Colon and Rectal Cancers: Pathologic Staging and Assessment

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Pathologic Staging: TNM Stage Groupings for Colorectal Cancer

The stage groupings defined in the 7th Edition of the AJCC Cancer Staging Manual reflect outcomes data gathered since the previous edition of the staging system.1 The stages reflect increasing risk of death from disease.

STAGE GROUPINGS
Stage T N M
0 Tis N0 M0
I T1 N0 M0
  T2 N0 M0
IIA T3 N0 M0
IIB T4a N0 M0
IIC T4b N0 M0
IIIA T1-T2 N1 M0
  T1 N2a M0
IIIB T3-T4a N1 M0
  T2-T3 N2a M0
  T1-T2 N2b M0
IIIC T4a N2a M0
  T3-T4a N2b M0
  T4b N1-N2 M0
IV Any T Any N M1

Modifiers of Pathological Stage

L Classification

Tumor identified within lymphatic vessels anywhere in the colorectal wall is an independent adverse prognostic factor and should be assessed and reported pathologically in all cases.3

The relative impact, if any, of the location of involved lymphatics within the colorectal wall (e.g., submucosal or extramural) is unknown but may be noted as optional detail. Strictly speaking, it is not possible to distinguish lymphatic vessels from post-capillary venules on histological preparations, but all thin-walled vessels lacking muscle are presumed to be lymphatics by convention. Lymphatic invasion is coded as follows in the AJCC staging system as follows:1

Lymphatic Vessel Invasion (L)

LX
Lymphatic vessel invasion cannot be assessed
L0
No lymphatic vessel invasion
L1
Lymphatic vessel invasion

V Classification

Venous invasion also is a stage-independent, adverse prognostic factor. Invasion of veins located in the extramural soft tissue has been shown specifically to be associated with increased risk of occurrence of hepatic metastasis.43

The significance of intramural venous invasion is less clear, because data specific to this issue are lacking. Nevertheless, the CAP recommends that the presence or absence of venous invasion and its anatomic location should be reported in all cases.3 Venous invasion is coded in the AJCC staging system as follows:1

Venous Invasion (V)

VX
Venous invasion cannot be assessed
V0
No venous invasion
V1
Microscopic venous invasion
V2
Macroscopic venous invasion

Perineural Invasion

Perineural tumor invasion has been recognized as a stage-independent, site-specific adverse prognostic factor by the AJCC.1

This feature has been shown to be correlated with increased local recurrence rates, decreased survival, and increased likelihood of metastasis at the time of surgical resection.44-55 The presence or absence of this histopathological feature should be assessed and recorded as either present or absent in every case. It is easily recognized under the microscope as tumor encasing mural nerves, sometimes distant/discontinuous from the deepest advancing edge of the carcinoma. The AJCC recommends the clinical documentation of perineural invasion status in every case summary as follows:1

Perineural Invasion (PN)

  • Present
  • Absent
  • Not recorded

R classification

The R classification is an annotation system that codifies the completeness of the surgical excision of the primary tumor and regional nodes (referable to T and N parameters).1 It does not refer to the presence or absence of distant disease. The classification was originally devised as a means for surgeons to record their assessment of the operative success in removing all local-regional disease. Complete removal of all local disease corresponds to resection margins that are free of tumor. For the pathologist, therefore, the R classification corresponds to surgical resection margin evaluation.3

R classification

RX
Presence of residual tumor cannot be assessed
R0
No residual tumor
R1
Microscopic residual tumor
R2
Macroscopic residual tumor

The 'y' Modifier and Microscopic Evaluation of Neoadjuvantly Treated Rectal Cancers

In reporting pathological stage for colorectal cancers treated with neoadjuvant radiation and/or chemotherapy before undergoing surgical resection, a modification of the TNM annotation is used.1,3 The pathologic staging criteria applied in this setting are identical to those for untreated tumors, but the y prescript is used to denote the pretreatment status (ypTNM). In these cases, clinical stage assigned before therapeutic intervention is the definitive stage assignment for the untreated tumor at presentation.

Neo-adjuvant chemo-radiation improves resectability and patient outcomes in rectal cancer and is now the standard of care. The degree of response of the tumor to neoadjuvant therapy may have prognostic significance and should be reported separately according to the CAP guidelines for Tumor Regression Grade adapted from Ryan et al.3,58 Although the data are not definitive, the elimination of histologically viable tumor may be associated with a better prognosis.56-58 Minimal residual disease may result in a better outcome than gross residual disease, and failure of the tumor to respond to neoadjuvant treatment at all is particularly dire.

Resection specimens should be thoroughly examined (see Resection Margin Assessment below), which may require microscopic examination of the entire site of the primary tumor. The assessment for response also should include regional nodes and any peritumoral satellite nodules in the specimen.

Tumor Regression Grade 3,58

Description
Tumor Regression Grade
No viable cancer cells
0 (Complete response)
Single cells or small groups of cancer cells
1 (Moderate Response)
Residual cancer outgrown by fibrosis
2 (Minimal response)
Minimal or no tumor kill; extensive residual cancer
3 (Poor response)

Resection Margin Assessment

The goal of all cancer-directed surgery is the complete removal of all detectable tumor, and the status of resection margins of the resultant excision specimen constitutes an important measure of successful attainment of the goal.

Pertinent margins of a colorectal cancer resection specimen include the proximal and distal transverse margins, mesenteric pedicle margin, and where applicable, the circumferential resection (radial) margin (CRM).

Transverse (Proximal and Distal) Margins. Transverse margins are typically the least problematic for both pathologist and surgeon. If the distance between tumor and the nearest transverse margin is ≥5 cm, anastomotic recurrence is very rare. Thus, it can be argued that histological examination of the proximal and/or distal margin is unnecessary if these margins are ≥5 cm from the tumor.59 In fact, guidelines of the Royal College of Pathologists in the United Kingdom suggest that donuts from stapling devices, which are the true margins of resection, need not be examined histologically if the tumor is >3 cm from the cut end of the main specimen.4 In low anterior rectal resection specimens of rectal cancers, however, wide distal cuffs of normal mucosa may be difficult or impossible to achieve due to anatomic constraints. In this circumstance, a margin of 2 cm is accepted as adequate for tumors with transmural penetration, and for sphincter preservation, a 1 cm margin may be adequate, particularly if the tumor does not penetrate the wall. As standard practice, the distance of the tumor from the transverse margins should be measured on gross pathologic examination, but microscopic examination may be considered optional if the closest distance is >5 cm.

Circumferential Margins The CRM represents the retroperitoneal or perineal adventitial soft tissue margin of the resected portion of bowel.3,10 In all segments of the large intestine that are either incompletely encased (ascending colon, descending colon, upper rectum) or not encased (lower rectum) by peritoneum, CRM is created at operation by dissection of the retroperitoneal or subperitoneal aspect away from the sidewall of the abdomen or perineum, respectively.

In contrast to the transverse margins, the issues and challenges regarding CRM are significant for both pathologist and surgeon. In rectal cancer in particular, CRM has been demonstrated to be the factor of greatest importance in predicting risk of local recurrence, which is itself a strong predictor of survival in this disease.60,67 Emerging data on CRM involvement in the colon suggests a similar relationship to risk of local recurrence.68 Therefore, routine assessment of CRM is recommended in all applicable colorectal cancers, and measurement of the distance from the tumor to the nearest CRM, corresponding to the "surgical clearance" around the tumor, is suggested.3 Based on published data from clinical trials, the risk of local recurrence is strongly increased if tumor is ≤1 mm from the nonperitonealized surface of the specimen.62 In contrast, risk of recurrence is very low with clearance >2 mm and can be considered "negative." Accordingly, the AJCC recommends that clearance of ≤1 mm should be considered a "positive" CRM and should be annotated as R1.1 Reporting of the actual clearance measurement (rather than assignment of "positive" or "negative" status alone) also is recommended by the CAP.3

Because CRM involvement is associated with increased risk of local recurrence, patient management is directly affected, and such involvement is typically an indication for adjuvant radiation directed at the anatomic site corresponding to the positive CRM. Therefore, it is extremely important that the pathologist carefully differentiate peritonealized from nonperitonealized surfaces of the resection specimen and examine them separately. For example, if tumor is present on a peritonealized surface, it is categorized as pT4, but may not require adjuvant radiation if the resection margins (including the CRM) are free of tumor. However, if tumor is present on a nonperitonealized surface (i.e., the CRM), adjuvant radiation may be appropriate, irrespective of the T category of the tumor. It should be recognized that radiation therapy does not always compensate for a positive CRM, underscoring the importance of optimal surgical technique in achieving adequate clearance.63

In segments of the colon that are completely encased by a peritonealized (serosal) surface (e.g., transverse and sigmoid colon), the resection margin of the mesenteric pedicle also may be a relevant "radial margin," as tumors may extend to this margin with (pT4) or without (pT3) penetrating the serosal surface. Examination of the mesenteric pedicle is essential if the point of deepest tumor penetration is on the mesenteric aspect of the colon, especially if the mesentery has been trimmed close to the colonic wall. In tumors limited to an antimesenteric peritonealized aspect of the bowel, the mesenteric margin usually is not relevant.

Macroscopic Evaluation of Rectal Resection Specimens

The quality of the surgical technique is the paramount factor in the success of surgical treatment for rectal cancer, both in the prevention of local recurrence and in long-term survival. Numerous studies have demonstrated that total mesorectal excision (TME) improves local recurrence rates dramatically 69-71.

The TME surgical technique entails precise sharp dissection within the areolar plane outside (lateral to) the visceral mesorectal fascia in order to remove the rectum.72 This plane encases the rectum, its mesentery, and all regional nodes and constitutes Waldeyer's fascia. High-quality TME surgery reduces local recurrence from 20% to 30%, to 8% to 10% or less.71 Radiation therapy in the presence of a high-quality TME may further reduce local recurrence.70,73

Pathologic evaluation of the resection specimen has been shown to be a sensitive means of assessing the quality of rectal surgery. It may be superior to indirect measures of surgical quality assessment, such as perioperative mortality, rates of complication, number of local recurrences, and 5-year survival. It has been shown that macroscopic pathologic assessment of the completeness of the mesorectum of the specimen, accurately predicts the adequacy of the TME.73,74 The nonperitonealized surface of the fresh specimen is examined circumferentially, and the completeness of the mesorectum is scored as described below. The entire specimen is scored according to the worst area.

Incomplete

  • Little bulk to the mesorectum
  • Defects in the mesorectum down to the muscularis propria
  • After transverse sectioning the circumferential margin appears very irregular

Nearly Complete

  • Moderate bulk to the mesorectum
  • Irregularity of the mesorectal surface with defects greater than 5 mm, but none extending to the muscularis propria
  • No areas of visibility of the muscularis propria except at the insertion site of the levator ani muscles

Complete

  • Intact bulky mesorectum with a smooth surface
  • Only minor irregularities of the mesorectal surface
  • No surface defects greater than 5 mm in depth
  • No coning toward the distal margin of the specimen
  • After transverse sectioning the circumferential margin appears smooth

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