New polyps, old tricks: controversy about removing benign bowel lesionsBMJ 2013; 347 doi: https://doi.org/10.1136/bmj.f5843 (Published 08 October 2013) Cite this as: BMJ 2013;347:f5843
All rapid responses
There have been several responses to our article on serrated polyps (SP) (1) – largely concluding that the benefits outweigh harms to favor a more aggressive approach than proposed by us, but at the same time admitting that we have limited knowledge and well-designed studies are needed. In effect, this is what we are suggesting. We would not leave screenees with SPs unattended with their in-situ SPs in view of our present level of knowledge. Still, this is actually what we have been doing for decades all over the world from lack of better knowledge. We now share a fear that this may have been an underestimation of the risks associated with SPs, but we do not know if removal of SPs will prevent CRC and we are not able to quantify any benefits there may be.
Screenees without symptoms are primarily seeking confirmation that they are healthy and they are probably not very willing to accept risks to obtain such confirmation. Most will remain healthy with or without polyps. A diagnosis of SP would most likely never have been made unless for the unknown minority of them that may be associated with cancer development during the next 10-15 years.
There are several clinical studies to be considered. First of all, what happened to patients with SPs left in situ with no surveillance 10 or more years ago? No doubt several research groups are able to look into this. Secondly, the prevalence of SPs is unclear, and the highly variable SP detection rates among endoscopists reported in the literature indicate that a substantial number of SPs are still left untreated. There is no established target detection rate for SPs, although 5% has been arbitrarily proposed for proximal SPs (2). Prospective studies encouraging biopsying lesions suspicious of SPs followed by resection of dysplastic and close surveillance of non-dysplastic lesions may possibly increase detection and improve outcomes compared to current practice. Proper surveillance of lesions left in situ will, however, require adequate diagnostic tools to detect ominous changes triggering resection. As pointed out, imaging tools including virtual microscopy can still not substitute real microscopy of tissue samples. Tissue sampling with cold forceps may cause submucosal fibrosis, but concerns about subsequent problematic polypectomy may be exaggerated (3). We are presently recalling patients with SPs left in situ more than 10 years after biopsying in the NORCCAP trial (4), and we have not experienced problems with lifting and resection of these lesions. This suggests that possible post-biopsy fibrosis may have subsided not to cause problems. Suggesting 2 years to be a critical time period for fibrosis to subside and performing polypectomy before 3 weeks after any biopsy if indicated, then biennial colonoscopy for this group of patients may be proposed within the framework of a comparative effectiveness study on screening.
We recognize that our suggestions are controversial and very much appreciate a discussion on this – particularly in the historical perspective of overtreating adenomas for decades due to too much trust in guidelines and a call for research which was not done.
1. Hoff G, Bretthauer M, Garborg K, Eide TJ. New polyps, old tricks: controversy about removing benign bowel lesions. Bmj. 2013;347:f5843. PubMed PMID: 24103540.
2. Kahi CJ, Li X, Eckert GJ, Rex DK. High colonoscopic prevalence of proximal colon serrated polyps in average-risk men and women. Gastrointestinal endoscopy. 2012 Mar;75(3):515-20. PubMed PMID: 22018551.
3. Friedland S, Shelton A, Kothari S, Kochar R, Chen A, Banerjee S. Endoscopic management of nonlifting colon polyps. Diagnostic and therapeutic endoscopy. 2013;2013:412936. PubMed PMID: 23761952. Pubmed Central PMCID: 3666422.
4. Hoff G, Grotmol T, Skovlund E, Bretthauer M. Risk of colorectal cancer seven years after flexible sigmoidoscopy screening: randomised controlled trial. BMJ. 2009 2009;338:b1846.
Competing interests: No competing interests
Hoff et al recently wrote an interesting analysis article in the context of the Too Much Medicine campaign of the BMJ . In this article the authors raise their concern about the increased removal of benign polyps, especially serrated polyps (SPs). They doubt the rationale and safety of the existing international guideline recommending that all SPs proximal to the sigmoid colon and all SPs in the rectosigmoid ≥5 mm in size should be removed completely .
The fine balance between the risk for colorectal cancer (CRC) and the risk of preventive measures should definitely be prioritized, but we also have to face the disappointing protective effect of colonoscopy for right-sided carcinomas [3–5]. In our opinion the authors seem to underestimate the malignant potential of SPs in the development of right-sided CRC and overestimate the complication risk of SPs compared to adenomas. Our advice on sporadic SPs therefore differs from that published in the BMJ.
Malignant potential of serrated polyps
Several studies have shown the malignant potential of benign SPs via a distinct neoplasia route; the serrated neoplasia pathway [6–9]. Identical BRAF mutations demonstrated in CRC and the surrounding SP further demonstrated the existence of this pathway . A recent study proved the existence of three molecularly distinct subtypes of CRC in which one subtype shows highly similar gene expression to sessile serrated adenomas and is correlated to a poor prognosis .
To question the association between CRC and SPS, Hoff et al used data from a study published by Hiraoka et al. This study showed a slightly higher association between CRC and SPs ≥10mm than the association between CRC and age >65 years (adjusted odds ratios (OR) of 3.34 and 2.63 respectively) and were used by Hoff et al to demonstrate the overall minor adjusted CRC-risk for patients with SPs . However, the same study showed an adjusted OR of 1.56 for CRC in the presence of an adenoma ≥10mm and of 1.65 in the presence of four or more adenomas, regardless of their size, suggesting that the odds for CRC in the presence of a large SP are twice as high as in the presence of a large adenoma or multiple adenomas.
Another study demonstrated that patients with a sessile serrated adenoma (SSA) have an increased risk for metachronous CRC. Of 55 patients with a SSA without dysplasia, seven patients (12,5%) developed CRC during 7.2 years of follow up, in comparison to only one patient developing CRC in the matched control group that either had a hyperplastic polyp (HP) or a tubular adenoma (TA) . These data are in concordance with a study showing increased risk for interval neoplasia when a proximal SP was detected at baseline colonoscopy . The malignant potential of SPS should therefore not be underestimated.
Complication risk of endoscopic removal of serrated polyps
The authors suggest a higher complication risk for endoscopic removal of proximal SPs in comparison to adenomas. They base their statement on a prospective study that analysed the complication rates of snare polypectomies . In this study, risks are differentiated between distal and proximal polyps and sessile and pedunculated polyps. Hoff et al cite that removing large proximal sessile polyps ≥20mm is associated with an 11.7% risk of major complications in comparison to a lower risk of 5.3% for removal of same-sized sessile polyps in the distal colon. For large polyps 10-19 mm these risks were 3.5% and 0.9%, respectively. In their opinion these data demonstrate a higher risk in the removal of SPs, as they are more often located in the proximal than in the distal colon and generally have a sessile or flat morphology. The evidence presented for this argument is however weak. First of all, 77.8% of polyps included in the above mentioned study are adenomas, while only 10.4% are SPs. Therefore, conclusions from this study cannot be directly extrapolated towards the risk for SPs. Besides, the complication risk for polyps >20mm is of lesser interest because the malignant potential of these lesions is high and these polyps should therefore be removed, irrespective of location, morphology or even risk.
In an unpublished prospective endoscopic follow up study in patients with serrated polyposis syndrome from our research group, 1131 SPs were removed in 41 patients during 203 colonoscopies. 128 polyps were 10mm or larger and 650 polyps were situated in the proximal colon (Hazewinkel et al, unpublished). In these polypectomies, no perforations or post-procedure bleedings resulting in hospital admission or re-colonoscopy occurred. These data suggest that endoscopic removal of SPs is relatively safe in the proximal as well as the distal colon in an expert setting.
Natural course of serrated polyps
To gain a better understanding of the natural course of SPs, the authors suggest randomised trials of polypectomy and different intervals of surveillance compared with watchful waiting, serial biopsies or “optical biopsy”  and close surveillance. This is an interesting suggestion, but for the performance of these trials endoscopic differentiation between neoplastic and non-neoplastic lesions is of utmost importance. Studies have shown a poor diagnostic accuracy of the optical diagnosis of colonic polyps in non academical setting [17,18], which means that a substantial amount of premalignant adenomas will be left in situ when performing the proposed trials via watchful waiting. The mentioned option of serial biopsies seems not feasible because the risk of re-colonoscopies in case of in hindsight histologically detected but unresected adenomas. Furthermore serial biopsies can make necessary polypectomies more difficult and risky due to fibrosis. Finally the histologically difficult distinction between HP and SSA in biopsies will potentially disturb decision-making in studies using serial biopsies [19,20].
We support the appeal of Hoff et al for the need of a better understanding of the natural course of SPs. However, today the balance between harm and benefit of removal of SPs during colonoscopy seems in favour of a more aggressive approach than proposed by Hoff et al. Until better markers for CRC risk analysis are developed, following the international, evidence-based guidelines on this topic seems the best option to reduce the significant incidence of interval carcinomas .
1 Hoff G. New polyps, old tricks: controversy about removing benign bowel lesions. 2013;5843:8–11.
2 Rex DK, Ahnen DJ, Baron J a, et al. Serrated lesions of the colorectum: review and recommendations from an expert panel. The American journal of gastroenterology 2012;107:1315–29; quiz 1314, 1330.
3 Baxter NN, Warren JL, Barrett MJ, et al. Association between colonoscopy and colorectal cancer mortality in a US cohort according to site of cancer and colonoscopist specialty. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2012;30:2664–9.
4 Doubeni CA, Weinmann S, Adams K, et al. Screening Colonoscopy and Risk for Incident Late-Stage Colorectal Cancer Diagnosis in Average-Risk Adults. Annals of Internal Medicine 2013;158:312-20.
5 Brenner H, Hoffmeister M, Arndt V, et al. Protection from right- and left-sided colorectal neoplasms after colonoscopy: population-based study. Journal of the National Cancer Institute 2010;102:89–95.
6 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. Gastroenterology clinics of North America 2008;37:25–46.
7 Snover DC. Update on the serrated pathway to colorectal carcinoma. Human pathology 2011;42:1–10.
8 Leggett B, Whitehall V. Role of the serrated pathway in colorectal cancer pathogenesis. Gastroenterology 2010;138:2088–100.
9 Bettington M, Walker N, Clouston A, et al. The serrated pathway to colorectal carcinoma: current concepts and challenges. Histopathology 2013;62:367–86.
10 Boparai KS, Dekker E, Polak MM, et al. A serrated colorectal cancer pathway predominates over the classic WNT pathway in patients with hyperplastic polyposis syndrome. The American journal of pathology 2011;178:2700–7.
11 De Sousa E Melo F, Wang X, Jansen M, et al. Poor-prognosis colon cancer is defined by a molecularly distinct subtype and develops from serrated precursor lesions. Nature medicine 2013;19:614–8.
12 Hiraoka S, Kato J, Fujiki S, et al. The presence of large serrated polyps increases risk for colorectal cancer. Gastroenterology 2010;139:1503–10.
13 Lu F-I, van Niekerk DW, Owen D, et al. Longitudinal outcome study of sessile serrated adenomas of the colorectum: an increased risk for subsequent right-sided colorectal carcinoma. The American journal of surgical pathology 2010;34:927–34.
14 Schreiner M a, Weiss DG, Lieberman D a. Proximal and large hyperplastic and nondysplastic serrated polyps detected by colonoscopy are associated with neoplasia. Gastroenterology 2010;139:1497–502.
15 Heldwein W, Dollhopf M, Meining A, et al. The Munich Polypectomy Study ( MUPS ): Prospective Analysis of Complications and Risk Factors in 4000 Colonic Snare Polypectomies. Endoscopy 2005; 37:1116-22.
16 Mori Y, Kudo S, Ikehara N, et al. Comprehensive diagnostic ability of endocytoscopy compared with biopsy for colorectal neoplasms: a prospective randomized noninferiority trial. Endoscopy 2013;45:98–105.
17 Kuiper T, Marsman W a, Jansen JM, et al. Accuracy for optical diagnosis of small colorectal polyps in nonacademic settings. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 2012;10:1016–20.
18 Ladabaum U, Fioritto A, Mitani A, et al. Real-Time Optical Biopsy of Colon Polyps With Narrow Band Imaging in Community Practice Does Not Yet Meet Key Thresholds for Clinical Decisions. Gastroenterology 2013;144:81–91.
19 Glatz K, Pritt B, Glatz D, et al. A multinational, internet-based assessment of observer variability in the diagnosis of serrated colorectal polyps. American journal of clinical pathology 2007;127:938–45.
20 Farris AB, Misdraji J, Srivastava A, et al. Sessile serrated adenoma: challenging discrimination from other serrated colonic polyps. The American journal of surgical pathology 2008;32:30–5.
Competing interests: No competing interests
Hoff et al provide an informative article which addresses the specific issue of polypectomy for serrated polyps during colonoscopy . It also has relevance for the broader issue of medical overtreatment. We are in complete agreement with the main argument, that more research is required before post-polypectomy surveillance of serrated lesions is considered. Their other point, that the benefit of removing such polyps may not outweigh the risk, deserves further discussion.
As stated by Hoff et al, current guidelines recommend removal of all polyps during colonoscopy, except for small rectal/distal sigmoid hyperplastic polyps . This is because it is widely accepted that colorectal cancers arise from precursor polyps and polypectomy interrupts this process, preventing cancer. [3,4,5] The Flexiscope study, which incorporated removal of all polyps detected, demonstrated a 33% reduction in incidence of bowel cancer . Rarely, even small lesions may harbour high grade dysplasia or malignancy, although the risk is small . Optical diagnosis is not yet sufficiently refined to be used widely to distinguish neoplastic from non-neoplastic polyps nor in accurate identification of serrated polyps, therefore all polyps should be removed to permit histological assessment. Moreover, surveillance intervals are currently determined by the size and number of adenomas . Thus without removal of polyps to allow histological typing, the need for surveillance cannot be determined accurately.
Regarding serrated polyps, as Hoff et al outline, their natural history is currently poorly understood. There are, however, biological and observational data to support the serrated neoplasia pathway [9,10]. There is additionally a widely held view that the relative failure of screening programmes to impact on right-sided colonic cancer may relate to under-diagnosis and under-treatment of right-sided serrated lesions. Until further evidence is available, a policy of leaving serrated polyps in situ cannot be supported.
The harm associated with polypectomy of small lesions is minimal: the risk of complications increases with increasing size of the polyp,  thus although we concur that small polyps carry a much smaller risk of malignant progression, their endoscopic removal also carries a much smaller risk of complication. Conversely, the risk of leaving a larger polyp to progress is felt to outweigh the risk of polypectomy .
More and more colonoscopies are being performed worldwide, largely due to the implementation of colorectal cancer screening programmes. This debate highlights the necessity for high quality research to study the importance of different types of colonic polyps and to establish optimal management and surveillance strategies.
1. Hoff G, Bretthauer M, Garborg K, Eide TJ. New polyps, old tricks: controversy about removing benign bowel lesions. BMJ 2013;347:f5843.
2. Segnan N, Patnick J, von Karsa L (eds). European guidelines for quality assurance in colorectal cancer screening and diagnosis- first edition. Publishing office of the European Union. Luxemburg. 2011.
3. Hardcastle JD, Chamberlain JO, Robinson MH, et al. Randomised controlled trial of faecal-occult-blood screening for colorectal cancer. Lancet 1996;348:1472-1477.
4. Kronberg O, Fenger C, Olsen J, et al. Randomised study of screening for colorectal cancer with faecal occult blood test. Lancet 1996;348:1467-71.
5. Mandel JS, Church TR, Ederer F, et al. Colorectal Cancer Mortality: Effectiveness of Biennial Screening for fecal occult blood. J Nat Cancer Inst 1999;91(5):434-437.
6. Atkin WS, Edwards R, Kralj-Hans I, Woolridge K, Hat AR, Northover JMA, Parkin DM, Wardle J, Duffy SW, Cuzick J, UK Flexible Sigmoidoscopy Trial Investigators. Once-only flexible sigmoidoscopy screening in prevention of colorectal cancer: a multicentre randomised controlled trial. Lancet 2010;375:1624-33
7. Kolligs FT, Crispin A, Graser A, et al. Risk factors for advanced neoplasia within subcentimetric polyps: implications for diagnostic imaging. Gut 2013;62:863-70
8. Atkin W S, Saunders B P. Surveillance guidelines after removal of colorectal adenomatous polyps. Gut 2002;51(Suppl V):v6–v9
9. Leggett B, Whitehall V. Role of the serrated pathway in colorectal cancer pathogenesis.Gastroenterology. 2010 Jun;138(6):2088-100.
10. Schreiner MA, Weiss DG, Lieberman DA. Proximal and large hyperplastic and nondysplastic serrated polyps detected by colonoscopy are associated with neoplasia. Gastroenterology. 2010;139:1497-502.
11. Heldwein W, Dollhopf M, Rosch T, et al. The Munich Polypectomy Study (MUPS): Prospective analysis of complications and risk factors in 4000 colonic snare polypectomies. Endoscopy 2005;37:1116-1122.
12. Eide T, Risk of colorectal cancer in adenoma bearing individuals within a defined population. Int J Cancer 1986;38:173-6.
Competing interests: No competing interests
Surely this is a matter of informed consent? When a surgeon or endoscopist goes ahead with a procedure then likely scenarios require some discussion. The relative risks here are very relevant,the arguments long-standing. Personally, I would prefer not to have a colonoscopy by those who aim for a cosmetically satisfying result without previous discussion. Of course I accept that this might mean a repeat procedure at an earlier stage than might otherwise have been necessary.
Competing interests: No competing interests
The right approach if there turns out to be one, to deal with subclinical colorectal polyps will always be problematic; unless you remove and analyze them you can never be armed with sufficient histologic certainties to proffer unassailable evidence of their biologic tendencies and clinical prognostications without mere statistical forecasting dominating the debate.
Yet it is also desirable to have a way of knowing what level if any of routine 'polyp harvesting' is complementary to safe epidemiologic practice or prophylaxis .
Endoscopic harvesting us not without its inconveniences to the patient and costs to the system quite apart from iatrogenic morbidity.
Hence it is easy to see why debates such as evident in this write up will continue to rear its head without prospects of ending anytime soon.
Viral staining as a worthwhile field of study and application in these areas cannot but come to mind as a means if realisable,of distinguishing the 'chaff from the grain' in polyp selections for extirpation.
Conjecturally,it may just be the case that any neoplastic mucosa heap given enough time and provocation will enter into the cancer sequence pathway.
That the safe colon is only that with a 'flat' surface.
Competing interests: No competing interests