Villous Adenoma ?>

Villous Adenoma

Villous Adenoma

Introduction
Background

Adenomatous polyps are, by definition, neoplastic. Although benign, they are the direct precursors of adenocarcinomas and follow a predictable cancerous temporal course unless interrupted by treatment. They can be either pedunculated or sessile. Polyps are generally asymptomatic but may occasionally ulcerate and bleed; uncommonly, they may result in obstruction if very large. Adenomas are divided into 3 subtypes based on histologic criteria, as follows: (1) tubular, (2) tubulovillous, and (3) villous. According to World Health Organization (WHO) criteria, villous adenomas are composed of greater than 80% villous architecture. Tubular adenomas are encountered most frequently (80-86%). Tubulovillous adenomas are encountered less frequently (8-16%), and villous adenomas are encountered least frequently (5%).

Villous adenomas are associated more often with larger adenomas and more severe degrees of dysplasia. These adenomas occur more frequently in the rectum and rectosigmoid, although they may occur anywhere in the colon. They generally are sessile structures that appear as velvety or cauliflowerlike projections. Although rare, villous adenomas of the duodenum and the small bowel, particularly at the ampulla, can occur. Villous adenomas are of concern primarily because of the risk of malignant transformation (approximately 15-25% overall but higher once >2 cm).

The primary focus of this article is colonic villous adenomas. Where appropriate, certain aspects of small bowel villous adenomas are addressed.

Pathophysiology

Adenomas are believed to have an abnormal process of cell proliferation and apoptosis. The proliferative component is not confined to the crypt base and accumulates onto the surface and infolds downward. In villous adenomas, mesenchymal proliferation results in longer projections and larger polyps.

Clinical, autopsical, and epidemiological studies provide evidence of adenoma-to-carcinoma progression. The mean age of adenoma diagnosis is 10 years earlier than with carcinoma, and progression to carcinoma takes a minimum of 4 years. Multiple sources have provided evidence for an adenoma-to-carcinoma progression: one third of operative specimens containing colon cancer contain one or more synchronous adenomas. The risk of colon cancer is increased with the number of adenomatous polyps. Adenomatous tissue is frequently found contiguous to frank carcinoma. Patients who refuse polypectomy for adenomas develop colon cancer at a rate of about 4% after 5 years and 14% after 10 years.

Molecular genetic studies also describe an adenoma-to-carcinoma sequence through accumulation of lesions in a variety of genes, with activation of oncogenes and inactivation of tumor suppressor genes. Genetic mutations lead to progressively disordered local DNA replication. The progressive accumulation of multiple genetic mutations results in the transition from normal mucosa to adenoma to severe dysplasia and finally to carcinoma. The K-ras oncogene is described in 9% of small adenomas, 58% of adenomas larger than 1 cm, and 46% of colorectal carcinomas. Inactivation of tumor suppressor genes on arms 5q, 18q, and 17p are thought to be essential in tumorigenesis. The APC gene, on 5q, has an important role in adenoma formation. The gene is mutated in 30-60% of persons with sporadic adenomas and adenocarcinomas. Mutations in the APC gene occur early in adenoma development and are often found in aberrant crypt foci, the earliest identifiable dysplastic crypts.

Mutation on the TP53 gene, on 17p, results in malignant transformation of adenomas. The loss of TP53 is frequent in patients with adenomas (50%) and occurs in more than 75% of patients with adenocarcinomas.

The loss of the DCC (deleted in colon cancer) gene, on 18q, occurs in 50% of patients with adenomas and 70% of patients with carcinomas. The loss of the normal DCC gene is important in the transition from an intermediate adenoma to a late adenoma.
Frequency
United States

The prevalence of adenomas closely parallels the risk of colorectal cancer in a region. Adenomas are found in 30-40% of persons aged 60 years or older; in some areas, as many as 50% have adenomas.
International

In regions of low risk for colon carcinoma (eg, Costa Rica, Columbia), prevalence rates are 12%. This rate increases drastically in high-risk regions (eg, United States, Canada, western Europe, Argentina, New Zealand, Australia) to 30-40%. In some areas, rates approach 50%.
Mortality/Morbidity

The immediate risks of adenomas include hemorrhage, obstruction with intussusception, and, possibly, torsion. However, the main concern is malignant progression of the villous adenoma. Studies have defined the risk of progression of adenomas to adenocarcinoma.
Precolonoscopy studies show the cumulative risk for carcinoma from polyps larger than 1 cm to be 4%, 14%, and 37% with 5, 10, and 20 years of follow-up, respectively. The risk for persons with carcinoma at sites other than the reference polyp is 4 times greater than that of the general population. Increasing polyp size and villous histology correlate with the development of colorectal cancer. The likelihood that an adenoma contains villous tissue, high-grade dysplasia, or invasive carcinoma is proportional to its size.
Using complete colonoscopies, the National Polyp Study (NPS) prospectively followed 1418 patients diagnosed with 1 or more adenomas. An incidence reduction rate of 76-90% of colorectal cancers occurred, with only 10-24% of cancers that would be predicted from a reference population. This study found that the only independent predictive factors for progression from adenoma to adenocarcinoma were adenoma size and villous histology. The NPS study defined advanced polyps as larger than 1 cm or as those containing villous tissue or high-grade dysplasia.
Overall, villous adenomas have a malignant risk of 15-25%. The risk of adenocarcinoma approaches 40% in villous adenomas larger than 4 cm in diameter. Patients with a rectosigmoid adenoma larger than 1 cm (or villous histology) had a 3.6-fold risk of developing adenocarcinoma compared to the general population. Villous adenomas of the ampulla of Vater contain carcinoma in 30-50% of cases, and carcinoma is found in 20-25% of duodenal villous adenomas.
Race

Race is not an independent factor for adenoma prevalence, although region is considered to be a factor.
This is well described in the Hawaiian-Japanese population, which has much higher rates of adenoma than the Japanese population.
A similar situation exists with black Americans (higher rates) and black South Africans.
Sex

Generally, adenoma risk is independent of sex, although some authorities suggest a slight male predominance.
Age

The prevalence and distribution of adenomas varies with patient age.
The prevalence of adenomas increases with age. The prevalence of polyps at 50 years is 30%, at 60 years is 40-50%, and at 70 years is 50-65%.
Distribution of polyps differs with age. In patients aged 55 years or younger, 75% of polyps 10 mm or larger were located distally. In patients aged 65 years and older, 50% of polyps 10 mm or larger were located proximally.
Clinical
History

Note that the vast majority of patients are asymptomatic and have unremarkable laboratory findings. Approximately two thirds of colorectal polyps are asymptomatic. Any nonspecific intestinal symptoms are more likely to be coincidental. For example, bright red rectal bleeding in a patient in whom a small colonic polyp is eventually found is still most likely to be hemorrhoidal in origin. Polyps greater than 1 cm are more likely to produce symptoms, usually rectal bleeding, abdominal pain, and a change in bowel habits.
The most common presenting symptom is occult/overt bleeding (hematochezia) with an anemia, which may be microcytic. Polyps may bleed only intermittently into the stromal component, thus accounting for inconsistent findings.
Nonspecific symptoms include diarrhea, constipation, and flatulence. A change in stool caliber (ie, the classic pencil-thin stools), although still described in older textbooks, is an entirely nonspecific and unreliable symptom. Pencil-thin stools, if truly present, would be secondary to large distal adenomas or frank carcinomas.
When intense cramping occurs, torsion or episodic intussusception due to larger adenomas may be considered.
Villous adenomas rarely cause a secretory diarrhea syndrome. The tumor usually is located at the rectosigmoid or rectum and often is 3-4 cm in diameter. Stool volumes of 350-3000 mL are reported and may cause hypovolemia and metabolic imbalances.
Patients may have a family history of polyps and colon cancer.
Patients with villous adenomas of the ampulla usually present with intermittent or progressive jaundice, abdominal pain, intestinal hemorrhage, or pancreatitis.
Physical
Patients often have no findings on bedside physical examination.
Occasionally, a palpable mass is present upon digital rectal examination.
Jaundice may be present with villous adenoma of the ampulla.
Causes
Genetic factors: From the NPS data, relatives of patients with polyps have an increased risk of carcinoma. This includes siblings of patients with adenomas detected prior to age 60 years or siblings of patients with adenomas detected at any age if either parent has colorectal cancer. Offer these patients screening colonoscopy every 5 years after age 40 years.
Lifestyle and diet: Foods and vitamins that have a protective effect against adenomas include dietary fiber, plant foods, carbohydrates, and folate supplementation. Excess fat and alcohol are positively correlated with adenoma risk. A strong association exists between cigarette smoking and adenoma size. Supplemental vitamins C and E are not considered protective.
Acromegaly: Patients with acromegaly have an increased risk of adenomas and colon cancer. Prevalence rates of 14-35% for adenomas are reported. The mechanism for increased risk is not known.
Streptococcus bovis bacteremia: This causes an increased risk of adenomas, carcinomas, and, possibly, familial adenomatous polyposis (FAP). These patients should undergo colonoscopy. Patients with endocarditis from Streptococcus agalactiae infection are reported to have an increased risk of rectal villous adenoma and should be evaluated.
Atherosclerosis and cholesterol: Autopsy studies report a positive correlation between the degree of atherosclerosis and adenoma size, dysplasia, and multiplicity.
Uterosigmoidostomy sites: Patients who undergo urinary diversion procedures are at increased risk of developing polyps or carcinomas at uterosigmoidostomy sites as many as 38 years later. Prevalence rates of 29% are reported.
Inflammatory bowel disease (IBD): In patients with IBD who develop carcinomas, 50% of the lesions are found to be juxtaposing serrated or villous adenomas. These possibly are the lesions from which the carcinomas originate. However, a dysplasia-associated lesion or mass is reported to be the premalignant lesion of adenocarcinoma in ulcerative colitis, in which the adenoma-carcinoma sequence is not preserved.
Other conditions: Historically, some conditions have been thought to be correlated with increased incidence of polyps. These conditions include acrochordons (skin tags), breast cancer, and cholecystectomy, for which no evidence exists of an increased risk for adenoma.

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