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.
