eMedicine Specialties > Oncology > Carcinomas of the Gastrointestinal Tract

Colon Cancer, Adenocarcinoma

Author: Tomislav Dragovich, MD, PhD, Associate Professor of Medicine and Director of Clinical Gastroenterology Oncology Program, Arizona Cancer Center, University of Arizona College of Medicine
Coauthor(s): Vassiliki L Tsikitis, MD, Assistant Professor of Surgery, Section of Surgical Oncology, University of Arizona Medical Center
Contributor Information and Disclosures

Updated: Aug 31, 2009

Introduction

Background

Invasive colorectal cancer is a preventable disease. Early detection through widely applied screening programs is the most important factor in the recent decline of colorectal cancer in developed countries (see Deterrence/Prevention). Full implementation of the screening guidelines1 can cut mortality rate from colorectal cancer in the United States by an estimated additional 50%; even greater reductions are estimated for countries where screening tests may not be widely available at present. New and more comprehensive screening strategies are also needed.

Fundamental advances in understanding the biology and genetics of colorectal cancer are taking place. This knowledge is slowly making its way into the clinic and being employed to better stratify individual risks of developing colorectal cancer, discover better screening methodologies, allow for better prognostication, and improve one’s ability to predict benefit from new anticancer therapies.

In the past 10 years, an unprecedented advance in systemic therapy for colorectal cancer has dramatically improved outcome for patients with metastatic disease. Until the mid 1990s, the only approved agent for colorectal cancer was 5-fluorouracil. New agents that became available in the past 10 years include cytotoxic agents such as irinotecan and oxaliplatin,2 oral fluoropyrimidines (capecitabine and tegafur), and biologic agents such as bevacizumab, cetuximab, and panitumumab.3

Though surgery remains the definitive treatment modality, these new agents will likely translate into improved cure rates for patients with early stage disease (stage II and III) and prolonged survival for those with stage IV disease. Further advances are likely to come from the development of new targeted agents and integration of those agents with other modalities such as surgery, radiation therapy, and liver-directed therapies.

Pathophysiology

Genetically, colorectal cancer represents a complex disease, and genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Sequence of molecular and genetic events leading to transformation from adenomatous polyps to overt malignancy has been characterized by Vogelstein and Fearon.4  The early event is a mutation of APC (adenomatous polyposis gene), which was first discovered in individuals with familial adenomatous polyposis (FAP). The protein encoded by APC is important in activation of oncogene c-myc and cyclin D1, which drives the progression to malignant phenotype. Although FAP is a rare hereditary syndrome accounting for only about 1% of cases of colon cancer, APC mutations are very frequent in sporadic colorectal cancers.

In addition to mutations, epigenetic events such as abnormal DNA methylation can also cause silencing of tumor suppressor genes or activation of oncogenes, compromising the genetic balance and ultimately leading to malignant transformation.

Other important genes in colon carcinogenesis include KRAS oncogene , chromosome 18 loss of heterozygosity (LOH) leading to inactivation of SMAD4 (DPC4), and DCC (deleted in colon cancer) tumor suppression genes. Chromosome arm 17p deletion and mutations affecting p53 tumor suppressor gene confer resistance to programmed cell death (apoptosis) and are thought to be late events in colon carcinogenesis.

A subset of colorectal cancers is characterized with deficient DNA mismatch repair. This phenotype has been linked to mutations of genes such as MSH2, MLH1, and PMS2. These mutations result in so-called high frequency microsatellite instability (H-MSI), which can be detected with an immunocytochemistry assay. H-MSI is a hallmark of hereditary nonpolyposis colon cancer syndrome (HNPCC, Lynch syndrome), which accounts for about 6% of all colon cancers. H-MSI is also found in about 20% of sporadic colon cancers.

Frequency

United States

The American Cancer Society estimated that 148,810 individuals would be diagnosed with colorectal cancer and 49,960 would die from this disease in the United States in 2008.5

International

In 2003, the World Health Organization estimated that approximately 940,000 individuals were be diagnosed with colorectal cancer worldwide and 492,000 died from it that year.

Mortality/Morbidity

Colorectal cancer is a major health burden worldwide. The incidence and mortality from colon cancer has been on a slow decline over the past 20 years in the United States; however, colon cancer remained the third most common cause of cancer-related mortality in 2008. A multitude of risk factors have been linked to colorectal cancer, including heredity, environmental exposures, and inflammatory syndromes affecting gastrointestinal tract.

Race

Recent trends in the United States suggest a disproportionally higher incidence and death from colon cancer in African Americans than in whites. Hispanic persons have the lowest incidence and mortality from colorectal cancer.

Sex

The incidence of colorectal cancer is about equal for males and females.

Age

Age is a well-known risk factor for colorectal cancer, as it is for many other solid tumors. The timeline for progression from early premalignant lesion to malignant cancer ranges from 10-20 years. The incidence of colorectal cancer peaks at about age 65 years.

Clinical

History

Due to increased emphasis on screening practices, colon cancer is now often detected during screening procedures. Other common clinical presentations include iron-deficiency anemia, rectal bleeding, abdominal pain, change in bowel habits, and intestinal obstruction or perforation. Right-sided lesions are more likely to bleed and cause diarrhea, while left-sided tumors are usually detected later and could present with bowel obstruction.

Physical

Physical findings could be very nonspecific (fatigue, weight loss) or absent early in the disease course. In more advanced cases, abdominal tenderness, macroscopic rectal bleeding, palpable abdominal mass, hepatomegaly, and ascites could be present on physical examination.

Causes

Colorectal cancer is a multifactorial disease process, with etiology transcending genetic factors, environmental exposures (including diet), and inflammatory conditions of digestive tract. 

Though much about colorectal cancer genetics remains unknown, current research indicates that genetic factors have the greatest correlation to colorectal cancer. Hereditary mutation of the APC gene is the cause of familial adenomatous polyposis (FAP), where affected individuals carry an almost 100% risk of developing colon cancer by age 40 years.

Hereditary nonpolyposis colon cancer syndrome (HNPCC, Lynch syndrome) carries about 40% lifetime risk of developing colorectal cancer; individuals with this syndrome are also at increased risk for urothelial cancer, endometrial cancer, and other less common cancers. Lynch syndrome is characterized by deficient mismatch repair (dMMR) due to inherited mutation in one of the mismatch repair genes, such as hMLH1, hMSH2, hMSH6, hPMS1, hPMS2, and possibly other undiscovered genes. HNPCC is a cause of about 6% of all colon cancers. Although the use of aspirin may reduce the risk of colorectal neoplasia in some populations, a study by Burn et al found no effect on the incidence of colorectal cancer among carriers of Lynch syndrome with use of aspirin, resistant starch, or both.6

Dietary factors are the subject of intense and ongoing investigations.7 Epidemiological studies have linked increased risk of colorectal cancer with a diet high in red meat and animal fat, low-fiber diet, and low overall intake of fruits and vegetables. Factors associated with lower risk include folate intake, calcium intake, and estrogen replacement therapy. However, most of these studies were retrospective epidemiological studies and have yet to be validated in prospective, placebo-controlled, interventional trials.

Lifestyle choices such as alcohol and tobacco consumption, obesity, and sedentary habits have also been associated with increased risk for colorectal cancer.

Association between body mass index (BMI) and risk of colorectal adenomas and cancer has been reported, but few studies have had adequate sample size for conducting stratified analyses. Jacobs et al pooled data from 8,213 participants in 7 prospective studies of metachronous colorectal adenomas to assess whether the association between BMI and metachronous neoplasia varied by sex, family history, colorectal subsite, or features of metachronous lesions. Exploratory analyses indicated that BMI was significantly related to most histologic characteristics of metachronous adenomas among men but not among women. The researchers concluded that body size may affect colorectal carcinogenesis at comparatively early stages, particularly among men.8

Inflammatory bowel diseases such as ulcerative colitis and Crohn’s disease also carry an increased risk of developing colorectal adenocarcinoma. The risk for developing colorectal malignancy increases with the duration of inflammatory bowel disease and the greater extent of colon involvement.

More on Colon Cancer, Adenocarcinoma

Overview: Colon Cancer, Adenocarcinoma
Differential Diagnoses & Workup: Colon Cancer, Adenocarcinoma
Treatment & Medication: Colon Cancer, Adenocarcinoma
Follow-up: Colon Cancer, Adenocarcinoma
Multimedia: Colon Cancer, Adenocarcinoma
References
Further Reading
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References

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Keywords

colon cancer, colorectal cancer, adenocarcinoma, gastrointestinal cancer, colorectal malignancy, colon cancer prevention, colon cancer treatment, colon cancer medications, colon cancer detection, colon cancer screening, colon cancer diagnosis, colorectal adenoma, adenomatous polyp, colon polyp, colorectal polyp, adenomatous polyposis, hereditary nonpolyposis colon cancer syndrome, HNPCC, Lynch syndrome, familial adenomatous polyposis, FAP, inflammatory bowel disease, IBD, colitis, Crohn’s disease, Crohn disease

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Contributor Information and Disclosures

Author

Tomislav Dragovich, MD, PhD, Associate Professor of Medicine and Director of Clinical Gastroenterology Oncology Program, Arizona Cancer Center, University of Arizona College of Medicine
Tomislav Dragovich, MD, PhD is a member of the following medical societies: American Association for Cancer Research and American Society of Clinical Oncology
Disclosure: Genentech Oncology Honoraria Speaking and teaching; Sanofi-Aventis Honoraria Speaking and teaching

Coauthor(s)

Vassiliki L Tsikitis, MD, Assistant Professor of Surgery, Section of Surgical Oncology, University of Arizona Medical Center
Vassiliki L Tsikitis, MD is a member of the following medical societies: American College of Surgeons, American Society of Colon and Rectal Surgeons, and Association of Women Surgeons
Disclosure: Nothing to disclose.

Medical Editor

Philip Schulman, MD, Chief, Medical Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center; Clinical Professor, Department of Medicine, New York University School of Medicine
Philip Schulman, MD is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, American Society of Hematology, and Medical Society of the State of New York
Disclosure: celgene Honoraria Speaking and teaching; Amgen Honoraria Speaking and teaching; genetech/idec Honoraria Speaking and teaching

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

CME Editor

Rajalaxmi McKenna, MD, FACP, Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

Jules E Harris, MD, Clinical Professor of Medicine, Division of Hematology/Medical Oncology, Department of Internal Medicine, University of Arizona College of Medicine at Tucson; Consulting Staff, Arizona Cancer Center
Jules E Harris, MD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Association of Immunologists, American Society of Hematology, and Central Society for Clinical Research
Disclosure: GlobeImmune Salary Consulting; Amplimed Consulting fee Consulting; FibroGen Consulting fee Consulting

 
 
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