Pediatric and Developmental Pathology 18, 49–58, 2015 DOI: 10.2350/14-07-1531-MISC.1 ª 2015 Society for Pediatric Pathology

MISCELLANEOUS

Rhabdoid Tumor Predisposition Syndrome SIMONE T. SREDNI1,2,3*

AND

TADANORI TOMITA1,2

1 Ann and Robert H. Lurie Children’s Hospital of Chicago–Division of Pediatric Neurosurgery, 225 E. Chicago Avenue, Box #28, Chicago, IL 60611, USA 2 Northwestern University–Feinberg School of Medicine, 420 East Superior Street, Chicago, IL 60611, USA 3 Stanley Manne Children’s Research Institute, 2430 North Halstead Street, Chicago, IL 60614, USA

Received July 28, 2014; accepted December 10, 2014; published online December 10, 2014.

ABSTRACT

INTRODUCTION

Rhabdoid tumors (RT), or malignant rhabdoid tumors, are among the most aggressive and lethal forms of human cancer. They can arise in any location in the body but are most commonly observed in the brain, where they are called atypical teratoid/rhabdoid tumors (AT/RT), and in the kidneys, where they are called rhabdoid tumors of the kidney. The vast majority of rhabdoid tumors present with a loss of function in the SMARCB1 gene, also known as INI1, BAF47, and hSNF5, a core member of the SWI/SNF chromatin-remodeling complex. Recently, mutations in a 2nd locus of the SWI/SNF complex, the SMARCA4 gene, also known as BRG1, were found in rhabdoid tumors with retention of SMARCB1 expression. Familial cases may occur in a condition known as rhabdoid tumor predisposition syndrome (RTPS). In RTPS, germline inactivation of 1 allele of a gene occurs. When the mutation occurs in the SMARCB1 gene, the syndrome is called RTPS1, and when the mutation occurs in the SMARCA4 gene it is called RTPS2. Children presenting with RTPS tend to develop tumors at a younger age, but the impact that germline mutation has on survival remains unclear. Adults who carry the mutation tend to develop multiple schwannomas. The diagnosis of RTPS should be considered in patients with RT, especially if they have multiple primary tumors, and/or in individuals with a family history of RT. Because germline mutations result in an increased risk of carriers developing RT, genetic counseling for families with this condition is recommended.

Rhabdoid tumors are among the most aggressive and lethal forms of human cancer [1–5]. They are typically diagnosed in infants and children, but they can occur at any age. Initially, Beckwith and Palmer described rhabdoid tumors in the kidney as an aggressive form of Wilms tumor. Since then, rhabdoid tumors have been described in virtually every anatomic site, including the brain, soft tissue, lungs, ovaries, and liver [3,6–9], but they most frequently originate in the kidneys and brain. Rhabdoid tumors originating in any location receive the generic name of malignant rhabdoid tumors (MRT). However, when MRT arise in the kidney they are specifically called rhabdoid tumors of the kidney (RTK), and when they arise in the brain, they are called atypical teratoid/rhabdoid tumors (AT/RT). The name AT/RT was conceived by Rorke and colleagues [10] when rhabdoid tumors of the central nervous system were defined as a new entity. It reflects the ‘‘unusual combination of mixed cellular elements similar to but not typical of teratomas’’ observed in that group of tumors. Currently, rhabdoid tumors originating at any anatomic location are recognized as the same tumor type, with similar morphology, biology, and clinical behavior [11]. The cell origin of MRT remains unknown. In a previous report [12] based on a microarray gene expression study, we suggested that rhabdoid tumors may arise through a developmental arrest of neural crest stem cells. Rhabdoid tumors are associated with a dismal outcome, with a median survival of less than 1 year [2,13–17]. The most significant factor that has been associated with survival is the patient’s age at the time of diagnosis. Patients who are younger at the time of diagnosis typically have a worse survival rate [18]. Treatment options depend on the tumor’s location, clinical staging, and the patient’s age [15,17,19–22]. Treating AT/RT requires surgically resecting as much of the tumor as possible while preserving neurologic function, followed by an intensive multimodal regimen.

Key words: AT/RT, malignant rhabdoid tumors, rhabdoid tumor predisposition syndrome, schwannomatosis, SMARCA4, SMARCB1

*Corresponding author, e-mail: [email protected]

Figure 1. Survival curve (Kaplan-Mayer) of 24 atypical teratoid/rhabdoid tumor (AT/RT) patients treated at our institution between 2002 and 2012 showing 25% survival probability in 5 years.

Chemotherapy may include vincristine, cisplatin, cyclophosphamide, etoposide, actinomycin D, and temozolomide. The addition of intrathecal chemotherapy and radiation therapy depends on the child’s age and the extent of the disease [15]. This regimen has significantly improved patients’ survival rates. Regrettably, despite the progress, the treatments’ toxic side effects are substantial, and most patients still rapidly succumb to their diseases. In our own experience, the 24 AT/RT patients treated at our institution between 2002 and 2012 had a 5-year survival probability of 25% (Fig. 1).

GENETICS Regardless of their site of origin, the vast majority of MRT demonstrate abnormalities in chromosome 22 [23,24]. These abnormalities are characterized by the loss of function of a member of the SWI/SNF chromatinremodeling complex located at 22q11.2, known as hSNF5, INI1, BAF47, or SMARCB1 [25]. Although all of these aliases are widely used, this review article will use the official nomenclature of SMARCB1, which stands for SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily b, member 1. The SWI/SNF chromatin-remodeling complex consists of 12–15 subunits and uses energy obtained from adenosine triphosphate (ATP) hydrolysis to remodel nucleosomes and modulate gene transcription. Mutations in genes encoding these subunits, structural abnormalities, or epigenetic modifications that lead to reduced or aberrant expression of members of the SWI/SNF complex have been reported in 20% of human cancers [26,27]. The member of this complex encoded by the SMARCB1 gene is recruited to various chromatin regions, including gene

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promoters, that regulate cell cycle, growth, and differentiation [25,28–30]. The SMARCB1 abnormalities in rhabdoid tumors are characterized as somatically acquired biallelic inactivating truncating mutations within tumors with or without a predisposing germline mutation [4,5,31–33]. This characteristic implicates SMARCB1 as a tumor suppressor gene, as defined by Knudson in the ‘‘two-hit model’’ [34,35]. Despite the highly malignant nature of rhabdoid tumors, Lee and colleagues proposed that rhabdoid tumors have a ‘‘remarkably simple genome.’’ This was recognized after whole-exome sequencing and single neucleotide pholymorphisms array analysis identified an extremely low rate of recurring mutations, with SMARCB1 inactivation being the main recurrent genetic event involved in rhabdoid tumor development [36–38]. Recently, a 2nd core element of the SWI/SNF chromatin-remodeling complex, the SMARCA4 gene, also known as BRG1 and located at 19p13.2, was found to be inactivated in rare cases of rhabdoid tumors that retained SMARCB1 expression, as detected by immunohistochemistry [39–42].

A 2ND LOCUS FOR MRT Evidence of an alternative tumor suppressor locus for MRT was demonstrated for the 1st time in 2006. In that report, Fruhwald and colleagues describe a family of 3 children. Among them, 1 child was affected by an AT/RT and another by an RTK. Extensive analyses were performed to confirm the above-mentioned diagnoses while eventually rejecting SMARCB1 involvement [42]. Upon further evaluation of the family for germline and somatic inactivation of other members of the SWI/SNF chromatin-remodeling complex, the subunit SMARCA4 was found to be implicated [40]. After that, a sporadic case of AT/RT with retention of SMARCB1 expression and loss of SMARCA4 expression by immunohistochemistry due to homozygous SMARCA4 mutation was described [43]. The SMARCA4 gene (which stands for SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4) is also known as BRG1, SNF2, or BAF190. It encodes a catalytic ATPase subunit of the SWI/SNF complex and functions as a tumor suppressor, as does SMARCB1. SMARCA4 mutations have been observed in pediatric cancers such as medulloblastomas [44–46], Burkitt lymphomas [47,48], and in multiple adult tumors, including lung tumors [49– 52], mesotheliomas [53], small cell carcinomas of the ovary hypercalcemic type [54,55], and hepatocellular carcinomas [56]. Although the clinical significance of SMARCA4 mutation in MRT is still not known, it has been suggested that SMARCA4-mutated AT/RT may be associated with a worse prognosis and a higher frequency of germline mutations when compared to SMARCB1-deficient AT/RT [57].

HISTOLOGY The histology of rhabdoid tumors can be fairly variable, and the diagnosis may be difficult to establish based solely on histopathological criteria. Malignant rhabdoid tumors may display a combination of cellular elements consisting of undifferentiated ‘‘small round blue cells,’’ mesenchymal and epithelial components besides the classic rhabdoid phenotype characterized by large cells with eccentrically placed nuclei, a prominent nucleolus, well-defined cell borders, and abundant eosinophilic cytoplasm containing occasional pale cytoplasmic inclusion bodies that correspond to aggregates of intermediate filaments [58] (Fig. 2A–C). The rhabdoid component can be absent or undetected and tumors may consist mainly of the small cell embryonal component (Fig. 2D). Because the rhabdoid component may be limited to small focal areas, sampling limitations may present an additional challenge to diagnose these tumors. The mesenchymal component is usually represented by spindle cells within a basophilic background (Fig. 2E,F), and the epithelial component, which is very rarely observed, can be represented by squamous, papillary, adenomatous, or ribbon-like structures. Malignant rhabdoid tumors are highly proliferative tumors, and, therefore, mitoses are frequently observed. Architecturally, they frequently grow as solid sheets of noncohesive tumor cells.

IMMUNOHISTOCHEMISTRY Malignant rhabdoid tumors are polyphenotypic tumors that express markers of divergent differentiation. Rhabdoid tumors have a classic immune profile that shows diffuse expression of smooth muscle actin, epithelial membrane antigen (EMA) (Fig. 2I), and vimentin (Fig. 2H). These markers are associated with variable expression of neuron-specific enolase, Leu7, and S100; absence of expression of muscle markers such as desmin and myogenin; and loss of expression of SMARCB1 [59,60]. Documenting loss of SMARCB1 protein expression (Fig. 2G) is particularly useful to characterize the tumor and should be included in the final diagnosis. Tumors that retain the expression of SMARCB1 but that exhibit MRT features should be tested for loss of SMARCA4 protein expression by immunohistochemistry [41,43,54]. These tumors may be classified among a very recently described group of SMARCA4-mutated MRT [43,57].

DIFFERENTIAL DIAGNOSIS Loss of SMARCB1 protein expression is not unique to MRT. A growing number of tumor types with loss of SMARCB1 expression have been described [58,61]. These tumors include epithelioid sarcomas [62–69], chordomas [70,71], epithelioid malignant peripheral nerve sheath tumors [58,72], myoepithelial carcinomas [73], the newly described cribriform neuroepithelial tumor [74–77], primitive neuroectodermal tumors [78,79], choroid plexus carcinomas [80], myoepithelial

tumors [69], schwannomatosis [81–84], and meningiomas [85,86], among others [69,87–89] (Table 1). As mentioned before, the morphology of MRT is fairly variable, and indistinctive pathologic features can make the diagnosis challenging. The above-mentioned tumors should be considered within the differential diagnoses when SMARCB1 expression is lost. In children, the most important differential diagnoses are epithelioid sarcomas and chordomas. Epithelioid sarcomas (ES) are slow growing tumors with a high rate of recurrence and metastasis. They affect primarily adolescents and young adults, arising most commonly on distal upper extremities. Both conventional-type and proximal-type ES have a distinctive immunohistochemical staining with expression of EMA, high- and low-molecular-weight cytokeratins, and CD34. Significantly, almost 90% of ES have loss of SMARCB1 expression [58,63,64]. Proximal-type ES are usually more aggressive than conventional-type ES, and they often show focal rhabdoid features [63,64,92,93]. These similarities may suggest a potential connection between ES and MRT. However, ES lack the characteristic lethality and high metastatic potential observed in MRT. Furthermore, differently from MRT, no cases of ES have been reported in families with somatic mutations of the SMARCB1 gene, which suggests that ES and MRT may indeed be distinct entities [63]. Among tumors with loss of SMARCB1 expression, the diagnosis of chordomas should also be considered. Chordomas are malignant tumors that are assumed to originate from notochordal remnants. They are slow-growing tumors that frequently present multiple recurrences. They usually grow in the sacrum and clivus. Pediatric chordomas are rare and often more aggressive than those found in adults. Loss of SMARCB1 expression was observed in pediatric chordomas with a higher frequency when compared to adults [70]. The immunohistochemical profile shows expression of cytokeratins, EMA, S100, vimentin, and epithelial growth factor receptor. Antibody anti-brachyury, a transcription factor required for posterior mesoderm differentiation and notochord development, has been recognized as a specific diagnostic marker for chordoma and should be included in the diagnostic panel [94]. Although rare, myoepithelial carcinomas of soft tissue in children should not be forgotten among the differential diagnoses of MRT. Their characteristic cytologic heterogeneity, in which myoepithelioid cells may resemble rhabdoid cells, loss of SMARCB1 expression in almost half of the tumors, and their potentially aggressive clinical behavior make it important to rule out this entity among tumors originating in soft tissues [58,73].

RHABDOID TUMOR PREDISPOSITION SYNDROME It has been estimated that up to one third of patients with rhabdoid tumors harbor SMARCB1 germline inactivating

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Table 1.

Tumors with loss of SMARCB1 expression Described in No. of cases with pediatric/ documented loss of SMARCB1 expression adolescent patients

SMARCB1-deficient tumors

Reference

Epithelioid sarcomas Epithelioid sarcomas Epithelioid sarcomas Epithelioid sarcomas Epithelioid sarcomas Epithelioid sarcomas Epithelioid sarcomas Epithelioid sarcomas of the bone Chordomas Chordomas, poorly differentiated Chondrosarcoma with thoracic MRT Extraskeletal myxoid chondrosarcoma Myoepithelial carcinomas CRINET CRINET CRINET CRINET CNS-PNET CNS-PNET Choroid plexus carcinomas Myoepithelial tumors Familial schwannomatosis Familial schwannomatosis with meningiomas Sporadic schwannomatosis Schwannomatosis with leiomyoma Meningiomas with schwannomas Familial meningiomas Carcinomas of the sinonasal tract Synovial sarcomas Renal medullary carcinomas Mucinous carcinomas with rhabdoid features

Le Loarer and colleagues [64] 37 Sullivan and colleagues [65] 12 Rekhi and Jambhekar [69] 23 Kosemehmetoglu and colleagues [66] 2 Gasparini and colleagues [67] 25 Hornick and colleagues [63] 127 Modena and colleagues [62] 6 Raoux and colleagues [68] 1 Yadav and colleagues [70] 5 Mobley and colleagues [71] 4 Forest and colleagues [90] 1 Kohashi and colleagues [91] 4 Gleason and colleagues [73] 9 Arnold and colleagues [74] 1 Park and colleagues [76] 1 Ibrahim and colleagues [77] 1 Hasselblatt and colleagues [75] 2 Miller and colleagues [78] 5 Haberler and colleagues [79] 9 Zakrzewska and colleagues [80] 1 Rekhi and Jambhekar [69] 4 Smith and colleagues [82] 14 Melean and colleagues [83] 8 Rousseau and colleagues [84] 5 Hulsebos and colleagues [81] 1 van den Munckhof and colleagues [85] 11 Christiaans and colleagues [86] 5 Bishop and colleagues [87] 9 Rekhi and Jambhekar [69] 1 Cheng and colleagues [88] 5 Cho and colleagues [89] 1

X X X X X X X X X X X X X X X X X X X X

MRT indicates malignant rhabdoid tumors; CRINET, cribriform neuroepithelial tumor; CNS-PNET, central nervous system primitive neuroectodermal tumors.

mutations [18,95–97]. Although most of these mutations seem to occur de novo, familial cases have been reported in which an inherited constitutional SMARCB1 mutation of 1 allele predisposes a patient to developing a rhabdoid tumor. This condition is known as rhabdoid tumor predisposition syndrome (RTPS). Families with inherited SMARCA4 mutations predisposing to rhabdoid tumor development have also been described [40–42]. As a result of the 2 possible mutation loci for RTPS, the syndrome has split into 2 types: when a mutation occurs in the SMARCB1 gene it is called rhabdoid tumor predisposition syndrome type 1 (RTPS1: OMIM#609322), and when a mutation occurs in the SMARCA4 gene, it is called rhabdoid tumor predisposition syndrome type 2 (RTPS2: OMIM#613325). The typical RTPS pedigree contains at least 2 individuals who carry germline mutations of the gene. In these families, there is usually more than one individual affected by rhabdoid tumors, in addition to carriers of the mutant alleles [97–104]. If children are affected by a de novo germline SMARCB1 mutation and

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survive to adulthood, they can potentially transmit the mutation to their offspring. In 1999, Sevenet and colleagues [102] first described a hereditary syndrome in which constitutional mutations of the SMARCB1 gene could predispose patients to rhabdoid tumors. Almost concurrently, Proust and collaborators [101] published a case report describing 2 sisters of consanguineous parents who were diagnosed with AT/RT almost simultaneously and died shortly after the diagnosis. Sixteen years prior to the description of the syndrome, Lynch and collaborators [105] reported 2 sisters with paravertebral rhabdoid tumors occurring within their 1st year of life. Both tumors possessed identical pathological features that were characteristic of rhabdoid tumors. The patients’ disease rapidly progressed and eventually led to their deaths. This may have been the 1st time that a case of RTPS was reported. Children with germline mutations of the SMARCB1 gene have a higher incidence of multiple rhabdoid tumors [96]. There are 2 reported infants with germline SMARCB1 mutations who developed primary RTK

Figure 2. Histology of atypical teratoid/rhabdoid tumors (AT/RT) shows (A–C) areas of rhabdoid phenotype containing rhabdoid cells with eccentric nuclei, prominent nucleoli, and abundant eosinophilic cytoplasm with occasional cytoplasmic inclusions (hematoxylin and eosin [H&E], 340; inserts, 3160 digital). (D) Primitive undifferentiated component (H&E, 340). (E) Mesenchymal component with spindle cells and collagen deposition (H&E, 340). (F) Primitive undifferentiated (p), mesenchymal (m), and rhabdoid cells (r) side by side (H&E, 340). Characteristic immunohistochemical expression pattern showing (G) loss of SMARCB1 protein expression in tumor cells and retention of expression in endothelial cells (BAF47/ hSNF5, 340; insert 3160 digital); (H) diffuse expression of epithelial membrane antigen (EMA, 340; insert 380 digital) and (I) vimentin (Vim, 340; insert 380 digital).

followed by a 2nd primary AT/RT [106]. Another report [33] describes a 4-month-old child who developed an AT/ RT and then subsequently developed an RTK with identical SMARCB1 mutations. Patients with RTPS tend also to develop tumors at a younger age, when compared to children with sporadic tumors [18,97,104]. Presently, the effect of germline mutations on survival remains unclear. Nevertheless, incomplete penetrance and gonadal mosaicism may be present in familial cases, which might confound the assessment of an individual’s cancer risk [96]. Therefore, recommendations for surveillance of carriers of the mutations have not been established yet [107]. As the field develops and more cases are diagnosed, the reported number of long-term survivors among RTPS families is growing significantly [108–110]. Cases of familial-associated rhabdoid tumors are still uncommon but are rising in frequency. This suggests that either their incidence is increasing or that this condition is

now more readily recognized and therefore increasingly diagnosed [18,41,42,96,98–105,108,111].

GENETIC DIAGNOSIS The genetic diagnosis of RTPS should be considered in individuals with a family history of MRT and/or patients with MRT, especially if they have multiple primary tumors. If loss of SMARCB1 or SMARCA4 expression is detected by immunohistochemistry in a tumor with histological features of MRT, a sample of the tumor (either frozen or formalin-fixed, paraffin-embedded) should then be screened for somatic mutations of SMARCB1 or SMARCA4. This includes direct sequencing of the entire gene coding region. Although fresh-frozen tissue is preferable, formalin-fixed, paraffin-embedded samples can be evaluated if frozen tissue is not available. The somatic mutations should then be investigated in patient’s blood. Once constitutional genetic alterations are

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Figure 3. (A) Pedigree diagram of a rhabdoid tumor predisposition syndrome type1 family. Solid black indicates children affected by atypical teratoid/rhabdoid tumors (AT/RT) (subjects 4, 6); black diagonal lines indicate carriers of the mutation that are also affected by schwannomatosis (subjects 1 and 2); subject 8 corresponds to a child who has been presumably affected by an AT/RT. (B, C) Axial T2-weighted magnetic resonance images showing (B) AT/RT from subject 4, 2-month-old female with a large cerebellopontine angle tumor, and (C) AT/RT from subject 6, 7-month-old male with an intraventricular tumor.

detected in the patient, the parents’ blood should then be examined and screened for the constitutional mutations carried by the patient. If the examination does not reveal the same genetic alterations in the patient’s parents, it can be inferred that the patient developed the mutation de novo and did not inherit it from his or her parents. In RTPS, genetic counseling should be included as part of the patient’s treatment plan.

RHABDOID TUMOR PREDISPOSITION SYNDROME AND SCHWANNOMATOSIS Schwannomas are benign nerve sheath tumors that most frequently occur as solitary, encapsulated subcutaneous masses. Several syndromes are associated with an increased frequency of schwannomas. Of these syndromes, the most widely known are the neurofibromatoses. The characteristic tumors of neurofibromatosis type 2 (NF2) are vestibular schwannomas, and those of neurofibromatosis type 1 (NFl) are neurofibromas. Schwannomatosis is the 3rd major form of neurofibromatosis. It is characterized by the development of multiple spinal, peripheral, and cranial nerve schwannomas in the absence of vestibular schwannomas [112,113]. It has been reported that schwannomatosis patients harbor somatic mutations in the NF2 gene, but linkage studies have excluded NF2 as the transmissible germline schwannomatosis gene [114, 116]. Recently, the SMARCB1 gene has been found to harbor alterations in both familial and sporadic schwannomatosis patients [84,117–120]. Hulsebos and colleagues [117] identified a family in which 2 of the members had schwannomatosis with an inactivating germline mutation of 1 allele of SMARCB1, somatic mutation of the 2nd SMARCB1 allele, and partial loss of the SMARCB1 protein expression within the tumors.

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These findings pointed to SMARCB1 as a candidate predisposing gene in familial schwannomatosis. Almost simultaneously, Boyd and collaborators [120] found that over two thirds of schwannomatosis kindreds (13/19) had constitutional alterations in the SMARCB1 transcript. Forty to 50% of familial cases of schwannomatosis and 8 to 10% of sporadic cases demonstrated constitutional mutations in SMARCB1 [69–74]. Germline mosaicism may also occur in schwannomatosis [121]. Sestini and collaborators [118] suggested that a 4-hit mechanism involving SMARCB1 and NF2 would trigger schwannomatosis-related tumorigenesis. SMARCB1 is located fairly close (approximately 6 megabases centromeric) to NF2 on chromosome 22. It is currently accepted that tumorigenesis may occur through this 4-hit, 3-step model, ‘‘starting with a germline mutation in SMARCB1 (hit 1) and subsequent loss of a portion of chromosome 22 that contains the second SMARCB1 allele and one NF2 allele (hits 2 and 3). This is then followed by a mutation in the remaining wild-type NF2 allele (hit 4)’’ [122]. Recently, exon analysis of 23 patients with familial schwannomatosis identified 61% of probands with SMARCB1 germline point mutations. These data confirmed the previous finding that the majority of the constitutional alterations of SMARCB1 in familial schwannomatosis are nontruncating and therefore do not inactivate SMARCB1 protein expression. This is in contrast to mutations found in RTPS that did lead to a complete loss of protein expression [4,31,82,123]. Interestingly, schwannomatosis-related mutant SMARCB1 proteins seem to be biologically functional and retain the ability to repress cyclinD1 transcription [82]. This might be of fundamental significance for the pathway that defines which tumor type develops. Although somatic and germline SMARCB1 mutations have been identified in both rhabdoid tumors and

schwannomatosis, few reports note their co-occurrence within families that carry these mutations [72,124,125]. We have in our institution a RTPS1 family in which 2 of the 4 children are being treated for AT/RT (Fig. 3). Multiple members of this family have the same germline SMARCB1 mutation. Both affected children inherited the mutation from their father, who inherited the mutation from his mother. Both carriers of the mutation, the father and the grandmother, developed schwannomatosis as adults. Of interest, a paternal grandmother’s brother died at the age of 18 months from a brain tumor in the 1960s. Rhabdoid tumors were not recognized at that time, and this boy received a different diagnosis. However, in light of the current knowledge we can consider this individual to be ‘‘presumably affected’’ by an AT/RT. This case illustrates a typical RTPS type 1 family, in which there are multiple children affected by AT/RT and carriers of the mutation who developed schwannomatosis as adults.

CONCLUSIONS Rhabdoid tumors are extremely aggressive tumors that can occur at multiple anatomical locations and usually affect young children. The diagnosis of these tumors is confirmed by loss of expression of 1 of 2 components of the SWI/SNF chromatin-remodeling complex, SMARCB1 and SMARCA4, due to inactivating mutations in either of these genes. These tumors may develop sporadically or as part of a hereditary syndrome called RTPS. The diagnosis of RTPS should be considered in patients with MRT, especially if they have multiple primary tumors and/or if there are multiple family members with a history of MRT. Germline mutations result in an increased risk of rhabdoid tumor development. Although rare, the diagnosis of MRT and RTPS should be considered by the pathologist, and genetic counseling should be provided for families with this condition. ACKNOWLEDGMENTS The authors thank the Rally Foundation for Childhood Cancer Research in memory of Hailey Trainer and the Vs. Cancer Foundation for financial support. The authors also thank Pauline M. Chou, MD, for histology support; Chiang-Ching Huang, PhD, for assistance with survival analysis; and Abby L. Halpern, BA, and Maya Behn for editorial support. REFERENCES 1. Heck JE, Lombardi CA, Cockburn M, Meyers TJ, Wilhelm M, Ritz B. Epidemiology of rhabdoid tumors of early childhood. Pediatr Blood Cancer 2013;60:77–81. 2. Tomlinson GE, Breslow NE, Dome J, et al. Rhabdoid tumor of the kidney in the National Wilms’ Tumor Study: age at diagnosis as a prognostic factor. J Clin Oncol Off J Am Soc Clin Oncol 2005;23: 7641–7645. 3. Rorke LB, Packer R, Biegel J. Central nervous system atypical teratoid/rhabdoid tumors of infancy and childhood. J Neuro-Oncol 1995;24:21–28.

4. Versteege I, Sevenet N, Lange J, et al. Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Nature 1998;394:203– 206. 5. Biegel JA, Tan L, Zhang F, Wainwright L, Russo P, Rorke LB. Alterations of the hSNF5/INI1 gene in central nervous system atypical teratoid/rhabdoid tumors and renal and extrarenal rhabdoid tumors. Clin Cancer Res Off J Am Assoc Cancer Res 2002;8:3461– 3467. 6. Beckwith JB, Palmer NF. Histopathology and prognosis of Wilms tumors: results from the First National Wilms’ Tumor Study. Cancer 1978;41:1937–1948. 7. Tsuneyoshi M, Daimaru Y, Hashimoto H, Enjoji M. The existence of rhabdoid cells in specified soft tissue sarcomas. Histopathological, ultrastructural and immunohistochemical evidence. Virchows Arch A Pathol Anat Histopathol 1987;411:509–514. 8. Parham DM, Weeks DA, Beckwith JB. The clinicopathologic spectrum of putative extrarenal rhabdoid tumors. An analysis of 42 cases studied with immunohistochemistry or electron microscopy. Am J Surg Pathol 1994;18:1010–1029. 9. Wick MR, Ritter JH, Dehner LP. Malignant rhabdoid tumors: a clinicopathologic review and conceptual discussion. Semin Diagn Pathol 1995;12:233–248. 10. Rorke LB, Packer RJ, Biegel JA. Central nervous system atypical teratoid/rhabdoid tumors of infancy and childhood: definition of an entity. J Neurosurg 1996;85:56–65. 11. Grupenmacher AT, Halpern AL, Bonaldo Mde F, et al. Study of the gene expression and microRNA expression profiles of malignant rhabdoid tumors originated in the brain (AT/RT) and in the kidney (RTK). Child’s Nervous Syst Off J Int Soc Pediatr Neurosurg 2013; 29:1977–1983. 12. Gadd S, Sredni ST, Huang CC, Perlman EJ. Rhabdoid tumor: gene expression clues to pathogenesis and potential therapeutic targets. Lab Invest 2010;90:724–738. 13. Burger PC, Yu IT, Tihan T, et al. Atypical teratoid/rhabdoid tumor of the central nervous system: a highly malignant tumor of infancy and childhood frequently mistaken for medulloblastoma: a Pediatric Oncology Group study. Am J Surg Pathol 1998;22:1083–1092. 14. Packer RJ, Biegel JA, Blaney S, et al. Atypical teratoid/rhabdoid tumor of the central nervous system: report on workshop. J Pediatr Hematol Oncol 2002;24:337–342. 15. Chi SN, Zimmerman MA, Yao X, et al. Intensive multimodality treatment for children with newly diagnosed CNS atypical teratoid rhabdoid tumor. J Clin Oncol Off J Am Soc Clin Oncol 2009;27: 385–389. 16. Bourdeaut F, Freneaux P, Thuille B, et al. Extra-renal non-cerebral rhabdoid tumours. Pediatr Blood Cancer 2008;51:363–368. 17. Hilden JM, Meerbaum S, Burger P, et al. Central nervous system atypical teratoid/rhabdoid tumor: results of therapy in children enrolled in a registry. J Clin Oncol Off J Am Soc Clin Oncol 2004; 22:2877–2884. 18. Bourdeaut F, Lequin D, Brugieres L, et al. Frequent hSNF5/INI1 germline mutations in patients with rhabdoid tumor. Clin Cancer Res Off J Am Assoc Cancer Res 2011;17:31–38. 19. Strother D. Atypical teratoid rhabdoid tumors of childhood: diagnosis, treatment and challenges. Expert Rev Anticancer Ther 2005;5:907–915. 20. Fidani P, De Ioris MA, Serra A, et al. A multimodal strategy based on surgery, radiotherapy, ICE regimen and high dose chemotherapy in atypical teratoid/rhabdoid tumours: a single institution experience. J Neuro-Oncol 2009;92:177–183. 21. Tekautz TM, Fuller CE, Blaney S, et al. Atypical teratoid/rhabdoid tumors (ATRT): improved survival in children 3 years of age and older with radiation therapy and high-dose alkylator-based chemotherapy. J Clin Oncol Off J Am Soc Clin Oncol 2005;23:1491–1499. 22. Gardner SL, Asgharzadeh S, Green A, Horn B, McCowage G, Finlay J. Intensive induction chemotherapy followed by high dose chemotherapy with autologous hematopoietic progenitor cell rescue in young children newly diagnosed with central nervous system atypical teratoid rhabdoid tumors. Pediatr Blood Cancer 2008;51:235–240.

RHABDOID TUMOR PREDISPOSITION SYNDROME

55

23. Biegel JA, Burk CD, Parmiter AH, Emanuel BS. Molecular analysis of a partial deletion of 22q in a central nervous system rhabdoid tumor. Genes Chromosomes Cancer 1992;5:104–108. 24. Biegel JA, Allen CS, Kawasaki K, Shimizu N, Budarf ML, Bell CJ. Narrowing the critical region for a rhabdoid tumor locus in 22q11. Genes Chromosomes Cancer 1996;16:94–105. 25. Roberts CW, Biegel JA. The role of SMARCB1/INI1 in development of rhabdoid tumor. Cancer Biol Ther 2009;8:412–416. 26. Biegel JA, Busse TM, Weissman BE. SWI/SNF chromatin remodeling complexes and cancer. Am J Med Genet Part C Semin Med Genet 2014;166:350–366. 27. Helming KC, Wang X, Roberts CW. Vulnerabilities of mutant SWI/ SNF complexes in cancer. Cancer Cell 2014;26:309–317. 28. Wilson BG, Roberts CW. SWI/SNF nucleosome remodellers and cancer. Nat Rev Cancer 2011;11:481–492. 29. Reisman D, Glaros S, Thompson EA. The SWI/SNF complex and cancer. Oncogene 2009;28:1653–1668. 30. Roberts CW, Orkin SH. The SWI/SNF complex—chromatin and cancer. Nat Rev Cancer 2004;4:133–142. 31. Biegel JA, Zhou JY, Rorke LB, Stenstrom C, Wainwright LM, Fogelgren B. Germ-line and acquired mutations of INI1 in atypical teratoid and rhabdoid tumors. Cancer Res 1999;59:74–79. 32. Kalpana GV, Marmon S, Wang W, Crabtree GR, Goff SP. Binding and stimulation of HIV-1 integrase by a human homolog of yeast transcription factor SNF5. Science 1994;266:2002–2006. 33. Biegel JA, Fogelgren B, Wainwright LM, Zhou JY, Bevan H, Rorke LB. Germline INI1 mutation in a patient with a central nervous system atypical teratoid tumor and renal rhabdoid tumor. Genes Chromosomes Cancer 2000;28:31–37. 34. Knudson AG Jr. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 1971;68:820–823. 35. Knudson AG. Hereditary cancer: two hits revisited. J Cancer Res Clin Oncol 1996;122:135–140. 36. Jackson EM, Sievert AJ, Gai X, et al. Genomic analysis using highdensity single nucleotide polymorphism-based oligonucleotide arrays and multiplex ligation-dependent probe amplification provides a comprehensive analysis of INI1/SMARCB1 in malignant rhabdoid tumors. Clin Cancer Res Off J Am Assoc Cancer Res 2009;15:1923–1930. 37. Lee RS, Stewart C, Carter SL, et al. A remarkably simple genome underlies highly malignant pediatric rhabdoid cancers. J Clin Invest 2012;122:2983–2988. 38. Kieran MW, Roberts CW, Chi SN, et al. Absence of oncogenic canonical pathway mutations in aggressive pediatric rhabdoid tumors. Pediatr Blood Cancer 2012;59:1155–1157. 39. Foulkes WD, Clarke BA, Hasselblatt M, Majewski J, Albrecht S, McCluggage WG. No small surprise—small cell carcinoma of the ovary, hypercalcaemic type, is a malignant rhabdoid tumour. J Pathol 2014;233:209–214. 40. Schneppenheim R, Fruhwald MC, Gesk S, et al. Germline nonsense mutation and somatic inactivation of SMARCA4/BRG1 in a family with rhabdoid tumor predisposition syndrome. Am J Hum Genet 2010;86:279–284. 41. Witkowski L, Lalonde E, Zhang J, et al. Familial rhabdoid tumour ‘avant la lettre’—from pathology review to exome sequencing and back again. J Pathol 2013;231:35–43. 42. Fruhwald MC, Hasselblatt M, Wirth S, et al. Non-linkage of familial rhabdoid tumors to SMARCB1 implies a second locus for the rhabdoid tumor predisposition syndrome. Pediatr Blood Cancer 2006;47:273–278. 43. Hasselblatt M, Gesk S, Oyen F, et al. Nonsense mutation and inactivation of SMARCA4 (BRG1) in an atypical teratoid/rhabdoid tumor showing retained SMARCB1 (INI1) expression. Am J Surg Pathol 2011;35:933–935. 44. Robinson G, Parker M, Kranenburg TA, et al. Novel mutations target distinct subgroups of medulloblastoma. Nature 2012;488:43–48. 45. Pugh TJ, Weeraratne SD, Archer TC, et al. Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations. Nature 2012;488:106–110.

56

S.T. SREDNI AND T. TOMITA

46. Northcott PA, Korshunov A, Pfister SM, Taylor MD. The clinical implications of medulloblastoma subgroups. Nat Rev Neurol 2012; 8:340–351. 47. Oike T, Ogiwara H, Nakano T, Yokota J, Kohno T. Inactivating mutations in SWI/SNF chromatin remodeling genes in human cancer. Jpn J Clin Oncol 2013;43:849–855. 48. Wong AK, Shanahan F, Chen Y, et al. BRG1, a component of the SWI-SNF complex, is mutated in multiple human tumor cell lines. Cancer Res 2000;60:6171–6177. 49. Imielinski M, Berger AH, Hammerman PS, et al. Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell 2012;150:1107–1120. 50. Matsubara D, Kishaba Y, Ishikawa S, et al. Lung cancer with loss of BRG1/BRM, shows epithelial mesenchymal transition phenotype and distinct histologic and genetic features. Cancer Sci 2013;104: 266–273. 51. Rodriguez-Nieto S, Canada A, Pros E, et al. Massive parallel DNA pyrosequencing analysis of the tumor suppressor BRG1/SMARCA4 in lung primary tumors. Hum Mutat 2011;32:E1999–E2017. 52. Medina PP, Romero OA, Kohno T, et al. Frequent BRG1/ SMARCA4-inactivating mutations in human lung cancer cell lines. Hum Mutat 2008;29:617–622. 53. Yoshikawa Y, Sato A, Tsujimura T, et al. Biallelic germline and somatic mutations in malignant mesothelioma: multiple mutations in transcription regulators including mSWI/SNF genes. Int J Cancer 2015;136:560–571. 54. Foulkes WD, Clarke BA, Hasselblatt M, Majewski J, Albrecht S, McCluggage WG. No small surprise—small cell carcinoma of the ovary, hypercalcaemic type, is a malignant rhabdoid tumour. J Pathol 2014;233:209–214. 55. Bailey S, Murray MJ, Witkowski L, et al. Biallelic somatic SMARCA4 mutations in small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). Pediatr Blood Cancer (in press). 56. Endo M, Yasui K, Zen Y, et al. Alterations of the SWI/SNF chromatin remodelling subunit-BRG1 and BRM in hepatocellular carcinoma. Liver Int Off J Int Assoc Study Liver 2013;33:105–117. 57. Hasselblatt M, Nagel I, Oyen F, et al. SMARCA4-mutated atypical teratoid/rhabdoid tumors are associated with inherited germline alterations and poor prognosis. Acta Neuropathol 2014;128:453– 456. 58. Hollmann TJ, Hornick JL. INI1-deficient tumors: diagnostic features and molecular genetics. Am J Surg Pathol 2011;35:e47– e63. 59. Judkins AR, Mauger J, Ht A, Rorke LB, Biegel JA. Immunohistochemical analysis of hSNF5/INI1 in pediatric CNS neoplasms. Am J Surg Pathol 2004;28:644–650. 60. Hoot AC, Russo P, Judkins AR, Perlman EJ, Biegel JA. Immunohistochemical analysis of hSNF5/INI1 distinguishes renal and extra-renal malignant rhabdoid tumors from other pediatric soft tissue tumors. Am J Surg Pathol 2004;28:1485–1491. 61. Agaimy A. The expanding family of SMARCB1(INI1)-deficient neoplasia: implications of phenotypic, biological, and molecular heterogeneity. Adv Anat Pathol 2014;21:394–410. 62. Modena P, Lualdi E, Facchinetti F, et al. SMARCB1/INI1 tumor suppressor gene is frequently inactivated in epithelioid sarcomas. Cancer Res 2005;65:4012–4019. 63. Hornick JL, Dal Cin P, Fletcher CD. Loss of INI1 expression is characteristic of both conventional and proximal-type epithelioid sarcoma. Am J Surg Pathol 2009;33:542–550. 64. Le Loarer F, Zhang L, Fletcher CD, et al. Consistent SMARCB1 homozygous deletions in epithelioid sarcoma and in a subset of myoepithelial carcinomas can be reliably detected by FISH in archival material. Genes Chromosomes Cancer 2014;53:475–486. 65. Sullivan LM, Folpe AL, Pawel BR, Judkins AR, Biegel JA. Epithelioid sarcoma is associated with a high percentage of SMARCB1 deletions. Mod Pathol Off J US Can Acad Pathol 2013;26:385–392. 66. Kosemehmetoglu K, Kaygusuz G, Bahrami A, et al. Intra-articular epithelioid sarcoma showing mixed classic and proximal-type

67. 68.

69.

70.

71.

72.

73.

74.

75.

76.

77.

78.

79.

80.

81.

82.

83.

84.

85.

features: report of 2 cases, with immunohistochemical and molecular cytogenetic INI-1 study. Am J Surg Pathol 2011;35: 891–897. Gasparini P, Facchinetti F, Boeri M, et al. Prognostic determinants in epithelioid sarcoma. Eur J Cancer 2011;47:287–295. Raoux D, Peoc’h M, Pedeutour F, Vaunois B, Decouvelaere AV, Folpe AL. Primary epithelioid sarcoma of bone: report of a unique case, with immunohistochemical and fluorescent in situ hybridization confirmation of INI1 deletion. Am J Surg Pathol 2009;33:954– 958. Rekhi B, Jambhekar NA. Immunohistochemical validation of INI1/ SMARCB1 in a spectrum of musculoskeletal tumors: an experience at a tertiary cancer referral centre. Pathol Res Pract 2013;209:758– 766. Yadav R, Sharma MC, Malgulwar PB, et al. Prognostic value of MIB-1, p53, epidermal growth factor receptor, and INI1 in childhood chordomas. Neuro-Oncol 2014;16:372–381. Mobley BC, McKenney JK, Bangs CD, et al. Loss of SMARCB1/ INI1 expression in poorly differentiated chordomas. Acta Neuropathol 2010;120:745–753. Carter JM, O’Hara C, Dundas G, et al. Epithelioid malignant peripheral nerve sheath tumor arising in a schwannoma, in a patient with ‘‘neuroblastoma-like’’ schwannomatosis and a novel germline SMARCB1 mutation. Am J Surg Pathol 2012;36:154–160. Gleason BC, Fletcher CD. Myoepithelial carcinoma of soft tissue in children: an aggressive neoplasm analyzed in a series of 29 cases. Am J Surg Pathol 2007;31:1813–1824. Arnold MA, Stallings-Archer K, Marlin E, et al. Cribriform neuroepithelial tumor arising in the lateral ventricle. Pediatr Dev Pathol 2013;16:301–307. Hasselblatt M, Oyen F, Gesk S, et al. Cribriform neuroepithelial tumor (CRINET): a nonrhabdoid ventricular tumor with INI1 loss and relatively favorable prognosis. J Neuropathol Exp Neurol 2009; 68:1249–1255. Park JY, Kim E, Kim DW, Chang HW, Kim SP. Cribriform neuroepithelial tumor in the third ventricle: a case report and literature review. Neuropathol Off J Jpn Soc Neuropathol 2012;32: 570–576. Ibrahim GM, Huang A, Halliday W, et al. Cribriform neuroepithelial tumour: novel clinicopathological, ultrastructural and cytogenetic findings. Acta Neuropathol 2011;122:511–514. Miller S, Ward JH, Rogers HA, Lowe J, Grundy RG. Loss of INI1 protein expression defines a subgroup of aggressive central nervous system primitive neuroectodermal tumors. Brain Pathol 2013;23:19– 27. Haberler C, Laggner U, Slavc I, et al. Immunohistochemical analysis of INI1 protein in malignant pediatric CNS tumors: lack of INI1 in atypical teratoid/rhabdoid tumors and in a fraction of primitive neuroectodermal tumors without rhabdoid phenotype. Am J Surg Pathol 2006;30:1462–1468. Zakrzewska M, Wojcik I, Zakrzewski K, et al. Mutational analysis of hSNF5/INI1 and TP53 genes in choroid plexus carcinomas. Cancer Genet Cytogenet 2005;156:179–182. Hulsebos TJ, Kenter S, Siebers-Renelt U, Hans V, Wesseling P, Flucke U. SMARCB1 involvement in the development of leiomyoma in a patient with schwannomatosis. Am J Surg Pathol 2014;38:421–425. Smith MJ, Walker JA, Shen Y, Stemmer-Rachamimov A, Gusella JF, Plotkin SR. Expression of SMARCB1 (INI1) mutations in familial schwannomatosis. Hum Mol Genet 2012;21:5239–5245. Melean G, Velasco A, Hernandez-Imaz E, et al. RNA-based analysis of two SMARCB1 mutations associated with familial schwannomatosis with meningiomas. Neurogenetics 2012;13:267–274. Rousseau G, Noguchi T, Bourdon V, Sobol H, Olschwang S. SMARCB1/INI1 germline mutations contribute to 10% of sporadic schwannomatosis. BMC Neurol 2011;11:9. van den Munckhof P, Christiaans I, Kenter SB, Baas F, Hulsebos TJ. Germline SMARCB1 mutation predisposes to multiple meningio-

mas and schwannomas with preferential location of cranial meningiomas at the falx cerebri. Neurogenetics 2012;13:1–7. 86. Christiaans I, Kenter SB, Brink HC, et al. Germline SMARCB1 mutation and somatic NF2 mutations in familial multiple meningiomas. J Med Genet 2011;48:93–97. 87. Bishop JA, Antonescu CR, Westra WH. SMARCB1 (INI-1)deficient carcinomas of the sinonasal tract. Am J Surg Pathol 2014;38:1282–1289. 88. Cheng JX, Tretiakova M, Gong C, Mandal S, Krausz T, Taxy JB. Renal medullary carcinoma: rhabdoid features and the absence of INI1 expression as markers of aggressive behavior. Mod Pathol Off J US Can Acad Pathol 2008;21:647–652. 89. Cho YM, Choi J, Lee OJ, Lee HI, Han DJ, Ro JY. SMARCB1/INI1 missense mutation in mucinous carcinoma with rhabdoid features. Pathol Int 2006;56:702–706. 90. Forest F, David A, Arrufat S, et al. Conventional chondrosarcoma in a survivor of rhabdoid tumor: enlarging the spectrum of tumors associated with SMARCB1 germline mutations. Am J Surg Pathol 2012;36:1892–1896. 91. Kohashi K, Oda Y, Yamamoto H, et al. SMARCB1/INI1 protein expression in round cell soft tissue sarcomas associated with chromosomal translocations involving EWS: a special reference to SMARCB1/INI1 negative variant extraskeletal myxoid chondrosarcoma. Am J Surg Pathol 2008;32:1168–1174. 92. Fisher C. Epithelioid sarcoma of Enzinger. Adv Anat Pathol 2006; 13:114–121. 93. Guillou L, Wadden C, Coindre JM, Krausz T, Fletcher CD. ‘‘Proximal-type’’ epithelioid sarcoma, a distinctive aggressive neoplasm showing rhabdoid features. Clinicopathologic, immunohistochemical, and ultrastructural study of a series. Am J Surg Pathol 1997;21:130–146. 94. Barresi V, Ieni A, Branca G, Tuccari G. Brachyury: a diagnostic marker for the differential diagnosis of chordoma and hemangioblastoma versus neoplastic histological mimickers. Dis Markers 2014;2014:514753. 95. Biegel JA. Molecular genetics of atypical teratoid/rhabdoid tumor. Neurosurg Focus 2006;20:E11. 96. Eaton KW, Tooke LS, Wainwright LM, Judkins AR, Biegel JA. Spectrum of SMARCB1/INI1 mutations in familial and sporadic rhabdoid tumors. Pediatr Blood Cancer 2011;56:7–15. 97. Kordes U, Gesk S, Fruhwald MC, et al. Clinical and molecular features in patients with atypical teratoid rhabdoid tumor or malignant rhabdoid tumor. Genes Chromosomes Cancer 2010;49:176–181. 98. Lee HY, Yoon CS, Sevenet N, Rajalingam V, Delattre O, Walford NQ. Rhabdoid tumor of the kidney is a component of the rhabdoid predisposition syndrome. Pediatr Dev Pathol Off J Soc Pediatr Pathol Paediatr Pathol Soc 2002;5:395–399. 99. Fernandez C, Bouvier C, Sevenet N, et al. Congenital disseminated malignant rhabdoid tumor and cerebellar tumor mimicking medulloblastoma in monozygotic twins: pathologic and molecular diagnosis. Am J Surg Pathol 2002;26:266–270. 100. Janson K, Nedzi LA, David O, et al. Predisposition to atypical teratoid/rhabdoid tumor due to an inherited INI1 mutation. Pediatr Blood Cancer 2006;47:279–284. 101. Proust F, Laquerriere A, Constantin B, Ruchoux MM, Vannier JP, Freger P. Simultaneous presentation of atypical teratoid/rhabdoid tumor in siblings. J Neuro-Oncol 1999;43:63–70. 102. Sevenet N, Sheridan E, Amram D, Schneider P, Handgretinger R, Delattre O. Constitutional mutations of the hSNF5/INI1 gene predispose to a variety of cancers. Am J Hum Genet 1999;65: 1342–1348. 103. Taylor MD, Gokgoz N, Andrulis IL, Mainprize TG, Drake JM, Rutka JT. Familial posterior fossa brain tumors of infancy secondary to germline mutation of the hSNF5 gene. Am J Hum Genet 2000;66:1403–1406. 104. Bruggers CS, Bleyl SB, Pysher T, et al. Clinicopathologic comparison of familial versus sporadic atypical teratoid/rhabdoid tumors (AT/RT) of the central nervous system. Pediatr Blood Cancer 2011;56:1026–1031.

RHABDOID TUMOR PREDISPOSITION SYNDROME

57

105. Lynch HT, Shurin SB, Dahms BB, Izant RJ Jr, Lynch J, Danes BS. Paravertebral malignant rhabdoid tumor in infancy. In vitro studies of a familial tumor. Cancer 1983;52:290–296. 106. Savla J, Chen TT, Schneider NR, Timmons CF, Delattre O, Tomlinson GE. Mutations of the hSNF5/INI1 gene in renal rhabdoid tumors with second primary brain tumors. J Natl Cancer Inst 2000;92:648–650. 107. Samuel N, Villani A, Fernandez CV, Malkin D. Management of familial cancer: sequencing, surveillance and society. Nat Rev Clin Oncol 2014;11:723–731. 108. Ammerlaan AC, Ararou A, Houben MP, et al. Long-term survival and transmission of INI1-mutation via nonpenetrant males in a family with rhabdoid tumour predisposition syndrome. Br J Cancer 2008;98:474–479. 109. Kordes U, Bartelheim K, Modena P, et al. Favorable outcome of patients affected by rhabdoid tumors due to rhabdoid tumor predisposition syndrome (RTPS). Pediatr Blood Cancer 2014;61: 919–921. 110. Modena P, Sardi I, Brenca M, et al. Case report: long-term survival of an infant syndromic patient affected by atypical teratoidrhabdoid tumor. BMC Cancer 2013;13:100. 111. Harris TJ, Donahue JE, Shur N, Tung GA. Case 168: rhabdoid predisposition syndrome—familial cancer syndromes in children. Radiology 2011;259:298–302. 112. MacCollin M, Woodfin W, Kronn D, Short MP. Schwannomatosis: a clinical and pathologic study. Neurology 1996;46:1072–1079. 113. MacCollin M, Chiocca EA, Evans DG, et al. Diagnostic criteria for schwannomatosis. Neurology 2005;64:1838–1845. 114. Jacoby LB, Jones D, Davis K, et al. Molecular analysis of the NF2 tumor-suppressor gene in schwannomatosis. Am J Hum Genet 1997;61:1293–1302. 115. Kaufman DL, Heinrich BS, Willett C, et al. Somatic instability of the NF2 gene in schwannomatosis. Arch Neurol 2003;60:1317–1320.

58

S.T. SREDNI AND T. TOMITA

116. MacCollin M, Willett C, Heinrich B, et al. Familial schwannomatosis: exclusion of the NF2 locus as the germline event. Neurology 2003;60:1968–1974. 117. Hulsebos TJ, Plomp AS, Wolterman RA, Robanus-Maandag EC, Baas F, Wesseling P. Germline mutation of INI1/SMARCB1 in familial schwannomatosis. Am J Hum Genet 2007;80:805–810. 118. Sestini R, Bacci C, Provenzano A, Genuardi M, Papi L. Evidence of a four-hit mechanism involving SMARCB1 and NF2 in schwannomatosis-associated schwannomas. Hum Mutat 2008;29:227–231. 119. Hadfield KD, Newman WG, Bowers NL, et al. Molecular characterisation of SMARCB1 and NF2 in familial and sporadic schwannomatosis. J Med Genet 2008;45:332–339. 120. Boyd C, Smith MJ, Kluwe L, Balogh A, Maccollin M, Plotkin SR. Alterations in the SMARCB1 (INI1) tumor suppressor gene in familial schwannomatosis. Clin Genet 2008;74:358–366. 121. Hulsebos TJ, Kenter SB, Jakobs ME, Baas F, Chong B, Delatycki MB. SMARCB1/INI1 maternal germ line mosaicism in schwannomatosis. Clin Genet 2010;77:86–91. 122. Plotkin SR, Blakeley JO, Evans DG, et al. Update from the 2011 International Schwannomatosis Workshop: from genetics to diagnostic criteria. Am J Med Genet Part A 2013;161A:405–416. 123. Patil S, Perry A, Maccollin M, et al. Immunohistochemical analysis supports a role for INI1/SMARCB1 in hereditary forms of schwannomas, but not in solitary, sporadic schwannomas. Brain Pathol 2008;18:517–519. 124. Swensen JJ, Keyser J, Coffin CM, Biegel JA, Viskochil DH, Williams MS. Familial occurrence of schwannomas and malignant rhabdoid tumour associated with a duplication in SMARCB1. J Med Genet 2009;46:68–72. 125. Rizzo D, Freneaux P, Brisse H, et al. SMARCB1 deficiency in tumors from the peripheral nervous system: a link between schwannomas and rhabdoid tumors? Am J Surg Pathol 2012;36: 964–972.