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Updated Protocol for the Examination of Specimens From Patients With Carcinomas of the Colon and Rectum, Excluding Carcinoid Tumors, Lymphomas, Sarcomas, and Tumors of the Vermiform Appendix.

A Basis for Checklists

This protocol is intended to assist pathologists in providing clinically useful and relevant information as a result of the examination of surgical specimens. Use of this protocol is intended to be entirely voluntary. If equally valid protocols or similar documents are applicable, the pathologist is, of course, free to follow those authorities. Indeed, the ultimate judgment regarding the propriety of any specific procedure must be made by the physician in light of the individual circumstances presented by a specific patient or specimen.

It should be understood that adherence to this protocol will not guarantee a successful result. Nevertheless, pathologists are urged to familiarize themselves with the document. Should a physician choose to deviate from the protocol based on the circumstances of a particular patient or specimen, the physician is advised to make a contemporaneous written notation of the reason for the procedure followed.

The College recognizes that this document may be used by hospitals, attorneys, managed care organizations, insurance carriers, and other payers. However, the document was developed solely as a tool to assist pathologists in the diagnostic process by providing information that reflects the state of relevant medical knowledge at the time the protocol was first published. It was not developed for credentialing, litigation, or reimbursement purposes. The College cautions that any uses of the protocol for these purposes involve considerations that are beyond the scope of this document.
PROTOCOL FOR THE EXAMINATION OF SPECIMENS
FROM PATIENTS WITH CARCINOMAS OF THE COLON
AND RECTUM: VERSION 3, UPDATED 1999

I. Incisional (Endoscopic) Biopsy

A. Clinical information

1. Patient identification

a. Name

b. Identification number

c. Age (birth date)

d. Sex

2. Responsible physician(s)

3. Date of procedure

4. Other clinical information

a. Relevant history

(1) Previous colon adenoma(s)/carcinoma(s)

(2) Familial adenomatous polyposis syndrome

(3) Hereditary nonpolyposis colon cancer
syndrome

(4) Familial hamartomatous polyposis syndrome

(5) Inflammatory bowel disease

b. Relevant findings (eg, colonoscopic and/or
imaging studies)

c. Clinical diagnosis (eg, Crohn disease)

d. Procedure (eg, colonoscopic biopsy)

e. Operative findings

f. Anatomic site(s) of specimen(s)

B. Macroscopic examination

1. Specimen

a. Unfixed/fixed (specify fixative)

b. Number of pieces

c. Largest dimension of each piece

d. Description of other tissues (as appropriate)

2. Submit entire specimen for microscopic evaluation

3. Special studies (specify) (eg, histochemistry,
immunohistochemistry, morphometry, DNA
analysis [specify type], cytogenetic analysis

C. Microscopic evaluation

1. Tumor (note A)

a. Histologic type (note B)

b. Histologic grade (note C)

c. Extent of invasion, as appropriate

2. Additional pathologic findings, if present

a. Colitis

b. Adenoma

c. Other(s)

3. Results/status of special studies (specify)

4. Comments

a. Correlation with other specimens, as appropriate

b. Correlation with clinical information, as appropriate

II. Excisional Biopsy, Polypectomy

A. Clinical information

1. Patient identification

a. Name

b. Identification number

c. Age (birth date)

d. Sex

2. Responsible physician(s)

3. Date of procedure

4. Other clinical information

a. Relevant history

(1) Previous colon adenoma(s)/carcinoma(s)

(2) Familial adenomatous polyposis syndrome

(3) Hereditary nonpolyposis colon cancer
syndrome

(4) Familial hamartomatous polyposis syndrome

(5) Inflammatory bowel disease

b. Clinical diagnosis

c. Procedure (eg, polypectomy)

d. Operative findings

e. Anatomic site(s) of specimen(s)

B. Macroscopic examination

1. Specimen

a. Tissue(s) included

b. Unfixed/fixed (specify fixative)

c. Number of pieces

d. Dimensions

e. Orientation (if indicated by surgeon)

f. Descriptive features (eg, color, consistency)

2. Polyp

a. Configuration (eg, pedunculated, sessile)

b. Size (3 dimensions)

c. If pedunculated, length of stalk (margin of
stalk may be inked)

d. Dimension of carcinoma (diameter), if possible

3. Tissue(s) submitted for microscopic evaluation

a. Transverse (coronal) section(s) through polyp,
include

(1) Polyp apex and stalk or base in same section,
if possible

(2) Carcinoma, point of deepest invasion

(3) Longitudinal section of polyp stalk (as
appropriate)

4. Special studies (specify) (eg, histochemistry,
immunohistochemistry, morphometry, DNA
analysis [specify type], cytogenetic analysis)

C. Microscopic evaluation

1. Polyp

a. Histologic type

2. Tumor (carcinoma within polyp)

a. Histologic type (note B)

b. Histologic grade (notes C and D)

c. Extent of invasion (note D)

d. Blood/lymphatic vessel invasion (note D)

e. Distance of carcinoma from margin in millimeters
(note D)

3. Results/status of special studies (specify)

4. Comments

a. Correlation with other specimens, as appropriate

b. Correlation with clinical information, as appropriate

III. Local Excision (Transanal Disk Excision)

A. Clinical information

1. Patient identification

a. Name

b. Identification number

c. Age (birth date)

d. Sex

2. Responsible physician(s)

3. Date of procedure

4. Other clinical information

a. Relevant history

(1) Previous colon adenoma(s)/carcinoma(s)

(2) Familial adenomatous polyposis syndrome

(3) Hereditary nonpolyposis colon cancer
syndrome

(4) Familial hamartomatous polyposis syndrome

(5) Inflammatory bowel disease

b. Relevant findings (eg, colonoscopic and/or
imaging studies)

c. Clinical diagnosis

d. Procedure (eg, transanal resection)

e. Operative findings

f. Anatomic site(s) of specimen(s)

B. Macroscopic examination

1. Specimen

a. Unfixed/fixed (specify fixative)

b. Number of pieces

c. Dimensions

d. Orientation of specimen (if indicated by surgeon)

e. Descriptive characteristics (eg, color, consistency)

f. Layers of colon/rectum present (if grossly
discernible)

g. Results of intraoperative consultation

2. Tumor (note A)

a. Configuration (note E)

b. Dimensions (3 dimensions)

c. Distance of tumor edge from closest margin

d. Estimated depth of invasion

e. Lesions in noncancerous colon/rectum (eg,
colitis, polyps)

3. Additional pathologic findings, if present

4. Tissue(s) submitted for microscopic evaluation

a. Carcinoma, including

(1) Points of deepest penetration (at least 3
sections; optimally 5 sections)

(2) Interface with adjacent colon

(3) Margin(s) closest to tumor edge

b. Frozen section tissue fragment(s)

5. Special studies (specify) (eg, histochemistry,
immunohistochemistry, morphometry, DNA
analysis [specify type], cytogenetic analysis)

C. Microscopic evaluation

1. Tumor

a. Histologic type (note B)

b. Histologic grade (note C)

c. Depth of invasion (note F)

d. Blood/lymphatic vessel invasion (note G)

e. Perineural invasion (note G)

f. Extramural venous invasion (note H)

g. Intratumoral or peritumoral lymphocytic response
(note I)

h. Pattern of growth at tumor periphery (note J)

(1) Infiltrating border

(2) Pushing border

2. Margins

a. Distance of carcinoma from closest mucosal
margin and/or deep margin

3. Additional pathologic findings, if present

a. Colitis

b. Dysplasia

c. Adenomas

d. Hyperplastic polyps

e. Other(s)

4. Results/status of special studies (specify)

5. Comments

a. Correlation with intraoperative consultation

b. Correlation with other specimens, as appropriate

c. Correlation with clinical information, as appropriate

IV. Segmental Resection

A. Clinical information

1. Patient identification

a. Name

b. Identification number

c. Age (birth date)

d. Sex

2. Responsible physician(s)

3. Date of procedure

4. Other clinical information

a. Relevant history

(1) Previous colon adenoma(s)/carcinoma(s)

(2) Familial adenomatous polyposis syndrome

(3) Hereditary nonpolyposis colon cancer
syndrome

(4) Familial hamartomatous polyposis syndrome

(5) Inflammatory bowel disease

b. Relevant findings (eg, colonoscopic and/or
imaging studies)

c. Clinical diagnosis

d. Procedure (eg, right colectomy, transverse
colectomy, left colectomy, sigmoidectomy,
abdomino-perineal resection)

e. Operative findings

f. Anatomic site(s) of specimen(s) (eg, cecum,
right, transverse, descending, sigmoid colon,
or rectum)

B. Macroscopic examination

1. Specimen

a. Organ(s)/tissue(s) included

b. Unfixed/fixed (specify fixative)

c. Number of pieces

d. Dimensions

e. Orientation of specimen (if indicated by surgeon)

f. Results of intraoperative consultation

2. Tumor

a. Location (note A)

b. Configuration (note E)

c. Dimensions (3 dimensions)

d. Descriptive characteristics (eg, color, consistency)

e. Ulceration/perforation

f. Distance from margins (note K)

(1) Proximal

(2) Distal

(3) Radial (soft tissue margin or serosa closest
to deepest tumor penetration)

g. Estimated depth of invasion (note F)

3. Lesions in noncancerous colon/rectum (eg, colitis,
other polyps)

4. Regional lymph nodes (note F)

5. Nonregional lymph nodes (note F)

6. Metastasis to other organ(s) or structure(s)
(note F)

7. Colon/rectum uninvolved by tumor

8. Other tissue(s)/organ(s)

9. Tissues submitted for microscopic evaluation

a. Carcinoma, including

(1) Points of deepest penetration (at least 3
sections; optimally 5 sections)

(2) Interface with adjacent colon/rectum

(3) Visceral serosa overlying tumor

b. Margins (note K)

(1) Proximal

(2) Distal

(3) Radial [circumferential] (soft tissue margin
closest to deepest tumor penetration)

c. All lymph nodes (note F)

d. Other lesions (eg, polyps/colitis)

e. Frozen section tissue fragment(s)

10. Special studies (specify) (eg, histochemistry,
immunohistochemistry, morphometry, DNA
analysis [specify type], cytogenetic analysis)

C. Microscopic evaluation

1. Tumor

a. Histologic type (note B)

b. Histologic grade (note C)

c. Extent of invasion (note F)

d. Blood/lymphatic vessel invasion (note G)

e. Perineural invasion (note G)

f. Extramural venous invasion (note H)

g. Intratumoral or peritumoral lymphocytic response
(note I)

h. Pattern of growth at tumor periphery (note J)

(1) Infiltrating border

(2) Pushing border

i. Associated pericolorectal abscess formation
(if present)

j. Associated pneumatosis intestinalis (if present)

2. Margins (note K)

a. Proximal

b. Distal

c. Radial (specify distance of carcinoma from
closest radial margin in mm)

3. Regional lymph nodes (note F)

a. Number

b. Number with metastases

4. Additional pathologic findings, if present

a. Inflammatory bowel disease

b. Dysplasia

c. Adenomas

d. Other types of polyps

5. Distant metastasis, specify site (note F)

6. Other tissue(s)/organ(s)

7. Results/status of special studies (specify)

8. Comments

a. Correlation with intraoperative consultation

b. Correlation with other specimens, as appropriate

c. Correlation with clinical information, as appropriate


EXPLANATORY NOTES

A: Anatomic Sites.--The protocol applies to all carcinomas arising in the colon and rectum.[1]

The colon is divided into 4 parts: the right (ascending), the middle (transverse), the left (descending), and the sigmoid. The right colon is subdivided into the cecum (peritoneally located and measuring about 6 x 9 cm) and the ascending colon (located retroperitoneally and measuring 15 to 20 cm long). The descending colon, also located retroperitoneally, is 10 to 15 cm in length. The descending colon becomes the sigmoid colon at the origin of the mesosigmoid, and the sigmoid colon becomes the rectum at the termination of the mesosigmoid. The upper third of the rectosigmoid segment is covered by peritoneum on the front and both sides. The middle third is covered by peritoneum only on the anterior surface. The lower third (also known as the rectum or rectal ampulla) has no peritoneal covering.[1]

Tumors located at the border between 2 subsites of the colon (eg, cecum and ascending colon) are registered as tumors of the subsite that is more involved. If 2 subsites are involved to the same extent, the tumor is classified as an "overlapping" lesion. The rectum is defined clinically as the distal large intestine, which commences opposite the sacral promontory and ends at the upper border of the anal canal. When measuring below with a rigid sigmoidoscope, it extends 16 cm from the anal verge. A tumor is classified as rectal if its inferior margin lies less than 16 cm from the anal verge or if any part of the tumor is located at least partly within the supply of the superior rectal artery.[2] A tumor is classified as rectosigmoid when differentiation between rectum and sigmoid, according to these guidelines, is not possible.[3]

B: Histologic Types.--For consistency in reporting, the histologic classification proposed by the World Health Organization is recommended.[4] However, this protocol does not preclude the use of other systems of classification or histologic types.

World Health Organization Classification of Colorectal Carcinoma

Adenocarcinoma in situ/severe dysplasia(*)

Adenocarcinoma

[Medullary carcinoma]([dagger])

Mucinous (colloid) adenocarcinoma ([is greater than] 50% mucinous)([double dagger])

Signet-ring cell carcinoma ([is greater than] 50% signet-ring cells)([sections])

[Squamous cell (epidermoid) carcinoma

Adenosquamous carcinoma

Small cell (oat cell) carcinoma([sections])

Undifferentiated carcinoma([sections])

Other (specify)([parallel])

(*) To avoid confusion with the term carcinoma in situ as it applies to pTis in the TNM staging (see note F), the term intraepithelial carcinoma should be used to refer to histologically malignant epithelium that does not penetrate the basement membrane (ie, shows no evidence of stromal [lamina propria] invasion).[5,6]

([dagger]) Medullary carcinoma has been added to the revised World Health Organization histologic classification that will be published in 2000. Medullary carcinoma is a histologic type that is strongly associated with a high degree of microsatellite instability (MSI-H) indicative of loss of normal DNA repair gene function.[6-8] With loss of function of any of the genes involved in the repair of mitosis-associated mistakes in DNA synthesis (ie, replication errors), mutations in daughter cells are rapidly accumulated. Ultimately, tumors with defective DNA repair acquire inactivating mutations of genes necessary for complex biological activities such as metastasis. For this reason, tumors with MSI-H, such as most (if not all) medullary carcinomas, have a favorable prognosis compared with microsatellite stable tumors or tumors with low levels of microsatellite instability. Medullary carcinoma may occur either sporadically[7] or in association with the hereditary nonpolyposis colon cancer syndrome.[8] This tumor type is characterized by uniform polygonal tumor cells that exhibit solid growth in nested, organoid, or trabecular patterns and that only focally produce small amounts of mucin. In addition, medullary carcinomas are typically infiltrated by lymphocytes (tumor-infiltrating lymphocytes) and have no immunohistochemical evidence of neuroendocrine differentiation.

([double dagger]) In most previous studies on prognostic factors in colorectal cancer, the impact of genetic status (ie, loss of DNA repair gene function with microsatellite instability) on the relationship between histologic type and outcome has not been considered. This shortfall is particularly relevant to mucinous carcinoma, a histologic type that is common among tumors with MSI-H. Overall most mucinous carcinomas are microsatellite stable. Thus, it is not surprising that the prognostic significance of mucinous carcinoma has proven controversial.[6,9] A few studies, largely limited to univariate analyses, have indicated that mucinous adenocarcinoma may be an adverse prognostic factor. Alternatively, mucinous carcinoma has been linked with adverse outcome only when occurring in specific anatomic regions of the bowel (eg, the rectosigmoid) or in a specific subset of patients (ie, those younger than 45 years). In yet other studies, mucinous carcinoma has been linked to adverse outcome only when mucinous and signet-ring cell carcinomas have been grouped together and compared with typical adenocarcinoma. Data of this type may merely reflect the aggressive biological behavior of most signet-ring cell tumors. Only one multivariate analysis has shown mucinous carcinoma to be a stage-independent predictor of adverse outcome, but the study was limited to tumors presenting with large bowel obstruction, which itself is an adverse prognostic factor.[9]

([sections]) By convention, signet-ring cell carcinomas, small cell carcinomas, and undifferentiated (histologic type) carcinomas are high grade. The only histologic types of colorectal carcinoma that have been shown to have adverse prognostic significance independent of stage are signet-ring cell carcinoma and small cell carcinoma.[9] Nevertheless, signet-ring cell carcinoma may occur in hereditary nonpolyposis colon cancer syndrome in association with MSI-H.[10] Thus, in cases of MSI-H signet-ring cell carcinoma, the prognostic significance may be determined by the molecular pathogenesis and may be favorable.

([parallel]) The term carcinoma, NOS (not otherwise specified) is not part of the World Health Organization classification.

C: Histologic Grade.--A number of grading systems have been suggested in the literature, but a single widely accepted and uniformly used standard for grading is lacking. Among the suggested grading schemes, the number of grades and the criteria for distinguishing among different grades vary markedly. In some systems, grades are defined on the basis of a single microscopic feature, such as the degree of gland formation, and in other systems, a large number of features are included in the evaluation. Irrespective of the complexity of the criteria, however, most systems stratify tumors into 3 or 4 grades as follows:
Grade 1 Well differentiated
Grade 2 Moderately differentiated
Grade 3 Poorly differentiated
Grade 4 Undifferentiated


Appearance of individual histologic features may vary widely enough to make implementation of even the simplest grading systems problematic and, ultimately, subjective. Thus, a significant degree of interobserver variability in the grading of colorectal cancer has been shown to exist.[9,11] Nevertheless, despite this variability, histologic grade has repeatedly been shown by multivariate analysis to be a stage-independent prognostic factor.[9,12,13] Specifically, it has been demonstrated that high tumor grade is an adverse prognostic factor. In most studies documenting the prognostic power of tumor grade,[9] the number of grades has been collapsed to produce a 2-tiered stratification for data analysis as follows:
Low grade Well differentiated and moderately differentiated
High grade Poorly differentiated and undifferentiated


In general practice, a 2-tiered grading system would also be expected to greatly reduce interobserver variability, since the widest variations in grading concern the stratification of low-grade tumors into well- or moderately differentiated categories. Pathologic identification of poorly differentiated or undifferentiated tumors is more consistent, and interobserver variability in diagnosing high-grade carcinoma is relatively small. Therefore, in light of its proven prognostic value, relative simplicity, and reproducibility, a 2-tiered grading system for colorectal carcinoma (ie, low grade and high grade) is recommended.[6] The grading should be based on gland formation alone as follows[6]:
Low grade [is greater than or equal to] 50% gland formation
High grade <50% gland formation


D: Carcinoma in an Adenomatous Polyp.--Colorectal adenomas containing invasive adenocarcinoma that extends through the muscularis mucosae into the submucosa have been defined as malignant polyps. These polyps constitute a form of early (ie, curable) colorectal carcinoma. The definition of malignant polyps excludes adenomas containing in situ carcinoma (also known as intraepithelial carcinoma) and carcinoma either limited to the lamina propria of the polyp mucosa or invading no deeper than the muscularis mucosae (intramucosal carcinoma), because these polyps possess no biological potential for metastasis. The term malignant polyp encompasses both polypoid carcinomas in which the entire polyp head is replaced by carcinoma and adenomas with focal malignancy.

Malignant polyps removed by endoscopic polypectomy require evaluation of histologic parameters that have been determined to be significant prognostic factors related to the risk of adverse outcome (ie, lymph node metastasis or local recurrence from residual malignancy) following polypectomy.[9,14-30] Pathologic features that have been shown to have independent prognostic significance and are crucial for evaluating risk and determining the possible need for further surgical treatment (ie, segmental colectomy) include the following: histologic grade of the carcinoma, extent (level) of invasion of the carcinoma within the polyp, status of the resection margin, and lymphatic/venous vessel involvement.

Specifically, an increased risk of adverse outcome has been shown to be associated with high-grade (poorly differentiated) carcinoma, tumor at or less than 1 mm from the resection margin, and presence of lymphatic/venous vessel involvement.

E: Tumor Configuration.--Configurations include exophytic (fungating), endophytic (ulcerative), and diffusely infiltrative (linitis plastica) or annular, but overlap among these types is common. Exophytic is divided into pedunculated and sessile. Overall gross tumor configuration has no independent influence on prognosis.[6,9] The uncommon linitis plastica type represents a possible exception. It has an unfavorable prognosis, but its association with adverse outcome is probably related to the underlying histologic type of tumor (signet-ring cell carcinoma) rather than the macroscopic configuration itself.

F: TNM and Stage Groupings.--Surgical resection remains the most effective therapy for colorectal carcinoma, and the best estimation of prognosis is related to the pathologic findings on the resection specimen. The anatomic extent of disease is by far the most important prognostic factor.[12]

The protocol recommends the TNM staging system of the AJCC/UICC[1,31] but does not preclude the use of other staging systems.
Tumor (T)(*)

TX Primary tumor cannot be assessed

TO No evidence of primary tumor

Tis Carcinoma in situ, intraepithelial or invasion of the
 lamina propria or muscularis mucosae([dagger])

T1 Tumor invades the submucosa

T2 Tumor invades the muscularis propria

T3 Tumor invades through the muscularis propria
 into the subserosa or into the nonperitonealized
 pericolic or perirectal tissues([double dagger])

 pT3a Minimal invasion: <1 mm beyond the border
 of the muscularis propria

 pT3b Slight invasion: 1 to 5 mm beyond the border
 of the muscularis propria

 pT3c Moderate invasion: >5 to 15 mm beyond
 the border of the muscularis propria

 pT3d Extensive invasion: >15 mm beyond the
 border of the muscularis propria

T4 Tumor directly invades other organs or structures[sections]
 (T4a) or perforates the visceral peritoneum([parallel]) (T4b)


(*) The designation T refers to the first resection of a primary tumor The symbol pT refers to the pathologic classification of the TNM as opposed to the clinical classification. Pathologic classification is based on gross and microscopic examination. pT entails a resection of the primary tumor or biopsy sample adequate to evaluate the highest pT category; pN entails removal of nodes adequate to validate lymph node metastasis; and pM implies microscopic examination of distant lesions. Clinical classification (cTNM) is usually performed by the referring physician before treatment during initial evaluation of the patient or when pathologic classification is not possible and is typically based on information obtained by physical examination, serologic analyses, imaging studies, etc.[1]

Tumor remaining in a patient after primary therapy (eg, surgical resection) is categorized by a system known as R classification.[1,6,12] For example, this classification may be used by the surgeon to indicate the known or assumed status of the completeness of the surgical resection. For the pathologist, the R classification is relevant only to the margins of surgical resection specimens. That is, tumor involving the proximal distal or radial (circumferential) resection margin (see note K) on pathologic examination may be assumed to correspond to residual tumor in patient and classified as to whether the involvement is macroscopic or microscopic.[6]
RX Presence of residual tumor cannot be assessed
R0 No residual tumor
R1 Microscopic residual tumor
R2 Macroscopic residual tumor


Tumor remaining in a resection specimen following previous (neoadjuvant) treatment of any type (radiation therapy alone, chemotherapy therapy alone, or any combined modality treatment) is codified by the TNM using a prescript "y" to indicate the posttreatment status of the tumor (eg, ypT1).[1,6] For many therapies, the classification of residual disease has been shown to be a strong predictor of postoperative outcome. In addition, the ypTNM classification provides a standardized framework for the collection of data needed to accurately evaluate new neoadjuvant therapies.

Tumor that is locally recurrent after a documented disease-free interval following surgical resection is classified according to the TNM categories but modified with the prefix "r" (eg, rpT1). By convention, the recurrent tumor is topographically assigned to the proximal segment of the anastomosis unless that segment is small intestine.[1,13]

([dagger]) For colorectal carcinomas, carcinoma in situ (Tis) as a staging term includes cancer cells confined within the glandular basement membrane (intraepithelial carcinoma) or invasive into the mucosal lamina propria, up to but not through the muscularis mucosae (intramucosal carcinoma). This may be confusing because, in all other organ systems, the term carcinoma in situ is used to refer exclusively to malignant neoplasms that do not invade the underlying stroma. Therefore, for colorectal cancer, the terms intraepithelial carcinoma and intramucosal carcinoma are recommended as descriptive terms to subclassify pTis and to clarify the status of the tumor.[5,6] Tumor extension through the muscularis mucosae into the submucosa is classified as T1. Some pathologists classify intraepithelial carcinoma as severe or high-grade dysplasia, especially in cases of inflammatory bowel disease.

([double dagger]) The extent of perimuscular invasion has been reported to influence prognosis, regardless of whether regional lymph node metastasis is present. Thus, an optional expansion pT3 has been proposed.[3] Extramural extension greater than 5 mm has been shown to be the critical subdivision associated with adverse outcome in most studies. Thus, a simpler subdivision, based on extension of 5 mm or less versus greater than 5 mm (ie, pT3a,b vs pT3c, d), may be justified.[3] Extension of the tumor within lymphatics or veins does not count as local spread of tumor as defined by the T classification.[3]

([sections]) Direct invasion of other organs or structures includes invasion of other segments of colorectum by way of the serosa or mesocolon, for example, invasion of the sigmoid colon by carcinoma of the cecum. Intramural extension of tumor from one subsite (segment) of the large intestine into an adjacent subsite or into the ileum (eg, for a cecal carcinoma) or anal canal (eg, for a rectal carcinoma) does not affect the pT classification.[3]

([parallel]) Perforation of carcinoma through a peritonealized surface of the colon is classified as T4b.[3] Subdivision of T4 into T4a and b is justified, because a number of large studies that have evaluated serosal penetration as an independent prognostic variable have demonstrated by multivariate analysis that it has a strong negative impact on prognosis.[32-35] Specifically, it has been shown that the frequency of distant metastasis is higher in cases with perforation of the visceral peritoneum compared with cases with direct invasion of adjacent organs or structures without perforation of the visceral peritoneum (occurring in about 50% and 30% of cases, respectively).[3] Furthermore, the median survival time following surgical resection for cure has been shown to be shorter for patients with pT4b tumors compared with those with pT4a tumors (with or without distant metastasis) as follows.[3]
 5-Year Median
 Survival Survival
Tumor Rate, % Time, mo

pT4a, M0 49 58.2
pT4b, M0 43 46.2
pT4a, M1 12 22.7
pT4b, M1 0 15.5


A study by Shepherd et al[34] has suggested that the prognostic power of local peritoneal involvement in curative resections may supersede that of either local extent of tumor (T category) or regional lymph node status (N category). However, serosal penetration is often difficult to assess histopathologically and may be underdiagnosed. Documentation of peritoneal involvement by tumor demands meticulous pathologic analysis and may require extensive sampling and/or serial sectioning and can be missed on routine histopathologic examination. It has been shown that cytologic examination of serosal scrapings reveals malignant cells in as many as 26% of tumor specimens categorized as pT3 by histologic examination alone.[34,36] In addition, the histopathologic findings associated with peritoneal penetration are heterogeneous, and standard guidelines for their diagnostic interpretation are lacking. Therefore, interobserver variability in the diagnosis of peritoneal penetration may be substantial and since most pathologists tend to err on the side of conservative interpretation, underdiagnosis is likely for this reason as well.

Shepherd et al[34] analyzed the spectrum of microscopic features that may be seen with local peritoneal involvement by tumor and defined 3 types of local peritoneal involvement as follows:

(1) A mesothelial inflammatory and/or hyperplastic reaction with tumor close to, but not at, the serosal surface

(2) Tumor present at the serosal surface with inflammatory reaction, mesothelial hyperplasia, and/or erosion/ ulceration

(3) Free tumor cells on the serosal surface (in the peritoneum) with underlying ulceration of the visceral peritoneum

All 3 types of local peritoneal involvement were associated with decreased survival whereas tumor well clear of the serosal had no independent adverse effect on prognosis. Therefore, the diagnosis of T4b should encompass these 3 types of serosal involvement.[6]
Regional Lymph Nodes (N)(*)

NX Regional lymph nodes cannot be assessed

NO No regional lymph node metastasis

N1 Metastasis in 1 to 3 lymph nodes

N2 Metastasis in 4 or more lymph nodes([dagger])
 ([double dagger])


(*) The regional lymph nodes for the anatomic subsites of the large intestine are as follows:

Cecum--anterior cecal posterior cecal ileocolic, right colic

Ascending colon--ileocolic, right colic, middle colic

Hepatic flexure--middle colic, right colic

Transverse colon--middle colic

Splenic flexure--middle colic, left colic, inferior mesenteric

Descending colon--left colic, inferior mesenteric, sigmoid

Sigmoid colon--inferior mesenteric, superior rectal sigmoidal, sigmoid mesenteric

Rectosigmoid--perirectal, left colic, sigmoid mesenteric, sigmoidal, inferior mesenteric, superior rectal, middle rectal

Rectum--perirectal, sigmoid mesenteric, inferior mesenteric, lateral sacral, presacral, internal iliac, sacral promontory, superior rectal, middle rectal inferior rectal

([dagger]) Nodes along the sigmoid arteries are considered pericolic nodes, and their involvement is classified as N1 or N2 according to the number involved.

([double dagger]) Perirectal lymph nodes include the mesorectal (paraproctal), lateral sacral, presacral, sacral promontory (Gerota), middle rectal (hemorrhoidal), and inferior rectal (hemorrhoidal) nodes. Metastasis in the external iliac or common iliac nodes is classified as distant metastasis.[3]

Important Notes on Lymph Nodes

Submission of Lymph Nodes for Microscopic Examination.--All grossly negative or equivocal lymph nodes are to be submitted entirely.[6] Grossly positive lymph nodes may be partially submitted for microscopic confirmation of metastasis.

It has been shown that 12 negative lymph nodes predict for regional node negativity. Therefore, if fewer than 12 nodes are found, additional techniques (ie, visual enhancement techniques) should be considered. If fewer than 12 nodes are found after the use of visual enhancement techniques, this should be communicated in the pathology report. The pathology report should clearly state the total number of lymph nodes examined and the total number involved by metastases. Data are insufficient to recommend routine use of tissue levels or special/ancillary techniques.[6]

Nonregional Lymph Nodes.--For microscopic examination of lymph nodes in large resection specimens, lymph nodes must be designated as regional versus nonregional according to the anatomic location of the tumor. Metastasis to nonregional lymph nodes is classified as distant metastasis and designated as M1.

Lymph Nodes Replaced by Tumor.--A tumor nodule greater than 3 mm in diameter in the perirectal or pericolonic adipose tissue without histologic evidence of residual lymph node in the nodule is classified as regional perirectal/pericolonic node metastasis. However, a tumor nodule less than or equal to 3 mm in diameter is classified in the T category as discontinuous extension (ie, T3).[1,3] Multiple metastatic foci seen microscopically only in the pericolonic fat should be considered as metastasis in a single lymph node for classification.[1]

Micrometastasis.--Routine assessment of regional lymph node metastasis is limited to the use of conventional pathologic techniques (gross assessment and histologic examination). A solitary focus of tumor in a single lymph node that is visualized by routine histologic examination and measures 2.0 mm or less may be defined as a micrometastasis. The biological significance of micrometastatic disease (a single focus in a single node, multiple foci within a single node, or micrometastatic involvement of multiple nodes) as yet is unproved. Pending definitive studies, it is recommended that micrometastases be classified as pN1 but reported with a note explaining that the biological significance is unknown. The number of lymph nodes involved by micrometastases should be clearly stated.[6]

The biological significance of metastasis detected only by special studies (eg, immunohistochemical staining or molecular analysis) is also unproved at present. It is recommended that metastasis diagnosed using special studies alone also be reported with a note explaining the unknown significance of the findings but, in contrast to histologically identified micrometastases, be classified as pN0.[6] Currently, the data are insufficient to recommend either the routine examination of multiple tissue levels of paraffin blocks or the use of special/ancillary techniques such as immunohistochemistry for epithelial and/or tumor-associated antigens (eg, cytokeratin, carcinoembryonic antigen, etc) or polymerase chain reaction techniques to identify tumor RNA and DNA.[6]
Distant Metastasis (M)

MX Presence of distant metastasis cannot be assessed
M0 No distant metastasis
MI Distant metastasis(*)


(*) Seeding of abdominal organs is classified as M1.
TNM Stage
Groupings Modified Astler-Coller Stage

Stage 0
 Tis N0 M0 Stage A
Stage I
 T1 N0 M0 Not applicable
 T2 N0 M0 Stage B1
Stage II
 T3 N0 M0 Stage B2
 T4 N0 M0 Stage B3
Stage III
 Any T N1 M0 Stage C1 (T2), C2 (T3), C3 (T4)
 Any T N2 M0 Stage C1 (T2), C2 (T3), C3 (T4)
Stage IV
 Any T any N M1 Stage D


G: Lymphatic (Thin-Walled) Vessel and Perineural Invasion.--In several studies, both lymphatic invasion and perineural invasion have been shown by multivariate analysis to be independent indicators of poor prognosis.[13,30,32,37,38] The prognostic significance, if any, of the anatomic location of these structures is not defined. Furthermore, it is not always possible to distinguish lymphatic vessels from postcapillary venules, since both are small thin-walled structures. Thus, the presence or absence of tumor invasion of small thin-walled vessels should be reported in all cases and its anatomic location within the colonic wall noted.[6]

H: Venous Invasion.--Extramural venous invasion has been demonstrated by multivariate analysis to be an independent adverse prognostic factor.[13,32,38-41] Invasion of extramural veins, in particular, has been shown to be an independent indicator of unfavorable outcome and increased risk of occurrence of hepatic metastasis.[40,41] It has been shown that the submission of 5 or more blocks of tumor significantly enhances the likelihood of finding extramural venous invasion when it exists and reduces false negativity due to sampling error.[42]

The significance of intramural venous invasion is less clear, because data specific to this issue are lacking. Nevertheless, it is recommended that the presence or absence of venous invasion and its anatomic location should be reported in all cases.[6]

I: Lymphocytic Response to Tumor.--A conspicuous lymphoid reaction at the leading edge of invasive tumor and the presence of lymphoid aggregates in the surrounding tissues (muscularis external and pericolonic or perirectal fat) have both been shown in small studies to be independent favorable prognostic factors.[11,41,43-45] Intratumoral lymphocytic infiltrates are closely associated with microsatellite instability and medullary architecture and should be distinguished from peritumoral infiltrates. Only moderate and high-density intratumoral lymphocytes (approximately 4 or more per high-power field) should be considered significant.[6] Reporting of host lymphoid response is optional. If reported, distinction should be made between peritumoral and intratumoral lymphoid infiltrates.

J: Tumor Periphery: Growth Pattern.--The growth pattern of the tumor at the advancing edge has been shown to have prognostic significance independent-of stage and may predict liver metastasis.[46-52] Specifically, an infiltrating pattern of growth at the tumor border as opposed to a pushing border is an adverse prognostic factor.

Infiltrating borders have been defined as follows[47]:

Naked eye examination

* Inability to define limits of invasive border of tumor and/or

* Inability to resolve host tissue from malignant tissue

Microscopic Examination of Slides

* "Streaming dissection" of muscularis propria (dissection of tumor through the full thickness of the muscularis propria without stromal response) and/or

* Dissection of mesenteric adipose tissue by small glands or irregular clusters or cords of cells and/or

* Perineural invasion

Irregular growth at the tumor periphery has also been referred to as focal dedifferentiation and tumor budding and defined as microscopic clusters of undifferentiated cancer cells just ahead of the invasive front of the tumor.

K: Margins.--It may be helpful to mark the margin(s) closest to the tumor with ink. Margins marked by ink should be designated in the macroscopic description. Margins include the proximal distal and radial margins. The radial margin represents the adventitial soft tissue margin closest to the deepest penetration of tumor. For all segments of the large intestine that are either incompletely encased (ascending colon, descending colon, sigmoid colon, upper rectum) or not encased (lower rectum) by peritoneum, the radial margin is created by blunt dissection of the retroperitoneal or subperitoneal aspect, respectively, at operation.

The radial margin has been demonstrated to be of importance in relation to risk of local recurrence after surgical resection of the rectal carcinomas.[53-55] Multivariate analysis has suggested that tumor involvement of the radial margin is the most critical factor in predicting local recurrence in rectal cancer.[53-55] For this reason, routine assessment of the radial margin is suggested in all colorectal cancers, and measurement of the distance from the tumor to the radial margin, representing the surgical clearance around the tumor is suggested.[56] For segments of the colon that are completely encased by a peritonealized (serosal) surface (eg, transverse colon), the only radial margin is the mesenteric resection margin, and it is relevant when the point of deepest penetration of the tumor is on the mesenteric aspect of the colon and extends to this margin, with or without penetrating the serosal surface. For those tumors limited to an antimesenteric peritonealized aspect of the bowel the radial margin is not relevant.

Because of its association with local recurrence, involvement of the radial margin has implications for adjuvant therapy. Whether the primary tumor is T3 (without serosal penetration) or T4b (with serosal penetration), resection is considered complete only if all surgical margins are negative, including the radial margin. That is, whether or not the tumor penetrates a serosal surface, resection is considered complete if the resection margins (proximal distal and radial) do not contain tumor. If a radial margin is involved by tumor, adjuvant therapy (eg, local radiation) may be appropriate.

Sections to evaluate the proximal and distal resection margins can be obtained in 2 orientations: (1) en face sections parallel to the margin or (2) longitudinal sections perpendicular to the margin. Depending on the closeness of the tumor to the margin, select the orientation(s) that best demonstrate the status of the margin. The distance from the tumor edge to the closest resection margin(s) should be measured. In cases of carcinoma arising in a background of inflammatory bowel disease, proximal and distal resection margins should be evaluated for dysplasia and active inflammation.

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Accepted for publication January 6, 2000.

From the Department of Pathology, Massachusetts General Hospital, Boston.

This protocol was developed by the Cancer Committee of the College of American Pathologists and submitted for editorial review and publication. It represents the views of the Cancer Committee and is not the official policy of the College of American Pathologists.

Reprints: Joe Schramm, College of American Pathologists, 325 Waukegan Rd, Northfield, IL 60093-2750.
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