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Annex - Annotations of colorectal lesions

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Authors


Michael Vieth, Germany
Phil Quirke, United Kingdom
René Lambert, IARC
Lawrence von Karsa, IARC
Mauro Risio, Italy



Acknowledgements


Phil Quirke is supported by a programme grant by Yorkshire Cancer Research and by the Experimental Cancer Medicine Centre initiative.



Table of contents


Annex - Annotations of colorectal lesions


7A.1 Introduction

7A.2 Grading of neoplasia

7A.3 Classification of serrated lesions
7A.3.1 Terminology
7A.3.2 Hyperplastic polyp
7A.3.3 Sessile serrated lesion
7A.3.4 Traditional serrated adenoma
7A.3.5 Mixed polyp
7A.3.6 Risk of progression

7A.4 Assessment of T1 adenocarcinoma
7A.4.1 Size
7A.4.2 Tumour grade
7A.4.3 Budding
7A.4.4 Site
7A.4.5 Definition of invasion

7A.5 References


7A.1 Introduction


European Guidelines for quality assurance of pathology in colorectal cancer screening and diagnosis should provide multidisciplinary standards and best practice recommendations that can be implemented routinely across the EU. The authors therefore chose to limit the scope of Chapter 7 and to describe in greater detail in an annex some issues raised in the chapter, particularly details of special interest to pathologists. We also felt that an annex would be the appropriate place to point out new insights not yet widely adopted in Europe in routine practice that may be included in future updates of the Guidelines.



7A.2 Grading of neoplasia


In the present Guidelines, a classification system for colorectal neoplasia has been recommended based on a modified version of the revised Vienna classification (Section 7A.3). For readers not yet familiar with the Vienna classification, it may be helpful to note that it is the first classification to include a clinical recommendation for each neoplastic category. Furthermore, the system was developed to improve diagnostic reproducibility in the interpretation of biopsy specimens and subsequent resection specimens (Schlemper, Kato & Stolte 2000; Schlemper et al. 2000; Schlemper, Kato & Stolte 2001). Strictly speaking, the Vienna classification is only valid for biopsy specimens, since a clinical recommendation should follow. However, to avoid diagnostic inconsistencies, the Vienna classification can be used for resection specimens as well.


In the Vienna classification and hence in the European Guidelines, the term neoplasia rather than dysplasia is used to refer to epithelial tumours associated with chronic inflammatory diseases. Whereas the Vienna classification differentiates between strictly intraepithelial lesions and those involving the lamina propria, the European Guidelines only refer to mucosal neoplasia that may or may not involve the lamina propria (see Section 7A.3). More importantly, the EU Guidelines recommend a two-tiered grading of mucosal neoplasia. The pathologist must decide whether a neoplastic mucosal lesion can be categorised as low or as high grade; for criteria, see Table 7A.1.

As always in neoplasia, the lesion should reach the mucosal surface (no epithelial maturation). Undermining edges of an adjacent carcinoma should be excluded.

The criteria in Table 7A.1 can be weighted. The most important criteria for the diagnosis of carcinoma are the lateral expansion and the number of nuclear rows. In carcinoma, the number of nuclear rows should change within a single gland. High-grade neoplasia is diagnosed when the nuclear rows do not exceed 2-5 nuclei, and the glands do not show lateral expansion. Low-grade neoplasia is diagnosed when the nuclear rows do not exceed 2-3 nuclei (Wolber & Owen 1991; Ajioka et al. 1994; Ajioka et al. 2000).

In histopathology, the entity of carcinoma in situ is generally defined as carcinoma confined to the epithelial layer. In squamous epithelium such an entity can be readily diagnosed. In columnar epithelium, an analogous entity should theoretically also exist. However, to date there are no exact criteria that would permit diagnosis and that would enable the histopathologist to distinguish high-grade intraepithelial neoplasia from mucosal carcinoma that is invasive in the lamina propria. Therefore, throughout the entire gastrointestinal tract, use of the term carcinoma in situ is not recommended for respective lesions in columnar epithelium. The term intramucosal carcinoma is widely introduced in the upper GI tract but not yet in the lower GI tract (see also Section 7A.4.5). We prefer the term mucosal neoplasia to intraepithelial neoplasia as high-grade dysplasia can contain epithelial neoplasia and invasion into the lamina propria according to the TNM classification.


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Table 7A.1: Grading of gastrointestinal neoplasia



Normal Low-grade mucosal / intraepithelial neoplasia (LGMN) High-grade mucosal / intraepithelial neoplasia (HGMN) Invasive Cancer
Glands non-branching villous branching, cribri-form, irregular, solid branching, cribriform, irregular, solid
Expansion up/down till surface till surface lateral expansion
Epithelial differentation up/down top-down and exceptional down-top no maturation towards surface
Goblet cells + + (+) -/(+) retronuclear, atypic
Nuclear rows 1 2-3 2-5 changing
Nuclear size small, basal palisading enlarged vesicular
Chromatin few + ++ ++/+++
Nucleoli none none few small several/ prominent


Modified from (Borchard et al. 1991; Borchard 2000; Vieth & Stolte 2005)

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7A.3 Classification of serrated lesions


7A.3.1 Terminology


The terminology is still under discussion. Serrated lesions can be regarded as a continuous spectrum of colorectal lesions with increasingly more pronounced serrated morphology starting with a hyperplastic polyp and progressing to sessile serrated lesions (SSLs, sometimes referred to as sessile serrated adenomas or sessile serrated polyps), traditional serrated adenomas (TSA), and leading, finally, to adenocarcinoma. Not only the adenomatous component but also other alterations associated with more pronounced serrated morphology may potentially progresses to cancer (see Table 7A.2).

The situation involving sessile serrated lesions is complicated as these lesions only reveal complex structural abnormalities, not adenomatous changes. Therefore, these lesions are neither adenomatous nor are they neoplastic. This is why Kudo et al. (2008) and Lambert et al. (2009) recommended that these lesions no longer be called adenomas; instead they should be referred to as sessile serrated lesions (SSLs). Few of these lesions are reported to rapidly progress to invasive carcinoma, (Oono et al. 2009). Those few cases that do progress rapidly, particularly in the right colon, may be expected to appear more frequently as interval cancers. Traditional serrated adenomas (TSAs), unlike SSLs, do contain adenomatous alterations, albeit sometimes quite subtle (Longacre & Fenoglio-Preiser 1990); they are therefore termed correctly and treatment and surveillance should correspond to that of ade-nomas (see Chapters 8 and 9).

Due to the continuous spectrum in the serrated pathway to colorectal cancer, lesions with combina-tions of serrated morphology and adenomatous cytology can be observed. If more than one histopa-thologic type in the serrated spectrum (HP, SSL, TSA) is discernible in a given lesion, or at least one type in combination with adenomatous tissue, such lesions are referred to as mixed polyps.

The different histopathologic types (e.g. HP and SSL, SSL and TSA, adenoma and SSL, etc.) must be stated in the diagnosis.

Table 7A.2: Continuous spectrum of serrated lesions and possible combinations of histo-pathologic types. Every lesion can give rise to adenocarcinoma. Most of the adenocarcinomas are believed to derive from adenomatous components.



Lesion Neoplasia Risk of malignant transformation

Hyperplastic polyp

no

minimal

Sessile serrated lesion

no

slightly increased but exact data are missing (rapid transformation may be possible in a short time)

Traditional serrated adenoma

yes

increased and suggested worse prognosis than carcinomas arising in sessile serrated lesions

Mixed polyp

yes

increased, but exact data are not available

Adenoma (tubular, villous)

yes

increased, 17 years on average


7A.3.2 Hyperplastic polyp


Hyperplastic polyps (HPs) are composed of elongated crypts (no complex architecture) with serrated architecture in the upper half of the crypt. These polyps usually show some proliferation in the basal (non-serrated) part of the crypts (regular proliferation). Nuclei are small, regular, basal-orientated and lacking hyperchromasia, but with stratification of the upper (serrated) half of the crypts, and without cytological or structural signs of neoplasia.

Differences in the appearance of the cytoplasma permit recognition of three types:


  • Microvesicular type (MVHP);

  • Goblet-cell-rich type (GCHP); and

  • Mucin-poor type (MPHP)

The microvesicular variant greatly predominates, but distinction between types is subject to wide interobserver variation, especially in small lesions, and is not always possible. Currently, routine sub-classification is therefore neither feasible, nor has it been shown to be beneficial.

At the molecular level the microvesicular variant of HP may be the precursor lesion for sessile serrated lesion, and a goblet-cell-rich HP may be the precursor lesion for a traditional serrated adenoma (Torlakovic et al. 2003; O'Brien 2007; O'Brien et al. 2008). Routine distinction of these types is not necessary.



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7A.3.3 Sessile serrated lesion



Sessile serrated lesions are described in the literature as "sessile serrated adenoma" and are often found in the right colon. This is a misnomer since sessile serrated lesions do not contain adenomatous changes (Higuchi & Jass 2004; Kudo et al. 2008; Lambert et al. 2009).

To date, four synonymously used terms exist for these lesions: sessile serrated adenoma (Torlakovic & Snover 1996), superficial serrated adenoma (Oka et al. 2004), Type 1 serrated adenoma (Jaramillo, Tamura & Mitomi 2005), and serrated polyp with abnormal proliferation (Torlakovic et al. 2003).

We recommend using only the term sessile serrated lesion and avoiding use of any other terms for this entity. This recommendation is given in full awareness that sessile serrated lesions do not show histological signs of an adenoma, but, like adenomas, they should be excised if detected during an endoscopic examination. Currently even in the hands of expert GI pathologists the agreement on the sub-types of serrated lesions is only moderate (Wong et al. 2009).

The vast majority of SSLs will not progress to adenocarcinoma. Histological criteria of these sessile, usually larger lesions include an abnormal proliferation zone with structural distortion, usually most pronounced in dilatation of the crypts, particularly near the base. Abundant mucus production is usually also observed as pools of mucin in the lumen of the crypts and on the surface of the mucosa. SSLs are found mainly in the right colon and may be misdiagnosed as hyperplastic polyps. Clues to the correct diagnosis include location and large size. As discussed above, cytological signs of "neoplasia" are lacking, but structural abnormalities are present, i.e. glandular branching (Higuchi & Jass 2004).

Sessile serrated lesions have an elevated serration index and serration in the basal half of crypts with basal dilation of crypts. The epithelium/stroma-ratio is believed to be >50% in SSL. There is crypt branching with horizontal growth (above muscularis mucosae; e.g. T- and L-shaped glands) and often pseudoinvasion into the submucosal layer, rectangular dilation of whole crypts with and without pres ence of mucus, increased number of goblet cells at the base of the crypts, vesicular nuclei with prominent nucleoli and proliferation zone in the middle of the crypts. Currently there is insufficient evidence available in the literature for weighting of these criteria.

A well-oriented polypectomy is mandatory for the identification of such histological features. Correct assessment of the deepest portions of the mucosa is impossible in superficial or tangentially cut lesions (O'Brien 2007; O'Brien et al. 2008).

Further criteria include an often asymmetrical expansion of the proliferation zone into the middle third of crypts. Often mild cytological atypia (slightly enlarged vesicular nuclei, nucleoli) is found without clear signs of neoplasia (dysplasia).

BRAF-Mutations depend on the type and location of lesion (see Table 7A.3).

Other abnormalities include:


  • The majority of SSL and TSA show CIMP and promoter methylation of hMLH1

  • BRAF mutations in 8-10% of all CRC (27-76% of CIMP and sporadic MSI-H CRC)

  • BRAF mutations in the majority of SSL and TSA (also microvesicular variant of HP, especially proximal), but rarely (0-5%) in adenoma. (Toyota et al. 1999; Toyota et al. 2000; Ogino et al. 2006; Jass 2007; Samowitz et al. 2007; Ogino et al. 2007; Shen et al. 2007; Grady & Carethers 2008; Kawasaki et al. 2008; Ogino & Goel 2008; Suehiro et al. 2008; Ogino et al. 2009).

Table 7A.3: Prevalence of serrated lesions with BRAF Mutation: A prospective study of patients undergoing colonoscopy

Lesion Number(n=414)
(% of all lesions)
Proximal location
(% of BRAF mutations)
Distal location
(% of BRAF mutations)
Hyperplastic polyp 120 (29%) 35 (29%) 85 (71%)
Sessile serrated lesion 36 (9%) 27 (75%) 9 (25%)
Trad. serrated adenoma 3 (1%) 2 (66%) 1 (33%)
Mixed polyp 7 (2%) 4 (57%) 3 (43%)
Tubular adenoma 237 (57%) 176 (74%) 61 (26%)
Villous adenoma 11 (3%) 6 (55%) 5 (45%)


Source: modified from (Spring et al. 2006)

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The frequency of sessile serrated lesions in small retrospective series is estimated at 2-11% of all mucosal lesions in the colon (Jass et al. 2006; Carr et al. 2009); between 8% and 23% are misdiagnosed as hyperplastic polyps with an interobserver variation of up to 40% (Torlakovic et al. 2003; Goldstein et al. 2003; Montgomery 2004; Higuchi, Sugihara & Jass 2005).

Table 7A.4: Comparison of proliferative activity in adenoma, hyperplastic polyps, sessile serrated lesion and traditional serrated adenoma.

Ki-67 Adenoma Hyperplastic polyps Sessile serrated lesion
upper 1/3 68.8% 0.1% 1.6%
middle 1/3 48.7% 9.1% 20.3%
lower 1/3 29.6% 60.3% 64.9%


Source: modified from (Higuchi, Sugihara & Jass 2005; Sheridan et al. 2006)

The histological features separating HPs from SSLs constitute a continuous spectrum, and intermingled features can often be seen. This could explain the moderate interobserver concordance (k=0.47) and the overlapping proliferative activity, and may justify establishing semi-quantitative criteria for diagnosis (e.g. >30% of undifferentiated cells) (Sandmeier, Seelentag & Bouzourene 2007; Farris et al. 2008). Only a few immunohistochemical markers (Ki67, Ki67 + CK20, MUC6) have been tested for differentiating HPs and SSAs, and their usefulness in colorectal screening and diagnosis remains to be validated (Torlakovic et al. 2008; Owens, Chiosea & Kuan 2008). At present, such an additional immunohistochemical analysis cannot be recommended (see Table 7A.4).

In all likelihood, lesions formerly interpreted as mixed hyperplastic and adenomatous polyp are, in fact, SSLs complicated by conventional neoplasia (Sheridan et al. 2006). Special care must be taken in such cases to document the respective histopathologic components in such mixed polyps. Sometimes the conventional neoplastic part shows features other than in classical adenomas. The nuclei are prominent, less palisading and smaller than in classical adenomas. It is not clear whether this type of morphology is distinct for serrated lesions and whether any clinical implications can be drawn.

Prospective studies with risk stratification are needed to develop more precise methods of diagnosis and recommendations for classification. Sessile serrated lesions appear to take a long time (average 17 years) to develop into an invasive carcinoma. In contrast, an ill-defined, small subsample of SSLs seems to rapidly progress (Sheridan et al. 2006; Oono et al. 2009). Therefore, SSLs should be completely excised, particularly if they are located on the right side of the colon (O'Brien et al. 2008; Noffsinger 2009).

Diagnosis on a biopsy is not adequate to exclude SSL since the most severe histologic changes might only appear focally within a lesion that otherwise appears to be a hyperplastic polyp (Schreiner, Weiss & Lieberman 2010).

The German guidelines for colorectal cancer (Schmiegel et al. 2008) recommend complete removal and follow-up of SSL similar to adenomas. An intensive surveillance protocol is recommended for sessile serrated lesions (surveillance colonoscopy after 3-5 years subsequent to complete excision of non-neoplastic SSL, after one year following excision of SSL HGIEN (Schmiegel et al. 2008).

The UK guidelines (NHS Bowel Cancer Screening Programme 2007; Williams, Quirke & Shepherd 2007a; Williams, Quirke & Shepherd 2007b; Williams, Quirke & Shepherd 2007c) recommend complete excision but classify these lesions in the same risk category as hyperplastic polyps. The existing evidence base is not definitive as to the level of risk, and follow up decisions should be made locally until more evidence is forthcoming.


7A.3.4 Traditional serrated adenoma

Traditional serrated adenomas show neoplastic crypts with a serrated structure (WHO 2000). Compared to hyperplastic polyps, the most striking diagnostic feature of traditional serrated adenomas are the complex serrated morphology and the eosinophilic, "dysplastic" cytoplasm that still can be identified in cases with invasive adenocarcinoma. These lesions also frequently show BRAF mutations and CIMP with hMLH1.promoter.methylation. Additionally, so-called intraepithelial microacini can be observed in the upper half of the mucosa (ectopic crypt formation). Often these lesions are located in the distal colon and can be found more frequently in elderly female individuals (Longacre & Fenoglio-Preiser 1990; Higuchi & Jass 2004; Torlakovic et al. 2008).


7A.3.5 Mixed polyp

A mixed polyp may contain partially hyperplastic, classical adenomatous or traditional serrated adenoma or sessile serrated lesion components. Rather than a continuous spectrum such lesions most probably represent several evolutionary lines, depending on the order of certain abnormalities in genes such as APC, BRAF and KRAS (O'Brien 2007; O'Brien et al. 2008). It has to be determined whether mixed polyps represent serrated lesions complicated by conventional neoplasia (Snover et al. 2005).

Focal, hyperplastic-like narrowing of the basal region of a few crypts in SSL and the findings of flat sectors or ectopic crypt formation in SSL/TSA (Torlakovic et al. 2008) are examples of combinations of serrated and adenomatous components. However, these features add no information of further diagnostic value; they probably result from the continuous developing nature of serrated lesions. We therefore recommend that the diagnosis of mixed polyp should be restricted to the definition given in Section 7A.3.1. Mixed polyps are serrated lesions in which more than one histopathologic type in the serrated spectrum (HP, SSL, TSA) is discernible in a given lesion or at least one type in combination with classical (unserrated) adenomatous tissue. The different histopathological types must be mentioned in the diagnosis, e.g. mixed polyp (HP and SSL, adenoma and SSL).


7A.3.6 Risk of progression

The vast majority of hyperplastic polyps and serrated lesions will not undergo malignant transformation. Only a fraction, especially in the group of sessile serrated lesions, may progress to rapidly aggressive carcinoma (Spring et al. 2006; Carr et al. 2009).

Hyperplastic polyps rarely progress to carcinoma. A single case report can be found in the literature (Watanabe & Suda 1984) and a second (unpublished) case has been reported in southern Germany. Interestingly, these carcinomas show features of gastric differentiation.

Little evidence is available on which the risk of colorectal cancer associated with serrated lesions other than hyperplastic polyps could be reliably judged. The risk assessment for sessile serrated lesions is not yet defined, but a subset of these lesions appears to give rise to carcinoma often less than a few millimetres in size. In a series of 110 traditional serrated adenomas, 37% exhibited foci of significant neoplasia and 11% contained areas of intramucosal carcinoma (Longacre & Fenoglio-Preiser 1990). Mixed polyps (e.g., HP/TSA/SSL or HP/adenoma) seem to have at least the same rate of progression to colorectal carcinoma as adenomas, and the risk might be higher (Leggett et al. 2001; Hyman, Anderson & Blasyk 2004).


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7A.4 Assessment of T1 adenocarcinoma


Careful assessment in T1 adenocarcinoma is mandatory because a decision is required on local excision or a major operation.


7A.4.1 Size


Firstly, accurate measurement is very important, and measurement must be to the nearest mm (and not rounded-up to the nearest 5 or 10 mm). The maximum size of the lesion should be measured from the histological slide and if the lesion is disrupted or too large, from the formalin-fixed macroscopic specimen. If a biopsy is received it should be stated that size cannot be assessed.


7A.4.2 Tumour grade


Poorly differentiated carcinomas are identified by the presence of either irregularly folded, distorted and often small tubules, or the lack of any tubular formation and showing marked cytological pleomorphism. In the absence of good evidence, we recommend that a grade of poor differentiation should be applied in a pT1 cancer when ANY area of the lesion is considered to show poor differentiation. It should be noted that this is not in accordance with the WHO classification that recommends a certain proportion of lesion showing poor differentiation before diagnosing a lesion as G3. Poor differentiation includes undifferentiated and poorly differentiated as defined by the WHO classification (Washington et al. 2009).


7A.4.3 Budding


Budding describes the biological behaviour of the tumour at the front of invasion (Deinlein et al. 2003). Budding or tumour cell dissociation (Gabbert et al. 1992) can be divided into slight, moderate and marked and is known from the Japanese literature of the 1950s (Imai 1954) and 1990s (Kobayashi et al. 1994).

At this time, evidence is lacking concerning reproducibility of the numerous methods for tumour budding measurement (see Table 7A.5). It is good practice but not mandatory to document the presence or absence of single tumour cells at the front of invasion, and we therefore recommend providing this additional information in the written report with an explanatory comment, as budding has been suggested as a prognostic factor in colorectal cancer (Nakamura et al. 2008; Ogawa et al. 2009; Sy et al. 2010).


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7A.4.4 Site


The site of origin of each specimen should be individually identified by the clinician and reported to the pathologist on the histopathology request form. The pathologist should record this on the proforma. This is important information because the risk of lymph node metastasis from a T1 adenocarcinoma varies depending on the site and size of the lesion (rectum vs. other locations) (Poeschl et al. 2010).


Table 7A.5: Measurement of tumour budding.

Source: modified from (Konishi & Morson 1982; Haggitt et al. 1985; Cooper et al. 1995; Volk et al. 1995; Nascimbeni et al. 2002; Ueno et al. 2004; Nakamura et al. 2008)



Author Year pT Count Magnif. Object. Area (mm2) Classification Cut-off Notes
Ueno 2004 H&E 20X 0,785 negative/positive 5
Ueno 2002 H&E 25X 0,385 <10/>10 10 degree of grading agreement
Ueno 2004 H&E 250 25X 0,385 low (<10)/high (>10) 10
Shinto 2005 IHC:MNF 116 20X low (<10/high (>10) moderate (10-19), severe (>20) identification of cytoplasmic fragments
Shinto 2006 3 IHC:MNF 116 20X low (<10/high (>10) moderate (10-19), severe (>20) scoring of cytoplasmic fragments called now podia
Okuyama 2002 1 and 2 H&E n.a. n.a. n.a. present/absent 1 endoscopically resected tumors were excluded
Okuyama 2003 3 H&E n.a. n.a. n.a. present/absent 1
Okuyama 2003 3 H&E n.a. n.a. n.a. present/absent 1
Prall 2005 IHC:MNF 116 250 0,785 low/high 25 ROC metastatic progression; 0-120 buds range; 14 median 20, 46 mean
Kazama 2006 1 IHC: CAM5.2 and AE1/AE3 n.a. n.a. n.a. present/absent 1
Kanazawa 2007 H&E n.a. n.a. n.a. none/mild/ moderate/marked
Nakamura 2008 H&E n.a. n.a. n.a. None/mild/ =low moderate/markded=high
Choi 2007 2 or more H&E 20X (0-3)/(4-5)/(6-10)/(11-38)
Park 2005 2 or more H&E 20X (0-3)/(4-5)/(6-9)/(10-38) mean intensity: (+/-SD) 6,6+/-5,6
Hori 2005 H&E 200 40X 0,05 5% of the horizontal length of the invasive front
Yasuda 2007 H&E present/absent
Ishikawa 2008 IHC: MNFIIb 400 negative/positive 5



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7A.4.5 Definition of invasion


In columnar epithelium, it is difficult to define the onset of invasive carcinoma and reliably distinguish it from high-grade intraepithelial neoplasia. Criteria such as single tumour cells are more likely to be seen in more advanced carcinomas, but not in early carcinomas. Desmoplastic stromal reactions are also seldom seen in very early carcinomas. However, basal membrane structures are frequently discernible in well-differentiated early carcinomas (Borchard et al. 1991; Borchard 2000; Vieth & Stolte 2005), so that definitions using "invasion through the basement membrane" are incorrect.

The WHO definition of adenocarcinoma in use when the EU Guidelines were developed excluded diagnosis of intramucosal carcinoma in the colon or rectum, in contrast to the accepted WHO definitions for the stomach, oesophagus and small bowel. In the latter cases, a decision on surgical vs. local therapy is made based on respective protocols. Comparable lesions in the colon and rectum are reported as high-grade mucosal neoplasia because a carcinoma in the colon is defined by infiltration of the submucosa according to the WHO classification.

The discussion on this issue among the authors of the pathology chapter in the EU Guidelines reflects, among other things, concern about potential overtreatment of early T1 carcinomas which are detected much more frequently in a screening setting. The clinical management of a lesion where invasion of the lamina propria has occurred is no different from that where high-grade changes are confined to the glands. This legitimate concern as to increased morbidity and mortality due to miscommunication of diagnostic criteria may be dealt with more effectively in the future, as multidisciplinary management of lesions detected in and outside of screening programmes advances. The authors hope that such advances and their effective dissemination will be stimulated by the publication of the new EU guidelines. This, in turn, may lead to revision of the current WHO definition of colorectal adenocarcinoma in a future revision of the WHO classification of gastrointestinal tumours. Pathologists should report on what version of the WHO and TNM classifications their diagnosis is based.

In those cases in which intramucosal colorectal cancer is suspected, and particularly in countries in which this diagnosis is documented in addition to the WHO terminology, explicit comments by the pathologist are recommended. Based on the cytological characteristics of the case, the pathologist should indicate whether local endoscopic or surgical removal is recommended, and the basis for this recommendation should be indicated. This recommendation should be discussed in a multidisciplinary conference prior to surgery. The Japanese criteria for such stratification have been published by Watanabe & Suda (1984). The updated Paris classification based on a workshop in February 2008 in Kyoto (Kudo et al. 2008) permits such subclassification based on improved grouping and explains in detail the grading criteria (Lambert et al. 2009).

The use of the term colonic carcinoma in situ introduced by the TNM system is inadequate because the criteria are too vague and cannot be used for columnar epithelium.

A subclassification of all carcinomas into low risk and high risk based on risk of lymph node involvement should always be undertaken. For exact criteria, please see Chapter 7 and the updated Paris classification (Kudo et al. 2008; Lambert et al. 2009).

Perineural invasion

Perineural invasion (PNI) was recently described as an independent risk factor for colorectal cancer (Liebig et al. 2009a; Poeschl et al. 2010). PNI is significantly associated with high tumour stage, grade and metastases. Furthermore, PNI serves as an independent predictor of disease-free and cancer survival (Liebig et al. 2009a; Poeschl et al. 2010). Recently, an association with other criteria indicating an aggressive course of disease, such as lymphatic vessel permeation, venous invasion, tumour growth pattern and budding (Jass, Love & Northover 1987) were described by Poeschl et al. (2010). Also, it was described that PNI-positive tumours are more likely to be incompletely resected and more likely to progress after Mayo regimen chemotherapy than PNI-negative tumours. Lately Poeschl et al. were able to show that PNI is an additional independent factor for local tumour relapse.

It is recommended to record PNI in routine sections of colorectal cancer. According to recent studies (Liebig et al. 2009a; Liebig et al. 2009b; Poeschl et al. 2010; Marshall et al. 2010) immuno-histochemistry or special stains are not necessary to detect PNI. Prospective studies are needed to show the clinical relevance of PNI, its relationship to other features such as lymphatic and vascular invasion and the benefit of alternative treatment for such more aggressive tumours that are PNI positive.

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7A.5 References


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Ajioka Y, Watanabe H, Kobayashi M, Maeo S & Yoshida M (1994), Macroscopic classification of colorectal (minute) neoplasia., I to Cho, vol. 29, p. 89.

Borchard F (2000), [Forms and nomenclature of gastrointestinal epithelial expansion: what is invasion?], Verh.Dtsch.Ges.Pathol., vol. 84, pp. 50-61.

Borchard F, Heilmann KL, Hermanek P, Gebbers JO, Heitz PU, Stolte M, Pfeifer U, Schaefer HE, Wiebecke B & Schlake W (1991), [Definition and clinical significance of dysplasia in the digestive tract. Results of a meeting of the Society of Gastroenterologic Pathology of the German Society of Pathology 25 November 1989 in Kronberg], Pathologe, vol. 12, no. 1, pp. 50-56.

Carr NJ, Mahajan H, Tan KL, Hawkins NJ & Ward RL (2009), Serrated and non-serrated polyps of the colorectum: their prevalence in an unselected case series and correlation of BRAF mutation analysis with the diagnosis of sessile serrated adenoma, J.Clin.Pathol., vol. 62, no. 6, pp. 516-518.

Cooper HS, Deppisch LM, Gourley WK, Kahn EI, Lev R, Manley PN, Pascal RR, Qizilbash AH, Rickert RR & Silverman JF (1995), Endoscopically removed malignant colorectal polyps: clinicopathologic correlations, Gastroenterology, vol. 108, no. 6, pp. 1657-1665.

Deinlein P, Reulbach U, Stolte M & Vieth M (2003), [Risk factors for lymphatic metastasis from pT1 colorectal adenocarcinoma], Pathologe, vol. 24, no. 5, pp. 387-393.

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Gabbert HE, Meier S, Gerharz CD & Hommel G (1992), Tumor-cell dissociation at the invasion front: a new prognostic parameter in gastric cancer patients, Int.J.Cancer, vol. 50, no. 2, pp. 202-207.

Goldstein NS, Bhanot P, Odish E & Hunter S (2003), Hyperplastic-like colon polyps that preceded microsatellite unstable adenocarcinomas, Am.J.Clin.Pathol., vol. 119, no. 6, pp. 778-796.

Grady WM & Carethers JM (2008), Genomic and epigenetic instability in colorectal cancer pathogenesis, Gastroenterology, vol. 135, no. 4, pp. 1079-1099.

Haggitt RC, Glotzbach RE, Soffer EE & Wruble LD (1985), Prognostic factors in colorectal carcinomas arising in adenomas: implications for lesions removed by endoscopic polypectomy, Gastroenterology, vol. 89, no. 2, pp. 328-336.

Higuchi T & Jass JR (2004), My approach to serrated polyps of the colorectum, J.Clin.Pathol., vol. 57, no. 7, pp. 682-686.

Higuchi T, Sugihara K & Jass JR (2005), Demographic and pathological characteristics of serrated polyps of colorectum, Histopathology, vol. 47, no. 1, pp. 32-40.

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