Pathologic Prognostic Factors in the Recurrence of Rectal Cancer

Comprehensive

Review Pathologic Prognostic Factors in the Recurrence of Rectal Cancer Carolyn C. Compton Abstract For rectal cancer, local recurrence following surgical treatment is a grave complication that occurs in as many as 25% of cases. Pathological examination of the surgical resection specimen plays a primary role in assessing both the surgery- and tumor-related factors that contribute to the risk of recurrence.Among the tumor-related factors, stage has long been considered the single most accurate indicator of survival. However, recent evidence strongly suggests that the most powerful predictor of both local recurrence and overall outcome in the absence of distant metastatic disease is the macroscopic quality of the mesorectum in the resection specimen and the proximity of the tumor to the circumferential (radial) resection margin. Additional pathologic features have been shown to have stage-independent prognostic significance in colorectal cancer and may help to further define risk of adverse outcome. Such features include: tumor grade; histologic type; extent of extramural penetration by tumor; neural, venous, and/or lymphatic invasion; tumor border configuration; tumor budding; and host lymphoid response.The predictive value of tumor-specific molecular features is currently under investigation and may help to further improve prognostication and refine individual patient management in rectal cancer. Clinical Colorectal Cancer, Vol. 2, No. 3, 149-160, 2002 Key words: Predictive factors, Circumferential resection margin, Total mesorectal excision, Stage

Introduction Local recurrence (LR) of rectal cancer after curative resection (ie, surgical removal of all visible tumors) is a major clinical problem. When LR occurs, it causes severe morbidity that profoundly compromises quality of life and usually leads to death.1 In rectal cancer, most LR consists of isolated tumor deposits unaccompanied by distant metastasis. This pattern differs from that of colon carcinoma, in which LR is most often accompanied by disseminated disease. Two major categories of factors are thought to influence LR in rectal cancer: surgery-related (technical) and tumor-related (biological) factors. For successful treatment of rectal cancer, the quality of the surgical technique is critical and affects both LR and overall survival (OS). The most important technical factor is the adequacy of excision of the mesorectal envelope, which contains all of the lymphatic, lymph node, and neural tissue around the rectum.2-12 Numerous studies have shown that LR and OS differ markedly among surgeons, indicating a wide range of quality in technique. Local recurrence rates ranging from 15%-45% are reported for rectal cancers resected with cur-

Department of Pathology, McGill University, Montreal, Quebec, Canada Submitted: Sep. 3, 2002; Revised: Sep. 30, 2002; Accepted: Oct. 15, 2002 Address for correspondence: Carolyn C. Compton, MD, PhD, McGill University Department of Pathology, 3775 University Street, Montreal, Quebec H3A 2B4 Canada Fax: 514-389-7446; e-mail: [email protected]

ative intent using conventional nonstandardized techniques.5,13 However, the adoption of total mesorectal excision (TME) techniques by surgeons performing rectal cancer resections dramatically improves LR rates (Table 1)14,15 and corresponding OS rates; reported rates of LR following TME performed by surgeons specifically trained in this technique are ≤ 7%. Adjuvant radiation therapy in the presence of a high-quality TME may further reduce LR to 2%-3%.5 Thus, there is little doubt that high-quality TME is essential if outcome is to be optimized for rectal cancer patients. The impact of other surgical prognostic factors, such as the type of operation (low anterior resection Table 1

Study

Local Recurrence Rates with Total (Sharp) Mesorectal Excision Compared to Conventional (Blunt) Mesorectal Excision (Historical Controls) Surgery (Years)

Local Recurrence Rate

Conventional Surgery (1984-1986)

23%

TME (1990-1992)

8%

Conventional Surgery (1974-1984)

39%

TME (1985-1991)

10%

Sweden14

Germany15

Abbreviation: TME = total mesorectal excision

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Predicting Recurrence in Rectal Cancer [LAR] vs. abdominoperineal resection [APR]), use of circular stapling devices, postoperative anastomotic leakage, and inadvertent tumor perforation during operation, is less clear.1,16 Independent data from pathological studies of rectal cancer resection specimens have strongly reinforced clinical evidence that TME is important in optimizing outcome for patients with operable rectal cancer. The pathological features of the resection specimen that most powerfully predict LR in rectal cancer are the integrity of the mesorectum on macroscopic examination and the status of the circumferential (radial) resection margin (CRM) determined microscopically. In addition, because mesorectal completeness and CRM status directly reflect the quality of the mesorectal excision performed surgically, the pathologic assessment of these features has emerged as an important form of quality control in rectal surgery.12 Other tumorrelated features that have been shown to help predict risk of LR and shortened survival include: histologic type; tumor grade; pathologic stage; presence or absence of neural, venous, or lymphatic invasion; tumor border configuration; and host lymphoid response to tumor. All of these pathologic features can be assessed using standard techniques. They require no special studies and incur no extra costs. The pathologic features that are part of macroscopic evaluation (including resection margin assessment and stage assignment) and those features that have been identified as stage-independent predictors of LR in rectal cancer (ie, predictive factors) and/or of OS in colorectal cancer in general (prognostic factors) are reviewed individually below. A variety of tumor-specific molecular features are currently under active investigation as prognostic and predictive of response to adjuvant or neoadjuvant therapies. Although several biomarkers have been identified as having potential clinical significance, none have yet been validated in clinical trials or used for routine patient management.

The Status of Surgical Resection Margins The fundamental assumption in the pathologic assessment of surgical resection margins is that involvement by tumor, seen either grossly or microscopically, is indicative of incomplete resection and is essentially equivalent to residual tumor within the corresponding operative site in the patient. Therefore, the tumor that grossly or microscopically involves a resection margin is categorized in the R classification (for residual tumor in the patient) of the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC) as R1 or R2, respectively (Table 2).17 In this circumstance, adjuvant therapy is usually indicated.

Local Excision Specimens The pertinent margins of a locally resected rectal cancer (ie, transanal disk excision) include the lateral margins circumferentially and the deep margin. The location of these landmarks can only be established on pathologic examination when the tumor is excised en bloc to yield a single intact tissue specimen. Segmental (ie, piecemeal) resection yielding multiple separate fragments of tumor usually precludes iden-

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Table 2

R Classification for Residual Tumor in the Patient17

Classification

Indication

RX

Presence of residual tumor cannot be assessed

R0

No residual tumor

R1

Microscopic residual tumor

R2

Macroscopic residual tumor

tification of resection margins on pathologic examination. If segmental resection is unavoidable, the surfaces that represent true resection margins must be identified for the pathologist by the surgeon, if possible. In one clinical study, piecemeal local resection itself proved to be an adverse prognostic factor with a much higher rate of LR among cancers resected in this fashion (6 failures among 15 cases) compared to en bloc resection (11 failures among 46 cases).18

Segmental Resection Specimens (Low Anterior Resection and Abdominoperineal Resection Specimens) The pertinent margins of an LAR or APR specimen include the proximal and distal transverse margins and the CRM. Involvement of the proximal resection margin is rare because margins of ≥ 3 cm are almost always technically feasible. Involvement of the distal margin is more common but still infrequent. Distally, a margin of 2 cm of normal tissue is accepted as adequate to prevent LR, and in many cases, distal margins of ≤ 1 cm also prove sufficient, especially for tumors that have not penetrated the rectal wall.12,16,19,20 However, due to the coneshaped anatomy of the lower rectum and its surrounding soft tissues, it may be difficult or impossible to obtain a 2-cm cuff of marginal tissue, especially posteriorly near the sacrococcygeal raffe.12 The CRM is the nonperitonealized surface of the rectal specimen created by mesorectal dissection at operation. The circumferential dissection of the mesorectum is the most problematic and technically demanding aspect of rectal surgery. In contrast to the blunt dissection techniques that typically disrupt the visceral mesorectal fascia, TME techniques involve sharp dissection under direct visualization of the plane between the endopelvic fascia and the mesorectum.20 The fascia propria of the mesorectum and the pelvic fascia are both maintained intact. Total mesorectal excision preserves the pelvic autonomic nerve complexes lateral to the mesorectum and protects the vagina or prostate anteriorly.21,22 It also maximizes the ability to preserve the anal sphincter. Therefore, conservation of bladder, sexual, and sphincter function, which are important secondary goals of rectal cancer surgery, can be realized in most cases. The most important goal, however, is cure achieved through local control of the tumor.23 Since the majority of rectal cancers with transmural spread (with or without regional nodal metastases) are confined to the mesorectum, removal of the entire mesorectum intact maximizes the likelihood of surgical cure. Total mesorectal excision optimizes the surgical clearance around the tumor

Carolyn C. Compton and removes all of the regional lymph nodes en bloc including those distal to the site of the primary tumor that may be involved by metastatic disease. In prospective studies demonstrating significantly improved patient outcomes after surgeons have been trained in proper techniques for TME, the quality of the surgery has been judged in large part by the quality of the resection specimen.12,24 Pathological assessment of the degree of integrity of the mesorectal surface has been shown to correlate clinically with both LR and distant recurrence and pathologically with CRM involvement.24 An incomplete mesorectum on gross pathological examination, defined as having little bulk and macroscopic defects down to the muscularis propria and/or a very irregular circumferential surface, has been found to predict a higher rate of both CRM involvement and LR as compared to a complete or nearly complete mesorectum. A complete or nearly complete mesorectum, which correlates with the highest cure rates, is recognized by full to moderate bulk and only minor to moderate irregularities of the mesorectal surface (Table 3). Thus, the macroscopic quality of the rectal resection specimen as judged by the amount of extramural soft tissue within the mesorectal envelope, and the degree of integrity of the mesorectal fascia directly reflects the adequacy of the surgical technique. On microscopic examination, the distance of the tumor from the CRM (the periphery of the resected mesorectum) may be the single most critical factor in predicting LR.12,25,26 The CRM involvement by tumor also has been shown to predict distant recurrence and OS.25,27 Unfortunately, in North America, the clinical importance of the CRM has not been widely recognized by pathologists, and routine pathologic evaluation of the CRM has been lacking. An assessment of Table 3

Irregularity of the mesorectal surface with defects > 5 mm but none extending to the muscularis propria

Anatomic Location of Tumor

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

Nearly Complete

No areas of visibility of the muscularis propria except at the insertion site of the levator ani muscles Intact bulky mesorectum with a smooth surface Only minor irregularities of the mesorectal surface Complete

The circumferential resection margin shows infiltrating tumor at the inked surface, which corresponds to R1 disease (microscopic residual disease in the patient following surgical resection of the tumor).

Moderate bulk to the mesorectum

Indication Little bulk to the mesorectum

Incomplete

Tumor Involvement of Circumferential Resection Margin

data from 3 rectal cancer treatment protocols conducted by the North Central Cancer Treatment Group (NCCTG) between 1979 and 1992 showed that the CRM was evaluated pathologically in only 21% of cases.16 Based on clinicopathological correlative data, this margin should be regarded as positive if tumor is present within 0-1 mm of the closest CRM (ie, the surgical clearance around the tumor is ≤ 1 mm; Figure 1).12 Within this range, both LR and OS rates are significantly elevated compared with clearance that is > 1 mm.12,16,26,28 In the NCCTG study, the LR rate was 25% if the CRM clearance was 0-1 mm and 3% if the clearance was > 1 cm.16 Any tumor, whether present as a direct extension, an intravascular growth, or a lymph node metastasis, is relevant to the CRM assessment. Measurement of the surgical clearance in all rectal resection specimens, even those with a negative CRM, is also justified because LR decreases and OS increases proportionally with increased surgical clearance.4 The overriding clinical relevance of tumor involvement of or proximity to the CRM mandates careful pathological evaluation and reporting of the microscopic status of the CRM for all rectal cancer resection specimens.

Macroscopic Scoring of the Mesorectal Envelope*

Score

Figure 1

No surface defects > 5 mm in depth No coning toward the distal margin of the specimen After transverse sectioning, the circumferential margin appears smooth

*The entire specimen is scored according to the worst area.

A number of studies have shown an increased incidence of LR for low-lying rectal tumors.29-34 Although cutoff points differ among studies, tumors located in the lower third of the rectum or < 11 cm from the anal verge generally have been shown to have increased rates of LR compared to those occurring more proximally. These findings are explained by the space limitations of the lower pelvis, which increase both the probability of direct tumor extension into an adjacent structure and the difficulty of achieving sufficient lateral surgical clearance around the tumor. An increased probability of microscopic involvement of the CRM is implied by these studies, but the status of this margin was not specifically analyzed.

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Predicting Recurrence in Rectal Cancer Histologic Type In the pathologic reporting of rectal cancer, the internationally accepted histologic classification of colorectal carcinomas proposed by the World Health Organization (WHO; Table 4) is recommended by the College of American Pathologists (CAP).35 By this classification, the majority of rectal cancers are adenocarcinomas of no special type. Other histologic types of carcinomas are unusual in the rectum but do occur. Aside from a few notable exceptions, histologic type has no stage-independent prognostic significance.36-48 The exceptions include the non–gland-forming tumor types such as signet-ring cell carcinoma, small-cell carcinoma, and undifferentiated carcinoma, which are prognostically unfavorable49 and medullary carcinoma, which is prognostically favorable.50 Medullary carcinoma, added to the revised WHO classification in 2000,51 is a distinctive type of carcinoma composed of large polygonal tumor cells and abundant tumor infiltrating lymphocytes (Figure 2). Previously, this tumor type would have been classified as undifferentiated carcinoma in the WHO system. The importance of this unique histologic type is its strong association with defective DNA replication fidelity and high microsatellite instability (MSI-H)—molecular features that are, in turn, associated with a more favorable stage distribution and prognosis compared to microsatellite-stable tumors.52-56 However, most tumors of this type occur in the proximal colon in association with the hereditary non-polyposis colon cancer syndrome and are rarely found in the rectum. To date, no large studies on prognostic factors in rectal cancer have systematically considered the relationship between the genetic status of the tumor, histologic type, and outcome. This oversight is particularly relevant to mucinous carcinoma, a histologic type that lacks microsatellite stability in most cases but represents a high proportion of microsatellite-stable colorectal cancers. Thus, overall, the prognostic significance of mucinous carcinoma remains the most controversial. A few studies largeTable 4

World Health Organization Classification of Colorectal Carcinoma*

Adenocarcinoma Mucinous (colloid) adenocarcinoma (> 50% mucinous) Signet-ring cell carcinoma (> 50% signet-ring cells) Squamous cell (epidermoid) carcinoma Adenosquamous carcinoma Small-cell (oat cell) carcinoma Medullary carcinoma Undifferentiated carcinoma Other (eg, papillary carcinoma) *The term carcinoma, NOS (not otherwise specified) is not part of the World Health Organization classification. Adapted with permission from Hamilton S, et al. Carcinoma of the colon and rectum. In: Hamilton S, Aaltonen L, eds. World Health Organization Classification of Tumours. Tumours of the Digestive System. Lyon, France: IARC Press, 2000:101-119.

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Figure 2

Medullary Carcinoma

This histologic type, invariably associated with high microsatellite instability, is characterized by sheets of large polygonal cells with vesicular nuclei and abundant eosinophilic cytoplasm and abundant intratumoral lymphocytes.

ly limited to univariate analyses have indicated that mucinous adenocarcinoma may be an adverse prognostic factor.48,57-59 More specifically, mucinous carcinoma has been linked with adverse outcome if occurring in specific anatomic regions of the bowel (eg, the rectosigmoid)57-59 or in specific subsets of patients (ie, patients < 45 years of age).60 In other studies, shortened OS compared to typical adenocarcinoma has been demonstrated only when mucinous carcinoma has been grouped together with signet-ring cell carcinoma (a subtype known to behave aggressively).61-63 A single multivariate analysis has shown mucinous carcinoma to be a stage-independent predictor of adverse outcome, but the study was limited to tumors presenting with large bowel obstruction, itself an adverse prognostic factor.64

Tumor Grade In general, the grading of colorectal carcinoma is based on both architectural features and cytological features (eg, pleomorphism and hyperchromatism), but the degree of gland formation is widely regarded as the most important feature in grading. Therefore, the non–gland-forming histologic types of colorectal cancer (eg, signet-ring cell carcinoma, small-cell carcinoma, and undifferentiated carcinoma) are always assigned a high tumor grade.22 For adenocarcinoma, however, the estimation of the degree of gland formation and assignment of grade are largely subjective. The 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.44,49,64-74 Furthermore, the published systems have varied markedly as to the number, type, and relative importance of the specific features used to distinguish different grades. In some systems, grade is based on a single architectural feature, such as the degree of gland formation, and in others, a large number of features are included in the evaluation. Exceptionally, a suggested grading system has

Carolyn C. Compton been based solely on cytological criteria. Irrespective of the type or complexity of the criteria, however, most systems stratify tumors into 3 or 4 grades as follows: Grade 1 - Well differentiated Grade 2 - Moderately differentiated Grade 3 - Poorly differentiated Grade 4 - Undifferentiated In routine practice, the pathologic diagnosis of grades 3 and 4 is relatively consistent, but differentiation between grades 1 and 2 is associated with a more significant degree of interobserver variability.44,71,75 Even in the diagnosis of grade 3 and grade 4 adenocarcinomas, however, some variation in approach exists. Pathologists may base the assignment of the overall tumor grade on the highest grade anywhere in the neoplasm (whatever its size),66 the relative proportion of undifferentiated tumor,68,73 or the degree of differentiation along the advancing edge of the tumor.72 Despite the lack of standardization and the existent interobserver variation in assessment, histologic grade has been repeatedly shown by multivariate analyses to be a stage-independent prognostic factor.36,76-88 More specifically, high tumor grade has been shown to be an adverse prognostic factor. In most studies documenting the prognostic power of tumor grade, 3- or 4tiered grading schemas have been collapsed for data analysis as low grade (grades 1 and 2) or high grade (grades 3 and 4). Based on these data, a 2-tiered grading system for colorectal carcinoma (ie, low grade and high grade) has been recommended by a multidisciplinary colorectal working group of a consensus conference sponsored by the CAP.49 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 or not an undifferentiated tumor at the advancing edge of the cancer should be evaluated and reported separately or incorporated into the overall tumor grade. At present, the data available are insufficient to support one approach over the other, and the issue remains problematic.

Pathologic Stage Pathologic staging following complete resection has long been considered the most powerful prognostic indicator in colorectal cancer and typically has determined the appropriateness of systemic adjuvant treatment as well.89 Although a large number of staging systems have been developed for colorectal cancer over the years, use of the TNM staging system of the AJCC and UICC (Table 5) is recommended by the CAP and the Colorectal Cancer Pathology Committee for Common Data Elements sponsored by the National Cancer Institute.35,49,90,91 The TNM staging systems have recently been updated and published in the sixth editions of the staging manuals of the AJCC and UICC. For the first time since the development of the TNM staging system, there is complete concordance between the AJCC and the UICC versions. The updated versions are mandated for use beginning January 1, 2003. Pathologic TNM classification (pTNM) is based on gross and microscopic examination of the resection specimen of a previ-

Table 5

TNM Staging System for Colorectal Carcinoma

Primary Tumor (T) TX

Primary tumor cannot be assessed

TO

No evidence of primary tumor

Tis

Carcinoma in situ (intraepithelial or intramucosal carcinoma)

T1

Tumor invades the submucosa

T2

Tumor invades the muscularis propria

T3

Tumor invades through the muscularis propria into the subserosa or into the nonperitonealized pericolic or perirectal tissues

T4

Tumor directly invades other organs or structures (T4a) or perforates the visceral peritoneum (T4b)

Regional Lymph Nodes (N) NX

Regional lymph nodes cannot be assessed

NO

No regional lymph node metastasis

N1

Metastasis in 1-3 lymph nodes

N2

Metastasis in ≥ 4 lymph nodes

Distant Metastasis (M) MX

Presence of distant metastasis cannot be assessed

M0

No distant metastasis

M1

Distant metastasis TNM Stage Groupings

Stage 0

Modified Astler-Coller

Dukes

Tis

N0

M0

NA

NA

T1

N0

M0

Stage A

A

T2

N0

M0

Stage B1

A

Stage IIA

T3

N0

M0

Stage B2

B

Stage IIB

T4

N0

M0

Stage B3

B

Stage IIIA

T1-T2

N1

M0

Stage C1

C

Stage IIIB

T3-T4

N1

M0

Stage C2; C3

C

Stage IIIC

Any T

N2

M0

Stage C1; C2; C3

C

Stage IV

Any T

Any N

M1

Stage D

NA

Stage I

Abbreviation: NA = not applicable Reproduced with permission from Greene F, et al. AJCC Cancer Staging Manual. New York, NY: Wiley-Liss, 2002.

ously untreated primary tumor. Clinical classification (cTNM) is usually determined by imaging techniques carried out before treatment during the initial evaluation of the patient or whenever pTNM is not possible.90,92 It is the grouping of the T, N, and M parameters, rather than a single parameter alone, that determines the stage of the tumor and relates to prognosis. By convention, pathologically determined T and N are considered more accurate than the clinically derived T and N. Therefore, the pT and pN replace the initially determined cT and cN in the

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Predicting Recurrence in Rectal Cancer final staging, when pathological data become available from the examination of the surgical resection specimen. If distant metastasis is not confirmed pathologically, assignment of pMX is appropriate, and the clinically derived M category is used to construct the stage grouping. In pT3 tumors, one feature that has been reported to affect prognosis, whether or not regional lymph node metastasis is present, is the extent of extramural invasion. An optional expansion of pT3 that reflects the incremental adverse influence of extramural extension has been proposed by the UICC.92 Extramural extension that exceeds 5 mm appears to have the most profound adverse effect on prognosis in most studies. Pathologically, extramural tumor extension within lymphatics or veins is not defined as pT3 but instead is classified separately in the TNM system as L1 or V1 disease, respectively.91,92 The highest category of local extent is pT4, which includes both penetration of an adjacent organ or structure (pT4a) and penetration of the parietal peritoneum with or without involvement of an adjacent structure (pT4b).92 A free perforation of a colorectal carcinoma into the peritoneal cavity (ie, a hole or transmural defect within the tumor) is also classified as T4b and is a dire prognostic factor. Unfortunately, in the definition of the T4 category, the word perforates is the descriptor for a tumor that penetrates/involves the visceral peritoneum whether or not a hole is present on gross examination. This semantic problem has caused confusion as to the appropriate assignment of the T4b category. Pathologic assessment of serosal penetration by tumor is relevant only to the upper rectum, which is covered anteriorly by a visceral peritoneum, but is exceedingly important. Numerous studies have evaluated serosal penetration as a separate pathologic variable and have demonstrated by multivariate analysis that it has independent adverse prognostic significance. The median survival time following surgical resection for cure is significantly shorter for pT4 tumors that penetrate the visceral peritoneum compared to pT4 tumors without serosal involvement with or without distant metastasis. A careful pathologic study of local peritoneal involvement by Shepherd et al has suggested that the prognostic power of this feature alone may supersede that of either local extent of tumor (T category) or regional lymph node status (N category).93 Despite its biologic importance, serosal penetration is often underdiagnosed by pathologists. Documentation of peritoneal involvement by tumor demands meticulous pathologic analysis and may require extensive sampling and/or serial sectioning. Thus, it can be missed on routine histopathologic examination. In fact, it has been shown that cytologic examination of serosal scrapings reveals malignant cells in as many as 26% of tumor specimens categorized as pT3 by histologic examination alone.94 In addition, the histopathologic findings associated with peritoneal penetration are heterogeneous, and standard guidelines for their diagnostic interpretation are lacking. These problems result in both substantial interobserver variation and underdiagnosis of peritoneal involvement since most pathologists tend to err on the side of conservative interpretation. In the pathologic study by Shepherd et al, tumors present at the seros-

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al surface with inflammatory reaction, mesothelial hyperplasia, and/or erosion/ulceration or free tumor cells on the serosal surface (in the peritoneum) with underlying ulceration of the visceral peritoneum were both associated with shorter survival compared with tumors well clear of the serosal surface.93

Regional Lymph Node Examination The TNM stage-related outcome data are derived from studies in which conventional pathologic evaluation of macroscopically identified regional lymph nodes has been performed. For the rectum, regional nodes include the perirectal, sigmoid mesenteric, inferior mesenteric, lateral sacral, presacral, internal iliac, sacral promontory, superior rectal, middle rectal, and inferior rectal nodal groups. Perirectal lymph nodes include the mesorectal (paraproctal), lateral sacral, presacral, sacral promontory (Gerota), middle rectal (hemorrhoidal), and inferior rectal (hemorrhoidal) nodes.90 Typically, none of these are present in a local resection (eg, transanal disk excision) specimen, and the number present in an LAR or APR specimen may vary with surgical technique and completeness of the mesorectal resection.1 Metastasis to regional lymph nodes is a strong adverse prognostic factor and is the cardinal element of stage III rectal carcinoma. With progression of disease to stage III, 5-year survival rates drop precipitously from 70%-75% (stage II, node-negative mural/transmural disease) to 35%-40%.89 Thus, assessment of regional lymph node status is a critical part of the pathological examination of the rectal resection specimen. It has been shown repeatedly that at least 12-15 regional lymph nodes must be examined to accurately determine node negativity in colorectal cancer.49,75,95,96 Therefore, an absence or dearth of regional lymph nodes in the resection specimen may severely limit the predictive value of the assigned pN. Discrete nodules of tumor are sometimes found in the extramural adipose tissue on pathologic examination that may represent lymph nodes replaced by tumor but, in the absence of residual nodal tissue, cannot be identified as nodal metastasis with certainty. Recent data have suggested that extramural tumor deposits of any size correlate with decreased survival and do so independently of definable regional lymph node status.97 These data have also suggested that the number of pericolonic tumor deposits also is important, with increasing numbers being inversely proportional to disease-free survival. Thus, in the updated TNM guidelines, each discrete extramural tumor nodule with smooth contours, irrespective of size, is included in the N category as a positive lymph node.

Venous, Lymphatic, or Perineural Invasion by Tumor The importance of venous and lymphatic invasion by tumor as stage-independent adverse prognostic factors is strongly suggested and largely confirmed by the literature. Venous invasion by tumor (Figure 3) has been demonstrated by numerous multivariate analyses to be an independent adverse prognostic factor in colorectal cancer.36,39,40,60,61,76,77,81,88,89,98 In some studies, the location of the involved vessels (eg, extramural as

Carolyn C. Compton Figure 3

Venous Involvement by Tumor

Muscular veins in the perirectal soft tissue show intraluminal tumor plugs, a finding that is codified as V1 disease.

opposed to submucosal location) has been a strong determinate of prognostic significance.61,75 In particular, extramural venous invasion has been linked with increased risk of hepatic metastasis. In some studies, invasion of vascular structures of any type, without distinction between venous and lymphatic vessels, has been found to be prognostically significant by multivariate analysis. More disparate results have been reported for lymphatic vessel invasion alone.38,39,43,98-103 Most of the data linking small vascular space (presumed to be lymphatic) involvement to adverse outcome have come from studies on cancers in polypectomized adenomas (pT1 tumors) and have shown an associated risk of regional lymph node metastasis.102-113 In one study specifically focused on pT1 and superficial pT2 rectal cancers, a significant association of small vessel involvement anywhere in the specimen and regional nodal metastasis was demonstrated.64 It is likely that the disparities among existing studies on vessel invasion are directly related to inherent problems in the

Figure 4

Lymphatic Involvement by Tumor

Thin-walled, endothelial-lined channels contain clusters of tumor cells, a finding that is codified as L1 disease.

pathologic analysis of this feature. Definitive diagnosis of vessel invasion requires the identification of tumor within an endothelial-lined channel (Figure 4). However, this may be difficult when tumor-induced vascular fibrosis or endothelial destruction is present. In addition, fixation artifact in the tumor may mimic small vessel involvement. For these reasons, interobserver variation may be substantial in the interpretation or recognition of vessel invasion. Special techniques such as immunohistochemical staining of endothelium or elastic tissue stains of venous walls may or may not increase the accuracy of evaluation. Moreover, these techniques are labor intensive, time consuming, and expensive. Thus, they are not routinely performed. Additional limitations in the detection of vessel invasion are related to specimen sampling. For example, it has been shown that the reproducibility of detection of extramural venous invasion increases proportionally from 59% with examination of 2 blocks of tissue at the tumor periphery to 96% with examination of 5 blocks.75

Tumor Border Configuration, Tumor Budding, and Perineural Invasion For colorectal cancer, the configuration of the tumor at the advancing edge (tumor border) has been shown to have prognostic significance that is independent of stage and may predict liver metastasis. Specifically, an irregular, infiltrating pattern of growth (Figure 5) as opposed to a smooth pushing (expanding) border (Figure 6) has been demonstrated to be an independent adverse prognostic factor by several multivariate analyses.37,44,45,93,114-116 However, Jass et al showed that interobserver variation existed among pathologists evaluating tumor border configuration in general practice when no specific definitions or guidelines for assessment were provided.44 Agreement in diagnosis of infiltrating growth pattern was only 70%. They also found that concordance improved to 90% when specific diagnostic criteria for defining infiltrating growth were employed (Table 6).44 It is significant that one of the microscopic criteria by which infiltrating growth can be

Figure 5

Carcinoma Infiltrating Into Perirectal Tissue

Irregular streaming of infiltrating tumor into perirectal soft tissues creates a jagged appearance to the tumor border.

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Predicting Recurrence in Rectal Cancer Figure 6

Colorectal Carcinoma with Smooth, Expanding Border

separately as a potentially important stage- and grade-independent prognostic factor.

Host Lymphoid Response to Tumor

The border of the tumor has a blunt, rounded contour and lacks irregular infiltration of tumor cells into the surrounding soft tissues.

recognized is perineural invasion. This pathologic feature is not routinely assessed or specifically reported in colorectal cancers, yet perineural invasion itself has been shown by multivariate analysis in a number of studies to be an independent indicator of poor prognosis.77,78,95,116 Tumor budding is another specific feature found at the tumor border that is variably ignored, reported separately, included in the overall assessment of tumor border configuration, or included in the overall assessment of tumor grade.64 It is defined as microscopic clusters of undifferentiated cancer cells just ahead of the invasive front of the tumor112 and has also been referred to as focal dedifferentiation.103 It may be seen in an otherwise well or moderately differentiated tumor, and data from some studies have suggested that it is of greater prognostic value than overall grade.112 It has been found to predict regional lymph node metastasis in APR specimens of T1 and superficial T2 rectal cancers, suggesting that it may be useful as an indicator for patients at risk of recurrence after local excision (transanal disk excision) alone.64 In the absence of definitive data on the biologic significance of tumor budding and of consensus on histologic grading in colorectal cancer, it would seem prudent to report this feature Table 6

Lymphocytic infiltration of tumor or peritumoral tissue is indicative of a host immunologic response to the invasive malignancy and has been shown by multivariate analysis in several studies to be a favorable prognostic factor.44,61,80,114 In contrast, other studies have either failed to confirm the prognostic significance of a peritumoral lymphoid reaction27,113 or demonstrated its significance only by univariate analysis.41,117120 The results of these studies are difficult to compare since the histologic criteria for qualitative and quantitative evaluation differ from study to study. Some of the specific features that have been studied include perivascular lymphocytic cuffing in the muscularis propria, perivascular lymphocytic cuffing in the pericolonic fat or subserosa, lymphocytic infiltration at the tumor edge, and a transmural Crohn’s-like lymphoid reaction (Figure 7). However, in some reports, little if any explanation of the criteria used for evaluation of this parameter have been offered. Therefore, although this feature appears promising as a favorable prognostic factor, further studies using comparable criteria are needed for confirmation. Agreement has emerged, however, that large numbers of tumor-infiltrating lymphocytes (TILs) are uniquely associated with MSI in colorectal cancers119 and, for that reason, may be a favorable prognostic factor. Indeed, large numbers of TILs are one of the diagnostic features of medullary carcinomas of the colorectum, but they may be found in other histologic types of tumors with MSI.121 Therefore, it is recommended that TILs be distinguished from peritumoral lymphocytic infiltrates and that moderate to high densities of TILs (approximately 4 per high-power field) be reported.49

Tumor-Specific Molecular Features Despite the prognostic power of stage in colorectal cancer,

Figure 7

Crohn’s-Like Host Lymphoid Reaction to Colorectal Carcinoma

Diagnostic Criteria for Infiltrating Tumor Border Configuration

Naked Eye Examination of a Microscopic Slide of the Tumor Border • Inability to define limits of invasive border of tumor and/or • Inability to resolve host tissue from malignant tissue Microscopic Examination of the Tumor Border • Streaming dissection of muscularis propria (dissection of tumor through the full thickness of the muscularis propria without stromal response) and/or • Dissection of mesenteric adipose tissue by small glands, irregular clusters, or cords of tumor cells and/or • Perineural invasion

156 • Clinical Colorectal Cancer November 2002

Numerous lymphoid follicles (germinal centers) are seen at the periphery of the advancing border of the tumor (top).

Carolyn C. Compton Table 7

Putative Prognostic Markers in Colorectal Cancer CD44

Mn superoxide dismutase

Ki-ras

C-reactive protein

Bcl-2, Bax

Vitamin D receptor

Hyaluronic acid

Thymidine phosphorylase

PCNA

Si LeA

VEGF

NM23

Si LeX

Thymidylate synthase

Ki67

CEA

Prolactin receptor

Cyclin D1

Sucrase-isomaltase

DCC/18q LOH

Ploidy

evaluated factors including tumor differentiation, vascular invasion, and TNM stage. In stage II disease, 18q LOH has been found to predict shortened disease-free survival and OS in some studies122,123 but not in others.124-126 If validated as a predictor of adverse outcome in stage II disease, diagnosis of deleted in colon cancer loss may be used in the future to identify patients for whom adjuvant chemotherapy is needed.

Microsatellite Instability: A Marker of Favorable Outcome

In colorectal cancer, altered DNA repair is characterized by nucleotide mismatch, also known as p21 Chromosome 11 aneuploidy UPA receptor replication error (RER). Tumor RER status has p27 Microsatellite instability Matrix metalloproteinases been implicated as a predictor of outcome and treatment responsiveness in colorectal cancer. C-myc E-cadherin Cathepsin B RER can be identified by alterations (instability) HER2/neu TGF-α, TGF-β Tissue inhibitor of metaloprotease in inherited patterns of nucleotide repeats (microsatellites) scattered throughout the genome. Abbreviations: CEA = carcinoembryonic antigen; DCC = deleted in colon cancer; LOH = loss of heterozygosity; Tumors displaying alterations in ≥ 30% of miMn = manganese; PCNA = proliferating cell nuclear antigen; Si LeA = sialyl Lewis A carbohydrate; Si LeX = sialyl crosatellite markers tested are defined as MSI-H. Lewis X carbohydrate; TGF = transforming growth factor; UPA = urokinase-type plasminogen activator; VEGF = vascular endothelial growth factor The MSI-H status has been correlated with increased survival rates for tumors of like stage in outcome for patients with tumors of like stage is heterogesome studies.126-131 Despite the correlation with favorable outneous. In order to more accurately individualize prognosis come, most (but not all) studies have suggested that MSI-H tuand plan appropriate adjuvant therapy, additional tissue-based mors are less responsive to chemotherapy than microsatelliteprognostic indicators have been sought on a molecular level. stable tumors. A large number of molecular biomarkers are being investigated as possible prognostic factors but none have yet been Conclusion validated for direct patient care49; these molecular biomarkThe quality of the rectal surgery and the pathological feaers include genotypic alterations such as c-myc amplification, tures of the resection specimen constitute the most powerful HER2/neu overexpression, or loss of heterozygosity (LOH) at predictors of postoperative outcome in rectal cancer. Pathovarious chromosomal sites (eg, 1p, 8p, 17p, or 18q) as well logic features of strong prognostic value include the macroas markers of cell proliferation or angiogenesis, proteases or scopic appearance of mesorectal envelope, the microscopic their receptors, and the expression of plasma membrane glystatus of the CRM, and the pathologic stage. Other histologic coproteins that may contribute to cell adhesion. A partial list features that have stage-independent prognostic value include of putative prognostic markers in colorectal cancer taken histologic grade, vascular invasion, perineural invasion, and from reports published in the past decade is presented in tumor border features. Molecular features that further predict Table 7. Most of the studies on these putative prognostic tumor behavior are currently under intensive study. Additionmarkers are single-marker, retrospective, or small prospecal studies are needed to more precisely define guidelines for tive investigations. Interpretation of these studies has often assessment of important prognostic factors and to eliminate been hampered by poor quality clinical databases, heterovariation in pathologic practice and technical variation in tisgeneity of adjuvant therapies, lack of standardization or sue-based biomarker analysis and interpretation. Of unique quality control of the laboratory methodologies, or variation importance in rectal cancer, the pathologic evaluation of the in of statistical methodologies. Thus, none of these potential rectal resection specimen serves as an objective indicator of markers has been validated for patient care to date, but large the quality of the surgery. prospective cooperative group studies are currently ongoing that will clarify the prognostic value of many of these facReferences 001. Abulafi AM, Williams NS. Local recurrence of colorectal cancer: tors. Two of the most promising molecular prognostic facthe problem, mechanisms, management and adjuvant therapy. Br J tors, are discussed below. Plasminogen activator

p53/17p LOH

Chromosome 1 aneuploidy

Loss of Heterozygosity at 18q: A Marker of Adverse Outcome In retrospective studies, 18q LOH has been found to be predictive of shortened survival after adjustment for all other

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