NF1 (Neurofibromatosis type 1) – risk management

Neurofibromatosis type 1 (NF1) is an autosomal dominant benign and malignant tumour predisposition syndrome, characterised by the development of benign peripheral nerve sheath tumours (neurofibromas). Approximately 50% of cases are de novo and, of these, a small proportion is mosaic, often with milder, asymmetrical or segmental disease.^r

This risk management guideline has been developed for individuals who have NOT been diagnosed with a relevant cancer. The care of affected individuals should be individualised based on their clinical situation, and the monitoring they need as part of their treatment and post-treatment follow-up.

The risk management of an individual with a pathogenic variant in two or more genes that confer a predisposition to cancer should also be individualised.

• Known or obligate carrier of a pathogenic variant in the NF1 gene
• Individual meeting clinical diagnostic criteria for NF1, but for whom genetic testing has not been performed or is uninformative
• Individual under age 16 years with no features of NF1 who has a first degree relative with NF1 and that relative has not had genetic testing or has had an uninformative result^*
• Child under age 5 years where the clinical or molecular diagnosis is uncertain (e.g. a child with >6 café au lait patches who does not otherwise fulfil clinical diagnostic criteria or NF1^*)

Exclusion criteria

• Individual who has a first degree relative who meets clinical diagnostic criteria for NF1, but does not have any clinical signs of NF1 after age 16 years (unlikely to be affected if no phenotypic features by 16 years)^*
• Individual with proven or suspected mosaic NF1 (surveillance should be individualised)
• Individual with proven or suspected spinal neurofibromatosis but for whom genetic testing is uninformative or has not been performed (surveillance should be individualised)
• Individual with NF1-microdeletion syndrome who has a large deletion involving multiple genes including the NF1 gene (surveillance should be individualised)^r
• Individual with a SPRED1 pathogenic variant

^* Caution should be taken in excluding the diagnosis of NF1 based on clinical criteria due to the possibility of minimally manifesting pathogenic variant carriers.^r

The published literature is biased towards NF1 families with higher tumour incidence. The published data expresses some cancer risk estimates as observed/expected rather than age-related penetrance. 

** Source: Australian Institute of Health and Welfare (AIHW) 2020 Cancer Data in Australia; Canberra: AIHW. <https://www.aihw.gov.au/reports/cancer/cancer-data-in-australia/>. (2016 data)

There are a broad spectrum of additional health problems associated with NF1, and these are summarised elsewhere.^rr See Review Checklist for NF1. Tumour-related manifestations are listed below.  

All children with NF1 should be managed by a paediatrician and/or a multidisciplinary team. Most adults with NF1 can be managed by their general practitioner with referral to specialised services as necessary. More complex cases could be referred to a NF1 clinic or multidisciplinary team who have experience with the condition.

Individuals with mosaic or segmental NF1 may require less intensive review depending on their clinical presentation.

The choice of risk management strategy should take into account current age, other health issues and residual cancer risk.

MMG - mammogram; MRI - magnetic resonance imaging; US - ultrasound
*** The impact of lifestyle on cancer risk should be discussed e.g. exercise regularly, maintain a healthy weight, have a healthy diet, limit alcohol intake, do not smoke and avoid excessive sun exposure.

For a summary of management of other NF1-associated manifestations see Review Checklist for NF1.^

^Acknowledgement: This document is adapted and reproduced with permission of the Neurofibromatosis Service, Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK. 

There is a lack of data about the optimal surveillance for individuals with NF1. There is some evidence for genotype-phenotype correlation, however there is currently insufficient data to support variant-specific surveillance protocols.^r These management guidelines are based on expert consensus opinion.^rrr

Cancer (all)

In NF1 there is an increased risk of a broad range of cancers/tumours.^r Some types of cancer are associated with poorer survival when compared with general population controls, particularly in those diagnosed at age <40 years.^rr Concerning symptoms should be investigated promptly.

The type, timing and degree of intervention/surgery, chemotherapy or radiation therapy treatment of NF1 patients (if any) should be made by a multidisciplinary team with experience in managing NF1.^rr 

Breast cancer (female)

A recent meta-analysis of 4 cohort studies (total of 4178 females) found women with NF1 have a three-fold increased risk of developing breast cancer compared to the general population (SIR = 3.07; 95% CI 2.16-4.38).^r Age at diagnosis was available for 181/286, and in this subgroup the mean age at diagnosis was 49.3 years (median 46 years; interquartile range 38.3-58.0 years). Approximately half (53%) were diagnosed age <50 years, with 28% diagnosed between age 35-44 years and 15% age <35 years.

Women with NF1 have poorer breast cancer survival rates compared with women in the general population (estimated 65% vs 90% 5-year survival).^rr

Breast surveillance

Recommendations for breast cancer surveillance are extrapolated from cancer surveillance studies in other groups at increased risk of breast cancer.

As there is increased risk of early breast cancer, surveillance is recommended from age 30 years. Breast MRI is recommended; although there is no data specific to women with NF1, MRI is likely to have higher sensitivity compared with mammography. MRI is also preferred over mammography in young women to reduce ionising radiation exposure.

Breast surgical

There is no data regarding the potential benefit of risk-reducing mastectomy in women with NF1. The lifetime risk of breast cancer is in the moderate risk range, therefore risk-reducing mastectomy is not generally recommended.

Malignant peripheral nerve sheath tumour (MPNST)

MPNSTs are aggressive sarcomas that arise in plexiform neurofibroma and are associated with a poor survival. The median age of diagnosis for MPNST is age 30-34 years. Individuals with deep, truncal location of plexiform neurofibroma, previous radiation and an NF1 microdeletion have an increased risk of MPNSTs.

There is no evidence that radiologic surveillance has benefit above early reporting of symptoms. Where available, offer recruitment to research projects to evaluate surveillance protocols using whole body MRI (e.g. SMOC+: see ANZSA Clinical Trials and Studies).

Optic nerve pathway glioma

Most optic nerve gliomas occur between age 3–5 years and do not require intervention.^r Optic pathway glioma are rare outside childhood, and lifelong surveillance is not required. Individuals with NF1 are also at risk of other ophthalmological disorders (e.g. retinal vascular abnormalities) and may develop ophthalmological disorders that are common in the general population (e.g. refractive errors, glaucoma, cataract). Recommend review by an optometrist or ophthalmologist as needed based on symptoms, family history and population recommendations.^r

Other cancers/tumours

Other possible NF1-associated cancers include juvenile myelomonocytic leukaemia, thyroid cancer, malignant fibrous histiocytomas and rhabdomyosarcoma.^rr The absolute risks of these cancer/tumour types is small.

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Bibliography

Evans, D. G., M. E. Baser, J. McGaughran, et al. 2002. "Malignant peripheral nerve sheath tumours in neurofibromatosis 1." J Med Genet 39(5):311-314.

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BACKGROUND: Cross sectional studies have shown that 1-2% of patients with neurofibromatosis 1 (NF1) develop malignant peripheral nerve sheath tumours (MPNST). However, no population based longitudinal studies have assessed lifetime risk. METHODS: NF1 patients with MPNST were ascertained from two sources for our north west England population of 4.1 million in the 13 year period 1984-1996: the North West Regional NF1 Register and review of notes of patients with MPNST in the North West Regional Cancer Registry. RESULTS: Twenty-one NF1 patients developed MPNST, equivalent to an annual incidence of 1.6 per 1000 and a lifetime risk of 8-13%. There were 37 patients with sporadic MPNST. The median age at diagnosis of MPNST in NF1 patients was 26 years, compared to 62 years in patients with sporadic MPNST (p <0.001). In Kaplan-Meier analyses, the five year survival from diagnosis was 21% for NF1 patients with MPNST, compared to 42% for sporadic cases of MPNST (p=0.09). One NF1 patient developed two separate MPNST in the radiation field of a previous optic glioma. CONCLUSION: The lifetime risk of MPNST in NF1 is much higher than previously estimated and warrants careful surveillance and a low threshold for investigation.

Ferner, R. E., S. M. Huson, N. Thomas, et al. 2007. "Guidelines for the diagnosis and management of individuals with neurofibromatosis 1." J Med Genet 44(2):81-88.

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Neurofibromatosis 1 (NF1) is a common neurocutaneous condition with an autosomal dominant pattern of inheritance. The complications are diverse and disease expression varies, even within families. Progress in molecular biology and neuroimaging and the development of mouse models have helped to elucidate the aetiology of NF1 and its clinical manifestations. Furthermore, these advances have raised the prospect of therapeutic intervention for this complex and distressing disease. Members of the United Kingdom Neurofibromatosis Association Clinical Advisory Board collaborated to produce a consensus statement on the current guidelines for diagnosis and management of NF1. The proposals are based on published clinical studies and on the pooled knowledge of experts in neurofibromatosis with experience of providing multidisciplinary clinical and molecular services for NF1 patients. The consensus statement discusses the diagnostic criteria, major differential diagnoses, clinical manifestations and the present strategies for monitoring and management of NF1 complications.

Madanikia, S. A., A. Bergner, X. Ye, et al. 2012. "Increased risk of breast cancer in women with NF1." Am J Med Genet A 158A(12):3056-3060.

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Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder associated with increased risk for neoplasms. Two studies in the United Kingdom have indicated that women with NF1 (particularly women under 50) may also be at increased risk of breast cancer. No such study has been done to date in the United States. Chart review for breast cancer diagnoses was undertaken for 126 women with NF1 followed at Johns Hopkins who were 20 years of age or older. Four of 126 women who met eligibility criteria were diagnosed with breast cancer (3.2% over 15 years). The unadjusted standardized incidence ratio (SIR) for breast cancer in the NF1 population between the ages of 20 and 49 was 2.68 (P = 0.076, 95% CI 0.68-7.29) based on incidence rates of breast cancer in the general population taken from the Surveillance Epidemiology and End Results (SEER) database. The unadjusted SIR for women with NF1 >/=50 was 0.81 (P = 0.84, 95% CI 0.041-4.01). When adjusted for race, the rate of NF1 in the general population and time of diagnosis, the SIR was 4.41 (P = 0.0049, 95% CI 1.12-12.00) for women <50 versus 0.94 (P = 0.95, 95% CI 0.047-4.65) for women >/=50. The trend of a higher-than-expected number of breast cancer cases in women <50 with NF1 agrees with the prior studies from the literature. Cumulatively, the data suggests an increased risk of breast cancer for women with NF1 < 50 years old, implying a need for closer surveillance and the establishment of screening guidelines for this patient population.

Sharif, S., A. Moran, S. M. Huson, et al. 2007. "Women with neurofibromatosis 1 are at a moderately increased risk of developing breast cancer and should be considered for early screening." J Med Genet 44(8):481-484.

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BACKGROUND: Malignancy risks in patients with neurofibromatosis 1 (NF1) are increased, but those occurring outside of the nervous system have not been clearly defined. AIM: To evaluate the risk of breast cancer in women with NF1 in a population-based study. METHODS: The risk of breast cancer in a cohort of 304 women with NF1 aged >or=20 years was assessed and compared with population risks over the period 1975-2005 using a person-years-at-risk analysis. RESULTS: There were 14 cases of breast cancers in the follow-up period, yielding a standardised incidence ratio (SIR) of 3.5 (95% CI 1.9 to 5.9). However, six breast cancers occurred in women in their 40s, and the SIR of breast cancer in women aged <50 years was 4.9 (95% CI 2.4 to 8.8). INTERPRETATION: Women with NF1 aged <50 years have a fivefold risk of breast cancer, are in the moderate risk category and should be considered for mammography from 40 years of age.

Sung, L., J. R. Anderson, C. Arndt, et al. 2004. "Neurofibromatosis in children with Rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma study IV." J Pediatr 144(5):666-668.

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We identified all children enrolled in the Intergroup Rhabdomyosarcoma Study Group-IV with neurofibromatosis type I (NF1) and rhabdomyosarcoma. Among 1025 eligible patients, 5 (0.5 %) had NF1. Three children had relapses, two of whom died of progressive disease. Patients with NF1 and rhabdomyosarcoma should be treated with intensive contemporary therapy protocols.

Upadhyaya, M., S.M. Huson, M. Davies, et al. 2007. "An absence of cutaneous neurofibromas associated with a 3-bp inframe deletion in exon 17 of the NF1 gene (c.2970-2972 delAAT): evidence of a clinically significant NF1 genotype-phenotype correlation." Am J Hum Genet 80(1):140-151.

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Neurofibromatosis type 1 (NF1) is characterized by cafe-au-lait spots, skinfold freckling, and cutaneous neurofibromas. No obvious relationships between small mutations (<20 bp) of the NF1 gene and a specific phenotype have previously been demonstrated, which suggests that interaction with either unlinked modifying genes and/or the normal NF1 allele may be involved in the development of the particular clinical features associated with NF1. We identified 21 unrelated probands with NF1 (14 familial and 7 sporadic cases) who were all found to have the same c.2970-2972 delAAT (p.990delM) mutation but no cutaneous neurofibromas or clinically obvious plexiform neurofibromas. Molecular analysis identified the same 3-bp inframe deletion (c.2970-2972 delAAT) in exon 17 of the NF1 gene in all affected subjects. The Delta AAT mutation is predicted to result in the loss of one of two adjacent methionines (codon 991 or 992) ( Delta Met991), in conjunction with silent ACA-->ACG change of codon 990. These two methionine residues are located in a highly conserved region of neurofibromin and are expected, therefore, to have a functional role in the protein. Our data represent results from the first study to correlate a specific small mutation of the NF1 gene to the expression of a particular clinical phenotype. The biological mechanism that relates this specific mutation to the suppression of cutaneous neurofibroma development is unknown.

Walker, L., D. Thompson, D. Easton, et al. 2006. "A prospective study of neurofibromatosis type 1 cancer incidence in the UK." Br J Cancer 95(2):233-238.

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Neurofibromatosis type 1 (NF1) is an autosomal dominant condition affecting around one in 3000 live births. The manifestations of this condition are extremely variable, even within families, and genetic counselling is consequently difficult with regard to prognosis. Individuals with NF1 are acknowledged to be at increased risk of malignancy. Several studies have previously attempted to quantify this risk, but have involved relatively small study populations. We present prospective data from 448 individuals with NF1 with a total of 5705 years of patient follow-up. These data have been collected via the UK NF1 association for patients. Demographic information on the affected individuals was cross-referenced with UK cancer registry data by the UK Office of National Statistics. The overall risk of cancer was 2.7 times higher in this cohort of NF1 patients than in the general population (95% confidence interval (CI) 1.9-3.7). The cumulative risk of a malignancy by age 50 years was 20% (95% CI 14-29%); beyond this age, the risk of cancer was not significantly elevated (P=0.27). The most frequent types of cancer were connective tissue (14% risk by age 70, 95% CI 7.8-24%) and brain tumours (7.9, 95% CI 3.9-16%). There was no statistically significant excess of cancers at other sites (P=0.22).

Watson, K. L., G. A. Al Sannaa, C. M. Kivlin, et al. 2017. "Patterns of recurrence and survival in sporadic, neurofibromatosis Type 1-associated, and radiation-associated malignant peripheral nerve sheath tumors." J Neurosurg 126(1):319-329.

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OBJECTIVE: Malignant peripheral nerve sheath tumors (MPNSTs) are an aggressive group of soft tissue sarcomas that can arise sporadically, in the context of neurofibromatosis Type 1 (NF1) or at a site of prior irradiation. Large series profiling the features and outcomes of sporadic, NF1-associated, and radiation-associated MPNSTs are limited. The goal of this study was to elucidate differences between MPNST etiologies in a large single-institution retrospective study. METHODS: Patients (n = 317) were identified through the tumor registry of The University of Texas MD Anderson Cancer Center. Clinicopathological features were retrospectively collected. Features were compared among MPNST subtypes for patients who had sufficient clinical history (n = 289), and clinicopathological features were used to identify adverse predictors of recurrence and survival outcomes. RESULTS: Five-year local recurrence-free survival (LRFS), distant recurrence-free survival (DRFS), and disease-specific survival (DSS) estimates were 56.6%, 49.6%, and 53.6%, respectively, for the high-grade MPNST cohort. Five-year DSS was lower in NF1-associated and radiation-associated MPNST than in sporadic MPNST (52%, 47%, and 67%, respectively, p = 0.140). Patients with radiation-associated MPNST had worse 5-year LRFS than those with the sporadic and NF1-associated subtypes (RT-associated vs sporadic, p = 0.010; RT-associated vs NF1-associated, p = 0.232). Truncally located tumors, positive surgical margins, local recurrence, and metastasis were predictors of adverse DSS in multivariate analysis. CONCLUSIONS: Radiation-associated MPNSTs are associated with poorer local recurrence-free and disease-specific survival than sporadic and NF1-associated tumors. NF1-associated MPNSTs may have worse survival outcomes owing to large tumor size, compromising truncal location, and lower rate of negative resection margins compared with sporadic tumors.

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