Patients with neurofibromatosis type 1 (NF1), caused by mutations in the NF1 gene on chromosome 17, are known to be at high risk for both benign and malignant tumors.
For example, previous studies have shown that these patients have a high incidence of intracranial glioblastomas and malignant peripheral nerve sheath tumors (MPNSTs).
Now, a study from Finnish researchers published online March 1 in the Journal of Clinical Oncology has shown these patients to be at a 5-fold increased risk for cancer compared with the general population.
In addition, the investigators found a high incidence of breast cancer in these patients and a related worse survival — a new finding in these patients.
"Our results demonstrate that cancer in patients with NF1 manifests in multiple and previously unrecognized ways. The NF1 gene may have wider effects on carcinogenesis than suggested previously," write the authors, led by Juha Peltonen, MD, from the University of Turku, Finland.
"Much of what has been known has been corroborated and expanded upon in our study," Dr Peltonen told Medscape Medical News. "Uniquely, we have created the Finnish NF1 Registry over a long period and have captured all the NF1 cases in Finland," Dr Peltonen said about the population-based cohort.
The study also showed that NF1 patients have inferior survival compared with patients with similar cancers in the general population.
"Although the increased risk of NF1 patients to develop cancer has been long recognized, the reason this study is important is because the Finnish researchers were able to determine the risks to a greater degree of precision," said Matthias Karajannis, MD, director of the NF Clinical Research Program at New York University Langone Medical Center in New York City.
"The study is strong because it is not referral based, but population based, which provides for a more accurate assessment of risk," he told Medscape Medical News.
The Finnish Study
The researchers built a Finnish NF1 registry that captured NF1 patients from 1987 to 2011 in the 5.4 million Finnish population. Patients who did not meet the National Institutes of Health criteria were excluded.
Cancer diagnoses were identified through the Finnish Cancer Registry. Mortality information was obtained from Statistics Finland and from the National Population Register Centre.
Data were presented as standardized incidence rates (SIRs) and standardized mortality ratios (SMRs) for 1404 patients — 667 men and 217 women.
There were 244 cancers, which was much higher than the expected 48.5 cancers.
With a SIR of 5.03, NF1 patients were at a 5-fold higher risk for cancer.
The cumulative risk for cancer was 25.1% by age 30 years (compared with 0.8% for the general population) and 38.8% by age 50 years (compared with 3.9% for the general population). Risk was highest for females at all ages; for example, at age 50 years, risk was 45.2% for women compared with 32.0% for men. SIRs were 87.6 for girls and 45.6 for boys.
SIR for MPNST was the most inflated — 2056, with the cumulative risk increasing over life: 8.5% by age 30 years, 12.3% by age 50 years, and a lifetime risk of 15.8%.
Based on their findings, the authors proposed three categories of cancer in NF1. First, NF1-specific cancers including intracranial gliomas and MPNSTs, which are know to be common in NF1 patients and occur predominantly early in life. Second, NF1-related cancers, a group of cancers including breast cancer, gastrointestinal stroma tumor (GIST), and thyroid cancer, with elevated SIR/SMR in NF1 patients. Third, cancers observed in NF1 patients at a similar rate compared with those of the normal population and with an uncertain relationship to NF1.
The SIR for breast cancer was 11.1, with the excess incidence highest in young women.
"We have always suspected this; the impression among clinicians was that breast cancer incidence was more common in patients with NF1 compared with the general population. Now we have the data to support that impression," Dr Karajannis said.
Although SMR for cancer mortality was similar for men (2.01) and women (2.48), SMR for breast cancer was 5.20. In addition, the researchers showed that 5-year survival was significantly worse for NF1 patients with any cancer compared with that for patients in the general population.
"Again, the data on worse survival in patients with NF1 who have aggressive cancers support impressions from clinical practice. But what makes tumors behave more aggressively in the setting of NF1 needs to be determined," Dr Karajannis said.
"The accumulation of mutations that lead to malignancy may occur earlier in patients with NF1 than in the control population, leading to the increased risk of more cancer types than previously have been observed," the Finnish researchers note in their discussion.
"These findings should translate to clinical practices to determine clinical interventions and focused follow-up of patients with NF1," they conclude.
NF1 Patient Journey
The signs of an NF1 mutation include, in a newborn child, one or two café-au-lait spots, which increase at subsequent visits.
"It is the most common genetic disease in the newborn, with an incidence of 1 in 3,000 and a pediatrician should be aware of the significance of these spots," Dr Karajannis said.
A patient with café-au-lait spots should be referred to an NF center or to a specialist for evaluation," The significance of the spots often goes unrecognized, and an opportunity for early diagnosis is missed, Dr Karajannis added.
A comprehensive family history and a complete physical examination are important in establishing a diagnosis of NF1.Family history is factored into the diagnosis because the NF1 gene is inherited in an autosomal dominant manner.
However, Dr Peltonen said that half of the new cases are in patients who do not have a family history.
A diagnosis needs to satisfy the National Institutes of Health criteria. In addition to the café-au-lait spots, the most common symptoms are freckles under the arm or around the groin, Lisch nodules (asymptomatic lesions of the iris), and neurofibromas.
"At present, there is no genetic test that diagnoses NF1 with 100% accuracy," Dr Peltonen said. "Although mutations in the NF1 gene can be detected with very high accuracy in a reference laboratory, the test may not be positive in founders due to mosaicism," Dr Karajannis added.
Once diagnosed with NF1, the clinical management is tailored to each patient, Dr Karajannis explained.
Patients may develop optic pathway gliomas, neurofibromas, malignancies (MPNSTs, pheochromocytomas, GISTs, rhabdomyosarcomas), bone deformities (rare, but often severe), learning disabilities, and behavioral issues.
That is why a multidisciplinary team is involved in the optimal management of patients, including ophthalmologists, pediatric neurologists, neuro-oncologists, dermatologists, surgical oncologists, medical oncologists, and genetic counselors.
In a patient journey, careful long-term health surveillance by an NF1 expert is critical, which includes annual physical evaluations, annual ophthalmologic screenings (for children and less frequent for young adults and adults), monitoring for nervous system disorders, and other evaluations dictated by symptoms.
In patients with NF1, symptom management differs compared with that in the general population, Dr Karajannis explained. For example, an NF1 patient with an MPNST may present with subtle signs or symptoms such as pain, and early recognition is of utmost importance to be able to diagnose the disease at an early stage where it is still curable.
Many cancers require radiation therapy, said Dr Karajannis. However, radiation therapy should be avoided in patients with NF1 who require cancer therapy because it is associated with the development of secondary cancers, he explained. Even diagnostic tests that use a significant amount of ionizing radiation such as CT scans should be minimized as much as possible in these patients, he said.
"Many may question whether genetic counselling is beneficial for patients with NF1," Dr Peltonen said. "In my opinion, it is extremely vital for the well-being of the individual," he added. Genetic counselors will make the family aware of severe consequences that may follow and may explain why children may or may not perform as well as the normal child, he explained. It is important for a better quality of life, he indicated.
For Dr Karajannis, genetic counseling may help family planning. If a patient wants to have children, preimplanting diagnostics will play a role in selecting an appropriate embryo free of NF1 mutation, he told Medscape Medical News.
"There is no one size fits all," Dr Karajannis said, implying that each patient journey is unique. Even in patients with the same NF1 mutation in the same family, each patient is affected very differently, he added.
"The awareness of NF1 is lacking and it is critical that patients with NF1 are managed by clinicians experienced in their care. Often the opportunity to detect a malignancy is missed before it metastasizes," Dr Karajannis said.
Dr Peltonen reported no relevant financial relationships. Some of the study authors reported receiving industry support. Dr Karajannis reported no relevant financial relationships.
J Clin Oncol. Published online March 1, 2016. Full text