Human Colorectal Cancer

The development of the gastrointestinal system is initiated during gastrulation with the formation of the primitive gut. The gastrointestinal system begins as an endoderm-lined tube with three major divisions: the midgut, which opens into the yolk sac; the foregut, which is continuous with the midgut and extends cranially behind the heart; and the hindgut, which extends caudally from the midgut. Gastrulation begins at approximately day 17 of human gestation and at day 7 in the mouse, and by day 22 (day 8 in the mouse) the gut tube is largely closed. The foregut gives rise to the pharynx, lower respiratory tract, liver, gall bladder, pancreas, esophagus, stomach, and the duodenum proximal to the opening of the bile duct. The midgut gives rise to the small intestine (including the duodenum distal to the opening of the bile duct), the cecum, appendix, ascending colon and the proximal part of the transverse colon. The derivatives of the hindgut are the distal part of the transverse colon, the descending and sigmoid colon, the rectum, superior portion of the anal canal, the epithelium of the urinary bladder and most of the urethra (11,12).

Rapid elongation and movements of the midgut that occur between the sixth and tenth week of gestation establish the adult orientation of the large and small intestines. By the beginning of the sixth week (day 10 for mouse embryos), the midgut projects into the umbilical cord. While within the umbilical cord, the midgut loop rotates 90 degrees bringing the cranial limb of the loop to the right and the caudal loop to the left. During this rotation, coiling and elongation of the midgut forms the loops of the small bowel (jejunum and ileum). During the tenth week (days 15-16 for mouse embryos), the intestine undergoes a further 180-degree rotation as it returns to the abdomen, establishing the ultimate position of the ascending, transverse and descending colon with respect to the small intestine (11,12).

The overall histological organization of the digestive system is similar throughout the length of the tract. The lumen is lined with a mucosa that consists of: epithelium with glandular invaginations; a supporting layer of loose connective tissue, the lamina propria; and an underlying layer of smooth muscle, the muscularis mucosae. Submucosal connective tissue surrounds the mucosa and, in the esophagus and duodenum, contains mucus-secreting glands. Two layers of smooth muscle, the inner circular layer and the outer longitudinal layer, make up the muscularis externa that surrounds the submucosa. A simple squamous epithelium, the serosa, covers the outer surface of the wall except at places where the wall is attached by connective tissue to neighboring structures. The enteric nervous system consists of the submucosal plexus and the myenteric plexus that lies between the circular and longitudinal layers of the muscularis externa. The epithelial lining of most of the digestive tract is derived from the endoderm of the primitive gut. The muscular and connective tissue components are derived from the splanchnic mesenchyme surrounding the primitive gut (13,14).

Several anatomical and histological features distinguish the large intestine from other regions of the digestive tract. There are no villi and plicae circulares, thus the luminal surface of the mucosa in the colon is smooth, but when the colon is undistended the mucosa and submucosa exhibit numerous temporary folds. In addition, lymphoid aggregates of varying sizes are located in the lamina propria and submucosa of the colon wall. The epithelium of the large intestine contains numerous goblet cells that secrete mucus to lubricate the lumen and facilitate passage of hardened feces.

For reviews on the molecular basis of gastrointestinal system development see references 15-19.

For additional information about the development and function of the gastrointestinal system see:
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Tumor Classification and Staging

The classification of tumors is based on the microscopic appearance of hemotoxylin and eosin-stained tumor sections. The World Health Organization (WHO) tumor classification system is the most widely accepted schema for the histologic typing of CRC tumors.

CRC can arise spontaneously or in the context of hereditary predispositions such as familial adenomatous polyposis coli (FAP) or HNPCC (also called Lynch I [colon only] and Lynch II [colonic and extracolonic involvement] Syndromes). CRC can also arise from dysplasia in ulcerative colitis. The vast majority of CRCs are adenocarcinomas. Approximately 75% are located in the colon and 25% are located in the rectum (i.e., below the peritoneal reflection). The distinction between these two anatomic locations of the primary tumor is important because of the implications regarding venous drainage and predominant sites of metastases (e.g., liver for colon; lung for rectum) and the need for additional local therapy following surgical resection (e.g., chemotherapy with radiotherapy for locally advanced rectal cancer vs. chemotherapy alone for colon cancers). Non-epithelial tumors such as lymphomas, endocrine tumors, and mesenchymal tumors are only rarely found in the colon and rectum. A thorough description of the internationally recognized standard for histological and genetic classification of colorectal tumors is presented in Hamilton et al. 2000 (20).

CRCs vary in their macroscopic features depending on their location in the colon or rectum and the stage of the lesion. Carcinomas occurring in the right colon or cecum tend to be bulky exophytic masses, while those in the left colon are often endophytic and constricting and may produce colonic obstruction. Those with exophytic growth may be pedunculated, and attached to the underlying wall by a narrow stalk, or sessile. Signet ring cell carcinomas typically produce a linitis plastica growth pattern, in which the tumor diffusely infiltrates the bowel wall, with only subtle thickening of the bowel on gross examination. Carcinomas arising in ulcerative colitis often arise in plaque-like areas of dysplasia, and exhibit predominantly endophytic growth.

The main precursor lesion of sporadic CRCs is the adenoma. Adenomas vary greatly in size and, while most are polypoid, depressed and flat lesions also occur. Microscopically, adenomas consist of columnar epithelial cells with elongated, hyperchromatic, crowded nuclei, with loss of the normal maturation gradient of the crypt. Typical adenomas are considered low-grade dysplastic lesions in which nuclear polarity of the neoplastic cells is maintained with respect to the basement membrane. Progression along the adenoma-carcinoma sequence is often reflected in morphologic changes. In high-grade dysplasia, neoplastic cells are confined by the basement membrane to an intact glandular space but show features of tumor progression such as cytologic features of malignancy, loss of nuclear polarity, and formation of complex glandular outlines. Foci of Paneth cell, goblet cell, and neuroendocrine cell differentiation may be seen in adenomas.

Aberrant Crypt Focus from human colon stained with methylene blue.	Single crypt adenomas, readily identifiable by the increase in nucleus to cytoplasm ratio and nuclear crowding and hyperchromasia, may be found in histological sections of grossly normal mucosa in individuals with familial adenomatous polyposis coli.

The typical sporadic CRC consists of large cribiform glands lined by tall columnar tumor cells infiltrating a desmoplastic stroma. Invasion of the neoplastic cells into the submucosa and deeper layers of the bowel wall is necessary for a diagnosis of invasive carcinoma. Lesions that are similar morphologically, but are confined to intact glandular structures or extend only into the lamina propria, have little to no risk of metastasis and are referred to as high grade dysplasia, intramucosal carcinoma, or intramucosal neoplasia. Most CRCs are well to moderately differentiated adenocarcinomas, with few solid areas. Poorly differentiated adenocarcinomas have less than 50% recognizable gland formation.

Grading of Colorectal Carcinomas
Grading of colorectal adenocarcinomas is subjective and is thus subject to interobserver variation. Multiple grading schemes have been proposed, and there is currently no consensus agreement. The basis of assignment of grade is controversial, with some pathologists basing grade on overall impression, some on the worst area of the tumor, some on the amount of gland formation, and some on a combination of features such as gland formation and nuclear grade (Compton CC, Fielding P, Burgart LJ, et al. Prognostic factors in colorectal cancer: College of American Pathologists consensus statement. Arch Pathol Lab Med 124: 979-994, 2000).

The Association of Directors of Anatomic and Surgical Pathology has published recommendations for the reporting of resected colorectal carcinomas (2). Their system is based on a modification of the WHO classification and is recommended only for adenocarcinomas of no special type:

Some groups recommend using a two-tiered grading system formed by collapsing well and moderately differentiated categories into a single category of low grade, and defining poorly differentiated and undifferentiated tumors as high grade. This two-tiered system retains prognostic significance and has the advantage of better reproducibility.

Some of the special types of carcinoma should not be graded by these schemes. For instance, medullary carcinoma has a solid growth pattern with little glandular differentiation (3) but generally has a more favorable prognosis than high grade adenocarcinoma, NOS. It may not be appropriate to grade mucinous carcinomas.

Typical colorectal adenocarcinoma composed of cribriform glands, often with luminal necrosis.	Adenocarcinomas arising in ulcerative colitis often invade the colon wall without forming an exophytic mass.

Several histopathological types of colorectal carcinoma are recognized. Mucinous adenocarcinoma is a morphologic subtype of colorectal carcinoma in which, greater than 50% of the lesion is composed of mucin. These tumors, also called colloid carcinoma, contain large pools of extracellular mucin. Mucinous carcinomas are most often located in the proximal colon. Another variant, signet-ring carcinoma, also produce abundant mucin that is intracytoplasmic rather than extracellular. Medullary carcinoma is characterized by a solid growth pattern, relatively little nuclear pleomorphism, and expansive rather than infiltrative growth, and frequently exhibits microsatellite instability.

Medullary carcinoma characterized by tumor cell growth in sheets, with minimal gland formation. Tumor infiltrating lymphocytes are prominent.	Mucinous carcinoma characterized by large pools of extracellular mucin.
Mucinous carcinoma with clusters and strips of tumor cells within the mucin pools.	Signet-ring cell carcinomas are composed of cells that accumulate intracytoplasmic mucin and infiltrate the stroma in strands or as single cells, with little gland formation.

Small-cell undifferentiated carcinoma is a rare but highly aggressive neoplasm that is most often widely metastatic at presentation. It is characterized by cells with scant cytoplasm with some signs of neuroendocrine differentiation. Other rare subtypes of human colorectal carcinoma that have been reported in small series or case reports include: spindle cell, pleomorphic (giant cell), pigmented, clear cell, stem cell and Paneth cell-rich (crypt cell) carcinoma, and carcinoma with choriocarcinoma. Mixtures of histopathological subtypes are also observed.

Tumor stage is the most important factor influencing the prognosis of CRC. Two staging systems are commonly used: one is the American Joint Commission on Cancer (AJCC) staging system - based on TNM classification of tumors - that divides colorectal cancers into Stages I, II, III, and IV and the other is the Dukes' staging system that categorizes colorectal cancers into Stages A, B, C, and D. Stage I (Dukes' Stage A) cancers have not spread beyond the mucosa into the submucosa or muscularis propria. Stage II (Dukes' Stage B) cancers have invaded through the muscularis propria and into neighboring tissues (fat or other organs). Stage III (Dukes' Stage C) cancers have spread to local lymph nodes. Stage IV (Dukes' Stage D) cancers have metastasized to distant organs.