Colon and Rectal Cancers: Pathologic Staging and Assessment

A Continuing Medical Education Activity sponsored by InforMEDical Communications, Inc.

InforMEDical Communications, Inc. • 83 Acton Street • Carlisle, MA 01741
tel: 978-318-9582 • fax: 978-318-9583 • email: info@informedicalcme.com

Modifiers of Stage-Based Prognosis

Histological Type

In the pathologic reporting of colorectal cancer, the internationally accepted histological classification of colorectal carcinomas proposed by the World Health Organization (WHO) is recommended by CAP.3,75 According to this classification, most colorectal cancers are adenocarcinomas of no special type. Aside from a few notable exceptions, histological type has no stage-independent prognostic significance. Exceptions include the nongland-forming tumor types, such as signet-ring cell carcinoma, small cell carcinoma, and undifferentiated carcinoma, which are prognostically unfavorable, and medullary carcinoma, which is prognostically favorable. Of note, histopathologic types that are by convention always considered to be of high tumor grade are associated with adverse outcome. Thus, grade, rather than histological type, is likely to be the dominant prognostic factor. The single exception is medullary carcinoma, a distinctive type of nongland-forming carcinoma composed of large polygonal tumor cells and abundant tumor infiltrating lymphocytes, which was added to the revised WHO classification in 2000.75 Previously, this tumor type would have been classified as an undifferentiated carcinoma in the WHO system. The importance of this unique histological type is its strong association with defective DNA replication fidelity and high microsatellite instability, molecular features that are, in turn, associated with a more favorable stage distribution and prognosis than are microsatellite stable tumors. Most tumors of this type occur in the proximal colon in association with hereditary nonpolyposis colon cancer syndrome.

The histological types of colorectal carcinoma as defined by the WHO classification are as follows:75

  • Adenocarcinoma
  • Mucinous (colloid) adenocarcinoma (greater than 50% mucinous)
  • Signet-ring cell carcinoma (greater than 50% signet-ring cells)
  • Squamous cell carcinoma
  • Adenosquamous carcinoma
  • Medullary carcinoma
  • Small cell carcinoma (high-grade neuroendocrine carcinoma)
  • Undifferentiated carcinoma
  • Other

Histological Grade

In general, the grading of colorectal carcinoma is based on architectural features, as well as cytological features (e.g., pleomorphism and hyperchromatism). However, the degree of gland formation is widely regarded as the most important feature in grading.

Therefore, the nongland-forming histological types of colorectal cancer (e.g., signet-ring cell carcinoma, small cell carcinoma, and undifferentiated carcinoma) are always assigned a high tumor grade. In adenocarcinoma, however, estimation of the degree of gland formation and assignment of grade are largely subjective. Lack of uniformity in histopathologic grading is further complicated by the existence in the literature of a number of different grading schemas without widespread acceptance and uniform use of any single system by practicing pathologists. Furthermore, the published systems vary markedly with regard to number, type, and relative importance of the specific features used to distinguish different grades.10 In some systems, grade is based on a single architectural feature, such as degree of gland formation, and in others, a large number of features are included in the evaluation. In rare cases, a suggested grading system has been based solely on cytological criteria. Irrespective of the type or complexity of the criteria, however, most systems stratify tumors as well differentiated (grade 1), moderately differentiated (grade 2), poorly differentiated (grade 3), and sometimes, undifferentiated (grade 4). Grade 4 is somewhat redundant as a category because tumors that shown no histological evidence of differentiation are classified as a specific histological type by the WHO.

In routine practice, the pathologic diagnosis of grades 3 and 4 is relatively consistent, but discrimination between grades 1 and 2 is associated with a more significant degree of interobserver variability. Even in assignment of grade 3 (and grade 4), however, some variation in approach exists. Pathologists may base overall tumor grade on a qualitative impression of the sum of global histological features or on the highest grade features seen anywhere in the neoplasm (whatever their extent), relative proportion of undifferentiated tumor, or degree of differentiation along the advancing edge of the tumor.

Despite the lack of standardization and the documented interobserver variation in assessment, histological grade has been shown repeatedly by multivariate analysis to be a stage-independent prognostic factor.10

More specifically, high tumor grade has been shown to be an adverse prognostic factor. In almost all studies documenting the prognostic power of tumor grade, three- or four-tiered grading schemas have been collapsed for data analysis as follows: low grade (grades 1 and 2) and high grade (grades 3 and 4). Based on these data, a two-tiered grading system (i.e., low-grade and high-grade) for colorectal carcinoma has been recommended by CAP.3 Use of such a system would be expected to maintain the prognostic value of grade in colorectal cancer, while increasing simplicity and reproducibility of assessment; however, consensus is needed as to whether undifferentiated tumor at the advancing edge of the cancer should be evaluated and reported separately or incorporated into the overall tumor grade. At present, available data are insufficient to support one approach over the other.

Serological Factors

For colorectal cancers, pre-operative serum levels of carcinoembryonic antigen (CEA) have long been known to be a site-specific factor of prognostic significance.76,77 Most studies have shown that a pre-operative CEA level of >5-10 ng/ml is associated with poorer outcome compared to lower levels in stage-matched cases. The AJCC recommends recording the pre-operative level of serum CEA in ng/ml in every case.1

The pre-operative CEA level is annotated as follows:

CX
Serum CEA cannot be assessed
C0
Serum CEA not elevated (<5 ng/ml)
C1
Serum CEA elevated (≥5 ng/ml)

Molecular Features

The only molecular feature recommended for routine comment as a site-specific prognostic factor for colorectal carcinoma is microsatellite stability status, a reflection of the functionality of the DNA repair enzyme system that function during replication to detect and repair replication errors.1 Mutations in one of several DNA mismatch repair genes are found in the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome and in 15-20 percent of sporadic colon cancers. The characteristic genetic signature of these tumors is a high number of DNA replication errors and high levels of DNA microsatellite instability (MSI-H), defined as instability in ≥30 percent of microsatellite loci.75,78 The term MSI refers to the expansion or contraction of short repeated DNA sequences that are caused by the insertion or deletion of repeated units.

MSI-H is associated with longer survival than either MSI-low (MSI-L) or microsatellite-stable (MSS), both in HNPCC and in sporadic cases. The biological basis for this finding is unknown. Large bowel tumors with MSI-H have distinctive histological features; they are more common in the right colon, are more often of the mucinous histological type, and they typically contain large numbers of tumor infiltrating lymphocytes (TILs). Approximately 3 or more TILs per high-power field using hematoxylin-eosin-stained sections should be considered significant.3,79

The AJCC recommends recording of MSI status as a site-specific prognostic factor as follows:1

Microsatellite instability (MSI)

  • Stable
  • Low
  • High
  • Not recorded

NEXT > >