6. Endoscopy: Performance and Polyp management – Colorectal Cancer
6.1 Role of Endoscopy in the Diagnostics of Polyps and Colorectal Cancer
6.1.1 Sigmoidoscopy versus Colonoscopy
In case of a positive FOBT/FIT test, suspicion of a tumour, or sigmoidoscopic evidence of neoplastic polyps, a full colonoscopy has to be performed.
Background
Work-up of a positive FOBT test or suspicion of a tumour requires a complete colonoscopy, since this method is also able to detect adenomas and cancer in the right hemicolon. Relevant neoplastic lesions proximal to the sigmoid colon are detected in 25-55% of cases. Screening studies showed that the rectosigmoid colon is free of adenomas in 30 to 46% of cases with proximal advanced neoplasms in the right hemicolon [102][123][405][406][407].
Sigmoidoscopy should only be performed in exceptional cases when complete bowel preparation is not possible. A complete colonoscopy is possible in a high percentage of cases and can usually be performed with a lower rate of side effects in elderly patients as well [408][409][410][411][412]. However, regarding risks and comorbidities, the stress caused by the bowel preparation and the sedation must also be taken into consideration in this group [413][414][415][416]. Sigmoidoscopy has no authority for the primary diagnosis if a tumour is suspected and plays no significant role as a screening method in Germany or in the majority of other European countries [417].
6.1.2 Chromoendoscopy and Related Procedures
Chromoendoscopy can be performed in patients with chronic inflammatory bowel disease and HNPCC for improved detection of neoplastic lesions.
Background
When carried out to high quality standards, colonoscopy is the most reliable method for detecting colorectal carcinomas and polyps. Important quality characteristics include an endoscopic examination all the way to the caecum, optimal preparation of the colon with few or no remaining stool residues and a thorough inspection of the intestinal mucosa when withdrawing the endoscope. The so-called adenoma detection rate (ADR) is the most important surrogate parameter for the outcome of the colonoscopy (screening) [Corley, D. A. et al. 2014][Kaminski, M. F. et al. 2010].
Several quality guidelines from Europe and the US have recently been published, and the quality characteristics of a colonoscopy described therein partly differ from one another [454][Rembacken, B. et al. 2012][Valori, R. et al. 2012][Rees, C. J. et al. 2016][Rex, D. K. et al. 2006]. The main quality parameters specific to the individual procedures are listed below. They do not affect recommendations that in general apply to all endoscopies (sedation, complications, device disinfection, etc.), even if the practical implementation of individual parameters (recording and auditing of complication, number of procedures) would be interesting topics for discussion.
Background
Alongside chromoendoscopy with dyes such as methylene blue or indigo carmine, numerous image processing procedures have been developed in recent years that aim to replace the direct application of dyes (narrow band imaging - NBI, Fujinon intelligent colour enhancement-FICE, iScan, etc.). In patients with ulcerative colitis [418][419][420][421][422] or HNPCC [423][424], a higher detection rate of neoplastic lesions by chromoendoscopy is likely, however, an effect on the overall outcome has not been demonstrated [422]. It is still unclear whether the detection of an increased rate of predominantly smaller lesions is useful for the patient and justifies the greater amount of time required for direct chromoendoscopy.
The number of meta-analyses regarding virtual chromoendoscopy procedures has increased [425][426][427][428][429][430][431]. NBI was not found to have an effect on the ADR in any of the meta- analyses; and while FICE is included in one of the meta-analyses, it was also not found to have an impact on the ADR [426]. The results of another recently published three-arm study with NBI and FICE point in the same direction [432]. For I-Scan, two smaller (n=200 and n=67) randomised studies show a benefit [433][434] which, however, could not be confirmed by a larger, randomised tandem study (n=389) [435]. Interestingly, the latest and most comprehensive meta-analysis attributed an effect on the ADR to conventional chromoendoscopy only [426], and this on the basis of 9 such studies, the majority of which showed an improved detection of small adenomas only, while others had significant methodological flaws.
The aim of chromoendoscopy procedures, on the other hand, is to enable a better delimitation of flat and sunken lesions from the surrounding healthy mucosal tissue [436][437][428][429][430][431]. Chromoendoscopy can thus be employed prior to the endoscopic removal of flat adenomas.
All in all, mechanical procedures appear to be superior to chromoendoscopy in achieving better results in the detection of adenomas; however, this does not apply to the simple, transparent distance caps, which have already been analysed in 6 meta-analyses [426][438][439][440][441]. Multiple randomised studies suggest that newer so-called endocuffs increase the adenoma detection rate [442][443][444][445], which also appears to apply to balloons that are attached to the endoscope [446].
A classification of the mucosal pattern (pit pattern) and of the microarchitecture of the mucosal and submucosal vessels (vessel pattern) may be useful along with an assessment according to the Paris classification [447]. The goal of zoom endoscopy is to differentiate between hyperplastic and neoplastic lesions based on the pit pattern classification in order to determine – without a histological analysis – which lesions have to be removed endoscopically. Recently, however, the resolution of HD endoscopes with or without image enhancement has improved in a way that makes magnifying endoscopy appear obsolete [448]. Thus, new classifications were also recommended, for example, the so-called NICE classification [449], which is based on the device technology of a specific company.
Numerous papers on the consideration of the endoscopic differential diagnosis of polyps (endoscopic histology) [448] have been published with the goal of no longer histologically analysing smaller polyps (“Resect and Discard” [450][451], DISCARD policy for short), mainly due to financial reasons [452][453]. The follow-up recommendations are then mainly based on the endoscopic differential diagnosis between adenomas and hyperplastic lesions, since histological results are no longer available.
Since this procedure has not been sufficiently validated yet, the histological analysis of removed polyps should still be considered the standard procedure in accordance with the S2K guideline on endoscopy quality [454].
Confocal laser scanning microscopy is still subject to further evaluation in clinical studies [455].
The adenoma detection rate (ADR) is defined as the main outcome parameter of colonoscopy (screening) and shows a virtually negative linear correlation of the ADR with interval carcinomas. However, the studies have multiple methodological flaws (for a detailed discussion see the DGVS S2K guideline on quality requirements for gastrointestinal endoscopy [454]). Opinions differ on how high the adenoma detection rate, which is evaluated only for colonoscopy screening, should be. In women, an ADR of 20% is required, while in men, an ADR of 30% is required! ([Aranda-Hernandez, J. et al. 2016]).
Withdrawal time is also frequently listed as a quality indicator; in this regard, many but not all studies showed a correlation between the polyp detection rate and the withdrawal time after reaching the caecum, whereby the limit was 6 min [Barclay, R. L. et al. 2006][Barclay, R. L. et al. 2008][Butterly, L. et al. 2014][Sawhney, M. S. et al. 2008]. However, other studies also showed that the adenoma rate does not continue to increase with a further increase in the withdrawal time > 6 min [Adler, A. et al. 2013][Gellad, Z. F. et al. 2010] and that the mentioned cut-off of 6 min does not correlate with the ADR in larger-scale database analyses [Moritz, V. et al. 2012].
In case of pathological findings during colonoscopy, a classification by endoscopic- anatomic structures and by diaphanoscopy is insufficient. Details of the distance in cm device length from the anus should only be used for the rectum and lower sigmoid colon. For findings that are either unclear or worthy of surgery, marking by means of a clip (only at a time close to surgery) or ink (in the proximity of the lesion, not in the actual lesion) should be performed to facilitate a later retrieval (possibly also X-ray screening during the colonoscopy).
Colonoscopy does, however, have its limitations. For example, cancers and (relevant) adenomas are missed. These so-called interval cancers are mainly attributable to missed lesions. Additional factors are incomplete polypectomy (and failure of the patient to come for prompt surveillance colonoscopy) as well as rapidly growing de novo tumours ([578], [577], [579]). Older retrospective studies with database matching speak of 4-6% missed cancers [Hosokawa, O. et al. 2003][580][Leaper, M. et al. 2004]. In polyp follow-up studies, up to 1% of so-called missed cancers or interval cancers following colonoscopy, especially right-sided cancer, were reported in a Canadian study over a period of 3 years [577]. This difference between the sides was also confirmed in a German study, but to a considerably lesser extent [110]. In the two previously cited large-scale studies conducted in Poland and in the US, the rate of interval cancers following colonoscopy was 0.09% [Kaminski, M. F. et al. 2010] and 0.22% [Corley, D. A. et al. 2014] within 52 and 35-39 months, respectively, and thus also considerably lower. In Canada, the stronghold of interval cancers, the rate of interval cancers also appears to have halved between 1996 and 2010 (and, ultimately, was found to be 0.04% per follow-up year) [Murthy, S.K., Ducharme R., Rostom A., Dube C., James P.D., Benchimol E. et al. 2016].
Alternatives and supplementation to colonoscopy: The use of radiation for screening purposes, i.e. in healthy persons, is permitted in Germany only in exceptional cases (breast cancer screening). This is one of the reasons why CT colonography is not used here. Theoretically, incomplete colonoscopy and patients’ refusal of (diagnostic) colonoscopy are possible indications for radiological procedures. The sensitivity and specificity of CT colonography have improved in the past years since the publication of the last guideline. In reviews published in recent years, CT colonography either decreased by 10-20% (depending on size) for all neoplasms in the screening setting [169], achieved good (88%) accuracy for adenomas >5 mm in screening candidates with a positive stool test (however only with a specificity of 75% [Plumb, A. A. et al. 2014]), and was found to be highly accurate for cancers in a radiological review in all indications [460]. Concerning the patients’ preference for CT versus colonoscopy, the results appear to depend mainly on the journal of publication (radiology vs. gastroenterology/internal medicine) and on the extent of bowel preparation for the CT [Lin, O. S. et al. 2012]. All in all, however, there are still no available outcome studies for screening, even less so for MR colonography [Zijta, F. M. et al. 2010], which is why the use of this procedure cannot be recommended at the time being. Double contrast barium enemas of the colon are meanwhile obsolete.
Remaining stool and poor expansion of the colorectal lumen can give rise to diagnostic difficulties during CT colonography. It is more difficult to detect flat, sunken and small polyps than prominent polyps. Owing to a lack of standardisation, the results currently depend strongly on the centre performing the procedure.
Due to the above reasons, a complete colonoscopy is considered the gold standard for a positive faecal occult blood test (FOBT) or to clarify a suspected tumour. It allows for both the simultaneous collection of a biopsy for a histological diagnosis and the performance of a polypectomy during the same therapeutic intervention.
In patients with stenotic tumours or incomplete colonoscopies due to other reasons, proximal tumours or polyps were detected in case series using CT [456][457][458][459] or MR colonography [Hartmann, D. et al. 2005][Ajaj, W. et al. 2005]. As a result, the use of CT colonography in these cases was recommended in joint guidelines of the ESGE and ESGAR published in 2014 [Spada, C. et al. 2014]. Meanwhile, however, there is evidence to support the use of colon capsule endoscopy in patients with an incomplete colonoscopy (but obviously not in the presence of stenoses), since this procedure detected twice as many adenomas ≥6mm as CT colonography (24.5% vs. 12.2%) in a smaller randomised study (n=100) published in 2015 [Spada, C. et al. 2015]. Colon capsule endoscopy was evaluated as the primary method in several studies that were methodologically partly limited and was found to achieve a similar detection rate as CT colonography depending on the size of the adenomas; however, the number of cancers was insufficient for a valid analysis [Spada, C. et al. 2016]. As a screening method, capsule colonoscopy also achieved good values for adenomas ≥6 mm (sensitivity 81%, specificity 93%). However, one in four cancers was missed and 21% of the patients that were initially enrolled in the study were excluded from the final analysis [Rex, D. K. et al. 2015]. Because of these limitations, colon capsule endoscopy currently cannot be recommended as the primary screening method.
The last review performed in 2016 on colonoscopy complications during colonoscopy screening from 21 large, population-based studies reported a pooled rate of perforations, secondary bleeding and mortality of 0.05%, 0.3% and 0.003%, respectively. Following polypectomy, perforations were reported in 0.08% and secondary bleeding in nearly 1% of the procedures. The complication rate was lower for colonoscopy screening/follow-up than for diagnostic colonoscopy [Reumkens, A. et al. 2016].
The complete colonoscopy is the standard procedure for the detection of colorectal polyps and cancer. It has the highest sensitivity and specificity for the detection of CRC and colorectal polyps. The examination quality is crucial for the effectiveness of colonoscopies. The examination quality is influenced by technical factors and the endoscopist.
- Level of evidence
- 1b
- Consensus
- Strong consensus
- References
- [169]
Grade of Recommendation 0:
If a colonoscopy was incomplete due to a stenosing tumour, an additional preoperative CT colonography can be performed.
Grade of Recommendation A:
A complete colonoscopy shall be performed postoperatively.
Table 5: Overview of Guideline-Based Specific Procedural Quality Indicators of Colonoscopy
| DGVS[415] | ESGE[416] | EU[417] | UK[418] | US[419]*** | |
| Caecal intubation rate | > 90% | > 90% | > 90% | > 90% | yes |
| Withdrawal time | > 6 min | > 6 min | yes | > 6 min | > 6 min |
| ADR | > 20% | individual | individual | > 15%** | yes |
| Bowel preparation | > 90% good | > 90% good | yes | > 90% | no |
| Polyp retrieval |
Complete-ness (endoscop.) |
detailed* | vague | detailed* | yes |
| Interval lesions | no | yes | vague | recommen | no |
| F-up adherence | no | no | >90% | no | no |
* ESGE/UK: retrieval rate, tattooing, ESGE: referral rate ** > 20% “aspirational” *** 2006, in most cases, no rates yet
6.2 Polypectomy
6.2.1 Endoscopic Resection
Level of Evidence: 1c (Oxford 2009)
Polyps shall be removed and retrieved with exact recording of the localisation of the polyp. In case of multiple polyps, the removal of polyps can be performed in more than one session.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Consensus
- Strong consensus
To obtain a representative histological specimen and achieve a definitive therapy, polyps >5 mm shall be completely removed using a snare.
In general, diagnostic colonoscopies shall only be performed if the possibility of performing a polypectomy using a snare is given in the same session.
- Consensus
- Strong consensus
6.2.2 Endoscopic Assessment Prior To Removal
The goal of any colonoscopy must be to achieve a polyp-free colon (clean colon). To prevent double examinations, a colonoscopy should only be performed if the possibility of performing interventions is given. If the removal of a lesion is not possible or sensible (risk situation in an outpatient setting, inadequate expertise with larger polyps), the patient should be referred to a specialist centre. Forceps biopsy of larger polyps (>5 mm) is not useful if removal is technically possible. Forceps biopsy is also unreliable with an underestimation of the histopathological diagnosis in 10% of all polyp biopsies and in 60% of advanced neoplasms [461]. Furthermore, extensive biopsies can cause scarring, which can make it more difficult to perform a complete endoscopic removal of the polyp in a subsequent procedure. However, biopsies are mandatory in the presence of clear malignancy criteria with a primary indication for surgery.
The realistic option of a complete removal of the polyp with a low risk of bleeding and perforation is a requirement and limitation for the endoscopic removal of larger polyps. The experience of the endoscopist and the localisation of the polyp can also be limiting factors. Other factors that should be considered include the increased rate of cancer with increasing size of neoplastic polyps (up to 15% in polyps >3 cm), growth pattern, localisation, patient’s overall health, increased risk of bleeding and increased risk of perforation in the proximal colon [462][463][464][465][466][467]. In case of multiple polyps, polypectomy can be performed in multiple sessions.
For larger flat adenomas (known as laterally spreading tumours or adenomas, LST), the predictive value of the so-called non-granular type for the prediction of malignancy is emphasised, which has a ratio of around 15% to 1-3% for the granular growth pattern [468][469][470][471][472][473] – see also the detailed discussion in the S2K guideline of the DGVS on quality requirements for gastrointestinal endoscopy [454]. Regarding the so-called non-lifting sign [474][475], it is disputed whether this is a reliable sign of malignancy [474][476]. However, it can lead to a technically difficult and incomplete resection in low-grade adenomas as well [472].
Exclusively depressed, flat lesions (IIc) that appear suspicious in the endoscopy should as a rule be treated by primary surgery, especially when they fail to lift after an injection, since most of these lesions no longer present so-called early invasive T1 cancer and complete endoscopic removal (R0) is seldom possible. In isolated cases, endoscopic full- thickness resection (eFTR) can be considered (see below). Apart from that, it has been shown repeatedly that the primary assessment of the endoscopic “removability” of a polyp depends on the experience of the endoscopist and that the majority of “non- removable” polyps can be successfully removed in specialist centres [477][478][479][480][481][482].
Hyperplastic polyps
Small (£5 mm), often multiple, typical hyperplastic polyps in the rectum do not have to be removed if they are clearly identified as such by endoscopy. When located further proximally, polyps that appear hyperplastic should always be removed, since they are frequently classified as serrated adenomas as they increase in size.
Serrated polyposis syndrome (SPS), previously hyperplastic polyposis syndrome, appears to be one of the most frequent colorectal polyposis syndromes. To date, no gene defect has been identified. The current WHO definition (26) for the diagnosis of serrated polyposis syndrome (SPS) consists of three criteria:
1. At least 5 histologically confirmed serrated polyps proximal to the sigmoid colon, two of which are >1 cm
or
2. Any number of serrated polyps proximal to the sigmoid colon in patients with a first-degree relative with hyperplastic polyposis
or
3. More than 20 serrated polyps of any size in the colon.
Serrated polyposis syndrome is associated with an increased risk of cancer and requires regular surveillance colonoscopies.
Endoscopic resection techniques
The complete removal and retrieval (in particular when parts are removed by so-called fractionated endoscopic mucosal resection - EMR) of a polyp is always required, since high-grade intraepithelial neoplasia or cancer may still be present in residual polyp tissue. To enable a classification, polyps should be retrieved individually for a histological analysis, specifying their localisation. If several small and non-suspicious polyps are present in a segment, combined retrieval of these polyps is acceptable. In so doing, however, the oncological resection margins must be respected in case of unexpected histological findings. Marking of the colon segment where polypectomy has been performed is useful when subsequent surgical resection is required.
The following endoscopic procedures are available:
- Removal of small polyps up to 5 mm by forceps or snare
- Polypectomy by snare for polyps >5 mm
- Endoscopic mucosal resection (EMR)
The individual procedures are discussed in detail in the S2K guideline of the DGVS on quality requirements for gastrointestinal endoscopy [454]. For small polyps up to 5 mm it was shown that adenoma tissue is frequently left behind during removal by forceps [483] and that this presumably depends on the degree of diligence and the number of biopsies. The best-studied procedure is cold snare polypectomy, which must arguably be given preference for small polyps [484][485][486]. In two smaller randomised studies (around 60 polyps per arm) with a histological follow-up, the rate of completely removed adenomas in the cold snare group was 93.2% and 96.6% versus 75.9% and 82.6% in the forceps removal group, respectively [487][488].
Larger polyps are removed with the snare, flat polyps usually after prior injection; larger (flat) polyps generally require removal using the piecemeal method (endoscopic mucosal resection/EMR). The size of the removed polyp, the histological adenoma classification and the severity of intraepithelial neoplasia determines the degree of risk for local recurrences and metachronous polyps. In principle, and for methodological reasons, a differentiation should be made between residual adenoma tissue (diagnosed in the first control examination usually performed shortly after resection) and recurrent adenomas (i.e. recurrence after one or two negative endoscopic control biopsies, depending on the definition). For polyps >2 cm, recent studies have shown a residual/recurrent adenoma rate of up to 20% and higher [489][490][491][492][493][494]. However, these recurrences can generally be treated by a repeat endoscopy, so that very high success rates of >95% can be expected on the whole.
To improve the histological assessment of the resected tissue and to lower the recurrence rate, the en-bloc resection of larger, flat polyps by endoscopic submucosal dissection (ESD) has been propagated for several years. The advantages of this procedure are, however, offset by a markedly increased complexity, usually considerably longer interventions and higher complication rates compared to EMR. In addition, the removal in one piece of benign lesions such as colon adenomas generally has fewer advantages than in the oncological setting of (early) cancers.
The literature on colon ESD is complicated by a strong dominance of studies from the Far East, from Japan in particular, and the local common practice of histological blending of mucosal cancer (= high-grade dysplasia or Tis tumours) and submucosal cancer [495]. Comparative retrospective, and thus non-randomised, studies of ESD with EMR are also only available from the Far East [496][497][498][499][500][501][502]. Western results of colon ESD usually [503] show a markedly lower R0 rate with partly considerable (but generally endoscopically manageable) complications [504][505][506][507]. For submucosal cancers, which thankfully are mostly analysed separately in these Western studies (only cases of rectal cancer!), the vast majority of patients did indeed undergo secondary surgery following the endoscopy. The data show a problem relating to the selection or indication: The most recent publication [507] also showed that more than 50% of patients with T1 cancers had to undergo secondary oncological resection, because there was no low-risk situation. It remains unclear which polypous cancer benefits from ESD “ex ante”. While the technique is considered the best oncological one-piece treatment method for early colorectal cancer, it is currently reserved for only a few special cases in specialist centres for the above reasons and is not suitable for widespread use in the western colon. ESD is not essential for the removal of benign polyps. EMR remains the standard procedure for the removal of benign colorectal polyps.
Removed flat and sessile polyps should be marked with a pin or dye for identification. Fixing on a cork plate is also useful for the histological examination of flat polyps.
If surgical treatment is possible or expected to be necessary, preoperative marking of the polyp area with clips or ink must be performed (exception: caecum and distal rectum); marking must be done slightly proximal and/or distal to the lesion and not in the actual lesion. Intraoperative colonoscopy is an alternative way of locating the polyp or its removal site. To facilitate re-identification of the site (difficult identification during surveillance examinations), the polypectomy site can also be marked as outlined above in cases of difficult localisation after an endoscopic intervention.
Alternative procedures to remove polyps (open or laparoscopic resection, rendezvous procedures, TEM, transanal removal) may be considered in individual cases. Removed flat and sessile polyps should be marked with a pin or dye for identification. Fixing on a cork plate is also mandatory for these flat polyps.
Endoscopic full-thickness resection (eFTR) is a reserve procedure ([508]) in which the area to be removed is pulled into a hollow cylinder attached to the tip of the endoscope by means of pincers; and, in principal, a snare removal as well as a closure of the defect in the colon wall using a larger clip is performed simultaneously. Possible indications include: residual adenoma tissue, recurrent adenomas, submucosal non-neoplastic polyps, etc. Low-risk early cancer, either in the primary intention or (after receiving the results of the EMR histology) in the secondary intention to ensure R0 resection (see section 6.4 Approach for pT1 Cancer) can be yet another indication. The limitations are: size ≥3 cm, failure to mobilise the lesion into the cylinder, inadequate accessibility of the equipment during the endoscopy, and operator errors concerning the technology used. The available data are insufficient for a final assessment at this time. Little is known about the complication rates as well. For this reason, this treatment method can only be carried out in isolated clinical cases in specialist centres. Widespread use of this method cannot (yet) be recommended.
Complications
Concerning the published complication rates associated with colonoscopy, reference is made to a review of the ASGE [509] and to a review related specifically to colonoscopy screening [510]. The S2K guideline on quality requirements for gastrointestinal endoscopy [454] provides an overview of the most relevant German [511][512][513][514][495][515][516] and international larger-scale studies [516][517][518][519][520][521][522][523][524][525]. In a large, prospective German study, independent factors for the risk of perforation included polyps larger than 1 cm as well as localisation in the right colon, and for the risk of bleeding, only polyp sizes >1 cm [526]. The risk of serious bleeding (requiring transfusion or surgery, recurrent secondary bleeding) was 0.9%; the risk of perforation was 1.2% in the right colon and 0.4% in the left colon.
For details on prophylactic measures to prevent (secondary) bleeding after endoresection and on polypectomy under dual platelet inhibition, reference is made to the S2K guideline on quality requirements for gastrointestinal endoscopy [454].
6.3 Histological Examination
The histological examination of each polyp is mandatory. The histological reporting of polyps shall follow WHO criteria [568] with a statement about the completeness of removal. Conventional adenomas are classified according to histological type of growth (tubular, tubulovillous, and villous) and the level of intra-epithelial neoplasia (low- and high-grade intraepithelial neoplasia); serrated lesions are subclassified as hyperplastic polyps, sessile serrated adenomas, mixed polyps (with IEN grade) and traditional, serrated adenomas (with IEN grade) [568, 569].
- Consensus
- Strong consensus
Background
In recent years, molecular genetic findings have shown that other paths of cancer development exist alongside the “classic adenoma-carcinoma sequence”. On the one hand, there is the so-called “serrated pathway in colorectal carcinogenesis”, whose precursor lesion is considered to be the relatively new entity of the sessile serrated adenoma (SSA). On the other hand, there is a “mixed type” which combines molecular characteristics of the two other carcinogenesis pathways and whose precursor lesions can be traditional serrated adenoma (TSA) or villous adenomas. The primary key mutation for the alternative serrated pathway lies in the BRAF gene with a disruption of apoptosis, followed by senescence with (CpG) methylation and consecutive gene silencing (e.g. hMLH1, MGMT, p16) and the development of generally high-grade microsatellite instability (MSI-H) ([527], [528]).
Since the serrated pathway in colorectal carcinogenesis may progress more rapidly, the knowledge and diagnosis of precursor lesions is of vital importance. The new entities sessile serrated adenoma (SSA) and traditional serrated adenoma (TSA) were first defined in 2010 ([529]). Hyperplastic polyps (HP) are formally classified as non-neoplastic lesions and are thus “innocent”. Based on current data and on the relatively similar, but not identical, morphology of hyperplastic polyps and sessile serrated adenomas, it must, however, be assumed that SSAs were misclassified as hyperplastic polyps in the past. For lesions >0.5 cm, the “misclassification rate” is around 30% ([528]).
Sessile serrated adenomas (SSA)
Sessile serrated adenomas are typically >5 mm, located in the right hemicolon and have a flatter profile. They do not protrude into the intestinal lumen as polyps do. SSAs are relatively difficult to recognise during endoscopy; they can be delimited from their surroundings by means of a layer of mucus (known as a mucus cap). Owing to their morphology and localisation, they could be a considerable cause of so-called interval cancer. Meanwhile, it is undisputed that SSAs are precursor lesions of the “serrated pathway in colorectal carcinogenesis”. The differential diagnosis of HP and SSA is based on the typical overall appearance of the SSA with L- and T-shaped branching at the base of the crypt, serration down to the base of the crypt, the presence of dilated, frequently “angular” basal crypts and occasional “inverted crypts” extending from under the lamina muscularis mucosae.
Traditional serrated adenomas (TSA)
Unlike SSAs, traditional serrated adenomas protrude into the intestinal lumen similar to polypoid lesions. They combine the serrated architecture of hyperplastic polyps with the IEN of classic adenomas. They account for around 1% of all colorectal adenomas and are located predominantly in the left hemicolon and rectum. From a molecular perspective, TSAs are characterised by a high number of K-RAS gene mutations.
“Mixed polyp”
The term “mixed polyp” is used to summarise a heterogeneous group of lesions that may contain elements of serrated adenomas, hyperplastic polyps and tubular, tubulovillous or villous adenomas.
Risk assessment of serrated lesions
While it is not known how long it takes for serrated lesions to undergo malignant transformation, the presence of serrated lesions in itself, however, appears to indicate an increased risk for developing colorectal neoplasms. Analogous to oesophageal and pulmonary tumours, serrated lesions are a sign of cancerisation of the colon. They indicate that the affected person has a predisposition to develop (pre-)neoplastic lesions with a carcinogenic potential in multiple sites inside the colon.
Numerous studies have shown that serrated "polyps" are associated with synchronously and metachronously advanced colorectal neoplasms in the sense of indicator lesions. A meta-analysis ([530]) summarises the results of nine studies with 34,480 patients. Serrated polyps were detected in 15.6% of the patients. When serrated polyps were detected, the patient had a 2.05-fold risk of developing advanced neoplasia. The diagnosis of proximal serrated polyps was associated with a 2.77-fold risk increase. When polyps were large serrated polyps (>1 cm), the risk increased 4-fold. Serrated lesions thus appear to be lesions that indicate an increased risk of advanced colorectal neoplasia. Patients with large serrated adenomas in the proximal hemicolon are particularly at risk of developing advanced colorectal neoplasia.
Only few data on the long-term course of serrated lesions are available, which do not provide for a conclusive evaluation. The risk of developing colorectal cancer depending on the presence of adenomas in the follow-up was investigated in a population-based randomised study ([531]). The risk of colorectal cancer was increased 2.5-fold in patients with a large serrated polyp, 2-fold in patients with advanced (conventional) adenomas and was 0.6% for patients with non-advanced adenomas. The authors concluded that a large serrated adenoma can be considered an independent risk factor for colorectal cancer, even after correcting the risk with the histology, size and multiplicity of accompanying adenomas.
A retrospective national population-based case control study conducted by Erichsen [532] in a total of 272,342 colonoscopies showed that SSAs with cytological markers of dysplasia were associated with the development of adenocarcinomas. Women with SSAs were at a higher risk of developing colorectal cancer than men: an SSA increased the risk of colorectal cancer fivefold in women, compared to twofold in men. Patients with an SSA proximal to the left flexure were found to have the highest risk of developing colorectal cancer.
In summary, at present it can be assumed that patients with large serrated adenomas have an increased risk of developing colorectal cancer, comparable to the risk of advanced conventional adenomas.
Regarding follow-up recommendations after polypectomy, the histological work-up of removed lesions is of crucial importance. Consequently, it is mandatory to histologically examine all removed lesions. For this reason, the concept of removing and discarding small polyps (Resect and Discard) proposed by individual experts is rejected ([533]).
In case of cancer, the histology report has to contain the following characterisations:
- a measure of the depth of infiltration (pT category), for sessile polyps the submucosal invasion in μm,
- the histological differentiation grade (grading),
- presence or absence of lymphatic vessel infiltration (L classification),
- and an assessment of the resection margins (R classification) with regard to the local removal in healthy tissue (for depth and on the sides).
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- 3a
- Consensus
- Strong consensus
- References
- [534]
The extent of tumour budding can be rated as an additional parameter.
- Consensus
- Strong consensus
Concerning further therapeutic consequences for completely removed pT1 cancer, a final classification into “low-risk” (G1, G2 and no lymph vessel invasion (L0)) or “high-risk” (G3, G4, and/or lymph vessel invasion (L1)) shall be performed.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- 3a
- Consensus
- Consent
Tumour cell budding greater than 1 can also be rated as “high-risk“.
- Consensus
- Consent
Background
The necessity of a statement on the distance of the tumour from the resection in healthy tissue in patients with pT1 cancer is disputed.
Tumour grading and budding
The degree of tumour differentiation is defined according to the rules of the WHO (WHO 2010) which state that the degree of tumour differentiation is governed by those parts of the tumour that are most difficult to differentiate. The tumour invasion front should not be taken into consideration. However, daily practice has shown that the tumour invasion front in particular is characterised by a phenomenon known as tumour budding. This phenomenon refers to individual tumour cells or also tumour cell clusters at the invasion front which are usually poorly differentiated and have characteristics similar to those of stem cells. These cells are also genetically different from those found in the primary tumour. However, a standardised definition of how to assess or grade tumour bedding has not yet been developed. From now on, a proposal made by Japanese authors is to be implemented: according to this proposal, tumour budding is to be defined as histological proof of tumour cell clusters (five cells or fewer) of dedifferentiated or isolated tumour cells at the invasion front. Here, the invasion front should undergo microscopic analysis with 200-fold magnification and the degree of budding should be determined as grade 1 with 0-4, grade 2 with 5-9 or grade 3 with >9 buddings or tumour cell clusters. In several studies, grade 2 or 3 tumour budding, i.e. >4 buddings or clusters at the invasion front, was considered an additional parameter indicating an increased risk of lymph node metastases ([535], [536], [537]).
Since the analyses on tumour budding originate mainly from Japan and tumour budding grading is not yet standard practice in Germany, the grade of recommendation to take tumour budding into account in the risk assessment of T1 cancers was lowered to “can”.
A checklist to ensure standardised histopathological analysis of colorectal polyps should be used ([534]).
6.4 Approach for pT1 Cancer
In the context of an endoscopically R0-removed polyp with a pT1 cancer, no additional oncological resection shall be performed if there is a low-risk situation with a cancer-free polyp base (R0). In the high-risk situation, radical surgical therapy shall be performed, even if the lesion has been completely removed.
With incompletely removed low-risk pT1 cancer, a complete endoscopic or local surgical removal has to follow. If an R0 situation cannot be achieved or it is doubtful that a pT1 situation exists, an oncological-surgical resection shall be performed.
Background
The prognosis of pT1 cancer varies widely depending on the situation. The major determinant of a risk stratification into a low-risk and a high-risk group is the probability of lymph node metastases. As a whole, the group of T1 cancer has a lymph node metastasis rate (N+) of 0-20% [538][539][540]. There are a number of prognostic criteria for estimating the rate of metastases [541][542][543][544]; in this context, the risk of lymph node metastases in the low-risk situation is defined as around 1% or less [538][539][545], [541][542][546][547][548][549][550], [551].
The following factors are important for the risk stratification of pT1 cancer:
- Grading: G1 and G2 are considered low-risk criteria (G1 well differentiated, G2 moderately differentiated, G3 poorly differentiated, G4 undifferentiated).
- Invasion in lymphatic vessels (L classification) or blood vessels (V classification): The absence of invasion (L0 V0) determines the low-risk category. Proof of vascular invasion (V classification) should be mentioned, however, its significance for local therapy has not been conclusively confirmed.
- Tumour cell budding, i.e. the presence of isolated, “scattered” tumour cells at the tumour invasion front (see Recommendation 6.12).
- Submucosal invasion, as measured in biopsies removed during surgery or polypectomy (especially with sessile/flat lesions). In this context it has proven useful to divide the submucosa into three layers for surgical biopsies. In biopsies of sessile polyps removed during endoscopic polypectomy, however, only the measurement of the depth of submucosal invasion in μm is useful, since the submucosal layer is not available as a total layer and/or no muscularis propria is present. With 0-6%, the so-called early invasive forms (sm1 = submucosal invasion £1000 μm) have a low risk of N+ [447][538][539][540][541]. In contrast, the risk of lymph node metastases in sm3 cancer is around 20% [447][552]. Caution: The measurement of submucosal infiltration in pedunculated/stalked polyps in μm is not useful and/or is misleading, because the thickness of the submucosal layer depends on the length of the stalk. In practice, the classification of polyps according to Haggitt [553][554] is difficult to perform. With the exception of advanced stalk invasion (>3000 μm) [555], T1 cancer in pedunculated polyps is classified as sm1.
- In multivariate analyses, lympathic vessel invasion is given the highest significance as a risk factor for the presence of lymph node metastases. An L+ status is associated with a 20% rate of N+ ([556]). For L0 and G2, a submucosal invasion depth of 1000 μm to 2000 μm appears to increase the rate of lymph node metastases (N+) by only 1% to 2% ([557], [558]).
Important additional comments on the resection (R) status:
For endoscopically/locally removed low-risk T1 cancer, the reliable assessment of complete removal (R0) is an absolute prerequisite for a follow-up without oncological resection. Where possible, stalked lesions should be removed in one piece. For sessile/flat lesions and en-bloc removal, the lateral and basal margins can be assessed histopathologically; for piecemeal removal, only the basal margins can be reliably assessed by histology. The necessity of a safety distance of 1 mm to the base is controversial [541]; here, the endoscopic literature does not provide conclusive information. In patients with a low-risk situation and a confirmed R0 status (see below), a subsequent radical surgical resection according to oncological criteria is not required.
As a rule, endoscopic cancer therapy in the context of polypectomy is performed without prior knowledge of the cancer diagnosis. Removal using the piecemeal technique appears adequate here [559]. Here, the evaluation of the lateral R situation is performed macroscopically during endoscopy, the evaluation of the vertical infiltration is done histologically (basal R0). However, early (2-6 months) endoscopic re-examination of the local R0 situation by means of a biopsy is necessary.
In selected cases of an incomplete resection, endoscopic full-thickness resection (eFTR) can help achieve a curative R0 situation in low-risk tumours through secondary endoscopic resection of the removal site (see also section 6.2.1 Endoscopic Resection).
In every case of a definitive Rx basal or R1 basal or unclear vertical resection margin, surgical resection (usually performed as an oncological resection) is required in operable patients!
Randomised studies comparing endoscopic and surgical procedures in T1 cancer are not available. Retrospective studies show that relapses in the form of local recurrences or distant metastases can be expected in around 3% of cases following endoscopic treatment of low-risk T1 cancer ([560]; [551]). For this reason, the oncological situation should be discussed with the individual patient, and surgical risks associated with the oncological resection should be discussed and weighed against the risks of endoscopic local therapy alone.
Care should be taken with sessile lesions, especially if a cancer diagnosis was already confirmed by biopsy prior to the therapy. In this case, a situation is frequently present in which the lesions cannot be treated adequately using endoscopic means. Endoscopic warning signs include: ulceration, depressed lesions, contact bleeding and absence of the lifting sign when injecting under the lesion. Any such known malignant lesions should only be removed endoscopically in centres with sufficient expertise in primary assessments and endoscopic resection techniques.
For known or suspected T1 cancer, endoscopic removal as an en-bloc resection is the optimal procedure for oncological reasons. The method of choice for lesions located in the rectum is ESD (see 6.2.1 Endoscopic Resection).
After complete removal (R0) of low-risk (pT1, low-grade (G1, G2, L0)) cancer, endoscopic surveillance examinations of the local resection site shall be performed after six months.
A complete colonoscopy shall be performed after three years.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- 4
- Consensus
- Strong consensus
Background
The above recommendations serve to enable the recognition of local recurrences. A complete colonoscopy for the early detection and treatment of recurrences should be performed according to the recommendations for adenoma surveillance.
6.5 Polyp Management (Follow-Up)
Background
Patients with small (<1 cm) hyperplastic polyps and a negative family history do not appear to have an increased risk of developing colorectal cancer. Here, the general recommendations for CRC prevention apply, i.e. colonoscopy screening every 10 years [561][562][563]. Exceptions include non-neoplastic polyposis syndromes (hyperplastic, juvenile, Peutz-Jeghers and SSA polyposis) with an increased risk of malignant transformation [564].
The timing of the surveillance colonoscopy after complete removal of neoplastic polyps (adenomas) shall depend on the number, size and histology of the removed adenomas.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- 2b
- Consensus
- Strong consensus
- References
- [565]
For patients who have 1 or 2 adenomas <1 cm without higher-grade intraepithelial neoplasia, a surveillance colonoscopy should be performed after 5-10 years.
If, however, no or only 1-2 adenomas <10 mm without a mostly villous histology or HGIEN are discovered during this surveillance colonoscopy, the next surveillance colonoscopy should be performed after 10 years.
For patients who have 3-4 adenomas, or one adenoma that is ≥1 cm, or an adenoma with a mostly villous histology or HGIEN, the first surveillance colonoscopy should be performed after 3 years.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 3b
- Consensus
- Consent
- References
- [568]
For patients with adenomas with high-grade intraepithelial neoplasia and histologically confirmed complete removal, a surveillance colonoscopy should be performed after three years.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 1b
- Consensus
- Strong consensus
- References
- [568]
In adenomas > 5 mm with histologically non-confirmed complete removal even if macroscopically the removal was complete, a control should be performed after 6 months.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 5
- Consensus
- Consent
In case of ≥5 adenomas of any size, the control interval should be <3 years.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 5
- Consensus
- Consent
After removal of large adenomas in piecemeal technique, a short-term control of the removal area shall be performed after 2-6 months.
After complete removal of a traditional serrated adenoma or sessile serrated adenoma, the follow-up should be the same as for classic adenomas.
Background
After removal of adenomas, interval adenomas are again detected in around 50% of the patients ([565]). Surveillance examinations after polypectomy account for around 20% of all colonoscopies and are thus an important cost factor ([576]). The target structure of polypectomy follow-up is cancer on the one hand, and advanced adenoma on the other hand. After removal of adenomas, so-called interval cancer is diagnosed in 0.7% to 0.9% of patients within 3 years at surveillance colonoscopies [577].
Table 6: Follow-Up Intervals After Polypectomy
| Starting situation | Interval of surveillance colonoscopy |
| 1 or 2 small tubular adenomas (<1 cm) without a villous component or high-grade intraepithelial neoplasia | 5-10 years |
| 3 or 4 adenomas or ≥1 adenoma ≥1 cm or villous component or high-grade intraepithelial neoplasia | 3 years |
| ≥5 adenomas | <3 years |
| Serrated adenomas | As for classic adenomas |
| Removal in piecemeal technique | Control of the removal site after 2-6 months |
This is caused by missed lesions (miss rate), incomplete polypectomies and the occurrence of rapidly growing tumours [578][579][580][581]. The definition of surveillance intervals after polypectomy depends on the patient’s individual risk. The risk depends fundamentally on the number, size and histology of the removed adenomas [565]. The risk of cancer is not significantly increased in patients with 1 or 2 small tubular adenomas [208], [566], [567]. Therefore, surveillance colonoscopy after 5 to 10 years seems sufficient. If only 1 or 2 small tubular adenomas are again detected during the surveillance colonoscopy, there is no significantly increased risk, so that the next surveillance colonoscopy should then be repeated after 10 years. After removal of 3 or 4 adenomas or at least 1 adenoma ≥10 mm or with a mostly villous histology (not tubulovillous adenomas!) or high-grade intraepithelial neoplasia, surveillance colonoscopy should be performed after 3 years due to the increased risk of advanced neoplasia. These recommendations are based on the data of the National Polyp Study, in which an examination after 3 years showed a similar rate of advanced neoplasia as after 1 year [568]. A pooled analysis showed that patients with 5 or more adenomas have a markedly increased risk of advanced neoplasia of 24.9% [565], especially if 1 of the adenomas is ≥10 mm [582]. For this reason, a shorter surveillance interval appears appropriate in these cases.
The follow-up interval of the second surveillance colonoscopy depends on the findings of the index colonoscopy and the first surveillance colonoscopy. There are no relevant data available from randomised studies, only from retrospective analyses. A possible algorithm is shown in the table above. It must be taken into account that patients diagnosed with advanced adenomas in the index colonoscopy continue to be at an increased risk of advanced neoplasms, as are they if 1 or 2 tubular adenomas are diagnosed in the first surveillance colonoscopy ([583]) ([584]), ([585]), ([586]), so that another control examination after 3 years appears reasonable in this case. Again, randomised studies assessing different follow-up intervals after the removal of serrated adenomas have not been conducted. Only case control studies and case series were identified in the literature search. These studies identified a similar rate of advanced adenomas in the surveillance colonoscopy as after the removal of adenomas ([532]), ([574]), ([575]). For this reason, it appears reasonable that the same follow-up recommendations for non-serrated adenomas should apply after the removal of serrated adenomas (for details see section 6.3).
An incomplete endoscopic removal of adenomas is generally associated with an increased risk of interval cancer ([587]). The goal is therefore to achieve a complete removal which is pathologically confirmed. Consequently, it also appears useful to perform a control examination of the removal site after the removal of adenomas >5 mm for which a complete removal cannot be confirmed histologically. Even if no comparative data are available, it is recommended that the control should be carried out after around 6 months, analogous to the removal using the piecemeal technique. For smaller adenomas, the assessment of the completeness of the removal by forceps can be difficult to impossible for the pathologist. The clinical relevance of small adenomas is also unclear. For this reason, the endoscopic assessment of the completeness of the removal is decisive in these cases, and a repeated examination of the removal site is superfluous.
After removal of flat or sessile adenomas in piecemeal technique, the recurrence rate is significantly increased, especially with larger adenomas (9-28%) [569][570][571][572][573]. The use of argon plasma coagulation to remove remaining tissue to ensure a complete removal can be helpful [570][573]. In this case, however, a complete histological examination cannot be performed. The special group of patients with removal of flat or sessile adenomas in piecemeal technique should undergo surveillance endoscopy of the removal site after 2- 6 months due to the higher rate of local recurrences ([588]).
Concerning the follow-up recommendations for HNPCC, FAP and CED patients see section 10.6.
6.6 Secondary Chemoprevention of Adenomas
Background
Even though a limited preventive effect has been demonstrated for low-dose aspirin in several prospectively randomised studies with high levels of evidence (1b) [589][590], an intake of aspirin to lower the risk of adenoma recurrences cannot be recommended owing to the limited effect (reduction of the adenoma recurrence rate by max. 35%) and the risks posed by taking the drug [592]. The same holds true for COX-2 inhibitors, for which a reduction in the adenoma recurrence rate of 24 to 45% has been shown [80][81][82]. The COX-2 inhibitors, however, have been associated with a significantly increased rate of cardiovascular side effects [593][594] which outweigh their potential benefit [595]. The reduction of the adenoma recurrence rate of 12% with calcium appears to be too low to recommend the longer-term administration for this indication [591].
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