Colorectal Tumours the Histology Report G Lanza Et Al

Digestive and Liver Disease 43S (2011) S344–S355

Colorectal tumors: The histology report

Giovanni Lanzaa,*, Luca Messerini b, Roberta Gafà c, Mauro Risiod

On behalf of the “Gruppo Italiano Patologi Apparato Digerente (GIPAD)” and of the “Società Italianadi Anatomia Patologica e Citopatologia Diagnostica”/International Academy of Pathology,

Italian division (SIAPEC/IAP)aDepartment of Experimental and Diagnostic Medicine, Section of Anatomic Pathology, University of Ferrara, ItalybDepartment of Medical and Surgical Critical Care, Section of Pathological Anatomy, University of Florence, Italy

cDepartment of Imaging Diagnostics and Laboratory Medicine, Anatomic Pathology, Azienda Ospedaliero-Universitaria of Ferrara, ItalydUnit of Pathology, Institute for Cancer Research and Treatment, Candiolo-Torino, Italy

Abstract

Epithelial colorectal tumors are common pathologic entities. Their histology report should be comprehensive of a series of pathologicparameters essential for the correct clinical management of the patients. Diagnostic histologic criteria of adenomatous, serrated, inflammatory,and hamartomatous polyps and of polyposis syndromes are discussed. In addition, the pathologic features of early and advanced colorectalcancer are described and a checklist is given. Finally, molecular prognostic and predictive factors currently employed in the treatment ofcolorectal cancer are discussed.© 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Keywords: Adenocarcinoma; Adenoma; Colorectal; GIPAD report; KRAS; Microsatellite instability; Polyposis syndromes; Serrated polyps

1. Introduction

Epithelial tumors of the colon and rectum are frequentpathologic entities and deserve to be histologically reportedwith accuracy and completeness. Colorectal cancer is one ofthe commonest malignant tumors worldwide and representsin Italy the second cause of cancer-related death. Epithelialpolyps of the large intestine are often sampled or removed en-doscopically. Adenomas are the precursors of most colorectalcancers, whereas about 15% of colorectal carcinomas developthrough an alternative morphogenetic pathway from serratedpolyps.

Correspondence to: Prof. Giovanni Lanza, Department of Experimental andDiagnostic Medicine, Section of Anatomic Pathology, University of Ferrara,Via Fossato di Mortara 64/b, 44100 Ferrara, Italy.

1590-8658/$ – see front matter © 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

2. Polypoid and nonpolypoid colorectal adenomas [1–3]

Polypoid adenoma is a circumscribed lesion projecting intothe bowel lumen composed of mucosal neoplasia, encompass-ing categories 3–4 of the revised Vienna classification (i.e.:low and high grade dysplasia/intraepithelial neoplasia, non in-vasive carcinoma/carcinoma in situ, intramucosal carcinoma)[2] (Table 1).

Polypoid adenoma consists of the peduncolated and sessile(broad base) morphology, whereas nonpolypoid adenomasinclude flat and depressed adenomas, that are histologicallydefined as those in which the thickness of the lesion is lessthan twice that of the height of the adjacent normal colonicmucosa, or even thinner than the surrounding mucosa. Thehistological identification of nonpolypoid lesions needs thecomplete endoscopical removal and the well-oriented paraffinembedding of tissue samples. The endoscopy-based Parisclassification compares the height of the lesion to that ofclosed cups of a biopsy forceps (2.5 mm) and allows to

G. Lanza et al. / Digestive and Liver Disease 43S (2011) S344–S355 S345

Table 1Grading of superficial colorectal neoplasia

WHO 1989 WHO 2000 Revised Vienna Classification

Category 1: Negative for neoplasia

Category 2: Indefinite for neoplasia

Low grade dysplasia (mild and moderatedysplasia)

Low grade intraepithelial neoplasia (mild andmoderate dysplasia)

Category 3: Mucosal low grade neoplasiaLow grade adenomaLow grade dysplasia

High grade dysplasia (severe dysplasia)

Carcinoma in situ (carcinoma in situ,intramucosal carcinoma)

High grade intraepithelial neoplasia(severe dysplasia, adenocarcinoma in situ)

Intramucosal neoplasia(intramucosal adenocarcinoma)

Category 4: Mucosal high grade neoplasia4.1. High grade adenoma/dysplasia4.2. Non-invasive carcinoma (carcinoma in situ)4.3. Suspicious for invasive carcinoma4.4. Intramucosal carcinoma

Invasive carcinoma (spreading into thesubmucosa)

Invasive carcinoma (invasion into thesubmucosa)

Category 5: Submucosal invasion by carcinoma

distinguish sessile polypoid lesions (Type 0-Is, protrudingabove 2.5 mm) from the nonpolypoid ones (Type 0-IIaprotruding below 2.5 mm), the distinction being crucial giventhe highly significative differences in cancerization ratesbetween nonpolypoid and sessile polypoid (adenomatous andserrated) lesions [4]. The histological report for nonpolypoidlesions should therefore confirm the adenomatous nature ofthe lesion, determine the degree of neoplasia, exclude invasionand, when possible, state the likelihood of consistency withthe endoscopical typing according to the Paris classification.

2.1. Gross specimens and handling

Size should be carefully measured identifying the max-imum diameter of the adenomatous component, length anddiameter of the stalk, if present. The resection margin shouldbe identified, described, and sliced in a way that allowscomplete assessment. Polyps need to be sliced and totallyembedded. At least three levels should be cut and H&Estained through each block.

2.2. Pathology report

Since size, villous histology, and grade of neoplasia rep-resent the most important determinants for the malignantprogression of colorectal adenomas, as well as for the risk ofdevelopment of synchronous and/or metachronous large bowelneoplasia, histological report should focus on all of them.

2.3. Size [Diagnostic strength: Level 2]

The size of adenomas influences surveillance intervals, andan accurate measurement by the pathologist to the nearestmillimeter is required. Grossly, measurement of the size canbe done from the formalin-fixed specimen, excluding the stalk,if present. Microscopy allows the precise measurement of theadenomatous sectors of polyps, excluding non neoplastictissues. When the two measurements significantly differ,microscopic size should be made explicit in the report andauditable.

2.4. Villous histology [Diagnostic strength: Level 3]

Villous structures form at least 80% of villous adenomas,and more than 20% of tubulovillous adenomas. Villi canassume different morphologies, all of them equally contribut-ing to villous histology of an adenoma: classical villi (long,slender, finger-like processes), palmate villi (leaf-like, broad,branched processes), foreshortened villi (isolated, slender out-growths). The presence of at least one identifiable villusin polyp biopsies or fragments deserves to be reported as“predominantly tubular histology”.

2.5. Grade of neoplasia [Diagnostic strength: Level 3]

Severity of both architectural (crypt branching and bud-ding, complex glandular crowding, intraluminal papillarytufting) and cytological features (loss of cell polarity anddifferentiation, nuclear stratification, enlarged and roundednuclei with nucleoli) distinguish mucosal low grade neoplasia(Category 3, equating low grade dysplasia) from mucosal highgrade neoplasia (Category 4.1, equating high grade dysplasiain older systems) (Table 1). Only one or two glands withhigh grade dysplasia and identifiable at low power exam-ination are needed to classify an adenoma as high grade.Trauma, erosion, prolapse and bleeding, mainly occurring inthe superficial portions of polyps, elicit reparative changesin the adenomatous epithelium (loss of polarity and nuclearstratification), mimicking high grade neoplasia, but these arenot to be overinterpreted as such. Cribriform or solid pat-tern of epithelial growth consistent with carcinoma in situand invasion by the neoplastic epithelium into the laminapropria or muscularis mucosae consistent with intramucosalcarcinoma are included (categories 4.2 and 4.4, respectively)within the spectrum of mucosal high grade neoplasia and assuch reported.

S346 G. Lanza et al. / Digestive and Liver Disease 43S (2011) S344–S355

3. Cancerized adenoma, malignant polyp (pT1 colorectalcancer) [3]

Neoplastic invasion into the submucosa through the mus-cularis mucosae (Category 5 in accordance with the revisedVienna Classification) is diagnostic of cancerized adenoma[Diagnostic strength: Level 3]. Colonic intramucosal carci-noma behaves like a benign adenoma and for this reasonpolyps harbouring “in situ” or “intramucosal” cancer (Cate-gories 4.2 and 4.4, respectively) are not generally regardedas “malignant” polyps and classified as high grade dys-plasia, high grade intraepithelial neoplasia or mucosal highgrade neoplasia (Table 1). Cancerized adenomas representthe earliest form of clinically relevant colon cancer in mostpatients. Invasion of the submucosa, in fact, opens the way tometastasis via the haematogenous and lymphatic routes, andthe choice between surveillance and major surgery when anendoscopically removed polyp is found to be an ACIC willhinge on its metastatic potential, taking into account that postoperative mortality (within 30 days) ranges from 0.6 to 4.4%in T1 cancers. At present, histopathologic parameters alonedetermine whether a high (35%) or low (7%) risk of nodalmetastases exists [5–8]. Histologic risk factors – namely posi-tive resection margin, poor differentiation of cancer, vascularinvasion and tumor budding – do not only predict lymph nodedisease rate but also distant metastasis and mortality rates.

3.1. Carcinoma grading [Diagnostic strength: Level 3]

Histologic grade should be in accordance with the systemused in advanced colorectal cancer and distinguish well/moderately (low grade) from poorly differentiated (highgrade) tumors. It is based on the worst area, independentlyfrom its extension. An anaplastic component (even in the formof small, single or scattered foci) should be identified, as itsoccurrence strongly correlates with the risk of lymph nodemetastases. Signet ring cell carcinoma should be graded aspoorly differentiated. Tumor budding at the front of invasionshould not influence carcinoma grading and should be scoredseparately (see below).

3.2. Vascular invasion [Diagnostic strength: Level 2]

Lymphatic invasion requires the presence of cancer cellswithin endothelial-lined channels or spaces, distinguishingsuch features from retraction artefacts. Venous invasion isdefined as tumor emboli within endothelial-lined channelssurrounded by a smooth muscle wall. Uncertainty in theassessment (presence vs absence) of neoplastic vascularinvasion, even after the examination of serial and deeperroutinely H&E stained sections, should be reported. Evidenceis lacking for the additional use of immunohistochemistry indetecting vascular invasion.

3.3. Margin involvement [Diagnostic strength: Level 3]

A negative deep (basal) margin is reported in the absenceof cancer within the diathermy and one high-power fieldfrom diathermy, or more than 1 mm from the actual marginof resection The presence of adenomatous tissue in thelateral mucosal resection margin should also be independentlyreported as an indication for further endoscopic treatment.

3.4. Tumor budding [Diagnostic strength: Level 2]

An isolated single cancer cell and a cluster composedof fewer than 5 cancer cells are defined as “budding” foci.Although several studies have shown that tumor buddingis independently associated with lymph node and distantmetastasis as well as shorter disease free and overall survivalin colorectal cancer, there is no consensus with regard to theassessment methods and cut-off values.

Due to the usually small dimension of the submucosal in-vasive front in cancerized adenomas, tumor budding should beassessed in the area where the highest activity is identified onH&E, reserving immunohistochemistry for the better assess-ment of this feature. Awaiting the results from reproducibilitystudies, a quantitative, two-grade system (low vs. high grade)is advisable, counting tumor buds (< or ≥10) within a 0.385mm2 area using a ×25 lens.

3.5. Microstaging [Diagnostic strength: Level 2]

The level of submucosal invasion, assessed as Haggitt lev-els I–IV in peduncolated polyps and as sm1–3 Kikuchi levelsin sessile polyps, is important in predicting the outcome ofcancerized adenomas. On the other hand, cancerized adeno-mas with slight submucosal invasion to the depth of 200–300micrometers are very unlikely to have metastatic lymph nodesand the quantitative measurements of both depth (< or >2000micrometers) and width (< or >4000 micrometers) of thecancerous submucosal invasion are strongly indicative of thenodal involvement and worthy reporting. In this setting therough estimate of the ratio of adenomatous to carcinomatoustissue is meaningful, indicating the prevalence of the poten-tially metastatic cancerous tissue within the polyp, the risk oflymph node metastasis being likely high (even in the absenceof other risk parameters) in pT1 polypoid adenocarcinoma,consisting entirely of cancer without adenoma.

4. Serrated polyps [3,9,10]

Epithelial serration, namely the saw-toothed outline de-rived from infolded epithelial tufts in the crypt and inthe luminal surface can be found in several histotypes ofcolorectal polyps. Transient serration associated with hyper-proliferation can be seen in inflammatory polyps, above allof myoglandular type. Steady serration is displayed in thecommon hyperplastic polyps of the large bowel and, coupledwith focal or diffuse epithelial neoplastic changes, in serrated


adenomas and mixed polyps. Furthermore, cell maturationand differentiation are altered in serrated epithelium, particu-larly in the mucus-producing process, so that abnormal gobletcell, microvesicular, and mucus-poor cell components can befound allowing the identification of different cytotypes ofserrated polyps: these, however, seem unrelated to differentrisks of tumor progression.

4.1. Hyperplastic (metaplastic) polyps [Diagnostic strength:Level 3]

Epithelial serration together with minimal architecturalchanges, and without cytological atypia are the diagnosticfeatures of hyperplastic polyps of the large bowel. They aresmall-sized (0.2–0.5 cm) mucosal bumps of the sigmoid colonand rectum, consisting of straight, parallel, slightly elongatedcrypts lined by serrated epithelium in the intermediate andupper third, and by undifferentiated cells in the lower third.The nuclei are round or oval and located at the base with littleor no stratification.

4.2. Sessile serrated adenomas (SSA)/sessile serrated polyps[Diagnostic strength: Level 2]

SSA are mainly right-sited, large-sized (>1 cm) sessileserrated lesions displaying patchy or diffuse distorsions oftissue organization: branching of crypts, serration of foveolarcell phenotype at the base of the crypt, dilatation at the baseof the crypt, horizontal crypt growth [11]. Most findings areonly suggestive for SSA, and are localized in the deepersectors of the mucosa and require well-oriented samples foridentification. Subtle nuclear changes, when present, are focaland include small prominent nucleoli, open chromatin, andirregular contours. Frankly dysplastic nuclear abnormalities,indicative of the initial transition toward traditional serratedadenomas should be reported, in terms of extension andneoplasia grade, in order to manage patient surveillance.Intermingling and/or intermediate features of SSA and hy-perplastic polyps can often be seen in the same histolgicalsection, impairing diagnostic reproducibility. The term “ses-sile serrated polyp” has therefore been suggested for equivocallesions and even as a synonym of SSA, considering the im-proper use of “adenoma” for lesions lacking true neoplasticchanges.

4.3. Traditional serrated adenomas (TSA) [Diagnosticstrength: Level 2]

Nuclear (elongated, hyperchromatic, stratified nuclei) andcytological frankly dysplastic features are seen within theserrated epithelium, besides architectural changes and are di-agnostic for TSA [12]. Rapid and protuberant growth parallelsnuclear dysplasia and, grossly, TSA can be indistinguishablefrom villous or tubulovillous colorectal adenomas.

4.4. Mixed polyps [Diagnostic strength: Level 2]

In these polyps one or more serrated components (hyper-plastic, SSA, TSA) are associated and/or intermingled withclassical adenomatous tissue (tubular, tubulovillous and vil-lous). Extension and grading of neoplastic sectors should beexhaustively described in the diagnosis, in order to supportclinical decision making.

5. Inflammatory polyps [13]

Inflammatory polyps are defined as mucosal elevationsresulting from an inflammatory process. They may occur inpatients with inflammatory bowel disease (IBD), as well as inpatients with other forms of colitis, such as infectious colitis,ischemic colitis, or diverticulitis. They may be also inducedby a mucosal trauma due to an inappropriate peristalsis andin such cases are defined as mucosal prolapse-related inflam-matory polyps. Different entities such as inflammatory cappolyp, colitis cistica profunda and inflammatory myoglandu-lar polyp are considered to belong to the mucosal prolapsesyndrome. Inflammatory polyps do not show an increased riskof neoplastic transformation.

Inflammatory polyps may be sessile or pedunculated, andtheir gross appearance varies from rounded lesions to finger-like projections (filiform polyps, usually associated with IBD).They may be single or multiple and their size generally rangesfrom few mm to 2 cm; sometimes, they may be extremelylarge (“giant” inflammatory polyps) and can cause intestinalobstruction.

5.1. Histological features [Diagnostic strength: Level 3]

The lamina propria shows an intense inflammatory cellinfiltrate and contains dilated and branched colonic crypts;neutrophilic cryptitis and crypt abscess may be prominent.The colonic surface epithelium and the colonic crypts mayshow both epithelial damage and regeneration. Intense vascu-lar congestion and hemorrhage may also be present. Mucosalprolapse-related inflammatory polyps show additional histo-logical features such as thickening and vertical extension ofthe muscularis mucosae toward the lamina propria.

5.2. Differential diagnosis [Diagnostic strength: Level 2]

The differential diagnosis between reactive epithelialchanges and epithelial dysplasia or neoplasia is the mainpotential pitfall that can occur in evaluating inflammatorypolyps. The regenerating epithelium usually shows maturationtoward the surface while dysplastic or neoplastic epitheliumdo not show surface maturation. Moreover, the presence of aninflammatory background should be carefully considered toavoid an overdiagnosis of dysplasia or neoplasia, particularlyin patients with IBD.

Inflammatory polyps may contain bizarre stromal cells,that may be mistaken for a sarcoma (“pseudosarcomatous”


change). The location of these cells underneath areas ofulceration, the presence of an inflammatory infiltrate togetherwith the absence of atypical mitoses can help in the differen-tial diagnosis. Inflammatory polyps may also mimic juvenilepolyps, since the histological features of both are very similar;the clinical data can help in the distinction between these twotypes of polyps.

6. Hamartomatous polyps and polyposes

Hamartomatous polyps are characterized by a disorganizedovergrowth of tissues native to the anatomic area in whichthey arise. They may occur as solitary polyps or in the contextof polyposis syndromes, and are defined by their histology.

6.1. Solitary juvenile polyp (JP)

Most JPs are located in the distal large intestine and theirsize is generally less than 1–2 cm; their surface is smooth andlobulated and they are usually pedunculated. Rectal bleedingis the most frequent symptom; sometimes autoamputation ofthe polyp can occur. Solitary JPs have no increased risk ofmalignancy.

JP is composed of an expanded lamina propria with irregu-lar glands that are often cistically dilated. The lamina propriacontains a variable amount of inflammatory cells but there isno proliferation of smooth muscle. JP is the most frequenthamartomatous colorectal polyp, and is especially commonbefore 10 years of age; however, it may occur also in adults.

6.2. Juvenile polyposis [14]

The polyps are histologically similar to solitary JPs.Juvenile polyposis should be suspected when three or moreJPs are found; however the diagnostic criteria for Juvenilepolyposis are the following: five or more juvenile polypsof the colorectum and/or juvenile polyps throughout thegastrointestinal tract and/or any number of juvenile polypswith a family history of Juvenile polyposis.

There are three types of Juvenile polyposis: (1) Juvenilepolyposis of infancy, that is usually fatal from non-neoplasticconditions; (2) Juvenile polyposis coli, that shows an in-creased risk of colorectal cancer; (3) Generalized Juvenilepolyposis, which shows an increased risk of development ofgastrointestinal carcinomas.

Most patients with Juvenile polyposis show mutations ofthe SMAD4/DPC4 gene. Polyps closely resembling juvenilepolyps are found in other conditions such as Cowden disease,Bannayan-Riley-Ruvalcaba syndrome and Cronkhite-Canadasyndrome. The first two syndromes are related to inher-ited mutation of the PTEN gene, whereas Cronkhite-Canadasyndrome is a non-hereditary gastrointestinal polyposis ofunknown etiology. Patients with these syndromes show gas-trointestinal multiple polyps, but they may also have extra-gastrointestinal clinical manifestations as well as an increasedrisk of malignancy.

6.3. Peutz-Jeghers syndrome [15]

Peutz-Jeghers polyps mainly occur in the small bowel,and less frequently in the large bowel and the stomach.They are variable in size, being sessile or pedunculated.They are generally multiple, but solitary Peutz-Jeghers typepolyps have been described. Mucocutaneous hyperpigmenta-tion around the mouth, eyes, perianal area, and on the fingersoften precede gastrointestinal manifestations. The diagnosisof Peutz-Jeghers syndrome is based upon clinical findingsand the histological appearance of the polyps [Diagnosticstrength: Level 3]. The incidence of gastrointestinal canceras well as extra-gastrointestinal neoplasms in Peutz-Jegherssyndrome is greater than in the normal population [16]. Mu-tations of the LKB1/STK11 gene have been found in nearly60% of affected patients.

The main histological feature is the presence of arborizingbands of smooth muscle, derived from muscularis mucosae,that are covered by normal or hyperplastic glandular epithe-lium. Epithelial misplacement into the intestinal wall may bepresent and may mimic invasive adenocarcinoma. It can berecognized by normal differentiation of the epithelium, lackof stromal reaction and haemosiderin deposition.

7. Adenomatous polyposis [17]

Familial adenomatous polyposis (FAP) and its variant syn-dromes (Gardner syndrome and Turcot syndrome) are differ-ent phenotypic manifestations caused by germline mutationsof the adenomatous polyposis coli gene. FAP is characterizedby hundreds of adenomatous polyps in the large bowel, thatgenerally begin to emerge in the second decade of life. Ifadenomas are not removed, colorectal cancer is inevitable,since the penetrance of the disease is very high, reachingnearly 100%. [Diagnostic strength: Level 3]

Extracolonic manifestations associated with FAP are: up-per gastrointestinal adenomas and adenocarcinomas, adeno-carcinoma of the ampulla of Vater, gastric fundic glandspolyposis, desmoid tumors, central nervous system tumors,cancer of the thyroid, hepatoblastoma, hypertrophy of theretinal pigment epithelium, osteomas, epidermoid cysts, anddental abnormalities.

Duodenal cancer and desmoid tumors are the main causesof death in FAP patients treated with prophylactic colectomy.

Attenuated familial adenomatous polyposis (AFAP) [18] ischaracterized by multiple adenomas of the colon. In thissyndrome the number of adenomas is lower than in classicalFAP and it ranges from 2 to 100, averaging around 20–30adenomas, with prominent variations among family members.[Diagnostic strength: Level 3]

AFAP is associated with germline mutations of the APCgene in only a small proportion of cases (approximately 10%).Furthermore, adenomas are frequently flat and often localizedin the proximal colon. Extra-colonic manifestations may ornot be present, but upper gastrointestinal lesions are generally


present. AFAP patients have a high risk of colorectal cancer.These patients develop colorectal cancer 10 years earlier thanindividuals with sporadic colorectal cancer, but 15–20 yearslater than patients with classical FAP.

MUTYH-associated adenomatous polyposis (MAP) [19]. Mul-tiple adenomas can also occur in a subset of APC mutation-negative patients. These patients harbor germline mutationsin the repair gene MUTYH (MYH). The number of ade-nomas ranges from 15 to more than 100. These patientspresent a very high risk of developing colorectal cancer.Furthermore, the incidence of extra-colonic tumors, especiallyduodenal cancer, is higher than that of the general population.[Diagnostic strength: Level 3]

8. Hyperplastic polyposis (HP) [20]

The following criteria have been proposed to diagnose HP:1) at least five histologically diagnosed hyperplastic polypsproximal to the sigmoid colon of which two are greater than10 mm in diameter, or 2) any number of hyperplastic polypsoccurring proximal to the sigmoid colon in an individualwho has a first degree relative with HP, or 3) more than 30hyperplastic polyps of any size, but distributed throughout thecolon. [Diagnostic strength: Level 2]

Individuals with HP develop colorectal cancer on a back-ground of multiple polyps that are mainly hyperplastic polyps.However, SSAs, TSAs and mixed polyps can also be foundin these patients; therefore it the suggestion is to consider alltypes of serrated polyps in diagnosing HP.

9. Surgically resected colorectal cancer

Careful pathologic reporting of colorectal cancer resectionspecimens is of paramount importance to determine theprognosis and to plan the treatment of individual patients.In addition, pathologists have an increasing role in theidentification of hereditary tumors and in prediction oftumor response to specific type of therapy. There is clearevidence that the use of checklists improves the standard ofcolorectal cancer reporting and therefore their use is stronglyrecommended (Table 2). Pathologic parameters that needto be absolutely reported on the basis of their prognosticvalue or that are required for therapy will be discussed. Inaddition, molecular prognostic and predictive factors recentlyintroduced in the clinical setting will be examined.

9.1. Histologic type [1,21] [Diagnostic strength: Level 2]

Histologic type should be evaluated according to the WHOclassification as follows [1].• Adenocarcinoma• Mucinous adenocarcinoma• Signet-ring cell carcinoma• Small cell carcinoma

• Squamous cell carcinoma• Adenosquamous carcinoma• Medullary carcinoma• Undifferentiated carcinoma

Most colorectal carcinomas (nearly 85%) are usual ade-nocarcinomas, and 10 to 15% are classified as mucinousadenocarcinomas (mucinous component >50%). The othertumor types are rare. Tumor typing does not have majorprognostic relevance, but signet-ring cell carcinoma and smallcell carcinoma have been demonstrated to have adverse prog-nostic significance independent of stage. Notwithstanding,the various subtypes of colorectal cancer are characterizedby different genetic alterations and probably more detailedprognostic information will be obtained in the future by anintegrated histologic and molecular classification [22].

With respect to usual adenocarcinomas, mucinous tumorshave a greater tendency to develop peritoneal metastases, toinvade adjacent organs and to show extensive lymph nodeinvolvement [21]. Mucinous carcinomas are evenly distributedin the right and left colon and more frequently than commonadenocarcinomas harbour defects in the DNA mismatch repair(MMR) system [23]. Mucinous adenocarcinomas differ fromcommon adenocarcinomas also on the basis of other molec-ular features, such as higher frequency of CIMP phenotypeand rare p53 mutations, suggesting that these tumors reallyrepresent a distinct pathologic entity [22]. A less favourableclinical outcome for patients with mucinous cancers has beendemonstrated in many studies but not in others and theprognostic significance of the mucinous phenotype remains atpresent undetermined. In addition, the prognosis of mucinouscarcinomas with microsatellite instability (MSI) has been re-ported to be better than that of microsatellite stable mucinouscarcinomas.

Signet-ring cell carcinoma is composed of at least 50%signet-ring cells. It represents less than 1% of all colorectalcarcinomas and occurs more frequently in individuals youngerthan 50 years of age and in patients with ulcerative colitis.Histologically, colorectal signet-ring cell carcinomas differfrom gastric ones for the common presence of abundantextracellular mucin and infrequent diffuse tissue infiltration.Signet-ring cell carcinomas are often at an advanced stageat diagnosis and are associated with a worse outcomethan common adenocarcinomas. Peritoneal carcinomatosisdevelops in the majority of patients who die of the disease.About 30% of signet-ring cell carcinomas display defect ofMMR function; however, MSI status does not appear to be asignificant predictor of survival in this tumor type.

Small cell carcinomas are histologically identical to thosearising in the lungs. They often appear to develop within anadenoma and usually express neuroendocrine markers. Partof the cases show a distinct adenocarcinomatous component.Most patients have distant metastases at diagnosis and theprognosis is very poor. Large cell poorly differentiatedneuroendocrine carcinomas may also occur in the colorectumand their clinical behaviour is similar to that of small cellcarcinomas.

Medullary carcinomas are generally described as tumors


Table 2Surgically resected specimens of colorectal cancer – Checklist

Tumor siteCecumAscending colonHepatic flexureTransverse colonSplenic flexureDescending colonSigmoid colonRectosigmoid junctionRectum

Tumor sizeMaximum tumor diameter: cm

Histologic typeAdenocarcinomaMucinous adenocarcinomaSignet-ring cell carcinomaSmall cell carcinomaSquamous cell carcinomaAdenosquamous carcinomaMedullary carcinomaUndifferentiated carcinomaOther (specify):

Grade of differentiationLow grade (well or moderately differentiated)High grade (poorly differentiated or undifferentiated)High grade component (%):

Depth of tumor invasionNo evidence of primary tumorTumor invades submucosa (pT1)Tumor invades muscularis propria (pT2)Tumor invades through the muscularis propria into the subserosal adipose

tissue or the nonperitonealized pericolic or perirectal soft tissues (pT3)Tumor penetrates to the surface of the visceral peritoneum (serosa)

(pT4a)Tumor directly invades other organs or structures

(specify: ) (pT4b)Tumor penetrates to the surface of the visceral peritoneum (serosa) and

directly invades other organs or structures(specify: ) (pT4b)

Margins of resectionProximal/distal margin

Cannot be assessedInvasive carcinoma presentInvasive carcinoma absentDistance of invasive carcinoma from closest margin: mm

Circumferential (radial) marginNot applicableCannot be assessedInvasive carcinoma presentInvasive carcinoma absentDistance of invasive carcinoma from non-peritonealised margin: mm

Regional lymph nodesNumber examined:Number involved:

Tumor depositsNot identifiedPresent (number: )

Response to neoadjuvant therapyNot applicable (no prior treatment)Complete regressionMinimal residual tumorNo marked regression

Table 2 (continued)

Extramural venous invasionNot identifiedPresent

Pathologic staging (pTNM)TNM descriptors (required only if applicable)

m (multiple primary tumors)r (recurrent)y (posttreatment)

Primary tumor (pT)pTX: Cannot be assessedpT0: No evidence of primary tumorpTis: Carcinoma in situ, intraepithelial or invasion of lamina propriapT1: Tumor invades submucosapT2: Tumor invades muscularis propriapT3: Tumor invades through the muscularis propria into pericolorectal

tissuespT4a: Tumor penetrates the visceral peritoneumpT4b: Tumor directly invades other organs or structures

Regional lymph nodes (pN)pNX: Cannot be assessedpN0: No regional lymph node metastasispN1a: Metastasis in 1 regional lymph nodepN1b: Metastasis in 2 to 3 regional lymph nodespN1c: Tumor deposit(s) in the subserosa, or nonperitonealized pericolic

or perirectal tissues without regional lymph node metastasispN2a: Metastasis in 4 to 6 regional lymph nodespN2b: Metastasis in 7 or more regional lymph nodes

Distant metastasis (pM)Not applicablepM1: Distant metastasis

Specify site(s):pM1a: Metastasis to single organ or site (e.g., liver, lung, ovary,

nonregional lymph node)pM1b: Metastasis to more than one organ/site or to the peritoneum

Additional pathologic findingsNone identifiedDiverticular disease, ulcerative colitis, Crohn’s disease, familial

adenomatous polyposis, other forms of polyposis, synchronouscarcinoma(s) (complete a separate form for each cancer), etc.Specify:

Polyps present (specify type and number):

Comment(s):

characterized by solid growth pattern and marked intratumoraland peritumoral lymphocytic infiltration, and composed bycells with vesicular nuclei, prominent nucleoli, and abundanteosinophilic cytoplasm [1,24]. Tumor cells form sheets ormay have an organoid or trabecular architecture; focal mucinproduction or glandular differentiation are often present.In our experience, medullary carcinomas often display aclearly evident glandular and/or mucinous component andare generally formed by quite uniform cells with mild ormoderate nuclear atypia and variable amount of cytoplasm[25]. Moreover, intense intratumoral and peritumoral lym-phocytic infiltration is not always present. At the molecularlevel, the great majority of medullary carcinomas show MSI,which probably explains their better prognosis with respect tocommon poorly differentiated adenocarcinomas [25].

Undifferentiated carcinomas are tumors lacking morpho-logical evidence of differentiation beyond that of an epithelialtumor [1]. Some authors include in this category tumors


showing a minimal component of gland formation (<5%).Undifferentiated carcinomas may form sheets of cells, cords,or trabecular structures. Grade of anaplasia is variable, sometumors displaying marked nuclear atypia and pleomorphism,and others having relatively uniform and less atypical cy-tologic features. The clinical outcome of undifferentiatedcarcinomas is quite unpredictable and seems to be mainlyrelated to the MMR status of the tumor.

Other subtypes of large bowel carcinoma (such as sarcoma-toid carcinoma, choriocarcinoma, and clear cell carcinoma)are extremely rare. Furthermore, in the recent years newsubtypes of large bowel adenocarcinoma – named serrated,micropapillary, and villous adenocarcinoma – have been de-scribed, but their clinico-pathologic and molecular featuresneed to be more precisely defined.

9.2. Grade of differentiation [1,24,26] [Diagnostic strength:Level 2]

Diverse grading systems for colorectal cancer are currentlyemployed. We recommend the use of a 2-tiered gradingsystem based on the WHO classification:• Low grade: well differentiated and moderately differenti-

ated• High grade: poorly differentiated and undifferentiated

A 2-tiered stratification demonstrated greater reproducibil-ity and prognostic relevance than stratification into 3 or 4categories. Specifically, high grade tumors have repeatedlybeen shown to behave more aggressively than low gradecarcinomas in multivariate analysis. According to the WHOcriteria, grading should be based on the evaluation of theworst area, excluding areas of focal dedifferentiation presentat the invasive margin of the tumor. However, the gradingsystems proposed by the College of American Pathologists[26] and the Royal College of Pathologists [27] are both basedon the assessment of the predominant grade of differentiation.We suggest that, using the WHO system, the percentage ofhigh grade tumor area when present should be also reported.

9.3. Depth of tumor invasion [28,29] [Diagnostic strength:Level 3]

This is evaluated as the pT component of the TNMclassification [28,29]:• Tumor invades submucosa (pT1)• Tumor invades muscularis propria (pT2)• Tumor invades through the muscularis propria into pericol-

orectal tissues (pT3)• Tumor penetrates to the surface of the visceral peritoneum

(pT4a)• Tumor directly invades other organs or structures (pT4b)

The TNM classification includes a pTis “carcinoma insitu” level comprising intraepithelial carcinoma (confinedwithin the glandular basement membrane) and carcinomashowing invasion of the lamina propria (intramucosal). Ascolorectal neoplasia does not have metastatic potential until ithas invaded the submucosa, it is preferable to avoid the term

pTis and use the term high grade dysplasia to indicate theselesions.

The outer edge of the muscolaris propria represents the lineof demarcation between pT2 and pT3. pT3 indicates spread incontinuity beyond the bowel wall and does not apply to lym-phatic or venous invasion. At variance with the sixth edition,according to the new TNM and AJCC classifications tumordeposits in the mesenteric fat are no longer classified in the pTcategory as discontinuous extramural extensions. If a tumorspreads to the outer edge of the muscolaris propria but notbeyond and no muscle separates cancer cells from the perivis-ceral tissues, then the tumor should be classified as pT3.

Tumors that have penetrated the visceral peritoneum as aresult of direct extension through the wall and subserosa areassigned to the pT4 category, as tumors that directly invadeother organs or structures, whether or not they penetrate theserosal surface. Identification of visceral peritoneal involve-ment needs adequate tumor sampling and eventually multiplelevels sectioning and microscopic examination. The histo-logic findings considered to represent carcinomatous serosalinvolvement are [26,30].• Tumor present at the serosal surface with inflammatory

reaction, mesothelial hyperplasia, and/or erosion or ulcera-tion

• Free tumor cells on the serosal surface with underlyingulceration of the visceral peritoneumPrevious studies indicated that serosal involvement was

associated with worse outcome than invasion of adjacentorgans. However, recent data obtained from a very largecohort of colorectal cancer patients indicate that penetrationof the visceral peritoneum carries a 10% to 20% better5-year survival rate than invasion of adjacent organs foreach category of N [31,32]. Therefore, designation of theT4 subsets was changed in the seventh edition of the TNMclassification.

9.4. Margins of resection [24,26,27] [Diagnostic strength:Level 3]

Proximal, distal, circumferential, and mesocolic marginsof resection need to be evaluated in colorectal cancer surgicalspecimens. It is very useful to mark the margin(s) closest tothe tumor with ink after careful examination of the serosalsurface.

Proximal and distal resection margins are rarely involvedunless close (<2 cm) to the tumor or the tumor showshistologically poor differentiation or a diffusely infiltratingpattern of growth. Sections to assess proximal and distalmargins can be obtained either by longitudinal sectionsperpendicular to the margin or by en face sections parallel tothe margin. The distance from the tumor edge to the distalresection margin is very important for low anterior resectionand a clearance of 2 cm (1 cm for T1 and T2 tumors) isconsidered adequate.

The circumferential (radial) margin represents the adven-titial soft tissue margin closest to the deepest penetrationof tumor and is created surgically. Tumor involvement of


the radial margin is the most critical factor in predictinglocal recurrence in rectal cancer and is also associated withan increased risk of death from the disease [33]. The cir-cumferential margin is considered positive if the tumor islocated 1 mm or less from the nonperitonealized surface.This assessment includes tumor within veins, lymphatics orlymph nodes and tumor deposits, as well as direct tumorextension. However, if circumferential margin involvementis based only on intranodal tumor, this should be stated. Inrectal cancer, the distance of the tumor from the radial marginshould be always reported. The circumferential margin shouldbe also assessed in colonic segments incompletely encasedby peritoneum (e.g., cecum, ascending colon, and descendingcolon). The clinical relevance of pathologic examination ofthe surgical mesocolic plane of dissection has been recentlyrecognized [34].

9.5. Regional lymph nodes [28,29] [Diagnostic strength:Level 3]

The number of metastatic lymph nodes and the totalnumber of lymph nodes examined must always be reported.Regional lymph node status should be assessed according tothe new TNM classification [28,29], as follows.pN0 No regional lymph node metastasispN1 Metastasis in 1–3 regional lymph nodes

pN1a Metastasis in 1 regional lymph nodepN1b Metastasis in 2–3 regional lymph nodespN1c Tumor deposit(s), i.e., satellites, in the sub-

serosa, or in non-peritonealized pericolic orperirectal soft tissue without regional lymphnode metastasis

pN2 Metastasis in 4 or more regional lymph nodespN2a Metastasis in 4–6 regional lymph nodespN2b Metastasis in 7 or more regional lymph nodes

With respect to the previous edition a subdivision of pN1and pN2 categories has been introduced, reflecting differencesin clinical outcome observed within each category on thebasis of the number of affected lymph nodes [31,32].

Histological examination of a regional lymphadenectomyspecimen ordinarily includes 12 or more lymph nodes. Ifthe lymph nodes are negative, but the number ordinarilyexamined is not met, the tumor will be classified as pN0. Allmacroscopically evident lymph nodes in the surgical specimenshould be dissected and examined histologically. Many factorsinfluence lymph node recovery and evaluation, such as extentof surgical resection, quality of pathologic examination,patient factors, and tumor characteristics [35,36]. The meannumber of nodes detected in a series of dissections is nowconsidered to be indicative of colon cancer quality care [37]and should be comprised between 12 and 15 [24]. As nodalmetastases in colorectal cancer are often found in small lymphnodes (<5 mm in diameter), meticulous search is required ongross examination by the pathologist. If less than 12 lymphnodes are retrieved, re-examining the specimen could beuseful. Use of visual enhancement techniques and inclusion ofpericolic fat are not generally recommended. In rectal cancer

specimens from patients treated with neoadjuvant therapy thenumber of recovered lymph nodes is often lower than 12despite accurate search.

Several studies reported that the total number of lymphnodes evaluated after surgical resection is an importantprognostic factor in colorectal cancer. In particular, moststudies showed that increased survival of patients with stageII colon cancer is associated with increased number of lymphnodes examined [35]. A similar positive association was alsodemonstrated among patients with stage III colon cancer [35].In addition, recent investigations indicated that the ratio ofmetastatic to examined lymph nodes is related to clinicaloutcome in patients with colon and rectal cancer [38]. Thebiologic bases of these findings are not fully understood andfactors other than staging accuracy are probably involved.

Some studies suggested that identification of micrometas-tases in lymph nodes of patients with colorectal cancer stagedas pT3N0 by conventional pathologic examination could be ofprognostic value [39]. However, at present data are insufficientto recommend use of special measures to detect micrometas-tases or isolated tumor cells in the routine assessment ofregional lymph node status [26].

Peritumoral deposits (satellite nodules) are macroscopicor microscopic carcinomatous nests or nodules in the peri-colorectal adipose tissue lymph drainage area of a primarycarcinoma without histologic evidence of residual lymph nodetissue [28,29]. They may represent discontinuous spread ofthe tumor, venous invasion with extravascular spread or to-tally replaced lymph nodes. According to the latest editionof the TNM classification, if a nodule is considered by thepathologist to be a totally replaced lymph node (generallyhaving a smooth contour), it should be recorded as a positivelymph node and not as a satellite. In addition, pT1–2 lesionsthat lack regional lymph node metastasis but have tumordeposit(s) will be classified as pN1c whereas the pT categoryis unchanged. There is no general agreement on the classifi-cation of pericolic tumor nodules [24,40] and probably thesenew statements of the TNM classification will not be acceptedby part of the pathologists [41]. Tumor deposits are associatedwith unfavourable disease outcome [40] and therefore theirpresence and number should be separately recorded [29].[Diagnostic strength: Level 2]

9.6. Response to neoadjuvant therapy [27,42] [Diagnosticstrength: Level 2]

Preoperative (neoadjuvant) chemo- and radiotherapy forrectal cancer induces several secondary changes includingtumor regression and downstaging [42,43]. In the case ofrectal cancers treated with neoadjuvant therapy pathologicstaging should be performed according to the ypTNM systemand based on evaluation of viable cancer cells. Marked tumorregression and especially complete tumor eradication areassociated with better clinical outcome. Therefore, specimensfrom patients treated with neoadjuvant therapy should becarefully examined and extensively sampled in particularto demonstrate complete tumor regression. Several systems


for grading tumor regression have been proposed and thereis no general consensus on the histological classificationof this parameter. However, 3-tiered grading systems havebeen generally recommended by National and InternationalAssociations [24,26,27,29]. We suggest the use of the gradingsystem proposed by the Royal College of Pathologists, whichincludes the following categories:• No residual tumor cells and/or mucus lakes only (complete

regression)• Minimal residual tumor, i.e. only occasional microscopic

tumor foci are identified with difficulty• No marked regression

According to the TNM classification, cases with completeregression are recorded as ypT0.

9.7. Vascular invasion [26,27] [Diagnostic strength: Level 2]

Venous invasion has been shown in several studies to be anindependent negative prognostic factor in colorectal cancer.In particular, invasion of large extramural veins has beenrepeatedly associated with increased risk of cancer-relateddeath. The prognostic value of intramural venous invasion andof invasion of lymphatics or thin-walled vessels is less clear.We believe that extramural vein invasion should be alwaysreported, whereas reporting of intramural and thin-walledstructures is optional.

Elastic fiber stains could help in the recognition of venousinvasion, when suspected, on haematoxylin and eosin stainedsections; however routine use of elastic stains, as recentlysuggested, is not at present recommended.

9.8. Additional histologic prognostic factors

Several other histopathologic variables, including perineu-ral invasion, pattern of growth, lymphocytic infiltration atthe tumor margin, tumor infiltrating lymphocytes (TILs),Crohn-like reaction, and tumor budding have been proposedas prognostic factors in colorectal cancer. These parametersare not commonly employed in the clinical setting and theirreporting is optional. Nowadays, tumor budding [44] andgrade of intratumoral lymphocytic infiltration [45] representthe most promising prognostic factors to be introduced inthe pathologic evaluation of these tumors, provided that theirassessment will be standardized and their prognostic valueclearly defined.

10. Molecular prognostic and predictive factors [46,47]

Much effort has been produced to identify immunohisto-chemical, biologic and molecular prognostic and predictivefactors to be utilized in the management of patients withcolorectal cancer [46,47]. Actually, only KRAS mutationalstatus analysis and evaluation of proficiency of the DNAmismatch repair (MMR) system by immunohistochemistryand microsatellite instability (MSI) analysis are employed inclinical practice.

10.1. KRAS mutation [48,49] [Diagnostic strength: Level 3]

Presence of KRAS gene mutations (codons 12 and 13)is associated with lack of clinical response to therapy withmonoclonal antibodies (cetuximab and panitumumab) di-rected against the epidermal growth factor receptor (EGFR)in metastatic colorectal cancer. Actually, tumors of patientswith metastatic disease who are candidates for anti-EGFRantibody therapy have to be tested for KRAS mutations andonly patients whose tumors show absence of KRAS mutationsat codon 12 or 13 can be treated with anti-EGFR antibodies.However, only a fraction of patients with KRAS wild typecarcinomas will respond to anti-EGFR antibody treatment andfurther predictive molecular markers are actively investigatednowadays [49].

10.2. DNA mismatch repair status [50] [Diagnostic strength:Level 2]

About 15% of colorectal cancers are characterized by MSI(or MSI-H, high frequency MSI), which is determined by im-paired function of the MMR system. Most MSI-H carcinomas(about 70%) are sporadic and produced by somatic biallelicpromoter methylation of the MLH1 gene. It is believed thatsporadic MSI colorectal carcinomas develop through the CpGisland methylator pathway. The other MSI-H tumors arehereditary and caused by germline mutation of a MMR gene(MLH1, MSH2, and less frequently MSH6 and PMS2) withsomatic inactivation of the remaining wild type allele (Lynchsyndrome). Genetic or epigenetic inactivation of MMR genesis nearly always associated with immunohistochemical lossof expression of the corresponding protein. Furthermore,as MMR proteins work as heterodimers (MSH2 dimerizeswith MSH6, and MLH1 with PMS2) abnormalities of theobligatory partners (MSH2 and MLH1) will result in prote-olytic degradation of their dimer and concurrent loss of boththe obligatory and secondary partner proteins (MSH2/MSH6and MLH1/PMS2). Conversely, mutations in genes of thesecondary partner proteins (MSH6 and PMS2) will be char-acterized by selective loss of MSH6 and PMS2 expressionrespectively, as their function may be compensated by otherproteins [51]. Therefore, immunohistochemical pattern ofMMR protein expression allows the identification of the genethat is most likely inactivated. Several studies demonstratedan excellent correlation of the results obtained by immunohis-tochemistry and MSI analysis and both methods can be usedconfidently for the identification of MMR-deficient colorectalcarcinomas. However, a small fraction of hereditary caseshaving a missense mutation (generally of MLH1) that lead toa nonfunctional protein with intact antigenicity might result inMSI-H with intact expression of MMR proteins.

Lynch syndrome accounts for 2–3% of the total burdenof large bowel carcinomas. MSI testing and immunohisto-chemical analysis of MMR proteins expression are worldwideemployed for the identification of colorectal cancer patientswith presumptive Lynch syndrome, to be tested for MMRgenes germline mutations after appropriate genetic coun-


selling. It is recommended that MSI testing should be carriedout on tumors from patients clinically at high risk or selectedon the basis of the revised Bethesda guidelines [52]. However,molecular screening investigations performed by MSI and/orimmunohistochemical analysis on large series of unselectedsurgically removed colorectal cancers followed by MMRgenes mutation analysis have indicated that a large fraction ofLynch syndrome cases would go unrecognized using commoncriteria of selection, and some Authors suggest screening allcolorectal carcinomas for MSI or abnormal MMR proteinexpression.

Recent studies have shown that sporadic MSI-H MLH1-negative tumors frequently harbour BRAF V600E gene mu-tation. Conversely, BRAF mutations have not been detectedin MSI-H MLH1-negative tumors from patients with Lynchsyndrome. Therefore, BRAF gene mutation analysis couldbe employed as an aid for discriminating hereditary fromsporadic MLH1-negative MMR-deficient carcinomas [53].

MMR status has been demonstrated to be an independentprognostic factor in colorectal cancer. In fact, several studiesdisplayed higher survival rates for patients with stage II and IIIMSI carcinomas with respect to patients with non-MSI tumors[54,55]. In addition, emerging data suggest that patients withMSI tumors do not have significant benefit from adjuvant 5-fluorouracil-based chemotherapy [54,56]. However, the use ofMMR status assessment as a prognostic and predictive test hasnot yet been validated and incorporated into clinical practice.

Conflict of interest

The authors declare no conflict of interest.

References

[1] Hamilton SR, Vogelstein B, Kudo S, et al. Carcinoma of the colon andrectum. In: Hamilton et al., editors. World Health Organization classi-fication of tumours. Pathology and genetics. Tumors of the digestivesystem. Lyon, France: IARC Press; 2000, pp. 103–19.

[2] Dixon MF. Gastrointestinal epithelial neoplasia: Vienna revisited. Gut2002;51:130–1.

[3] Quirke P, Risio M, Lambert R, et al. Quality assurance in pathologyin colorectal cancer screening and diagnosis – European recommenda-tions. Virchows Arch 2011;458:1–19.

[4] Soetikno RM, Kaltenbach T, Rouse RV, et al. Prevalence of nonpoly-poid (flat and depressed) colorectal neoplasms in asymptomatic andsymptomatic adults. Jama 2008;299:1027–35.

[5] Haggitt RC, Glotzbach RE, Soffer EE, et al. Prognostic factors incolorectal carcinomas arising in adenomas: implications for lesionsremoved by endoscopic polypectomy. Gastroenterology 1985; 89:328–36.

[6] Coverlizza S, Risio M, Ferrari A, et al. Colorectal adenomas containinginvasive carcinoma. Pathologic assessment of lymph node metastaticpotential. Cancer 1989;64:1937–47.

[7] Ueno H, Mochizuki H, Hashiguchi Y, et al. Risk factors for an ad-verse outcome in early invasive colorectal carcinoma. Gastroenterology2004;127:385–94.

[8] Hassan C, Zullo A, Risio M, et al. Histologic risk factors and clinicaloutcome in colorectal malignant polyp: a pooled-data analysis. DisColon Rectum 2005;48:1588–96.

[9] Snover DC. Serrated polyps of the large intestine. Semin Diagn Pathol2005;22:301–8.

[10] O’Brien MJ, Yang, S., Huang, C.S., et al. The serrated polyp pathwayto colorectal carcinoma. Diagn Histopathol 2008;14:78–93.

[11] Farris AB, Misdraji J, Srivastava A, et al. Sessile Serrated Adenoma:Challenging Discrimination From Other Serrated Colonic Polyps. AmJ Surg Pathol 2008;32:30–5.

[12] Torlakovic EE, Gomez JD, Driman DK, et al. Sessile Serrated Ade-noma (SSA) vs. Traditional Serrated Adenoma (TSA). Am J SurgPathol 2008;32:21–9.

[13] Hornick JL, Odze RD. Polyps of the large intestine. In: Odze RD,editor. Surgical pathology of the GI tract, liver, biliary tract, andpancreas. Philadelphia: Saunders, 2009:481–533.

[14] Schreibman IR, Baker M, Amos C, et al. The hamartomatous poly-posis syndromes: a clinical and molecular review. Am J Gastroenterol2005;100:476–90.

[15] McGarrity TJ, Kulin HE, Zaino RJ. Peutz-Jeghers syndrome. Am JGastroenterol 2000;95:596–604.

[16] van Lier MG, Wagner A, Mathus-Vliegen EM, et al. High cancerrisk in Peutz-Jeghers syndrome: a systematic review and surveillancerecommendations. Am J Gastroenterol 2010;105:1258–64; author reply,1265.

[17] Galiatsatos P, Foulkes WD. Familial adenomatous polyposis. Am JGastroenterol 2006;101:385–98.

[18] Soravia C, Berk T, Madlensky L, et al. Genotype-phenotype corre-lations in attenuated adenomatous polyposis coli. Am J Hum Genet1998;62:1290–301.

[19] Sieber OM, Lipton L, Crabtree M, et al. Multiple colorectal adenomas,classic adenomatous polyposis, and germ-line mutations in MYH. NEngl J Med 2003;348:791–9.

[20] Burt R, Jass JR. Hyperplastic polyposis. In: Hamilton SR et al., editor.World Health Organization classification of tumors. Pathology andgenetics. Tumours of the digestive system. Lyon, France: IARC Press,2000:135–6.

[21] Redston M. Epithelial neoplasms of the large intestine. In: Odze RD,editor. Surgical pathology of the GI tract, liver, biliary tract, andpancreas. Philadelphia: Saunders, 2009:597–637.

[22] Jass JR. Classification of colorectal cancer based on correlationof clinical, morphological and molecular features. Histopathology2007;50:113–30.

[23] Gafà R, Maestri I, Matteuzzi M, et al. Sporadic colorectal ade-nocarcinomas with high-frequency microsatellite instability. Cancer2000;89:2025–37.

[24] Jass JR, O’Brien J, Riddell RH, et al. Recommendations for thereporting of surgically resected specimens of colorectal carcinoma:Association of Directors of Anatomic and Surgical Pathology. Am JClin Pathol 2008;129:13–23.

[25] Lanza G, Gafà R, Matteuzzi M, et al. Medullary-type poorly differen-tiated adenocarcinoma of the large bowel: a distinct clinicopathologicentity characterized by microsatellite instability and improved survival.J Clin Oncol 1999;17:2429–38.

[26] Washington MK, Berlin J, Branton P, et al. Protocol for the examinationof specimens from patients with primary carcinoma of the colon andrectum. Arch Pathol Lab Med 2009;133:1539–51.

[27] Williams GT, Quirke P, Sheperd NA. Dataset for Colorectal Can-cer (2nd ed.). The Royal College of Pathologists; 2007, pp. 1–27.www.rcpath.org

[28] Sobin LH, Gospodarowicz MK, Wittekind CH. TNM Classification ofMalignant Tumours. Seventh Edition. UICC, Wiley-Blackwell; 2009,pp. 100–5.

[29] Edge SB, Byrd DR, Compton CC et al. AJCC Cancer Staging Manual.Seventh Edition. Springer, 2009; pp. 143–59.

[30] Shepherd NA, Baxter KJ, Love SB. The prognostic importance ofperitoneal involvement in colonic cancer: a prospective evaluation.Gastroenterology 1997;112:1096–102.

[31] Gunderson LL, Jessup JM, Sargent DJ, et al. Revised tumor and nodecategorization for rectal cancer based on surveillance, epidemiology,


and end results and rectal pooled analysis outcomes. J Clin Oncol2010;28:256–63.

[32] Gunderson LL, Jessup JM, Sargent DJ, et al. Revised TN categorizationfor colon cancer based on national survival outcomes data. J Clin Oncol2010;28:264–71.

[33] Nagtegaal ID, Quirke P. What is the role for the circumferential marginin the modern treatment of rectal cancer? J Clin Oncol 2008;26:303–12.

[34] West NP, Morris EJ, Rotimi O, et al. Pathology grading of colon cancersurgical resection and its association with survival: a retrospectiveobservational study. Lancet Oncol 2008;9:857–65.

[35] Chang GJ, Rodriguez-Bigas MA, Skibber JM, et al. Lymph node eval-uation and survival after curative resection of colon cancer: systematicreview. J Natl Cancer Inst 2007;99:433–41.

[36] Morris EJ, Maughan NJ, Forman D, et al. Identifying stage III col-orectal cancer patients: the influence of the patient, surgeon, andpathologist. J Clin Oncol 2007;25:2573–9.

[37] Bilimoria KY, Bentrem DJ, Stewart AK, et al. Lymph node evaluationas a colon cancer quality measure: a national hospital report card. JNatl Cancer Inst 2008;100:1310–7.

[38] Rosenberg R, Friederichs J, Schuster T, et al. Prognosis of patientswith colorectal cancer is associated with lymph node ratio: a single-center analysis of 3,026 patients over a 25-year time period. Ann Surg2008;248:968–78.

[39] Messerini L, Cianchi F, Cortesini C, et al. Incidence and prognosticsignificance of occult tumor cells in lymph nodes from patients withstage IIA colorectal carcinoma. Hum Pathol 2006;37:1259–67.

[40] Puppa G, Ueno H, Kayahara M, et al. Tumor deposits are encounteredin advanced colorectal cancer and other adenocarcinomas: an expandedclassification with implications for colorectal cancer staging systemincluding a unifying concept of in-transit metastases. Mod Pathol2009;22:410–5.

[41] Quirke P, Williams GT, Ectors N, et al. The future of the TNMstaging system in colorectal cancer: time for a debate? Lancet Oncol2007;8:651–7.

[42] Ryan R, Gibbons D, Hyland JM, et al. Pathological response followinglong-course neoadjuvant chemoradiotherapy for locally advanced rectalcancer. Histopathology 2005;47:141–6.

[43] Dworak O, Keilholz L, Hoffmann A. Pathological features of rec-tal cancer after preoperative radiochemotherapy. Int J Colorectal Dis1997;12:19–23.

[44] Prall F. Tumour budding in colorectal carcinoma. Histopathology2007;50:151–62.

[45] Guidoboni M, Gafà R, Viel A, et al. Microsatellite instability andhigh content of activated cytotoxic lymphocytes identify colon cancerpatients with a favorable prognosis. Am J Pathol 2001;159:297–304.

[46] Zlobec I, Lugli A. Prognostic and predictive factors in colorectalcancer. J Clin Pathol 2008;61:561–9.

[47] Walther A, Johnstone E, Swanton C, et al. Genetic prognostic andpredictive markers in colorectal cancer. Nat Rev Cancer 2009;9:489–99.

[48] Monzon FA, Ogino S, Hammond ME, et al. The role of KRAS mu-tation testing in the management of patients with metastatic colorectalcancer. Arch Pathol Lab Med 2009;133:1600–6.

[49] van Krieken JH, Jung A, Kirchner T, et al. KRAS mutation testingfor predicting response to anti-EGFR therapy for colorectal carcinoma:proposal for an European quality assurance program. Virchows Arch2008;453:417–31.

[50] de la Chapelle A, Hampel H. Clinical relevance of microsatelliteinstability in colorectal cancer. J Clin Oncol 2010;28:3380–7.

[51] Shia J. Immunohistochemistry versus microsatellite instability testingfor screening colorectal cancer patients at risk for hereditary nonpoly-posis colorectal cancer syndrome. Part I. The utility of immunohisto-chemistry. J Mol Diagn 2008;10:293–300.

[52] Umar A, Boland CR, Terdiman JP, et al. Revised Bethesda Guidelinesfor hereditary nonpolyposis colorectal cancer (Lynch syndrome) andmicrosatellite instability. J Natl Cancer Inst 2004;96:261–8.

[53] Bessa X, Balleste B, Andreu M, et al. A prospective, multicenter,population-based study of BRAF mutational analysis for Lynch syn-drome screening. Clin Gastroenterol Hepatol 2008;6:206–14.

[54] Popat S, Hubner R, Houlston RS. Systematic review of microsatelliteinstability and colorectal cancer prognosis. J Clin Oncol 2005;23:609–18.

[55] Lanza G, Gafà R, Santini A, et al. Immunohistochemical test forMLH1 and MSH2 expression predicts clinical outcome in stage II andIII colorectal cancer patients. J Clin Oncol 2006;24:2359–67.

[56] Sargent DJ, Marsoni S, Monges G, et al. Defective mismatch repair asa predictive marker for lack of efficacy of fluorouracil-based adjuvanttherapy in colon cancer. J Clin Oncol 2010;28:3219–26.

Documents

Colorectal Tumours the Histology Report G Lanza Et Al