Atypical teratoid tumor/rhabdoid tumor (AT/RT) of
the central nervous system is an extremely rare and aggressive tumor
of early childhood [1-6]. Because of both the rarity and the aggressive
behavior of central nervous system AT/RT, there is no standard therapy
to recommend when faced with a patient with this tumor. Parents
and treating physicians had to rely on anecdotal evidence at best.
This rarity, and the poor outcomes with conventional infant brain
tumor therapy, has resulted in a lack of clear treatment guidelines,
and thus multiple approaches have been undertaken. It is for this
reason that a registry of patients with CNS AT/RT, their therapy,
and their outcomes, was developed by Dr. Joanne Hilden MD, Dr. Jaclyn
A Biegel Ph.D. and Jan Watterson BA. This registry was to create
an outcomes database that would track patients through the continuum
of the illness, and was to facilitate biology studies for this tumor
through a linked but separate study.
AT/RT was originally described as a variant of Wilms'
tumor with rhabdomyosarcomatous features [7]. Subsequently the features
differentiating AT/RT from Wilms' tumor were clarified [8, 9]. Reports
of extra-renal rhabdoid tumors ensued, with debate over a different
or common cell of origin [10]. The association of renal and CNS
AT/RT [11] led to cytogenetic studies mapping abnormalities in tumors
from both sites to a region on chromosome 22 [12] [13]. Molecular
genetic studies have led to the identification of a putative tumor
suppressor gene (INI1/hSNF5) at 22q11, and the current hypothesis
is that mutations in this gene predispose children to the development
of AT/RT [14, 15]. While this represents tremendous progress, not
all mutations have been elucidated, as 14% of cases studied have
no identified mutation (Biegel communication at NCI workshop Jan
2001). Thus biologic and molecular genetic studies need to continue,
and we are not yet able to design tumor-specific therapy.
In terms of treatment outcomes, the early literature
reflects a time course from diagnosis to death of about 12 months
in the great majority of patients with "standard" [5,
6, 16]. Subsequent reports document the use of more aggressive therapies
(including surgery, chemotherapy with or without stem cell support,
intrathecal chemotherapy, and early radiation), with some prolongation
of the natural history of this tumor [1, 2, 3] [17]. From these
reports it is not possible to clarify the role of a specific treatment
modality, as many different regimens were used. This fact was born
out in a workshop co-sponsored by the Pediatric Brain Tumor Foundation
and the National Cancer Institute[18]. The role of surgery has not
been addressed in the literature nor has the role of radiotherapy
or intrathecal chemotherapy for this tumor.
While the registry originated at Children's Hospital
in St. Paul, the main center for collection of data for the registry
will now be the Cleveland Clinic Foundation due to Dr. Hilden's
relocation to Chair of the Department of Pediatric Hematology/Oncology.
At the inception of the registry in 1995, expedited review at Children's
St. Paul IRB was accomplished. According to regulations acceptable
at that time, some institutions did and some did not have IRB approval
at their own sites.
PURPOSE The purpose of this project is to collect information
about the therapy and clinical course of patients with Teratoid/Rhabdoid
tumor for a AT/RT registry, so that in the future, the medical literature
will include information about the treatment of this tumor, and
about outcomes.
METHODS When the diagnosis of Teratoid/Rhabdoid tumor
is made, after written consent has been obtained, clinical information
(such as age, sex, tumor size, X-ray reports, surgical reports,
type of treatment given) from the child's chart will be sent to
the tumor registry, using data capture forms. The forms will be
filled out so that only the child's initials and date of birth are
used, so that a child cannot be identified. The parents will not
be contacted by the registry personnel, although there are cases
where parents make the first contact with us.
Cases will be referred to the registry by either treating
physician, evaluating pathologist, or by parent (through internet
information sources regarding AT/RT). In the case of parent referral,
information will be obtained from the treating physician. Institutional
IRB approval will be obtained from each institution participating
in the registry. Our approach is to require that the diagnosis be
confirmed by one of the pathologists who described this entity,
Drs. Peter Berger, Lucy Rorke, or Bernd Scheithauer. Cases will
be classified as AT/RT if the initial diagnosis had been made or
verified by one of the above pathologists. If this is not the case,
Dr. Rorke will seek material for review.
A standardized data sheet will be provided to treating
physicians listing the reports that are to be sent to the registry
for abstraction. The registry will ask for radiology reports, operative
notes, pathology reports, cytogenetics reports, discharge summaries,
and treatment records in addition to patient demographics. Registry
personnel will abstract the information; follow-up information on
surviving patients will be sought twice yearly from the treating
physicians. We do so by initiating contact.
Therapy delivered to registry patients, primary and
secondary resection of tumors, radiotherapy given, stem cell rescue,
intrathecal chemotherapy will be documented in the registry. Recurrent
or progressive disease, death from disease, status of alive with
disease, toxicity, status of alive with no evidence of disease will
also be documented in registry. Dr. Jacquelyn Biegel will independently
ask physicians to obtain a separate informed consent from parents
so archived or frozen tumor tissue can be sent to her for molecular
genetic analysis. While parents are made aware by literature and
by treating physicians that this is necessary testing for confirmation
of diagnosis and to determine whether the disease is familial, our
approach is to maintain a consent process that is separate from
the registry.
1. Hilden JM, et al., Central nervous system
atypical teratoid tumor/rahbdoid tumor: Response to intensive therapy
and review of the literature. Jounral of Neuro-Oncology, 1998. 40:
p. 265-275.
2. Olson TA, et al., Successful treatment of disseminated central
nervous system malignant rhabdoid tumor. Journal Pediatric Hematology
Oncology, 1995. 17: p. 71--75.
3. Weinblatt M and K. J, Rhabdoid tumor of the central nervous system
(letter). Med Pediatr Oncol, 1992. 20: p. 258.
4. Lefkowitz IB, et al., Atypical teratoid tumor of infancy: definition
of an entity (abstract 133). Ann Neurol, 1987. 22.
5. Rorke LB, Packer RJ, and Biegel JA, Central nervous sytem atpical
teratoid/rhabdoid tumors of infancy and childhood: definition of
an entity. J Neurosurg, 1996. 85: p. 56-65.
6. Burger PC, et al., Atypical teratoid/rhabdoid tumor of the central
nervous system. A highly malignant tumor of infancy and childhood
frequently mistaken for a medulloblastoma. (A Pediatric Oncology
Group Study). Am J Surg Pathol, 1998. 22: p. 1083-1092.
7. Beckwith JB and Palmer NF, Histopathology and Prognosis of Wilms'
Tumors: Results from the First National Wilms' Tumor Study. Cancer,
1978. 41: p. 1937-1948.
8. Haas JE, et al., Ultrastructure of malignant rhabdoid tumor of
the kidney. A distinctive renal tumor of children. Hum Pathol, 1981.
12: p. 646-657.
9. Weeks DA, et al., Report of 111 cases from the National Wilms'
Tumor Study Pathology Center. Am J Surg Pathol, 1989. 13: p. 439-458.
10. Parham DM, Weeks DA, and 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: p. 1919-1029.
11. Bonnin JM, et al., The assoication of embryonal tumors originating
in the kidney and in the brain. A report of seven cases. Cancer,
1984. 54: p. 2137-2146.
12. Biegel JA, et al., Monosomy 22 in rhabdoid or atypical tumors
of the brain. J Neurosurg, 1990. 73: p. 710-714.
13. Biegel JA, et al., Narrowing the critical region for a rhabdoid
tumor locus in 22q11. Genes, Chromosomes, & Cancer, 1996. 16:
p. 94-105.
14. Biegel JA, et al., Germ-Line and Acquired mutations of INI1
in Atypical Teratoid and Rhabdoid Tumors. Cancer Res, 1999. 59:
p. 74-79.
15. Biegel JA, et al., Germline InI1 mutation in a patient with
a central nervous system atypical teratoid tumor and renal rhabdoid
tumor. Genes, Chromosomes & Cancer, 2000. 28: p. 31-37.
16. Fisher BJ, et al., Malignant Rhabdoid Tumor of the Brain: An
Aggressive Clinical Entity. Can J Neurol Sci, 1996. 23: p. 257-263.
17. Finlay JL, The role of high-dose chemotherapy and stem cell
rescue in the treatment of malignant brain tumors: a reappraisal.
Pediatric Transplantation, 1999. 1(3 Suppl): p. 87-95.
18. Packer RJ, Biegel JA, and M. Smith, Atypical Teratoid/Rhabdoid
Tumor of the Central Nervous System Workshop. submitted for publication.
