Colon and Rectal Cancers: Pathologic Staging and Assessment

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Pathologic Staging: Assessing pN

The adverse impact of regional lymph node metastasis on prognosis for colon cancers that have no distant metastasis is directly proportional to the number of nodes involved, which is definitively determined by pathological evaluation. It is critical to accurately determine whether or not any nodal metastasis exists, and if so, what proportion of the regional nodes are involved. Therefore, a thorough lymph node examination by the pathologist is essential for accurate staging.

The N category for regional lymph nodes in colorectal cancer staging is subclassified as follows:¹

N Category Subclassification in Colorectal Cancer

NX

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1

Metastasis in 1 to 3 regional lymph nodes

N1a: Metastasis in 1 regional lymph node
N1b: Metastasis in 2-3 regional lymph nodes

N2

Metastasis in 4 or more regional lymph nodes

N2a: Metastasis in 4 to 6 regional lymph nodes
N2b: Metastasis in 7 or more regional lymph node

Issues faced by the pathologist in the assessment of lymph nodes for colorectal cancer staging are discussed below.

What counts as a regional lymph node?

Colectomies for colon carcinoma that are performed with curative intent are designed to remove all regional lymph nodes for the anatomic subsite of origin of the tumor. Rectal resections performed using total mesorectal excisional technique are designed to remove all perirectal nodes. The role of the pathologist is to harvest all regional nodes in the resection specimen for microscopic assessment. Regional lymph node groups corresponding to anatomic subsites of the colorectum as follows:^1,3

Segment: Regional Lymph Nodes
Cecum: Pericolic, anterior cecal, posterior cecal, ileocolic, right colic
Ascending colon: Pericolic, ileocolic, right colic, middle colic
Hepatic flexure: Pericolic, middle colic, right colic
Transverse colon: Pericolic, middle colic
Splenic flexure: Pericolic, middle colic, left colic, inferior mesenteric
Descending colon: Pericolic, left colic, inferior mesenteric, sigmoid
Sigmoid colon: Pericolic, inferior mesenteric, superior rectal (hemorrhoidal), sigmoidal, sigmoid mesenteric
Rectosigmoid: Pericolic, perirectal, left colic, sigmoid mesenteric, sigmoidal, inferior mesenteric, superior rectal (hemorrhoidal), middle rectal (hemorrhoidal)
Rectum: Perirectal, sigmoid mesenteric, inferior mesenteric, lateral sacral presacral, internal iliac, sacral promontory, internal iliac, superior rectal (hemorrhoidal), middle rectal (hemorrhoidal), inferior rectal (hemorrhoidal)

In colorectal cancers that involve more than one site or subsite by continuous longitudinal extension, regional lymph nodes are defined as those in all involved sites and subsites.^8,11 In rare cases, regional nodes of the primary tumor site are free of malignancy, but nodes in the drainage area of an organ directly invaded by a T4 tumor contain metastasis. In this circumstance, the lymph nodes of the invaded site are considered as those of the primary site and classified in the N category.

What is an adequate lymph node examination?

The thoroughness of the surgical technique in removing all regional nodes and the thoroughness of the pathologic examination in identifying and harvesting all regional lymph nodes for microscopic assessment each contribute to the adequacy of a node exam for colorectal cancer staging.

It has been shown repeatedly that a minimum of 12-18 lymph nodes must be examined to accurately predict regional node negativity in colorectal cancer.^8-10 Therefore, the AJCC and the CAP have recommended examination of at least 12 lymph nodes to assign stage II disease,^3,8 and on recommendation from the American College of Surgeons, the National Quality Forum has listed this as a quality measure in the care of the colorectal cancer patient.¹⁴

Although the lower limit of acceptability for a nodal exam has been set at 12 nodes, the optimum number has not yet been defined. Increasingly, the evidence suggests that the greater the number of nodes examined, the greater the likelihood that metastasis will be found. In one study of T3 tumors, for example, nodal metastasis was found in about 22% of cases if <15 lymph nodes were harvested from the specimen, compared with 85% of cases if ≥15 nodes were recovered.¹⁵ In a study of more than 2400 patients with pT3 colorectal cancer resected at a single institution over 45 years, Goldstein et al. showed by mathematical analysis that the predictive probability of identifying a single positive node increased in a continuous manner as the number of recovered lymph nodes increased, suggesting that no minimum number of nodes accurately or reliably stages all patients.¹⁶

In stage II disease in particular, it has been shown that clinical outcome is linked to lymph node harvest.

Numerous studies have shown that conventional pathologic examination of increasing numbers of lymph nodes is itself associated with an increasing survival advantage in stage II disease.^15,17-25 In contrast, survival is significantly worse in patients with stage II colon cancer (i.e., roughly equivalent to stage III disease) in cases in which fewer than seven to nine lymph nodes are harvested from the resection specimen.^26-28 The effect is not limited to stage II disease. A large study involving 3759 patients with stage III or high-risk stage II colorectal cancer, showed that both overall and cause-specific survival increased as more lymph nodes were examined, suggesting that the number of lymph nodes analyzed is itself an independent prognostic variable.¹⁷

Despite the strength of the data demonstrating the critical nature of adequate lymph node assessment in colorectal cancer, significant variation in lymph node recovery from resection specimens exists within and among medical centers.^29-32 In addition, the average number of lymph nodes examined per specimen is often found to be lower than the minimal recommended number, suggesting that a large number of patients with colorectal cancer are staged inadequately.^33-34

The number of lymph nodes recovered from resection specimen is dependent on several factors. Surgical technique, surgery volume and patient factors (e.g., age and anatomic variation) alter the actual number of nodes in a resection specimen.^29,31-32 The NCI guidelines for colorectal cancer resection published in 2001³⁵ highlight several technical pitfalls in cancer-directed surgery that could lead to inadequate removal of regional lymph nodes groups. They are summarized below:

Pitfalls That Can Lead to Inadequate Removal of Regional Lymph Nodes

Mesentery trimmed too close to wall
Feeding artery not ligated at its origin
Inadequate TME technique incomplete removal of regional nodes
<10 cm normal colon resected on either side of the tumor
Lymph nodes not removed en bloc
Adherent/infiltrated organs separated from the tumor leaving behind regional nodes of the infiltrated organs that are part of pN assessment

However, the diligence and skill of the pathologist in identifying and harvesting lymph nodes in the resection specimen also are major factors in the adequacy of the lymph node examination in colorectal cancer.³⁶ Diligent search for lymph nodes on gross examination of resection specimens is an absolute requirement. Dissection aids such as magnification lens or chemical visual enhancement techniques such as fat clearing techniques with organic solvents or intra-arterial methylene blue injection may be required. Despite the size-based criteria used clinically to diagnose lymph node metastasis for cN assignment, it has been shown that nodal metastasis in colorectal cancer is often found in small lymph nodes (<5 mm in diameter).^37-38

If fewer than 12 nodes are found after careful gross pathological examination, additional techniques (i.e., visual enhancement techniques, such as fat clearing) should be considered, despite the lack of formal standards for this practice.³

All grossly negative or equivocal lymph nodes should be submitted entirely or microscopic examination.³ Currently, histological examination of one tissue level is the minimum requirement, and additional tissue levels are optional;³ however, thorough examination of large nodes may include serial sectioning on gross examination and submission of all slices for standard microscopic assessment.

What qualifies as a metastasis?

On microscopic examination, tumor in a regional lymph node, whether arriving via afferent lymphatics or direct invasion through the capsule, is regarded as metastatic disease. If tumor arrives via afferent lymphatic vessels, it must already have entered the subcapsular sinus to qualify in the N category as metastasis. If tumor is seen only within lymphatic vessels, the finding is categorized as lymphatic involvement and annotated as L1 according to AJCC convention (see L/V classifications below), but the tumor is classified as pN0.

Definitive data are lacking on the biological significance and clinical impact on outcome of very small amounts of tumor in regional nodes. Although some studies have supported the concept of "upstaging" patients with stage II colon cancer using immunohistochemical identification of tumor cells in regional nodes with or without sentinel node assessment,^38-39 the overall evidence is not definitive.^39-40 Currently, stage-related outcome statistics from large data bases, such as the National Cancer Data Base, are derived entirely from studies in which the pathologic evaluation of regional lymph nodes has been performed by conventional histological staining of macroscopically identified lymph nodes. Therefore, at present, the AJCC, UICC, and CAP continue to recommend standard hematoxylin and eosin techniques for the nodal assessment of colon cancer.³ Changes in these recommendations are under consideration, but will ultimately be based on the validation of other approaches, including immunohistochemical or molecular analysis by outcome analysis.

Until the clinical impact of minute amounts of tumor in either regional lymph nodes or distant metastatic sites has been validated, it is necessary to collect data in a uniform manner using standardized diagnostic and reporting criteria, such as those defined by AJCC and UICC. Isolated tumor cells (ITCs) are defined as small numbers of tumor cells detected only by special techniques or seen histologically, but measuring 0.2 mm. According to current recommendations, ITCs are classified as N0 or M0. It has not yet been proven that ITCs (as either a single focus or multiple foci in a single node or in multiple nodes) have an adverse impact on outcome. Therefore, if ITC represent the only tumor involvement of a metastatic site, assignment of N0 or M0, as appropriate, is considered justified. In contrast, small amounts of metastatic tumor that measure >0.2 mm, but <2.0 mm, are defined as "micrometastasis" but are classified as N1 or M1.^1,3,41

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

Currently, the data are considered 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 (e.g., cytokeratin, carcinoembryonic antigen, etc.) or polymerase chain reaction, to identify tumor RNA/DNA. Furthermore, these techniques increase the cost of pathologic analysis and currently lack quality control standards. Pending definitive data, it is recommended that any pathologist-reported ITC be accompanied by a note stating that the biologic significance of this finding is currently unknown. To date, data on the prognostic impact of ITCs in colorectal cancer are conflicting.

The convention for annotation of micrometastasis or ITCs is as follows (note: "i" connotes "isolated tumor cells" not "immunohistochemstry"): ^1,3,41

Isolated Tumor Cell Annotation

pN0(i-): No ITC detected morphologically
pN0(i+): Positive morphological (H&E or immunohistochemical) findings for ITC
pN0(mol-): No regional lymph node metastasis histologically, negative molecular findings for ITC
pN0(mol+): No regional lymph node metastasis histologically, positive molecular findings for ITC

Micrometastasis Annotation

pN1(mi): Metastatic tumor in regional node, no larger than 2.0 mm but > 0.2 mm in dimension
pM1(mi): Metastatic tumor in distant site, no larger than 2.0 mm but > 0.2 mm in dimension

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