Hereditary nonpolyposis colorectal cancer overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1], Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [2]
Overview
Lynch syndrome was first described by Dr. Henry T. Lynch, an American physician, in 1966. Hereditary nonpolyposis colorectal cancer may be classified into 2 types: Lynch syndrome I (familial colon cancer) and Lynch syndrome II (hereditary nonpolyposis colorectal cancer associated with other cancers). Other variants such as Muir-Torre syndrome and Turcot syndrome are considered subtypes of hereditary nonpolyposis colorectal cancer. Hereditary nonpolyposis colorectal cancer is an autosomal dominant genetic disease characterized by an early onset of colon cancer, endometrial cancer, and other malignant tumors. Development of hereditary nonpolyposis colorectal cancer is the result of multiple genetic mutations. The genes involved in the pathogenesis of hereditary nonpolyposis colorectal cancer include: MSH-2, MLH-1, MSH-6, PMS-2 , PMS-1, TGF-BR2, and MLH-3. This syndrome occurs most commonly in the proximal colon (60% to 80%). Endometrial cancer is the most common sentinel cancer among female patients with hereditary nonpolyposis colorectal cancer. Hereditary nonpolyposis colorectal cancer is caused by germline mutations in one of the four MMR genes (MLH1, MSH2, MSH6, or PMS2), that results in defective repair of DNA sequence. Deletions in the EPCAM gene also cause hereditary nonpolyposis colorectal cancer. Hereditary nonpolyposis colorectal cancer must be differentiated from other diseases that cause familial colorectal cancer, such as: juvenile polyposis, familial adenomatous polyposis, Cowden syndrome, and MYH-associated polyposis. Incidence of HNPCC is not well known but it is estimated that 0.5 to 13% of the cases of colorectal cancer are due to hereditary nonpolyposis colorectal cancer. The prevalence of hereditary nonpolyposis colorectal cancer is approximately 2 - 7% of all the diagnosed cases of colorectal cancer. Hereditary nonpolyposis colorectal cancer commonly affects young adult population. The median age of diagnosis is between 40 to 45 years. Hereditary nonpolyposis colorectal cancer affects males and females equally. Hereditary nonpolyposis colorectal cancer usually affects individuals of the white race more commonly. Ethnically-diverse individuals are less likely to develop MMR mutations related with hereditary nonpolyposis colorectal cancer. The most potent risk factor in the development of hereditary nonpolyposis colorectal cancer is gene mutations caused by defective DNA mismatch repair. According to the Bethesda guidelines and Amsterdam criteria, screening for hereditary nonpolyposis colorectal cancer by genetic testing is recommended among patients with family history or/and a confirmed diagnosis of colorectal cancer under age 50 years. If left untreated, hereditary nonpolyposis colorectal cancer progression occurs rapidly and is then followed by sentinel organ cancer or metastasis. Hereditary nonpolyposis colorectal cancer is an aggressive syndrome characterized by early onset of cancer. Affected organs include endometrium (second most common after colon), ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. Complications of hereditary nonpolyposis colorectal cancer are usually related to the surgery. The 5-year relative survival of patients with hereditary nonpolyposis colorectal cancer is approximately 79.3%. A feature associated with worse prognosis is late stage diagnosis. The hallmark of hereditary nonpolyposis colorectal cancer is a first-degree relative with known MMR/EPCAM gene mutation. A positive family history of colorectal cancer and meeting Amsterdam I or II criteria or revised Bethesda guidelines is highly suggestive of hereditary nonpolyposis colorectal cancer. Some symptoms that are associated with colorectal cancer are change in bowel habits, hematochezia, and rectal pain. Patients with hereditary nonpolyposis colorectal cancer usually appear healthy. Physical examination of patients with hereditary nonpolyposis colorectal cancer may show the presence of the fordyce granules. Laboratory findings consistent with the diagnosis of hereditary nonpolyposis colorectal cancer may include positive germline testing for hereditary nonpolyposis colorectal cancer genes (MLH1, MSH2, MSH6, and PMS2), positive EPCAM gene testing, and elevated serum concentration of CEA and CA-125. There are no ECG findings associated with hereditary nonpolyposis colorectal cancer. There are no x-ray findings associated with hereditary nonpolyposis colorectal cancer. There are no echocardiography findings associated with hereditary nonpolyposis colorectal cancer. There are no ultrasound findings associated with hereditary nonpolyposis colorectal cancer. However, an ultrasound may be helpful as a screening tool for the diagnosis of endometrial cancer which is commonly found in women with this syndrome. CT scan is not routinely used for the diagnosis of hereditary nonpolyposis colorectal cancer. However, in some cases, CT scan can be useful in the detection of extracolonic lesions and also right-sided colon lesions (especially in the cecum) which are not easily seen with colonoscopy. Magnetic resonance colonography (MRC) is not routinely used for the diagnosis of hereditary nonpolyposis colorectal cancer. Although it is associated with less discomfort as compared to colonoscopy, it has poor sensitivity in detecting small polyps, limiting its utility in adenoma screening at this time. There are no associated additional imaging findings for the diagnosis of hereditary nonpolyposis colorectal cancer. According to the American College of Gastroenterology, patients with hereditary nonpolyposis colorectal cancer should undergo colonoscopy every 2 years beginning at age 20 - 25 years, until the age of 40, followed by an annual colonoscopy. Diagnostic and screening endoscopy is recommended in the case of hereditary nonpolyposis colorectal cancer. There is no medical treatment for hereditary nonpolyposis colorectal cancer. However, hereditary nonpolyposis colorectal cancer patients should consider diet optimization and pharmacological prevention. Surgery is the mainstay of treatment for hereditary nonpolyposis colorectal cancer. Surgical resection is recommended for patients with hereditary nonpolyposis colorectal cancer because of the high rate of metachronous colorectal cancer. Subtotal colectomy with ileo-rectal anastomosis and postsurgical endoscopic rectal surveillance are advised when colorectal cancer develops in the setting of hereditary nonpolyposis colorectal cancer. There is no established method for the primary prevention of hereditary nonpolyposis colorectal cancer.There are no established measures for the primary prevention of hereditary nonpolyposis colorectal cancer. Secondary prevention strategies following hereditary nonpolyposis colorectal cancer include genetic testing, colonoscopy, urine cytology, pelvic exam, and endometrial biopsy.
Historical Perspective
Lynch syndrome was first described by Dr. Henry T. Lynch, an American physician, in 1966.
Classification
Hereditary nonpolyposis colorectal cancer may be classified into 2 types: Lynch syndrome I (familial colon cancer) and Lynch syndrome II (hereditary nonpolyposis colorectal cancer associated with other cancers). Other variants such as Muir-Torre syndrome and Turcot syndrome are considered subtypes of hereditary nonpolyposis colorectal cancer.
Pathophysiology
Hereditary nonpolyposis colorectal cancer is an autosomal dominant genetic disease characterized by an early onset of colon cancer, endometrial cancer, and other malignant tumors. Development of hereditary nonpolyposis colorectal cancer is the result of multiple genetic mutations. The genes involved in the pathogenesis of hereditary nonpolyposis colorectal cancer include: MSH-2, MLH-1, MSH-6, PMS-2 , PMS-1, TGF-BR2, and MLH-3. This syndrome occurs most commonly in the proximal colon (60% to 80%). Endometrial cancer is the most common sentinel cancer among female patients with hereditary nonpolyposis colorectal cancer.
Causes
Hereditary nonpolyposis colorectal cancer is caused by germline mutations in one of the four MMR genes (MLH1, MSH2, MSH6, or PMS2), that results in defective repair of DNA sequence. Deletions in the EPCAM gene also cause hereditary nonpolyposis colorectal cancer.
Differentiating Hereditary Nonpolyposis Colorectal Cancer from other Diseases
Hereditary nonpolyposis colorectal cancer must be differentiated from other diseases that cause familial colorectal cancer, such as: juvenile polyposis, familial adenomatous polyposis, Cowden syndrome, and MYH-associated polyposis.
Epidemiology and Demographics
Incidence of HNPCC is not well known but it is estimated that 0.5 to 13% of the cases of colorectal cancer are due to hereditary nonpolyposis colorectal cancer. The prevalence of hereditary nonpolyposis colorectal cancer is approximately 2 - 7% of all the diagnosed cases of colorectal cancer. Hereditary nonpolyposis colorectal cancer commonly affects young adult population. The median age of diagnosis is between 40 to 45 years. Hereditary nonpolyposis colorectal cancer affects males and females equally. Hereditary nonpolyposis colorectal cancer usually affects individuals of the white race more commonly. Ethnically-diverse individuals are less likely to develop MMR mutations related with hereditary nonpolyposis colorectal cancer.
Risk Factors
The most potent risk factor in the development of hereditary nonpolyposis colorectal cancer is gene mutations caused by defective DNA mismatch repair.
Screening
According to the Bethesda guidelines and Amsterdam criteria, screening for hereditary nonpolyposis colorectal cancer by genetic testing is recommended among patients with family history or/and a confirmed diagnosis of colorectal cancer under age 50 years.
Natural History, Complications and Prognosis
If left untreated, hereditary nonpolyposis colorectal cancer progression occurs rapidly and is then followed by sentinel organ cancer or metastasis. Hereditary nonpolyposis colorectal cancer is an aggressive syndrome characterized by early onset of cancer. Affected organs include endometrium (second most common after colon), ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. Complications of hereditary nonpolyposis colorectal cancer are usually related to the surgery. The 5-year relative survival of patients with hereditary nonpolyposis colorectal cancer is approximately 79.3%. A feature associated with worse prognosis is late stage diagnosis.
History and Symptoms
The hallmark of hereditary nonpolyposis colorectal cancer is a first-degree relative with known MMR/EPCAM gene mutation. A positive family history of colorectal cancer and meeting Amsterdam I or II criteria or revised Bethesda guidelines is highly suggestive of hereditary nonpolyposis colorectal cancer. Some symptoms that are associated with colorectal cancer are change in bowel habits, hematochezia, and rectal pain.
Physical Examination
Patients with hereditary nonpolyposis colorectal cancer usually appear healthy. Physical examination of patients with hereditary nonpolyposis colorectal cancer may show the presence of the fordyce granules.
Laboratory Findings
Laboratory findings consistent with the diagnosis of hereditary nonpolyposis colorectal cancer may include positive germline testing for hereditary nonpolyposis colorectal cancer genes (MLH1, MSH2, MSH6, and PMS2), positive EPCAM gene testing, and elevated serum concentration of CEA and CA-125.
Electrocardiogram
There are no ECG findings associated with hereditary nonpolyposis colorectal cancer.
X Ray
There are no x-ray findings associated with hereditary nonpolyposis colorectal cancer.
Echocardiography/Ultrasound
There are no echocardiography findings associated with hereditary nonpolyposis colorectal cancer. There are no ultrasound findings associated with hereditary nonpolyposis colorectal cancer. However, an ultrasound may be helpful as a screening tool for the diagnosis of endometrial cancer which is commonly found in women with this syndrome.
CT scan
CT scan is not routinely used for the diagnosis of hereditary nonpolyposis colorectal cancer. However, in some cases, CT scan can be useful in the detection of extracolonic lesions and also right-sided colon lesions (especially in the cecum) which are not easily seen with colonoscopy.
MRI
Magnetic resonance colonography (MRC) is not routinely used for the diagnosis of hereditary nonpolyposis colorectal cancer. Although it is associated with less discomfort as compared to colonoscopy, it has poor sensitivity in detecting small polyps, limiting its utility in adenoma screening at this time.
Other Imaging Findings
There are no associated additional imaging findings for the diagnosis of hereditary nonpolyposis colorectal cancer.
Other Diagnostic Studies
According to the American College of Gastroenterology, patients with hereditary nonpolyposis colorectal cancer should undergo colonoscopy every 2 years beginning at age 20 - 25 years, until the age of 40, followed by an annual colonoscopy. Diagnostic and screening endoscopy is recommended in the case of hereditary nonpolyposis colorectal cancer.
Medical Therapy
There is no medical treatment for hereditary nonpolyposis colorectal cancer. However, hereditary nonpolyposis colorectal cancer patients should consider diet optimization and pharmacological prevention.
Surgery
Surgery is the mainstay of treatment for hereditary nonpolyposis colorectal cancer. Surgical resection is recommended for patients with hereditary nonpolyposis colorectal cancer because of the high rate of metachronous colorectal cancer. Subtotal colectomy with ileo-rectal anastomosis and postsurgical endoscopic rectal surveillance are advised when colorectal cancer develops in the setting of hereditary nonpolyposis colorectal cancer.
Primary Prevention
There is no established method for the primary prevention of hereditary nonpolyposis colorectal cancer.There are no established measures for the primary prevention of hereditary nonpolyposis colorectal cancer.
Secondary Prevention
Secondary prevention strategies following hereditary nonpolyposis colorectal cancer include genetic testing, colonoscopy, urine cytology, pelvic exam, and endometrial biopsy.