We’re continuing our discussion from last month’s blog of the newly released American College of Medical Genetics and Genomics (ACMG) clinical practice resource for adults with NF1. This document summarizes current knowledge of clinical care and proposes an approach to management for general practitioners and other healthcare professionals providing care to adults with NF1. Previously, I reviewed some of the recommendations related to malignant peripheral nerve sheath tumors (MPNST). Next, I’d like to focus on recommendations related to other types of tumors. 

Breast Cancer

In recent years, it has become clear that women with NF1 are at an increased risk for breast cancer, with the risk two to three times higher in women with NF1 than in those in the general population. The increased risk is greatest in women below age 40, with the earliest cases occurring around age 30. The increased risk of breast cancer in women with NF1 is not necessarily an expected outcome, as breast tissue is different from that usually affected by the NF phenotype, such as the tissue comprising neurofibromas.  

The risk of breast cancer in women with NF1 is not as high as the risk of breast cancer in women with mutations in the BRCA1or BRCA2genes; women with mutations in BRCA1or BRCA2have a much higher risk of both breast and ovarian cancer.  The reason for the increased risk of breast cancer in women with NF1 is not understood. Notably, mutations in the NF1gene have been found in the breast cancer tissue of women who do not have NF1. It is known that cancer is the result of the accumulation of genetic alterations that cause cells to behave abnormally. The fact that the NF1gene has been shown to be mutated in some common cancers, including breast cancer, might indicate that the NF1 mutation puts an individual one step closer to developing other cancers.  

A genetic panel of tests is often performed in women who have been diagnosed with breast cancer or have a family history of breast cancer, to detect mutations that might be associated with the cancer. The NF1 gene is now being tested as part of this panel, as well as other genes including BRAC1and BRCA2. We sometimes receive referrals to our clinic from women who have undergone genetic testing for a breast cancer diagnosis and have been found to have a mutation for NF1.There are three possible reasons for this finding: first, the individual has NF1 and the clinical features have gone unrecognized; second, the individual has a mosaic form of NF1 that is detected in the blood but may not be present in all cells of the body; third, genetic variants are sometimes found in testing that are not pathogenic, and are referred to as “variants of unknown significance,” and do not necessarily equate with having a condition such as NF.

Due to the increased risk of breast cancer in women with NF1, the National Comprehensive Cancer Network (NCCN), an organization that issues screening guidelines for various cancers, has recently recommended that women with NF1 be screened for breast cancer at an earlier age than the general population, with mammograms starting at age 30. Also, the NCCN recommends consideration of use of contrast enhanced breast MRI between the ages of 30 and 50. After this, the guidelines shift back to that of the general population.  Because it isn’t uncommon for women with NF1 to have neurofibromas around the beast, most commonly around the areola, some patients are concerned that neurofibromas in the breast may be mistaken for breast tumors during imaging. While this issue may sometimes make it more difficult to interpret masses in the breast, neurofibromas are clinically distinguishable from tumors in breast tissue. However, it is important for radiologists to know the NF history when reading imaging results for these patients.

Pheochromocytoma

A tumor of the adrenal gland called pheochromocytoma affects fewer than 5% of people with NF1, although it’s an important tumor to recognize. The adrenal glands produce the hormones epinephrine and norepinephrine that trigger the body’s fight-or-flight response to a perceived threat, causing an increase in heart rate and blood pressure. A pheochromocytoma causes the irregular and excessive release of these hormones, resulting in symptoms of high blood pressure, rapid heart rate and palpitations, episodes of flushing, and excessive sweating. 

When a patient presents with these symptoms, a blood test is done to measure plasma free metanephrines, which assesses the amounts of metabolic byproducts of epinephrine and norepinephrine present in the blood. A positive blood test result requires a confirmatory 24-hour urine collection for measurement of the same substances. If laboratory tests indicate the possibility of a tumor, abdominal imaging is performed to locate a possible tumor and may include CT scan and a form of PET scanning technology that can detect radioactive compounds taken up by a tumor.

Gastrointestinal Stromal Cell Tumors

Gastrointestinal stromal cell tumors (GISTs) are tumors of the GI tract that most commonly occur in the stomach or small intestine. Although rare, there is an increased risk of development of GIST in people with NF1. The primary symptoms of GISTs include abdominal pain and GI bleeding. These tumors are diagnosed using endoscopy, a procedure used to examine the digestive tract.