Distinctive Cancer Associations in Patients With Neurofibromatosis Type 1

Uusitalo, Elina; Rantanen, Matti; Kallionpää, Roope A.; Pöyhönen, Minna; Leppävirta, Jussi; Ylä‐Outinen, Heli; Riccardi, Vincent M.; Pukkala, Eero; Pitkäniemi, Janne; Peltonen, Sirkku; Peltonen, Juha

doi:10.1200/jco.2015.65.3576

Cited by 291 publications

(279 citation statements)

References 31 publications

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“…For the vast majority of cases, the aetiology is unknown, although there are certain genetic associations, such as the 10% lifetime risk of malignant peripheral nerve sheath tumour (MPNST) in individuals with familial neurofibromatosis, caused by mutations in the NF1 gene [19, 20]. There is an increased risk of sarcomas, both bone and soft tissue, in patients who have had a familial retinoblastoma, caused by inherited mutations in the RB gene [21].…”

Section: Aetiologymentioning

confidence: 99%

UK guidelines for the management of soft tissue sarcomas

Dangoor¹,

et al. 2016

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Soft tissue sarcomas (STS) are rare tumours arising in mesenchymal tissues, and can occur almost anywhere in the body. Their rarity, and the heterogeneity of subtype and location means that developing evidence-based guidelines is complicated by the limitations of the data available. However, this makes it more important that STS are managed by teams, expert in such cases, to ensure consistent and optimal treatment, as well as recruitment to clinical trials, and the ongoing accumulation of further data and knowledge. The development of appropriate guidance, by an experienced panel referring to the evidence available, is therefore a useful foundation on which to build progress in the field. These guidelines are an update of the previous version published in 2010 (Grimer et al. in Sarcoma 2010:506182, 2010). The original guidelines were drawn up following a consensus meeting of UK sarcoma specialists convened under the auspices of the British Sarcoma Group (BSG) and were intended to provide a framework for the multidisciplinary care of patients with soft tissue sarcomas. This current version has been updated and amended with reference to other European and US guidance. There are specific recommendations for the management of selected subtypes of disease including retroperitoneal and uterine sarcomas, as well as aggressive fibromatosis (desmoid tumours) and other borderline tumours commonly managed by sarcoma services. An important aim in sarcoma management is early diagnosis and prompt referral. In the UK, any patient with a suspected soft tissue sarcoma should be referred to one of the specialist regional soft tissues sarcoma services, to be managed by a specialist sarcoma multidisciplinary team. Once the diagnosis has been confirmed using appropriate imaging, plus a biopsy, the main modality of management is usually surgical excision performed by a specialist surgeon. In tumours at higher risk of recurrence or metastasis pre- or post-operative radiotherapy should be considered. Systemic anti-cancer therapy (SACT) may be utilized in some cases where the histological subtype is considered more sensitive to systemic treatment. Regular follow-up is recommended to assess local control, development of metastatic disease, and any late-effects of treatment. For local recurrence, and more rarely in selected cases of metastatic disease, surgical resection would be considered. Treatment for metastases may include radiotherapy, or systemic therapy guided by the sarcoma subtype. In some cases, symptom control and palliative care support alone will be appropriate.

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Section: Aetiologymentioning

confidence: 99%

UK guidelines for the management of soft tissue sarcomas

Dangoor¹,

et al. 2016

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“…Thus, some 28–52% of patients with MPNSTs also have NF1 (Ducatman et al 1986; Evans et al 2002). The estimated lifetime risk of an MPNST in all NF1 patients is 8–13% (Evans et al 2002, 2012) or 15.8% according to Uusitalo et al (2016). However, individuals with NF1 microdeletions have an even higher lifetime MPNST risk, in the range of 16–26% (De Raedt et al 2003; Mautner et al 2010).…”

Section: Genotype–phenotype Relationships In Patients With Nf1 Microdmentioning

confidence: 99%

Emerging genotype–phenotype relationships in patients with large NF1 deletions

2017

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The most frequent recurring mutations in neurofibromatosis type 1 (NF1) are large deletions encompassing the NF1 gene and its flanking regions (NF1 microdeletions). The majority of these deletions encompass 1.4-Mb and are associated with the loss of 14 protein-coding genes and four microRNA genes. Patients with germline type-1 NF1 microdeletions frequently exhibit dysmorphic facial features, overgrowth/tall-for-age stature, significant delay in cognitive development, large hands and feet, hyperflexibility of joints and muscular hypotonia. Such patients also display significantly more cardiovascular anomalies as compared with patients without large deletions and often exhibit increased numbers of subcutaneous, plexiform and spinal neurofibromas as compared with the general NF1 population. Further, an extremely high burden of internal neurofibromas, characterised by >3000 ml tumour volume, is encountered significantly, more frequently, in non-mosaic NF1 microdeletion patients than in NF1 patients lacking such deletions. NF1 microdeletion patients also have an increased risk of malignant peripheral nerve sheath tumours (MPNSTs); their lifetime MPNST risk is 16–26%, rather higher than that of NF1 patients with intragenic NF1 mutations (8–13%). NF1 microdeletion patients, therefore, represent a high-risk group for the development of MPNSTs, tumours which are very aggressive and difficult to treat. Co-deletion of the SUZ12 gene in addition to NF1 further increases the MPNST risk in NF1 microdeletion patients. Here, we summarise current knowledge about genotype–phenotype relationships in NF1 microdeletion patients and discuss the potential role of the genes located within the NF1 microdeletion interval whose haploinsufficiency may contribute to the more severe clinical phenotype.

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“…MPNST MPNST is a rare tumor occurring in only one per million annually in the general population, and between 20% and 50% of patients with MPNSTs have NF1 (38), with NF1 patients having an 8% to 12% lifetime risk (38,39). MPNSTs are rare in childhood, and a rapidly growing deep-seated tumor with pain or neurologic deficit needs to be investigated.…”

Section: Malignancies In Nf1mentioning

confidence: 99%

“…Women ages 30 to 50 should be advised of the increased breast cancer risks of 4-to 5-fold (39,66) and to access extra breast screening according to guidelines for moderate (20%) lifetime risk or high risk if additional family history of breast cancer. Because of the risk of MPNST being associated with high internal tumor burden, whole-body MRI should be considered between ages 16 and 20 years to assess this (30-32, 52, 67).…”

Section: Recommendations For Transition To Adulthoodmentioning

confidence: 99%

Cancer and Central Nervous System Tumor Surveillance in Pediatric Neurofibromatosis 1

Evans

Salvador

Chang

et al. 2017

Clinical Cancer Research

145

120

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Although the neurofibromatoses consist of at least three autosomal dominantly inherited disorders, neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), and schwannomatosis, NF1 represents a multisystem pleiotropic condition very different from the other two. NF1 is a genetic syndrome first manifesting in childhood; affecting multiple organs, childhood development, and neurocognitive status; and presenting the clinician with often complex management decisions that require a multidisciplinary approach. Molecular genetic testing (see article for detailed discussion) is recommended to confirm NF1, particularly in children fulfilling only pigmentary features of the diagnostic criteria. Although cancer risk is not the major issue facing an individual with NF1 during childhood, the condition causes significantly increased malignancy risks compared with the general population. Specifically, NF1 is associated with highly elevated risks of juvenile myelomonocytic leukemia, rhabdomyosarcoma, and malignant peripheral nerve sheath tumor as well as substantial risks of noninvasive pilocytic astrocytoma, particularly optic pathway glioma (OPG), which represent a major management issue. Until 8 years of age, clinical assessment for OPG is advised every 6 to 12 months, but routine MRI assessment is not currently advised in asymptomatic individuals with NF1 and no signs of clinical visual pathway disturbance. Routine surveillance for other malignancies is not recommended, but clinicians and parents should be aware of the small risks (<1%) of certain specific individual malignancies (e.g., rhabdomyosarcoma). Tumors do contribute to both morbidity and mortality, especially later in life. A single whole-body MRI should be considered at transition to adulthood to assist in determining approaches to long-term follow-up. Clin Cancer Res; 23(12); e46–e53. ©2017 AACR. See all articles in the online-only CCR Pediatric Oncology Series.

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Distinctive Cancer Associations in Patients With Neurofibromatosis Type 1

Abstract: Our results emphasize the general cancer proclivity of patients with NF1. These findings should translate to clinical practices to determine clinical interventions and focused follow-up of patients with NF1.

Cited by 291 publications

References 31 publications

UK guidelines for the management of soft tissue sarcomas

UK guidelines for the management of soft tissue sarcomas

Emerging genotype–phenotype relationships in patients with large NF1 deletions

Cancer and Central Nervous System Tumor Surveillance in Pediatric Neurofibromatosis 1

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