PERSPECTIVE, PATTERNS OF SPREAD, AND PATHOLOGY
There are multiple steps in gene and mutational events: a series of deletions and mutations that result in carcinogenesis.
PERSPECTIVE AND PATTERN OF SPREAD
The colon, including the rectum, accounts for the majority of digestive system cancers. There has been intensive study of adenomas in relation to genetic defects that lead to their transformation from benign polyps to dysplasia and neoplasia. Portions of chromosomes 5, 17, and 18 are mutated or deleted. The gene deletion associated with the multistep process leading to malignancy and metastases has been documented by Fearon and Vogelstein. Large intestine has no villi, and the feathered mucosa is characterized by haustral markings. Except for the absence of Paneth cells, the cellular makeup of the crypts of Lieberkühn is similar. The number of goblet cells increases from cecum to sigmoid colon. The major colon function is to absorb water and electrolytes; it also compacts feces. The array of histopathology is largely similar to intestinal tumors, but the staging system applies only to carcinomas, not lymphomas, sarcomas, or carcinoids (Table 29.1).
The Ras oncogene, the deleted in colorectal cancer (DCC) gene, the p53 tumor suppressor gene, and DNA mismatch repair leads to carcinogenesis.
This paradigm of adenoma to adenocarcinoma has been modified and applied to other gastrointestinal sites—stomach and small intestine—in addition to colon and rectum.
Genetic conditions that increase the risk of developing colon cancer include the following:
• Genetic conditions that increase the risk of developing a large bowel cancer include familial adenomatous polyposis syndrome (FAP) and its variants and hereditary nonpolyposis colorectal cancer. FAP is a hereditary disease with an autosomal dominant transmission pattern characterized by pancolonic adenomatous polyps. It is not treated by surgical removal of the large bowel, and most patients die of colorectal cancer before age 60 years.
• The incidence and distribution of colon cancers are as follows: cecum, ascending colon (25%), transverse (15%), descending (5%), sigmoid (25%), rectosigmoid (10%), and rectum (20%). Incidence of inflammatory conditions, such as ulcerative colitis, with a disease duration of 7 years, increases 10% per decade, reaching approximately 30% at 25 years.
Figure 29.1 | Variants of hyperplastic polyps. A. Microscopically, sessile serrated adenoma features irregular, asymmetric crypts that are often dilated by mucin. B. Mixed hyperplastic adenomatous polyp. Two adenomatous crypts in the upper right contrast with the three hyperplastic crypts. Adenocarcinoma of the colon. C. Microscopically, this colon adenocarcinoma consists of moderately differentiated glands with a prominent cribriform pattern and frequent central necrosis.
• Gardner syndrome includes desmoid tumors, osteomas, and fibromas in addition to colorectal adenomas. The risk for developing adenocarcinoma is similar to that of patients with FAP.
• Peutz–Jeghers syndrome and juvenile polyposis are also associated with an increased risk of developing large bowel or other gastrointestinal cancers.
Inherited familial cancer syndromes also have been described in which affected members have fewer polyps than are seen with FAP. The genetic condition is inherited in an autosomal dominant pattern and includes Lynch syndromes I and II. Patients are typically young, have multiple large bowel lesions, and have a higher incidence of other intra-abdominal malignancies.
The Patterns of Spread are similar in different parts of the colon with invasion of a multilayered wall or retro colon area of posterior abdominal wall. The major difference is dependent on the anatomic segment of the colon when the wall is penetrated and cancer invades adjacent to viscera (Figure 29.2; Table 29.2).
Figure 29.2 | A. Colon cancer patterns of spread. B. T categories. The patterns of spread and the primary tumor classification are similarly color coded: Tis (cancer in situ of mucosa), yellow; (infiltrates the submucosa), green; T2 (penetrates the muscularis externa), blue; T3 (reaches the subserosa), purple; and T4 (invades through the serosa into a neighboring viscera), red. The six patterns of spread–superior, inferior, medial, lateral, anterior, and posterior—are presented in SIMLAP Table 29.2 under ascending, transverse, and descending colon, respectively. The concept of visualizing patterns of spread to appreciate the surrounding anatomy is well demonstrated by the six-directional pattern, i.e., SIMLAP Table 29.2.
PATHOLOGY
The array of histopathology is largely similar to intestinal tumors, but the staging system applies only to carcinomas, not lymphomas, sarcomas, or carcinoids (Table 29.1; Figure 29.1). The vast majority of colon tumors are adenocarcinomas (>90%), and neuroendocrine neoplasms occur and are staged separately. It is recommended that low-grade (G1, G2, well to moderately differentiated) and high-grade (G3, G4, poorly to undifferentiated) designations be used.
TNM STAGING CRITERIA
TNM STAGING CRITERIA
The patterns of cancer spread are determined by the mucosal and muscle layers until it penetrates the serosa and invades adjacent structures. Because the posterior wall is often without serosa, direct infiltration of abdominal wall is possible. Polyps are mucosal tumors that are either pedunculated on stalks or sessile with a broad base. Adenomatous polyps are more likely to progress than hyperplastic polyps. Risk factors are size >2 cm, sessile, and villous features with evidence of dysplasia. Colon cancers invade their wall, and the staging system reflects the cancer penetration in depth: T1, mucosal; T2, muscular; and T3, serosal. T4 is transmural into adjacent structures and surrounding organs. As cancers encircle the bowel wall, it is important to recognize the absence of peritoneal lining and mesentery in the ascending and descending colons on their posterior surfaces. Such anatomic features reduce the size of margins of resection as compared to mobile mesenteric portions, that is, the transverse and sigmoid segments.
Generally, there is no overarching principle or context design for the digestive system (gastrointestinal tract) or major digestive glands (MDGs). Stages are frequently expanded to six by subdividing stages into A and B. The T and N categories are assigned to a stage grouping, specifically for division of a stage into more (a) versus less (b) favorable groupings. This occurs at different stages for different sites.
Specifically, this site has a clear separation of T progression I/II from N progression III/IV. Stages IIIA and IIIB are node progression, stage IIIC is for venous invasion (V1), and stage IV is for metastatic. Because this site is the dominant cancer, this staging system impacts other gastrointestinal and MDG sites.
SUMMARY OF CHANGES SEVENTH EDITION AJCC
• In the sixth edition, Stage II was subdivided into IIA and IIB on the basis of whether the primary tumor was T3N0 or T4N0, respectively, and Stage III was subdivided into IIIa
(T1-2N1M0), IIIB (T3-4N1M0), or IIIC (any TN2M0). In the seventh edition, further substaging of Stage II and III has been accomplished, based on survival and relapse data that was not available for the prior edition (Fig. 29.3; Table 29.3).
• Expanded data sets have shown differential prognosis within T4 lesions based on extent of disease. Accordingly T4 lesions are subdivided as T4a (tumor penetrates the surface of the visceral peritoneum) and as T4b (tumor directly invades or is histologically adherent to other organs or structures).
• The potential importance of satellite tumor deposits is now defined by the new site-specific factor Tumor Deposits (TD) that describes their texture and number. T1-2 lesions that lack regional lymph node metastasis but have tumor deposit(s) will be classified in addition as N1c.
• The number of nodes involved with metastasis influences prognosis within both N1 and N2 groups. Accordingly N1 will be subdivided as N1a (metastasis in 1 regional node) and N1b (metastasis in 2–3 nodes), and N2 will be subdivided as N2a (metastasis in 4–6 nodes) and N2b (metastasis in 7 or more nodes).
• Stage Group II is subdivided into IIA (T3N0), IIB (T4aN0) and IIC (T4bN0).
• Stage Group III:
• A category of N1 lesions, T4bN1, that was formerly classified as IIIB was found to have outcomes more akin to IIIC and has been reclassified from IIIB to IIIC.
• Similarly, several categories of N2 lesions formerly classified as IIIC have outcomes more akin to other stage groups; therefore, T1N2a has been reclassified as IIIA and T1N2b, T2N2a-b, and T3N2a have all been reclassified as IIIB.
• M1 has been subdivided into M1a for single metastatic site vs. M1b for multiple metastatic sites.
• The justification is based on 70,131 patients, SEER analysis and these are classified as major (3+).
The TNM Staging Matrix is color coded for identification of Stage Group once T and N stages are determined (Table 29.3).
COLON ADENOCARCINOMA
Figure 29.3 | TNM staging diagram presents a vertical arrangement with color bars encompassing TN combinations showing progression. Colon cancers are resectable in stage IIIA/B (purple), N1, and become more advanced with nodal progression, N2; stage III (red) is less resectable, and stage IV (black) is metastatic. Stage 0, yellow; I, green; II, blue; III, purple; IV, red; and IV (metastatic), black. Definitions of TN on left and stage grouping on right.
T-ONCOANATOMY
ORIENTATION OF THREE-PLANAR ONCOANATOMY
The three-planar anatomic isocenter for the colon occupies the L2/L3 level in the abdomen (Fig. 29.4).
T-oncoanatomy
The T-oncoanatomy is displayed in three planar views. A. Coronal, B. Sagittal, C. Transverse axial (Figure 29.5).
• Coronal: The colon is a large structure that frames the entire abdominal visceral contents. It begins at the cecum and continues as the right ascending, transverse, left descending, and sigmoid segments of the colon. The colon is partially covered by a peritoneal surface. Tumors arise on the mucosal surface and penetrate into the muscularis and the serosa; therefore, their manifestations relate to their location. Depending on where the cancer arises, it can invade surrounding structures such as the liver at the hepatic flexure, which is at the junction of the ascending and the transverse colon. The stomach and spleen are at risk when the cancer arises at the splenic flexure or the junction of the transverse and the descending colon. The large intestine, or colon, extends from the terminal ileum to the anal canal. It may be subdivided into sections, exclusive of the rectum: right, middle, and left, or ascending, transverse, descending, and sigmoid portions, respectively. The large intestine may also be divided into the intraperitoneal colon and the rectum.
• Sagittal: The peritoneal cavity consists of the greater sac and omental bursa. The superior recess of the omental bursa is between the liver and the posterior attachment of the diaphragm. The inferior recess of the omental bursa is between the two double layers of the greater omentum. In the adult, the inferior recess usually only extends inferiorly as far as the transverse colon because of fusion of the two double peritoneal layers at birth.
• Transverse: The transverse colon is located anteriorly, with the ascending colon on the right and the descending colon on the left. Note that this is at the lower pole of the kidney.
Figure 29.4 | Orientation and overview of oncoanatomy. The three-planar anatomic isocenter for the colon is at L3/L4. A. Coronal. B. Sagittal.
Figure 29.5 | T-oncoanatomy. Connecting the dots. Structures are color coded for cancer stage progression.
N-ONCOANATOMY AND M-ONCOANATOMY
N-ONCOANATOMY
Regional nodes follow the vascular arcades for each colon segment along its marginal arteries on the mesocolic border. Specifically, the regional lymph nodes for each segment are shown and listed. The recent major revisions in staging relate to nodules in the pericolic fat: If such nodules are smooth, they are considered to be nodes; if irregular, they are considered to be vascular or venous invasion (Fig. 29.6A; Table 29.4).
Regional Lymph Nodes
Regional lymph nodes are located (i) along the course of the major vessels supplying the colon and rectum, (ii) along the vascular arcades of the marginal artery, and (iii) adjacent to the colon—that is, located along the mesocolic border of the colon. Specifically, the regional lymph nodes are the pericolic and perirectal nodes and those found along the ileocolic, right colic, middle colic, left colic, inferior mesenteric, superior rectal (hemorrhoidal), and internal iliac arteries.
In the assessment of pN, the number of lymph nodes sampled should be recorded. The number of nodes examined from an operative specimen has been reported to be associated with improved survival, possibly because of increased accuracy in staging. It is important to obtain at least 10 to 14 lymph nodes in radical colon and rectum resections in patients without neoadjuvant therapy, but in cases in which tumor is resected for palliation of patients who have received preoperative radiation, fewer lymph nodes may be removed or present. In all cases, however, it is essential that the total number of regional lymph nodes recovered from the resection specimen be described since that number is prognostically important. A pN0 determination is assigned when these nodes are histologically negative, even though fewer than the recommended number of nodes has been analyzed. However, when fewer than the number of nodes recommended by the College of American Pathologists have been found, it is important that pathologists report the degree of diligence of their effort to find the lymph nodes in the specimen.*
M-ONCOANATOMY
The entire portal circulation should be considered as a unit with regard to the venous anatomy of the gastrointestinal tract below the diaphragm (see Fig. 29.6B). The two major trunks are the inferior mesenteric and superior mesenteric veins. The inferior mesenteric vein drains the left colon and sigmoid colon tributaries, which covers the vascular drainage to the left of the midline originating from the superior rectal veins. On the right side, the superior mesenteric vein originates from the tributaries draining the ileum, jejunum, and ileocolic right and middle colic veins. The inferior mesenteric vein usually joins the splenic vein, which coalesces with the superior mesenteric vein and forms the portal vein. The splenic vein, which is a major tributary of the portal system, also drains much of the stomach along its greater curvature and includes the short gastric veins and left and right gastric epiploic veins. The right gastroepiploic vein also flows into the superior mesenteric vein. The entire drainage of the lesser curvature of the stomach, including the left and right gastric veins, drains directly into the portal vein. Because the portal vein then drains directly into the liver, it is the target metastatic organ and the most commonly involved organ in hematogenous spread from the venous system of the gastrointestinal tract, as compared with other parts of the body, where the drainage is directly into the lung by way of the caval system.
The incidence of liver metastases exceeds that of other sites. According to a variety of reports in the literature, the range is 40% to 100% at autopsy. Other sites are mainly bone metastases 20% to 35% and lung metastases 40% to 60%, with only occasional metastases to brain.
*Preceding passage from Edge SB, Byrd DR, and Compton CC, et al., AJCC Cancer Staging Manual, 7th edition. New York, Springer, 2010, pp. 145–146.
Figure 29.6 | A. N-oncoanatomy. Sentinel nodes of the colon include the pericolic nodes of the superior mesenteric (blue) and inferior mesenteric (red) nodes. Depending upon the T site colon segment of origin, the pericolic nodes adjacent are the sentinel nodes (Table 29.4). Para-aortic nodes are gray. B. M-oncoanatomy. The venous drainage of the colon is complex because of its length, which frames the small intestine. The right side of the colon, right hepatic flexure, and the transverse colon drain into the superior mesenteric vein, whereas the left side of the colon and splenic flexure drain into the inferior mesenteric vein and into the splenic vein, and eventually the drainage is into the portal vein, resulting predominantly in liver metastases.
STAGING WORKUP
RULES OF CLASSIFICATION AND STAGING
Clinical Staging and Imaging
Extension of diagnostic imaging to staging is gaining in popularity. Virtual colonoscopy and sigmoidoscopy are challenging endoscopic colonoscopy as to accuracy in diagnosing adenocarcinomas. Endoscopic ultrasound shows the layers of the colon and rectal wall and their penetration by cancer. Endorectal magnetic resonance imaging (MRI) is most valuable to demonstrate extracolonic and extrarectal invasion into adjacent structures. Computed tomography (CT) is preferred for detecting liver and lung metastases (Table 29.5; Fig. 29.7).
Pathologic Staging
The surgically resected colon and associated lymph nodes are assessed. Tumor extension and location of both primary and nodes should be documented. Accurate radial margins should be marked and recorded and are defined “as the surgically dissected surface adjacent to the deepest point of tumor invasion beyond the wall of the large bowel.” The completeness of resection depends on the clearing of the deepest point of invasion: R0, complete; R1, microscopic; and R2, macroscopic.
Figure 29.7 | Axial CTs of L3 and L4 level correlate with the T-oncoanatomy transverse section (Figure 29.5D). Oncoimaging with CT is commonly applied to staging cancers, often combined with PET to determine true extent of primary cancer and involved lymph nodes. 1. Transverse colon. 2. Descending colon. 3. Ascending colon. 4. Duodenum. LK, left kidney; RK, right kidney.
PROGNOSIS AND CANCER SURVIVAL
Oncoimaging Annotations
• Although colonoscopy is more accurate in assessment for small polyps, overall cost effectiveness is greater when double-contrast barium enema examinations are used.
• CT colonography is a recent addition to the modalities used to screen for colorectal cancer and polyps. This modality requires further refinement and testing before being more widely adopted.
• Transrectal ultrasonography and MRI can demonstrate the extent of tumor through the rectal wall and provide some assessment for lymphadenopathy.
• If there is clinical suspicion of metastasis or elevated carcinoembryonic antigen level, CT and MR scanning are useful for determining the presence and site of recurrent disease. Overall accuracy for the detection of recurrent disease with these modalities is 90% to 95%. This evaluation may require fine-needle aspiration biopsy under direct CT guidance.
• Other noninvasive means to determine the presence or absence of recurrent or metastatic tumor are nuclear medicine scanning techniques with radiolabeled monoclonal antibodies and positron emission tomography techniques using fluorodeoxyglucose. Some of these have shown great potential.
PROGNOSIS
A significant number of prognostic factors are listed in Table 29.6.
CANCER STATISTICS AND SURVIVAL
The digestive system, or gastrointestinal tract, which includes the MDG, accounts for 274,337 new patients annually, with colon and rectum responsible for >50%, or about 142,500 new diagnoses annually. Approximately half of these patients eventually die of these cancers. MDG cancers as a group are more lethal; only a handful of patients become long-term survivors. Fortunately, colon and rectal cancers are the most common, with the majority of patients becoming 5-year survivors (63%) responding to chemoradiation programs, often with the sparing of the rectal sphincter with conservative surgery. Anal cancers are the most responsive to chemoradiation (5-fluorouracil and cisplatin), eliminating the need for surgery. The 5-year survival rate is >90%, with anal sphincter preservation. This regimen has been proven to be very effective in clinical trials and to result in more long-term survivors, which is currently reflected in the literature. Liver, bile duct, and pancreatic cancers are among the poorest in terms of survival, which is often measured in months rather than years (see Table 22.6).
Specifically, the colon accounted for 102,900 new cancer cases and 51,370 cancer deaths (50%), with a 5-year survival rate improvement over the last five decades of 22%. Currently, relative 5-year survival for all stages is 62.3%, but, when localized, it improves to 90.1% (see Table 23.8). Colon cancer (T3T4), when resected plus multinodal therapy, decreases from 70% to 80% for N0 to 50% ± 3% for N1, N2 nodal involvement (Figs. 29.8 and 29.9).
Figure 29.8 | Five-year observed survival adenocarcinoma of the colon. (Data from Edge SB, Byrd DR, Compton CC, et al., AJCC Cancer Staging Manual, 7th edition. New York, Springer, 2010.)
Figure 29.9 | Cancer statistics and survival rates.