Only recently has the genetic basis of colorectal cancer and its precursors begun to be understood.⁴^,⁵ The data suggest that the development of colorectal cancer is a multistep process that involves a successive activation or deletion of genes and their protein products.⁶ This process is mediated by regulatory genes. Advances in molecular biology techniques have allowed characterization of the genetic changes thought to be responsible for this multistep process.⁷

Numerous molecular markers examined to date, such as microsatellite instability (MSI),⁸ 18q,⁹ TP53,¹⁰ and others such as proliferation, apoptosis, defective DNA mismatch repair, and p53 overexpression.¹¹ However, they are not currently incorporated in the staging system and T and N classification remain the most predictive factors. But this is rapidly changing, and US intergroup trials now prospectively collect tissue. The phase III ECOG 5202 trial for patients with high-risk stage II colon cancer assigns treatment based on MSI/18q status. In the near future, more-individualized therapeutic recommendations based on genetic markers may be possible.¹²

Anatomy

The large bowel is divided into the colon and rectum.¹³^,¹⁴ The cecum, transverse colon, and sigmoid loop are mobile structures that lie free in the peritoneal cavity and are completely covered with serosa (visceral peritoneum). The dorsal or posterior aspect of the ascending and descending colon, and both flexures are frequently without serosa. Tumor spread from these segments may involve the retroperitoneal soft tissues, kidney, ureter, and pancreas. Although the rectum is frequently considered to be extraperitoneal, the anterior surface of the proximal third of the rectum is covered with serosa and is therefore intraperitoneal. Anatomically, the transition from sigmoid colon to rectum is marked by the fusion of the tenia of the sigmoid colon to the circumferential longitudinal muscle of the rectum at the level of the sacral promontory. This occurs approximately 12 to 15 cm from the dentate line. Patterns of recurrence of proximal rectal cancer may depend upon whether the location of the tumor is anterior or posterior.

The overall rationale of the use of adjuvant radiation therapy in colon cancer is based on the patterns of failure following potentially curative surgery. The primary determinant of failure patterns in colorectal cancer is the location of the tumor in reference to the posterior peritoneal reflection. In contrast to tumors located at or below the posterior peritoneal reflection (rectosigmoid and rectum), most tumors located above the peritoneal reflection (cecum-sigmoid), have a higher incidence of failure within the abdominal cavity.¹⁵^–¹⁸ This is because colon tumors have easier access to a free peritoneal surface.

Representative series examining the patterns of failure after potentially curative surgery are seen in Table 40-2. There is much variation as to what defines failure, the method by which failure is determined, the staging system used, and whether patients with metastatic disease are excluded from analysis. Failure patterns will be lowest in series which use clinical and/or radiographic evidence of first failure,¹⁵ whereas they will be highest in series which use reoperation and/or autopsy evidence of cumulative failure.¹⁸

Table 40-2 Failure Patterns Following Potentially Curative Surgery for Colon Cancer (All Stages)

Treatment recommendations are based on stage and the location of tumor in reference to the posterior peritoneal reflection. If the tumor is completely above the posterior reflection it is treated as a colon cancer. If any portion is at or below the reflection, it is treated as a rectal cancer. However, if a sigmoid or cecal cancer is adherent to a pelvic structure (cT4), the local recurrence rate is similar to a rectal cancer, and it is treated as such with preoperative combined chemotherapy and radiation.

Pathology

Gross Appearance

Tumor configuration may be divided into fungating (exophytic), ulcerating, stenosing, or constricting (annular, circumferential). Although there are data to suggest that ulcerative tumors have a worse prognosis compared with exophytic tumors, it is unclear whether this independent of stage.

Histologic Subtypes

The most common histologic type of large bowel cancer is adenocarcinoma, which accounts for 90% to 95% of all large bowel tumors.¹³ It is the only histologic type further classified by grade. A number of histologic types of large bowel cancer have been identified. The World Health Organization has developed a classification of both benign and malignant tumors. Colloid or mucinous adenocarcinoma represent approximately 17% of large bowel tumors.¹⁹ These adenocarcinomas are defined by large amounts of extracellular mucin retained within the tumor. A separate classification is the rare signet-ring cell carcinoma (2% to 4% of mucinous carcinomas), which contains abundant intracellular mucin, pushing the nucleus to one side. Some signet-ring tumors form a linitis plastica–type appearance, tend to present at later stages, and, thus, have a poor prognosis.²⁰^,²¹

Other rare variants of epithelial tumors include squamous cell carcinomas, adenosquamous carcinoma (adenoacanthoma), undifferentiated carcinomas, small cell,²² and neuroendocrine cancers.²³ Gastrointestinal stromal tumors should be treated as sarcomas.²⁴ Sarcomas account for 0.1 to 0.3% of all malignancies of the colorectum.²⁵ The most common type is leiomyosarcoma. It may arise from the smooth muscle of the muscularis propria, muscularis mucosa, or blood vessels.²⁶ Primary colorectal malignant lymphomas are usually diffuse large B-cell lymphomas.²⁷ Squamous cell cancers of the rectum should be treated as an anal cancer with fluorouracil (5-FU)/mitomycin-C and radiation, reserving surgery for salvage.²⁸

Grade

Broders classified adenocarcinomas by their degree of differentiation. He designated four grades based on the percentage of differentiated tumor cells. Well-differentiated in Broders’ system meant well-formed glands resembling an adenoma. Broders included the mucinous carcinomas in his system. Dukes considered mucinous carcinomas separately.²⁹ There is no uniform agreement on the grading criteria, but most investigators agree on the use of a three-grade system similar to that described in other adenocarcinomas.

Other Clinicopathologic Factors

The influence of clinical and pathologic factors on the patterns of failure and survival following surgery colorectal cancer has been the subject of numerous investigations. By univariate analysis, a number of factors have been reported to be of prognostic importance. Many of these factors are interrelated and merely reflections of the same overall characteristic of the cancer. Using a multivariate (proportional hazards) analysis, a variety of independent factors for survival have been reported. However, the majority of investigators agree that the most important independent pathologic factor for survival and/or recurrence following surgery is stage (depth of penetration through the bowel wall and the presence and number of positive lymph nodes).³⁰^,³¹ Prognosis is related to the number of tumors rather than the volume of tumor present in the nodes.³² The presence of lymphatic vessel (L) or venous (V) invasion is now indicated as an additional descriptor in the TNM staging system.

Selected adverse clinical factors include: age <40 years, blood transfusions, long duration of symptoms, obstruction or perforation, ulceration, and various primary tumor locations. Selected adverse pathologic/molecular factors include: perineural invasion, high grade, colloid, signet ring cell, blood vessel invasion, lymphatic vessel invasion, aneuploidy, elevated carcinoembryonic antigen (CEA) levels, collagen, local immune response, cell surface antigen 19-9, and various growth factors, receptors, oncogenes, and blood group antigens.¹³ Except for CEA, none of these tumor markers have independently been shown to be helpful in prospective follow-up following treatment.³³

In summary, it is difficult to draw firm conclusions from the data, and treatment recommendations based solely on the presence or absence of the above pathologic features should be made with caution. Prospective trials are needed in order to determine whether these pathologic factors should be used to select patients for adjuvant therapy.

Clinical Presentation

Symptoms of colon cancer include intermittent abdominal pain, nausea, vomiting, unintentional weight loss, or a change in bowel habits. Bleeding may be acute and most commonly appears as red blood mixed with stool. Dark blood is most commonly associated with a more proximal source (right colon) and black tarry stools reflect small bowel or stomach as a source. However, any lower gastrointestinal hemorrhage, even in the presence of known pathology (i.e., diverticuli, hemorrhoidal disease) requires a full colonoscopic evaluation. Tumors of the left colon tend to present earlier and with more obstructive symptoms than the right colon, given the reduced diameter of the bowel distally. Patients who present with complete bowel obstruction or perforation have a less favorable prognosis.

Routes of Spread

After the initial mucosal growth, there are several directions in which colorectal cancer may progress.

Bowel Wall

The tumor penetrates through the bowel wall and extracolonic tissues, then directly invades adjacent organs or structures. An additional pattern of local spread is perineural invasion, which may extend as far as 10 cm from the primary tumor.

Lymph Nodes

The risk of lymph node metastases increases with increasing tumor grade. In addition, there is a clear relationship between lymphatic vessel invasion and the incidence and number of lymph node metastases in colorectal cancer.³⁴^,³⁵ At least 12 to 14 lymph nodes must be examined for an accurate classification of nodal status.³⁶^,³⁷ Although they may be confused with lymph nodes, pericolonic tumor deposits are a harbinger of intra-abdominal metastasis in colon cancer.³⁸ In the sixth edition of the American Joint Commission on Cancer (AJCC) TNM Staging System, smooth metastatic nodules in the pericolic or perirectal fat are considered lymph node metastasis, whereas irregularly contoured metastatic nodules in the fat are considered vascular invasion.³⁹

In colon cancer, the normal lymphatic flow is through the lymphatic channels along the major arteries, with three echelons of lymph nodes: pericolic, intermediate, and principal lymph nodes (Table 40-3).¹³ If tumors lie between two major vascular pedicles, lymphatic flow may drain in either or both directions. If the central lymph nodes are blocked by tumor, lymphatic flow can become retrograde along the marginal arcades both proximally and distally.

Table 40-3 Regional Lymph Nodes in Colon Cancer

Site	Regional Nodes
Cecum	Anterior and posterior cecal, ileocolic, right colic
Ascending colon	Ileocolic, right and middle colic
Hepatic flexure	Middle and right colic
Transverse colon	Middle colic
Splenic flexure	Middle and left colic, inferior mesenteric
Descending colon	Left colic, inferior mesenteric, sigmoid
Sigmoid loop	Inferior mesenteric, superior rectal (hemorrhoidal), sigmoid, sigmoid mesenteric

In rectal cancer, the disease metastasizes to the perirectal nodes at the level of the primary tumor, immediately above it and up to 5 cm distal to the primary tumor.⁴⁰^,⁴¹ Then, the chain accompanying the superior hemorrhoidal vessels is involved. Discontinuous or skip metastases are rare. The pericolic lymph nodes along the mesenteric border of the pelvis usually are not involved by these rectal tumors unless there is very extensive tumor with lymphatic blockage.

Distant Metastasis

The liver is the primary site of hematogenous metastases, followed by the lung. In approximately 40% of autopsy studies the liver is the only site involved.⁴² Involvement of other distant sites in the absence of liver or lung involvement is rare.

Diagnostic and Staging Studies

The work-up for colon carcinoma is seen in Table 40-4. Fluorodeoxyglucose-positron emission tomography (FDG-PET) scanning shows promise, but remains investigational.⁴³^,⁴⁴ The staging of colorectal carcinoma has been complicated by the fact that it has evolved over a century and various authors have developed systems that use the same terms to represent different stages. Because of these discrepancies in coding for the same stages, the comparison of clinical studies reported in the literature is often impossible.

Table 40-4 Workup for Colon Cancer