SPECIFIC TUMOURS TYPES IN NF1
Neurofibromas are benign Tumours that usually involve the skin, although they can be subcutaneous or, rarely, visceral. Solitary neurofibromas may occur in an individual without a germline NF1 mutation. The number of cutaneous neurofibromas increases with advancing age but shows a wide variation (Huson et al. 1989) (Fig. 1). Two types of neurofibroma are distinguished: the common discrete variety in which the lesion arises from a single site along a peripheral nerve and has well-defined margins. Cutaneous neurofibromas are usually present in adults with NF1 and are most common on the trunk. About 20 % have head and neck lesions, and more than 100 neurofibromas are found in most older patients. Though cutaneous neurofibromas usually do not become apparent until puberty but can continue to increase in size and number throughout adulthood.
Plexiform neurofibromas are peripheral nerve Tumours that extend along the nerve and can involve multiple nerve branches. Plexiform neurofibromas are often associated with local soft tissue overgrowth and, when the cranial nerves are involved, cause marked disfigurement. Plexiform neurofibromas appear as large, soft, subcutaneous swellings with ill-defined margins and may be present in about 25 % of NF1 patients (usually on the trunk), but facial involvement is rare (Huson et al. 1988). The principal complication of neurofibromas is cosmetic disfigurement, but there is also the risk of malignant change (malignant peripheral nerve sheath Tumours, MPNST) (Evans et al. 2002; De Raedt et al. 2003). Malignant change is usually signaled by pain and rapid increase in size, and all patients should be alerted to the significance of these events. Plexiform neurofibroma is locally aggressive and may grow along the nerve of origin to involve the spinal cord or brain. The risk of malignant change was estimated to be 2–4 % (Huson et al. 1988), but a population-based longitudinal study reported a lifetime risk of 8–13 % (median age at diagnosis 26 years) (Evans et al. 2002).
Optic glioma is the most frequently reported CNS lesion in NF1, and about a third of children with optic glioma have NF1. Estimates of the incidence of optic glioma in NF1 patients vary: Huson et al. (1988) found in a population-based study that less than 2 % of patients with NF1 had asymptomatic glioma, but Lewis et al. (1984) observed a frequency of up to 15 % with routine cranial magnetic resonance imaging. Symptomatic optic gliomas usually present before 6 years of age. Histologically, optic gliomas are pilocytic astrocytomas, and these are generally nonprogressive Tumours and are usually treated conservatively.
Other CNS gliomas reported in NF1 include brain stem gliomas, pilocytic astrocytomas of the hypothalamus and third ventricle, and, infrequently, diffuse gliomas of the cerebral hemispheres, cerebellum, or spinal cord.
Although brain stem glioma may produce aqueduct stenosis and hydrocephalus, NF1 patients are also at risk for nonneoplastic lesions, such as dural ectasia and aqueduct stenosis without mass lesions. NF1 is a well-recognized, but infrequent, the cause of pheochromocytoma.
The most frequent age at diagnosis of phaeochromocytoma in NF1 patients is in the fifth decade (Walther et al. 1999b). Onset before the age of 20 years is uncommon, and this tumour is virtually unknown in childhood (Knudson and Strong 1972).
The other endocrine Tumours that have been associated with NF1 is duodenal carcinoid. Typically, this is somatostatinoma with distinctive histological appearance (psammoma bodies) and somatostatin immunoreactivity (Griffiths et al. 1987; Swinburn et al. 1988). A variety of embryonal Tumours have been reported in children with NF1, including rhabdomyosarcoma, Wilms Tumours, and neuroblastoma (McKeen et al. 1978; Hartley et al. 1988). In addition, children with NF1 are predisposed to myeloid malignancies (200–500 times the normal risk), particularly juvenile myelomonocytic leukemia (Bader and Miller 1978; Clark and Hutter 1982).
The NF1 gene maps to chromosome 17 and was identified in 1990 (Wallace et al. 1990; Viskochil et al. 1990). The NF1 gene product (neurofibromin) is a negative regulator of Ras GTPase proteins, and the NF1 gene appears to function as a classical Tumours suppressor gene such that NF1 wild-type allele loss has been detected in both malignant neurofibroma. NF1 is a large gene (61 exons contained within 300 kb of DNA) and has a high mutation rate. De novo mutations usually arise in the paternal germline though microdeletions may be most often of maternal origin. Comprehensive mutation analysis can identify NF1 mutations in >90 % of patients satisfying NIH diagnostic criteria (Boyd et al. 2009). Mutation analysis of the NF1 gene is helpful in individuals who do not fulfill clinical diagnostic criteria or if prenatal or preimplantation diagnosis is being considered. Though in general the precise nature of an NF1 mutation does not correlate with clinical phenotype, up to 5 % of cases have a complete NF1 gene deletion which is associated with increased numbers of neurofibromas, more severe intellectual impairment, facial dysmorphisms, and increased risk of MPNST. Germline mutations in SPRED1 cause Legius syndrome which is characterized by similar cutaneous findings to NF1 (multiple cafe-au-lait macules and axillary freckling) but not Lisch nodules or neurofibromas.
Patients with NF1 should be kept under surveillance, with annual clinical examination (every 2 years in children), but routine biochemical or radiological screening is probably not indicated in a service setting (Huson et al. 1988). The affectation status for most at-risk relatives can be reliably established on clinical criteria because penetrance is close to 100 % for offspring of unequivocal cases (Riccardi and Lewis 1988). Although presymptomatic diagnoses of NF1 by mutation analysis or linked DNA markers should be possible for most cases, it is not usually undertaken unless clinical diagnostic criteria are equivocal. Although detection of a NF1 mutation might allow prenatal diagnosis, a limitation of molecular genetic testing is that the severity of the disorder usually cannot be predicted as NF1 characteristically has very wide variations in expression. Parents of apparently sporadic cases should undergo the careful assessment for subclinical signs of NF1 (e.g., detailed skin examination with Wood’s light and ophthalmological testing for Lisch nodules). Mosaic NF1 may be segmental, generalized (when a disease is usually mild) or gonadal. Segmental mosaics present with localized cutaneous involvement (CALs/neurofibromas).