Rhabdoid Tumor Predisposition Syndrome

Clinical characteristics.

Rhabdoid tumor predisposition syndrome (RTPS) is characterized by a markedly increased risk of developing rhabdoid tumors – rare and highly aggressive malignant tumors occurring predominantly in infants and children younger than age three years. Rhabdoid tumors can occur in almost any anatomic location, commonly in the central nervous system (i.e., atypical teratoid/rhabdoid tumor [AT/RT]); more than 50% occur in the cerebellum.

Other common locations include extracranial extrarenal malignant rhabdoid tumors (e.g., rhabdoid tumors of the head and neck, paravertebral muscles, liver, bladder, mediastinum, retroperitoneum, pelvis, and heart) (eMRT), rhabdoid tumor of the kidney (RTK), and possibly small-cell carcinoma of the ovary (hypercalcemic type). Individuals with RTPS typically present before age 12 months with synchronous tumors that exhibit aggressive clinical behavior.

Diagnosis/testing.

The diagnosis of RTPS is established in a proband with a rhabdoid tumor and/or a family history of rhabdoid tumor and/or multiple SMARCA4- or SMARCB1-deficient tumors (synchronous or metachronous) and identification of a germline heterozygous pathogenic variant in SMARCA4 or SMARCB1 by molecular genetic testing.

Management.

Treatment of manifestations: Due to the rarity of RTPS, standards for management are evolving. Most individuals are treated by intensive multimodal therapeutic strategies, according to institutional preference combining surgery, radiotherapy, and chemotherapy.

Prevention of primary manifestations: Prophylactic bilateral oophorectomy may be discussed after childbearing.

Prevention of secondary manifestations: Consider risk-reducing treatment strategies (e.g., postpone or replace radiotherapy with high-dose chemotherapy or proton beam therapy; targeted therapy used concomitantly with, or before, standard chemotherapy).

Surveillance: From birth to age one year:

• Monthly physical and neurologic examination, head ultrasound, and abdominal and pelvic ultrasound recommended.
• If not feasible for patients with AT/RT, monthly head ultrasound plus abdominal and pelvic ultrasound every two to three months is a minimum requirement. If fontanelle closes prematurely consider head MRI every two to three months.
• For patients with eMRT, RTK: monthly head, abdominal, and pelvic ultrasound examination.
• If ultrasound is not sufficient consider MRI at least every two to three months for affected site and ultrasound for all other sites. Whole-body MRI is desirable but not universally available.

From age one year to age four to five years:

• For patients with AT/RT: brain and total spine MRI every three months
• If available, consider whole-body MRI. (Note: Whole-body MRI resolution may not be sufficent for brain MRI, which would then need to be performed separately).
• For patients with eMRT, RTK: abdominal and pelvic ultrasound or MRI (or whole-body MRI) every three months.

After age four years:

• Twice-yearly physical examination in a tumor predisposition clinic with targeted imaging for symptomatic areas.
• For patients with SMARCA4-related SCCOHT: abdominal and pelvic ultrasound every six months.

Evaluation of relatives at risk: It is appropriate to evaluate apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of screening, treatment, and preventive measures.

Genetic counseling.

RTPS is inherited in an autosomal dominant manner. The vast majority of individuals diagnosed with RTPS have the disorder as the result of a de novo germline SMARCB1 pathogenic variant. Most reported individuals diagnosed with SMARCA4-related RTPS inherited a pathogenic variant from an unaffected parent. Each child of an individual with a germline SMARCA4 or SMARCB1 pathogenic variant has a 50% chance of inheriting the pathogenic variant. However, penetrance appears to be incomplete and the types of RTPS-related tumors can vary among different members of the same family. Prenatal testing and preimplantation genetic testing are possible if the pathogenic variant in the family is known.

Suggestive Findings

Rhabdoid tumor predisposition syndrome (RTPS) should be suspected in an individual with any of the following clinical or laboratory features.

Clinical features. Any rhabdoid tumor with the following features is particularly suspicious:

• Congenital presentation (i.e., prenatal diagnosis or symptoms within the first 28 days of life)
• Early-onset rhabdoid tumor (age <12 months)
• Advanced stage of rhabdoid tumor (RT) at diagnosis (e.g., >M₁ by Chang classification; Stage ≥II in extracranial RT [Harisiadis & Chang 1977])
• Synchronous rhabdoid tumors (>1 primary rhabdoid tumor)
• Family history of rhabdoid tumor, small-cell carcinoma of the ovary hypercalcemic type, or other malignant entities such as cribriform neuroepithelial tumor, malignant peripheral nerve sheath tumor, and non-malignant schwannoma or meningioma
• Family history of RTPS

Given the limited patient data available, germline molecular genetic testing for RTPS is recommended in any individual with:

• A rhabdoid tumor (at any age), familial rhabdoid tumors, multifocal tumors, or congenital-onset tumors;
• A SMARCB1-deficient tumor (as defined by histology, rhabdoid and non-rhabdoid) with a familial history of rhabdoid tumor OR non-specified cancer in early childhood (age <5 years);
• A SMARCA4-deficient tumor (as defined by histology, rhabdoid and non-rhabdoid) with a familial history of rhabdoid tumor OR non-specified cancer in early childhood (age <5 years).

Note: (1) It remains to be determined whether adult-onset rhabdoid tumors are caused by germline pathogenic variants in SMARCA4 or SMARCB1. (2) As morphologic rhabdoid features may not be present in all rhabdoid tumor biopsies because of inter- and intratumoral heterogeneity, any small blue round cell tumors in infants and young children should be evaluated for absence of nuclear SMARCA4 or SMARCB1 staining.

Laboratory features on tumor tissue

• Immunohistochemistry. Absence of SMARCA4 (formerly BRG-1) or SMARCB1 (formerly INI-1) staining in tumor tissue
• Molecular genetic testing. Somatic SMARCA4 or SMARCB1 pathogenic variants identified in a rhabdoid tumor. Note: Fresh-frozen tumor is preferable; formalin-fixed, paraffin-embedded samples may also be suitable.

Establishing the Diagnosis

There is currently no consensus regarding formal diagnostic criteria for rhabdoid tumor predisposition syndrome (RTPS).

The diagnosis of RTPS is established in a proband with both of the following:

• A rhabdoid tumor and/or a family history of rhabdoid tumor and/or multiple SMARCA4- or SMARCB1-deficient tumors (synchronous or metachronous)
• Identification of a germline pathogenic variant in SMARCA4 or SMARCB1 by molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include serial single-gene testing and use of a multigene panel.

Serial single-gene testing may be considered in individuals with absence of SMARCA4 or SMARCB1 identified on tumor immunohistochemistry:

• Absence of SMARCA4. Sequence analysis and gene-targeted deletion/duplication analysis of SMARCA4 may be performed first.
• Absence of SMARCB1. Sequence analysis and gene-targeted deletion/duplication analysis of SMARCB1 may be performed first.

A multigene panel that includes SMARCA4, SMARCB1, and other genes of interest (see Differential Diagnosis) may be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel provides the best opportunity to identify the genetic cause of the condition at the most reasonable cost while limiting identification of pathogenic variants in genes that do not explain the underlying phenotype. 3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Description

Rhabdoid tumor predisposition syndrome (RTPS) is characterized by a markedly increased risk of developing rhabdoid tumors.

Rhabdoid tumors are rare and highly aggressive malignant tumors occurring predominantly in infants and children younger than age three years. The term rhabdoid is derived from the histologic resemblance of tumor cells to rhabdomyoblast. Rhabdoid tumors are characterized by heaps of cells with an eccentric nucleus and prominent nucleolus, abundant cytoplasm with eosinophilic inclusion bodies, and distinct cellular membranes. Immunohistochemically rhabdoid tumor cells are characterized by increased expression of vimentin (a nonspecific marker), epithelial membrane antigen (EMA), cytokeratins, and loss of SMARCB1 protein (a strong indicator for rhabdoid tumor).

As morphologic rhabdoid features may not be present in all rhabdoid tumor biopsies because of inter- and intratumoral heterogeneity, any small blue round cell tumor in infants and young children should be evaluated for absence of nuclear SMARCB1 staining.

Primary rhabdoid tumor locations include the following:

• Central nervous system (atypical teratoid/rhabdoid tumor [AT/RT]; >50% are cerebellar)
• Head and neck, paravertebral muscles, liver, bladder, mediastinum, retroperitoneum, pelvis, and heart (extracranial malignant rhabdoid tumor [eMRT])
• Kidney (rhabdoid tumor of the kidney [RTK])
• Ovary (small-cell carcinoma of the ovary [SCCOHT] ‒ hypercalcemic type)

Rhabdoid tumors have been reported in nearly all anatomic locations [Brennan et al 2013, Sredni & Tomita 2015, Frühwald et al 2016a].

Individuals with RTPS typically present before age 12 months with synchronous tumors that exhibit aggressive clinical behavior, often in one of the following clinical settings:

• Prenatally detected synchronous rhabdoid tumors
• Infantile-onset or congenital rhabdoid tumor, presentingat median age of four to seven months (range: prenatally – 60 months) (compared to individuals with sporadic rhabdoid tumor: median age 13-30 months; range: age 1 day - 228 months) [Bruggers et al 2011, Geller et al 2015, Frühwald et al 2016b]. Note: A bias toward increased molecular testing in younger individuals may confound the data.
• Synchronous (multiple primary) rhabdoid tumors. Individuals with RTPS have a higher incidence of multiple rhabdoid tumors [Eaton et al 2011]. 28% of patients with RTPS in the EU-RHAB Registry had synchronous tumors; eight individuals had AT/RT and eMRT, four individuals had AT/RT and RTK, and two individuals with congenital synchronous tumors had AT/RT, multiple eMRT, and RTK [Frühwald et al 2016b].
• Family history of rhabdoid tumor, cribriform neuroepithelial tumor (CRINET), and/or distinct combinations of rhabdoid tumor with one of the following: schwannoma, malignant peripheral nerve sheath tumor, meningioma, or CRINET [van den Munckhof et al 2012]
• Family history of small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT) for SMARCA4-related RTPS (germline SMARCB1 pathogenic variants have not been reported in individuals with SCCOHT) [Moes-Sosnowska et al 2015, Witkowski et al 2017]
• Clinically aggressive rhabdoid tumor. Tumor progression at the time of follow up was identified in 91% of individuals with RTPS. Progression occurred while on chemotherapy in 58% of individuals with RTPS [Sredni & Tomita 2015, EU-RHAB ‒ Author, personal communication].
• Rhabdoid tumor and syndromic features suggestive of 22q11.2 distal deletion syndrome (OMIM 611867)

Prognosis. Individuals with RTPS potentially have a worse prognosis than those with a sporadic rhabdoid tumor; although long-term survival has been reported in some [Ammerlaan et al 2008, Modena et al 2013, Kordes et al 2014, Seeringer et al 2014b].

Phenotype Correlations by Gene

SMARCA4. Small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT) has been reported in individuals with SMARCA4-related RTPS and has not been reported in individuals with germline SMARCB1 pathogenic variants.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

Penetrance

SMARCA4. Most individuals with SMARCA4-related RTPS have inherited the pathogenic variant from an unaffected, healthy parent. In SMARCA4-related RTPS the penetrance for rhabdoid tumor in the preceding generation of seven informative families was zero. However, in one family, two sibs with a SMARCA4 pathogenic variant were both affected [Schneppenheim et al 2010, Hasselblatt et al 2014].

SMARCB1. There are reports of reduced penetrance. Rarely a SMARCB1 pathogenic variant is inherited from an unaffected parent or a parent with late-onset or undiagnosed RTPS [Ammerlaan et al 2008]. Germline mosaicism accounts for at least half of the families with sibs affected by RTPS.

Nomenclature

Rhabdoid tumor predisposition syndrome may also be referred to as familial posterior fossa brain tumor syndrome.

Current data suggest the value of subgroup determination for diagnostic and therapeutic decision making [Torchia et al 2015, Johann et al 2016]:

• ATRT-TYR is characterized by infratentorial location, younger age at diagnosis (<1year), and overexpression of the genes TYR and MITF.
• In the subgroup ATRT-MYC tumors are mostly supratentorial, affected individuals are older (age 4-5 years) at diagnosis, and the genes MYC, HOTAIR, and HOX are overexpressed.
• The subgroup ATRT-SHH tumor location may be infratentorial or supratentorial, diagnosis is between ages two and five years, and sonic hedgehog pathway genes are overexpressed.

Note: Torchia et al [2016] presented data on three subgroups that was similar to the subgroups described by Johann et al [2016]. A consensus on simplifying subgroup nomenclature is currently being sought.

Prevalence

Among newly diagnosed individuals with rhabdoid tumors, 25%-35% will have a germline pathogenic variant in SMARCB1 [Bourdeaut et al 2011, Eaton et al 2011, Hasselblatt et al 2014].

The incidence of rhabdoid tumors may be estimated according to the following data:

• The age-standardized annual incidence rate is between five (extracranial rhabdoid tumors) and 8.1 per million (atypical teratoid/rhabdoid tumor) in children younger than age one year, and decreases to between 0.6 and 2.2 per million at ages one to four years [Brennan et al 2013, Frühwald et al 2016a].
• In the US, annual incidence among children younger than age 15 is 0.89 per million for AT/RT, 0.32 per million for eMRT, and 0.19 per million for RTK [Heck et al 2013].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with rhabdoid tumor predisposition syndrome (RTPS), the following are recommended:

• Refer individuals with RTPS who have not yet developed a rhabdoid tumor to a pediatric oncologist or tumor surveillance program.
• Consider consulting a radiologist, prior to the planning of therapy, to assist in the selection and review of subsequent imaging, to evaluate the size and location of the primary tumor, and to evaluate for the presence of synchronous tumors and/or metastases (whole-body MRI).
• For individuals with atypical teratoid/rhabdoid tumor (AT/RT), examine cerebrospinal fluid (CSF) and determine classification according to Chang staging [Harisiadis & Chang 1977].
• Refer for genetic counseling.

Treatment of Manifestations

Current data suggest the value of subgroup determination for diagnostic and therapeutic decision making [Torchia et al 2015, Johann et al 2016]:

• ATRT-TYR is characterized by infratentorial location, younger age at diagnosis (<1year), and overexpression of the genes TYR and MITF.
• In the subgroup ATRT-MYC tumors are mostly supratentorial, affected individuals are older (age 4-5 years) at diagnosis, and the genes MYC, HOTAIR, and HOX are overexpressed.
• The subgroup ATRT-SHH tumor location may be infratentorial or supratentorial, diagnosis is between ages two and five years, and sonic hedgehog pathway genes are overexpressed.

Note: Torchia et al [2016] presented data on three subgroups that was similar to the subgroups described by Johann et al [2016]. A consensus on simplifying subgroup nomenclature is currently being sought.

Due to the rarity of RTPS, standards for management are evolving. Most individuals are treated by intensive multimodal therapeutic strategies, combining surgery, radiotherapy, and chemotherapy according to institutional preference:

• The Children's Oncology Group has employed a combination of surgery, two cycles of induction chemotherapy (cisplatinum, cyclophosphamide, etoposide, vincristine, methotrexate), three cycles of high-dose chemotherapy with stem cell rescue (thiotepa, carboplatinum) as consolidation therapy, and radiotherapy according to age and stage [protocol ACNS0333 clinicaltrials.gov, Reddy et al 2016].
• The Dana Faber Consortium has tested combination therapy with surgery, radiotherapy, and chemotherapy (vincristine, dactinomycin, cyclophosphamide, cisplatinum, doxorubicin, temozolomide and intrathecal methotrexate, cytarabine, and hydrocortisone) [clinicaltrials.gov, Chi et al 2009].
• The EU-RHAB Registry recommends using combination therapy for rhabdoid tumors of any location (e.g., AT/RT, rhabdoid tumor of the kidney [RTK], extracranial malignant RT [eMRT]) including gross total resection, conventional chemotherapy (vincristine, dactinomycin, cyclophosphamide, doxorubicin, ifosfamide, carboplatinum, etoposide), intrathecal methotrexate, and permissive use of high-dose chemotherapy with stem cell rescue (carboplatinum, thiotepa) and radiotherapy (in individuals age >18 months). The feasibility of intensive multimodal regimen even in the youngest individuals including those affected by RTPS has been demonstrated [Seeringer et al 2014a, Bartelheim et al 2016].
• The Canadian Brain Tumour Consortium retrospectively evaluated children diagnosed with rhabdoid tumors between 1995 and 2007. Among 40 individuals, 22 received conventional chemotherapy and 18 received high-dose chemotherapy (HDCT) regimens; 15 received adjuvant radiation. Notably, six of 12 long-term survivors never received any radiotherapy [Lafay-Cousin et al 2012].
• Zaky et al evaluated the Head Start III experience for newly diagnosed patients with AT/RT. Between 2003 and 2009, 19 patients were treated with a combination of surgery and five courses of induction chemotherapy followed by consolidation with myeloablative chemotherapy and autologous hematopoietic progenitor cell rescue and radiotherapy according to age and stage. In five patients toxicity-related deaths occurred; ten patients died due to disease progression. The three-year overall survivial (OS) and event-free survival rates were 26±10% and 21±9%, respectively [Zaky et al 2014].
• Schrey et al summarized HDCT data by an individual pooled data analysis of 12 manuscripts and 389 publications including prospective and retrospective studies focused on the treatment of children diagnosed with AT/RT. Data of 332 patients demonstrated an improved outcome in those treated with HDCT-SCR and radiotherapy [Schrey et al 2016].
• Fischer-Valuck evaluated data of 361 children diagnosed with AT/RT between 2004 and 2012. The five-year OS rate was 29.9%, and it was significantly higher for patients with localized disease treated with multimodal therapy (surgery, chemotherapy, and radiotherapy) with a five-year OS of 46.8%. Patients younger than age three years at diagnosis showed significantly worse OS (5-year OS 27.7%) compared to older patients (5-year OS 37.5%) and were also significantly less likely to receive multimodal therapy (specifically, the radiotherapy component). The authors suggest early radiotherapy as an important factor for long-term cure [Fischer-Valuck et al 2017].

Note: RTPS most commonly affects infants; therapy presents a rather complex challenge due to the vulnerability of infants. The use of aggressive multimodal treatment on the developing nervous system and other organ systems of a young individual may profoundly affect developmental (e.g., neurodevelopmental) outcome, and entail significant short- and long-term side effects. Intensive induction chemotherapy may often achieve good responses and individuals may proceed with radiotherapy or (tandem) high-dose chemotherapy (HDCT) followed by autologous stem cell support.

It remains to be determined whether a subgroup of children may be cured by surgery and chemotherapy alone, thus avoiding the potential severe side effects of radiotherapy to the developing brain.

Prevention of Primary Manifestations

Prophylactic bilateral oophorectomy may be discussed with women with SMARCA4-related RTPS after childbearing because of the high risk of developing small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT).

Prevention of Secondary Complications

The intensive multimodal treatment strategies required for clinically aggressive tumors in children with RTPS lead to a higher rate of secondary complications. Therapies and interventions which may prevent secondary complications include the following:

• Consideration of risk-reducing treatment strategies (e.g., postpone or replace radiotherapy with HDCT or proton beam therapy; targeted therapy used concomitant with – or before – standard chemotherapy)
• Long-term or lifelong surveillance in RTPS survivors (see Surveillance)

Surveillance

Surveillance guidelines for patients with RTPS have been provided by Teplick et al [2011] and Foulkes et al [2017].

Birth to age one year. Monthly physical and neurologic examination, head ultrasound, and abdominal and pelvic ultrasound are desirable. If not feasible, alternate guidelines for patients with:

• AT/RT are physical and neurologic examination, including head ultrasound monthly plus every two to three months abdominal and pelvic ultrasound as a minimum requirement. If fontanelle closes prematurely consider head MRI every two to three months.
• eMRT or RTK are abdominal and pelvic plus head ultrasound examination monthly. If ultrasound is not sufficient consider MRI at least every two to three months for affected site and ultrasound for all other sites. Whole-body MRI is desirable but not universally available.

Age one year to age four to five years

• AT/RT. Brain and total spine MRI examination every three months. If available whole-body MRI may be considered. Note: Whole-body MRI resolution may not be sufficent for brain MRI, which would then need to be performed separately.
• eMRT or RTK. Abdominal and pelvic ultrasound examination or MRI every three months; alternatively, whole-body MRI

After age four years the risk of developing a new rhabdoid tumor dramatically decreases [Eaton et al 2011]. It remains worthwhile, however, to screen individuals with RTPS for other manifestations (e.g., schwannomas, SCCOHT). A practical approach would include annual physical examination with targeted imaging for symptomatic areas (e.g., neurologic deficit, change in physical features, menstrual disturbances) and referral to a tumor predisposition clinic.

Note: Individuals diagnosed with SMARCA4-related SCCOHT should be screened by abdominal and pelvic ultrasound examination every six months.

Agents/Circumstances to Avoid

Limit exposure to DNA-damaging agents including radiation (e.g., x-ray, CT, external beam radiotherapy), tobacco, UV light, and chemotherapy to minimize the lifetime risk of developing late-onset secondary cancers. Imaging tests utilizing radioactive compounds should only be used if absolutely necessary for essential health care.

Evaluation of Relatives at Risk

If a germline pathogenic variant in SMARCA4 or SMARCB1 has been identified in an affected individual, molecular genetic testing of apparently asymptomatic older and younger sibs and other at-risk relatives is appropriate. Early detection of individuals who are heterozygous for an SMARCA4 or SMARCB1 pathogenic variant allows prompt initiation of surveillance, treatment, and preventative measures.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

The following clinical trials are currently recruiting unless indicated otherwise:

• NCT02114229: Phase I/II trial of Alisertib as a Single Agent in Recurrent or Progressive Central Nervous System (CNS) Atypical Teratoid Rhabdoid Tumors (AT/RT) and Extra-CNS Malignant Rhabdoid Tumors (MRT) and in Combination Therapy in Newly Diagnosed AT/RT
• NCT02601937: Phase I trial of the EZH2 Inhibitor Tazemetostat in Pediatric Subjects with Relapsed or Refractory INI1-Negative Tumors or Synovial Sarcoma
• NCT02601950: Phase II trial Multicenter Study of the EZH2 Inhibitor Tazemetostat in Adult Subjects With INI1-Negative Tumors or Relapsed/Refractory Synovial Sarcoma
• NCT03213665: Phase II trial Pediatric MATCH: Tazemetostat in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With EZH2, SMARCB1, or SMARCA4 Gene Mutations (not recruiting)
• NCT01747876: Phase I, Multi-center, Open-label Study of LEE011 in Patients with Malignant Rhabdoid Tumors and Neuroblastoma [Geoerger et al 2017] (not recruiting)
• NCT02644460: Phase I trial, Abemaciclib in Children With DIPG or Recurrent/Refractory Solid Tumors (AflacST1501)

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.