only the large polyps and/or those that seem to be adenomatous. Finally, although the Heald et al.8 series could not reveal a genotype–GI phenotype correlation, we note here that all 10 individuals in this present have truncating mutations. We caution, however, that the current sample size is relatively small and we are unaware of the general genotypic spectrum in the population served by RMC. Nonetheless, we believe that our two series (Heald et al.;8 this study) begin to support routine GI surveillance on asymptomatic CS patients, confirming the suggestion that surveillance colonoscopies begin before 35 years of age. Because of the prominence of the upper GI phenotype, especially adenomas, upper GI surveillance has an important role as well. However, we do not know at what age to begin and how frequently. Because the PTEN-related GI phenotype includes multiple polyps, it may be conservative to utilize such technological advances as NBI endoscopy to differentiate adenomas. The place of NBI endoscopy and other modern strategies should be further characterized. From our initial experience with our PTEN mutation–positive CS patients, GI features including adenomas and cancer may be more prevalent than originally thought. However, our study included only 10 patients and only in about half of the cases the findings were detected by the screening program among asymptomatic patients. Therefore, we strongly urge that another independent large series be prospectively accrued for systematic study of prospective routine surveillance of the GI tract in PTEN mutation–positive CS. It is also important to emphasize that various component features arising from identical mutations may result in vastly different phenotypes in individuals of different ancestral backgrounds, and so the international community should come together to perform comparative phenotype studies. Finally, we suspect that lifelong mechanical removal of polyps annually might become unfeasible to patients and to our sagging health-care systems, and call upon a global collaborative trial of novel targeted therapeutic approaches as the use of mammalian target of rapamycin inhibitors (clinical trial NCT00971789).  Guarantor of the article: Zohar Levi, MD. Specific author contributions: Zohar Levi: study concept and design, acquisition and interpretation of data, drafting and critical revision of the manuscript; Yaron Niv: study supervision, drafting and critical revision of the manuscript; Inbal Kedar and Hagit N. Baris: acquisition of data, important intellectual content, and critical revision of the manuscript; Alex Geller, Rachel Gingold, and Eyal Gal: acquisition of data and critical revision of the manuscript; Sara Morgenstern and Susana Horn: technical and material support, and critical revision of the manuscript; Brandie Heald Leach: acquisition of data and critical revision of the manuscript; Mary P. Bronner: acquisition of data, analysis and interpretation of data, drafting and critical revision of the manuscript; Charis Eng: study concept and design, analysis and interpretation of data, drafting and critical revision of the manuscript. Financial support: This work was funded, in part, by P01CA124570 from the National Cancer Institute, Bethesda, MD (to C.E.). Potential competing interests: None. We thank members of the Eng lab, Genomic Medicine Institute, Cleveland Clinic for technical assistance. Prof Paul Rozen established the high-risk cancer clinic at the Rabin Medical Center and continues to contribute his unique knowledge to the clinic staff. C.E. is the Sondra J. and Stephen R. Hardis Chair of Cancer Genomic Medicine at the Cleveland Clinic, and is an ACS Clinical Research Professor, generously funded, in part, by the F.M. Kirby Foundation.

Upper and Lower Gastrointestinal Findings in PTEN Mutation–Positive Cowden Syndrome Patients Participating in an Active Surveillance Program