Gut Liver 2012; 6(2): 280-283 https://doi.org/10.5009/gnl.2012.6.2.280 Hyperplastic Polyposis Syndrome Identified with a BRAF Mutation
Author Information
Hyung Su Ahn*, Su Jin Hong**, Hee Kyung Kim

*Digestive Disease Center, Department of Internal Medicine, Soonchunhyang University College of Medicine, Bucheon, Korea.

Department of Pathology, Soonchunhyang University College of Medicine, Bucheon, Korea.



Correspondence to: Su Jin Hong. Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, 170 Jomaru-ro, Wonmi-gu, Bucheon 420-767, Korea. Tel: +82-32-621-5087, Fax: +82-32-621-5080, sjhong@schmc.ac.kr
© The Korean Society of Gastroenterology, the Korean Society of Gastrointestinal Endoscopy, the Korean Society of Neurogastroenterology and Motility, Korean College of Helicobacter and Upper Gastrointestinal Research, Korean Association the Study of Intestinal Diseases, the Korean Association for the Study of the Liver, Korean Pancreatobiliary Association, and Korean Society of Gastrointestinal Cancer. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Keywords: Hyperplastic polyposis syndrome, BRAF
Keywords: Hyperplastic polyposis syndrome, BRAF
INTRODUCTION

Colorectal cancer (CRC) is one of the most common cancers in the world. CRCs usually progress from adenomatous polyps, and the morphological and genetic progression of CRCs in an adenoma-adenocarcinoma sequence has been well described.1,2 A hyperplastic polyp (HP) is the most common histological type found among colorectal polyps, but they have been considered to have no malignant potential. However, recent studies have demonstrated that some HPs can develop into CRCs, especially in patients diagnosed with hyperplastic polyposis syndrome (HPS).3,4 Recent studies have proposed that HPs arising in HPS progress toward adenocarcinoma through a "serrated neoplastic pathway" and that a B type Raf kinase (BRAF) proto-oncogene mutation is one of the early genetic events in the initiation of this serrated pathway.4-6BRAF mutations have recently been found in 5% to 15% of CRCs.7-9 We present a case of a 34-year-old young woman with HPS who had a BRAF mutation.

CASE REPORT

A 34-year-old young woman visited our hospital for a general health check. She had no family or personal history of colorectal carcinoma or other bowel diseases. However, she underwent a fine-needle aspiration biopsy (FNAB) for incidentally discovered thyroid nodules 2 months previous. The FNAB of these nodules demonstrated bland-looking follicular cells. Her complete blood count showed no abnormal findings, and other laboratory tests and thyroid function tests were within the normal range. She underwent an esophagogastroduodenoscopy and colonoscopy. At the esophagogastroduodenoscopy, numerous 0.2 to 0.7-cm-sized polyps were seen in the body and antrum of the stomach (Fig. 1). However, no lesions were observed in the bulb or secondary portion of the duodenum. During the colonoscopy, numerous 0.2 to 1.0-cm-sized polyps were also observed in the transverse colon, sigmoid colon and rectum. The polyps were mainly distributed on the sigmoid colon and rectum. An upper gastrointestinal series showed no lesions in the small bowel. We removed 48 and 70 polyps from the stomach and colorectum, respectively. A histological examination of the resected polyps revealed HPs (Fig. 2). Based on our findings, the patient was diagnosed with coexisting HPS and gastric hyperplastic polyposis. We performed a BRAF and K-RAS mutation analysis as well as a microsatellite analysis on the representative HPs of the colon. BRAF mutations were found in the resected colon polyps (Fig. 3). The BRAF mutation identified was a missense mutation at codon 600, exon 15 replacing GTG (valine) with GAG (glutamic acid). A K-RAS mutation and microsatellite instability (MSI), however, were not detected. The patient was discharged without complications and is on regular follow-up.

DISCUSSION

Sporadic HPs are of a benign nature and are usually small in size, multiply, increase with old age, and are mainly distributed in the sigmoid colon and rectum. However, CRCs arising in colorectal HPs or serrated adenomas (SAs), especially in patients diagnosed with HPS have been reported.10-14 Additionally, recent studies proposed the HP-SA-carcinoma sequence as an alternative pathway for colorectal carcinogenesis.4,15,16 HPS is an uncommon syndrome characterized by a diverse range of polyp types including multiple, large HPs and smaller numbers of SAs, traditional adenomas, and admixed hyperplastic/adenomatous polyps in the colon and rectum. In the World Health Organization (WHO) HPS diagnostic criteria, Burt and Jass17 defined HPS as at least five histologically diagnosed HPs occurring proximal to the sigmoid colon and of which more than two are greater than 1 cm in diameter, or more than 30 HPs in the whole colon and rectum, or any number of HPs proximal to the sigmoid colon in an individual who has a first-degree relative diagnosed with HPS. In such patients, polyps are usually sessile and 1-7 mm in diameter, but larger and/or pedunculated HPs may also be observed. Some patients had adenomas or CRCs.18-20 HPs of HPS progress to CRCs through the serrated pathway and a BRAF mutation is a key genetic event in the initiation of the serrated neoplastic pathway in the development of CRC.4-6 The risk of malignant changes in HPs seems much higher when the HPs have histologically dysplastic features such as admixed polyps and SAs or when they are large, numerous, located on the right-sided colon, and present in younger patients.21,22 Genetic and epigenetic alterations in colorectal carcinoma are present in HPS. These alterations in clude BRAF or K-RAS protooncogene mutations and MSI.14,23,24BRAF makes a protein called B-RAF which is one of the members of the RAF family of serine/ threonine kinases. B-RAF mediates cellular responses to growth signals through the RAS-RAF-MEK (mitogen-activated protein/extracellular signal-regulated kinase)-ERK (extracellular signal-regulated kinase)-MAP (mitogen-activated protein) kinase pathway.25,26BRAF mutations have been found in various human cancers including CRCs and melanomas.7,9,27-30 They have also been found in sporadic HPs and in SAs from patients with hyperplastic polyposis.6,31,32BRAF mutations are frequent in CRCs with a high level of MSI, but uncommon in microsatellite-stable CRCs.27-30 The frequency of BRAF mutations is much higher in HPS, especially younger patients and patients with large and right-sided polyps than in sporadic HPs which are predominantly present in the left-sided colon or rectum.23 In contrast, K-RAS mutations are infrequent in HPS, but frequent in sporadic HPs.14 Unlike BRAF, K-RAS mainly plays a key role in the development of CRC through the classical adenoma-adenocarcinoma sequence, allowing the growth and progression of adenomatous colorectal polyps.33 Some reports have demonstrated that BRAF and K-RAS mutations are strongly inversely correlated.7-9 It is rare that both BRAF and K-RAS mutations are present in different polyps from the same patient.24 Therefore, molecular data such as BRAF or K-RAS can help in diagnosing HPS. In our case, the 34-year-old young woman had 48 and 70 0.2 to 1.0-cm-sized HPs in the stomach and large bowel respectively. We diagnosed HPS with gastric hyperplastic polyposis according to the WHO diagnostic criteria. We confirmed a BRAF mutation in the colon polyps. But, she had no K-RAS mutation and MSI. A case of HPS identified with a BRAF mutation has been reported in only one case in Korea until now.34 Furthermore, HPS with multiple gastric HPs is very rare. We think that genetic alterations such as BRAF mutations in HPS may be frequently seen in patients who have hyperplastic polyposis in the stomach, colorectum or both. Although our case had no adenomatous or malignant changes, such patients may more frequently be accompanied with adenomatous or malignant changes in polyps. Because HPS with a BRAF mutation may carry a high risk for CRC, colonoscopic surveillance should be indicated. Endoscopic surveillance is recommended every 1 to 3 years for patients with hyperplastic polyposis.18 This endoscopic surveillance interval may be modified by other risk factors such as age, family or personal history of CRC, histology of polyps, and genetic mutations such as BRAF, and so on.35

Figures
Fig. 1. (A) Esophagogastroduodenoscopic findings revealed numerous 0.2- to 0.7-cm-sized polyps on the antrum of the stomach. (B) The colonoscopic findings revealed numerous 0.2- to 0.6-cm-sized polyps on the rectum.
Fig. 2. Photomicrographs of a colon polyp. A hyperplastic polyp exhibiting crypt serration and regular architecture with minimal crypt branching (H&E stain, ×100).
Fig. 3. B type Raf kinase (BRAF) mutation analysis. Direct DNA sequencing revealed a BRAF mutation at codon 600 and replacement in exon 15 of GAG (glutamic acid) with GTG (valine).
References
  1. Fearon ER, Dang CV. Cancer genetics: tumor suppressor meets oncogene. Curr Biol. 1999;9;R62-R65.
    Pubmed
  2. Chung DC. The genetic basis of colorectal cancer: insights into critical pathways of tumorigenesis. Gastroenterology. 2000;119;854-865.
    Pubmed
  3. Church JM, Fazio VW, Jones IT. Small colorectal polyps. Are they worth treating?. Dis Colon Rectum. 1988;31;50-53.
    Pubmed
  4. Jass JR, Whitehall VL, Young J, Leggett BA. Emerging concepts in colorectal neoplasia. Gastroenterology. 2002;123;862-876.
    Pubmed
  5. Hawkins NJ, Bariol C, Ward RL. The serrated neoplasia pathway. Pathology. 2002;34;548-555.
    Pubmed
  6. Kambara T, Simms LA, Whitehall VL, et al. BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum. Gut. 2004;53;1137-1144.
    Pubmed
  7. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417;949-954.
    Pubmed
  8. Rajagopalan H, Bardelli A, Lengauer C, Kinzler KW, Vogelstein B, Velculescu VE. Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature. 2002;418;934.
    Pubmed
  9. Yuen ST, Davies H, Chan TL, et al. Similarity of the phenotypic patterns associated with BRAF and K-RAS mutations in colorectal neoplasia. Cancer Res. 2002;62;6451-6455.
    Pubmed
  10. Hawkins NJ, Ward RL. Sporadic colorectal cancers with microsatellite instability and their possible origin in hyperplastic polyps and serrated adenomas. J Natl Cancer Inst. 2001;93;1307-1313.
    Pubmed
  11. Jass JR, Cottier DS, Pokos V, Parry S, Winship IM. Mixed epithelial polyps in association with hereditary non-polyposis colorectal cancer providing an alternative pathway of cancer histogenesis. Pathology. 1997;29;28-33.
    Pubmed
  12. Iino H, Jass JR, Simms LA, et al. DNA microsatellite instability in hyperplastic polyps, serrated adenomas, and mixed polyps: a mild mutator pathway for colorectal cancer?. J Clin Pathol. 1999;52;5-9.
    Pubmed
  13. Jass JR, Iino H, Ruszkiewicz A, et al. Neoplastic progression occurs through mutator pathways in hyperplastic polyposis of the colorectum. Gut. 2000;47;43-49.
    Pubmed
  14. Rashid A, Houlihan PS, Booker S, Petersen GM, Giardiello FM, Hamilton SR. Phenotypic and molecular characteristics of hyperplastic polyposis. Gastroenterology. 2000;119;323-332.
    Pubmed
  15. Williams GT. Metaplastic (hyperplastic) polyps of the large bowel: benign neoplasms after all?. Gut. 1997;40;691-692.
    Pubmed
  16. Jass JR. Serrated route to colorectal cancer: back street or super highway?. J Pathol. 2001;193;283-285.
    Pubmed
  17. Burt R, Jass JR. Hyperplastic polyposis. In: Hamilton SR, Aaltonen LA. Pathology and genetics of tumours of the digestive system. Lyon: IARC Press; 2000. p. 135-136.
  18. Ferrandez A, Samowitz W, DiSario JA, Burt RW. Phenotypic characteristics and risk of cancer development in hyperplastic polyposis: case series and literature review. Am J Gastroenterol. 2004;99;2012-2018.
    Pubmed
  19. Lage P, Cravo M, Sousa R, et al. Management of Portuguese patients with hyperplastic polyposis and screening of at-risk first-degree relatives: a contribution for future guidelines based on a clinical study. Am J Gastroenterol. 2004;99;1779-1784.
    Pubmed
  20. Hyman NH, Anderson P, Blasyk H. Hyperplastic polyposis and the risk of colorectal cancer. Dis Colon Rectum. 2004;47;2101-2104.
    Pubmed
  21. Torlakovic E, Skovlund E, Snover DC, Torlakovic G, Nesland JM. Morphologic reappraisal of serrated colorectal polyps. Am J Surg Pathol. 2003;27;65-81.
    Pubmed
  22. Goldstein NS, Bhanot P, Odish E, Hunter S. Hyperplastic-like colon polyps that preceded microsatellite-unstable adenocarcinomas. Am J Clin Pathol. 2003;119;778-796.
    Pubmed
  23. Beach R, Chan AO, Wu TT, et al. BRAF mutations in aberrant crypt foci and hyperplastic polyposis. Am J Pathol. 2005;166;1069-1075.
    Pubmed
  24. Carvajal-Carmona LG, Howarth KM, Lockett M, et al. Molecular classification and genetic pathways in hyperplastic polyposis syndrome. J Pathol. 2007;212;378-385.
    Pubmed
  25. Peyssonnaux C, Eych?ne A. The Raf/MEK/ERK pathway: new concepts of activation. Biol Cell. 2001;93;53-62.
    Pubmed
  26. Baccarini M. An old kinase on a new path: Raf and apoptosis. Cell Death Differ. 2002;9;783-785.
    Pubmed
  27. Domingo E, Esp?n E, Armengol M, et al. Activated BRAF targets proximal colon tumors with mismatch repair deficiency and MLH1 inactivation. Genes Chromosomes Cancer. 2004;39;138-142.
    Pubmed
  28. Frans?n K, Klinten?s M, Osterstr?m A, Dimberg J, Monstein HJ, S?derkvist P. Mutation analysis of the BRAF, ARAF and RAF-1 genes in human colorectal adenocarcinomas. Carcinogenesis. 2004;25;527-533.
    Pubmed
  29. Oliveira C, Pinto M, Duval A, et al. BRAF mutations characterize colon but not gastric cancer with mismatch repair deficiency. Oncogene. 2003;22;9192-9196.
    Pubmed
  30. Wang L, Cunningham JM, Winters JL, et al. BRAF mutations in colon cancer are not likely attributable to defective DNA mismatch repair. Cancer Res. 2003;63;5209-5212.
    Pubmed
  31. Chan TL, Zhao W, Leung SY, Yuen ST. BRAF and K-RAS mutations in colorectal hyperplastic polyps and serrated adenomas. Cancer Res. 2003;63;4878-4881.
    Pubmed
  32. Yang S, Farraye FA, Mack C, Posnik O, O'Brien MJ. BRAF and K-RAS mutations in hyperplastic polyps and serrated adenomas of the colorectum: relationship to histology and CpG island methylation status. Am J Surg Pathol. 2004;28;1452-1459.
    Pubmed
  33. Risio M, Malacarne D, Giaretti W. K-RAS transitions and villous growth in colorectal adenomas. Cell Oncol. 2005;27;363-366.
    Pubmed
  34. Seong MK, Shim JS, Hwang TS, Kim JH. Hyperplastic polyposis associated with two synchronous colon cancers. J Korean Soc Coloproctol. 2009;25;202-206.
  35. East JE, Saunders BP, Jass JR. Sporadic and syndromic hyperplastic polyps and serrated adenomas of the colon: classification, molecular genetics, natural history, and clinical management. Gastroenterol Clin North Am. 2008;37;25-46.
    Pubmed
Figures
Fig. 1. (A) Esophagogastroduodenoscopic findings revealed numerous 0.2- to 0.7-cm-sized polyps on the antrum of the stomach. (B) The colonoscopic findings revealed numerous 0.2- to 0.6-cm-sized polyps on the rectum.
Fig. 2. Photomicrographs of a colon polyp. A hyperplastic polyp exhibiting crypt serration and regular architecture with minimal crypt branching (H&E stain, ×100).
Fig. 3. B type Raf kinase (BRAF) mutation analysis. Direct DNA sequencing revealed a BRAF mutation at codon 600 and replacement in exon 15 of GAG (glutamic acid) with GTG (valine).
Search for
Article
Archives