Doctor talking to older male patient

Cowden Syndrome 

Current recommendations for the management of Cowden syndrome focus on primary and secondary prevention of breast cancer. Further, annual examinations beginning at age 18 to detect skin changes and monitor the thyroid gland for abnormalities are recommended. Those at high risk should receive a baseline thyroid ultrasound at age 18 and consider receiving this annually thereafter. Individuals should also consider undergoing annual dermatological examinations. Options for prophylactic mastectomy should be discussed on an individual, case-by-case basis. Both men and women identified as Cowden patients should have clinical breast examinations beginning at age 25. Further, women should be encouraged to conduct breast self-examinations monthly. Women with Cowden should have an annual MRI and mammogram at ages 30 to 35 or 5 to 10 years earlier than the earliest known breast cancer diagnosis in a family member. Pre-menopausal women should receive annual blind endometrial suction biopsies starting between ages 35-40 or 5 years before the earliest diagnosis of endometrial cancer in a family member. Postmenopausal women should receive an annual endometrial ultrasound.

Familial Adenomatous Polyposis

Patients with classical familial adenomatous polyposis should start colon cancer screening, usually with annual colonoscopy, in their early teens. Colectomy is recommended when endoscopic surveillance may not be adequate due to increasing numbers of adenomas or large adenomas, or when there is suspicion or evidence of colon cancer. After colectomy, annual endoscopy of the ileal pouch and biannual examination of the ileostomy should be performed. Use of sulindac for chemoprevention of polyp formation after colectomy may also be considered. Upper endoscopy with duodenoscopy and random sampling of fundic gland polyps should be initiated between the ages of 25 and 30. The interval of followup endoscopies is determined based on the extent of duodenal polyposis present. Surgical resection is a consideration when high-grade dysplasia is found. Annual examination of the thyroid with ultrasound is recommended by most groups. For children, screening for hepatoblastoma with ultrasound of the liver and serum alpha feta protein should also be offered to infants up to age 5-7 years. Some groups, such as the National Comprehensive Cancer Network, recommend screening for desmoid tumors with MRI of the abdomen for individuals from families with a history of symptomatic desmoids.

Those with attenuated familial adenomatous polyposis have recommendations similar to those with the classical form of the disease, but colonoscopy may be initiated at a later date, dependent on the family history of disease onset.

Familial Medullary Thyroid Cancer

For patients with familial medullary thyroid cancer, thyroidectomy is recommended in childhood. The specific timing of this surgery varies on the risk status associated with the specific mutation but ranges from before the age of 1 year for those with the mutations at highest risk to before the age of 10 years for those with lower-risk mutations. If there is suspicion for MEN2A, monitoring of metanephrines and/or normetanephrines in the serum and urine may be appropriate for evaluation for pheochromocytoma, although again the starting age and frequency of these tests may be determined by the specific mutation identified. Testing to rule out pheochromocytoma would also be appropriate prior to prophylactic thyroidectomy. Calcium and parathyroid hormone levels may also be monitored in those who have mutations causing a predisposition to hyperparathyroidism.

Hereditary Breast and Ovarian Cancer

Individuals with hereditary breast and ovarian cancer (HBOC) should receive high-risk screening for both breast and ovarian cancer and consider preventative or risk-reducing surgeries. Breast cancer screening should include monthly breast self-exam starting at age 18 and twice yearly clinical breast exam starting at age 25. Annual screening breast MRI should be started between ages 25-30 with annual mammogram added after age 30. Chemoprevention with tamoxifen has been shown to reduce breast cancer risk in the BRCA-positive population. Raloxifene and aromatase inhibitors have been found to reduce risk of hormone-receptor positive breast cancer in the general population; however, data on the efficacy of these agents in the BRCA-positive population is lacking at this time. Preventative/risk-reducing mastectomies remain the most complete way to reduce the risk of breast cancer for women with HBOC. Ovarian cancer screening may include periodic transvaginal ultrasound and serum CA-125 testing starting at ages 30-35. Chemoprevention with oral contraceptives has been shown to be effective in preventing ovarian cancer for women with HBOC. Preventative/risk-reducing salpingo-oophorectomy (RRSO) should be performed at the completion of childbearing. RRSO has been shown to decrease the risk of breast and ovarian cancer and improve survival in women with BRCA1 and BRCA2 mutations. RRSO should be considered earlier for BRCA1 carriers (before 40) than for BRCA2 carriers given the earlier onset of ovarian cancer in BRCA1 mutation carriers.

Hereditary Diffuse Gastric Cancer

Individuals with hereditary diffuse gastric cancer (HDGC) and germline abnormalities in CDH1 are at significant risk for development of gastric cancer, breast cancer (lobular type) and possibly colon cancer. Individuals in HDGC families who are unaffected are recommended to have endoscopy every 6-12 months, starting at age 16, with consideration of prophylactic gastrectomy in early adulthood. Women in HDGC families are recommended to initiate breast cancer screening at age 35, with annual mammography and annual breast MRI. Colon cancer screening should be initiated for HDGC families with colon cancer in the family, starting at age 40 or 10 year younger than the youngest case of colon cancer in the family.

Individuals with newly diagnosed gastric cancer and pathogenic mutations in CDH1 should have total gastrectomies instead of partial gastrectomies.

Li-Fraumeni Syndrome 

Individuals with Li-Fraumeni syndrome (LFS) and germline mutations in TP53 are at high lifetime risk of developing many different types of cancer including a high risk of second primary cancers. The more common cancers include: early breast cancer, sarcoma (soft tissue and osteosarcoma), malignant brain tumors, leukemia/lymphoma and adrenocortical carcinoma. Screening protocols for unaffected individuals have been developed for both children and adults. Children should be screened for adrenocortical carcinoma, breast tumors, sarcoma, and leukemia/lymphoma while adults should be screened for early breast cancer, brain tumors, sarcoma, colon cancer, melanoma and leukemia/lymphoma.

Individuals diagnosed with cancer and found to have a germline TP53 mutation should avoid therapeutic radiation when possible due to the very high risk of radiation induced cancers. Additionally cancer survivors with LFS should be screened for additional cancers in a similar fashion as those in the general population.

Screening for both children and adults with LFS should include an annual physical examination (with a focus on skin and neurologic systems). Experts also recommend consideration of annual total body MRI and brain MRI in this population, although it is important to discuss the potential for false positive results requiring biopsy with this approach. Colon cancer screening should include colonoscopy every 2 years starting at age 40 or 10 years before the youngest case of colon cancer. Breast cancer screening for individuals with LFS should include monthly breast self-examination starting at age 18 and twice yearly clinical breast exam. Annual breast MRI is the strongly preferred modality for breast imaging and should be started at age 20-25, or 5-10 years before the earliest breast cancer in the family, whichever is earliest. Individuals who do not have access to breast MRI can consider annual mammograms, but this is a less favorable option for this population due to the radiation exposure. Prophylactic mastectomy can be considered. Screening for leukemia/lymphoma could include complete blood count, erythrocyte sedimentation rate, and lactate dehydrogenase every 4-12 months. For children, additional screening for adrenocortical carcinoma should be considered.

Lynch Syndrome

Individuals with Lynch syndrome are recommended to have colonoscopies every 1-2 years, usually starting at age 20-25 or 2-5 years prior to the age of the earliest colon cancer diagnosis in the family, whichever is earliest. Some groups recommend starting screening at age 25-30 for patients who carry mutations in the MSH6 and PMS2 genes. For women with Lynch syndrome, screening of the ovaries and uterus with transvaginal ultrasounds, serum CA-125 levels, and endometrial biopsies is often a consideration, although these tests are known to have poor predictive values. Prophylactic hysterectomy and bilateral salpingo-oophorectomy is an option to reduce cancer risk for these women once childbearing has been completed. Screening of the upper gastrointestinal tract with endoscopy and of the urinary tract with urinalysis, urine cytology, or renal ultrasound is controversial, as no clear benefit has been proven from these studies in this population; however, they may be applied to patients on an individualized basis, taking into consideration their personal and family histories. Aspirin use has been shown to decrease colorectal cancer in patients with Lynch syndrome (ie. CAPP2 study).

For individuals with Lynch syndrome who have a diagnosis of colon cancer, total or subtotal colectomy at the time of their cancer resection is often performed due to the high risk of a second synchronous or metachronous colon cancer. Prophylactic colectomy in patients without a history of colon cancer remains controversial but is usually not performed unless there is a barrier to regular colonoscopic surveillance.

von Hippel-Lindau Syndrome

Screening for individuals with von Hippel-Lindau syndrome includes monitoring of the eyes, adrenals, central nervous system, kidneys, and pancreas. Regular physical examination should evaluate for hypertension and neurologic symptoms. Annual ophthalmologic examinations should be initiated in infancy to evaluate for retinal hemangioblastoma. Assessment for hemangioblastomas in the central nervous system with MRI of the spine and brain are recommended on an annual to biannual basis starting at puberty or in the teens. Annual abdominal imaging is advised to image the kidneys, pancreas, and adrenal glands. For individuals from 8 to 18, ultrasound is recommended; for those over 15-18, CT scans or ultrasounds should alternate with MRIs. Plasma or urinary catecholamines and metanephrines should be collected annually, starting at age 2, to evaluate for pheochromocytoma. More frequent screening for pheochromocytoma may be necessary during pregnancy. Regular assessment by an audiologist should be performed in individuals with VHL who are over the age of 5. MRI imaging can also be considered for symptoms of hearing loss, tinnitus, or vertigo, but regular imaging is not currently recommended in the absence of these symptoms.

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