CHAPTER

PEDIATRIC ATYPICAL TERATOID/

RHABDOID TUMORS (AN OVERVIEW)

Krishan Kumar Bansal and Deepak Goel

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Table of contents

1. ABSTRACT

2. INTRODUCTION

3. EPIDEMIOLOGY

4. CLINICAL PRESENTATION OF CNS AT/RT

5. IMAGING OF AT/RT

6. GROSS AND MICROSCOPIC PATHOLOGY OF AT/RT

7. CYTOMORPHOLOGICAL FEATURES

8. MOLECULAR PATHOLOGY OF AT/RT

9. TREATMENT OF AT/RT: SURGERY

10. TREATMENT OF AT/RT: CHEMOTHERAPY

11. TREATMENT OF AT/RT: RADIOTHERAPY

12. OUTCOME

13. REFERENCES

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ABSTRACT
Paediatric Atypical teratoid/rhabdoid tumors (AT/RT) of the central nervous system (CNS)

are among the most malignant neoplasms and most often diagnosed in children smaller than 3

years of age and incidence is 1-2% of all brain tumors in children. 63% of the AT/RT of the

CNS is seen in infra-tentorial compartment, there are no precise imaging features that

differentiate AT/RT from the other posterior fossa tumor. The “rhabdoid” cells are

characteristic on cytopathology. It has been established now that CNS, AT/RT often shows

deletion of the long arm of chromosome 22q11.2. The initial treatment for most children with

AT/RT is surgical with and without cerebrospinal fluid diversionary procedure. Children with

less than 3 years of age offered chemotherapy but in older children radiotherapy is given in

addition.

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INTRODUCTION
Paediatric Atypical teratoid/rhabdoid tumors (AT/RT) of central nervous system (CNS) are

rare and very aggressive malignant lesion of early childhood. Because of both the

infrequency and rapid course of disease, consensus has not been made for the standard

treatment so far (Rorke et al., 1996; Strother, 2005; Hilden et al., 1998; Biegel et al., 1990;

Gandhi et al., 2004).

Beckwith and Palmer In 1978 first described a histological variant of Wilm’s tumor that

occurred primarily in infants and was correlated with extremely poor prognosis. It was

subsequently called malignant rhabdoid tumor - meant for the reason that the tumor looked

like a rhabdomyosarcoma, but the cells did not demonstrate usual morphological or immuno-

histo-chemical features of muscle (Haas et al., 1981). A CNS tumor composed of rhabdoid

cells was first reported in 1985 by Briner et al., but the unique clinical and pathological

features were not well defined until 1995-1996 (Rorke et al., 1996).

Since approximately 70% of these tumors contain fields indistinguishable from

Medulloblastoma or primitive neuroectodermal tumor, pathologists by and large gave one or

the other diagnosis. The histological diagnosis is not easy, as there may be considerable

microscopic overlap with these embryonal tumors (Biegel et al., 2000, 2002). However,

study of these tumors with high index of suspicion even in routine HandE stains disclosed

fields of rhabdoid cells with or without areas of primitive neuroepithelial cells and in a

quarter to a third of samples, mesenchymal and/or epithelial elements were seen as well.

Thus, even though such a combination of divergent tissue types suggested that these tumors

were teratomas, although they lacked the standard features essential for such a diagnosis.

The diagnostic term that seemed most suitable was AT/RT and so it was coined (Rorke et al.,

1995, 1996; Bhattacharajee et al., 1997). The histogenesis of this curious and highly

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malignant tumor of the early childhood has remained unidentified (Packer et al., 2002;

Burger et al., 1998; and Fisher et al., 1996). Regarding effective therapy of these tumors till

date no standard protocol has been setup and overall survival even after multidisciplinary

efforts like surgery, radiation and chemotherapy has not improved significantly (Rorke et al.,

1996; Tekautz et al., 2005; and Hilden et al., 2004).

EPIDEMIOLOGY

AT/RT of the CNS most frequently occurs in infants or neonates, the majority of patients

diagnosed being younger than 3 years of age (Rorke et al., 1996; and Gyure, 2005) although

it is not often seen in older children’s as well, 70% v/s 30% (Rorke et al., 1996; and Tekautz

et al., 2005). The mean age at diagnosis ranges from 17 to 29 months (Rorke et al., 1996;

Burger et al., 1998; Gandhi et al., 2004; and Gyure, 2005). These tumors are somewhat more

frequent in boys [3-4: 1-2, male: female ratio] in younger than 3 years age group but in

children’s older than 3 year the ratio is not consistent (Tekautz et al., 2005; and Hilden et al.,

2004). Their incidence is 1-2% of all brain tumors in children, while some investigators

report that 6.7% of CNS tumors in infants 0 to 2 years were AT/RT (Roberts et al., 2000;

Wong et al., 2005; Rickert and Paulus, 2001).

Most common location is infratentorial [60-70%] in the cerebellum or CP angle and rest in

supratentorial, spinal or multifocal. ATRT of CNS has recently shown some age specific site

preference, posterior fossa is the most common site in younger than 3 but in older than 3

preferred location for the development of this tumor is supratentorial (Rorke et al., 1996;

Rorke et al., 1995; Bhattacharjee et al., 1997; Tekautz et al., 2005; and Gyure, 2005).

AT/RT has been reported in an in-utero infant, a pregnant female and also in a patient of

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neurofibromatosis-1; in both of the later tumor was supratentorial (Erickson et al., 2005; and

Kababri et al., 2006).

Prognosis in patients younger than 3 years is very grim if compared with older then 3-year

children. Moreover, younger patients are more likely to present with metastatic disease at

diagnosis and tend to develop progression with higher frequency and earlier in the course of

treatment than older children’s (Rorke et al., 1995; and Tekautz et al., 2005). The results of

Hilden et al suggested that older children diagnosed with AT/RT have better survival (Hilden

et al., 2004).

CLINICAL PRESENTATION OF CNS AT/RT

Since rhabdoid tumors were originally found in the kidney, such tumors have been described

in many different organs and soft tissues, as well as in the CNS. 63% of the AT/RT of the

CNS is seen in infra-tentorial compartment, rest arises in supratentorial [27%] or 8% may be

multifocal (Rorke et al., 1996; Bhattacharjee et al., 1997; Burger et al., 1998; Wong et al.,

2005). While the cerebellum and cerebral hemispheres are the most common locations, these

tumors have a predilection for the cerebellopontine angle (Rorke et al., 1996). They may also

arise in the spinal cord, pineal gland and supra-sellar region (Burger et al., 1998; Wong et

al., 2005). Posterior fossa is a favourite location in children younger than 3 years, as opposed

to older children; the few examples in adults are almost exclusively in the cerebrum (Rorke

et al., 1996; Wong et al., 2005). A small group of children have both renal and CNS rhabdoid

tumors which most likely represent metachronous tumors, possibly due to a germ-line

mutation in the hSNF5 gene.

Infants whose cranial sutures have not yet fused tend to present with non-specific symptoms

such as macro-cephalic, lethargy, vomiting and/or failure to thrive (Gyure, 2005). Older

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children present with head tilts [IV nerve palsy], diplopia [VI nerve palsy], facial weakness

[VII nerve palsy], headache and/or hemiplegia. The majority of children with posterior fossa

AT/RT have hydrocephalus at presentation due to obstruction of the cerebrospinal fluid

(CSF) flow at the fourth ventricle. The set of clinical signs and symptoms in children with

AT/RT is similar to those children with PNET/medulloblastoma [PNET/MB] or any other

tumor in posterior fossa.

One-third of children with AT/RT present with Leptomeningeal spread of tumor at diagnosis,

a rate similar to that seen in children with PNET/MB (Gyure, 2005). There was no noticeable

difference in age of the patient for metastatic disease and those who do not, but recent studies

showing that dissemination of the disease is early and with higher frequency in patients

younger than 3-year (Tekautz et al., 2005). Examination of the CSF at the time of diagnosis

revealed malignant cells in one third of the patients and CSF may be positive even when

cranio-spinal imaging is negative (Burger et al., 1998).

IMAGING OF AT/RT

The imaging procedure of choice in children with AT/RT is a cranio-spinal MRI with and

without gadolinium [Fig. 1 and 2]. The tumor shows low signal intensity on T1 weighted

images and isointense or decreased signal on T2 weighted images (Rorke et al., 1996). Cysts

and haemorrhages are commonly seen. These tumors can be of heterogeneous intensity with

heterogeneous enhancement with peripheral cystic components (Cheng et al., 2005).

Obstructive hydrocephalus and peri-ventricular lucency may be seen, especially with tumors

located in the posterior fossa that block the fourth ventricle or its outlet foramina. The main

tumor mass enhances inhomogeneously after administration of gadolinium. Leptomeningeal

spread appears as diffuse enhancement of the meninges and/or enhancing clumps along the

spinal cord and cauda equina as drop metastasis. All of these features are similar to those

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seen in PNET/MB and, in fact, there are no precise imaging features that differentiate AT/RT

from the PNET/MB. Some children may undergo CT scanning as part of their diagnostic

workup. As with PNET/MB, the AT/RT appears as a hyperdense lesion on an unenhanced

CT scan, presumably due to the high cellularity of the tumor (Rorke et al., 1996).

GROSS AND MICROSCOPIC PATHOLOGY OF AT/RT

Macroscopic features of these tumors differ in no way from those of PNET/MB. They are

soft, pinkish-red, necrotic and/or hemorrhagic. Those with a prominent mesenchymal

component may be firm and contain tan-white foci. Tumors primarily in the cerebello-

pontine angle may incorporate cranial nerve roots in the vicinity. Leptomeningeal deposits

display no specific distinguishing features and are basically similar to PNET/MB. On section,

these tumors tend to infiltrate and have poorly-demarcated margins.

Microscopic characteristics of AT/RT are variable, although it is self-evident that they must

contain rhabdoid cells [Fig.3]. Some tumors consist of only this cell type, whereas more

commonly there is a mixture of rhabdoid fields and areas indistinguishable from classical

PNET/MB (Rorke et al., 1996; Bhattacharjee et al., 1997; and Oka and Scheithauer, 1999).

Although this portion may rarely contain Flexner-Wintersteiner or Homer Wright rosettes,

neither desmoplastic nor the nodularneuroblastic histological types have been observed.

Basically, the PNET/MB portions simply consist of small primitive appearing neuroepithelial

cells (Parwani et al., 2005).

The typical rhabdoid cell is of medium to large size and consists of an eccentric nucleus

adjacent to which is eosinophilic cytoplasm equal to or larger than the size of the nucleus

(Gyure, 2005). This tends to be round or slightly bulbous and may have a faint pink rim

accentuating a denser pink core. Many nuclei contain a prominent nucleolus. Mitotic figures

are frequent. The rhabdoid cells may range from small to large size, pale cells may

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sometimes-containing two nuclei, in a jumbled architectural arrangement (Burger et al.,

1998). The small cell component resembled Medulloblastoma and rarely had cords of cells in

a mucinous background, imitating chordoma. The cytoplasm of the larger cells is prominent

with a somewhat “rhabdoid” appearance, although rhabdoid features were not-always

prominent (Rorke et al., 1995).

Rhabdoid and PNET fields tend to remain separate, as do the epithelial and mesenchymal

components, although there are no sharply delineated margins. A recognizable epithelial

component, which may be adenomatous or squamous, occurs in about a quarter of the

tumors, although a much higher number of tumor cells express epithelial antigens. A small

group of these tumors may mimic Choroid plexus carcinoma; hence this possibility should be

kept in mind. In addition, about one-third of tumors contain neoplastic mesenchymal

elements, which, in the extreme, mimic sarcomas (Rorke et al., 1996). These tumors often

exhibit large areas of necrosis, mitoses and haemorrhage, but intrinsic vasculature generally

manifests no distinctive features (Bhattacharjee et al., 1997).

Certainty in making a specific histological diagnosis of AT/RT may be improved by studying

the tumor with a panel of monoclonal antibodies. Most helpful are the following: epithelial

membrane antigen (EMA), vimentin (V), smooth muscle actin (SMA), keratin (K), glial

fibrillary acidic protein (GFAP) and neurofilament protein (NFP) (Bhattacharjee et al., 1997;

Burger et al., 1998; and Gyure, 2005). Desmin is rarely expressed by the neuroepithelial

cells, but not by rhabdoid cells. Markers for germ cells are consistently negative (Rorke et

al., 1996).

The pattern of expression of these antigens is complex; hence attention must be paid to which

specific cellular component is expressing the antigen. The rhabdoid cells typically express

vimentin and EMA, but SMA less frequently (Gyure, 2005). They may also express K, GFAP

and/or NFP. The neuroepithelial cells express only GFAP and/or NFP, whereas the epithelial

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component expresses K plus or minus EMA; the mesenchymal cells typically express

vimentin and SMA (Rorke et al., 1996).

Ultra structural findings vary, depending upon sampling. The classical, but not

pathognomonic finding in the rhabdoid cell consists of large bundles of intermediate

filaments in the cytoplasm.

CYTOMORPHOLOGICAL FEATURES

For cytological study of these tumors materials can be obtained from smear scraping, squash

preparation or fine needle aspiration (Parwani et al., 2005). Cyto-morphological study of the

tumor shows hyper-cellularity, primarily large tissue fragments with tumor cells adjacent to

growing capillaries illustrating a “papillary-like” appearance and characteristic “rhabdoid”

cells i.e., intermediate-sized cells with granular or fibrillary, brilliantly eosinophilic

cytoplasm with or without globoid “inclusions”; large, eccentrically located, single nucleoli,

small, round, primitive “neuronal-appearing” cells with a high nuclear to cytoplasmic ratio,

speckled chromatin and atypical, occasionally multinucleated giant cells. In addition, few

apoptotic bodies, mitoses, considerable necrosis and prominent dystrophic calcification may

be found (Parwani et al., 2005).

MOLECULAR PATHOLOGY OF AT/RT

It has been established now that CNS, AT/RT often show deletion of the long arm of

chromosome 22q11.2, further molecular studies have led to the identification of a rhabdoid

suppressor gene [INI1/hSNF5] at said location (Hilden et al., 2004; Versteege et al., 1998;

and Biegel, 1997). Somatic mutations in this gene predispose children to develop AT/RT.

Earlier, this was often the only karyotypic change seen in this tumor and it was thought that a

tumor suppressor gene was contained to that region. Furthermore, it was suggested that loss

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of one copy of chromosome 22q could distinguish an AT/RT from a PNET/MB, which is

frequently associated with loss of 17p/isochromosome 17q. Later, Versteege et al. identified

deletions and truncating mutations of the hSNF5 gene on chromosome 22q11 in a series of

cell lines derived from renal rhabdoid tumors (Versteege et al., 1998).

The hSNF5 protein is highly conserved and is not greatly changed between flies, mice and

humans. The hSNF5 protein is the smallest member of a family of proteins that form a

complex, which regulates the DNA through changes in the nucleosome. By ‘winding’ and

‘unwinding’ DNA, this complex changes the configuration of genomic DNA, thus allowing

or denying transcription factors access to the DNA and changing gene expression patterns.

Biegel et al. subsequently identified somatic mutations of hSNF5 in a series of CNS AT/RT

(Biegel et al., 1999).

Some children with AT/RT are born with heterozygous germ-line mutations of the hSNF5

gene, suggesting that these children were predisposed to develop AT/RT. In most cases, these

germ line mutations are de novo (a new mutation, not inherited from the parents), but in some

instances, they may be inherited from phenotypically normal parents (Biegel et al., 1999; and

Taylor et al., 2000). Individuals and families with germ-line mutations of hSNF5 are also at

increased risk to develop carcinoma of the choroid plexus. However, it remains to be

determined whether these are true choroid plexus tumors or AT/RT which may sometimes be

misdiagnosed as a choroid plexus carcinoma.

Heterozygous mSNF5 ± ‘knockout’ mice develop tumors resembling AT/RT, supporting the

role of hSNF5 as a tumor suppressor gene. Although most AT/RTs show evidence of some

genetic derangement at the hSNF5 locus, mutational analysis of the hSNF5 gene in a series of

PNET/MBs discovered mutations in only 4/52 tumors (Biegel et al., 2000). Of those 4, 2/4

was re-classified, as AT/RT on re-examination of the pathology, but there was insufficient

clinical material to establish an accurate diagnosis in the other two cases. This suggests that

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tumors diagnosed as PNET/MB with hSNF5 are most likely AT/RT. Such confusion is not

surprising, given the large number of AT/RTs, which contain fields indistinguishable from

PNET/MB. While mutation/deletion of hSNF5 is not currently sufficient for a diagnosis of

AT/RT, it appears to be related to the clinical outcome and hence, searching for it is

becoming part of the diagnostic work-up. Over-expression of osteopontin gene has been

reported as a potential diagnostic marker for atypical teratoid/rhabdoid tumor (Kao et al.,

2005). In one study, Alpha-internexin expression is seen in the atypical teratoid/rhabdoid

tumors, indicate that these primitive tumors usually exhibit neuronal differentiation (Kaya et

al., 2003).

TREATMENT OF AT/RT: SURGERY

The initial treatment for most children with AT/RT is surgical. Children presenting in

extremis with severe hydrocephalus require a cerebrospinal fluid (CSF) diversionary

procedure, either a ventriculostomy, a ventriculo-peritoneal shunt or, more recently, an

endoscopic third ventriculostomy (Sainte-Rose et al., 2001).Most children undergo a

craniotomy, with maximal safe resection of tumor. The interface of the AT/RT and

cerebellum may be abrupt or infiltrative and ill defined (Burger et al., 1998). Total or near

total, resection of the tumor is feasible in about 50% of patients. While surgery is excellent

for reducing the mass effect, children who receive surgery alone with no adjuvant therapy

typically die within one month after surgery (Rorke et al., 1996).

There is no high quality, prospective data on the value of surgical resection in the

management of AT/RT, but in patients with PNET/MB, progression-free survival in children

without disseminated disease at diagnosis is 20% better if the amount of residual tumor post-

operatively is less than 1.5 cm3 compared to children where the amount of residual tumor

was greater than 1.5 cm3 (Albright et al., 1996). Gross total resection is feasible in 64% of

12
patients with younger than 3 year while it’s possible in 78% children more than 3-years of

age. 81% of patients younger than 3-year at diagnosis develop recurrent disease within 3

months after surgery and recurrence is mainly local in more than 70% of patients (Tekautz et

al., 2005).

TREATMENT OF AT/RT: CHEMOTHERAPY

Most children with AT/RT receive chemotherapy at some point during their clinical course,

especially those less than 2 years of age, in view to delay radiation therapy. Several different

chemotherapeutic regimens have been tried, including baby Paediatric Oncology Group

(POG) protocols, eight drugs in one day, single agent cyclophosphamide and single agent

ifosphamide (Rorke et al., 1996). Most of these regimens were chosen based on their efficacy

in treating PNET/MB. However, patients with AT/RT respond poorly to chemotherapy and

only 6/33 children who received chemotherapy alone after surgery or chemotherapy prior to

radiation had a ‘response’ as defined by greater than 50% reduction in tumor mass. In

addition, most responses were short-lived, the longest being 10 months (Rorke et al., 1996).

Some AT/RTs have been documented to progress during the course of chemotherapy (Burger

et al., 1998).

In contrast to the older children, recurrent or progressive AT/RT in children 3 years or

younger appears refractory to chemotherapy (Tekautz et al., 2005). Two children treated with

high-dose chemotherapy, followed by autologous bone marrow transplant had a good

response, with one child surviving 19 months and another alive and well at 46 months of

follow-up (Hilden et al., 1998). There is one report where chemotherapy previously described

for use in patients with parameningeal rhabdomyosarcoma, was administered to three patients

with AT/RT. Therapy included surgery, radiotherapy, chemotherapy and triple intra-thecal

chemotherapy. All three patients were reported to be alive and well, with no evidence of

13
disease at 5 years, 2 years and 9 months, respectively (Olson et al., 1995). This exciting result

awaits confirmation in larger, prospective trials. In one retrospective study, median survival

with chemotherapy in younger than 3-year is 0.3 yr and with Radiation in older than 3 was

0.4 yr and median survival is 0.6 yrs in those who received both chemotherapy and radiation

(Tekautz et al., 2005). Hilden et al. reported event free survival of 16 months in children

older than 3 in comparison to only 7.7 months in younger than 3 year, their patients treated

with surgery and chemotherapy only.

TREATMENT OF AT/RT: RADIOTHERAPY

Most children diagnosed with AT/RT are usually less than 2 years of age, so, because of

toxicity of radiation to young brains, radiotherapy is initially not offered. Currently, the goal

is to continue with chemotherapy until the child is at least 2 or 3 years of age, at which time,

radiation effects are less severe. As children with AT/RT commonly present with

Leptomeningeal spread or else develop it at the time of relapse, it is desirable to administer

cranio-spinal radiotherapy, in addition to treatment of the primary tumor. Some authors have

advocated a boost of radiation to the primary tumor by conventional means or by stereotactic

radiosurgery at the time cranio-spinal therapy are administered. However, radiotherapy does

not seem to alter the progression of disease in children with AT/RT; indeed, an objective

response to radiotherapy was obtained in only 2/10 patients (Burger et al., 1998).

Recently gamma knife has also been used; but there are only two reports of the use of gamma

knife performed in patients with AT/RT that resulted in local control of the post-operative

lesion (Bambakidis et al., 2002; and Hirth et al., 2003). In recent studies radiotherapy has

shown promising results with prolonged survival of older children and adults with ATRT and

it appears most effective if administered early in the course of treatment, though the

unacceptable sequelae of cranial radiation in infants and young’s preclude its use (Packer et

14
al., 2002). In spite of these inconsistent statistics, children who are between 2 and 3 years of

age and older will receive radiotherapy at some point in the course of their disease.

In conclusion the prognosis for children with AT/RT is bleak. The median time to

progression is 4.5 months and the median reported survivals range from 6-11 months (Burger

et al., 1998 and Tekautz et al., 2005). Currently, the longest reported surviving patient was a

3-year-old girl who survived 5.5 years after presenting with a thalamic tumor that was treated

with craniospinal irradiation. At relapse, the disease may be local (31%), in the

leptomeninges (11%) or both (58%). Rorke et al., 1996 had found at post-mortem

examination, that 10/11 children with AT/RT had widespread Leptomeningeal metastatic

disease. Obviously, current treatments for this tumor in the form of surgery, chemotherapy

and/or radiation are not sufficient. Identification and characterization of the rhabdoid tumor

predisposition gene on chromosome 22q may allow development of more focused, effective

therapeutic agents which may increase survival time.

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