Detailed Notes on Tumors of the Small and Large Intestine

Tumors of the Small and Large Intestines

Overview

• Epithelial tumors are a major cause of morbidity and mortality worldwide.
• Colorectal cancer is the most common GIT segment affected by tumors.
• The colon is host to more primary tumors than any other organ.
• Colonic carcinoma is second to bronchogenic carcinoma as a cause of death in the USA.
• Adenocarcinoma in the colorectum represents 70% of all GIT malignancies.
• Benign tumors, primarily epithelial, are present in 25% to 50% of older adults.

Terminology

• Polyp: A mucosal growth protruding into the gut lumen; can be sessile or pedunculated.
• Polyps result from abnormal mucosal maturation, inflammation, or epithelial proliferation with dysplasia.
• Polypoid lesions: Inflammatory masses, hamartomas, and tumors arising from the submucosa or muscle coat that protrude into the lumen.
• Polyposis: Multiple polyps.
• Polyposis syndrome: Hereditary condition characterized by multiple pedunculated or sessile mucosal tumors.

Classification of Intestinal Polyps

Non-Neoplastic Polyps (90% of large intestine epithelial polyps)

• Found in over half of people age 60 or older.

• Types:

  • Hyperplastic polyps
  • Hamartomatous polyps
    • Juvenile polyps
    • Peutz-Jeghers polyps
  • Inflammatory polyps
  • Lymphoid polyps

Neoplastic (Epithelial) Polyps

• Benign polyps (adenomas)

• Malignant lesions

  • Adenocarcinoma
  • Carcinoid
  • Anal zone carcinoma

Mesenchymal Lesions

• GIT stromal tumors (benign and malignant)

• Others: lipoma, neuroma, angioma, Kaposi sarcoma

Lymphoma

Non-Neoplastic Polyps

1. Hyperplastic Polyps

• Asymptomatic.
• Over 50% located in the rectosigmoid, 20% in the ascending colon.
• Smooth, moist, round, small (0.5 cm) sessile lesions.
• Multiple polyps are frequent.
• Composed of well-formed glands and crypts lined by differentiated goblet or absorptive cells.
• Pure hyperplastic polyps have no malignant potential.
• Larger hyperplastic polyps may have foci of adenomatous change.

2. Hamartomatous Polyps

Juvenile Polyps (Retention Polyps)

• Developmental malformations affecting glands and lamina propria, no malignant potential.
• Common in children under 5 in the rectum; in adults called retention polyps.
• Painless rectal bleeding after defecation.
• Large, rounded, smooth lesions with a stalk.
• Histology: mucus-filled, cystically dilated tubules lined by normal or inflamed mucosa.
• Juvenile polyposis syndrome: multiple hamartomatous polyps throughout the GI tract.

Peutz-Jeghers Polyps

• Uncommon hamartomatous polyps with mucosal and cutaneous pigmentation around the lips, oral mucosa, face, and genitalia.
• Rare, autosomal dominant.
• Caused by germ-line mutation in the $LKB1$ gene, encoding a serine threonine kinase.
• Polyps tend to be large and pedunculated.
• May occur anywhere in the GI tract.
• Increased risk of carcinoma of the pancreas, breast, lung, ovary, and uterus.

3. Inflammatory Polyps

• Occur in patients with longstanding IBD, especially chronic ulcerative colitis.
• Usually multiple.
• Represent an exuberant reparative response to longstanding mucosal injury (pseudopolyps).

4. Lymphoid Polyps

• (No specific details provided in the transcript)

Neoplastic Polyps (Adenomas)

Adenomatous Polyp

• Occur mainly in the large bowel.
• Prevalence: 20% to 30% before age 40, 50% after age 60.
• Males and females are equally affected.
• Sporadic and familial.
• Vary from small pedunculated to large sessile.
• Epithelial proliferation and dysplasia with loss of basal orientation of nuclei (pseudostratified).
• Divided into:
  • Tubular adenoma: less than 25% villous architecture.
  • Villous adenoma: villous architecture over 50%.
  • Tubulovillous adenoma: villous architecture between 25% and 50%.
• All adenomatous lesions arise from epithelial proliferation and dysplasia.

1. Tubular Adenoma

• Represents 75% of all neoplastic polyps.
• Occurs sporadically and in well-defined hereditary syndromes.
• Average age is 60 years.
• 75% occur in the distal colon and rectum.
• More than 50% occur singly.
• Size: few millimeters (sessile) to centimeters (stalk).
• Stalk: central core of fibrovascular tissue covered with dysplastic colonic mucosa.
• Severe dysplasia and invasive carcinoma may supervene.

2. Villous Adenoma

• Least common, largest, and most ominous of epithelial polyps.
• Age: 60 to 65 years, male to female ratio roughly equal.
• Present with rectal bleeding or anemia. Large ones may secrete copious mucoid material rich in protein.
• 75% located in the rectosigmoid area.
• Morphology:
  • Size: 1 to 10 cm in diameter.
  • Most are broad, sessile, velvety lesions projecting 1 to 3 cm.
  • Frondlike papillary projections of adenomatous epithelium with a delicate fibrovascular core.
  • All degrees of dysplasia with frank invasive carcinoma in up to 40%.

3. Tubulovillous Adenoma

• Intermediate in size, frequency of having a stalk, degree of dysplasia, and malignant potential between tubular and villous adenomas.

Clinical Features of Neoplastic Polyps

• Smaller adenomas are usually asymptomatic, occult bleeding.
• Villous adenomas are frequently symptomatic due to overt or occult rectal bleeding or mucoid material rich in protein and potassium, leading to hypoproteinemia or hypokalemia.
• Adenomas near the ampulla of Vater may cause biliary obstruction.

Relationship to Carcinoma

• Adenoma-to-carcinoma sequence is documented by observations and genetic alterations.
• Probability of carcinoma in a neoplastic polyp is related to:
  1. Size of the polyp.
  2. Proportion of villous features.
  3. Presence of significant cytologic atypia (dysplasia) in the neoplastic cells.

Familial Polyposis Syndrome

• Patients have genetic tendencies to develop neoplastic polyps, most often autosomal dominant.

Familial Polyposis Coli (FPC)

• Genetic defect on chromosome 5q21.
• Innumerable neoplastic polyps in the colon (500 to 2500).
• Polyps are also found elsewhere in the alimentary tract.
• Most polyps are tubular adenomas.
• The risk of colorectal cancer is 100% by midlife.

Gardener’s Syndrome

• Polyposis coli, multiple osteomas, epidermal cysts, and fibromatosis.

Turcot Syndrome

• Polyposis coli, glioma, and fibromatosis.

Malignant Tumors of Large Intestine: Adenocarcinoma

• Constitutes 98% of all cancers in the large intestine.
• Worldwide distribution, highest incidence in the West.
• Causes 15% of all cancer-related deaths in the USA.
• Higher mortality rate and incidence in blacks.
• Peak incidence in the sixth to seventh decade.

Predisposing Factors

• IBD, polyposis syndrome.
• Male:female ratio is 2:1 in rectal cancer, roughly equal in colon cancer; generally, males are affected about 20% more than females.

Dietary Factors

• Increased risk: low vegetable fiber, high refined carbohydrates, high-fat content, increased intake of nitrites/nitrates (nitrosamines)
• Reduced risk: increased intake of vitamins A, C, and E
• Protective effect: Aspirin and NSAIDs (cyclooxygenase-2 inhibitors)

Hereditary Factors

• Suspect preexisting ulcerative colitis or polyposis syndromes when colorectal cancer is found in a young person.
• Hereditary nonpolyposis colorectal cancer syndrome (HNPCC, Lynch syndrome) caused by germ-line mutations of DNA mismatch repair genes has a high risk of developing colorectal cancers.
• HNPCC patients are at risk of developing other tumors, such as cholangiocarcinomas.

Colorectal Carcinogenesis

• Two distinct pathways for colon cancer development, both resulting from multiple mutations:

  • The APC/B-catenin pathway: chromosomal instability resulting in stepwise accumulation of mutations in oncogenes and tumor suppressor genes.
    • Localized colon epithelial proliferation followed by small adenomas, becoming more dysplastic, and ultimately developing into invasive cancers.
    • Accounts for about 80% of sporadic colorectal cancers.
  • The DNA mismatch repair genes pathway:
    • 10% to 15% of sporadic cases.
    • Accumulation of mutations, but different genes are involved.
    • No clearly identifiable morphologic correlates.

Defective DNA Repair

• Inactivation of DNA mismatch repair genes is the fundamental and likely initiating event.
• Inherited mutations in DNA mismatch repair genes (MSH2, MSH6, MLH1, PMS1, and PMS2) give rise to HNPCC.
• The $MLH1$ gene is most commonly involved in sporadic colon carcinomas.

Microsatellite Instability (MSI)

• The molecular signature of defective DNA mismatch repair.
• Most microsatellite sequences are in noncoding regions, so mutations are often harmless.
• Some are located in coding or promoter regions of genes involved in cell growth regulation.

Caretaker Pathway

• Mutation of a caretaker gene allele (e.g., $hMSH2$) leads to HNPCC.
• Mutation of the second caretaker gene allele leads to genetic instability.

Gatekeeper Pathway

• Mutation of a gatekeeper gene allele (e.g., $APC$).
• Mutation of the second gatekeeper gene allele.
• Additional mutations of protooncogenes and other tumor suppressor genes lead to neoplasm.

Colorectal Carcinoma Morphology

• 60% to 70% are in the rectum, rectosigmoid, and sigmoid colon.
• Left-sided carcinomas: annular, encircling lesions with early obstruction symptoms.
• Neoplasms start superficially, slowly invading deeper layers with ulceration and eventual metastasis.
• Right-sided carcinomas: polypoid, fungating masses; obstruction is uncommon.
• Invasion of the wall and extension to the mesentery, regional lymph nodes, and distal sites.
• Mucinous adenocarcinoma: secretes abundant mucin that may dissect through cleavage planes in the wall.
• Small cell undifferentiated carcinomas are rare (arising from neuroendocrine cells).
• In UC, poorly differentiated infiltrative adenocarcinoma occurs without exophytic growth.

Clinical Features

• The condition tends to be present for a considerable time before producing symptoms.
• Left-sided lesions present earlier but have a more infiltrative growth pattern and poorer prognosis.
• Right-sided lesions present with weakness, malaise, weight loss, and unexplained anemia (secondary to early bleeding).

Spread

• Direct extension
• Metastasis through:
  • Lymphatics
  • Blood vessels
  • Favored sites: regional lymph nodes, liver, lungs, bones.
• Serum levels of carcinoembryonic antigen (CEA) are related to tumor size and extent of spread; helpful in monitoring for recurrence after resection.
• Overall 5-year survival is 35% to 49% in the United States.

Staging

• Stage groupings based on TNM (Tumor, Node, Metastasis) staging
  • Stage 0: $T_{is}$, N0, M0 (In situ)
  • Stage I: T1, N0, M0 or T2, N0, M0
  • Stage II: T3, N0, M0 or T4, N0, M0
  • Stage III: Any T, N1 or N2, M0
  • Stage IV: Any T, Any N, M1 (Metastasis)

Other Tumors

• Malignant spindle cell (mesenchymal) tumors and lymphomas.
• Grossly and microscopically resemble those arising elsewhere in the GI tract.
• Carcinoid tumors may arise anywhere in the colon, especially the rectum.
• Squamous cell carcinomas are largely limited to the rectal canal, initially presenting as plaque-like lesions, later becoming ulcerated or fungating.
• Malignant melanoma at the anal verge.

Small Intestinal Neoplasms

• 3-6% of GIT neoplasms, slight preponderance to benign tumors.

Benign

• Discovered incidentally: leiomyoma, adenoma, and lipoma.
• Large lesions may cause obstruction, bleeding, intussusception, volvulus.

Adenomas

• Single or multiple polyps, most often in the duodenum and ileum.
• Risk of malignancy with larger adenomatous polyps.

Malignant

• In descending order of frequency: carcinoid, adenocarcinomas, lymphomas, and leiomyosarcomas.
• Leiomyosarcomas have tyrosine kinase receptors and can be treated by STI-571.

Adenocarcinoma of Small Intestine

• Tumors grow as polypoid fungating ulcerating mass or encircling pattern.
• Site: duodenum (ampulla of Vater).
• Presentation: abdominal cramping pain, vomiting, and weight loss.
• Patients present late.
• 5-year survival is 70% after en bloc resection.

Carcinoid Tumors

• Neoplasms arising from endocrine cells (Kulchitsky or enterochromaffin cells) found along the length of GIT mucosa; cells have an affinity for silver salts.
• 60% to 80% appendix and terminal ileum, 10% to 20% rectum, remainder in the stomach, duodenum, or esophagus.
• Other locations: Lungs, pancreas, biliary tract, ovaries, and liver.
• Peak age: 6th decade; comprise 2% of colorectal carcinoma and 50% of small intestinal carcinoma.
• Tumors in the appendix and rectum, although spreading locally, seldom metastasize.
• Ileal, gastric, and colonic carcinoids are frequently malignant.

Morphology

• Round submucosal elevations that are bright yellow or yellow-gray; may be deeply infiltrative and penetrate muscle to the serosa.
• Gastric and ileal carcinoids are frequently multiple.
• Tumor cells arranged in trabecular, insular, glandular, or undifferentiated patterns are monotonously similar with regular round nuclei.
• Ultrastructural features: neurosecretory electron dense bodies in the cytoplasm.

Clinical Features

• Asymptomatic.
• May cause obstruction, intussusception, or bleeding.
• May elaborate hormones: Zollinger-Ellison, Cushing’s carcinoid, or other syndromes.
• 5-year survival rate is 90%; small bowel carcinoid with liver metastasis has a 5-year survival rate better than 50%.

Carcinoid Syndrome

• Occurs in 1% of all patients with carcinoid and in 20% of those with widespread metastasis.
• Paroxysmal flushing, episodes of asthma-like wheezing, right-sided heart failure, attacks of watery diarrhea, abdominal pain, edema, and pellagra-like lesions of the skin and oral mucosa.
• The principal chemical mediator is serotonin (5-hydroxy-tryptamine-5HT).
• 5-HT is decarboxylated in the liver and lungs to 5-hydroxy-indoleacetic acid (5HIAA).
• Classically associated with ileal carcinoids with hepatic metastases.

Lymphoma

• Up to 40% of lymphomas arise in sites other than lymph nodes; the gut is the most common.
• 1% to 4% of all gastrointestinal malignancies are lymphomas.
• Primary GIT lymphomas exhibit no evidence of liver, spleen, or bone marrow involvement at the time of diagnosis.

Sporadic Lymphoma

• Arise from the B cells of mucosa-associated lymphoid tissue (MALT).
• Usually affects adults, lacks a sex predilection, and may arise anywhere in the gut:
  • Stomach: 55% to 60%
  • Small intestine: 25% to 30%
  • Proximal colon: 10% to 15%
  • Distal colon: up to 10%

Gastric MALT Lymphomas

• Arise in the setting of mucosal lymphoid activation as a result of Helicobacter-associated chronic gastritis.
• Celiac disease is associated with a higher-than-normal risk of T-cell lymphomas.

Prognosis and Treatment

• Primary GIT lymphomas have a better prognosis than those arising in other sites.
• Treatment: combined surgery, chemotherapy, and radiation therapy.