Genetic Tumor Syndromes Involving the CNS

Main Text

Preamble

Historically, few CNS neoplasms were thought to result from a genetic predisposition to tumorigenesis. Within the last decade, new DNA sequencing methods and methylome profiling have led to increasing recognition and definition of high-risk cancer predisposition syndromes. Recent studies identified a cancer predisposition syndrome in 7-15% of pediatric patients with newly diagnosed CNS tumors. In certain tumor types (i.e., choroid plexus carcinoma), the predisposition rate can approach 50%.

The term familial cancer predisposition syndrome is used to describe familial cancers in which a clear mode of inheritance can be established. The CNS and PNS are frequently involved in these disorders. The 2021 WHO now classifies such familial cancers with CNS &/or PNS neoplasms as genetic tumor syndromes involving the CNS. While many of the index neoplasms occur sporadically and are described in detail in previous chapters of this book, here we consider the clinical spectrum, pathogenesis, and molecular genetics of syndromic-associated nervous system tumors.

Cancer predisposition syndromes are caused by pathogenic variation in genes that primarily function as tumor suppressors and protooncogenes. These variants are found in the germline or constitutional DNA. New insights into the underlying mechanisms of these cancer predisposition syndromes have used CRISPR/Cas9 gene-editing tools to model these disorders.

To date, 19 genetic tumor syndromes involving the CNS—including eight new ones since the 2016 WHO classification of CNS tumors—are formally recognized. In this chapter, we consider the major familial tumor syndromes that involve the nervous system, beginning with the neurofibromatoses. Major attention is also directed to tuberous sclerosis, von Hippel-Lindau disease (VHL), Li-Fraumeni syndrome, and constitutional mismatch repair deficiency (CMMRD) syndromes.

Some uncommon but nevertheless important syndromes, such as Turcot, Gorlin, and Cowden syndromes, rhabdoid tumor predisposition syndrome, DICER1 syndrome, familial retinoblastoma (RB), and BAP1 tumor predisposition syndrome, are also briefly considered in this chapter.

Neurofibromatosis and Schwannomatosis

Preamble

Neurofibromatoses are the most common CNS tumor predisposition syndromes. Two types of neurofibromatosis are widely recognized: Neurofibromatosis type 1 (NF1)and neurofibromatosis type 2 (NF2). Both are multisystem disorders with neoplastic as well as nonneoplastic manifestations. A third related disorder, schwannomatosis, is associated with inactivation of the NF2 gene in tumors (but not in the germline) and is considered a distinct genetic disease, so it, too, is included in this section.

Neurofibromatosis Type 1

NF1 is an autosomal dominant inherited genodermatosis and tumor predisposition syndrome with variable expression, a high rate of new mutations (nearly 50%), and virtually 100% penetrance by age 20.

Etiology

Genetics

A pathogenic NF1 variant is detected in > 95% of people with NF1. NF1 is caused by mutation of the NF1 gene on chromosome 17q11.2. Mutations inactivate the gene that encodes the tumor suppressor protein, neurofibromin 1, a negative regulator of the Ras signal transduction pathway that plays a key role in both tumor suppression and regulation of cell growth/proliferation. Neurofibromin also acts as a regulator of neural stem cell proliferation and differentiation; it is required for normal glial and neuronal development (44-1).

Approximately 1/2 of all NF1 cases are familial. Such patients already harbor a heterozygous germline NF1 mutation and develop neurofibromas upon somatic mutation of the second (wildtype) NF1 allele. Nearly 1/2 the individuals with NF1 have unaffected parents. These NF1 cases are caused by a pathogenic, de novo mutation in the NF1 gene.

Pathology

CNS lesions are found in 15-20% of patients. A variety of nonneoplastic lesions as well as benign and malignant tumors are associated with NF1. There is also an increased risk of non-CNS malignancies in NF1 patients.

Nonneoplastic CNS Lesions

Multiple waxing and waning cerebral dysplastic white matter (WM) lesions on T2/FLAIR are identified in ~ 70% of children with NF1(44-9). Histopathologically, these benign lesions—also called unidentified bright objects (UBOs) or focal areas of signal intensity (FASIs)—represent zones of myelin vacuolization and dysgenesis, not hamartomas, demyelination, or axonal degeneration (44-8). These lesions do not enhance with contrast and follow a benign course, initially waxing and then completely regressing by 20 years. Similar T2-hyperintense, nonenhancing lesions are seen in the spinal cords of 8% of children with NF1 (all reported cases exhibited similar brain T2 hyperintensities).

Dural ectasia may cause dilatation of the optic nerve sheaths, Meckel cave, or internal auditory canals (44-6). Spinal abnormalities, including dural ectasia, meningoceles, and bony deformities, occur in ~ 15% of patients with classic NF1(44-5) (44-4).

NF1 is associated with CNS vasculopathy in 2-6% of cases. A variety of vascular abnormalities, including vessel ectasia, moyamoya, hypoplasia, and vessel narrowing, have been associated (44-7). The most common manifestation is progressive intimal fibrosis with stenoocclusion of the supraclinoid internal carotid arteries, resulting in moyamoya disease (MMD). MMD can cause both ischemic and hemorrhagic strokes.

CNS Neoplasms

Patients with NF1 have a high risk for developing a spectrum of neoplasms in the CNS and PNS. CNS tumors occur in ~ 20% of individuals with NF1 and are a pathologically and biologically heterogeneous group of neoplasms.

Optic pathway gliomas (OPGs)—nearly always pilocytic astrocytomas—account for ~ 70% of all CNS tumors in children with NF1(44-15). The second most common brain tumor is brainstem glioma (15-17%).

Benign NF1-related neoplasms include neurofibromas. Malignant tumors include malignant peripheral nerve sheath tumors (MPNSTs) and gliomas.

Neurofibromas

A spectrum of NF1-associated neurofibromas occurs. Dermal neurofibromas arise within a peripheral nerve and appear as soft, well-circumscribed, pedunculated or sessile lesions. Most patients develop more tumors as they age, and some have literally thousands of dermal neurofibromas (44-2) (44-22). More than 95% of adults with NF1 have at least one lesion.

Plexiform neurofibromas (PNFs) are distinct from dermal neurofibromas and are virtually pathognomonic of NF1. PNFs develop in 30-50% of individuals with NF1. PNF and atypical neurofibromatous neoplasm of unknown biologic potential (ANNUBP) are considered precancerous lesions that may develop into MPNSTs.

PNFs are generally large, bulky tumors usually associated with major nerve trunks and plexuses. PNFs are rope-like, diffusely infiltrating, noncircumscribed, transspatial lesions that resemble a bag of worms (44-10). The scalp and orbit are common sites for PNFs. Spinal neurofibromas and PNFs are found in ~ 40% of patients with NF1(44-13).

Malignant Peripheral Nerve Sheath Tumors

Although most PNFs remain benign, 10-15% become malignant. Individuals with NF1 have an 8-13% cumulative lifetime risk of developing an MPNST from a PNF (44-14). MPNST is an aggressive, deadly tumor with a high rate of metastases and poor overall prognosis.

Gliomas

Individuals with NF1 are prone to develop a wide variety of glial neoplasms. Gliomas arising in the setting of NF1 are a heterogeneous group of neoplasms that occur from childhood throughout adulthood. NF1-associated gliomas can arise anywhere in the neuraxis, including the optic pathway and spinal cord. These tumors can be histologically low or high grade and vary in biologic behavior from indolent to extremely aggressive.

Two different molecular subgroups of NF1-associated gliomas have been recently identified. Molecular low-grade NF1-associated gliomas—usually pilocytic astrocytomas (44-17), less commonly diffuse astrocytomas or gangliogliomas—occur primarily in children, can be found throughout the neuraxis, and generally behave in an indolent manner. The most common site is the optic pathway; the second most common site is the brainstem.

NF1-associated OPGs can be uni- or bilateral and may involve any part of the optic pathway. Some OPGs affect just the optic nerve, whereas others involve the optic chiasm and optic tracts (44-16). 2/3 of children with NF1-associated OPGs will not require an intervention, and some have even been reported to spontaneously regress over time. Less often, other low-grade gliomas in children with NF1 are found in the cerebral hemispheres, thalamus/brainstem, cerebellum, and spinal cord.

Molecular high-grade NF1-associated gliomas occur primarily during adulthood (mean age: 28 years), occur outside the optic pathway, and are histologically and genetically more diverse. These tumors are typically IDH1-wildtype, independent of histology (44-18). The most common genetic variants are NF1, EGFR, FGFR3, ATRX, CDKN2A/CDKN2B, TP53, TERT, and MSH2/MSH3 mutation.

Over 70% of adult NF1-associated gliomas involve midline structures, including the basal ganglia, thalamus and hypothalamus, corpus callosum, brainstem, cerebellar peduncles/vermis, or spinal cord. Adult NF1-associated gliomas often have an aggressive clinical course even if they are histologically low-grade lesions (44-19).

Most adult NF1-associated neoplasms are high-grade astrocytomas with piloid features (HGAPs)or IDH-wildtype glioblastomas (44-20). Whole-genome DNA methylation patterns have identified a specific HGAP subtype that is enriched in patients with NF1, is confined to the posterior fossa, and has decreased progression-free survival (44-21).

Rare NF1-associated tumors also include more difficult-to-classify gliomas with ambiguous features (44-19). Some exhibit morphologic similarities to subependymal giant cell astrocytomas (SEGAs) while others are high-grade astrocytomas, such as giant cell glioblastoma or anaplastic pleomorphic xanthoastrocytoma (44-24).

NF1-associated gliomas of the medulla, tectum, and pons are typically indolent neoplasms.

Non-CNS Neoplasms

NF1 is associated with an increased risk of leukemia (especially juvenile myelomonocytic leukemia and myelodysplastic syndromes), gastrointestinal stromal tumors (6%), breast cancers and adrenal or extraadrenal pheochromocytoma (0.1-5.0%). In children with multiple café au lait spots and malignant tumors, such as leukemia, the WHO suggests constitutive mismatch repair deficiency should also be considered.

Patients with NF1 have up to a 5x increased risk of breast cancer before age 50. Recent studies also suggest cutaneous and CNS lymphomas can also be associated with NF1. As these patients often have skin lesions &/or cutaneous/subcutaneous nodules or other tumors like neurofibromas, their prevalence may be underdiagnosed.

Clinical Issues

Presentation

NF1 is one of the most common CNS single-gene disorders, affecting 1:3,000 live births.

Characteristic features include cutaneous neurofibromas (present in almost all adults with NF1), hyperpigmentary skin abnormalities with café au lait macules (95%) (44-2), inguinal/axillary freckling (65-85%), and iris hamartomas or Lisch nodules (44-3). Funduscopic examination using near-infrared reflectance demonstrates bright, patchy choroidal nodules in 70% of pediatric patients and 80% of adults.

Other less common NF1-associated features include distinctive skeletal abnormalities, such as sphenoid dysplasia (3-11%), long bone deformities (1-4%), pseudarthroses, and progressive kyphoscoliosis (44-4). Cardiovascular anomalies occur in ~ 25% of individuals with NF1. Conotruncal cardiac defects, pulmonary valvular stenosis, and arterial hyperplasia are typical anomalies.

Clinical Diagnosis

Criteria for the clinical diagnosis of NF1 were originally established in 1988 by a National Institutes of Health (NIH) consensus conference. In the past, two or more of seven listed criteria must be met for a definitive diagnosis of NF1 to be made. However, many of these features are age dependent; nearly 1/2 of patients who are diagnosed with NF1 later in life do not meet these strict diagnostic criteria. Diagnostic consensus criteria for NF1 were revised in 2021 and now include detection of a pathogenic variant in the NF1 gene, which allows for early diagnosis in young children without a family history of the disease. The revised diagnostic criteria also include choroidal anomalies as a new ophthalmic symptom with high sensitivity and specificity for NF1.

Molecular diagnostic testing can distinguish NF1 from other disorders that share similar phenotypic features. With the exception of PNF, most clinical stigmata of NF1 also occur in other disorders (e.g., multiple café au lait macules in McCune-Albright syndrome). The new 2021 revised consensus criteria for the clinical diagnosis of NF1 are summarized in the next box.

Natural History

Prognosis in NF1 is variable and relates to its specific manifestations. Malignant gliomas and MPNSTs represent the two most common causes of cancer-related mortality for NF1 patients.

The foci of myelin vacuolization increase in number and size over the first decade, then regress, and eventually disappear. They are rarely identified in adults.

Imaging

Nonneoplastic CNS Lesions

Bone dysplasias occur in the skull, spine, and long bones (e.g., pseudarthroses). NECT scans may demonstrate a hypoplastic sphenoid wing and enlarged middle cranial fossa, with or without an associated arachnoid cyst (44-23). Protrusion of the anterior temporal lobe may result in ipsilateral proptosis. The globe is frequently enlarged (“buphthalmos”) (44-11)and a PNF is often present (44-12).

Dural dysplasia with patulous spinal dura as well as enlarged optic nerve sheaths, internal auditory canals, and Meckel caves can occur (44-6).

Dysplastic WM lesions (often termed “FASIs” for foci of abnormal signal intensity) are seen as multifocal hyperintensities on T2/FLAIR imaging (44-8). These foci represent zones of myelin vacuolization and are seen in 70% of children with NF1. They generally increase in size and number until ~ 10 years of age but then wane and disappear (44-9).

The most common sites are the globi pallidi (GP), centrum semiovale, cerebellar WM, dentate nuclei, thalamus, and brainstem (44-8). Most are smaller than 2 cm in diameter. Most FASIs are iso- or minimally hypointense on T1WI, although GP lesions are often mildly hyperintense. FASIs do not enhance following contrast administration.

Relentless endothelial hyperplasia can cause progressive stenosis of the intracranial internal carotid arteries, resulting in a moyamoya pattern. Careful scrutiny of the intracranial vasculature demonstrates attenuation of the middle cerebral artery “flow voids”(44-7)

CNS Neoplasms

Neurofibromas

Patients with cutaneous neurofibromas often demonstrate solitary or multifocal, discrete, round or ovoid scalp lesions that are hypointense to brain on T1WI and hyperintense on T2WI (44-22). A target sign with a hyperintense rim and relatively hypointense center is common. Strong but heterogeneous enhancement following contrast administration is typical.

PNFs are most common in the orbit, where they are seen as poorly marginated serpentine masses that infiltrate the orbit, extraocular muscles, and eyelids (44-10) (44-23). They often extend inferiorly into the pterygopalatine fossa and buccal spaces as well as superiorly into the adjacent scalp and masticator spaces. PNFs enhance strongly and resemble a bag of worms (44-12).

Malignant Peripheral Nerve Sheath Tumors

MPNSTs arising within a PNF can be difficult to detect and to differentiate from the parent tumor. MPNSTs tend to be more heterogeneous in signal intensity, often exhibiting intratumoral cysts, perilesional edema, and peripheral enhancement.

Gliomas

The most common NF1-associated glioma is pilocytic astrocytoma. Optic pathway glioma (OPG) is the most frequent type and occurs as a diffuse, fusiform, or bulbous enlargement of one or both optic nerves (44-15). Tumor may extend posteriorly into the optic chiasm, superiorly into the hypothalamus, and involve the optic tracts and lateral geniculate bodies. Extensive lesions can reach the cerebral peduncles and brainstem (44-16).

Most OPGs are isointense with brain on T1WI and iso- to moderately hyperintense on T2WI. Enhancement on T1 C+ FS scans varies from none to striking.

NF1-associated pediatric-type diffuse low-grade gliomas can be difficult to distinguish from FASIs. They are usually moderately hypointense on T1WI and hyperintense on T2WI, do not resolve spontaneously, and show slow progression on follow-up imaging.

High-grade astrocytoma with piloid features and glioblastoma are more aggressive, more heterogeneous tumors that demonstrate relentless progression (44-18) (44-21). A progressively enlarging mass that enhances following contrast administration in a child with NF1 should raise suspicion of malignant neoplasm.

Differential Diagnosis

In combination with appropriate clinical findings, the presence of FASIs on MR with or without OPG is diagnostic of NF1. Unusually large FASIs can cause mass effect and mimic  neoplasm  (i.e., pilocytic astrocytoma, diffuse astrocytoma). While FASIs and astrocytomas are both part of the NF1 spectrum, FASIs typically do not enhance.

Neurofibromatosis Type 2

Neurofibromatosis type 2 (NF2) is a distinct syndrome with totally different mutations, clinical features, and imaging findings from NF1. Neurofibromas characterize NF1 and are composed of Schwann cells and fibroblasts. Schwannomas—especially bilateral vestibular schwannomas (VSs)—are the major feature of NF2. Schwannomas contain only Schwann cells.

The associated neoplasms are also different from those in NF1. Astrocytomas are found in NF1, whereas ependymomas and meningiomas are the predominant tumors in NF2.

Etiology

General Concepts

Like NF1, NF2 is an autosomal dominant disorder. About 1/2 of all cases occur in individuals with no family history of NF2 and are caused by newly acquired germline mutations.

Genetics

NF2 is caused by mutations of the NF2 gene on chromosome 22q12.2. The NF2 gene encodes the protein merlin, which functions as a tumor suppressor gene and is a negative regulator of mTORC1. Inactivating NF2 mutations cause loss of merlin and result in predominantly benign neoplasms (schwannomas and meningiomas). Biallelic NF2 inactivation is also detected in 60% of sporadic meningiomas and nearly all schwannomas.

Pathology

Location

The most common NF2-related schwannomas are VSs (44-25). Approximately 50% of patients also have nonvestibular schwannomas (NVSs). The most common locations for NVSs are the trigeminal and oculomotor nerves (44-27). Trochlear and lower cranial nerve schwannomas occur but are rare.

Meningiomas occur in ~ 1/2 of all patients with NF2 and can be found anywhere in the skull and spine. The most frequent sites are along the falx and cerebral convexities.

Intracranial ependymomas are rare in NF2. Most are found in the spinal cord, especially within the cervical cord or at the cervicomedullary junction.

Size and Number

NF2-related schwannomas, meningiomas, and ependymomas are often multiple. The presence of bilateral VSs is pathognomonic of NF2(44-26).

Size varies from tiny to several centimeters. Innumerable tiny schwannomas (“tumorlets”) throughout the cauda equina are seen in the majority of patients. Intramedullary ependymomas are often small; multiple tumors are present in nearly 60% of patients.

Gross Pathology

NF2 is characterized by multiple schwannomas, meningiomas, and ependymomas. Virtually all patients have bilateral VSs, the hallmark of NF2(44-26). Most schwannomas are well-delineated, round or ovoid, encapsulated masses that are attached to—but do not infiltrate—their parent nerves.

Multiple meningiomas are the second pathologic hallmark of NF2(44-28). They are found in ~ 50% of patients and may be the presenting feature (especially in children). Meningiomas appear as unencapsulated but sharply demarcated masses.

Microscopic Features

Schwannomas are composed of neoplastic Schwann cells. Areas of alternating high and low cellularity (Antoni A pattern) are admixed with foci that exhibit microcysts and myxoid changes (Antoni B pattern).

Staging, Grading, and Classification

NF2-associated schwannomas are CNS WHO grade 1 tumors. Most NF2-associated meningiomas are also WHO grade 1 neoplasms. NF2-associated ependymomas—especially those in the spinal cord—are generally indolent and carry a favorable prognosis.

Clinical Issues

Presentation

NF2 is much less common than NF1. However, individuals with NF2 generally do not become symptomatic until the 2nd-4th decades; < 20% of patients with NF2 present under the age of 15. Multiple tumors may develop throughout the affected individual’s lifetime. Progressive sensorineural hearing loss, tinnitus, and difficulties with balance are typical. Other common symptoms include facial pain &/or paralysis, vertigo, and seizures.

Many NF2-related meningiomas are asymptomatic and discovered incidentally on imaging. Spinal cord ependymomas are asymptomatic in 75% of patients.

Clinical Diagnosis

The definitive diagnosis of NF2 is established by fulfilling the Manchester diagnostic criteria or by identifying a pathogenic NF2 mutation. Consensus criteria for the clinical diagnosis of NF2 as recently revised and updated are summarized in the box below.

Natural History

NF2-associated intracranial neoplasms often demonstrate a “saltatory” growth pattern characterized by alternating periods of growth and quiescence. As new tumors can develop and radiographic progression and symptom development are unpredictable, continued surveillance is necessary. Current recommended MR surveillance includes imaging at one, five, and 10 years after surgery.

Imaging

General Features

The cardinal imaging feature of NF2 is bilateral VSs.

CT Findings

NECT scans typically demonstrate a mass in one or both cerebellopontine angle (CPA) cisterns. Both schwannomas and meningiomas are typically iso- to slightly hyperdense on NECT (44-29A)and exhibit strong enhancement following contrast administration.

Nonneoplastic choroid plexus calcifications in atypical locations (e.g., temporal horn) are a rare manifestation of NF2 but can be striking. Bone CT typically shows that one or both internal auditory canals are widened.

MR Findings

MR findings of NF2-related schwannomas and meningiomas are similar to those of their sporadic counterparts. If NF2 is suspected on the basis of brain imaging, the entire spine and spinal cord should be screened. High-resolution T2WI and contrast-enhanced sequences disclose asymptomatic tiny schwannomas (44-30) (44-33)and intramedullary ependymomas (44-31)in at least 1/2 of all individuals with NF2(44-32).

Differential Diagnosis

The major differential diagnosis of NF2 is LZTR1-associated schwannomatosis, especially when one VS is present. Schwannomatosis is characterized by multiple NV Ss while meningiomas are less common (see box below). Multiple meningiomatosis is characterized by multifocal meningiomas without schwannomas.

Schwannomatosis

Schwannomatosis is related to—but differs from—NF2. Schwannomatosis is characterized by multiple peripheral and spinal schwannomas—less commonly, meningiomas—in the absence of bilateral VSs (44-34). The majority of cases are sporadic; only 15-25% are familial. Peak incidence is between ages 30-60 years (in contrast with NF1—typically diagnosed in the first decade—and NF2, usually diagnosed in the second or third decade).

Familial schwannomatosis is an autosomal dominant disorder characterized by inactivating mutations in the tumor suppressor genes SMARCB1 and LZTR1, which are both located on chromosome 22, centromeric to NF2. Tumors typically present in the second and third decades.

Approximately 75% of schwannomas affect the spine, and the peripheral nerves are affected in nearly 90%. Schwannomas of the cranial nerves are uncommon (< 10% of cases), and, when present, they affect mostly the trigeminal nerve. Unilateral VSs may occur; the presence of bilateral vestibular lesions is diagnostic of NF2, not schwannomatosis. Nonneurogenic tumors, such as lipomas and angiolipomas, occur in 5-10% of cases.

Imaging in schwannomatosis discloses multiple circumscribed, well-defined, round to oval or dumbbell-shaped lesions that are hypo- to isointense on T1WI and hyperintense on T2/FLAIR. Lesions enhance strongly on T1 C+ sequences (44-35). The risk of malignant degeneration is low.

Other Common Familial Tumor Syndromes

Tuberous Sclerosis Complex

Terminology

Tuberous sclerosis complex (TSC) is a neurocutaneous syndrome characterized by the formation of nonmalignant hamartomas and benign neoplastic lesions that affect the CNS and various nonneural tissues.

Etiology

Genetics

Approximately 50% of TSC cases are inherited and follow an autosomal dominant pattern while the other 50% represent de novo mutations. Two separate genes are mutated or deleted in TSC: TSC1 and TSC2. The TSC1 gene is located on chromosome 9q34 and encodes a protein called hamartin. The TSC2 gene is localized to chromosome 16p13.3 and encodes the tuberin protein. Mutations in either gene are identified in 75-85% of patients with TSC.

The TSC protein complex functions as a tumor suppressor. Hamartin/tuberin inhibits the mTORC1 signaling pathway (mammalian target of rapamycin complex 1). Mutations that lead to increased mTORC1 activation promote cellular disorganization, overgrowth, and abnormal differentiation. TSC2 mutations are associated with a more severe disease phenotype with more and larger tubers, more radial migration lines, and more subependymal nodules (SENs) compared with TSC1.

Pathology

The four major pathologic features of TSC in the brain are cortical tubers, SENs, WM lesions, and SEGA (44-37) (44-36).

Cortical Tubers

Cortical tubers are glioneuronal hamartomas and are found in > 90% of TS patients. They are firm, whitish, pyramid-shaped, elevated areas of smooth gyral thickening. Cortical tubers grossly resemble potatoes (“tubers”).

Cortical tubers consist of giant cells and dysmorphic neurons. Balloon cells similar to those seen in Taylor-type focal cortical dysplasia (FCD type IIb) are also commonly found in tubers. Tubers do not undergo malignant transformation.

Subependymal Nodules

SENs are located immediately beneath the ependymal lining of the lateral ventricles, along the course of the caudate nucleus.

SENs appear as elevated, rounded, hamartomatous lesions that grossly resemble candle guttering or drippings. They often calcify with increasing age. SENs along the caudothalamic groove adjacent to the foramen of Monro may undergo neoplastic transformation into SEGA.

White Matter Lesions

WM lesions are almost universal in patients with TSC. They appear as foci of bizarre dysmorphic neurons and balloon cells in the subcortical WM &/or fine radial lines extending outward from the ependymal ventricular surface toward the cortex. These radial migration lines often terminate in a tuber.

Subependymal Giant Cell Astrocytoma

SEGA is seen almost exclusively in the setting of TSC, occurring in 6-9% of patients. Grossly, SEGAs appear as well-circumscribed solid intraventricular masses located near the foramen of Monro (44-37B). SEGAs are CNS WHO grade 1 tumors that often cause obstructive hydrocephalus but do not invade adjacent brain. Although most SEGAs are unilateral, bilateral tumors occur in 10-15% of cases.

Clinical Issues

Epidemiology and Demographics

TSC is the second most common inherited tumor syndrome (after NF1). Almost 80% of cases are diagnosed before the age of 10.

Presentation

The classic clinical triad of TSC consists of facial lesions (“adenomata sebaceum”), seizures, and intellectual disability. All cutaneous features are age dependent and may not become apparent until later in childhood. A subset of patients have more subtle symptoms due to variable penetrance of the TSC1 gene inactivation and may not be diagnosed until adulthood.

Hypomelanotic macules (“ash leaf”) spots are seen in > 90% of cases and may be the first visible manifestation of TSC. Other common cutaneous findings, such as facial angiofibromas (“adenoma sebaceum”), and periungual fibromas usually do not appear until after puberty.

Natural History

Disease severity and natural course vary widely. Neurologic manifestations—primarily intractable seizures from brain hamartomas and obstructive hydrocephalus secondary to SEGA—are the leading cause of morbidity and mortality.

SEGAs are benign and usually slow-growing neoplasms. Although they can develop at any age, they are most frequent in patients between 5-19 years of age. Rapamycin inhibitors (“rapalogs”), such as everolimus and sirolimus, have been approved for the treatment of TSC-associated SEGAs in patients with TSC.

Imaging

CT Findings

Cortical Tubers

Neonatal and infantile cortical tubers are initially seen as hypodense cortical/subcortical masses within broadened and expanded gyri. The lucency decreases with age. Calcifications progressively increase with age. By 10 years, 50% of affected children demonstrate one or more globular or gyriform cortical calcifications.

Subependymal Nodules

SENs are a near-universal finding in TSC. Most are found along the caudothalamic groove. The walls of the atria and temporal horns of the lateral ventricles are less common sites.

SENs are rarely calcified in the first year of life. Like cortical tubers, SEN calcifications increase with age. Eventually, 50% demonstrate some degree of globular calcification (44-38B). SENs typically do not enhance on CECT scans. An enhancing or enlarging SEN—especially if located near the foramen of Monro—is suspicious for SEGA (44-38C).

Subependymal Giant Cell Astrocytoma

SEGAs show mixed density on NECT scans and frequently demonstrate focal calcification. Hemorrhage is rare. Moderate enhancement on CECT is typical.

MR Findings

In general, MR is much more sensitive than CT in depicting parenchymal abnormalities in TSC. Findings vary with lesion histopathology, patient age, and imaging sequence. Standard T2-weighted sequences, FLAIR, and sometimes T1WI with magnetization transfer contrast are particularly useful in detecting TSC-associated CNS lesions.

Cortical Tubers

In infants, tubers appear as thickened hyperintense cortex compared to the underlying unmyelinated WM on T1WI and become moderately hypointense on T2WI. “Streaky” linear or wedge-shaped T2-/FLAIR-hyperintense bands may extend from the tuber all the way through the WM to the ventricular ependyma (44-41A).

Signal intensity changes after myelin maturation. Tubers gradually become more isointense relative to cortex on T1WI (unless calcification is present and causes T1 shortening). Occasionally, the outer margin of a tuber is mildly hyperintense to gray matter, while the subcortical component appears hypointense relative to WM.

Tubers in older children and adults demonstrate mixed signal intensity on T2/FLAIR. The periphery of the expanded gyrus is isointense with cortex, while the deeper component is strikingly hyperintense (44-39C). Between 3-5% of cortical tubers show mild enhancement on T1 C+ imaging.

Cerebellar tubers are much less common than supratentorial cortical tubers and are rare under the age of eight years. Unique features reported in cerebellar tubers are retraction and “zebra-striped” enhancement.

Subependymal Nodules

SENs are seen as small (generally < 1.3 cm) nodular “bumps” or “candle gutterings” that protrude from the walls of the lateral ventricles (44-39). In the unmyelinated brain, SENs appear hyperintense on T1WI and hypointense on T2WI. With progressive myelination, the SENs gradually become isointense with WM.

Calcified SENs appear variably hypointense on T2WI or FLAIR and are easily identified on T2* sequences (GRE, SWI). They can be distinguished from blood products on the SWI phase map, as calcification is diamagnetic and appears bright, whereas paramagnetic substances (blood products) are hypointense.

Enhancement of SENs following contrast administration is variable (44-41). About 1/2 of all SENs show moderate or even striking enhancement, which—in contrast to enhancement on CECT—does not indicate malignancy.

SENs are stable lesions. However, as SENs near the foramen of Monro may become malignant, close interval follow-up is essential. It is the interval change in size seen on serial examinations—not the degree of enhancement—that is significant. Some investigators suggest an increase of > 20% demonstrated on two consecutive MR scans as defining a SEGA.

White Matter Lesions

WM lesions are seen in 100% of cases. Even though they are considered a “minor” criterion for TSC, their appearance is highly characteristic of the disease. Streaky linear or wedge-shaped lesions extend along radial bands from the ventricles to the undersurfaces of cortical tubers (44-41). In the unmyelinated brain, these linear foci (radial migration lines) appear mildly hyperintense to WM on T1WI. In older children and adults, they are hyperintense on T2/FLAIR sequences (44-40B).

Small, round, cyst-like parenchymal lesions are seen in nearly 50% of TSC cases. They are typically located in the deep periventricular WM (44-41A). They are often multiple and resemble CSF, i.e., they suppress on FLAIR and do not enhance (44-42).

Subependymal Giant Cell Astrocytoma

Although SEGAs can occur anywhere along the ventricular ependyma, the vast majority are found near the foramen of Monro. SEGAs are of mixed signal intensity on both T1- and T2WI (44-39). Virtually all enhance moderately strongly on T1 C+ scans (44-39B).

SEGAs become symptomatic when they obstruct the foramen of Monro and cause hydrocephalus. Even large SEGAs rarely invade brain.

Miscellaneous CNS Lesions

Cerebellar tubers can be identified in 10-40% of cases and are always associated with supratentorial lesions. Other uncommon abnormalities include hemimegalencephaly, cerebellar malformations, and linear, clump-like, or gyriform parenchymal calcifications. Aneurysms (mostly fusiform aortic and intracranial) are seen in 1% of TSC.

Differential Diagnosis

Focal cortical dysplasia (FCD) can appear identical to cortical tubers on imaging studies, but lesions are typically solitary, whereas cortical tubers are almost always multiple. Foci of subependymal heterotopic gray matter can resemble SENs, but most SENs calcify and often enhance on T1 C+ sequences.

SEGAs can resemble other frontal horn/septum pellucidum lesions, such as subependymoma. Subependymomas are tumors of middle-aged and older individuals, and other TSC stigmata, such as cortical tubers and SENs, are absent.

TSC: IMAGING

Cortical Tubers

• Broad, expanded gyrus

• CT: Initially hypodense; calcification increases with age

 50% of patients eventually develop ≥ 1 calcified tuber(s)

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