ORIGINAL CONTRIBUTION Molecular Classification of Patients With Unexplained Hamartomatous and Hyperplastic Polyposis Kevin Sweet, MS, CGC Context Significant proportions of patients with hamartomatous polyposis or with Joseph Willis, MD hyperplastic/mixed polyposis remain without specific clinical and molecular diagnosis Xiao-Ping Zhou, MD, PhD or present atypically. Assigning a syndromic diagnosis is important because it guides management, especially surveillance and prophylactic surgery. Carol Gallione, PhD Objective To systematically classify patients with unexplained hamartomatous or hy- Takeshi Sawada, MD, PhD perplastic/mixed polyposis by extensive molecular analysis in the context of central Pia Alhopuro, MD rereview of histopathology results. Sok Kean Khoo, PhD Design, Setting, and Patients Prospective, referral-based study of 49 unrelated patients from outside institutions (n=28) and at a comprehensive cancer center (n=21), Attila Patocs, MD, PhD conducted from May 2, 2002, until December 15, 2004. Germline analysis of PTEN, Cossette Martin, PhD BMPR1A, STK11 (sequence, deletion), SMAD4, and ENG (sequence), specific exon screen- Scott Bridgeman, BSc ing of BRAF, MYH, and BHD, and rereview of polyp histology results were performed. John Heinz, PhD Main Outcome Measures Molecular, clinical, and histopathological findings in pa- tients with unexplained polyposis. Robert Pilarski, MS, CGC Results Of the 49 patients, 11 (22%) had germline mutations. Of 14 patients with Rainer Lehtonen, BSc juvenile polyposis, 2 with early-onset disease had mutations in ENG, encoding endo- Thomas W. Prior, PhD glin, previously only associated with hereditary hemorrhagic telangiectasia; 1 had hemi- zygous deletion encompassing PTEN and BMPR1A; and 1 had an SMAD4 mutation. Thierry Frebourg, MD, PhD One individual previously classified with Peutz-Jeghers syndrome had a PTEN dele- Bin Tean Teh, MD, PhD tion. Among 9 individuals with an unknown hamartomatous polyposis, 4 had muta- tions in STK11 (1), BMPR1A (2), and SMAD4 (1). Of the 23 patients with hyperplastic/ Douglas A. Marchuk, PhD mixed polyposis, 2 had PTEN mutations. Substantial discrepancies in histopathology Lauri A. Aaltonen, MD, PhD results were seen. Charis Eng, MD, PhD Conclusions Systematic molecular classification of 49 patients with unexplained ham- artomatous or hyperplastic polyposis uncovered a potential novel susceptibility gene, HE INHERITED POLYPOSIS SYN- ENG, for juvenile polyposis. Importantly, given the substantial proportion of patients dromes, a heterogeneous found to have germline mutations, more extensive analysis of the known susceptibil- group of diseases, have been a ity genes is indicated. Rereview of histology results by a dedicated gastrointestinal pa- major focus of study for the thologist should be considered routinely, as organ-specific surveillance rests on defin- Tlast decade and provide critical insight ing syndromic diagnosis. into the molecular pathogenesis of JAMA. 2005;294:2465-2473 www.jama.com cancer. Despite intense study, these important syndromes are still clini- lesions—hamartomas, adenomas, and develops through the adenoma- cally confusing, and proper objective hyperplastic polyps—contribute to the carcinoma sequence, initiated by ger- 1 identification is necessary for appro- various forms, although the number mline mutations of the APC gene. priate clinical management. Three pri- and distribution of polyps differ mary histopathologic subtypes of among the syndromes. The classic Author Affiliations are listed at the end of this article. paradigm is familial adenomatous pol- Corresponding Author: Charis Eng, MD, PhD, Ge- yposis (involving Ͼ100 to Ͼ1000 nomic Medicine Institute, Cleveland Clinic Founda- For editorial comment see p 2498. tion, 9500 Euclid Ave, Mailstop NE-30, Cleveland, OH adenomas), in which colorectal cancer 44195 ([email protected]). ©2005 American Medical Association. All rights reserved. (Reprinted) JAMA, November 16, 2005—Vol 294, No. 19 2465 Downloaded from jama.ama-assn.org by guest on December 21, 2011 MOLECULAR CLASSIFICATION OF PATIENTS WITH UNEXPLAINED POLYPOSIS However, there is increasing evidence tion.3 Approximately 50% of all PJS tained because of distinctive mucocu- for several important categories of pol- cases are due to germline mutation in taneous lesions, benign and malignant yposis and colorectal carcinoma that the nuclear serine threonine kinase gene thyroid and breast disease, and macro- may develop from alternative routes. STK11.4 Germline mutations in the cephaly. Approximately 85% of pa- This includes the hamartomatous pol- genes of the signaling pathway of the tients with Cowden syndrome who yposis syndromes and the serrated transforming growth factor ␤ (TGF-␤) meet established diagnostic criteria have neoplasia pathway, whose morpho- superfamily (FIGURE) can lead to a mutations of the PTEN gene (Table 1). logic spectrum includes the hyperplas- range of common heritable disorders, It is widely believed that hyperplas- tic polyp and sessile serrated adenoma. including JPS (MIM 174900), and vas- tic polyps have no malignant poten- Given the attendant cancer risks and cular disorders, such as hereditary hem- tial. Commonly seen on colonoscopic medical management issues inherent orrhagic telangiectasia (HHT) (MIM examination (10% of patients younger in these forms of polyposis (TABLE 1), 187300) and primary pulmonary hy- than 50 years, 50% of those younger it is imperative that physicians recog- pertension (MIM 178600).5-7 For ex- than 70 years), they seldom exceed 0.5 nize that variability in histopathology ample, a combined syndrome consist- cm and are often localized to the distal and molecular etiology can hinder ing of both juvenile polyposis and colon and rectum.11,12 However, there appropriate diagnosis. hereditary HHT type 2 (MIM 175050) is evolving evidence linking the sessile The known forms of inherited ham- is known to be due to germline muta- serrated adenoma (SSA), a lesion artomatous polyposis include Peutz- tions in the SMAD4 gene.8 Mutations related to hyperplastic polyp, with Jeghers syndrome (PJS), juvenile pol- in another member of this pathway, neoplasia.13-16 SSAs tend to be multiple yposis syndrome (JPS), and Cowden BMPR1A, account for 20% to 30% of ad- and large (Ͼ1 cm), have a greater syndrome. Although collectively ac- ditional JPS cases, although appar- propensity for the proximal colon, counting for less than 1% of colorectal ently without stigmata of HHT.9 While and may comprise 15% to 20% cancer in North America,1 proper iden- other members of the TGF-␤ family of traditional hyperplastic polyps.17-20 tification of these clinically confusing would be ideal candidates for JPS, no The initiating event in the progression syndromes remains of critical impor- germline mutations in the genes from hyperplastic polyp to SSA may tance, because each syndrome carries BMPR2, ACRV1, SMAD1, SMAD2, be the activating somatic BRAF significant risks for extraintestinal ma- SMAD3, SMAD5, and SMAD7 have been (hotspot V600E) mutation.21-23 Impor- lignancy and other component fea- identified to date,10 leaving approxi- tantly, this process can be clinically tures that must be managed (Table 1). mately 50% of cases unexplained at the investigated in hyperplastic polyposis Peutz-Jeghers syndrome (Online Men- molecular level. A third hamartoma syndrome (HPS), as reappraisal of his- delian Inheritance in Man2 [MIM] syndrome, Cowden syndrome (MIM tological subtype supports the devel- 175200) causes gastrointestinal polyp- 158350), differs from both PJS and JPS opment of SSA.24-26 Interestingly, it osis, especially of the upper jejunum in that polyposis is not the defining fea- was recently shown in the serrated (78%), and mucocutaneous pigmenta- ture. Rather, most cases are ascer- adenoma mouse model that SMAD4 Table 1. Incidence and Cancer Risks for Known Polyposis Syndromes Patients Meeting Clinical Criteria Population Syndrome MIM No.* Gene(s) With Mutation, % Incidence Cancer Risks Familial adenomatous polyposis 175000 APC 90 1/5000 Colorectal, duodenal, papillary thyroid, pancreatic, hepatoblastoma, CNS tumors MYH-adenomatous polyposis 608456 MYH Unknown 1/5000 Colorectal tumors, other? Hyperplastic polyposis syndrome NA NA 1/100 000 Colorectal tumors, other? Hereditary mixed polyposis syndrome 601228 CRAC1 NA NA Colorectal tumors, other? Juvenile polyposis/hemorrhagic 175050 SMAD4 20-40 1/100 000 Colorectal, gastric, duodenal, telangiectasia syndrome pancreatic tumors Juvenile polyposis syndrome 174900 BMPR1A 20-40 1/100 000 Colorectal, gastric, duodenal, pancreatic tumors Cowden syndrome 158350 PTEN 80-85 1/200 000 Breast, thyroid, uterine, melanoma, renal cell tumors Peutz-Jeghers syndrome 175200 STK11 50 1/30 000-1/100 000 Colorectal, small intestine, stomach, breast, pancreatic, sex-cord tumors Birt-Hogg Dube syndrome 135150 BHD 50-70 1/200 000 Renal tumors, other? Abbreviations: CNS, central nervous system; MIM, Mendelian Inheritance in Man; NA, not available. *From Online Mendelian Inheritance in Man.2 2466 JAMA, November 16, 2005—Vol 294, No. 19 (Reprinted) ©2005 American Medical Association. All rights reserved. Downloaded from jama.ama-assn.org by guest on December 21, 2011 MOLECULAR CLASSIFICATION OF PATIENTS WITH UNEXPLAINED POLYPOSIS mutation results in serrated adenomas the pathological diagnosis from stan- individual also had to have tested nega- and mixed polyposis, suggesting the dard clinical pathology review from tive for mutations in SMAD4, BMPR1A, potential for involvement