Staging and Prognosis of Colon Cancer

Surg Oncol Clin N Am 15 (2006) 129–146

Staging and Prognosis of Colon Cancer Josh Kehoe, MD, Vijay P. Khatri, MD* Department of Surgery, University of California, Davis Cancer Center, 4501 X Street, Suite 3010, Sacramento, CA 95817, USA

Colorectal cancer (CRC) is the most common malignancy of the gastrointestinal tract. There will be an estimated 145,000 newly diagnosed cases and over 56,000 deaths from colorectal cancer in the United States in 2005 [1]. Surgery remains the mainstay of treatment for most of these patients, either for attempted curative resection or for palliation of symptoms such as bleeding, obstruction, or perforation. Appropriate staging is paramount in selecting appropriate therapeutic strategy for these patients. An oncologically sound surgical resection followed by a comprehensive pathologic evaluation of lymph node basins is critically important because this protocol identifies those patients who would benefit from adjuvant systemic chemotherapy. For patients who have rectal cancer, preoperative staging is critical for predicting both the extent of surgical resection necessary for a negative margin resection as well as identifying those patients who might benefit from neoadjuvant chemoradiation therapy, to offer the best chance of curative resection. Given the impact of preoperative staging on patient prognosis and therapeutic decision making, intensive research is being conducted in many areas concerning staging techniques and strategies. Outside of distant metastatic disease, the presence of nodal metastases is the most significant prognostic variable for patients. Because 20% to 40% of pathologically node-negative patients will die of recurrent colorectal cancer [2], an opportunity exists to determine which group of CRC patients may harbor undetected residual disease or aggressive tumor biology and, thus, benefit from additional therapy or a more aggressive surveillance program. A major focus of research continues in the precise detection of metastatic regional lymph node disease. This research includes scrutiny regarding both the minimum and optimum number of lymph nodes that need to be examined for accurate nodal (N)

* Corresponding author. E-mail address: [email protected] (V.P. Khatri). 1055-3207/06/$ - see front matter Ó 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.soc.2005.08.006 surgonc.theclinics.com

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staging. Attempts also have been made to improve nodal staging using sentinel lymph node biopsy and immunohistochemical analysis of nodes. Last, there has been increasing investigation of the genetic and histologic features of primary tumors that suggest aggressive tumor biology.

History In 1932, Cuthbert Dukes, a pathologist at St. Marks Hospital, introduced a staging system for rectal cancer based on the correlation between worsening patient prognosis and progressive tumor invasion of the bowel wall and regional lymph nodes [3]. Tumors with penetration limited to the bowel wall were classified as stage A, with penetration into the perirectal tissue classified as stage B. Involvement of regional lymph nodes designated the patient as stage C, regardless of the depth of penetration. Several modifications of this alphabetical system have since been introduced, allowing for additional classifications based on tumor, nodal, and metastatic characteristics. The Kirklin system subdivided stage B into B1 and B2, representing infiltration of the submucosa or muscularis propria and penetration of the muscularis propria, respectively [4]. The Astler-Coller ‘‘modified Dukes’’ system took the Kirklin system and stratified node-positive patients (stage C) into stages C1 (B1 depth of tumor penetration) and C2 (B2 depth of tumor penetration) [5]. The ‘‘modified Astler-Coller’’ system, which was introduced later by Gunderson, classified locally advanced tumor types (Astler-Coller B or C stages) into tumors that invaded adjacent structures or organs and those that did not, thereby creating the B3 (node-negative) and C3 (node-positive) stages that included these locally invasive tumors [6]. Stage D, which had been added previously by Turnbull, represented incurable disease secondary to distant spread, peritoneal implantation, or adjacent organ invasion [7]. In contrast to the alphabetical staging systems, the tumor node metastasis (TNM) system derives overall disease stages from the combination of subcategory classifications. Pierre Denoix, a French surgeon, first suggested this concept of cancer staging based on the TNM categories used in the 1940s. The first staging manual based on the TNM system was introduced in 1953 [8]. This system has undergone a constant evolution, and the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC) have jointly developed the TNM staging system currently in use. Correlating the TNM and Dukes systems, TNM stages 0 and 1 correspond to Dukes’ stage A, and TNM stages II and III correspond with Dukes’ stages B and C, respectively. Metastatic spread, stage IV using the TNM system, correlates with stage D in later modifications of the Dukes system. Although classifications parallel one another, the TNM system eliminates possible confusion associated with the use of the various modifications of the Dukes system, thereby allowing for a meaningful comparison between published studies from various institutions.

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Current staging Current staging uses the TNM system. The sixth editions of both the AJCC ‘‘Cancer Staging Manual’’ [9] and the UICC ‘‘Classification of Malignant Tumours’’ [10] went into effect in January 2003 (Tables 1 and 2). The evaluation of outcome data from large patient databases is used to constantly update the TNM system. Notable changes were made between the fifth and sixth iterations, foremost of which were stratifications of stages II and III. Stage II (T3–4 N0 M0 in the fifth edition) was split into stages IIa (T3 N0 M0) and IIb (T4 N0 M0) in the sixth edition, indicating that greater tumor penetration should, on average, correlate with a worse prognosis, even in the absence of detectable nodal or distant disease. Stage III underwent and even greater stratification, from one group in the fifth edition (T any N1 M0) to three groupings within stage III in the sixth edition. The new stages include IIIa (T1–2 N1 M0), IIIb (T3–4 N1 M0), and IIIc (T any N2 M0), which account for worse prognosis for both increasing tumor penetration and nodal disease burden. These changes were based on accumulating data suggesting significant survival differences between subgroups of node-positive patients. A German study conducted by Merkel and colleagues [11] generated survival curves for 1453 stage III CRC patients (788 patients with rectal cancer) by dividing patients into a number of subgroups comprising combinations of T and N stages. The most significant survival difference among these groups was between T1–2 N1 and T3–4 N1 patients. Although stratifying patients who have N2 disease (T1–2 N2 and T3–4 N2) gave significant survival Table 1 Stages as defined by the AJCC sixth edition staging system Stage

Categories

Definition

Primary tumor (T)

Tx T0 Tis T1 T2 T3

Nx

Primary tumor cannot be assessed No evidence of primary tumor Carcinoma in situ Tumor invades into the submucosa Tumor invades the muscularis propria Tumor invades through the muscularis propria into the subserosa or into nonperitonealized pericolic tissue Tumor directly invades other organs or structures and/or perforates visceral peritoneum Regional lymph nodes cannot be assessed

N0 N1 N2 Mx M0 M1

No regional lymph node metastases Metastases to 1–3 nearby regional lymph nodes Metastases to 4 or more regional lymph nodes Presence of distant metastases cannot be assessed No distant metastases Distant metastases present

T4 Regional lymph node metastases (N)

Distant metastases (M)

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Table 2 AJJCC-UICC (sixth edition), Dukes’, and modified Astler-Coller stage groupings Staging system

T stage

N stage

M stage

Dukes’

Modified Astler-Coller

0 I

Tis T1 T2 T3 T4 T1 or T2 T3 or T4 Any T Any T

N0 N0 N0 N0 N0 N1 N1 N2 Any N

M0 M0 M0 M0 M0 M0 M0 M0 M1

N/A A A B B C C C N/A

N/A A B1 B2 B3 C1 C2, C3 C1, C2, C3 D

IIa IIb IIIa IIIb IIIc IV

Abbreviation: N/A, not applicable.

differences, the magnitude was not as great as for N1 patients. This is in agreement with analyses of 50,042 patients who had stage III colon [12] and 5987 patients who had stage III rectal [13] cancer. These studies also found significant differences among survival curves when patients were stratified into the three categories used in the most recent AJCC and UICC TNM staging manuals (T1–2 N1 versus T3–4 N1 versus Tany N2). Future changes The sixth editions of the AJCC-UICC staging systems allow for greater patient stratification and prognostication than previous editions. One assumption inherent in the concept of a staging system is that patients will have a worse prognosis (decreased survival) as their stage progresses. However, a recent analysis of patient survival by TNM staging has unveiled a conundrum in regard to sixth edition staging. Using the Surveillance, Epidemiology, and End Results (SEER) [14] data from January 1, 1991 to December 31, 2000, patient survival was retrospectively calculated for both the fifth and sixth edition AJCC-UICC staging criteria [15]. Using this dataset, survival was found to be higher in stage IIIa (T1–2 N1 M0) patients than for stage IIb (T4 N0 M0). The authors believed this was likely because of the routine use of adjuvant therapy in IIIa but not IIb patients, although this could not be directly analyzed because the SEER data do not include information regarding adjuvant therapy. This finding has led at least one author to suggest that the sixth edition staging for use in research be disregarded until this discrepancy is resolved [16], which highlights the potential problem of understaging of nodal disease. Lymph node metastases have significant prognostic and therapeutic implications in colorectal cancer. This underscores the necessity of accurate retrieval and analysis of lymph nodes in the surgical specimen. The minimum

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number of lymph nodes that need to be assessed for accurate identification of regional metastases has been debated. This concern is greatest for locally advanced (T3–4) tumors that particularly carry an increased risk of nodal disease. The current recommendation from the AJCC, UICC, and College of American Pathologists is that 12 or more nodes be examined [9,10,17]. For TNM stage II (T3–4 N0 M0) cancers, it has been shown that patients who had six or fewer lymph nodes recovered had a lower survival than those who had more than six nodes recovered [18]. Another analysis of 2427 patients who had T3 tumors also showed survival differences based on the number of analyzed nodes, in which the recovery of seven or fewer nodes correlated with a 62.2% 5-year overall survival rate compared with 75.8% survival in those patients who had 17 or more nodes recovered (an example of the Will Rogers effect) [19]. In both studies, the survival differences pertained to patients classified with node-negative disease on final pathologic staging, suggesting that understaging likely occurred among patients in whom fewer nodes were examined. Because adjuvant chemotherapy is not offered routinely to patients who have stage II disease, understaging could contribute to decreased survival in these patients. This conclusion is supported by another analysis that found a benefit in 5-year overall survival for node-negative T3 and T4 rectal cancers if 14 or more lymph nodes were examined, compared with 9 to 13 lymph nodes [20]. This difference disappeared for node-positive patients, suggesting that understaging occurred in stage II patients in that study. It is therefore incumbent on the surgeon to obtain adequate node-bearing tissue for evaluation and the pathologist to identify and analyze as many nodes as possible. Sentinel lymph node biopsy Given the evidence that examining fewer lymph nodes can result in missed nodal disease, it has been suggested that node-negative patients who experience a relapse did in fact have a false-negative nodal evaluation. A more focused examination of a subset of lymph nodes in specimen can be facilitated with the use of sentinel lymph node (SLN) biopsy. Sentinel lymph node biopsy uses blue dye or radiolabeled colloid in conjunction with intraoperative gamma probe localization or both to identify the metastatic spread of tumor to lymph nodes (Fig. 1). Advanced histopathologic studies of a few nodes can be performed, which would be prohibitively time consuming and expensive for larger specimens containing numerous lymph nodes. These techniques have proven to be effective in both cutaneous melanoma [21,22] and breast cancer [23]. In those diseases, the focused examination of one or a few nodes allows for the detection of micrometastatic disease that might be missed on standard hematoxylin-eosin (H&E) microscopic evaluation. This approach also limits the morbidity of formal lymph node dissection in patients who do not show evidence of disease in the sentinel node.

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Fig. 1. (A) Sigmoid carcinoma showing subserosal injection of 1% lymphozurin. The puckering caused by the colon cancer can be seen. (B) Two pericolic sentinel lymph nodes stained with lymphozurin dye. (C) Closer view of the dissected sentinel lymph node identified with silk sutures.

Although SLN sampling would not be expected to alter the extent of surgical resection in colorectal cancer, it would allow for a detailed and focused analysis of one or a few lymph nodes, potentially reducing the rate of falsenegative nodal staging. SLN biopsy may also identify lymph nodes outside standard segmental resection margins. Direct metastases to para-aortic lymph nodes without involvement of intervening regional nodes have been shown to occur, albeit infrequently [24]. These ‘‘skip metastases’’ may be identified using SLN techniques, whereas they would not be included in standard resections. Drainage to lymph nodes outside the expected basin, such as nodes to the left of the middle colic vessels for right-sided tumors, has been reported [25] and could alter the extent of resection when identified. Many variables exist regarding the exact technique of SLN mapping, such as the use of blue dye, radiolabeled colloid, or both. Also, the optimal injection technique (submucosal versus subserosal) and timing regarding both injection and dissection (in vivo versus ex vivo) have yet to be standardized. Given the number of variables involved, it is not surprising that variations between 70% [26] and 100% [27] have been reported in successful SLN identification. Additionally, there have been reports of a high

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proportion of patients who had a normal sentinel lymph node (no cancer) with tumor-bearing nodes within the complete pathologic specimen, for a false-negative rate of 45% to 58% [28,29]. The common use of immunohistochemical staining or polymerase chain reaction amplification of lymph node DNA to identify lymph node metastases and micrometastases in these studies makes further comparison even more difficult. Using these more sensitive markers, nodal status is often upstaged compared with standard H&E evaluation, but the clinical significance is uncertain. Some studies have shown a negative prognostic effect on survival from this upstaging [30,31], whereas others show no difference [32]. In conclusion, SLN biopsy has the potential to offer information not available using conventional techniques, but the clinical implications of such information have not currently been resolved. After the initial enthusiasm for SLN technique in CRC, interest in validating this technique within the context of a prospective randomized trial has waned considerably. Apart from allowing accurate staging, the benefit of SLN is for the accurate identification of lymph node-positive patients within stage II who would therefore be treated with systemic chemotherapy instead of the current standard of surgery alone. If the Multicenter International Study of Oxaliplatin/5FU-LV in the Adjuvant Treatment of Colon Cancer (MOSIAC) trial identifies a survival advantage for adjuvant 5-fluorouracil, leucovorin, and oxaliplatin therapy in stage II cancer patients, this reduces the importance nodal positivity in determining therapy and further diminishes the importance of SLN for colon carcinoma. Staging of rectal cancer As is the case for adenocarcinoma of the colon, the treatment of rectal cancer is primarily surgical. Traditionally, mid and high rectal cancer (5– 15 cm from the anal verge) were treated with low anterior resection, with abdominoperineal resection used for lower tumors (%5 cm from the anal verge). Several significant advances have been made in the last 20 years to promote less morbid treatment of rectal cancer. Advancements in surgical technique and neoadjuvant treatment regimens have been used to reduce local and distant disease recurrence. The proper use of these modalities depends highly on pretreatment pelvic (local-regional) staging. Endorectal ultrasonography (EUS), CT scanning, and MRI have been used widely in an attempt to obtain the most accurate staging to assist with treatment decisions. Advances in surgical therapy have aimed at reducing the local recurrence rate of rectal cancers. The concept of the circumferential resection margin highlighted the importance of the lateral extension of tumor into the mesorectum, with positive lateral margins correlating with higher rates of local recurrence compared with margin negative surgical specimens [33]. In addition to increased local recurrence, a positive circumferential margin also has been associated with decreased overall survival [34]. Around the same time,

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the concept of total mesorectal excision (TME) was introduced as a method to allow for adequate mesorectal fat clearance while allowing for more sphincter-preserving operations [35]. TME subsequently has proven to be effective in reducing local recurrence rates [36,37,38]. This effect on local recurrence has been maintained even under conditions of preoperative radiation therapy, as shown by the recent study by Kapiteijn and colleagues [39], although an improvement in overall survival was not seen. The use of adjuvant radiation therapy with or without chemotherapy has been recognized in the improvement of outcomes in patients who have rectal cancer. US National Institutes of Health [40] guidelines released in 1990 recommended adjuvant chemoradiation therapy for all locally advanced rectal cancers (TNM stages II and III). Preoperative radiation therapy also has shown a reduction in local recurrence [39], although only one trial has found a significant overall survival difference at 2 years [41]. Given the known benefit of chemoradiation therapy compared with radiation therapy alone, a trial comparing pre- and postoperative chemoradiation therapy was recently concluded. Preoperative chemoradiation therapy resulted in improved local control and less toxicity compared with postoperative therapy; however, no difference in overall survival was noted [42]. Even before these trial results were published, there was a trend toward the increased use of neoadjuvant chemoradiation therapy for all locally advanced rectal carcinomas in an attempt to not only decrease local recurrence and increase overall survival but also to increase the rates of sphincter preservation through tumor downsizing and decreased treatment toxicity [43]. Given the reported benefits of TME and radiation therapy with or without chemotherapy, accurate pretreatment staging of rectal cancer has become critical to optimize the integration of these advances and provide a true multidisciplinary approach. Particularly, understaging can result in withholding beneficial therapy, whereas overstaging exposes the patient to unnecessary treatment toxicities. Digital rectal examination (DRE), rigid or flexible sigmoidoscopy, CT scanning, MRI, and EUS have been used to locally stage rectal cancer. DRE relies on a tumor within reach of the examiner’s finger and an assessment of tumor fixation to determine local spread. This limits usefulness to low tumors, and differentiating between fixity caused by locally advanced disease versus surrounding inflammatory changes is difficult, with reported accuracies varying between 40% and 80% and a significant rate of interobserver variation [44,45]. Endoscopy can determine the extent of intraluminal disease but not the depth of penetration or nodal involvement. CT, EUS, and MRI have been used for an accurate assessment of these latter two factors. Studies using CT scanning for tumor staging began to appear in the early 1980s and proved to be very accurate for staging advanced tumors, especially those that invaded adjacent organs [46]. However, because CT scanning cannot delineate layers of the bowel wall or microinvasion of

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perirectal fat, its usefulness in tumor staging is limited to all but the more advanced tumors. An additional limitation is the inability to detect small lymph node metastases (%1 cm) or those located in close proximity to the tumor [47], further limiting the ability to detect locally advanced disease. EUS has several features that make it attractive in the staging of rectal cancer. Unlike CT, EUS can differentiate the various layers of the rectal wall, which is advantageous in determining the T stage of the tumor. Combining the results from several studies, the accuracy for T staging is approximately 83%, with the lowest accuracy for T2 tumors and the highest for T3 [48]. This level of accuracy is explained partly by the recognition that overstaging is a particular problem of T2 tumors because inflammatory peritumoral changes often mimic deeper tumor invasions [49]. Understaging is less common but may occur in T4 tumors if adequate resolution is not obtainable at the interface between the tumor and the organ being invaded [50]. Difficulty in passing the transducer through a stenotic lesion can occur at rates of approximately 15% [51], although the use of a miniprobe passed through a channel in an endoscope may overcome this limitation [52]. The accuracy of nodal staging, 65% to 83%, has been reported to be less than that for T staging because differentiating between inflammatory and metastatic nodes can be difficult, as can the identification of small or distant lymph nodes [53]. MRI has also been used in pretreatment staging of rectal cancer. The initial results for staging accuracy using standard body coils were similar to CT scanning with regard to T staging, with a reported accuracy of 65% to 85% [54,55] because individual layers of the rectum could not be discerned. Endorectal coils allow for visualization of these layers [56], but the ability to distinguish the mesorectal fascia and more distant pelvic structures is compromised [57]. Difficulty in placing the endoluminal device, especially in stenotic or proximal rectal tumors, can occur [58]. As with endorectal ultrasonography, overstaging of T2 lesions can occur because of the inability to distinguish tumor extension from inflammatory changes [59,60,61]. Despite these limitations, the ability to readily visualize the distance between the depth of tumor invasion and the rectal fascia proper, which serves as the circumferential resection margin in TME, has been reported to be a major advantage of MRI [62]. Such preoperative information is valuable because the presence of a tumor at the radial margin is associated with high rates of local recurrence [33,34]. MRI, CT, and EUS have difficulty predicting nodal status, because of several factors, including difficulty in determining reactive from metastatic nodes, a relative inability to detect nodes smaller than 3 to 5 mm (which, despite their small size, can still harbor metastatic disease), and limited assessment of nodal disease distant from the tumor (especially in more distal tumors) when high-resolution images concentrate primarily on the area of the primary tumor at the expense of a broader image field. The use of neoadjuvant therapy greatly reduces the accuracy of clinical staging modalities. Limitations in imaging after neoadjuvant therapy are

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largely the result of tissue edema and fibrosis, which make identification of residual tumor difficult. Several studies evaluating the accuracy of EUS for T3 or T4 tumors after radiation therapy with or without chemotherapy have suggested that accuracy drops to approximately 50% [63,64]. Few data exist regarding the value of MRI after neoadjuvant therapy, but given that the inherent difficulties in differentiating fibrosis from residual tumor for EUS are similar for MRI, the accuracy of high-resolution MRI is unlikely to be higher than for EUS. Therefore, until the accuracy of imaging improves, pathologic staging following resection remains the most accurate method of staging after neoadjuvant therapy. In summary, several modalities exist to preoperatively stage rectal cancer, each with its own set of strengths and weaknesses. CT scanning is accurate for predicting extensive pelvic disease and invasion of adjacent structures, as well as for providing information regarding more distant metastatic disease, such as in the liver. However, CT is relatively inaccurate for assessing lesser degrees of local tumor extension or nodal disease. EUS is the most accurate method for assessing T and N staging, but it has a tendency to overstage T2 tumors because of peritumoral inflammatory changes and may not offer the resolution to identify tumor invasion of adjacent structures with bulky disease. Imaging difficulties secondary to stenotic or high tumors may be overcome by increasing the use of thin-probe devices delivered endoscopically, although their use currently is not widespread. MRI has less ability to differentiate between T1 and T2 tumors than EUS and suffers from the same overstaging difficulties for T2 tumors. However, good visualization of the mesorectal fascia and its relation to tumor depth, as well as the ability to visualize the anatomic relationship of tumor to pelvic structures, provide an advantage over EUS. Given the proven benefit of neoadjuvant chemoradiation, the ideal imaging study would delineate those patients who have locally advanced (T3 or Nþ) from those without (T1–2 N0) to avoid overstaging and the subsequent toxicity of neoadjuvant therapy. Currently, such an ideal has not been reached because of difficulty in differentiating T2 and early T3 lesions (minimal penetration of the rectal wall) and inaccurate nodal staging. In the German study by Sauer and colleagues [42] that compared pre- and postoperative chemoradiation therapy, 18% of patients in the postoperative therapy arm were found to have pathologic stage I (T1–2 N0) disease, and it can be assumed that a similar number of patients in the neoadjuvant arm were also overstaged and hence overtreated. Several studies evaluating the extent of the depth of penetration of T3 tumors to local recurrence have found that in the presence of %2-mm mesorectal invasion [65,66] or microscopic invasion [67] there was significantly lower recurrence rates when treated with surgery alone. Therefore, the limitations of T2 versus T3 staging using currently imaging modalities may prove not to be so limiting in the face of proper surgical technique and a circumferential resection margin negative for tumor, although this will need to be determined by controlled trials.

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Prognostic factors in colorectal cancer A large number of variables are known to be important in predicting tumor recurrence and death from colorectal cancer. The depth of tumor penetration and regional and distant lymph node metastases (ie, the TNM stage) remains the most accurate prognostic tool available [68]. Extensive research has been performed in the search for factors with prognostic significance independent of TNM staging. Particular points of interest include the identification of a subgroup of patients who have stage II (T3–4 N0) colon cancer who may benefit from adjuvant chemotherapy and in selecting patients who have rectal cancer who have favorable tumor pathology and low risk of harboring lymph node metastases, who would be candidates for local excision. An increased understanding of the molecular events that occur when benign colorectal mucosa progresses to invasive carcinoma has spurred interest in correlating tumor genotype with tumor behavior (phenotype). This has led to the recognition that several clinical, pathologic, and molecular variables not included in traditional TNM staging have potential clinical significance. Using multivariate analysis, several of these factors have been shown to be of prognostic significance independent of TNM staging. Many others, particularly genetic and molecular markers, show promise but need further elucidation of their significance independent of TNM staging. Clinical factors Several potential prognostic variables exist in patients who have colorectal cancer before treatment or pathologic evaluation of the tumors. Bowel obstruction as a presentation of colorectal cancer has long been recognized to portend a worse prognosis. Several studies have identified obstruction as significant in multivariate analysis [69,70,71]. Preoperative carcinoembryonic antigen (CEA) levels also have been studied, and a worse outcome has been shown with elevated levels (usually R3 or 5 ng/mL) [72,73], although other studies have not noted this association [69]. However, the bulk of the evidence points toward CEA levels R5 ng/mL as being significant, and both the American Joint Committee on Cancer and the College of American Pathologists recommend obtaining and reporting this information in addition to TNM staging [74,16]. Pathologic variables Foremost among the pathologic factors that affect prognosis in colorectal cancer are those included in TNM and Dukes’ staging systems, the depth of tumor penetration, the presence of lymph node metastases, and the presence of distant metastases. Several pathologic features not included in TNM staging have proven to have prognostic implications. Histologic grade is an important aspect in the pathologic evaluation of resected tumor, whether assessed from a biopsy

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specimen or within a resection specimen. Tumor grade is a well-recognized, independent prognostic factor in colorectal cancer in multiple studies [75,17]. Historically, tumor histology has been divided into several categories: well differentiated, moderately differentiated, poorly differentiated, and undifferentiated. However, the lines between categories are not always clear, and there exists the potential for significant interobserver variation within these categories [76,77]. Establishing a dichotomous system of low grade (well and moderately differentiated) and high grade (poor and undifferentiated tumors) has been proposed as a means to simplify and more accurately place tumors within the appropriate category [76,78] without losing any prognostic power. Additional work has focused on the histologic subtype of the tumor. Although the majority of tumors will be adenocarcinomas, there are certain subtypes noted to have an adverse effect on outcome, namely signet-ring cell and small-cell carcinomas [78], which are by definition considered high-grade (poorly or undifferentiated) tumors. The significance of mucinous adenocarcinomas is less certain because they occur in a high proportion of microsatellite-unstable tumors (discussed below), although the majority of mucinous tumors will still occur in microsatellite-stable tumors. Microsatellite-unstable tumors have been believed to carry a more favorable prognosis than their stable counterparts do, although a consensus agreement does not exist currently. Microscopic tumor invasion of neural tissue, lymphatics, or blood vessels is regarded generally as having an adverse outcome on tumor recurrence and patient survival. Rectal cancer patients undergoing either local excision or radical resection that demonstrate tumor invasion of one or more of the above structures heralds an increased risk of local recurrence [79,80] or lymph node metastases [81]. Other studies not limited to patients who have rectal cancer have found tumor invasion of these structures to be significant on univariate analysis but not in multivariate analysis [69,72]. This loss of significance on multivariate analysis can be explained partly by an increased incidence of these adverse microscopic factors with more advanced T and N stages [82], thereby limiting the contribution of these microscopic features relative to the TNM stage. By consensus, lymphovascular invasion generally is considered to be significant, with perineural invasion being less so [16]. For rectal cancer, these findings have clinical significance because they are believed to be relative contraindications to local excision unless adjuvant chemoradiation therapy is planned [83]. Genetic and molecular variables A tremendous amount of research delineating the progression of normal colonic mucosa into invasive adenocarcinoma has been performed in the last two decades. Although a full review of this progress is beyond the scope of this paper, several areas of interest are worth noting. A stepwise model of

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tumor progression from benign polyp to invasive cancer based on progressive genetic mutation was introduced in 1990 [84]. There were several genes identified in this model, including the adenomatous polyposis coli (APC) tumor-suppressor gene, K-ras, p53, and the deleted in colon cancer (DCC) gene. Loss of the long arm of chromosome 18, which contains the DCC gene, is observed in up to 70% of colorectal cancers [85]. This tumorigenic pathway is often referred to as the loss of heterozygosity (LOH) pathway because of the loss of genetic material from chromosomes 18 as well as segments from chromosomes 17 and 5, which contain the p53 [86] and APC genes [87], respectively. A second distinct pathway for tumorigenesis involves the dysfunction or loss of DNA mismatch repair genes and is identified through high rates of replication errors in short segments of DNA base-pair repeats called microsatellites. High mutation rates within these microsatellite regions have been identified in certain tumors occurring in approximately 15% of sporadic cancers [88] and in R90% of cancers occurring in patients who have hereditary nonpolyposis colorectal cancer (HNPCC) (Lynch syndrome) [89]. The loss of chromosomal material, as occurs in the LOH pathway, generally is not seen in the microsatellite-instability (MSI) pathway. Additionally, sporadic cases of colorectal cancer with MSI appear to arise not from germ line mutations in mismatch repair genes, as seen in HNPCC families, but rather from methylation of the promoter region of the mismatch repair gene hMLH1, with a resultant lack of protein production from this gene [90]. Tumors arising from MSI have been noted to occur more often in the proximal colon [88] and be of mucinous or undifferentiated histology [91]. The elucidation of these pathways has led to substantial research attempting to correlate specific gene loss, as seen in the LOH pathway, and MSI status with prognosis. A very thorough review examining the prognostic significance of mutations or loss of the genes for K-ras, p53, and DCC, as well as the significance of MSI positive tumors was published recently [92]. The authors have found conflicting data for each of these factors, with no clear consensus as yet to the value of these markers in clinical practice. Additionally, although MSI-positive status initially seemed to correlate with a better prognosis [88], a recent National Cancer Institute consensus panel [91] addressing MSI in colorectal cancer concludes that additional research was necessary before independent prognostic status could be granted to MSI-positive tumors. Although the clinical significance of individual genetic factors has yet to be proven, future research will most likely elucidate the correlation of tumor phenotype with clinical behavior. The use of DNA microarray techniques may be one method to help bridge the gap between complex tumor genetic alterations and biologic behavior [93]. Summary Significant advances have been made in all aspects of care relating to colorectal cancer. Although surgery will likely remain the mainstay of

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definitive treatment for the majority of colorectal malignancies, a better understanding of tumor progression and biology will help guide the choice of surgical therapy to best achieve a curative resection. Additionally, advances in the use of neoadjuvant and adjuvant therapies should continue to increase disease-free and overall survival when combined with appropriate operative resection. Although TNM staging remains our strongest tool at this point for establishing prognosis and directing therapy, expansion of our knowledge of the molecular events underlying colorectal tumorigenesis undoubtedly will lead to the refinement of our current staging and prognostic systems.

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