Fig. 8.1
Bilateral acoustic neuroma in NF2
Patients with NF2 can also develop intracranial, spinal, and optic nerve sheath meningiomas, ependymomas, and gliomas of the CNS. Most meningiomas of the cerebral hemispheres and spinal canal can be safely resected while those originating from optic nerve sheath and skull base might be associated with significant surgical morbidity. Medical therapies have not shown sufficient tumor control in nonacoustic tumors. Up to 18 % of NF2 patients presented before age 15 years and with an isolated feature of the disease and no suggestive family history. NF2 patients who present in childhood tend to have a more aggressive clinical course with a variety of tumors requiring multiple interventions.
Spinal Tumors
Since the advent of MRI, spinal tumors are detected in up to 90 % of patients. However, only 25–30 % of these are symptomatic. Ependymomas are the most common tumor type. When multiple, they can appear like a string of pearls on contrast-enhanced MRI. Early onset of symptoms such as back pain, weakness, or sensory disturbances best determines the timing for spinal intervention [2].
Clinical Applications
Children presenting with bilateral acoustic neuroma or multiple meningiomas or schwannomas should be suspected of having NF2, and genetic testing is recommended. There are established screening programs for children of affected parents and of individuals with an NF2-related tumor in childhood (family history, full craniospinal MRI, extensive dermatologic and ophthalmologic examination) [22]. It will permit early diagnosis, close surveillance, and development of treatment frameworks based on molecular pathogenesis and natural history of lesions. Presymptomatic genetic testing for children at risk of NF2 is now possible in most families.
Schwannomatosis
Schwannomatosis is an autosomal dominant disorder characterized by the predisposition to develop multiple schwannomas. Suggested clinical diagnostic criteria include the presence of at least two non-intradermal schwannomas with one pathologically confirmed schwannoma or intracranial meningioma and an affected first-degree relative. These criteria exclude patients with bilateral vestibular schwannoma or having a germline mutation in NF2 which fulfill diagnostic criteria for NF2.
Clinical Genetics
Recently, schwannomatosis was found to be associated with germline mutations in SMARCB1. Most cases are sporadic; only 15–25 % of cases have inherited the condition from an affected parent. Mutations in SMARCB1 are found in 40–60 % of familial cases of schwannomatosis and less than 10 % of simplex cases [25].
Tumor Spectrum
Schwannomas arising in the setting of schwannomatosis usually present in the second and third decades and are characteristically painful. Histologic examination reveals that a high proportion of tumors are hybrid neurofibroma/schwannoma. This hybrid histology is also frequently encountered in NF1 and NF2. Immunostaining for SAMRCB1 can be of diagnostic significance for these patients. A mosaic-type pattern of immunohistochemical positivity for SMARB1/INI-1 is specific for non-solitary schwannomas. Conversely, the absence of the mosaic-type pattern is a good indicator of nonfamilial tumors, which could be clinically helpful as part of genetic counseling.
Because two patients harbored a combination of SMARCB1 and NF2 mutations with LOH at both alleles, a four-hit mechanism involving the two tumor suppressor genes has been proposed [26]. Importantly, since the majority of schwannomatosis patients do not have a germline mutation in SMARCB1, other constitutional mutations are likely implicated in schwannomatosis tumorigenesis.
Rhabdoid Tumor Predisposition Syndrome
The rhabdoid tumor predisposition syndrome (RTPS) is an autosomal dominant disorder characterized by a predisposition to rhabdoid tumors in the kidney, other extrarenal locations, and the central nervous system [27]. There are no established criteria to diagnose RTPS. Rather, the presence of rhabdoid tumors could be enough to justify investigating further from a genetics standpoint.
Clinical Genetics
Mutations in INII/SMARCB1 are the initiating event for the development of rhabdoid tumors. SMARCB1 is a tumor suppressor gene located on the long arm of chromosome 22. The exact function of SMARCB1 is unknown, but the SMARC genes are important in chromatin modification. A germline mutation can be identified in about 35 % of patients with rhabdoid tumors. The majority of these tumors seem to be de novo, but families in which multiple siblings are affected have been reported. SMARCB1 is also implicated in schwannomatosis and families with both phenotypes have been reported. The penetrance of SMARCB1 is still unknown, but it is incomplete since asymptomatic carrier parents have been reported.
Tumor Spectrum
Rhabdoid tumors in all sites tend to present at an early age and have an extremely aggressive course. The most common location for extrarenal rhabdoid tumor is the CNS, where it is referred to as atypical teratoid/rhabdoid tumor (AT/RT). AT/RT and rhabdoid tumors of the kidney may present synchronously or at months of interval.
Atypical Teratoid/Rhabdoid Tumor of CNS
Since the first well-documented case of malignant rhabdoid tumor of the CNS published in 1986, atypical teratoid/rhabdoid tumor (AT/RT) has been recognized as a distinct pathological entity. AT/RT commonly affects very young children under 2 years of age at diagnosis. They are most commonly located in the posterior fossa (60 %), but also present supratentorially and often metastasize throughout the CNS at presentation (27 %). In the past AT/RT was often misdiagnosed as medulloblastoma or PNET. The first diagnostic clue came from the identification of deletion of chromosome 22q in these tumors. In 1999, Biegel et al. have reported germline and somatic mutations of SMARCB1 gene, a tumor suppressor gene, which maps to 22q11.2 in children with CNS AT/RT [28]. Most mutations result in loss of function of the gene and therefore lack of immunostaining of the corresponding antibody BAF47 is diagnostic for AT/RT. In 2008, the fourth edition of WHO classification of tumors of CNS included the newly described entity of AT/RT. AT/RT still confers poor outcome. However, the use of aggressive multimodality treatment combining extensive surgical excision with intensive systemic chemotherapy using myeloablative chemotherapy with autologous stem cell rescue, with or without brain irradiation has recently improved the prognosis [29–31]. Whether intrathecal chemotherapy can replace irradiation for young children is still unclear. The outcome of CNS AT/RT in the setting of rhabdoid predisposition syndrome has not yet been reported.
Clinical Applications
Children diagnosed with rhabdoid tumor of the kidney or with CNS AT/RT should have imaging of both the abdomen and the brain as a part of their initial work-up. Testing for germline mutations in SMARCB1 is highly recommended. A surveillance protocol has been developed for carriers [32]; however, since until recently most patients did not survive, the exact tumor spectrum and the significance of this approach in RTPS are still unknown.
Li-Fraumeni Syndrome
Li-Fraumeni syndrome (LFS) is considered the prototype of cancer predisposition syndromes. Although initially characterized by a predisposition to soft tissue sarcoma, premenopausal breast cancer, and brain tumors, individuals with LFS are at risk of developing cancer at any age and in almost any tissue.
Clinical diagnosis of classic LFS is defined by the following criteria: a proband with sarcoma diagnosed before age 45 years, and a first-degree relative with any cancer before age 45 years and a first- or second-degree relative with any cancer before age 45 years or a sarcoma at any age. In 2009, more detailed criteria were proposed to guide testing for TP53 (2009 Chompret criteria) [33]: a proband who has a tumor belonging to the LFS spectrum before age 46 and at least one first- or second-degree relative with an LFS tumor, or a proband with multiple tumors, two of which belong to the LFS spectrum and the first of which occurred before age 46 or a proband with adrenocortical carcinoma or choroid plexus tumor, irrespective of family history.
Clinical Genetics
LFS is inherited in an autosomal dominant fashion and is caused by germline mutations in the TP53 gene. Sequencing of TP53 detects about 95 % of all mutations in TP53. Deletion analysis can identify an additional 1 % of mutations in TP53. Most mutations are inherited and the exact frequency of de novo mutations in TP53 is not established. Penetrance is high but not complete. The risk of cancer in LFS is estimated to be 50 % by age 30 years and 90 % by age 60 years, with higher risks in women than men. Mutations in CHEK2 have been reported in a few families, but it is not thought to be a major underlying cause of LFS.
Tumor Spectrum
During childhood, LFS individuals are at high risk of developing adrenocortical carcinoma, soft sarcomas including rhabdomyosarcoma, osteosarcoma, and leukemia. Brain tumors associated with LFS are high-grade gliomas, choroid plexus carcinoma (CPC), and medulloblastoma.
Diffuse Astrocytoma (Grade II–IV)
Malignant gliomas are the most frequent brain tumors affecting individuals with LFS. However, they tend to occur during late childhood and adult life. In the setting of LFS, both de novo glioblastoma and diffuse astrocytomas with secondary transformation are reported. The prognosis for LFS-associated gliomas is just as poor as in sporadic cases.
The fact that brain tumors seem to cluster in certain families with LFS suggests that mutations in specific regions of TP53, such as those binding the minor groove of DNA, may exert some degree of organ-specific carcinogenesis. Mutations in IDH1, ubiquitous in secondary sporadic GBM, are also present in astrocytomas from LFS patients [34]. However, in all reported cases the acquired mutation was R132C, a rare occurrence in the setting of sporadic tumors (<5 %).
Choroid Plexus Carcinoma
TP53 alterations play a significant role in CPC tumorigenesis. Somatic TP53 mutations were observed in 50 % of CPC and germline mutations in 16–36 % of patients. Therefore, the new LFS guidelines include CPC as a part of the diagnostic criteria for LFS. P53 dysfunction is associated with poor outcome in CPC; however, the significance of germline TP53 mutations on survival is still unknown.
Medulloblastoma
Medulloblastomas account for 11 % of reported LFS-associated brain tumors. TP53 mutations are found in 5–10 % of medulloblastomas. Most LFS-associated medulloblastomas belong to the SHH group and are associated with the large cell type, anaplastic type, high degree of genomic instability, and poor outcome [35]. In contrast to CPC which occur at young age, most LFS-associated medulloblastomas occur in the second decade at older age than sporadic medulloblastomas.
Clinical Applications
Current recommendations are to screen every patient with CPC for tumor and germline TP53 mutations. Medulloblastomas which stain positive for P53 or belong to the SHH subgroup should be screened for TP53 mutations and if positive proceed to genetic counseling and germline testing. Since most childhood gliomas are not associated with LFS, testing should rely on family and patient history. Since surveillance protocol has been shown to improve survival for individuals with LFS [36], this protocol should be offered to all patients and family members (see Fig. 17.1 now).
Von Hippel-Lindau Disease
Von Hippel-Lindau (VHL) is an autosomal dominant disorder, and is suspected in the presence of characteristic lesions such as hemangioblastomas, multiple renal cysts and renal cell carcinoma, pheochromocytoma, and endolymphatic sac tumors.
Diagnosis of VHL is established clinically, using the following diagnostic criteria: in an individual with no family history of VHL, the presence of at least two characteristic lesions and in an individual with a positive family history of VHL, the presence of retinal angioma, spinal or cerebellar hemangioblastoma, pheochromocytoma, renal cell carcinoma, or multiple renal or pancreatic cysts.
VHL type 1 is the combination of retinal angioma, CNS hemangioblastoma, renal cell carcinoma, pancreatic cysts, and neuroendocrine tumors. It is characterized by a low risk of pheochromocytoma. VHL type 2 is associated with pheochromocytoma. VHL type 2A is the combination of pheochromocytoma, retinal angiomas, and CNS hemangioblastoma, with a low risk for renal cell carcinoma. VHL type 2B combines the characteristics of type 2A with pancreatic cysts, neuroendocrine tumors, and a high risk for renal cell carcinoma. VHL type 2C is associated with pheochromocytoma only.
Clinical Genetics
VHL is a major tumor suppressor in the hypoxia-induced factor (HIF) pathway. This oncogenic pathway is activated in many cancers and is responsible for angiogenesis in these tumors. VHL recruits ubiquitin ligase that targets HIF for degradation. In recent years, other tumor suppressive functions of VHL have been recognized, linking it to other cancer predisposition syndromes [37]. Molecular analysis identifies mutations in 95 % of classical VHL, partial or whole gene deletions accounting for 30–40 % of cases. Mutations are inherited in about 80 % of cases and de novo in 20 %. Truncating mutations or missense mutations that are predicted to grossly disrupt protein structure are associated with VHL type 1. Other missense mutations are typically associated with VHL type 2. Penetrance is high: almost all individuals with a mutation in VHL develop symptoms by age 65.
Tumor Spectrum
Central Nervous System Hemangioblastomas
Hemangioblastomas of the CNS are the most common tumor in VHL disease, affecting 60–80 % of all patients at an average age of 33 years. The earliest case reported was at 11 years of age. In a recent series of 6 children with solitary cerebellar hemangioblastoma, only those with other suggestive features of VHL had a germline mutation [38]. Although of benign nature, these tumors are a major cause of morbidity. Symptoms related to hemangioblastomas depend on tumor location and size, the presence of associated cysts (30–80 %), and/or edema. They arise anywhere along the craniospinal: spinal cord (13–50 %), the cerebellum (44–72 %), the brainstem (10–25 %), the lumbosacral nerve roots (<1 %), and the supratentorial region (<1 %). Hemangioblastomas of the CNS often grow at several sites simultaneously with an irregular and unpredictable growth pattern. They are best assessed by gadolinium-enhanced MRI. Preoperative embolization is done at some centers to reduce tumor vascularity before resection. Most of them can be safely and completely resected by surgery. Stereotactic radiation therapy is used in case of multiple craniospinal hemangioblastomas, especially those not associated with cysts. Erythrocytosis occurs in 5–20 % of cerebral hemangioblastomas and can necessitate periodic phlebotomies, but it responds to surgical resection [39].