Large Intestine

The large intestine is formed by several successive segments:

1. The cecum, projecting from which is the appendix.

2. The ascending, transverse, and descending colon.

3. The sigmoid colon.

4. The rectum.

5. The anus.

Plicae circulares and intestinal villi are not found beyond the ileocecal valve. Numerous openings of the straight tubular glands or crypts of Lieberkühn are characteristic of the mucosa of the colon.

The lining of the tubular glands of the colon consists of the following:

1. A surface simple columnar epithelium formed by absorptive enterocytes and goblet cells. Enterocytes have short apical microvilli, and the cells participate in the transport of ions and water. All regions of the colon absorb Na⁺ and Cl^– ions facilitated by plasma membrane channels that are regulated by mineralocorticoids. Aldosterone increases the number of Na⁺ channels and increases the absorption of Na⁺. Na⁺ ions entering the absorptive enterocytes are extruded by an Na⁺ pump. Goblet cells secrete mucus to lubricate the mucosal surface and serve as a protective barrier.

2. A glandular epithelium, lining the glands or crypts of Lierberkühn, consists of enterocytes and predominant goblet cells, stem cells, and dispersed enteroendocrine cells. Paneth cells may be present in the cecum.

A lamina propria and a muscularis mucosae are present, as are isolated lymphoid follicles (ILFs) penetrating the submucosa. Glands are not present in the submucosa. Unlike Peyer's patches, ILFs are not associated with M cells.

The muscularis has a particular feature: The bundles of its outer longitudinal layer fuse to form the taeniae coli. The taeniae coli consist of three longitudinally oriented ribbon-like bands, each 1 cm wide. The contraction of the taeniae coli and circular muscle layer draws the colon into sacculations called haustra.

The serosa has scattered sacs of adipose tissue, the appendices epiploicae, which is a unique feature, together with the haustra, of the colon.

The Appendix

The appendix is a diverticulum of the cecum and has layers similar to those of the large intestine. The characteristic features of the appendix are the lymphoid tissue, represented by multiple lymphatic follicles, and lymphocytes infiltrating the lamina propria. Lymphatic follicles extend into the mucosa and submucosa and disrupt the continuity of the muscularis mucosae. The submucosa contains adipocytes and dense irregular connective tissue. The inner circular layers of the muscularis is well developed in contrast with the outer longitudinal layer covered by the serosa.

The Rectum

The rectum, the terminal portion of the intestinal tract, is a continuation of the sigmoid colon. The rectum consists of two parts:

1. The upper part, or rectum proper.

2. The lower part, or anal canal.

The mucosa is thicker, with prominent veins, and the crypts of Lieberkühn are longer (0.7 mm) than in the small intestine and lined predominantly by goblet cells. At the level of the anal canal, the crypts gradually disappear and the serosa is replaced by an adventitia.

A characteristic feature of the mucosa of the anal canal are 8 to 10 longitudinal anal columns. The base of the anal columns is the pectinate line. The anal columns are connected at their base by valves, corresponding to transverse folds of the mucosa. Small pockets, called anal sinuses, or crypts, are found behind the valves. Anal mucous glands open into each sinus.

The valves and sinuses prevent leakage from the anus. When the canal is distended with feces, the columns, sinuses, and valves flatten, and mucus is discharged from the sinuses to lubricate the passage of the feces.

Beyond the pectinate line, the simple columnar epithelium of the rectal mucosa is replaced by a stratified squamous epithelium. This epithelial transformation zone has clinical significance in pathology: colorectal adenocarcinoma (gland-like) originates above the transformation zone; epidermoid (epidermis-like) carcinoma originates below the transformation zone (anal canal).

At the level of the anus, the inner circular layer of smooth muscle thickens to form the internal anal sphincter. The longitudinal smooth muscle layer extends over the sphincter and attaches to the connective tissue. Below this zone, the mucosa consists of stratified squamous epithelium with a few sebaceous and sweat glands in the submucosa (circumanal glands similar to the axillary sweat glands). The external anal sphincter is formed by skeletal muscle and lies inside the levator ani muscle, also with a sphincter function.

Pathology: Hirschsprung's Disease

During formation of the neural tube, neural crest cells migrate from the neuroepithelium along defined pathways to tissues, where they differentiate into various cell types.

One destination of neural crest cells is the alimentary tube, where they develop the enteric nervous system. The enteric nervous system partially controls and coordinates the normal movements of the alimentary tube that facilitate digestion and transport of bowel contents.

The large intestine, like the rest of the alimentary tube, is innervated by the enteric nervous system receiving impulses from extrinsic parasympathetic and sympathetic nerves and from receptors within the large intestine.

The transit of contents from the small intestine to the large intestine is intermittent and regulated at the ileocecal junction by a sphincter mechanism: When the sphincter relaxes, ileal contractions propel the contents into the large intestine.

Segmental contractions in an orad-to-aborad direction move the contents over short distances. The material changes from a liquid to a semisolid state when it reaches the descending and sigmoid colon. The rectum is usually empty.

Contraction of the inner anal sphincter closes the anal canal. Defecation occurs when the sphincter relaxes as part of the rectosphincteric reflex stimulated by distention of the rectum.

Delayed transit through the colon leads to severe constipation. An abnormal form of constipation is seen in Hirschsprung's disease (congenital megacolon) caused by the absence of the enteric nervous system in a segment of the distal colon.

This condition, called aganglionosis, results from an arrest in the migration of cells from the neural crest, the precursors of the intramural ganglion cells of the plexuses of Meissner and Auerbach. Aganglionosis is caused by mutations of the RET gene encoding a receptor tyrosine kinase.

RET signaling is required for:

1. The formation of Peyer's patches.

2. The migration of neural crest cells into the distal portions of the large intestine.

3. The differentiation of neural crest cells into neurons of the enteric nervous system.

The permanently contracted aganglionic segment does not allow the entry of the contents. An increase in muscular tone in the orad segment results in its dilation, thus generating a megacolon or megarectum.

This condition is apparent shortly after birth when the abdomen of the infant becomes distended and little meconium is eliminated.

The diagnosis is confirmed by a biopsy of the mucosa and submucosa of the rectum showing thick and irregular nerve bundles, abundant acetylcholinesterase detected by immunohistochemistry and a lack of ganglion cells.

Surgical removal of the affected colon segment is the treatment of choice but intestinal dysfunction may persist after surgery.

Pathology: Colorectal Tumorigenesis

Colorectal tumors develop from a polyp, a tumoral mass that protrudes into the lumen of the intestine. Some polyps are non-neoplastic and are relatively common in persons 60 years and older. Polyps can be present in large number (100 or more) in familial polyposis syndromes such as familial adenomatous polyposis (FAP) and the Peutz-Jeghers syndrome.

FAP is determined by autosomal dominant mutations, in particular in the APC (adenomatous polyposis coli) gene. FAP patients develop multiple polyps in the colon in their teenage years, increase in number with age and later become cancerous.

Mutations in the APC gene have been detected in 85% of colon tumors, indicating that, as with the retinoblastoma (Rb) gene, the inherited gene is also important in the development of the sporadic form of the cancer.

The APC gene encodes APC protein with binding affinity to beta-catenin, a molecule associated with a catenin complex linked to E-cadherin and also a transcriptional coactivator.

Mutations in the APC gene have also been found in people with desmoid tumors, a benign tumor of the connective tissue. Mutations in the APC gene are also observed in Turcot syndrome, characterized by an association of colorectal cancer with medulloblastoma, a brain tumor. The APC gene is located on the long (q) arm of chromosome 5.

When beta-catenin is not part of the catenin complex:

1. Free cytoplasmic beta-catenin can be phosphorylated by glycogen synthase kinase 3beta (GSK3beta) (coassembled with proteins APC, axin and casein kinase Ialpha, CKIalpha) and targeted for proteasomal degradation.

Phosphorylated beta-catenin is recognized by a ubiquitin ligase complex that catalyzes the attachment of polyubiquitin chains to phosphorylated beta-catenin. Polyubiquitin conjugates of beta-catenin are rapidly degraded by the 26S proteasome.

2. Alternatively, free cytoplasmic beta-catenin can enter the nucleus and interact with the transcription factors TCF (T cell factor) and LEF (lymphoid enhancer factor) to stimulates transcription of target genes.

A mutation in the APC gene results in a truncated nonfunctional protein unable to interact with beta-catenin and initiate its disposal when is no longer needed. Essentially, APC behaves as a tumor suppressor gene.

The APC gene is also a major regulator of the Wnt pathway, a signaling system expressed during early development and embryogenesis. Wnt proteins can inactivate GSK3beta, prevent the phosphorylation of beta-catenin, and abrogate its destruction by the 26S proteasome. Consequently, an excess of beta-catenin translocates to the cell nucleus to affect gene transcription.

A defective beta-catenin pathway can overexpress the microphthalmia-associated transcription factor (MITF). The MITF is significant in the survival and proliferation of melanoma cells.

Hereditary nonpolyposis colon cancer (HNPCC; Lynch syndrome) is an inherited form of colorectal cancer caused by mutations in DNA mismatch repair, MMR, genes, involved in the repair of DNA defects.

Mutation analysis of MMR genes (including MLH1, MSH2, MSH6, PMS2, and EPCAM genes) by microsatellite instability (MIS) screening testing using colon tumor tissue removed by colonoscopy or surgery, is carried out when there is evidence of a DNA repair defect in a tumor. Note that not all individuals who carry these mutations develop cancerous tumors.

DNA repair defects increase the frequency of somatic mutations leading to malignant transformation. HNPCC is an example of a cancer syndrome caused by mutations in DNA repair proteins.

Patients with the HNPCC syndrome do not show the very large number of colon polyps typical of the familial polyposis syndrome, but a small number of polyps occur frequently among gene carriers.