G. Lanza et al. / Digestive and Liver Disease 43S (2011) S344–S355 S345Table 1Grading of superﬁcial colorectal neoplasiaWHO 1989 WHO 2000 Revised Vienna Classiﬁcation Category 1: Negative for neoplasia Category 2: Indeﬁnite for neoplasiaLow grade dysplasia (mild and moderate Low grade intraepithelial neoplasia (mild and Category 3: Mucosal low grade neoplasiadysplasia) moderate dysplasia) Low grade adenoma Low grade dysplasiaHigh grade dysplasia (severe dysplasia) High grade intraepithelial neoplasia Category 4: Mucosal high grade neoplasia (severe dysplasia, adenocarcinoma in situ) 4.1. High grade adenoma/dysplasia 4.2. Non-invasive carcinoma (carcinoma in situ)Carcinoma in situ (carcinoma in situ, Intramucosal neoplasia 4.3. Suspicious for invasive carcinomaintramucosal carcinoma) (intramucosal adenocarcinoma) 4.4. Intramucosal carcinomaInvasive carcinoma (spreading into the Invasive carcinoma (invasion into the Category 5: Submucosal invasion by carcinomasubmucosa) submucosa)distinguish sessile polypoid lesions (Type 0-Is, protruding 2.4. Villous histology [Diagnostic strength: Level 3]above 2.5 mm) from the nonpolypoid ones (Type 0-IIaprotruding below 2.5 mm), the distinction being crucial given Villous structures form at least 80% of villous adenomas,the highly signiﬁcative differences in cancerization rates and more than 20% of tubulovillous adenomas. Villi canbetween nonpolypoid and sessile polypoid (adenomatous and assume different morphologies, all of them equally contribut-serrated) lesions . The histological report for nonpolypoid ing to villous histology of an adenoma: classical villi (long,lesions should therefore conﬁrm the adenomatous nature of slender, ﬁnger-like processes), palmate villi (leaf-like, broad,the lesion, determine the degree of neoplasia, exclude invasion branched processes), foreshortened villi (isolated, slender out-and, when possible, state the likelihood of consistency with growths). The presence of at least one identiﬁable villusthe endoscopical typing according to the Paris classiﬁcation. in polyp biopsies or fragments deserves to be reported as “predominantly tubular histology”.2.1. Gross specimens and handling 2.5. Grade of neoplasia [Diagnostic strength: Level 3] Size should be carefully measured identifying the max-imum diameter of the adenomatous component, length and Severity of both architectural (crypt branching and bud-diameter of the stalk, if present. The resection margin should ding, complex glandular crowding, intraluminal papillarybe identiﬁed, described, and sliced in a way that allows tufting) and cytological features (loss of cell polarity andcomplete assessment. Polyps need to be sliced and totally differentiation, nuclear stratiﬁcation, enlarged and roundedembedded. At least three levels should be cut and H&E nuclei with nucleoli) distinguish mucosal low grade neoplasiastained through each block. (Category 3, equating low grade dysplasia) from mucosal high grade neoplasia (Category 4.1, equating high grade dysplasia2.2. Pathology report in older systems) (Table 1). Only one or two glands with high grade dysplasia and identiﬁable at low power exam- Since size, villous histology, and grade of neoplasia rep- ination are needed to classify an adenoma as high grade.resent the most important determinants for the malignant Trauma, erosion, prolapse and bleeding, mainly occurring inprogression of colorectal adenomas, as well as for the risk of the superﬁcial portions of polyps, elicit reparative changesdevelopment of synchronous and/or metachronous large bowel in the adenomatous epithelium (loss of polarity and nuclearneoplasia, histological report should focus on all of them. stratiﬁcation), mimicking high grade neoplasia, but these are not to be overinterpreted as such. Cribriform or solid pat-2.3. Size [Diagnostic strength: Level 2] tern of epithelial growth consistent with carcinoma in situ and invasion by the neoplastic epithelium into the lamina The size of adenomas inﬂuences surveillance intervals, and propria or muscularis mucosae consistent with intramucosalan accurate measurement by the pathologist to the nearest carcinoma are included (categories 4.2 and 4.4, respectively)millimeter is required. Grossly, measurement of the size can within the spectrum of mucosal high grade neoplasia and asbe done from the formalin-ﬁxed specimen, excluding the stalk, such reported.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.
S346 G. Lanza et al. / Digestive and Liver Disease 43S (2011) S344–S3553. Cancerized adenoma, malignant polyp (pT1 colorectal 3.3. Margin involvement [Diagnostic strength: Level 3]cancer)  A negative deep (basal) margin is reported in the absence Neoplastic invasion into the submucosa through the mus- of cancer within the diathermy and one high-power ﬁeldcularis mucosae (Category 5 in accordance with the revised from diathermy, or more than 1 mm from the actual marginVienna Classiﬁcation) is diagnostic of cancerized adenoma of resection The presence of adenomatous tissue in the[Diagnostic strength: Level 3]. Colonic intramucosal carci- lateral mucosal resection margin should also be independentlynoma behaves like a benign adenoma and for this reason reported as an indication for further endoscopic treatment.polyps harbouring “in situ” or “intramucosal” cancer (Cate-gories 4.2 and 4.4, respectively) are not generally regarded 3.4. Tumor budding [Diagnostic strength: Level 2]as “malignant” polyps and classiﬁed as high grade dys-plasia, high grade intraepithelial neoplasia or mucosal high An isolated single cancer cell and a cluster composedgrade neoplasia (Table 1). Cancerized adenomas represent of fewer than 5 cancer cells are deﬁned as “budding” foci.the earliest form of clinically relevant colon cancer in most Although several studies have shown that tumor buddingpatients. Invasion of the submucosa, in fact, opens the way to is independently associated with lymph node and distantmetastasis via the haematogenous and lymphatic routes, and metastasis as well as shorter disease free and overall survivalthe choice between surveillance and major surgery when an in colorectal cancer, there is no consensus with regard to theendoscopically removed polyp is found to be an ACIC will assessment methods and cut-off values.hinge on its metastatic potential, taking into account that post Due to the usually small dimension of the submucosal in-operative mortality (within 30 days) ranges from 0.6 to 4.4% vasive front in cancerized adenomas, tumor budding should bein T1 cancers. At present, histopathologic parameters alone assessed in the area where the highest activity is identiﬁed ondetermine whether a high (35%) or low (7%) risk of nodal H&E, reserving immunohistochemistry for the better assess-metastases exists [5–8]. Histologic risk factors – namely posi- ment of this feature. Awaiting the results from reproducibilitytive resection margin, poor differentiation of cancer, vascular studies, a quantitative, two-grade system (low vs. high grade)invasion and tumor budding – do not only predict lymph node is advisable, counting tumor buds (< or ≥10) within a 0.385disease rate but also distant metastasis and mortality rates. mm2 area using a ×25 lens.3.1. Carcinoma grading [Diagnostic strength: Level 3] 3.5. Microstaging [Diagnostic strength: Level 2] Histologic grade should be in accordance with the system The level of submucosal invasion, assessed as Haggitt lev-used in advanced colorectal cancer and distinguish well/ els I–IV in peduncolated polyps and as sm1–3 Kikuchi levelsmoderately (low grade) from poorly differentiated (high in sessile polyps, is important in predicting the outcome ofgrade) tumors. It is based on the worst area, independently cancerized adenomas. On the other hand, cancerized adeno-from its extension. An anaplastic component (even in the form mas with slight submucosal invasion to the depth of 200–300of small, single or scattered foci) should be identiﬁed, as its micrometers are very unlikely to have metastatic lymph nodesoccurrence strongly correlates with the risk of lymph node and the quantitative measurements of both depth (< or >2000metastases. Signet ring cell carcinoma should be graded as micrometers) and width (< or >4000 micrometers) of thepoorly differentiated. Tumor budding at the front of invasion cancerous submucosal invasion are strongly indicative of theshould not inﬂuence carcinoma grading and should be scored nodal involvement and worthy reporting. In this setting theseparately (see below). rough estimate of the ratio of adenomatous to carcinomatous tissue is meaningful, indicating the prevalence of the poten-3.2. Vascular invasion [Diagnostic strength: Level 2] tially metastatic cancerous tissue within the polyp, the risk of lymph node metastasis being likely high (even in the absence Lymphatic invasion requires the presence of cancer cells of other risk parameters) in pT1 polypoid adenocarcinoma,within endothelial-lined channels or spaces, distinguishing consisting entirely of cancer without adenoma.such features from retraction artefacts. Venous invasion isdeﬁned as tumor emboli within endothelial-lined channelssurrounded by a smooth muscle wall. Uncertainty in the 4. Serrated polyps [3,9,10]assessment (presence vs absence) of neoplastic vascularinvasion, even after the examination of serial and deeper Epithelial serration, namely the saw-toothed outline de-routinely H&E stained sections, should be reported. Evidence rived from infolded epithelial tufts in the crypt and inis lacking for the additional use of immunohistochemistry in the luminal surface can be found in several histotypes ofdetecting vascular invasion. colorectal polyps. Transient serration associated with hyper- proliferation can be seen in inﬂammatory polyps, above all of myoglandular type. Steady serration is displayed in the common hyperplastic polyps of the large bowel and, coupled with focal or diffuse epithelial neoplastic changes, in serrated
G. Lanza et al. / Digestive and Liver Disease 43S (2011) S344–S355 S347adenomas and mixed polyps. Furthermore, cell maturation 4.4. Mixed polyps [Diagnostic strength: Level 2]and differentiation are altered in serrated epithelium, particu-larly in the mucus-producing process, so that abnormal goblet In these polyps one or more serrated components (hyper-cell, microvesicular, and mucus-poor cell components can be plastic, SSA, TSA) are associated and/or intermingled withfound allowing the identiﬁcation of different cytotypes of classical adenomatous tissue (tubular, tubulovillous and vil-serrated polyps: these, however, seem unrelated to different lous). Extension and grading of neoplastic sectors should berisks of tumor progression. exhaustively described in the diagnosis, in order to support clinical decision making.4.1. Hyperplastic (metaplastic) polyps [Diagnostic strength:Level 3] 5. Inﬂammatory polyps  Epithelial serration together with minimal architecturalchanges, and without cytological atypia are the diagnostic Inﬂammatory polyps are deﬁned as mucosal elevationsfeatures of hyperplastic polyps of the large bowel. They are resulting from an inﬂammatory process. They may occur insmall-sized (0.2–0.5 cm) mucosal bumps of the sigmoid colon patients with inﬂammatory bowel disease (IBD), as well as inand rectum, consisting of straight, parallel, slightly elongated patients with other forms of colitis, such as infectious colitis,crypts lined by serrated epithelium in the intermediate and ischemic colitis, or diverticulitis. They may be also inducedupper third, and by undifferentiated cells in the lower third. by a mucosal trauma due to an inappropriate peristalsis andThe nuclei are round or oval and located at the base with little in such cases are deﬁned as mucosal prolapse-related inﬂam-or no stratiﬁcation. matory polyps. Different entities such as inﬂammatory cap polyp, colitis cistica profunda and inﬂammatory myoglandu-4.2. Sessile serrated adenomas (SSA) /sessile serrated polyps lar polyp are considered to belong to the mucosal prolapse[Diagnostic strength: Level 2] syndrome. Inﬂammatory polyps do not show an increased risk of neoplastic transformation. SSA are mainly right-sited, large-sized (>1 cm) sessile Inﬂammatory polyps may be sessile or pedunculated, andserrated lesions displaying patchy or diffuse distorsions of their gross appearance varies from rounded lesions to ﬁnger-tissue organization: branching of crypts, serration of foveolar like projections (ﬁliform polyps, usually associated with IBD).cell phenotype at the base of the crypt, dilatation at the base They may be single or multiple and their size generally rangesof the crypt, horizontal crypt growth . Most ﬁndings are from few mm to 2 cm; sometimes, they may be extremelyonly suggestive for SSA, and are localized in the deeper large (“giant” inﬂammatory polyps) and can cause intestinalsectors of the mucosa and require well-oriented samples for obstruction.identiﬁcation. Subtle nuclear changes, when present, are focaland include small prominent nucleoli, open chromatin, and 5.1. Histological features [Diagnostic strength: Level 3]irregular contours. Frankly dysplastic nuclear abnormalities,indicative of the initial transition toward traditional serrated The lamina propria shows an intense inﬂammatory celladenomas should be reported, in terms of extension and inﬁltrate and contains dilated and branched colonic crypts;neoplasia grade, in order to manage patient surveillance. neutrophilic cryptitis and crypt abscess may be prominent.Intermingling and/or intermediate features of SSA and hy- The colonic surface epithelium and the colonic crypts mayperplastic polyps can often be seen in the same histolgical show both epithelial damage and regeneration. Intense vascu-section, impairing diagnostic reproducibility. The term “ses- lar congestion and hemorrhage may also be present. Mucosalsile serrated polyp” has therefore been suggested for equivocal prolapse-related inﬂammatory polyps show additional histo-lesions and even as a synonym of SSA, considering the im- logical features such as thickening and vertical extension ofproper use of “adenoma” for lesions lacking true neoplastic the muscularis mucosae toward the lamina propria.changes. 5.2. Differential diagnosis [Diagnostic strength: Level 2]4.3. Traditional serrated adenomas (TSA) [Diagnosticstrength: Level 2] The differential diagnosis between reactive epithelial changes and epithelial dysplasia or neoplasia is the main Nuclear (elongated, hyperchromatic, stratiﬁed nuclei) and potential pitfall that can occur in evaluating inﬂammatorycytological frankly dysplastic features are seen within the polyps. The regenerating epithelium usually shows maturationserrated epithelium, besides architectural changes and are di- toward the surface while dysplastic or neoplastic epitheliumagnostic for TSA . Rapid and protuberant growth parallels do not show surface maturation. Moreover, the presence of annuclear dysplasia and, grossly, TSA can be indistinguishable inﬂammatory background should be carefully considered tofrom villous or tubulovillous colorectal adenomas. avoid an overdiagnosis of dysplasia or neoplasia, particularly in patients with IBD. Inﬂammatory polyps may contain bizarre stromal cells, that may be mistaken for a sarcoma (“pseudosarcomatous”
S348 G. Lanza et al. / Digestive and Liver Disease 43S (2011) S344–S355change). The location of these cells underneath areas of 6.3. Peutz-Jeghers syndrome ulceration, the presence of an inﬂammatory inﬁltrate togetherwith the absence of atypical mitoses can help in the differen- Peutz-Jeghers polyps mainly occur in the small bowel,tial diagnosis. Inﬂammatory polyps may also mimic juvenile and less frequently in the large bowel and the stomach.polyps, since the histological features of both are very similar; They are variable in size, being sessile or pedunculated.the clinical data can help in the distinction between these two They are generally multiple, but solitary Peutz-Jeghers typetypes of polyps. polyps have been described. Mucocutaneous hyperpigmenta- tion around the mouth, eyes, perianal area, and on the ﬁngers often precede gastrointestinal manifestations. The diagnosis6. Hamartomatous polyps and polyposes of Peutz-Jeghers syndrome is based upon clinical ﬁndings and the histological appearance of the polyps [Diagnostic Hamartomatous polyps are characterized by a disorganized strength: Level 3]. The incidence of gastrointestinal cancerovergrowth of tissues native to the anatomic area in which as well as extra-gastrointestinal neoplasms in Peutz-Jeghersthey arise. They may occur as solitary polyps or in the context syndrome is greater than in the normal population . Mu-of polyposis syndromes, and are deﬁned by their histology. tations of the LKB1/STK11 gene have been found in nearly 60% of affected patients.6.1. Solitary juvenile polyp (JP) The main histological feature is the presence of arborizing bands of smooth muscle, derived from muscularis mucosae, Most JPs are located in the distal large intestine and their that are covered by normal or hyperplastic glandular epithe-size is generally less than 1–2 cm; their surface is smooth and lium. Epithelial misplacement into the intestinal wall may belobulated and they are usually pedunculated. Rectal bleeding present and may mimic invasive adenocarcinoma. It can beis the most frequent symptom; sometimes autoamputation of recognized by normal differentiation of the epithelium, lackthe polyp can occur. Solitary JPs have no increased risk of of stromal reaction and haemosiderin deposition.malignancy. JP is composed of an expanded lamina propria with irregu-lar glands that are often cistically dilated. The lamina propria 7. Adenomatous polyposis contains a variable amount of inﬂammatory cells but there isno proliferation of smooth muscle. JP is the most frequent Familial adenomatous polyposis (FAP) and its variant syn-hamartomatous colorectal polyp, and is especially common dromes (Gardner syndrome and Turcot syndrome) are differ-before 10 years of age; however, it may occur also in adults. ent phenotypic manifestations caused by germline mutations of the adenomatous polyposis coli gene. FAP is characterized6.2. Juvenile polyposis  by hundreds of adenomatous polyps in the large bowel, that generally begin to emerge in the second decade of life. If The polyps are histologically similar to solitary JPs. adenomas are not removed, colorectal cancer is inevitable,Juvenile polyposis should be suspected when three or more since the penetrance of the disease is very high, reachingJPs are found; however the diagnostic criteria for Juvenile nearly 100%. [Diagnostic strength: Level 3]polyposis are the following: ﬁve or more juvenile polyps Extracolonic manifestations associated with FAP are: up-of the colorectum and/or juvenile polyps throughout the per gastrointestinal adenomas and adenocarcinomas, adeno-gastrointestinal tract and/or any number of juvenile polyps carcinoma of the ampulla of Vater, gastric fundic glandswith a family history of Juvenile polyposis. polyposis, desmoid tumors, central nervous system tumors, There are three types of Juvenile polyposis: (1) Juvenile cancer of the thyroid, hepatoblastoma, hypertrophy of thepolyposis of infancy, that is usually fatal from non-neoplastic retinal pigment epithelium, osteomas, epidermoid cysts, andconditions; (2) Juvenile polyposis coli, that shows an in- dental abnormalities.creased risk of colorectal cancer; (3) Generalized Juvenile Duodenal cancer and desmoid tumors are the main causespolyposis, which shows an increased risk of development of of death in FAP patients treated with prophylactic colectomy.gastrointestinal carcinomas. Most patients with Juvenile polyposis show mutations of Attenuated familial adenomatous polyposis (AFAP)  isthe SMAD4/DPC4 gene. Polyps closely resembling juvenile characterized by multiple adenomas of the colon. In thispolyps are found in other conditions such as Cowden disease, syndrome the number of adenomas is lower than in classicalBannayan-Riley-Ruvalcaba syndrome and Cronkhite-Canada FAP and it ranges from 2 to 100, averaging around 20–30syndrome. The ﬁrst two syndromes are related to inher- adenomas, with prominent variations among family members.ited mutation of the PTEN gene, whereas Cronkhite-Canada [Diagnostic strength: Level 3]syndrome is a non-hereditary gastrointestinal polyposis of AFAP is associated with germline mutations of the APCunknown etiology. Patients with these syndromes show gas- gene in only a small proportion of cases (approximately 10%).trointestinal multiple polyps, but they may also have extra- Furthermore, adenomas are frequently ﬂat and often localizedgastrointestinal clinical manifestations as well as an increased in the proximal colon. Extra-colonic manifestations may orrisk of malignancy. not be present, but upper gastrointestinal lesions are generally
G. Lanza et al. / Digestive and Liver Disease 43S (2011) S344–S355 S349present. AFAP patients have a high risk of colorectal cancer. • Squamous cell carcinomaThese patients develop colorectal cancer 10 years earlier than • Adenosquamous carcinomaindividuals with sporadic colorectal cancer, but 15–20 years • Medullary carcinomalater than patients with classical FAP. • Undifferentiated carcinoma Most colorectal carcinomas (nearly 85%) are usual ade-MUTYH-associated adenomatous polyposis (MAP) . Mul- nocarcinomas, and 10 to 15% are classiﬁed as mucinoustiple adenomas can also occur in a subset of APC mutation- adenocarcinomas (mucinous component >50%). The othernegative patients. These patients harbor germline mutations tumor types are rare. Tumor typing does not have majorin the repair gene MUTYH (MYH). The number of ade- prognostic relevance, but signet-ring cell carcinoma and smallnomas ranges from 15 to more than 100. These patients cell carcinoma have been demonstrated to have adverse prog-present a very high risk of developing colorectal cancer. nostic signiﬁcance independent of stage. Notwithstanding,Furthermore, the incidence of extra-colonic tumors, especially the various subtypes of colorectal cancer are characterizedduodenal cancer, is higher than that of the general population. by different genetic alterations and probably more detailed[Diagnostic strength: Level 3] prognostic information will be obtained in the future by an integrated histologic and molecular classiﬁcation . With respect to usual adenocarcinomas, mucinous tumors8. Hyperplastic polyposis (HP)  have a greater tendency to develop peritoneal metastases, to invade adjacent organs and to show extensive lymph node The following criteria have been proposed to diagnose HP: involvement . Mucinous carcinomas are evenly distributed1) at least ﬁve histologically diagnosed hyperplastic polyps in the right and left colon and more frequently than commonproximal to the sigmoid colon of which two are greater than adenocarcinomas harbour defects in the DNA mismatch repair10 mm in diameter, or 2) any number of hyperplastic polyps (MMR) system . Mucinous adenocarcinomas differ fromoccurring proximal to the sigmoid colon in an individual common adenocarcinomas also on the basis of other molec-who has a ﬁrst degree relative with HP, or 3) more than 30 ular features, such as higher frequency of CIMP phenotypehyperplastic polyps of any size, but distributed throughout the and rare p53 mutations, suggesting that these tumors reallycolon. [Diagnostic strength: Level 2] represent a distinct pathologic entity . A less favourable Individuals with HP develop colorectal cancer on a back- clinical outcome for patients with mucinous cancers has beenground of multiple polyps that are mainly hyperplastic polyps. demonstrated in many studies but not in others and theHowever, SSAs, TSAs and mixed polyps can also be found prognostic signiﬁcance of the mucinous phenotype remains atin these patients; therefore it the suggestion is to consider all present undetermined. In addition, the prognosis of mucinoustypes of serrated polyps in diagnosing HP. carcinomas with microsatellite instability (MSI) has been re- ported to be better than that of microsatellite stable mucinous carcinomas.9. Surgically resected colorectal cancer Signet-ring cell carcinoma is composed of at least 50% signet-ring cells. It represents less than 1% of all colorectal Careful pathologic reporting of colorectal cancer resection carcinomas and occurs more frequently in individuals youngerspecimens is of paramount importance to determine the than 50 years of age and in patients with ulcerative colitis.prognosis and to plan the treatment of individual patients. Histologically, colorectal signet-ring cell carcinomas differIn addition, pathologists have an increasing role in the from gastric ones for the common presence of abundantidentiﬁcation of hereditary tumors and in prediction of extracellular mucin and infrequent diffuse tissue inﬁltration.tumor response to speciﬁc type of therapy. There is clear Signet-ring cell carcinomas are often at an advanced stageevidence that the use of checklists improves the standard of at diagnosis and are associated with a worse outcomecolorectal cancer reporting and therefore their use is strongly than common adenocarcinomas. Peritoneal carcinomatosisrecommended (Table 2). Pathologic parameters that need develops in the majority of patients who die of the disease.to be absolutely reported on the basis of their prognostic About 30% of signet-ring cell carcinomas display defect ofvalue or that are required for therapy will be discussed. In MMR function; however, MSI status does not appear to be aaddition, molecular prognostic and predictive factors recently signiﬁcant predictor of survival in this tumor type.introduced in the clinical setting will be examined. Small cell carcinomas are histologically identical to those arising in the lungs. They often appear to develop within an9.1. Histologic type [1,21] [Diagnostic strength: Level 2] adenoma and usually express neuroendocrine markers. Part of the cases show a distinct adenocarcinomatous component. Histologic type should be evaluated according to the WHO Most patients have distant metastases at diagnosis and theclassiﬁcation as follows . prognosis is very poor. Large cell poorly differentiated • Adenocarcinoma neuroendocrine carcinomas may also occur in the colorectum • Mucinous adenocarcinoma and their clinical behaviour is similar to that of small cell • Signet-ring cell carcinoma carcinomas. • Small cell carcinoma Medullary carcinomas are generally described as tumors
S350 G. Lanza et al. / Digestive and Liver Disease 43S (2011) S344–S355Table 2 Table 2 (continued)Surgically resected specimens of colorectal cancer – Checklist Extramural venous invasionTumor site Not identiﬁed Cecum Present Ascending colon Pathologic staging (pTNM) Hepatic ﬂexure TNM descriptors (required only if applicable) Transverse colon m (multiple primary tumors) Splenic ﬂexure r (recurrent) Descending colon y (posttreatment) Sigmoid colon Primary tumor (pT) Rectosigmoid junction pTX: Cannot be assessed Rectum pT0: No evidence of primary tumorTumor size pTis: Carcinoma in situ, intraepithelial or invasion of lamina propria Maximum tumor diameter: cm pT1: Tumor invades submucosaHistologic type pT2: Tumor invades muscularis propria Adenocarcinoma pT3: Tumor invades through the muscularis propria into pericolorectal Mucinous adenocarcinoma tissues Signet-ring cell carcinoma pT4a: Tumor penetrates the visceral peritoneum Small cell carcinoma pT4b: Tumor directly invades other organs or structures Squamous cell carcinoma Regional lymph nodes (pN) Adenosquamous carcinoma pNX: Cannot be assessed Medullary carcinoma pN0: No regional lymph node metastasis Undifferentiated carcinoma pN1a: Metastasis in 1 regional lymph node Other (specify): pN1b: Metastasis in 2 to 3 regional lymph nodes pN1c: Tumor deposit(s) in the subserosa, or nonperitonealized pericolicGrade of differentiation or perirectal tissues without regional lymph node metastasis Low grade (well or moderately differentiated) pN2a: Metastasis in 4 to 6 regional lymph nodes High grade (poorly differentiated or undifferentiated) pN2b: Metastasis in 7 or more regional lymph nodes High grade component (%): Distant metastasis (pM)Depth of tumor invasion Not applicable No evidence of primary tumor pM1: Distant metastasis Tumor invades submucosa (pT1) Specify site(s): Tumor invades muscularis propria (pT2) pM1a: Metastasis to single organ or site (e.g., liver, lung, ovary, Tumor invades through the muscularis propria into the subserosal adipose nonregional lymph node) tissue or the nonperitonealized pericolic or perirectal soft tissues (pT3) pM1b: Metastasis to more than one organ/site or to the peritoneum Tumor penetrates to the surface of the visceral peritoneum (serosa) Additional pathologic ﬁndings (pT4a) None identiﬁed Tumor directly invades other organs or structures Diverticular disease, ulcerative colitis, Crohn’s disease, familial (specify: ) (pT4b) adenomatous polyposis, other forms of polyposis, synchronous Tumor penetrates to the surface of the visceral peritoneum (serosa) and carcinoma(s) (complete a separate form for each cancer), etc. directly invades other organs or structures Specify: (specify: ) (pT4b) Polyps present (specify type and number):Margins of resection Comment(s):Proximal/distal margin Cannot be assessed Invasive carcinoma present characterized by solid growth pattern and marked intratumoral Invasive carcinoma absent and peritumoral lymphocytic inﬁltration, and composed by Distance of invasive carcinoma from closest margin: mm cells with vesicular nuclei, prominent nucleoli, and abundantCircumferential (radial) margin Not applicable eosinophilic cytoplasm [1,24]. Tumor cells form sheets or Cannot be assessed may have an organoid or trabecular architecture; focal mucin Invasive carcinoma present production or glandular differentiation are often present. Invasive carcinoma absent In our experience, medullary carcinomas often display a Distance of invasive carcinoma from non-peritonealised margin: mm clearly evident glandular and/or mucinous component andRegional lymph nodes are generally formed by quite uniform cells with mild or Number examined: moderate nuclear atypia and variable amount of cytoplasm Number involved: . Moreover, intense intratumoral and peritumoral lym-Tumor deposits phocytic inﬁltration is not always present. At the molecular Not identiﬁed level, the great majority of medullary carcinomas show MSI, Present (number: ) which probably explains their better prognosis with respect toResponse to neoadjuvant therapy common poorly differentiated adenocarcinomas . Not applicable (no prior treatment) Complete regression Undifferentiated carcinomas are tumors lacking morpho- Minimal residual tumor logical evidence of differentiation beyond that of an epithelial No marked regression tumor . Some authors include in this category tumors
G. Lanza et al. / Digestive and Liver Disease 43S (2011) S344–S355 S351showing a minimal component of gland formation (<5%). pTis and use the term high grade dysplasia to indicate theseUndifferentiated carcinomas may form sheets of cells, cords, lesions.or trabecular structures. Grade of anaplasia is variable, some The outer edge of the muscolaris propria represents the linetumors displaying marked nuclear atypia and pleomorphism, of demarcation between pT2 and pT3. pT3 indicates spread inand others having relatively uniform and less atypical cy- continuity beyond the bowel wall and does not apply to lym-tologic features. The clinical outcome of undifferentiated phatic or venous invasion. At variance with the sixth edition,carcinomas is quite unpredictable and seems to be mainly according to the new TNM and AJCC classiﬁcations tumorrelated to the MMR status of the tumor. deposits in the mesenteric fat are no longer classiﬁed in the pT Other subtypes of large bowel carcinoma (such as sarcoma- category as discontinuous extramural extensions. If a tumortoid carcinoma, choriocarcinoma, and clear cell carcinoma) spreads to the outer edge of the muscolaris propria but notare extremely rare. Furthermore, in the recent years new beyond and no muscle separates cancer cells from the perivis-subtypes of large bowel adenocarcinoma – named serrated, ceral tissues, then the tumor should be classiﬁed as pT3.micropapillary, and villous adenocarcinoma – have been de- Tumors that have penetrated the visceral peritoneum as ascribed, but their clinico-pathologic and molecular features result of direct extension through the wall and subserosa areneed to be more precisely deﬁned. assigned to the pT4 category, as tumors that directly invade other organs or structures, whether or not they penetrate the9.2. Grade of differentiation [1,24,26] [Diagnostic strength: serosal surface. Identiﬁcation of visceral peritoneal involve-Level 2] ment needs adequate tumor sampling and eventually multiple levels sectioning and microscopic examination. The histo- Diverse grading systems for colorectal cancer are currently logic ﬁndings considered to represent carcinomatous serosalemployed. We recommend the use of a 2-tiered grading involvement are [26,30].system based on the WHO classiﬁcation: • Tumor present at the serosal surface with inﬂammatory • Low grade: well differentiated and moderately differenti- reaction, mesothelial hyperplasia, and/or erosion or ulcera- ated tion • High grade: poorly differentiated and undifferentiated • Free tumor cells on the serosal surface with underlying A 2-tiered stratiﬁcation demonstrated greater reproducibil- ulceration of the visceral peritoneumity and prognostic relevance than stratiﬁcation into 3 or 4 Previous studies indicated that serosal involvement wascategories. Speciﬁcally, high grade tumors have repeatedly associated with worse outcome than invasion of adjacentbeen shown to behave more aggressively than low grade organs. However, recent data obtained from a very largecarcinomas in multivariate analysis. According to the WHO cohort of colorectal cancer patients indicate that penetrationcriteria, grading should be based on the evaluation of the of the visceral peritoneum carries a 10% to 20% betterworst area, excluding areas of focal dedifferentiation present 5-year survival rate than invasion of adjacent organs forat the invasive margin of the tumor. However, the grading each category of N [31,32]. Therefore, designation of thesystems proposed by the College of American Pathologists T4 subsets was changed in the seventh edition of the TNM and the Royal College of Pathologists  are both based classiﬁcation.on the assessment of the predominant grade of differentiation.We suggest that, using the WHO system, the percentage of 9.4. Margins of resection [24,26,27] [Diagnostic strength:high grade tumor area when present should be also reported. Level 3]9.3. Depth of tumor invasion [28,29] [Diagnostic strength: Proximal, distal, circumferential, and mesocolic marginsLevel 3] of resection need to be evaluated in colorectal cancer surgical specimens. It is very useful to mark the margin(s) closest to This is evaluated as the pT component of the TNM the tumor with ink after careful examination of the serosalclassiﬁcation [28,29]: surface. • Tumor invades submucosa (pT1) Proximal and distal resection margins are rarely involved • Tumor invades muscularis propria (pT2) unless close (<2 cm) to the tumor or the tumor shows • Tumor invades through the muscularis propria into pericol- histologically poor differentiation or a diffusely inﬁltrating orectal tissues (pT3) pattern of growth. Sections to assess proximal and distal • Tumor penetrates to the surface of the visceral peritoneum margins can be obtained either by longitudinal sections (pT4a) perpendicular to the margin or by en face sections parallel to • Tumor directly invades other organs or structures (pT4b) the margin. The distance from the tumor edge to the distal The TNM classiﬁcation includes a pTis “carcinoma in resection margin is very important for low anterior resectionsitu” level comprising intraepithelial carcinoma (conﬁned and a clearance of 2 cm (1 cm for T1 and T2 tumors) iswithin the glandular basement membrane) and carcinoma considered adequate.showing invasion of the lamina propria (intramucosal). As The circumferential (radial) margin represents the adven-colorectal neoplasia does not have metastatic potential until it titial soft tissue margin closest to the deepest penetrationhas invaded the submucosa, it is preferable to avoid the term of tumor and is created surgically. Tumor involvement of
S352 G. Lanza et al. / Digestive and Liver Disease 43S (2011) S344–S355the radial margin is the most critical factor in predicting specimens from patients treated with neoadjuvant therapy thelocal recurrence in rectal cancer and is also associated with number of recovered lymph nodes is often lower than 12an increased risk of death from the disease . The cir- despite accurate search.cumferential margin is considered positive if the tumor is Several studies reported that the total number of lymphlocated 1 mm or less from the nonperitonealized surface. nodes evaluated after surgical resection is an importantThis assessment includes tumor within veins, lymphatics or prognostic factor in colorectal cancer. In particular, mostlymph nodes and tumor deposits, as well as direct tumor studies showed that increased survival of patients with stageextension. However, if circumferential margin involvement II colon cancer is associated with increased number of lymphis based only on intranodal tumor, this should be stated. In nodes examined . A similar positive association was alsorectal cancer, the distance of the tumor from the radial margin demonstrated among patients with stage III colon cancer .should be always reported. The circumferential margin should In addition, recent investigations indicated that the ratio ofbe also assessed in colonic segments incompletely encased metastatic to examined lymph nodes is related to clinicalby peritoneum (e.g., cecum, ascending colon, and descending outcome in patients with colon and rectal cancer . Thecolon). The clinical relevance of pathologic examination of biologic bases of these ﬁndings are not fully understood andthe surgical mesocolic plane of dissection has been recently factors other than staging accuracy are probably involved.recognized . Some studies suggested that identiﬁcation of micrometas- tases in lymph nodes of patients with colorectal cancer staged9.5. Regional lymph nodes [28,29] [Diagnostic strength: as pT3N0 by conventional pathologic examination could be ofLevel 3] prognostic value . However, at present data are insufﬁcient to recommend use of special measures to detect micrometas- The number of metastatic lymph nodes and the total tases or isolated tumor cells in the routine assessment ofnumber of lymph nodes examined must always be reported. regional lymph node status .Regional lymph node status should be assessed according to Peritumoral deposits (satellite nodules) are macroscopicthe new TNM classiﬁcation [28,29], as follows. or microscopic carcinomatous nests or nodules in the peri-pN0 No regional lymph node metastasis colorectal adipose tissue lymph drainage area of a primarypN1 Metastasis in 1–3 regional lymph nodes carcinoma without histologic evidence of residual lymph node pN1a Metastasis in 1 regional lymph node tissue [28,29]. They may represent discontinuous spread of pN1b Metastasis in 2–3 regional lymph nodes the tumor, venous invasion with extravascular spread or to- pN1c Tumor deposit(s), i.e., satellites, in the sub- tally replaced lymph nodes. According to the latest edition serosa, or in non-peritonealized pericolic or of the TNM classiﬁcation, if a nodule is considered by the perirectal soft tissue without regional lymph pathologist to be a totally replaced lymph node (generally node metastasis having a smooth contour), it should be recorded as a positivepN2 Metastasis in 4 or more regional lymph nodes lymph node and not as a satellite. In addition, pT1–2 lesions pN2a Metastasis in 4–6 regional lymph nodes that lack regional lymph node metastasis but have tumor pN2b Metastasis in 7 or more regional lymph nodes deposit(s) will be classiﬁed as pN1c whereas the pT category With respect to the previous edition a subdivision of pN1 is unchanged. There is no general agreement on the classiﬁ-and pN2 categories has been introduced, reﬂecting differences cation of pericolic tumor nodules [24,40] and probably thesein clinical outcome observed within each category on the new statements of the TNM classiﬁcation will not be acceptedbasis of the number of affected lymph nodes [31,32]. by part of the pathologists . Tumor deposits are associated Histological examination of a regional lymphadenectomy with unfavourable disease outcome  and therefore theirspecimen ordinarily includes 12 or more lymph nodes. If presence and number should be separately recorded .the lymph nodes are negative, but the number ordinarily [Diagnostic strength: Level 2]examined is not met, the tumor will be classiﬁed as pN0. Allmacroscopically evident lymph nodes in the surgical specimen 9.6. Response to neoadjuvant therapy [27,42] [Diagnosticshould be dissected and examined histologically. Many factors strength: Level 2]inﬂuence lymph node recovery and evaluation, such as extentof surgical resection, quality of pathologic examination, Preoperative (neoadjuvant) chemo- and radiotherapy forpatient factors, and tumor characteristics [35,36]. The mean rectal cancer induces several secondary changes includingnumber of nodes detected in a series of dissections is now tumor regression and downstaging [42,43]. In the case ofconsidered to be indicative of colon cancer quality care  rectal cancers treated with neoadjuvant therapy pathologicand should be comprised between 12 and 15 . As nodal staging should be performed according to the ypTNM systemmetastases in colorectal cancer are often found in small lymph and based on evaluation of viable cancer cells. Marked tumornodes (<5 mm in diameter), meticulous search is required on regression and especially complete tumor eradication aregross examination by the pathologist. If less than 12 lymph associated with better clinical outcome. Therefore, specimensnodes are retrieved, re-examining the specimen could be from patients treated with neoadjuvant therapy should beuseful. Use of visual enhancement techniques and inclusion of carefully examined and extensively sampled in particularpericolic fat are not generally recommended. In rectal cancer to demonstrate complete tumor regression. Several systems
G. Lanza et al. / Digestive and Liver Disease 43S (2011) S344–S355 S353for grading tumor regression have been proposed and there 10.1. KRAS mutation [48,49] [Diagnostic strength: Level 3]is no general consensus on the histological classiﬁcationof this parameter. However, 3-tiered grading systems have Presence of KRAS gene mutations (codons 12 and 13)been generally recommended by National and International is associated with lack of clinical response to therapy withAssociations [24,26,27,29]. We suggest the use of the grading monoclonal antibodies (cetuximab and panitumumab) di-system proposed by the Royal College of Pathologists, which rected against the epidermal growth factor receptor (EGFR)includes the following categories: in metastatic colorectal cancer. Actually, tumors of patients • No residual tumor cells and/or mucus lakes only (complete with metastatic disease who are candidates for anti-EGFR regression) antibody therapy have to be tested for KRAS mutations and • Minimal residual tumor, i.e. only occasional microscopic only patients whose tumors show absence of KRAS mutations tumor foci are identiﬁed with difﬁculty at codon 12 or 13 can be treated with anti-EGFR antibodies. • No marked regression However, only a fraction of patients with KRAS wild type According to the TNM classiﬁcation, cases with complete carcinomas will respond to anti-EGFR antibody treatment andregression are recorded as ypT0. further predictive molecular markers are actively investigated nowadays .9.7. Vascular invasion [26,27] [Diagnostic strength: Level 2] 10.2. DNA mismatch repair status  [Diagnostic strength: Venous invasion has been shown in several studies to be an Level 2]independent negative prognostic factor in colorectal cancer.In particular, invasion of large extramural veins has been About 15% of colorectal cancers are characterized by MSIrepeatedly associated with increased risk of cancer-related (or MSI-H, high frequency MSI), which is determined by im-death. The prognostic value of intramural venous invasion and paired function of the MMR system. Most MSI-H carcinomasof invasion of lymphatics or thin-walled vessels is less clear. (about 70%) are sporadic and produced by somatic biallelicWe believe that extramural vein invasion should be always promoter methylation of the MLH1 gene. It is believed thatreported, whereas reporting of intramural and thin-walled sporadic MSI colorectal carcinomas develop through the CpGstructures is optional. island methylator pathway. The other MSI-H tumors are Elastic ﬁber stains could help in the recognition of venous hereditary and caused by germline mutation of a MMR geneinvasion, when suspected, on haematoxylin and eosin stained (MLH1, MSH2, and less frequently MSH6 and PMS2) withsections; however routine use of elastic stains, as recently somatic inactivation of the remaining wild type allele (Lynchsuggested, is not at present recommended. syndrome). Genetic or epigenetic inactivation of MMR genes is nearly always associated with immunohistochemical loss9.8. Additional histologic prognostic factors of expression of the corresponding protein. Furthermore, as MMR proteins work as heterodimers (MSH2 dimerizes Several other histopathologic variables, including perineu- with MSH6, and MLH1 with PMS2) abnormalities of theral invasion, pattern of growth, lymphocytic inﬁltration at obligatory partners (MSH2 and MLH1) will result in prote-the tumor margin, tumor inﬁltrating lymphocytes (TILs), olytic degradation of their dimer and concurrent loss of bothCrohn-like reaction, and tumor budding have been proposed the obligatory and secondary partner proteins (MSH2/MSH6as prognostic factors in colorectal cancer. These parameters and MLH1/PMS2). Conversely, mutations in genes of theare not commonly employed in the clinical setting and their secondary partner proteins (MSH6 and PMS2) will be char-reporting is optional. Nowadays, tumor budding  and acterized by selective loss of MSH6 and PMS2 expressiongrade of intratumoral lymphocytic inﬁltration  represent respectively, as their function may be compensated by otherthe most promising prognostic factors to be introduced in proteins . Therefore, immunohistochemical pattern ofthe pathologic evaluation of these tumors, provided that their MMR protein expression allows the identiﬁcation of the geneassessment will be standardized and their prognostic value that is most likely inactivated. Several studies demonstratedclearly deﬁned. an excellent correlation of the results obtained by immunohis- tochemistry and MSI analysis and both methods can be used conﬁdently for the identiﬁcation of MMR-deﬁcient colorectal10. Molecular prognostic and predictive factors [46,47] carcinomas. However, a small fraction of hereditary cases having a missense mutation (generally of MLH1) that lead to Much effort has been produced to identify immunohisto- a nonfunctional protein with intact antigenicity might result inchemical, biologic and molecular prognostic and predictive MSI-H with intact expression of MMR proteins.factors to be utilized in the management of patients with Lynch syndrome accounts for 2–3% of the total burdencolorectal cancer [46,47]. Actually, only KRAS mutational of large bowel carcinomas. MSI testing and immunohisto-status analysis and evaluation of proﬁciency of the DNA chemical analysis of MMR proteins expression are worldwidemismatch repair (MMR) system by immunohistochemistry employed for the identiﬁcation of colorectal cancer patientsand microsatellite instability (MSI) analysis are employed in with presumptive Lynch syndrome, to be tested for MMRclinical practice. genes germline mutations after appropriate genetic coun-
S354 G. Lanza et al. / Digestive and Liver Disease 43S (2011) S344–S355selling. It is recommended that MSI testing should be carried  Snover DC. Serrated polyps of the large intestine. Semin Diagn Patholout on tumors from patients clinically at high risk or selected 2005;22:301–8.on the basis of the revised Bethesda guidelines . However,  O’Brien MJ, Yang, S., Huang, C.S., et al. The serrated polyp pathway to colorectal carcinoma. Diagn Histopathol 2008;14:78–93.molecular screening investigations performed by MSI and/or  Farris AB, Misdraji J, Srivastava A, et al. Sessile Serrated Adenoma:immunohistochemical analysis on large series of unselected Challenging Discrimination From Other Serrated Colonic Polyps. Amsurgically removed colorectal cancers followed by MMR J Surg Pathol 2008;32:30–5.genes mutation analysis have indicated that a large fraction of  Torlakovic EE, Gomez JD, Driman DK, et al. Sessile Serrated Ade-Lynch syndrome cases would go unrecognized using common noma (SSA) vs. Traditional Serrated Adenoma (TSA). Am J Surg Pathol 2008;32:21–9.criteria of selection, and some Authors suggest screening all  Hornick JL, Odze RD. Polyps of the large intestine. In: Odze RD,colorectal carcinomas for MSI or abnormal MMR protein editor. Surgical pathology of the GI tract, liver, biliary tract, andexpression. pancreas. Philadelphia: Saunders, 2009:481–533. Recent studies have shown that sporadic MSI-H MLH1-  Schreibman IR, Baker M, Amos C, et al. The hamartomatous poly-negative tumors frequently harbour BRAF V600E gene mu- posis syndromes: a clinical and molecular review. Am J Gastroenteroltation. Conversely, BRAF mutations have not been detected 2005;100:476–90.  McGarrity TJ, Kulin HE, Zaino RJ. Peutz-Jeghers syndrome. Am Jin MSI-H MLH1-negative tumors from patients with Lynch Gastroenterol 2000;95:596–604.syndrome. Therefore, BRAF gene mutation analysis could  van Lier MG, Wagner A, Mathus-Vliegen EM, et al. High cancerbe employed as an aid for discriminating hereditary from risk in Peutz-Jeghers syndrome: a systematic review and surveillancesporadic MLH1-negative MMR-deﬁcient carcinomas . recommendations. Am J Gastroenterol 2010;105:1258–64; author reply, MMR status has been demonstrated to be an independent 1265.prognostic factor in colorectal cancer. In fact, several studies  Galiatsatos P, Foulkes WD. Familial adenomatous polyposis. Am J Gastroenterol 2006;101:385–98.displayed higher survival rates for patients with stage II and III  Soravia C, Berk T, Madlensky L, et al. Genotype-phenotype corre-MSI carcinomas with respect to patients with non-MSI tumors lations in attenuated adenomatous polyposis coli. Am J Hum Genet[54,55]. In addition, emerging data suggest that patients with 1998;62:1290–301.MSI tumors do not have signiﬁcant beneﬁt from adjuvant 5-  Sieber OM, Lipton L, Crabtree M, et al. Multiple colorectal adenomas,ﬂuorouracil-based chemotherapy [54,56]. However, the use of classic adenomatous polyposis, and germ-line mutations in MYH. N Engl J Med 2003;348:791–9.MMR status assessment as a prognostic and predictive test has  Burt R, Jass JR. Hyperplastic polyposis. In: Hamilton SR et al., editor.not yet been validated and incorporated into clinical practice. World Health Organization classiﬁcation of tumors. Pathology and genetics. Tumours of the digestive system. Lyon, France: IARC Press, 2000:135–6.Conﬂict of interest  Redston M. Epithelial neoplasms of the large intestine. In: Odze RD, editor. Surgical pathology of the GI tract, liver, biliary tract, and pancreas. Philadelphia: Saunders, 2009:597–637. The authors declare no conﬂict of interest.  Jass JR. 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