Atypical Teratoid/Rhabdoid Tumors
Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant central nervous system (CNS) tumor that can occur anywhere in the nervous axis but mostly commonly arises in the posterior fossa of very young children. The tumor was first described in 1987 by Lucy Rorke′s group.1 Over the last two decades, the tumor has become increasingly recognized, and the identification of an aberrant tumor suppressor gene, INI1/SMARCB1, has led to the availability of a specific tumor stain that readily identifies the tumor. AT/RT is the first nervous system tumor for which such a genetic etiology has been discovered. Early publications report a dismal outcome for patients, most of whom died of disease despite aggressive treatment. Intensified therapy with high-dose chemotherapy and the use of irradiation has improved survival for some patients. A better understanding of the role of the INI1/SMARCB1 gene may eventually lead to targeted treatment. Therapeutic treatment trials specifically designed to treat AT/RT are currently underway.
The pathophysiology of AT/RT is unique and garnered much attention in the neuropathology community. Prior to its recognition as a separate entity, AT/RT was often classified as a medulloblastoma, primitive neuroectodermal tumor, or choroid plexus carcinoma. This is understandable because approximately two thirds have components that resemble these primitive tumor types.2 Because it histologically resembles the rhabdoid tumor of the kidney, AT/RT had sometimes been referred to as malignant rhabdoid tumor of the brain or CNS prior to its recognition as a distinct tumor type.3 The World Health Organization began classifying AT/RT as an embryonal grade IV neoplasm in 1993.4
Histologically, AT/RT contains sheets of rhabdoid cells against a background of primitive neuroectodermal cells, mesenchymal cells, or epithelial cells.5 Some tumors are composed almost entirely of rhabdoid cells, whereas others show a combination of rhabdoid cells and areas resembling primitive neuroectodermal tumor or medulloblastoma. Immunohistochemical features help to identify the disease but vary depending on the cellular composition of the tumor. Rhabdoid cells express vimentin, epithelial membrane antigen (EMA), and smooth muscle actin (SMA). The primitive neuroectodermal cells variably express neurofilament protein (NFP), glial fibrillary acidic protein (GFAP), keratin, or desmin. AT/RT is a rapidly growing tumor that can have MIB-1 labeling indices of 50 to 100%4 ( Fig. 36.1; Table 36.1 ).
Molecular studies assist in the identification of AT/RT. Work by Biegel and colleagues6 has identified a candidate tumor suppressor gene, INI1/SMARCB1, which is abnormal in the majority (85%) of AT/RT. INI1/SMARCB1 is a component of the human SW1/SNF complex, an adenosine triphosphate (ATP)-dependent chromatin remodeling complex. The gene regulates transcription of a large variety of genes involved in cell signaling, growth, and differentiation. Functions such as a classic tumor suppressor gene and inactivation of both alleles must occur for a tumor to develop. It is believed that the presence of an INI1 mutation in a tumor with histological features suggestive of primitive neuroectodermal tumor without a clear rhabdoid component is sufficient to establish a diagnosis of AT/RT. In addition to somatic mutations, germline mutations in INI1 have been reported in some patients with AT/RT who may be predisposed to renal or other malignancies.7 Patients with germline mutations have a lower median age at diagnosis and a poorer prognosis.8 INI1/SMARCB1 gene mutations have also been found in patients with renal and extrarenal rhabdoid malignancies.6
Immunohistochemical staining for gene product INI1/SMARCB1 is a very helpful tool in distinguishing AT/RT tumor from primitive neuroectodermal tumor/medulloblastoma and other CNS tumors that can share the same histological features.9 Because most AT/RT cells do not make the normal gene product for INI1, the tumor cells do not stain. Many centers now routinely stain primitive CNS tumors for INI1 as part of their evaluation ( Fig. 36.2 ).
The exact incidence of AT/RT has been difficult to determine, especially because the tumor has been widely recognized only for the last decade. It is primarily a disease of young children, usually younger than 2 years of age, although there are reports of older children and adults with the disease.10 In Children′s Cancer Group study 9921, 10 to 15% of infants had AT/RT.11 Based on prior Pediatric Oncology Group and Pediatric Brain Tumor Consortium studies, approximately 15% of children younger than 36 months with malignant brain tumors have AT/RT (D. Strother, MD, and R. Geyer, MD, personal communication). In a series from Taiwan, the ratio of AT/RT to primitive neuroectodermal tumors was found to be 1:3.8 (26%) among patients younger than 3 years of age.12 This group also reported a female predominance, although no other series have found a gender difference. In a recent Austrian study of 311 newly diagnosed tumors, AT/RT was the sixth most common entity (6.1%).13 A peak incidence was found in the birth to 2-year age group, in which AT/RTs were as common as medulloblastomas.
The incidence in older patients is unknown, but interestingly, many of the published series report cases with patients older than 3 years of age. An AT/RT registry has been created and maintained at the Children′s Hospital at the Cleveland Clinic by Dr. Joanne Hilden. Twelve of 42 patients (29%) in the registry were older than 36 months at the time of diagnosis.14
Clinical and Radiographic Findings
There are no data to support the idea that clinical characteristics can distinguish AT/RT from other malignant brain tumors. Because AT/RT is a highly malignant tumor, patients typically have a fairly short history of progressive symptoms that can be measured in days to weeks. It is unusual for symptoms to have been present for more than a few months. Approximately half of AT/RTs arise in the posterior fossa.11 Young patients with posterior fossa tumors usually present with symptoms related to hydrocephalus, particularly early-morning headaches, vomiting, and lethargy. They may also develop ataxia or regression of motor skills. Cranial nerve palsies, particularly of nerves VI and VII, are not uncommon. Patients with cortical AT/RT may present with seizures, weakness, or headaches. Because young children have open sutures and fairly pliable skulls, a rapidly enlarging head size should alert the practitioner to evaluate the patient for a brain mass, as this may be the only symptom at presentation. Rarely, AT/RTs can arise in the spinal cord.
Imaging characteristics are also helpful but nonspecific for AT/RT. The computed tomography (CT) appearance is typically that of a hyperdense mass that enhances intensely with contrast.11 On T1-weighted magnetic resonance imaging (MRI), the tumor mass is typically isointense with frequent hyperintense foci secondary to intratumoral hemorrhage. The tumor does take up contrast intensely but in a heterogeneous pattern ( Fig. 36.3a ). On T2-weighted and fluid-attenuated inversion recovery (FLAIR) MRI, the tumor appears heterogeneous as a result of the mixture of tumor cellularity, hemorrhage, necrosis, and cysts ( Fig. 36.3b ). The tumors are often invasive. In the posterior fossa, the tumors often invade the cerebellopontine angle and may have areas of necrosis ( Table 36.2 ).
Neuraxis dissemination at diagnosis is not uncommon and occurs in about 25% of cases11 ( Fig. 36.4 ). Patients should undergo MRI of the complete spine at the time of diagnosis. Cases of diffuse leptomeningeal disease have recently been reported in which there was diffusely thickening and enhancing meninges without discrete primary mass.15,16 Magnetic resonance (MR) spectroscopy is similar to primitive neuroectodermal tumors with marked elevation of choline and low or absent N-acetylaspartate and creatine.