polyp pt1 colorectal cancer

7
Polyp pT1 colorectal cancer Lai Mun Wang Abstract With the introduction of NHS Bowel Cancer Screening Programme, coupled with advances made in endoscopic equipment and techniques, there is a higher detection rate for early pT1 polyp colorectal cancers (CRC). The current clinical trend is towards a conservative approach without surgical resection, if felt that there is successful endoscopic exci- sion and without unfavourable histology parameters. Nonetheless, the further management of malignant polyps, observation or resection, re- mains controversial. For the practising pathologists, these endoscopically removed malig- nant polyp specimens can present unique diagnostic dilemma. In addi- tion, the pathological criteria used lacks adequate evidence base and are not met with good inter-observer agreement that can be applied for pathological substaging of these malignant polyps into high and low risk categories. Keywords early pT1 colorectal cancer; malignant colorectal polyp Introduction The removal of polyp cancers is becoming increasingly frequent since the introduction of bowel cancer screening programmes. The incidence of malignant colorectal polyp is 9.8% of the bowel cancers detected after the first investigation of the first million people screened in England. 1 In 2012, there were 31 CRC cases detected under the NHS Bowel Cancer Screening Programme in the Oxford screening centre and 3 (9.7%) of these were polyp cancers. Malignant polyp by WHO definition for colorectal adenocarcinoma is the invasion beyond the muscularis mucosae into the submucosa. Terminology such as ‘intramucosal adeno- carcinoma’ for the rest of the gastrointestinal tract is therefore unaccepted in the colorectum and these cases are classified as ‘high grade dysplasia’. The recent interest in early polyp CRC stems from the fact that they are now more frequently encoun- tered due to bowel cancer screening programmes, public awareness to CRC and better endoscopic techniques, both in detection and surgical sparing local excision options. There is also a lack of large prospective studies with long term follow-up outcome data to provide satisfactory guidance in the manage- ment of early polyp CRC. Currently the usual and widely accepted practice is dependent on the recommendation from detailed local multidisciplinary team meeting discussion. The role of the pathologist is pivotal and it is mandatory to assess these early pT1 polyp cancers carefully as clinical decision for surveillance only without further intervention, local excision or major surgery which obviously carries a risk of mortality, is dependent on histology. The aim of this review is to provide pathologists with a brief outline on specimen handling and an overview of the issues and dilemma encountered in reporting malignant colorectal polyps. Specimen handling & macroscopy Early polyp CRC cancer is often an incidental finding in an adenomatous polyp and accurate histological assessment is dependent on the quality of the excision specimens. Correct handling of all colorectal polypectomy specimens is therefore vital for subsequent optimal histology reporting. The type of excision specimen has also changed based on advances made in endoscopic techniques. Endoscopic mucosal resection (EMR) is used for en bloc removal of flat and sessile colorectal lesions to allow optimal pathological staging. The endoscopist is likely to provide information on the morphologic appearances and the non-lifting sign after submucosal injection that indicates invasive carcinoma and precludes the procedure. Ideally removal of all neoplastic tissue in a single session is recommended, as subsequent later attempts are associated with an increase risk of complications and incomplete excision due to submucosal fibrosis. 2 For excision of >20 mm lesions, this is usually achieved with a piecemeal technique, that hampers pathological assessment of margin status. To overcome this problem, endoscopic submucosal dissection (ESD) has been developed. This en bloc excision technique for larger lesions provides a better specimen for more accurate histological ex- amination but is associated with higher perforation rate. Guidance on protocol is available by the European Guidelines for Quality Assurance in Colorectal Cancer Screening and Di- agnoses 3 and the Royal College of Pathologists. 4 Local excision specimens are pinned out on a cork board by the resecting gastroenterologist or surgeon. 5 Fixation should be by buffered 10% formalin. Specimens may shrink post fixation and therefore measurements taken after fixation can differ from those prior to fixation and endoscopic measurement. Fixation for at least 24 hours has also been recommended. Macroscopic description should include the size of the polyp especially the adenomatous component if that can be distin- guished readily. Document the type of specimen received: poly- pectomy, EMR, ESD or piecemeal resection. Comment on the presence of a stalk, present or not identified, and if present, re- cord the length in millimetres. Pathologists should avoid using ‘pedunculated’, ‘sub-pedunculated’ or ‘sessile’ for polyp description as these terms refer to endoscopic assessment of polyp type ‘in vivo’ prior to removal. Inking of the excision or polyp base margin requires care and attention to avoid smudging. Some would question if this is necessary because the cautery seen on the glass slide provides the final microscopic margin. For those who prefer to ink the margins, it should be done only if the polyp base can be identified macroscopically, taking into consideration of specimen retraction. The benefit of inking the base margin is that it serves as a quick reference for the margin on microscopic examination. On rare occasions, it may be necessary to make some adaptation if the submucosal excised specimen is pinned or orientated. If there is any concern, the endoscopist ideally should be available to discuss the more ‘complex’ polyp specimens. The entire specimen has to be sub- mitted for histological examination and to exclude incomplete Lai Mun Wang MB BCh MRCP FRCPath is a Consultant Histopathologist at the John Radcliffe Hospital, Oxford, UK. MINI-SYMPOSIUM: PATHOLOGY OF THE LOWER GASTROINTESTINAL TRACT DIAGNOSTIC HISTOPATHOLOGY 19:11 403 Ó 2013 Elsevier Ltd. All rights reserved.

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Page 1: Polyp pT1 colorectal cancer

MINI-SYMPOSIUM: PATHOLOGY OF THE LOWER GASTROINTESTINAL TRACT

Polyp pT1 colorectal cancerLai Mun Wang

AbstractWith the introduction of NHS Bowel Cancer Screening Programme,

coupled with advances made in endoscopic equipment and techniques,

there is a higher detection rate for early pT1 polyp colorectal cancers

(CRC). The current clinical trend is towards a conservative approach

without surgical resection, if felt that there is successful endoscopic exci-

sion and without unfavourable histology parameters. Nonetheless, the

further management of malignant polyps, observation or resection, re-

mains controversial.

For the practising pathologists, these endoscopically removed malig-

nant polyp specimens can present unique diagnostic dilemma. In addi-

tion, the pathological criteria used lacks adequate evidence base and

are not met with good inter-observer agreement that can be applied for

pathological substaging of these malignant polyps into high and low

risk categories.

Keywords early pT1 colorectal cancer; malignant colorectal polyp

Introduction

The removal of polyp cancers is becoming increasingly frequent

since the introduction of bowel cancer screening programmes.

The incidence of malignant colorectal polyp is 9.8% of the bowel

cancers detected after the first investigation of the first million

people screened in England.1 In 2012, there were 31 CRC cases

detected under the NHS Bowel Cancer Screening Programme in

the Oxford screening centre and 3 (9.7%) of these were polyp

cancers. Malignant polyp by WHO definition for colorectal

adenocarcinoma is the invasion beyond the muscularis mucosae

into the submucosa. Terminology such as ‘intramucosal adeno-

carcinoma’ for the rest of the gastrointestinal tract is therefore

unaccepted in the colorectum and these cases are classified as

‘high grade dysplasia’. The recent interest in early polyp CRC

stems from the fact that they are now more frequently encoun-

tered due to bowel cancer screening programmes, public

awareness to CRC and better endoscopic techniques, both in

detection and surgical sparing local excision options. There is

also a lack of large prospective studies with long term follow-up

outcome data to provide satisfactory guidance in the manage-

ment of early polyp CRC. Currently the usual and widely

accepted practice is dependent on the recommendation from

detailed local multidisciplinary team meeting discussion. The

role of the pathologist is pivotal and it is mandatory to assess

these early pT1 polyp cancers carefully as clinical decision for

surveillance only without further intervention, local excision or

major surgery which obviously carries a risk of mortality, is

dependent on histology.

Lai Mun Wang MB BCh MRCP FRCPath is a Consultant Histopathologist at

the John Radcliffe Hospital, Oxford, UK.

DIAGNOSTIC HISTOPATHOLOGY 19:11 403

The aim of this review is to provide pathologists with a brief

outline on specimen handling and an overview of the issues and

dilemma encountered in reporting malignant colorectal polyps.

Specimen handling & macroscopy

Early polyp CRC cancer is often an incidental finding in an

adenomatous polyp and accurate histological assessment is

dependent on the quality of the excision specimens. Correct

handling of all colorectal polypectomy specimens is therefore

vital for subsequent optimal histology reporting.

The type of excision specimen has also changed based on

advances made in endoscopic techniques. Endoscopic mucosal

resection (EMR) is used for en bloc removal of flat and sessile

colorectal lesions to allow optimal pathological staging. The

endoscopist is likely to provide information on the morphologic

appearances and the non-lifting sign after submucosal injection

that indicates invasive carcinoma and precludes the procedure.

Ideally removal of all neoplastic tissue in a single session is

recommended, as subsequent later attempts are associated with

an increase risk of complications and incomplete excision due to

submucosal fibrosis.2 For excision of >20 mm lesions, this is

usually achieved with a piecemeal technique, that hampers

pathological assessment of margin status. To overcome this

problem, endoscopic submucosal dissection (ESD) has been

developed. This en bloc excision technique for larger lesions

provides a better specimen for more accurate histological ex-

amination but is associated with higher perforation rate.

Guidance on protocol is available by the European Guidelines

for Quality Assurance in Colorectal Cancer Screening and Di-

agnoses3 and the Royal College of Pathologists.4 Local excision

specimens are pinned out on a cork board by the resecting

gastroenterologist or surgeon.5 Fixation should be by buffered

10% formalin. Specimens may shrink post fixation and therefore

measurements taken after fixation can differ from those prior to

fixation and endoscopic measurement. Fixation for at least 24

hours has also been recommended.

Macroscopic description should include the size of the polyp

especially the adenomatous component if that can be distin-

guished readily. Document the type of specimen received: poly-

pectomy, EMR, ESD or piecemeal resection. Comment on the

presence of a stalk, present or not identified, and if present, re-

cord the length in millimetres. Pathologists should avoid using

‘pedunculated’, ‘sub-pedunculated’ or ‘sessile’ for polyp

description as these terms refer to endoscopic assessment of

polyp type ‘in vivo’ prior to removal. Inking of the excision or

polyp base margin requires care and attention to avoid

smudging. Some would question if this is necessary because the

cautery seen on the glass slide provides the final microscopic

margin. For those who prefer to ink the margins, it should be

done only if the polyp base can be identified macroscopically,

taking into consideration of specimen retraction. The benefit of

inking the base margin is that it serves as a quick reference for

the margin on microscopic examination. On rare occasions, it

may be necessary to make some adaptation if the submucosal

excised specimen is pinned or orientated. If there is any concern,

the endoscopist ideally should be available to discuss the more

‘complex’ polyp specimens. The entire specimen has to be sub-

mitted for histological examination and to exclude incomplete

� 2013 Elsevier Ltd. All rights reserved.

Page 2: Polyp pT1 colorectal cancer

MINI-SYMPOSIUM: PATHOLOGY OF THE LOWER GASTROINTESTINAL TRACT

excision. A minimum of 3 levels should be looked at on each

block.

Diagnostic pitfalls

Epithelial misplacement

One of the well-recognized pitfalls in the diagnosis of early polyp

CRC is epithelial misplacement. Displacement of adenomatous

epithelium below the muscularis mucosae, may simulate cancer

and be misinterpretated as early submucosal invasion. This is

also synonymous to pseudoinvasion, pseudocarcinomatous

entrapment or adenoma with colitis cystica profunda. This oc-

curs in 2.3e11.4% of polyps.6 Cases commonly occur in the

sigmoid colon, large pedunculated polyps or previously biopsied

lesions. It is unusual in the rectum, unless there has been pre-

vious endoscopic deep biopsy or procedural interference.

Histologically, the submucosal component is of prolapsed

adenomatous epithelium, therefore the glandular architecture

and cytological atypia to dysplasia should resemble the overlying

mucosa. It is usually circumscribed and without an infiltrative

‘advancing’ edge. The misplaced glands are often surrounded by

lamina propria. Larger pedunculated polyps in the sigmoid may

experience torsion related mechanical displacement effect

resulting in glandular distortion, mucin extravasation, fresh

haemorrhage and haemosiderin deposition. Haemosiderin in the

lamina propria is not a reliable criterion as it is found in 90% of

polyps with pseudoinvasion and also in polyps with true inva-

sion, but less frequently.7 The glands may experience cystic

dilatation and the smaller distorted glands may impart an infil-

trating malignant gland appearance or resemble tumour budding

phenomenon at low power magnification examination. On

higher magnification, these glands are often partly lined by

attenuated epithelium with luminal debris including macro-

phages. The mucin leak may also incite histiocytic reaction.

Depending on the age of the polyp, especially for pedunculated/

subpedunculated polyps, there may be duplication of the mus-

cularis mucosae and stromal fibrosis. The latter may be mis-

interpreted as desmoplastic response (Figure 1).

Lamina propria around glands below the muscularis mucosae

is a definitive indicator of pseudoinvasion.7 Diagnosis becomes

more difficult when the submucosal misplaced epithelium ex-

hibits high grade dysplasia. In these circumstances immunohis-

tochemical studies with p53, E-cadherin, MMP-1 and collagen

IV8 and Ki67/MIB1 proliferation marker may be helpful. How-

ever from personal experience when faced with some of the most

challenging polyp CRC, rare cases of malignant transformation

has occurred in these displaced foci and desmoplasia becomes

the most reliable criterion for true invasion. Careful histological

examination is therefore pivotal in these unusual case senarios.

To avoid overcalling pseudoinvasion, it is therefore a

recommendation for all pT1 early polyp cancers to be double

reported.5

Risk stratification

At present, histological parameters such as margin status, lym-

phovascular invasion, tumour grade, tumour budding and level

of submucosal invasion have been used to determine if a ma-

lignant polyp is at low or high risk of adverse outcome.9e14

DIAGNOSTIC HISTOPATHOLOGY 19:11 404

Unfavourable histology for recurrent cancer and lymph node

metastasis is generally accepted as tumour at/or near the margin

(�1.0 mm), and/or grade 3 poor differentiation and/or lymphatic

and/or venous invasion.7 Lymphovascular invasion, tumour

budding and poor differentiation are regarded as indicators of

metastasis and the reported rate of nodal involvement was 21%

with one or more risk factors and fell dramatically to 1.7%

without any risk factors13 (Figures 2 and 3).

Polyp configuration and substaging by depth of invasion:

Haggitt, Kikuchi & Ueno systems

Substaging malignant polyps has historically been dependent on

polyp architecture and morphology, based upon the Haggitt16

and Kikuchi11 systems for pedunculated and sessile polyp CRCs

respectively.

The polyp configuration is taken to be the endoscopic

assessment and must be included on the request form. We often

do not encounter the ‘picture perfect’ Haggitt pedunculated

polyp. Endoscopic techniques in local excision of polyps often

result in augmentation of the polyp configuration. An example is

the injection of saline to create a lift to ensure complete clearance

of adenomatous area can stretch the stalk of a pedunculated

polyp, thus a Haggitt level 4 polyp CRC can potentially appear to

be level 3. The morphology of the excised specimen is dependent

on the level of diathermy transection. If the excision occurs at the

‘neck’ of the pedunculated polyp, it would appear to be ‘sessile’

on the glass slide to the pathologist. If the level of transection is

midway along the stalk, the pathologist often assumes the

margin to be the base of the pedunculated polyp and ‘incorrectly’

comment on the suspicion for level ‘4’ invasion but actually

endoscopically, there is residual polyp stalk in the patient that

has not been submitted. Some polyps may have a short broad

stalk that the endoscopist may find difficult to categorize as

pedunculated or sessile. Therefore infrequently the classification

of ‘sub-pedunculated’ has been designated.

For pedunculated polyp CRCs, the Haggitt system is applied:

level 1 e submucosal invasion and limited to the head; level 2 e

submucosal invasive carcinoma reaches the level of the neck and

this is defined as the junction of the head and stalk; level 3

carcinoma invading any part of stalk and level 4 is submucosal

invasion beyond the level of the stalk but above the muscularis

propria.

For sessile malignant polyps, the Kudo17 or Kikuchi11 method

is used which requires an imaginary division of the submucosal

region into thirds. It is essential for the muscularis propria to be

present, and therefore ideal for TEM (transanal endoscopic

microsurgery) resection specimen. However it is not quite as

practical for endoscopic polypectomy or submucosal resection

specimens when the muscularis propria is usually absent

(Figure 2).

Haggitt’s substaging is only applicable to pedunculated polyp

CRC which for instance only constitutes 16% (141 of 865) of

malignant polyps in Kitajima’s multi-institutional study,18 leav-

ing 84% cases unsuitable. As highlighted earlier, Haggitt’s

method has inherent problems: (a) the endoscopist and pathol-

ogist may not agree on the stalk length; (b) alteration of poly-

pectomy specimen by traction force, retraction of pedicle after

removal and shrinkage after fixation will all affect the final glass

slide appearance of the pedunculated polyp; (c) injection of

� 2013 Elsevier Ltd. All rights reserved.

Page 3: Polyp pT1 colorectal cancer

Figure 1 Pedunculated polyp cancer: (a) The invasive adenocarcinoma is limited to the head, Haggitt level 1. (b) Features of epithelial misplacement such

as haemosiderin and mucin pools may be seen within the adenocarcinoma. These features reflect the mechanical effect/trauma experienced by the polyp

and can create diagnostic difficulty. (c) Desmoplastic stroma in direct apposition to the submucosal dysplastic glands is the most reliable feature for

invasion.

MINI-SYMPOSIUM: PATHOLOGY OF THE LOWER GASTROINTESTINAL TRACT

saline to create a lift in aid of resection can make a sessile polyp

look subpedunculated with an arbitrary ‘neck’ and a level 4

Haggitt polyp CRC resemble a level 3 after stretching the pedicle;

(d) inter-observer disagreement regarding head (level 1) and

neck (level 2) invasion because some pedunculated polyp CRCs

may not have a defined ‘neck’ which also potentially lead to

another question of where does the neck ends and the stalk

begins.

Kikuchi’s study11 by depth of submucosal invasion for 182

sessile polyp CRCs based on Kudo’s17 description of upper (sm1),

Figure 2 The sessile polyp cancer B shown in the previous Figure also possess

differentiation, (c) lymphatic invasion and (d) vascular invasion.

DIAGNOSTIC HISTOPATHOLOGY 19:11 405

middle (sm2) and lower (sm3) third of submucosal invasion

demonstrated 0%, 10% and 25% lymph node metastasis

respectively. Nascimbeni’s study19 also confirmed that sm3 was

a significant predictor of lymph node metastasis (344 sessile

polyp CRCs 23% risk, 35 of 154 ‘sm3’ cases).

From the technical aspect, there are situations when neither

Haggitt nor Kikuchi can be applied due to suboptimal specimen

orientation and/or fragmentation of the material submitted for

pathologic evaluation. Substaging non-pedunculated polyps

without the muscularis propria included in the polypectomy

ed other unfavourable microscopic features: (a) tumour budding, (b) poor

� 2013 Elsevier Ltd. All rights reserved.

Page 4: Polyp pT1 colorectal cancer

Figure 3 Sessile pT1 polyp cancers. The depth and width of submucosal invasion of malignant polyp A is less than polyp B, and would deem to be

suitable for polypectomy without surgical resection in the absence of other bad histological features.

MINI-SYMPOSIUM: PATHOLOGY OF THE LOWER GASTROINTESTINAL TRACT

specimens is less than satisfactory. The European guidelines for

quality assurance in colorectal cancer diagnosis3 suggest using

the more objective approach advocated by Ueno et al.13 where

depth and width of invasive carcinoma beyond muscularis

mucosae is measured. Ueno’s method has the advantage of being

independent of polyp morphology. In their study of 292 early

invasive tumours, polyp CRC with a depth of <2000 mm had a

3.9% risk of lymph node metastasis versus 17.1% if depth was

�2000 mm. If the width of submucosal invasion was <4000 mm,

the risk of nodal involvement was 2.5% but 18.2% for widths

�4000 mm. This more objective and quantitative method of

assessing submucosal invasion has been used in a recent and

largest study of 865 malignant polyps. The investigators found

that in non-pedunculated early submucosal invasive CRC, no

lymph node metastasis is seen in cases with submucosal depth of

<1000 mm.18 They have also proposed the use of the a modified

Haggitt system to minimize subjectivity in the pathologists’

assessment: above the Haggitt line (i.e. level 1 & 2), and below

the Haggitt line (i.e. level 3 & 4). In their further analysis of the

141 pedunculated polyp CRCs, there was no lymph node me-

tastases when invasive component was limited to head (i.e.

above the Haggitt line) with a depth of invasion <3000 mm and

with exclusion of lymphatic invasion bad prognostic factor. A

recent study from Matsuda et al.,20 examined 384 pedunculated

polyp CRCs demonstrated no lymph node metastases when

invasive carcinoma is limited to the head and 6.2% when it is

beyond the Haggitt’s line.

Tumour grade

Grading of the tumour is based on the degree of glandular dif-

ferentiation and this is best appreciated at the 10� objective:

DIAGNOSTIC HISTOPATHOLOGY 19:11 406

Grade 1 e well differentiated intestinal type adenocarcinoma,

more than 95% glandular differentiation or with well-formed

glands with open lumina;

Grade 2 e moderately differentiated intestinal type adeno-

carcinoma, 50e95% glandular differentiation;

Grade 3 e poorly differentiated intestinal type adenocarci-

noma, signet ring cell or mucinous adenocarcinoma, 5e50%

glandular differentiation, solid sheets and absorptive glands

pattern;

Grade 4 e undifferentiated, less than 5% glandular

differentiation.

Most pT1 cancers are often well (grade 1) to moderately

(grade 2) differentiated. Grade 3 poor differentiation is seen in

5.7%e39.6% of polyp CRCs.9,15,19 Although it has not been

shown in earlier studies to be an independent risk factor for

lymph node metastases,9,11 it is associated with the presence of

other unfavourable histology21 and is therefore associated with a

significantly greater incidence of worse outcome.9 When present,

it therefore serves as a useful clue in search of other bad histo-

logical parameters. Unfavourable tumour grade when seen in

combination with vascular invasion and/or tumour budding

carries a 28%e29% incidence of nodal involvement.13

The wide range of the reported incidence of grade 3 in early

invasive CRC suggests considerable inter-observer disagree-

ment.15 Previous reports on inter-observer agreement for

reporting tumour grade have varied from substantial21 to fair.22

Conventional tumour grading in CRC is based on the overall

predominant histologic type and the area of least differentiated

component is omitted. In contrast, the invasive portion of the

polyp CRC, is often not extensive and therefore the tumour grade

in the submucosal deepest invasive portion is recognized as

� 2013 Elsevier Ltd. All rights reserved.

Page 5: Polyp pT1 colorectal cancer

MINI-SYMPOSIUM: PATHOLOGY OF THE LOWER GASTROINTESTINAL TRACT

important for the estimation of risk of nodal involvement.10,23

There is no consensus about the criteria for evaluation. A

recent publication15 proposed an objective assessment for area of

poor differentiation in early T1 invasive CRC. Their method in-

volves scanning under low magnification for the largest area of

poorly differentiated component (POR). After a ‘POR’ field is

selected, this is then examined under 40� objective lens. If POR

fills the entire field it is assigned as level 3. If the 40� objective

field contains 0e9 solid cancer nests, it is designated as level 2

and if 10 or more, it is considered as level 3. In mucinous car-

cinoma, if the tumour including the mucin component fills the

entire microscopic field under 40� objective it is designated

‘MUC’ level 3. Using this method, level 2 and level 3 ‘POR’ and

level 3 ‘MUC’ criteria were considered to be high grade “G3” with

a 27% incidence of nodal involvement versus 3.7% with level 1

‘POR’. The inter-observer variability using this method has not

been investigated.

Vascular invasion

Distant metastasis is based on cancer spread via haematogenous

or lymphatic routes. Therefore definite vascular invasion,

lymphatic or venous is thought to be associated with adverse

outcomes. Being such an important histological parameter, it is

unfortunate that the assessment is subjective with poor inter-

observer agreement even among the experienced patholo-

gists.21,24 Lymphatic space invasion requires the presence of

tumour cells within endothelial-lined channels without signifi-

cant red blood cells9 and venous invasion is tumour emboli

within endothelial-lined channels surrounded by smooth muscle

wall. Lymphatic invasion is best detected at low and medium

power scanning of the submucosa in close proximity to submu-

cosal veins. Distinguishing lymphatic from venous invasion is

frequently difficult. Retraction artifact when reactive fibroblasts

surround tumour cell clusters, mimic lymphatic space invasion

and these foci are mostly situated within the tumour. The inter-

observer variability probably accounts for the controversy and

conflicting results surrounding the predictive value of lympho-

vascular invasion for lymph node metastasis or local recur-

rence.11,12,14,21,25 Lymphatic invasion is often seen in association

with other unfavourable features.26 It has only been shown in

one study that definite vascular invasion is associated with an

adverse outcome in the absence of other unfavourable parame-

ters. Additional serial levels sections or the application of

immunohistochemical studies (D2-40, CD31, CD34) are recom-

mended to improve diagnostic rate of vascular invasion in diffi-

cult cases.3,7

Margin

Figure 4 Margin status: The free tissue edge along the line of diathermy is

the excision margin. Tumour cells are present at the field of diathermy and

is considered to be near the margin.

Identifying the stalk (if present) and the depth of the diathermy

burn is essential as cancer at or near the resection margin is

associated with an adverse outcome. The resection margin of

polypectomy specimen is defined as the actual free edge of the

submucosal connective tissue showing coagulative necrosis or

diathermy effect.9 Tumour at the margin is defined as tumour

cells seen microscopically at this actual transected margin with

diathermy. Definition for tumour near the margin is less

consistent and has been described as cancer cells � 1 mm from

the transected margin,21 cancer within the diathermy27 or within

one high power field of diathermy.28 The risk of relapse is

DIAGNOSTIC HISTOPATHOLOGY 19:11 407

between 0% and 2% in malignant polyps with a margin resection

�1 mm. When the tumour is at or near the margin, the relapse

rate rises to 21%e33%. Favourable results were also seen in the

‘doubtfully complete’ group27 and those <1 mm 13, i. e tumour

near the margin (Figure 4). The assumption was made that

diathermy coagulation would destroy any residual any residual

malignant tissue at the site of polypectomy. Therefore the

‘incomplete’ excision was not a judgement based on histological

evidence alone but a joint decision made with the endoscopist.27

Negative margin in the absence of unfavourable histology the

incidence is 1.7%.

The inter-observer agreement for resection margin status is

substantial for experienced pathologists (k ¼ 0.668).24

Tumour budding

The definition of tumour budding is the presence of isolated

tumour cells, singly or in clusters of <5 cells at the advancing

tumour front (Figure 5). This phenomenon describes the cellular

biology of epithelialemesenchymal interactions. Tumour buds

can be readily detected at low power scanning, set within

distinctive desmoplastic stroma and the morphology of these

cells sometimes appear ‘dedifferentiated’ adopting a sarcomatoid

phenotype. Despite being identified as a prognostic marker, there

is however no accepted consensus on methods of assessment and

the cut-off value.28e33 The diagnostic reproducibility was

significantly improved in early cancer using quantitative and

selective methods of evaluation of tumour bud cells.34 In ma-

lignant polyps, the area of invasive component is small and

therefore a comment on its presence or absence is probably

adequate. A remark on focal or conspicuous tumour buds can

potentially provide useful information. This may be centre-

biased, for example our endoscopist and surgical colleagues

will always expect this to be included in our pathology reports

and form part of the decision making.35

Early colorectal cancer biology

In contrast to advanced CRC, the metastatic potential of early pT1

cancer did not correlate with proliferative activity or DNA ploidy.

� 2013 Elsevier Ltd. All rights reserved.

Page 6: Polyp pT1 colorectal cancer

Figure 5 Tumour budding (20� objective): A tumour bud is defined as a

cluster of <5 tumour cells. They are usually seen at the invasive front and

may have a mesenchymal phenotype, bearing some resemblance to the

pseudopodia of the amoeba.

MINI-SYMPOSIUM: PATHOLOGY OF THE LOWER GASTROINTESTINAL TRACT

In the early stages, it is thought to be dependent on multiple and

sequential alterations of cellecell matrix, cellematrix in-

teractions and cell motility rather than on the derangement of cell

growth. Adhesion molecules, B-catenin and claudins, expressed

by cancer cells are not related to the lymph node status.36 Allelic

loss in the short arm of chromosome 17 have been found

advance CRC in the absence of TP53 mutation, suggesting that

genes in this region is involved in tumourigenesis36 and it has

been hypothesized that transition from early to advanced stages

is by loss of chromosome 17 versus 17p subtelomeric deletions.38

Summary

Careful selection of patients to be treated only by endoscopic

polypectomy is a multidisciplinary approach involving the

endoscopist, pathologist and surgeon and is based on several

considerations. Everyone must be aware of the limitations of

pathological an endoscopic methods.

All polyps should be excised intact to allow optimal technical

preparation for histological examination and pathology reporting

of these pT1 polyp CRCs. Important clinical decisions are made

from our pathology reports of these malignant polyps: surveil-

lance or major resection. However, the evidence base for the

microscopic features such as completeness of excision, high

grade differentiation, presence of lymphovascular invasion,

depth of invasion by Haggitt or Kikuchi classification or by depth

of invasion and tumour budding, used to decide on major

resection for pT1 polyp CRCs remains controversial and is

deemed inadequate. A balance needs to be struck between sur-

gical risk of morbidity and mortality and the benefit in avoiding

local recurrence and death from residual nodal disease. This

would depend on the age and health of the patient and whether it

is screen detected or symptomatic lesion. Population-based

data39 on 2077 patients (64.5% surgery and 35.5% poly-

pectomy) suggests comparable outcomes with polypectomy or

surgical resection. Predictors for polypectomy were older age,

greater comorbidity, no previous polyps, diagnosis in or after

DIAGNOSTIC HISTOPATHOLOGY 19:11 408

2002, left sided lesion, well differentiated tumour and colonos-

copy performed in outpatient setting.

The pathological assessment of malignant polyps is therefore

crucial to the appropriate selection of therapeutic option mini-

mizing individual patient’s risk without ultimately compromising

their chance of cure. Recommended pathology reporting for

polyp CRCs should include comment on margin status, level/

extent of invasion using the Haggitt,16 Kikuchi11 or Ueno13 sys-

tems when applicable, tumour differentiation, lymphovascular

space invasion and tumour budding. A

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Page 7: Polyp pT1 colorectal cancer

Practice points

C The entire colorectal polyp specimen must be submitted for

histological evaluation. Identify the stalk and base of excision

margin of the excision specimen. Document if excision margin

cannot be seen macroscopically

C Additional level sections are useful in circumstances where

there is suspicion for invasion and difficult cases of dis-

tinguishing invasion and epithelial misplacement

C Double reporting of all pT1 polyp CRCs

C Suggested Template for Reporting Polypectomy Specimens

with pT1 polyp CRC:

� Polyp configuration

� Level of submucosal invasion based on Haggitt or Kikuchi

� Depth and width of invasion

� Histological grade

� Vascular invasion

� Tumour budding

� Status of excision margin

C Pathological features that are considered to favour observa-

tion after polypectomy:

� Complete excision from endoscopist’s perspective

� Well differentiated tumour

� Negative for tumour cells at the cautery margin

� No involvement of the stalk in pedunculated lesion

� No lymphatic or venous invasion

� Polyp on a stalk

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