CHAPTER 205 Familial Tumors (Neurocutaneous Syndromes)
Neurofibromatosis Type 1
Epidemiology and Genetics
Neurofibromatosis type 1 (NF1; also known as von Recklinghausen’s disease) is the most common neurocutaneous syndrome, with a prevalence of 1 in 2190 to 7800.1 The NF1 gene encodes the protein neurofibromin; the NF1 mutation responsible for NF1 features autosomal dominant inheritance with complete penetrance but variable expression, although roughly half of cases appear sporadically, probably secondary to new mutations.2–4
The NF1 gene maps to the locus 17q11.2, where it spans more than 350 kilobases of DNA.5 The gene contains 59 exons encoding the protein product neurofibromin.6 Neurofibromin, a 2818–amino acid protein, bears significant homology with members of the guanosine triphosphatase (GTPase)-activating protein (GAP) superfamily, which led it to be dubbed the NF1-GAP–related protein (NF1-GRP).7 This protein interacts with the intrinsic GTPase of p21-Ras-guanosine triphosphate (GTP) by hydrolyzing GTP to guanosine diphosphate (GDP) and thus inactivating p21-Ras.8,9 Because p21-Ras plays a pivotal role in many growth factor signaling pathways, its unregulated function in the absence of neurofibromin—resulting in constitutive p21-Ras activation—leads to an overall tendency toward increased cell proliferation and survival.10,11
Diagnosis
The clinical diagnosis of NF1, as outlined by the National Institutes of Health (NIH) Consensus Development Conference Statement, hinges on the presence of two or more of seven distinct criteria, as noted in Table 205-1.12
TABLE 205-1 Diagnostic Criteria for Neurofibromatosis Type 1
From National Institutes of Health Consensus Development Conference Statement: Neurofibromatosis. Bethesda, Md., USA, July 13-15, 1987. Neurofibromatosis. 1988;1:172.
The aforementioned diagnostic features are the hallmarks of the disease, and the skin findings, in particular, are conducive to accurate identification of this patient population (Fig. 205-1). However, a pitfall in the diagnosis of pediatric patients is that these cutaneous manifestations may develop late and therefore younger affected individuals may appear free of NF1 stigmata. Consequently, the neurosurgeon must be cognizant of NF1 as a possible underlying diagnosis during patient evaluation because it may have an impact on the care of several neurosurgical lesions.
Clinical Features and Management
The care of patients with neurofibromatosis involves multiple medical specialties. Of particular importance to the neurosurgeon is the development of central nervous system (CNS) tumors in this patient population. Older series report an incidence of CNS tumors of roughly 10%, although studies using modern imaging techniques suggest that the rate may be much higher.13–15 The lesions most likely to come to neurosurgical attention include optic gliomas, plexiform or other neurofibromas, brainstem gliomas, and cerebellar gliomas.
Neurofibromas
Neurofibroma, one of the characteristic lesions of NF1, affects the peripheral nerves. Neurofibromas consist of Schwann cells and fibroblasts, in addition to perineural cells, endothelial cells, mast cells, pericytes, and other intermediate cell types; the fundamental architectural feature involves Schwann cells in increased number and with reduced association with axons, along with breakdown of the perineural layer and disorganization of supporting cells.10,16,17 Neurofibromas are nearly ubiquitous in NF1 patients and follow a characteristically indolent and benign course. For this reason, the optimal management of neurofibromas involves careful observation, with surgical intervention reserved for symptomatic cases.
Plexiform neurofibromas pose particular management challenges. These tumors, in contrast to simple neurofibromas, extend across the length of a nerve and involve multiple nerve fascicles or multiple branches of a large nerve, or both, thereby resulting in a potentially sizable mass of diffusely thickened nervous tissue (Fig. 205-2).18 Plexiform neurofibromas were identified on physical examination in 26.7% of individuals in one study and were detected on chest/abdomen/pelvic computed tomographic (CT) scans in the thoracic region of 20% of patients and in the abdomen/pelvis in 44% of patients.19,20 The lesions that are most likely to come to the attention of the neurosurgeon involve the spine or, less commonly, the brachial plexus.
FIGURE 205-2 Coronal magnetic resonance imaging scan showing plexiform neurofibroma affecting every nerve root.
Plexiform neurofibromas pose an unusual management challenge because they frequently involve nerve roots at multiple levels, which in turn leads to extensive spinal compression and resultant myelopathy and quadriparesis/paraparesis.21–23 The surgical goal of treatment in such cases is control of symptoms because these lesions are not amenable to cure without the profound, unacceptable morbidity associated with the resection of nerve roots at multiple levels. However, good results can be obtained with laminectomy for debulking and decompression of the involved spinal levels. Loss of neurological function is rare after surgery.22,24 Regrowth of tumor with recurrence of symptoms has been noted, with secondary reoperation typically providing some benefit. Progressive kyphosis is also a significant concern after multilevel laminectomies, and patients may require subsequent spinal fusion. Most authors, however, do not advocate undertaking fusion at the time of initial resection, and the risk for progression of kyphosis may be reduced with the use of osteoplastic laminotomy techniques to preserve some degree of competency of the posterior elements.21–25 Standard recommendations do not include routine spinal imaging for NF1 patients because the symptoms, not imaging characteristics, ultimately determine surgical management.22
Neurofibromas also carry the potential for degeneration to malignant peripheral nerve sheath tumors (MPNSTs). Independent studies have recently shown the lifetime risk for MPNST in NF1 patients to be 8% to 13% and 5.9% to 10.3%.15,26 Although conventional wisdom holds that these tumors affect adults with NF1, in 35% of patients with MPNST lesions first developed when younger than 20 years.27 In a more recent study, 15% of MPNST patients were initially seen when younger than 17 years and had a mean survival time of 30.5 months.28 In both studies, MPNSTs arose primarily from nodular neurofibromas or plexiform neurofibromas, with pain or enlargement of a mass being the typical initial signs. Although MPNST may be infrequent, an awareness of its relationship to neurofibromas in NF1 is essential because the possibility of underlying malignant degeneration might influence the surgeon to pursue earlier, more aggressive resection of plexiform or simple neurofibromas.
Optic Gliomas
Gliomas of the anterior optic pathway occur in up to 15% of NF1 patients and commonly affect the optic nerve or chiasm or the hypothalamus.14 Unlike sporadic optic pathway gliomas, which are seen almost exclusively in children younger than 7 years, optic gliomas in NF1 may occur at any time.29 Symptoms referable to these lesions include headache, visual complaints, proptosis, endocrine disturbances, and other findings stemming from local mass effect or hydrocephalus. Magnetic resonance imaging (MRI) is the preferred imaging modality for these lesions and may be useful in prognostication: evidence suggests that nonenhancing optic gliomas—which may constitute almost 60%—do not progress.30 The optic pathway gliomas in patients with NF1 are usually World Health Organization (WHO) grade I astrocytomas, although a recent study reported higher grade lesions occurring in this region as well.29,31
As with most neurosurgical lesions in patients with NF1, the optimal treatment strategy for optic gliomas probably involves conservative monitoring until MRI progression is documented or symptoms develop. However, treatment of optic gliomas in NF1 patients may be distinct from that of patients with sporadic optic gliomas in that the former patients may exhibit a much more indolent clinical course.32–41 A recent systematic review of prognostic factors in patients with optic pathway gliomas demonstrated the complex nature of this issue: although multiple studies have claimed NF1 to be prognostically beneficial, all but one had significant methodologic limitations, including a failure in some cases to differentiate NF1 status from tumor site or age in prognostication.42 Most authors recommend surgical intervention only in patients with an atypical appearance on MRI—which should encourage biopsy—or in patients with progressive symptoms, for which craniotomy and debulking should be undertaken.30,43 Subtotal resection may be acceptable or even preferable, given the significant morbidity associated with aggressive resection near the optic apparatus. Adjuvant therapy typically involves chemotherapy, with vincristine and carboplatin being first-line agents.44 Radiation therapy can also be considered but carries with it the risks of radiation necrosis, cognitive problems, visual loss, secondary malignancy, and even moyamoya disease.43,45 In planning optimal therapy, one must remain cognizant of the potential for lesion stability or even regression of lesions in NF1 patients.30,46
Brainstem Gliomas
Although brainstem gliomas (Fig. 205-3) generally represent one of the more malignant of childhood neoplasms, neurofibromatosis has long been recognized as a favorable prognostic indicator.47 In fact, studies have demonstrated that the brainstem gliomas in NF1, with their characteristically indolent course, exhibit such drastically different behavior from their counterpart lesions in non-NF1 patients that it could be suggested that they are entirely unique clinical entities. One concern in evaluating the natural history of these lesions arises in differentiating them from “unidentified bright objects” (UBOs) of the brainstem, which occur in more than half of NF1 patients and commonly involve the brainstem yet have no apparent predilection for evolving into gliomas. Inclusion of these UBOs in a study of the natural history of brainstem gliomas will lead to erroneous conclusions regarding the indolence of this type of tumor. Several studies have sought to separate these UBOs from actual gliomas and have still found gliomas to follow an indolent course. Indeed, brainstem gliomas in NF1 have been shown to undergo radiographic progression in less than 50% of cases and clinical progression in less than 20% of cases, irrespective of intervention with surgery, chemotherapy, or radiation therapy.48–50 A recent study restricted to the clinical outcomes of 23 patients with expansile brainstem lesions demonstrated that all but 1 exhibited clinical stability or regression over a median follow-up period of 67 months.50 It seems that current evidence suggests taking a conservative approach by monitoring these lesions with serial MRI and undertaking therapy only in the event of clear progression.
It is important to note that NF1 patients with brainstem gliomas will frequently have synchronous tumors at other locations in the CNS, including the optic pathways.50
Cerebellar Gliomas
The true incidence of cerebellar gliomas in patients with NF1 is not clear, although it has been estimated that a 10th of pediatric cerebellar gliomas are associated with NF1.51 The pathologic spectrum of these lesions includes pilocytic astrocytoma most commonly, although anaplastic astrocytoma, ganglioglioma, and pleomorphic xanthoastrocytoma have also been described.13,51–54 Several differences between cerebellar gliomas in NF1 and sporadic cerebellar gliomas have been highlighted. Anatomically, these lesions often occur in the subependymal white matter of the fourth ventricle, in contrast to the typical vermian or hemispheric location of sporadic gliomas.51 In terms of their clinical behavior, some authors have suggested that NF1-associated cerebellar gliomas exhibit a more malignant phenotype than the sporadic subtype, although modern clinical series have not necessarily borne this out.13,51,55 One point that seems less controversial relates to the management of cerebellar gliomas in NF1 patients: in contrast to the wait-and-see approach for optic or brainstem gliomas, cerebellar lesions should be resected whenever clinically feasible because their anatomic location is more amenable to complete resection, which will in many cases be curative. The pathologic grade of the lesion dictates the need for further adjuvant therapy.
Additional Features
Patients with NF1 suffer from a variety of other conditions, including macrocephaly or learning disabilities, or both, in nearly 50% and short stature or scoliosis, or both, in more than 20%.3 For a time it was thought that the learning disabilities might correlate with T2 signal abnormalities on MRI (UBOs), but studies have borne out an association only with bright lesions in the thalamus, not in other brain regions.56,57 Other authors, however, have suggested that UBOs might not be benign but instead might pose a risk for malignant transformation and hence deserve close follow-up with serial MRI.58,59 Recently, medulloblastomas have been proposed as an additional tumor to which NF1 patients may have a predisposition.60
Although there is a rare association between NF1 and moyamoya disease,61 some controversy exists regarding whether NF1 patients have a predilection for the development of intracranial aneurysms. Even though some case reports demonstrate the presence of aneurysms and aneurysmal subarachnoid hemorrhage in NF1 patients,62,63 a more exhaustive autopsy series has failed to demonstrate any association.64
Neurofibromatosis Type 2
Epidemiology and Genetics
Neurofibromatosis type 2 (NF2) is a disorder of autosomal dominant inheritance that affects 1 in 33,000 to 40,000 individuals, with 99% penetrance by the age of 60.65 Like NF1, NF2 patients have a predilection for intracranial, ocular, and skin lesions. Skin findings are less characteristic of NF2 than NF1, but clinical investigation has demonstrated a surprisingly high 60% incidence of skin tumors, including schwannomas, neurofibromas, and mixed tumors as well. Café au lait spots, too, are evident in a third of patients.66 The prototypical and pathognomonic finding in NF2 patients, however, remains the presence of bilateral acoustic schwannomas.
NF2 was first identified as having a distinct genetic basis from NF1 when the NF2 gene was mapped to chromosome 22, where it encodes a cytoskeletal protein dubbed merlin or schwannomin.67–69 Interestingly, the type of mutation in the NF2 gene appears to dictate disease severity, with single-codon/single–amino acid missense alterations, somatic mosaicism, splice site mutations, or large deletions (leading to no protein product) resulting in mild phenotypes. Protein-truncating mutations and frameshift mutations result in a severe phenotype.70–73 Ongoing studies have attempted to elucidate the role of the merlin protein, with evidence that it senses intercellular contact and regulates mitogenic signaling, as well as directs the function of membrane receptors active in cell proliferation and differentiation.74
Diagnosis
With the exception of patients with bilateral vestibular schwannomas, which are pathognomonic for NF2, the optimal diagnostic criteria for this disease remain in flux; current criteria are shown in Table 205-2.12,75 In evaluating the sensitivity and specificity of the four sets of criteria proposed for the diagnosis of NF2 (NIH 1987 and 1991, Manchester, and National Neurofibromatosis Foundation), Baser and colleagues found surprisingly low sensitivity—less than 15%—for each set of criteria in the initial assessment of 163 patients with NF2 but without bilateral acoustic neuromas.76 These sensitivities improved over time as patients were monitored longitudinally, but it is clear that the current criteria may not adequately address the diagnostic challenge posed by this disease.
TABLE 205-2 Diagnostic Criteria for Neurofibromatosis Type 2
| 1991 NATIONAL INSTITUTES OF HEALTH CRITERIA |
Data from National Institutes of Health Consensus Development Conference Statement: Neurofibromatosis. Bethesda, Md., USA, July 13-15, 1987. Neurofibromatosis. 1988;1:172; and Mulvihill JJ, Parry DM, Sherman JL, et al. NIH conference. Neurofibromatosis 1 (Recklinghausen disease) and neurofibromatosis 2 (bilateral acoustic neurofibromatosis). An update. Ann Intern Med. 1990;113:39.
Clinical Features and Management
NF2 patients may initially be seen with the following lesions: vestibular schwannomas, other schwannomas, meningiomas, gliomas, neurofibromas, and cataracts. Because of the varied clinical manifestations of NF2, referral to tertiary care centers for multidisciplinary management is vital for successful patient outcomes and has been identified, along with age at diagnosis, presence of intracranial meningiomas, and type of NF2 mutation, as one of the primary determinants of risk for mortality.77,78
A detailed discussion of the general management of vestibular schwannomas can be found elsewhere in this text. However, the occurrence of vestibular schwannomas in NF2 patients, especially when bilateral, can pose unique clinical challenges for the neurosurgeon. Vestibular schwannomas develop in more than 95% of NF2 patients and are commonly manifested as deafness (most often unilateral), tinnitus, and vertigo.79–81
The frequent bilaterality of vestibular schwannomas has generated controversy regarding optimal management strategies. Large tumors causing brainstem compression present less of a management dilemma because they should be resected microsurgically to prevent progressive neurological deficits. Conversely, smaller tumors that cause either no symptoms or only audiologic symptoms continue to confound the development of universal management guidelines. Complicating the planning of management strategies is the fact that the natural history of vestibular schwannomas in patients with NF2 remains somewhat unclear, with discordant findings in recent longitudinal studies; however, a recent review evaluating four recent studies does show that although significant variability exists, the growth rates of these tumors tend to decrease with increasing age.82–86 In any case, a multidisciplinary approach to care should be used, and consideration must also be given to patient and family education in sign language to facilitate ongoing communication. Recently, additional concern has been raised with regard to the risk associated with stereotactic radiosurgery in patients genetically predisposed to malignancy because of some evidence suggesting that secondary tumors such as MPNSTs or sarcomas might develop as a result of exposure to radiation (although this link is far from certain).87–90 The possibility of inducing a malignancy after treating a benign lesion again highlights the need for the treating physician to be cautious in the management of this complex disease entity.
The prevalence of posterior subcapsular opacities, which affect roughly 80% of NF2 patients, presents an important clinical consideration because preservation of vision becomes paramount in patients for whom hearing will probably be imperiled.81,91
