INTRODUCTION
A 45-year-old man with a family history of colon cancer undergoes a screening colonoscopy. No invasive carcinomas are identified, but two small pedunculated tubular adenomas are removed and one villous adenoma measuring 5 mm in diameter is biopsied.
· What is the most likely diagnosis?
· What are the syndromes that could predispose this individual to colon cancer?
· What other dietary factors could play a role in the development of colon cancer?
Summary: A 45-year-old man with a family history of colon cancer underwent colonoscopy for rectal bleeding. Colonoscopic findings included several small pedunculated polyps in the right colon, all measuring less than 5 mm.
· Most likely diagnosis: Hyperplastic polyps or tubular adenomas.
· Syndromes predisposing to colon cancer: Familial adenomatous polyposis (FAP) and hereditary nonpolyposis colon cancer (HNPCC) are two common inherited colon cancer syndromes.
· Dietary factors that play a role in the development of colon cancer: Diets rich in fat and red meat and low in fiber may contribute to the development of colon cancer.
CLINICAL CORRELATION
Introduction
Colon cancer is the third most common malignant neoplasm worldwide and the second leading cause of cancer death in the United States. The peak incidence is in the seventh decade of life. Recommended screening for colon cancer for patients without increased risk starts at age 50, but for at-risk patients with a positive family history, screening should start at age 40 (some recommend 10 years earlier than the age at which the youngest index case presents). Annual fecal occult blood tests should be performed as well as digital rectal examination and flexible sigmoidoscopy every 5 years. Additional screening can be done by colonoscopy every 10 years, or a double-contrast barium enema can be done every 5 to 10 years. These recommended screening intervals may be maintained after a negative examination. For patients at high risk for cancer or with polyps, rescreening by colonoscopy at 3-year intervals is recommended. New technologies such as virtual colonography and genetic testing of stool specimens are being examined for their appropriate clinical settings. In this patient, the colonic polyps showed proliferation of tubular glands, arising from a fibromuscular base with normal colonic epithelium consistent with a polyp stalk. The polyps showed no evidence of malignant transformation (i.e., carcinoma). The diagnosis was multiple tubular adenomas of the colon.
Approach to Colon Adenomas
Definitions
Adenoma: Neoplastic proliferation of colonic epithelium that results in the formation of a polyp.
Neoplasia: Usually implies abnormal, often clonal proliferation of cells that results in the formation of a tumor.
Dysplasia: Usually the result of additional genetic abnormalities in cells that lead to further dysfunction or abnormal cell maturation.
Adenoma-dysplasia-carcinoma sequence:Model for colon cancer development that outlines the genetic pathway involved in the progression from a benign neoplastic polyp (adenoma) to frankly invasive cancer (carcinoma).
Familial adenomatous polyposis syndrome: The prototypic inherited colon cancer phenotype; affected patients have hundreds to thousands of polyps and are at high risk for cancer development.
Hereditary nonpolyposis colorectal cancer: Also known as Lynch syndrome. Often presents as right-sided colon cancer and involves mutation in mismatch repair genes. It is inherited in an autosomal dominant fashion, and affected individuals are also at high risk for extracolonic malignancies such as endometrial carcinomas.
Discussion
Polyps of the colon can be classified broadly into inflammatory/reactive, hyperplastic, and neoplastic. Inflammatory polyps can be seen in chronic colitides such as ulcerative colitis and Crohn disease. Hyperplastic polyps are some of the more frequently encountered polyps and are thought to represent nonneoplastic proliferation of colonic epithelium. There is accumulating evidence that some hyperplastic polyps may transform to adenomas through a serrated adenoma pathway. Adenomas are truly neoplastic proliferations and have the potential to transform and progress to carcinomas (see Figure 4-1). With increasing age, there is an increased incidence of adenoma formation. About 50 percent of patients who have one adenoma have additional synchronous adenomas present. Most polyps present in the rectosigmoid colon, but with increasing age, there is a tendency to see more right-sided involvement by polyps.
Types of Adenomas
Adenomas can be classified on the basis of the pattern of growth: whether they are flat, sessile and broad without a stalk, or pedunculated and on a stalk. Histologically, depending on the extent of tubular gland formation versus fingerlike villous projections, they are classified as tubular adenomas, villous adenomas, or tubulovillous adenomas.
Polyposis and Inherited Colon Cancer Syndromes
Syndromes that involve the formation of multiple gastrointestinal polyps occur infrequently. Some, such as Peutz-Jeghers syndrome and Cowden disease, are autosomal dominant, resulting in the formation of nonneoplastic hamartomatous polyps; others, such as Canada-Chronkhite syndrome, are not hereditary and result in multiple juvenile polyps. Other clinically significant polyposis or colon cancer syndromes include familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer.
The autosomal dominant FAP gene on chromosome 5q21 contains the tumor suppressor gene APC (adenomatous polyposis coli). Affected individuals have hundreds to thousands of polyps, typically presenting in the left colon. Almost all individuals with APC gene mutations eventually develop colon cancer. Hence, carriers usually are candidates for prophylactic colectomy. Recent studies have shown that cyclooxygenase inhibitors can suppressor polyp formation and possibly carcinoma development in patients with FAP.
Adenoma-Dysplasia-Carcinoma Sequence
A variant of FAP is Gardner syndrome, which involves the formation of osteomas of the bone, desmoid fibromatosis. HNPCC also is known as Lynch syndrome, named after the gastroenterologist Dr. Henry Lynch. The autosomal dominant inherited disease presents early in life, often with right-sided cancer, and can be associated with polyps, although much less numerous (usually fewer than 10) than what is seen in FAP. Patients with HNPCC are also at risk for extra-gastrointestinal tract tumors.
There are also less-well-defined familial cancer syndromes involving glandular elements (adenocarcinomas) that are associated with a family history or personal history of breast, ovarian, endometrial, or colon cancer.
The development of colon cancer is a multifactorial process involving not only predisposition genes but also factors such as diet (low-fiber foods, red meat, and refined carbohydrates are nonfavorable), obesity, and inactivity. Genetically, it is known that adenomas can progress and transform through additional mutations (i.e., genetic "hits") and progressively grow in size, increase in the degree of dyplasia, and acquire full malignant potential (carcinoma). Additional genes that have been shown to be involved in this process include the K-ras oncogene, the DCC (deleted in colon cancer) adhesion molecule gene, and the p53 tumor suppressor gene.
COMPREHENSION QUESTIONS
[4.1] A 25-year-old man is discovered to have colon cancer. It is noted that several members of his family also developed colon cancer at relatively young ages. Which of the following genes is most likely to be involved?
A. Hereditary nonpolyposis colorectal cancer gene
B. Mismatch repair gene
C. p53 gene
D. K-ras oncogene
[4.2] A 55-year-old man is undergoing colonoscopy and has a polyp removed. It is noted on histologic analysis to be an adenoma. Which of the following is the most accurate description of these lesions?
A. An aging change with no malignant potential
B. A reactive, nonneoplastic proliferation of cells
C. More frequently seen in the left colon
D. Not associated with familial syndromes
E. Almost always pedunculated rather than flat
[4.3] A 50-year-old man asks what he can do to decrease his risk of colon cancer. Which of the following is the best answer?
A. Increase red meat in the diet.
B. Elevate dietary carbohydrates.
C. Drink red wine occasionally.
D. Take medication that inhibits cyclooxygenase pathways.
ANSWERS
[4.1] A. Hereditary nonpolyposis colorectal carcinoma, also known as Lynch syndrome, presents as an autosomal dominant disorder characterized by the formation of colon cancer, usually early in life. The disorder is associated with the hereditary nonpolyposis colorectal cancer gene and with the formation of multiple colonic polyps, although fewer than seen in the family adenomatous polyposis syndrome.
[4.2] C. Adenomas can be seen in polyposis syndromes such as FAP and more frequently involve the left side. The other statements are not true.
[4.3] D. Inhibitors of cyclooxygenase have been shown to reduce polyp formation and may decrease the incidence of colon cancer. The other answers are factors that increase the risk for colon cancer.
PATHOLOGY PEARLS
· Colonic adenomas are neoplastic proliferations with the potential for malignant transformation.
· Inherited syndromes such as FAP and HNPCC can predispose people to developing polyps and colon cancer. One pathway is the adenoma-dysplasia-carcinoma sequence.
· Additional factors, such as diet, obesity, and activity, can affect one's risk for developing colon cancer.
REFERENCES
Fenoglio-Preiser C, Noffsinger AE, Stemmermann GN, et al. Gastrointestinal pathology, 2d ed. Philadelphia: Lippincott-Raven, 1999.
Liu C, Crawford JM. The gastrointestinal tract. In: Kumar V, Assas AK, Fausto N, eds. Robbins and Cotran pathologic basis of disease, 7 ed. Philadelphia: Elsevier Saunders, 2004:856-870.
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