Inheritable Genetic Variations Predisposing to CNS Tumors



10.1055/b-0034-79094

Inheritable Genetic Variations Predisposing to CNS Tumors

Jonathan L. Finlay and Uri Tabori

Cancer is a genetic disease. However, not all cancers are inherited, and although some genetic variations predisposing to cancer are indeed of clear inheritance, others are not. Furthermore, genetic “variations” are not truly “conditions,” “syndromes,” or “diseases.” As an example, being of Asian extraction is not a “disease” simply because one has a higher predisposition to developing central nervous system (CNS) germ cell tumors. Humans are variations and polymorphisms upon a genetic template, some with more variations than others, carrying somewhat more susceptibilities to various diseases, including cancers, than others. What has been abundantly clear for decades, is that studying patients with genetic variations from the norm can teach us how the body regulates normal functions and, in the case of cancer susceptibility syndromes, how the body normally fends off the successful growth of aberrant clones of neoplastic cells. The pertinent phrase, coined by the late Robert Good in reference to the rare childhood primary immunodeficiency syndromes, is that these conditions are “experiments of nature” that teach us much about the normal workings, in his particular example, of the immune system.1 This chapter focuses on the molecular genetic pathways and their aberrations that appear to be pertinent to the development of CNS cancers in various cancer predisposition syndromes ( Table 7.1 ).


Improvement in the cure rates of children with CNS tumors arising as a consequence of cancer susceptibility syndromes will come not only through the improved techniques used for the specific brain tumors involved, but also through introduction of standardized screening procedures in individuals who are demonstrated to have such cancer predisposition syndromes. The “holy grail” for the management of such cancers is prevention; at present, prevention is limited to what might best be termed “surgical preemption,” such as colonic resection, bilateral mastectomy, and total thyroidectomy to prevent, respectively, colon, breast, and thyroid carcinomas. It is hoped that through genetic manipulations that may reactivate mutated and inhibited suppressor genes, activate inhibited suppressor tumor pathways, or, alternatively, suppress overexpressed and activated oncogenic pathways, less invasive prevention will one day be realized.



Specific Syndromes Associated with Central Nervous System Tumors


It is not the purpose of this chapter to provide clinical and epidemiological details of the individual syndromes; these are well described in other chapters in this book as well as in other pertinent texts,25 and we cite recommended disease-related reviews throughout the chapter. The salient clinical features of each syndrome are summarized in Table 7.2 , and an overview of the role of each gene in cancer is presented in Fig. 7.1 . We do focus on the particular CNS tumors associated with these syndromes, their prevalence, their clinical characteristics particular to each syndrome, and their molecular genetic associations and relevance to understanding of carcinogenesis.



Neurofibromatosis Type 1 (Von Recklinghausen′s Disease)


Neurofibromatosis type 1 (NF-1) is an autosomal dominant condition with a worldwide incidence of 1 per 2,500 to 3,000 individuals.6 This syndrome encompasses multiple organs, and diagnosis can be made based on clinical criteria.68 Individuals with NF-1 have significant morbidity and early mortality not necessarily due to cancer predisposition.9 Tumors associated with NF-1 are mostly of nervous system origin, including gliomas, benign neurofibromas, and malignant nerve sheath tumors. However, other rare cancers including chronic myelomonocytic leukemia are associated with this condition.



Optic Pathway Gliomas (Fig. 7.2)


Optic pathway gliomas (OPGs) are the most prevalent CNS tumors in patients with NF-1. An association between neurofibromatosis and optic pathway tumors was first noted in the English-language medical literature in 196810 and 1969.11 Such tumors were originally considered to be congenital nonneoplastic hamartomatous lesions. Since that time, these optic pathway tumors have been recognized to be neoplastic astrocytic tumors of almost uniformly low-grade character; transformation into more malignant optic pathway tumors in patients with neurofibromatosis has been reported only in the setting of previously irradiated tumors.


About 15% of individuals with NF-1 have been reported to harbor optic pathway gliomas; however, this figure is likely an underestimate, since routine screening with brain magnetic resonance imaging (MRI) is controversial and not widely practiced. A recent retrospective report of a chart review from Montreal Children′s Hospital12 identified 44 confirmed optic pathway gliomas (13%) among 331 NF-1 individuals. However, of note was that, with an average follow-up of 6 years, only eight patients (18% of those with OPG and just 2.4% of all patients with NF-1) were reportedly symptomatic (with either decreased vision or precocious puberty). Only five of the eight children required treatment for their symptoms. Thus, it is important to recognize that the demonstration of an OPG in patients with NF-1 should not lead to immediate introduction of treatment (in particular, chemotherapy), but should be closely observed with ophthalmologic, brain MRI, and endocrine (growth velocity, bone age, and pertinent serum hormone levels) monitoring. The trigger for initiation of chemotherapy should be deterioration in vision and not solely an increase in the size of the OPG.





























































Inheritable Cancer Predisposition Syndromes and Associated Neoplasms

Syndrome


Systemic Neoplasms


CNS Neoplasms


Neurofibromatosis type 1


Malignant peripheral nerve sheath tumors (MPNST)


Gastrointestinal stromal tumors (GIST) Pheochromocytomas


Optic pathway gliomas—pilocytic astrocytomas (grade I), diffuse astrocytomas (grade II)


Malignant gliomas (grades III–IV)—uncommon


Neurofibromatosis type 2


Schwannomas or neurilemomas uncommon


Cranial nerve schwannomas (vestibular most common, then oculomotor, trigeminal)


Jugular foramen schwannomas


Intracranial meningiomas (e.g. optic nerve sheath)


Spinal cord schwannomas (most common), meningiomas, ependymomas, and astrocytomas


Tuberous sclerosis complex


Renal angiomyolipoma (75%)


Cardiac rhabdomyoma (50% infants)


Renal cell carcinoma (rare)


Subependymal giant cell astrocytoma (SEGA) Tubers


Li-Fraumeni syndrome


Adrenocortical carcinoma


Breast cancer (females)


Osteogenic sarcoma & chondrosarcoma <45yo


Soft tissue and rhabdomyosarcoma <45yo


Myelodysplastic syndrome & acute myeloid leukemia Neuroblastoma


Head & neck carcinomas


Malignant gliomas (grades III–IV)


Diffuse astrocytoma (grade II)


Choroid plexus carcinoma


Medulloblastoma


Retinoblastoma predisposition syndrome


Unilateral retinoblastoma


Bilateral retinoblastoma


Second Malignant Neoplasms:


Osteogenic sarcoma


Soft tissue sarcomas (leiomyosarcoma most common) Melanoma


Epitheloid cancers (lung, bladder etc) in late adulthood


“Trilateral” retinoblastoma (RB) (bilateral RB with (usually) pineal region or (rarely) suprasellar PNET) in 5–15% hereditary RB


“Quadrilateral” RB (bilateral RB with pineal and suprasellar PNET)


Rhabdoid predisposition syndrome


Rhabdoid tumor of the kidney (RTK)


Extra-renal malignant rhabdoid tumors (MRT) of liver, soft tissues, skin, heart, and lungs


Atypical teratoid rhabdoid tumor (ATRT)


Gorlin syndrome


Basal cell carcinoma of skin—often multiple (90%)


Ovarian fibromas


Medulloblastoma (10%)


Mismatch repair cancer syndrome (Brain tumor–polyposis syndrome type 1; ‘Turcot syndrome’)


Colorectal adenomas and adenocarcinomas (HNPCC type)


Gastric carcinomas


Renal and endometrial carcinomas (adults)


Malignant glioma (grades III–IV)


Medulloblastoma/PNET


Brain tumor–polyposis syndrome type 2; ‘Turcot syndrome’)


Colorectal sessile tubular adenomas


Colorectal adenocarcinomas


Gastric adenocarcinoma (rare)


Desmoid tumors of fibrous tissue (abdomen most common)


Hepatoblastoma (rare)


Thyroid carcinoma


Multiple endocrine neoplasia Type 2B


Medulloblastoma


Von Hippel-Lindau syndrome


Hemangiomablastomas


Pheochromocytoma


Renal cell carcinoma


Retinal hemangioblastomas (angiomas)


Posterior fossa hemangioblastomas (67%)


Supratentorial hemangioblastomas (33%)


Spinal hemangioblastomas (<1%)


Multiple hamartoma syndrome (Cowden syndrome)


Breast carcinoma (20–36% females)


Thyroid follicular carcinoma


Endometrial carcinoma


Renal cell carcinoma


L′Hermitte-Duclos disease: dysplastic gangliocytoma of the cerebellum


Intracranial meningiomas


Fanconi anemia


Myelodysplastic syndrome and acute myeloid leukemia


Oro-pharyngeal quammous cell carcinomas


Esophageal cancer


Vulval cancer


Medulloblastoma


Gliomas (uncommon)











































































Inheritable Syndromes Predisposing to Brain Cancer

Syndrome


Incidence


Inheritance


Nonneoplastic Characteristics


Neurofibromatosis type 1 (Von Recklinghausen′s disease)


1:3,000 individuals


Inherited (50% individuals); autosomal dominant


Cutaneous manifestations: café-au-lait spots or hyperpigmented macules (six or more, ≥ 5 mm diameter if < 10 years of age or ≥ 15 mm in adults; axillary or inguinal freckling; subcutaneous or cutaneous neurofibromas; subcutaneous plexiform neurofibromas ± overlying hyperpigmentation or hypertrichosis


CNS manifestations: learning difficulties ± attention deficit/hyperactivity disorder (ADHD) (40%); mild/moderate developmental delay (10–15%); symmetric sensory axonal polyneuropathy—idiopathic (1%); cerebrovascular lesions—ectasias, stenoses, aneurysms, Moyamoya disease; macrocephaly (common);


Chiari type 1 malformations; precocious puberty—idiopathic


Ocular manifestations: multiple iris hamartomas (Lisch nodules); retinal “cork-screw” vascular lesions; patchy choroidal lesions


Osseous manifestations: long bone intramedullary fibrosis, bowing or tibial pseudarthrosis; cortical thinning; vertebral dural ectasia; sphenoid bone dysplasia; osteoporosis (increased bone resorption rate ± vitamin D deficiency)


Scoliosis ± kyphosis


Other manifestations: renovascular hypertension (due to fibromuscular dysplasia); coronary artery aneurysms Constitutional short stature (common)


Neurofibromatosis Type 2 (central neurofibromatosis)


1:37,000 individuals


Inherited (50% individuals); autosomal dominant


Ocular manifestations: posterior subcapsular “juvenile” cataracts; retinal hamartomas; epiretinal membranes


Cutaneous manifestations: far less common than in NF-1; subcutaneous schwannomas or neurilemomas; neurofibromas uncommon; café-au-lait spots (uncommon, small, few); axillary/inguinal freckling rare


Sensorimotor polyneuropathy—idiopathic


Cancer predisposition (see Table 7.2 )


Tuberous sclerosis complex (Bourneville disease)


1:5,800–30,000 individuals


Inherited (30–50% individuals); autosomal dominant


Mucocutaneous manifestations (> 90%): hypomelanotic “ash-leaf” macules, facial angiofibromas (“adenoma sebaceum”), ungual fibromas, periungual fibromas (Koenen tumors), forehead plaque fibromas, truncal connective tissue nevus (“Shagreen patch”), dental enamel pits (90%), gingival fibromas, “confetti” skin lesions


Ocular manifestations: multiple retinal nodular hamartomas (phakomas), hypopigmented iris spots


CNS manifestations: epilepsy (80–90%), developmental delay (60–70%), cortical and subcortical tubers, subependymal nodules


Other manifestations: bone cysts, pulmonary cystic lymphangiomatosis (recurrent pneumothoraces, dyspnea, cor pulmonale, respiratory failure)


Cancer predisposition (see Table 7.2 )


Li-Fraumeni syndrome


Unknown; < 1:200,000 individuals


Autosomal dominant


Cancer predisposition (see Table 7.2 )


Retinoblastoma predisposition syndrome


4:1,000,000 individuals age < 15 years;


10–14:1,000,000 age < 4 years


Inherited (25–30% individuals with retinoblastoma); autosomal dominant


Cancer predisposition (see Table 7.2 )


Rhabdoid predisposition syndrome


Unknown; < 1:200,000 individuals


Autosomal dominant with incomplete penetrance


Cancer predisposition (see Table 7.2 )


Gorlin syndrome (basal cell nevus syndrome; nevoid basal cell carcinoma syndrome)


1:50,000–150.000 individuals


Autosomal dominant


Superficial malformations: jaw cysts, palmar/plantar pits


Radiological manifestations: calcification of the falx cerebri (79% ≥ 20 years of age; 37% < 20 years of age), tentorium cerebelli (20%), bridging of the sella turcica (68%), spine abnormalities (43%), rib abnormalities (42%), metacarpal/phalangeal abnormalities 48%)


Cancer predisposition (see Table 7.2 )


Mismatch repair cancer syndrome (brain tumor—polyposis syndrome type 1; Turcot syndrome)


Unknown


Autosomal recessive


Colorectal adenomas (few, large, early onset) without polyposis


Café-au-lait spots, Lisch nodules, axillary freckling (Neurofibromatosis type 1–like characteristics)


Hepatic focal nodular hyperplasia


Cancer predisposition (see Table 7.2 )


Brain tumor—polyposis syndrome type 2; Turcot syndrome)


Unknown


Autosomal dominant


Colorectal polyposis (numerous, small, late onset) gastric fundic polyps


Congenital hypertrophy of the retinal pigment, epidermal inclusion cysts, dental anomalies, and osteosclerotic jaw lesions (Gardner syndrome–like)


Cancer predisposition (see Table 7.2 )


Von Hippel-Lindau syndrome


1:36,000 individuals


Inherited 80% individuals; autosomal dominant


Hearing loss/tinnitus (endolymphatic sac cysts)—10%


Cardiovascular and cerebrovascular disease


Hypertension—20%


Café-au-lait spots


Pancreatic, renal, and epididymal adenomatous cysts Cancer predisposition (see Table 7.2 )


Multiple hamartoma syndrome (Cowden syndrome)


1:200,000 individuals


Autosomal dominant


Mucocutaneous manifestations > 90%: trichilemmomas, acral keratoses, oral mucosal papillomatosis, palmoplantar keratoses


Hamartomas of gastrointestinal tract, bones, brain, eyes, and genitourinary tract


Cancer predisposition (see Table 7.2 )


Fanconi anemia


3:1 million individuals


Autosomal recessive


60% congenital malformations: abnormal thumbs, short stature, microcephaly, abnormal skin pigmentation


100% bone marrow failure: anemia, thrombocytopenia, leucopenia Cancer predisposition (see Table 7.2 )


The indolent natural history of an OPG in the setting of NF-1 contrasts sharply with the natural history of an OPG in the absence of NF-1. The latter tends to behave somewhat more aggressively, with shorter periods of growth stability. The tumors radiographically tend to be locally larger, more circumscribed and gadolinium-enhancing on MRI, and more productive of local mass effect on the optic apparatus as well as on the hypothalamus; these tumors are usually pilocytic astrocytomas, and are more amenable to surgical intervention than are the widely infiltrative, nonenhancing tumors more commonly seen in patients with NF-1. Such tumors are not amenable to radical surgical resection.


Patients with NF-1 are particularly sensitive to damaging effects of ionizing irradiation, leading both to increased incidence of irradiation-induced cancers as well as to cerebrovascular damage (Moyamoya syndrome). Although Moyamoya syndrome is well recognized in children without NF-1 who received cranial irradiation for brain tumors (particularly irradiation encompassing the circle of Willis for optic pathway tumors or craniopharyngiomas), a strong association has long been recognized in NF-1 children who have previously received irradiation.13,14 Thus, NF-1 children with OPGs, in particular, and brain tumors, in general, should avoid cranial irradiation unless there are highly exceptional circumstances.



Brainstem Gliomas (Fig. 7.3)


It has been recognized for over 20 years that patients with NF-1 manifesting brainstem lesions compatible with gliomas on imaging studies have a far more favorable prognosis than do patients with such lesions in the absence of NF-1.15 In the largest retrospective study to date16 conducted at Boston Children′s Hospital, brainstem mass lesions were identified in 23 (18.4%) of 125 patients with NF-1. Only six patients received treatment (surgery, irradiation, or chemotherapy) directed at the brainstem lesion. With a median follow-up in excess of 5 years, only one patient (previously untreated) demonstrated radiographic and clinical progression. Therefore, brainstem lesions in the setting of NF-1 are biologically indolent, and the majority of such patients do not require therapeutic intervention unless there is documentation of rapid growth on serial imaging studies as well as clinical deterioration.



High-Grade Gliomas


It has long been recognized that for a condition associated with an increased incidence of low-grade gliomas, an association with malignant gliomas, in particular glioblastoma multiforme (GBM), appears notably absent. One recent report17 suggests that NF-1 patients may have an increased risk of GBM, but that the GBM in association with NF-1 may have an improved prognosis compared with that of GBM in children in the absence of NF-1.

Role of genes involved in brain tumor predisposition syndromes in cancer development.


Molecular Genetics


Neurofibromatosis type 1 results in loss of function of the tumor suppressor protein neurofibromin. This large protein is a key negative regulator of the RAS pathway by catalyzing the hydrolysis of active guanosine triphosphate–bound RAS to inactive guanosine diphosphate–bound RAS.18 Dysfunctional neurofibromin results in constitutive activation of downstream oncogenic pathways including MAPK and mTOR. Mutations or deletions in the neurofibromin gene can be identified in more than 85% of individuals with NF-1. However, because the gene is very large and difficult to analyze, diagnosis and management can be made based on clinical criteria.



Clinical Implications


Because NF-1 is a multisystemic condition, careful monitoring is recommended in multidisciplinary clinics.6 The markedly variable clinical manifestations, as well as variability in tumor occurrence, make recommendations for follow-up difficult to determine. Currently, there is not enough evidence to suggest surveillance protocols for intracranial tumors. Because the risk of malignant transformation of peripheral neurofibromas is as high as 10%, protocols for monitoring these lesions are being developed. Individuals with NF-1 are particularly sensitive to the damaging effects of ionizing irradiation, leading both to an increased incidence of irradiation-induced cancers19 as well as to cerebrovascular damage (Moyamoya syndrome).13,14 This lends further support to the recommendation cited earlier that NF-1 children with OPGs should avoid cranial irradiation.


Finally, multiple inhibitors exist for the RAS and mTOR pathways, enhancing the possibility of novel therapeutic approaches for children with NF-1 with tumors within and beyond the CNS. Furthermore, involvement of the stroma around tumors may allow for additional NF-1–specific therapies for these patients.20,21



Neurofibromatosis Type 2


Neurofibromatosis type 2 (NF-2) is an autosomal dominant cancer predisposition syndrome characterized by the development of bilateral vestibular schwannomas and schwannomas of other cranial, spinal, and peripheral nerves. NF-2 individuals can also develop intracranial, spinal, and optic nerve sheath meningiomas, low-grade ependymomas, and gliomas of the CNS.22,23 There are no similarities in the genetic background and clinical manifestations between NF-1 and NF-2 except for the name, and they should not be confused.

(a) Initial screening MRI of a 4-year-old asymptomatic boy with multiple café-au-lait spots, revealing optic pathway tumor. Axial T1 postgadolinium image. (b) Axial T2-weighted screening MRI of the same asymptomatic boy at age 6 years with café-au-lait spots. (c) CT scan of child presenting with unilateral proptosis and an optic nerve glioma in the setting of neurofibromatosis type 1 (NF-1).


Intracranial Tumors (Fig. 7.4a–c)


The hallmark characteristic of NF-2 is the development of vestibular (acoustic) schwannomas, eventually and most commonly bilateral, with a lifetime penetrance of over 95% in NF-2 individuals. Although originally considered to be a syndrome of little pediatric relevance, a Manchester-based United Kingdom Tumor Registry study demonstrated that 18% of 334 NF-2 cases presented at younger than 15 years of age.24 Furthermore, only 43% of such pediatric cases presented with features pertaining to vestibular schwannomas (hearing loss, tinnitus, or facial paresis). The next most common presentations were features relating to nonvestibular schwannomas (33%), meningiomas (31%), and spinal tumors (11.5%); of note, the meningiomas of brain and spine are frequently multiple.


As a corollary to the above, the finding of an isolated meningioma or schwannoma in a child is sufficiently uncommon and should mandate a workup for NF-2 (family history, craniospinal MRI, and full dermatologic and ophthalmologic examination). Optic nerve sheath meningiomas are particularly rare in children but have been reported as more commonly associated with NF-2 and more aggressive in behavior than those of adults.25 It is important to remember that a family history of NF-2 is found in only 50% of individuals with NF-2.

A 12-year-old with diffuse brainstem glioma and dentate nuclei unidentified bright objects (UBOs) in the setting of NF-1.


Spinal Tumors (Fig. 7.4d)


The incidence of spinal tumors in patients with NF-2 is as high as that of vestibular schwannomas, cited in one study as 89%.26 The presence of multiple intra- and extramedullary (intradural and extradural) spinal cord tumors of different histologies in a single patient, commonly asymptomatic at presentation, is virtually pathognomonic for NF-2. About one third of spinal tumors in association with NF-2 are intramedullary, most frequently ependymomas and to a lesser extent astrocytomas. Of the extramedullary tumors, schwannomas are most common, followed by meningiomas, with neurofibromas being very uncommon.



Molecular Genetics


The gene responsible for NF-2 was discovered in 1993 as Neurofibromin 2 or Merlin located on chromosome 22q12.2.27,28 Interestingly, the exact function of this gene is still not entirely clear. The tumor suppressive effects of Merlin are partially mediated by its membrane organization of proteins, cell-to-cell adhesion, and cytosekeletal architecture. However, more direct nuclear effects have been recently described.17 There is a high rate of mosaicism in de novo individuals with NF-2. As a consequence, the diagnosis of this syndrome can be established on clinical criteria alone. Furthermore, transmission, which is autosomal dominant, may be less than 50% in such individuals.



Clinical Implications


A consensus meeting has produced surveillance guidelines for individuals with NF-2 since 2005.16 Parents of an asymptomatic child carrying the mutation are encouraged to initiate screening when the child is 10 years of age, to avoid unnecessary morbidity. Furthermore, recent advances in molecular understanding have facilitated the development of targeted therapies for vestibular schwannomas, permitting preservation of hearing in some patients.18 Other targeted therapies are under development and evaluation.19



Tuberous Sclerosis (Bourneville′s Disease) (Fig. 7.5)


Tuberous sclerosis (TS) is an autosomal dominant multisystem condition affecting both children and adults.29 Tumors outside the CNS arising in these patients are generally slow growing and include cardiac rhabdomyoma, renal angiomyolipoma, and pulmonary lymphangioleiomyomatosis. Although these lesions are termed benign by pathologists, they can cause significant morbidity and even mortality due to organ dysfunction. Additionally, individuals with TS can rarely develop malignant renal cell carcinomas.


The only CNS tumor seen in patients with TS complex is the subependymal giant cell astrocytoma (SEGA). This tumor develops in some 5 to 15% of patients with TS complex, usually in the first two decades of life, and is considered to occur only rarely in individuals without TS complex and then in older adults. These intraventricularly located tumors, usually in close proximity to the foramen of Monro, are histologically benign (considered World Health Organization [WHO] grade I) but can nevertheless lead to significant morbidity and mortality, due to development of intracranial hypertension from obstruction of cerebrospinal fluid (CSF) flow at the foramen, as well as due to subependymal invasion into eloquent brain parenchyma. Sequential brain MRI studies have suggested that most of these tumors develop from lesions indistinguishable from the commonly observed subependymal nodules, and that the nodules at high risk for growth or transformation into SEGAs are those greater than 5 mm in diameter, incompletely calcified, and gadolinium enhancing.30 Although the published guidelines for surveillance screening recommend imaging studies every 1 to 3 years, such lesions can grow fairly rapidly to cause obstruction (within 12 to 18 months) especially in childhood, a period of rapid growth, so that we would urge serial follow-up MRI scans to be obtained at least annually during childhood and adolescence, when the risk of SEGA development is greatest.31

(a) An 18-year-old boy with NF-2, bilateral cranial nerve schwannomas of cranial nerves III, V, VII, and VIII. (b) Coronal T1 post-gadolinium MRI revealing small left frontal convexity meningioma as well as cranial nerve schwannomas in same patient as in a. (c) Multiple meningiomas in a patient with NF-2. (d) Axial T1 postgadolinium of cervical spine in an adolescent with NF-2 showing left-sided C2 schwannoma indenting the spinal cord.

Surgical resection of the SEGA has been the only treatment modality considered, until the recent documentation that Everolimus, a drug that inhibits the mammalian target of rapamycin (an mTOR inhibitor), administered to 28 patients with TS complex and SEGAs, produced a 50% reduction in tumor volume in one third of SEGAs and a 30% reduction in tumor volume in 75% of SEGAs within 6 months of initiation of treatment.32 Coincidentally, seizure frequency was also reduced in these patients. Long-term follow-up is awaited to determine if the tumors recur following cessation of Everolimus. Nevertheless, the development of this drug now renders even more complicated the long-standing discussion as to when is the best time to surgically remove such tumors. Historically, surgery was deferred until patients became symptomatic. However, with the advent of improved imaging and neurosurgical techniques, reports have indicated that earlier surgery is associated with less perioperative mortality and less short-term morbidity.33 Recurrence following gross total resection of SEGA is unusual, so that the use of Everolimus in larger, more invasive tumors may ultimately facilitate gross total resections with avoidance of postoperative morbidity.

(a) A 16-year-old girl presenting with headaches. Subtle facial adenoma sebaceum and right lateral ventricular subependymal tumor are seen. The tumor was found to be a giant cell astrocytoma upon resection. (b) Axial FLAIR image MRI showing extensive left frontal cortical tubers as well as a right subependymal infiltrative mass, in same patient as in a. (c) Tubers and subependymal nodules in tuberous sclerosis.


Molecular Genetics


Linkage analysis enabled the discovery of two genes responsible for the TS syndrome. These are TSC1, also known as Hamartin, located on chromosome 9q34,34 and TSC2, or Tuberin, on chromosome 16p13. These genes exert their tumor suppressor activity by inhibition of Rheb, which is the major activator of mTOR. The AKT/mTOR pathway is one of the major pathways in carcinogenesis.



Clinical Implications


Tuberous sclerosis is a prototype of biological discoveries leading to novel targeted therapies, which may change the spectrum of a disease. The name mTOR stems from the term Mammalian Target Of Rapamycin. Rapamycin can inhibit mTOR directly, bypassing TSC1 and TSC2 dysfunction. This knowledge has resulted in several clinical trials revealing striking tumor regression of virtually all SEGAs32,35 and improvement in pulmonary function for patients with lymphangioleiomyomatosis.36 Additional evidence suggest that rapamycin analogues can improve other aspects of the syndrome including neurologic status.37 Primary prevention and protocols for long-term therapies with mTOR inhibitors are currently being developed.



The Li-Fraumeni Family Cancer Syndrome (Fig. 7.6)


The Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition syndrome affecting 1 in 5,000 to 10,000 individuals. This is perhaps the most devastating of the cancer predisposition syndromes. Individuals with the disease have a lifetime risk of 85 to 100% of developing cancer, with a 20 to 30% risk before the age of 30. Originally described by Li and Fraumeni in 196938 as a familial breast, soft tissue sarcoma, and brain tumor predisposition syndrome, we know now that this is not an organ-specific syndrome, and these individuals have a risk of developing cancer in many other organs, including the development of rare tumors such as adrenocortical carcinomas, as well as hematologic malignancies.



Molecular Genetics


In 1990 the association between LFS and germline mutations in the tumor suppressor TP53 gene was made.39 TP53 is located at chromosome 17p13.1 and is called the “gatekeeper of the genome” and is one of the major proteins that control genome integrity after DNA damage, hypoxia, and other stressors. TP53 activation results in cell cycle arrest, senescence, and apoptosis. We now know that TP53 is involved in many other cancer-associated pathways in the cell. More than 50% of adult tumors possess TP53 mutations, and greater than 80% of adult high-grade gliomas have disruption of the TP53 pathway.40


There are three brain tumors associated with LFS: high-grade glioma, choroid plexus carcinoma, and medulloblastoma. Brain tumors in the setting of LFS appear to have two peaks in incidence, the first in children less than 10 years of age, and the second in adults beyond 20 years of age; in the latter, the tumors are almost exclusively GBM, whereas in the former, the majority of the youngest of patients have choroid plexus carcinomas (CPCs) ( Table 7.2 ).


Brain tumors, predominantly GBMs, have been recognized as part of LFS from the earliest reports.38 Subsequent studies determined that, in the absence of a family or personal history suggestive of LFS, the incidence of TP53 germline mutations in patients with malignant gliomas was less than 2%, whereas among those with a family history suggestive of LFS, the incidence of TP53 mutations was almost 20% (Li Y-J et al, 1995). The prognosis for patients with GBM in the setting of LFS appears to be at least as poor as for patients without LFS. It is unclear as to whether GBM in the setting of LFS arises predominantly de novo as so-called primary GBM, or as a secondary GBM arising from the transformation of diffuse (WHO grade II) astrocytomas through anaplastic astrocytomas (WHO grade III) to GBM (WHO grade IV). Reports of both types appear in the literature.



Choroid Plexus Carcinomas


Choroid plexus carcinomas are one of the most common presentations of LFS in young children and were recently added to the criteria for the diagnosis of the syndrome.41 In a recent study, 50% of children with CPC tumors were found to harbor TP53 mutations, and this conferred a worse survival for these patients.42



Medulloblastomas


Medulloblastomas harbor 5 to 10% TP53 mutations. It is still controversial whether these mutations represent a survival disadvantage for these patients.43,44 However, because current therapy for medulloblastoma involves high-dose craniospinal irradiation and chemotherapy, LFS patients with medulloblastoma may have a high risk of treatment-related secondary cancers (see below).



Clinical Implications


Current recommendations are to screen any child with choroid plexus carcinoma, medulloblastoma with tumor TP53 mutation, and high grade-gliomas with a family history of LFS tumors for germline TP53 mutations. Surveillance protocols have been developed for individuals with LFS who have a high rate of tumor pickup.45 Recently, a striking survival benefit for children has been observed using these protocols, especially due to early detection of brain tumors. Although no targeted therapy for TP53 mutated tumors is currently available, detection of TP53 mutations in the tumor and in the germline have significant prognostic and therapeutic implications; although recently a subject of debate, both children and adults with LFS have been considered exquisitely sensitive to ionizing irradiation, with heightened development of irradiation-induced malignant tumors.46,47 Secondary myelodysplastic syndrome following specific chemotherapies have been reported in LFS carriers.48



Retinoblastoma Predisposition Syndrome (Fig. 7.7)


Retinoblastoma (RB) is an autosomal dominant condition and is the prototype of childhood cancer predisposition syndromes. It is the syndrome on which Knudson based his two-hit theory for cancer initiation.49 The hallmark of RB is the development of bilateral ocular retinoblastoma at a very young age, and the subsequent development of bone and soft tissue sarcomas.


The association between heritable RB and second primary intracranial tumors in the pineal or suprasellar regions was first report over 30 years ago50 and given the name of “trilateral” RB shortly thereafter.51 Unlike other second primary tumors, these highly malignant primitive neuroectodermal tumors (PNETs) develop within the first 5 years of life. An extensive review of the published literature between 1977 and 199752 found 94 cases of trilateral RB, in whom the median age for diagnosis of RB was 6 months and the diagnosis of intracranial tumor occurred in 89% of cases within the first 4 years following diagnosis of RB and 99% within the first 7 years following diagnosis of RB. The median time interval from diagnosis of RB to diagnosis of the intracranial tumor was 21 months.

(a) Choroid plexus carcinoma (CPC) at presentation in a 14-month-old boy with Li-Fraumeni syndrome. (b) Choroid plexus carcinoma found on surveillance MRI in the 6-year-old sister of the child with CPC in a, both with TP53 mutations. (c) T2-weighted axial screening MRI showing a right hippocampal infiltrative nonenhancing lesion, presumed to be a low-grade glioma, in the 6-year-old asymptomatic sister of the child with CPC in a, and with a TP53 mutation found on screening. (d) A 14-month-old boy with newly diagnosed CPC and posterior mediastinal mass (ganglioneuroblastoma) on routine spine MRI; a left anterior chest wall embryonal carcinoma was also resected. A constitutional TP53 mutation was found, but no family history was elicited.

The overall incidence of trilateral RB has been estimated to be 3% of all patients with RB, but 6% of those with bilateral RB and between 10% and 15% of those with a family history of RB. About 80% of cases of intracranial PNET and retinoblastoma do develop in the setting of bilateral RB (the “traditional” diagnosis of trilateral RB). However, in about 10% of children, the bilateral RB may be asynchronous in development. In about 7% of children, an intracranial PNET is diagnosed in the setting of unilateral RB yet with confirmed germline mutation, which has been termed a forme fruste of trilateral RB. Finally, rare cases have been reported of intracranial PNET in the absence of RB yet with germline mutations and a family history of RB.


Some 60 to 80% of these intracranial tumors arise primarily in the pineal region, and the remaining 20% to 40% develop in the suprasellar region. Of note, suprasellar tumors are reported to present earlier following diagnosis of RB than do the pineal region tumors (1 month versus 24 months). Furthermore, intracranial tumors in association with unilateral RB more commonly arise in the suprasellar region than in the pineal region52.

(a) Unilateral left-sided retinoblastoma at diagnosis in an 18-month-old boy. Coronal T2-weighted MRI. (b) Same patient, 17 months following diagnosis of retinoblastoma, now with pineal region mass. (c) Same patient with suprasellar mass and leptomeningeal dissemination. This tumor is termed quadrilateral retinoblastoma.

The first report of a child with bilateral RB as well as primary PNETs in both pineal and suprasellar regions, in the absence of intracranial and intraspinal metastases, was published in 1995 and termed “tetralateral” retinoblastoma.53 Subsequently, by the late 1990s the term tetralateral was replaced by quadrilateral for unclear reasons. The frequency of this occurrence is not known, but is clearly rare; in Paulino′s52 literature review of 94 cases over a 20-year period, not a single example was described.


Pineal cysts are recognized (since the advent of MRI) to be a fairly common normal variant, and it is important to avoid misdiagnosing such benign cysts as PNETs.54 To confuse matters further, some patients with trilateral RB have been found on biopsy of the pineal lesion to harbor pineocytoma rather than pineoblastoma; insufficient information is available in the literature to know if such patients ultimately develop transformation into pineoblastomas if left untreated.


Until recently, the outcome of children with trilateral retinoblastoma was considered uniformly dismal, with death occurring from recurrent intracranial PNET within 1 year of diagnosis, whether surgery, irradiation, chemotherapy, or some combination of all three modalities were utilized.55 More recently, reports have been published of the successful use of “baby” chemotherapy protocols without irradiation, using intensive conventional dose chemotherapy either alone56 or additionally incorporating marrow-ablative chemotherapy with autologous hematopoietic cell rescue following intensive induction chemotherapy.57


It has been suggested that the incidence of trilateral retinoblastoma has decreased with the advent of systemic chemotherapy for retinoblastoma. In one study including 100 patients with inheritable retinoblastoma who received systemic chemotherapy, trilateral retinoblastoma was not found in a single individual despite being expected in 5 to 15 patients.58 This begs the question as to whether all children with bilateral or inheritable retinoblastoma should receive systemic chemotherapy for their retinoblastoma!



Molecular Genetics


The RB gene was the first cancer susceptibility gene cloned in 1986.59 The RB gene is located on chromosome 13q14 and is a central regulator of the cell cycle. pRb functions as a general cell cycle inhibitor that restrains the G1/S transition by binding E2F and repressing E2F-dependent transcription. Retinoblastoma is a highly penetrant syndrome; individuals with germline mutations in RB have a more than 90% risk of developing retinoblastoma early in life.60 Dysfunction in pRb is common in most malignant cancers, but surprisingly, until recently, retinoblastoma was associated with only a limited number of cancers.

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Jun 28, 2020 | Posted by in NEUROLOGY | Comments Off on Inheritable Genetic Variations Predisposing to CNS Tumors

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