Brain Pathology Case of the Month - December 2015


Atypical teratoid rhabdoid tumor


Atypical teratoid rhabdoid tumor (ATRT), a WHO grade IV lesion, is a rare and highly aggressive intracranial tumor usually occurring in young children. First identified in 1987, these tumors bear pathological resemblance to malignant rhabdoid tumors of the kidney (9). The central nervous system is the most common non-renal location for rhabdoid tumor, and usually involves the posterior fossa. On MR imaging, most ATRT are hypointense in T1-weighted imaging, has variable T2 signal, and show inhomogeneous contrast enhancement. Presence of central cystic or necrotic areas and calcification is common. Diffusion restriction is usually present, and spectroscopy typically shows elevated levels of choline and decreased N-acetylaspartate. Incidence of hemorrhage is quoted at 40-60%. Altogether, these are features of a high-grade tumor and by themselves not specific for an ATRT. (1)

ATRT is an embryonal tumor consisting of rhabdoid cells admixed with cells resembling medullobastoma, primitive neuroectodermal tumor (PNET), spindle-shaped mesenchyme, and/or epithelial tissue. Recognized as a separate entity by the WHO in 2000, diagnosis is based on the absence of gene products (INI-1) from the tumor-suppressor gene (SMARCB1/INI1/SNF5/BAF47) on chromosome 22q11.2, and/or by the detection of monosomy 22 or deletions/mutations involving this gene segment. The INI-1 protein is a member of the ATP-dependent switching/sucrose non-fermentable (SWI/SNF) complex involved in chromatin remodeling and cell cycle regulation. This protein is generally ubiquitous in the cell nucleus, and the encoding tumor-suppressor gene SMARCB1 is inactivated or lost in most ATRT, a pathognomonic feature also shared with its renal counterpart, and serves as key to distinguish ATRT from PNET or medulloblastoma. (3) (2)

However, the loss of SMARCB1 expression is non-specific and has also been observed in a number of tumors, including epithelioid sarcomas, undifferentiated pediatric sarcomas, myoepithelial carcinoma, and some neuroepithelial tumors. (5) (8) (6) In addition, a rare number of ATRT, despite classic ATRT histological appearances, retains the nuclear expression of the INI-1 protein. In the genetic analyses of such a case, Schneppenheim et al have found another potential causative gene to be SMARCA4/BRG1, which encodes for another protein in the SWI/SNF complex, further supporting the important role of the SWI/SNF complex in the generation of the ATRT histophenotype. (10) The current ISN-Haarlem guidelines recommend that an integrated diagnosis of ATRT be made only in the presence of either INI-1 or BRG1 loss of protein expression or mutation. (7)

ATRT carries a poorer prognosis than PNET or medulloblastoma, and early literature suggests a median survival of 12 months from time of diagnosis to death with standard therapy. More recent reports show possible prolongation of survival using more aggressive therapies involving surgery, chemotherapy with or without stem-cell rescue, intrathecal chemotherapy, and early radiotherapy. (4) Because of its rarity and poor outcome, clear treatment guidelines are still in the process of development.


  1. Arslanoglu A, Aygun N, Tekhtani D, Aronson L, Cohen K, Burger PC, et al (2004) Imaging findings of CNS atypical teratoid/rhabdoid tumors. AJNR Am J Neuroradiol 25:476-80.
  2. Biegel JA, Fogelgren B, Zhou JY, James CD, Janss AJ, Allen JC, et al (2000) Mutations of the INI1 rhabdoid tumor suppressor gene in medulloblastomas and primitive neuroectodermal tumors of the central nervous system. Clin Cancer Res 6:2759-63.
  3. Biegel JA, Kalpana G, Knudsen ES, Packer RJ, Roberts CW, Thiele CJ, et al (2002) The Role of INI1 and the SWI/SNF complex in the development of rhabdoid tumors: Meeting summary from the Workshop on Childhood Atypical Teratoid/Rhabdoid Tumors. Cancer Res 62:323-8.
  4. Hilden JM, Meerbaum S, Burger P, Finlay J, Janss A, Scheithauer BW, et al (2004) Central nervous system atypical teratoid/rhabdoid tumor: results of therapy in children enrolled in a registry. J Clin Oncol 22:2877-84.
  5. Judkins AR, Mauger J, Ht A, Rorke LB, Biegel JA (2004) Immunohistochemical analysis of hSNF5/INI1 in pediatric CNS neoplasms. Am J Surg Pathol 28:644-50.
  6. Kreiger PA, Judkins AR, Russo PA, Biegel JA, Lestini BJ, Assanasen C, et al (2009) Loss of INI1 expression defines a unique subset of pediatric undifferentiated soft tissue sarcomas. Mod Pathol 22:142-50.
  7. Louis DN, Perry A, Burger P, Ellison DW, Reifenberger G, von Deimling A, et al (2014) International Society of Neuropathology-Haarlem Consensus Guidelines for Nervous System Tumor Classification and Grading. Brain Pathol doi:10.1111/bpa.12171
  8. Modena P, Lualdi E, Facchinetti F, Galli L, Teixeira MR, Pilotti S, et al (2005) SMARCB1/INI1 tumor suppressor gene is frequently inactivated in epithelioid sarcomas. Cancer Res 65:4012-9.
  9. Rorke LB, Packer RJ, Biegel JA (1987) Atypical teratoid tumor of infancy: Definition of an entity. Ann Neurol 22:448-9.
  10. Schneppenheim R, Fruhwald MC, Gesk S, Hasselblatt M, Jeibmann A, Kordes U, et al (2010) Germline nonsense mutation and somatic inactivation of SMARCA4/BRG1 in a family with rhabdoid tumor predisposition syndrome. Am J Hum Genet 86:279-84.

Contributed by Wai Kiu Tang, Ho Keung Ng, Danny Tat-Ming Chan, Xian Lun Zhu, Wai-Sang Poon

International Society of Neuropathology