colorectal cancer staging

Colorectal cancer is the third most common malignancy in both men and women, and the second leading cause of cancer-related death in western developed countries.

Currently, the tumor stage remains to be the most important determinant of prognosis in colorectal cancer and it is the basis for the authoritative patient management guidelines that influence most patient management decisions.

The International Union Against Cancer (UICC)/American Joint Committee on Cancer (AJCC) TNM classification system is the principal staging systems utilized and therapeutic decisions are most often based on this classification system.

Great changes in the TNM staging system for colorectal cancer have occurred from the 5th edition to the 7th edition, particularly regarding the pN classification.

N Lymph nodes

Stage-related outcome data are derived from studies in which the pathologic evaluation of the regional lymph nodes has been performed by conventional histologic staining of macroscopically identified lymph nodes.

Because it has been shown that many nodal metastases in colorectal cancer are found in small lymph nodes (less than 5 mm in diameter), diligent search for lymph nodes in resection specimens is essential.

The number of lymph nodes recovered from resection specimens varies widely and is dependent on several factors: patient factors such as age and anatomic variation, surgical technique, and diligence of the pathologist in harvesting all existing nodes.

It has been shown that a minimum of 12 to 18 lymph nodes must be examined to accurately predict regional node negativity in colorectal cancer.

For this reason it has been suggested that 12 lymph nodes be considered the minimum acceptable harvest from a careful specimen dissection. If fewer than 12 nodes are found after careful gross examination, additional techniques (ie, visual enhancement techniques such as fat clearing) may be considered.

It has been further recommended that all lymph nodes grossly negative or equivocal for tumor be submitted entirely for microscopic examination and that involvement of lymph nodes grossly positive for tumor be confirmed by either complete or partial microscopic examination.

At present, routine assessment of regional lymph node metastasis is limited to the use of conventional pathologic techniques (gross assessment and histologic examination of 1 tissue level).

Regional lymph nodes must be examined separately from lymph nodes outside of the anatomic site of the tumor because metastasis in any lymph node in the regional nodal group is classified as pN disease, whereas all other nodal metastases are classified as pM1.

On microscopic examination, tumor in a regional lymph node, whether arriving there via afferent lymphatics or direct invasion through the capsule, is regarded as metastatic disease.

Tumor deposits

Microscopic examination of the extramural adipose tissue may reveal discrete nodules of tumor that may represent lymph nodes that have been replaced by metastatic tumor but cannot be identified as such with certainty.

By AJCC/UICC convention, extramural tumor nodules of any size with smooth contours are counted as replaced regional lymph nodes.For purposes of pN assignment, each nodule is counted separately as a node positive for tumor.

This rule is based on evidence suggesting that pericolonic tumor deposits of any size correlate with shorter survival and do so independently of otherwise observable lymph node metastasis. The evidence also indicates that the number of pericolonic tumor correlates inversely with disease-free survival.

Multisite extension and lymph nodes

Occasionally, a colorectal cancer may involve more than 1 site or subsite by continuous longitudinal extension. For example, a cecal carcinoma may extend across the ileocecal valve into the ileum. In these cases, the regional lymph nodes are defined as those of all involved sites and subsites. In rare cases, the regional nodes of the primary tumor site are free of malignancy, but the nodes in the drainage area of an organ directly invaded by the primary tumor contain metastases.

In this circumstance, the lymph nodes of the invaded site are considered as those of the primary site and are classified in the N category.

Increasingly, attention is being focused on alternative methods of detection of very small amounts of metastatic tumor. To assess the biologic significance and clinical impact of minute amounts of tumor detected in metastatic sites, it is imperative to collect data using uniform diagnostic and reporting criteria such as those defined by the AJCC and UICC.

Isolated tumor cells (ITC)

Isolated tumor cells (ITC) have been defined as small numbers of tumor cells detected only by special techniques or seen histologically but measuring 0.2 mm or less.

According to current recommendations, ITCs are classified as N0 or M0, as appropriate.

Because the biologic significance of ITC (a single focus in a single node, multiple foci within a single node, or micrometastatic involvement of multiple nodes) is as yet unproved, N0 is considered justified.

In contrast, small amounts of metastatic tumor that measure greater than 0.2 mm but less than 2.0 mm are defined as micrometastases and classified as N1 or M1. The conventions for reporting of ITCs and micrometastases are shown in detail in Table 3.

The number of lymph nodes involved by micrometastases or ITC should be clearly stated in the pathology report.

Currently, however, 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) or polymerase chain reaction techniques to identify tumor RNA/DNA. Furthermore, all of these approaches are costly, and some can be difficult to quality control. Pending definitive data, it is recommended that any ITC reported by the pathologist be accompanied by a note stating that the biologic significance is unknown.

Vascular invasion

By AJCC/UICC convention, tumor cells within the lymphatics or veins of the primary tumor site do not affect the pT classification. Intravascular spread via lymphatic or venous vessels is recorded separately and classified as L1 and V1, respectively.

Conversely, L0 and V0 indicate the absence of lymphovascular and venous invasion, respectively, and always should be recorded explicitly in the pathology report to document that vascular invasion was sought and not found.

In the absence of explicit reporting, the absence of vessel invasion cannot be assumed. All lymphatic vessels are relevant, including those within the primary tumor and peripheral to the primary tumor.

Tumor contained solely within the afferent lymphatic vessels of regional lymph nodes is classified as L1 but N0. To qualify as N1, tumor cells must extend into the node proper (eg, into the subcapsular sinus subjacent to the capsule). In contrast, tumor within the lymphatics of a distant organ is classified as pM1.

Extramural tumor nodules with irregular contours

The UICC recommends that extramural tumor nodules with irregular contours (ie, not smooth and round) be regarded as discontinuous transmural extension and classified as pT3.

Based on the belief that discontinuous transmural extension often occurs as a result of intravenous extension of tumor through the wall followed by centripetal penetration of the vessel into the perivascular soft tissues, it is also recommended that V1 be assigned to irregularly shaped (often stellate) extramural tumor nodules.

pM1

In colorectal cancer, pM1 disease encompasses pathologically documented metastasis to:
 (1) any nonregional lymph node,
 (2) the parenchyma of any distant organ or tissue,
 and/or (3) the peritoneum of any abdominal structure.

Peritoneal fluid cytology positive for tumor and tumor present only in lymphatic vessels of a distant site are also considered pM1 disease. Serosal involvement away from the leading edge of the tumor or omental involvement are also classified as M1.

Excluded from pM1 designation are:
 (1) ITCs found in the bone marrow (such as nodal ITCs, distant ITCs are not classified as metastasis or assigned pM1 because their significance is as yet unproved25)
 (2) tumor foci in the mucosa or submucosa of adjacent bowel, also known as “satellite lesions” or “skip metastasis.”

However, the latter must be distinguished from synchronous primary tumors. Because it is a system designation, M0 can never be assigned from pathological assessment of biopsy or surgical specimens.

Although, strictly speaking, it would be appropriate to asign pMX (signifying that the pathologic status of distant metastasis is unknown and undocumented), this practice is confusing and is now discouraged by the CAP. Pathological assessment sufficient to assign pM0 would require autopsy examination.

Open References

 Compton CC (2006) Key issues in reporting common cancer specimens: problems in pathologic staging of colon cancer. Arch Pathol Lab Med 130: 318–324. http://www.archivesofpathology.org/doi/full/10.1043/1543-2165(2006)130[318:KIIRCC]2.0.CO;2 (Free)

 Colorectal cancer and the 7th revision of the TNM staging system: review of changes and suggestions for uniform pathologic reporting. Obrocea FL, Sajin M, Marinescu EC, Stoica D. Rom J Morphol Embryol. 2011;52(2):537-44. PMID: 21655640 [Free] http://www.rjme.ro/RJME/resources/files/520211537544.pdf

References

 Dukes C. The classification of cancer of the rectum. J Pathol Bacteriol. 1932;35:323-332

 Astler VB, Coller FA. The prognostic significance of direct extension of carcinoma of colon and rectum. Ann Surg. 1954;139:846-852

Michelassi F, Ayala JJ, Balestracci T, et al. Verification of a new clinicopathologic staging system for colorectal adenocarcinoma. Ann Surg. 1991;214:11-18

Fielding LP, Phillips RKS, Fry JS, et al. Prediction of outcome after curative resection for large bowel cancer. Lancet. 1986;8512:904-907

Greene FL, Stewart AK, Norton HJ. A new TNM staging strategy for node-positive (stage III) colon cancer: an analysis of 50042 patients. Ann Surg. 2002;236:416-421

Ueno H, Price AB, Wilkinson KH, et al. A new prognostic staging system for rectal cancer. Ann Surg. 2004;240:832-839

Japanese Society for Cancer of the Colon and Rectum. Japanese Classification of Colorectal Carcinoma. Tokyo, Japan: Kanehara; 1997

Sobin LH, Wittekind C (International Union Against Cancer [UICC]), eds. TNM Classification of Malignant Tumours. 5th ed. New York, NY: Wiley-Liss; 1997

Sobin LH, Wittekind C (International Union Against Cancer [UICC]), eds. TNM Classification of Malignant Tumours. 6th ed. New York, NY: Wiley-Liss; 2002

Akaike H. Information theory and an extension of the maximum likelihood principle. In: Petrov BN, Csaki F, eds. Proceedings of the Second International Symposium on Information Theory. Budapest, Hungary: Akademia Kiado; 1973:267-281