**3. Factors affecting risk of nodal disease**

#### **3.1. Morphology**

The Paris classification[13] of gastro-intestinal tumours recognises that adenomas may be polypoid or non polypoid. Non polypoid (0-II, 0-III ) lesions are not usually removed endo‐ scopically as they are more challenging to remove and are recognised to have high malig‐ nant potential.


**Table 1.** Paris Classification of Superficial Tumours of the Colon and Rectum.[13]

Polypoid lesions can be pedunculated (Type 0-1p) or sessile (Type 0-1s). Due to their shape malignant sessile polyps are harder to remove with clear margins and have more ready ac‐ cess to the deeper portions of the submucosa. They are therefore more likely to be classified as high risk. Seitz et al[9] presented a series of 114 endoscopically removed malignant pol‐ yps. Overall 46% of these polyps were sessile, but 65% of "high risk" (ie. requiring surgical removal) polyps were sessile. Conversely only 23% of "low risk" polyps were sessile.

An earlier literature series of 741 malignant polyps reported that 58.3% of sessile polyps had "high risk features" (Grade 3-4, vascular or lymphatic invasion, positive resection margin) whereas only 10% of pedunculated polyps were similarly classified.[11] One meta-analysis reported positive resection margins in 56.8% of sessile lesions verses 18.7% in polypoid le‐ sions (P < 0.0001).

Size and tubular or villous architecture are also well known to affect the malignant potential of polyps. However, in a similar fashion to flat or depressed areas of dysplasia, very large polyps are seldom excised endoscopically and are not relevant to the current topic.

#### **3.2. Grading**

The definition of colorectal carcinoma is dysplasia crossing the *muscularis mucosa,* so when high grade dysplasia in these polyps crosses this barrier the lesion is termed a malignant polyp. A malignant polyp is essentially a macroscopically benign lesion that contains malig‐ nant foci on further examination. When the totality of the polyp is comprised of malignancy

T1 lesions are therapeutically significant as they are the first lesions where nodal and distant metastases must be considered. The management of these polyps is based on the belief that the risk of spread can be stratified according to the histology of the resected polyp.[5] In the past authors used various criteria to define favourable or unfavourable histology and guide management.[1,2,6,7] For a large part, this has involved dividing patients into two groups. A "low risk" group, who are safe without further treatment and a "high risk group", for whom surgery should be considered.[8,9] Unfortunately published studies disagree about

The Paris classification[13] of gastro-intestinal tumours recognises that adenomas may be polypoid or non polypoid. Non polypoid (0-II, 0-III ) lesions are not usually removed endo‐ scopically as they are more challenging to remove and are recognised to have high malig‐

0-Is: Sessile

0-IIb: Flat

Polypoid lesions can be pedunculated (Type 0-1p) or sessile (Type 0-1s). Due to their shape malignant sessile polyps are harder to remove with clear margins and have more ready ac‐ cess to the deeper portions of the submucosa. They are therefore more likely to be classified as high risk. Seitz et al[9] presented a series of 114 endoscopically removed malignant pol‐ yps. Overall 46% of these polyps were sessile, but 65% of "high risk" (ie. requiring surgical

An earlier literature series of 741 malignant polyps reported that 58.3% of sessile polyps had "high risk features" (Grade 3-4, vascular or lymphatic invasion, positive resection margin)

removal) polyps were sessile. Conversely only 23% of "low risk" polyps were sessile.

0-IIc: Slightly depressed

the term polypoid carcinoma is often used.

142 Colonoscopy and Colorectal Cancer Screening - Future Directions

the factors that are most significant.[3,10-12]

**3.1. Morphology**

nant potential.

0-III: Ulcerated

**3. Factors affecting risk of nodal disease**

0-I: Polypoid 0-Ip: Pedunculated

0-II : Non-Polypoid, Non Ulcerated 0-IIa: Slightly elevated

**Table 1.** Paris Classification of Superficial Tumours of the Colon and Rectum.[13]

Polyps are defined by dysplasia and the varying degree displayed by different polyps is thought to explain a large degree of their different metastatic potential.[14]


**Table 2.** Revised Vienna classification of epithelial neoplasla for esophagus, stomach, and colon. [13]

The revised Vienna classification is widely used to define the degree of dysplasia colorectal polyp. By definition malignant polyps are 4-4. For colorectal carcinomas the WHO classifica‐ tion recognises 4 grades of differentiation, with G1 representing well differentiated, through moderate (G2) and poorly differentiated (G3) to undifferentiated (G4). G1-2 are convention‐ ally regarded as low grade and G3-4 as high grade.

In a meta-analysis of published series, Hassan *et al.*[1] reported a 3.9 (1.9-8.4) odds ratio for no‐ dal metastasis with regard to high vs low grade malignant polyps. The odds ratio for mortality was reported as 9.2 (4.7-18.2). Determining the exact risk from high grade dysplasia is compli‐ cated by their relative rarity. One study of 80 malignant polyps found only 2 poorly differenti‐ ated polyps.[12] In a meta-analysis 7.2% of 1612 malignant polys were high grade.[1]

It is interesting to note that despite poor differentiation being recognised as an important determinant of nodal disease, no universally accepted definition exists. Indeed in studies where the prevalence of highly dysplastic lesions was lower, the risk of nodal disease in these polyps was increased. (See Table 3). This suggests that poor differentiation, when a rigorous definition is used is an extremely important predictor of nodal disease. Those stud‐ ies that did not find the degree of dysplasia to be significant are hampered by the very small number of highly dysplastic lesions in their sample.


treatment after polypectomy for Sm1. In the absence of other risk factors most would agree

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The Kikuchi classification has been widely accepted for the assessment of T1 colorectal tu‐ mours but can be difficult to perform on endoscopy specimens as the *muscularis propria* is

Difficulty is also encountered when the *muscularis muscosa* cannot be identified. A large col‐ laborative Japanese study used Haggit level 2 (i.e. the border between the head and neck of the polyp) as a baseline for pedunculated polyps. Provided that there was no lymphatic in‐ vasion, they found no nodal disease if the depth of invasion from here was <3mm. For ses‐ sile polyps the superficial aspect of the lesion was used and again no nodal disease discovered if the invasion was <1mm, regardless of other lymphatic invasion. [17] Other Jap‐ anese studies have also found good correlation between quantitative measures of submucos‐

Although the study included operative specimens as well as endocsopically removed malig‐ nant polyps, Ueno[14] showed that the width of tumour invasion is also an important factor.

Involved resection margins have been shown to be strongly associated with poor outcomes. These patients have higher mortality, local recurrence and rates of residual disease. In one, all be it small, study 75% of incompletely resected polyps were associated with an adverse outcome.[20] It should be noted that even when incomplete resection is reported, absence of residual disease in the surgical specimen is the rule (94% in one study) rather than the ex‐

The European recommendations state that tumour cells within 1mm of the margin repre‐ sents a positive margin[22], with some authors arguing then >2mm represents the true safe

Incomplete removal is failure of primary therapy and requires further resection. Piecemeal removal of the polyp prevents proper histological assessment and surgery is mandated in all cases. For this reason endoscopic mucosal resection by the strip biopsy method is discour‐

Lymphatic invasion has been sighted by some authors as an important predictor of nodal disease. Controversy exists however as reported cases are rare and usually associated with poorly differentiated tumours or incomplete resection. Inter-observer variability and the ease of mistaking retraction artefact for lymphatic invasion also make interpretation diffi‐

Lymphatic invasion is usually associated with other high risk factors and in those cases with adverse outcomes, almost invariably so. Many authors would regard its status as an inde‐ pendent risk factor is unclear.[20] However a large multi-centre retrospective study from Ja‐

ception[21]. This is likely due to diathermy electrofulguration of the remnant.

for Sm2 lesions as well.[7]

not usually included in the specimen.[2]

**3.4. Incomplete or piecemeal resection**

margin[21].

cult.[6,12]

al invasion and risk of lymph node metastasis.[18,19]

aged for the removal of potentially malignant lesions.

**3.5. Lymphatic and vascular invasion**

**Table 3.** Incidence of G3 Poorly Differentiated T1 Colorectal Carcinoma and Incidence of Nodal Involvement. In those studied with a higher incidence of G3 carcinoma, incidence of nodal disease in those carcinomas falls. From[3]

#### **3.3. Depth of invasion**

Haggitt's classification is based on the greatest anatomical depth of invasion in pedunculat‐ ed polyps.[5] Haggitt 0 lesions are confined to the mucosa. Haggitt grades 1-3 breach the submucosa within the polyp, and they are confined to the head, neck and stalk of the polyp respectively. Only Haggitt 4 lesions invade past the stalk into the submucosa of the wall. Most authors would agree that only Haggit 4 lesions require further treatment. If adequately excised, Haggitt 0-3 lesions have a risk of recurrence (<1%) which is lower than the predict‐ ed mortality of an oncological resection.[15,16] Conversely, for level 4 lessions, Haggitt re‐ ported nodal disease rates of almost 13%.

All sessile lesions are Haggitt 4 by definition, but other authors have treated selected sessile lesions with polypectomy alone to good effect. Kudo produced a refinement for sessile pol‐ yps by dividing the submucosa into thirds.[13] This has become known as the Kikuchi clas‐ sification. [2] Lesions confined to the superficial third of the submucosa (called Sm1) demonstrated very low rates of nodal disease and many authors recommend no further treatment after polypectomy for Sm1. In the absence of other risk factors most would agree for Sm2 lesions as well.[7]

The Kikuchi classification has been widely accepted for the assessment of T1 colorectal tu‐ mours but can be difficult to perform on endoscopy specimens as the *muscularis propria* is not usually included in the specimen.[2]

Difficulty is also encountered when the *muscularis muscosa* cannot be identified. A large col‐ laborative Japanese study used Haggit level 2 (i.e. the border between the head and neck of the polyp) as a baseline for pedunculated polyps. Provided that there was no lymphatic in‐ vasion, they found no nodal disease if the depth of invasion from here was <3mm. For ses‐ sile polyps the superficial aspect of the lesion was used and again no nodal disease discovered if the invasion was <1mm, regardless of other lymphatic invasion. [17] Other Jap‐ anese studies have also found good correlation between quantitative measures of submucos‐ al invasion and risk of lymph node metastasis.[18,19]

Although the study included operative specimens as well as endocsopically removed malig‐ nant polyps, Ueno[14] showed that the width of tumour invasion is also an important factor.

#### **3.4. Incomplete or piecemeal resection**

**Study Number Of T1 Tumours Incidence of G3 Poorly**

144 Colonoscopy and Colorectal Cancer Screening - Future Directions

Yamamoto et al 2004 301 0.1 (4) -

Seitz et al 2004 116 3.4 (4) -

Morson et al 1984 61 5 (3) - Cooper et al 1995 140 5.7 (8) -

Hackelsberger et al 1995 87 11.5 (10) -

Nascimbeni et al 2002 344 34.0 (117) - Nascimbeni et al 2004 144 39.6 (57) -

**3.3. Depth of invasion**

ported nodal disease rates of almost 13%.

Wang et al 2005 159 4.4 (7) 85.7 (6)

Netzer et al 1998 62 8.1 (5) 40.0 (2)

Hassan et al 2005 380 14.7 (56) 23.2 (13)

**Table 3.** Incidence of G3 Poorly Differentiated T1 Colorectal Carcinoma and Incidence of Nodal Involvement. In those studied with a higher incidence of G3 carcinoma, incidence of nodal disease in those carcinomas falls. From[3]

Haggitt's classification is based on the greatest anatomical depth of invasion in pedunculat‐ ed polyps.[5] Haggitt 0 lesions are confined to the mucosa. Haggitt grades 1-3 breach the submucosa within the polyp, and they are confined to the head, neck and stalk of the polyp respectively. Only Haggitt 4 lesions invade past the stalk into the submucosa of the wall. Most authors would agree that only Haggit 4 lesions require further treatment. If adequately excised, Haggitt 0-3 lesions have a risk of recurrence (<1%) which is lower than the predict‐ ed mortality of an oncological resection.[15,16] Conversely, for level 4 lessions, Haggitt re‐

All sessile lesions are Haggitt 4 by definition, but other authors have treated selected sessile lesions with polypectomy alone to good effect. Kudo produced a refinement for sessile pol‐ yps by dividing the submucosa into thirds.[13] This has become known as the Kikuchi clas‐ sification. [2] Lesions confined to the superficial third of the submucosa (called Sm1) demonstrated very low rates of nodal disease and many authors recommend no further

Tominaga et al 2005 155 1.3 (2) 50.0 (1) Kurokawa et al 2005 180 1.1 (2) 50.0 (1) Whitlow et al 1997 59 1.7 (1) 0 (0) Haggitt et al 1985 64 3.1 (2) 0 (0) Geraghty et al 1991 81 2.5 (2) - Suzuki et al 2003 65 3.1 (2) 100 (2) Sakuragi et al 2003 278 2.5 (7) 57.1 (4)

**Differentiated/% (No. of Cases)**

**Incidence of Nodal Involvement / % (No. of Cases)**

> Involved resection margins have been shown to be strongly associated with poor outcomes. These patients have higher mortality, local recurrence and rates of residual disease. In one, all be it small, study 75% of incompletely resected polyps were associated with an adverse outcome.[20] It should be noted that even when incomplete resection is reported, absence of residual disease in the surgical specimen is the rule (94% in one study) rather than the ex‐ ception[21]. This is likely due to diathermy electrofulguration of the remnant.

> The European recommendations state that tumour cells within 1mm of the margin repre‐ sents a positive margin[22], with some authors arguing then >2mm represents the true safe margin[21].

> Incomplete removal is failure of primary therapy and requires further resection. Piecemeal removal of the polyp prevents proper histological assessment and surgery is mandated in all cases. For this reason endoscopic mucosal resection by the strip biopsy method is discour‐ aged for the removal of potentially malignant lesions.

#### **3.5. Lymphatic and vascular invasion**

Lymphatic invasion has been sighted by some authors as an important predictor of nodal disease. Controversy exists however as reported cases are rare and usually associated with poorly differentiated tumours or incomplete resection. Inter-observer variability and the ease of mistaking retraction artefact for lymphatic invasion also make interpretation diffi‐ cult.[6,12]

Lymphatic invasion is usually associated with other high risk factors and in those cases with adverse outcomes, almost invariably so. Many authors would regard its status as an inde‐ pendent risk factor is unclear.[20] However a large multi-centre retrospective study from Ja‐ pan found lymphatic involvement to be highly significant for nodal metastases (odds ratio 4.69 P<0.0001) in a multivariate analysis of risk factors.[17] They also found that in a small number of cases adverse outcomes were seen from cases of lymphatic invasion, despite in‐ vasion being confined to the head of the polyp (Haggit 1).

In the pathology laboratory, the polyp is fixed and sectioned so that it is possible to accurate‐ ly determine the depth of invasion, grade of differentiation, and completeness of excision of

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The margin of excision is not involved. Invasion of the stalk of a pedunculated polyp, by itself, is not an unfavourable prognostic finding, as long as the cancer does not extend to the

The European recommendations, while noting the potential of tumour budding and lym‐ phatic and vascular invasion as prognostic factors, decline to provide a guideline as they

Another perspective is given by Nicholls,[7] who instead offered an algorithmic approach. He differentiates between colonic and rectal polyps. For rectal lesions judged to be adenoma prior to resection he recommends that all poorly differentiated lesions be removed. For co‐ lonic polyps he suggested further resection solely for Haggit 4 polyps (including by defini‐

Systematic review of studies which selected low risk polyps using methodology broadly similar to the American criteria has demonstrated very low rates of nodal recurrence. (See Table 4). Mortality from oncological resection varies greatly by age and co-morbidity but is usually quoted around 3-5%.[26-28] Therefore, for these lesions, the safest course of action is

It should be noted that these criteria take no account of the depth of invasion and that these guidelines would encourage the removal of some lesions that have been safely treated by endoscopy. It may be that they are documenting many of the same characteristics but in a different way. It is not hard to imagine that Sm3 lesions are less likely to be excised with clear margins and are more likely to show poor differentiation. Indeed a large study of sur‐ gically resected sessile T1 colorectal tumours found Sm3 invasion in 68% of G3+4 tumours and on 33% in G1+2 (P=0.001). This study also found tumour grade not to be significant on

Given Japanese experience it maybe be better to refine the criteria for a low risk polyp as

Incomplete resection or other factors preventing adequate histological assessment of the le‐

the carcinoma.

margin of stalk resection.

multivariate analysis.[23]

High grade (G3-4) lesions.

Piecemeal resection

sion.

any polyp lacking all of these features:

Width of invasion greater than 4mm.

Depth of invasion greater than 2mm from *muscularis mucosa*

The cancer is not poorly differentiated.

There is no vascular or lymphatic involvement.

have not been statistically significant in all cases.[22]

tion all sessile polyps) with a depth of invasion >1000 µm.

surveillance rather than further resection.[8,29]

Vascular invasion is also considered difficult to identify, but where present, it is strongly as‐ sociated with nodal disease. Yasuda[18] studied T1 rectal tumours, including specimens from primary resections and resections after polypectomy. The odds ratio for the nodal metastasis with reference to the presence or absence of vascular invasion was 12.023 (3.751– 116.751 p=0.001). Another study of sessile T1 colorectal carcinomas found that vascular inva‐ sion was a significant factor in both univariate and multivariate analysis. However they ad‐ mit that the small number of cases of vascular invasion were found in lesions with deeper Sm3 invasion.[23]

An odds ratio of 7 (2.6–19.2) for lymph node metastasis was reported in the only meta-anal‐ ysis looking specifically at malignant polyps and the presence of vascular invasion.[1] How‐ ever, the same analysis demonstrated no such increased risk in polyps that would otherwise be considered low risk. It may well be that vascular invasion carries no special significance in itself and should not be emphasised in decision making.

#### **3.6. Tumour budding**

Tumour budding is the presence of microscopic islands of tumour cells out ahead of the main front of tumour invasion. At present there is no defined agree standard to reporting the phenomenon but several authors have found it to be highly significant. Yasuda reported an odds ratio of 11.11 (3.64–146.03)[18] for predicting nodal disease but until further study occurs it is difficult to make firm recommendations.

#### **3.7. Location**

T1 rectal tumours seem to be particularly likely to cause nodal disease, especially when lo‐ cated in the lower third.[15,23] However at this stage there have been no studies looking at this relationship specifically in malignant polyps.
