treatment and defining prognosis in patients with CRC. The tumor–node–metastasis (TNM) classification

developed by the UICC/AJCC is firmly established as the preferred staging system (Table 68-4). It

classifies CRC according to the extent of the primary tumor (T), the involvement of the regional lymph

nodes (N), and the presence or absence of distant metastasis (M). The TNM classification is important

for both clinical and pathologic staging. Most colon cancers, and many rectal cancers, are staged after

surgery and pathologic examination of the surgical specimen (pTNM). Many rectal cancer patients, and

a small but growing number of colon cancer patients, do not receive surgery as the initial therapy,

which makes clinical TNM (cTNM) staging based on medical history, physical examination, endoscopy,

and imaging, increasingly important. As tumors experience a variable degree of regression with

preoperative chemotherapy and/or radiation, it is important that patients receiving neoadjuvant therapy

are assigned an accurate cTNM stage before starting treatment. For patients who have received

neoadjuvant therapy, a modified pathologic staging is generated after surgical resection, annotated by

the prefix y (ypTNM). The 7th edition of the AJCC Cancer Staging Manual incorporates a four-tier

tumor regression grading (TRG) system for patients receiving neoadjuvant therapy. In this grading

system TRG 0 represents Complete Response, no viable tumor cells or complete pathologic response

(pCR); TRG 1, Moderate Response; TRG 2, Minimal Response; and TRG 3, Poor Response. Tumor

regression seems to correlate closely with prognosis and long-term oncologic outcome.41

HISTOLOGIC GRADE

Table 68-3 Histologic Grading

The AJCC staging system is updated periodically in response to newly acquired clinical data and

understanding of the biology of the tumor. The 7th edition of the AJCC Cancer Staging Manual, for all

cancers diagnosed after January 1, 2010, was updated based on observed survival outcomes obtained

from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program.42

Relative survival in CRC patients decreases according to the depth of tumor penetration into the bowel

wall and number of lymph nodes involved, but the presence of distant metastasis is the single most

important predictor of survival in these patients (Table 68-4). Other tumor and treatment-related

prognostic factors, in addition to the TNM stage, are listed in Table 68-5.

Quantitative parameters of lymph node evaluation – number of positive lymph nodes, total number of

lymph nodes examined, and lymph node ratio – have prognostic implications in CRC. The number of

nodes involved by tumor is included in the N category of the TNM system. The current staging system

recommends examining a minimum of 12 lymph nodes for adequate staging.42 The total number of

lymph nodes retrieved is lower in rectal cancer patients treated with preoperative chemotherapy and

radiation, but the minimal number of nodes required for adequate staging in these patients is unknown.

The total number of nodes examined has an important impact on outcome in patients with colon and

rectal cancer; in patients with all T and N combinations, the probability of survival increases linearly

with the number of lymph nodes examined. The lymph node ratio, defined as the number of positive

lymph nodes divided by the total number of retrieved nodes, has also been considered an independent

predictor of survival.43,44 However, the results have not been extensively validated and the lymph node

ratio is not currently included in staging. Irregular tumor deposits in the mesocolon or mesorectum

without surrounding lymph node tissue, are considered peritumoral tumor deposits; they are not

counted as lymph nodes but are classified as N1c, and contribute to stage III.42 These are considered to

represent large vessel or perineural invasion. The significance of micrometastasis detected by

immunohistochemistry (usually with anticytokeratin antibodies) in H&E negative nodes of patients with

stage II disease is controversial. Although some studies have reported an association between

micrometastasis, increased recurrence and reduced survival, the detection of micrometastasis has not

been incorporated into clinical practice, and at the present time should be considered

investigational.45,46

The location of the tumor also provides prognostic information. In general, tumors located in the

right colon have better prognosis compared with tumors located in the left or transverse colon. This

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may be attributed, in part, to the higher proportion of MSI tumors in the right side of the colon. In

patients with rectal cancer, tumors located in the distal rectum have worse prognosis compared to

tumors located in the upper rectum.

The quality of the surgery and the completeness of tumor resection also provide important prognostic

information. The distance of tumor to the circumferential resection margin (CRM) – defined as the

surgically dissected nonperitonealized surface of the specimen – provides important prognostic

information in both colon and rectal cancers. The presence of tumor at the CRM, because of advanced

stage or inadequate resection, is associated with a high rate of recurrence and decreased probability of

survival. In rectal cancer patients, the CRM is defined as positive if the tumor, either by direct tumor

extension or positive lymph node, is equal to or less than 1 mm from the resection margin.

The AJCC has established codes for completeness of the resection, which should be reported for each

procedure.42 A resection is defined as R0 when the entire tumor is resected and the margins are

histologically negative; R1 when the margins are grossly uninvolved but histologically positive; and R2

when the tumor is not completely resected, and there is gross residual tumor at the primary site,

regional lymph nodes, or metastatic sites.

Other factors associated with worse outcomes include elevated CEA levels before surgery, high

histologic grade, signet ring cell and small cell histopathologic type, lymphatic and blood vessel

invasion, and perineural invasion.47–52 Vascular invasion is considered a sign of aggressive behavior in

CRC, and has been associated with a higher risk of disease progression and poor prognosis. Capillary

invasion is often associated with lymphatic invasion, and these are commonly designated as

lymphovascular invasion. Large vessel invasion, detectable on magnetic resonance imaging (MRI), is

now reported separately.

While the TNM staging system provides important prognostic information, it is inadequate for

individual prognostication. Outcomes for individual patients within each tumor stage are variable.

Recently, nomograms using a number of clinical and pathologic characteristics have been designed to

improve prediction and survival beyond TNM staging in patients with colon or rectal cancer,

particularly in the setting of stage II tumors (Fig. 68-6).53 In addition to providing prognostic

information, nomograms may potentially guide clinical decisions, such as the use of adjuvant

chemotherapy or the regularity of surveillance. However, nomograms have not become part of the

treatment strategy.

A number of molecular markers such as MSI, 18q loss of heterozygosity, TP53, p21, among others,

have been associated with prognosis in CRC patients. But none of these are routinely incorporated into

clinical practice. Somatic RAS mutations have been associated with lack of response to anti–EGFR

targeted therapies, and clinical guidelines worldwide now recommend testing for both KRAS and NRAS

mutations if anti-EGFR therapy is contemplated in patients with stage IV disease.54 In addition, when a

KRAS or NRAS mutation is not found, some recommend V600E BRAF testing because the data suggest

that those tumors are also unresponsive to anti-EGFR therapy. However, these mutations have not been

incorporated into the staging system.

Based on recent advances in the molecular characterization of CRC, a number of multigene molecular

signatures have been designed as prognosticators of recurrence and outcomes. The Oncotype DX Colon

Cancer Assay, developed by Genomic Health, Inc. (Redwood City, CA, USA) is an assay based on the

expression of 12 genes that play roles in cell-cycle and stromal responses.55,56 The assay was designed

and validated using formalin-fixed, paraffin-embedded tissue samples from patients enrolled in the

Cancer and Leukemia Group B (CALGB) 9581 cohort.57,58 The predictive model provides a score

predicting 3-year recurrence risk in stage II colon cancers, and appears most effective in MMR-proficient

T3 tumors. Another commercially available tool is ColoPrint, developed by Agendia (Amsterdam, The

Netherlands). With a similar premise, this tool is an 18-gene signature found to be predictive of distant

metastasis in stage II colon cancers.59,60 ColDx, developed by Almac (Craigavon, UK) is a microarraybased tool that uses 634 probes to identify patients with stage II colon cancer at high risk of

recurrence.61 While these molecular signatures seem to determine risk of recurrence independent of

other well-established risk factors, they have not been fully incorporated into clinical practice.

Table 68-4 Clinical and Pathologic Staging4

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Table 68-5 Colorectal Cancer Prognostic Factors

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