Search

Atypical teratoid rhabdoid tumor of the brain is a rare embryonal tumor of infancy which has become more widely recognized due to specific immunostaining now more routinely available. These tumors still carry a poor prognosis and no standard therapy is currently available. However, the recent development of aggressive multimodality strategies seems to be associated with improved survival rates. In this chapter, we provide a review of our current knowledge on the demographics and epidemiology, pathology, and molecular characteristics. We review each individual therapeutic modality used (surgery, conventional chemotherapy, high-dose chemotherapy with stem cell rescue, intrathecal chemotherapy, and radiation) and the contribution of each to outcome when available. We provide an overview of the most recent therapeutic trials published and discuss the future options in development.

Ewing sarcoma/'peripheral' primitive neuroectodermal tumor (ES/pPNET) is the designation given to a family of small cell neoplasms that typically arise in bone or soft tissue and are unified by their common expression of the MIC2 antigen and specific translocations involving a gene on chromosome 22q12 [the most common being t(11;22)(q24;q12)]. ES/pPNET of intracranial origin is extraordinary. We report the case of a 6-year-old boy with a large left frontal region mass that adhered to dura and was extracerebral at surgery. Histologic study revealed a high-grade, undifferentiated-appearing neoplasm of small cell type that was negative on immunostudy for glial fibrillary acidic protein, synaptophysin, desmin, leukocyte common antigen, smooth muscle actin and epithelial membrane antigen, but positive for vimentin and neuron-specific enolase and diffusely labeled by antibody O13 (which recognizes the MIC2 gene product). RNA-based polymerase chain reaction assay confirmed the diagnosis of ES/pPNET by demonstrating fusion transcripts indicative of t(11;22) translocation. Bone scan, computerized tomography of the chest and bone marrow examination revealed no systemic tumor. The limited observations published to date suggest that primary intracranial ES/pPNET is most likely to present in childhood as a circumscribed, contrast-enhancing and dural-based extracerebral mass. It must be distinguished from a variety of small cell neoplasms, particularly PNETs of central neuroepithelial origin.

High dose chemotherapy (HDCT) with autologous (bone marrow or peripheral blood) stem cell rescue (ASCR) has had success in the treatment of some malignant pediatric brain tumors. We report a series of adults enrolled in one of three HDCT and ASCR protocols for malignant primary brain tumors. Overall toxic mortality was 18%; chemotherapy regimen, tumor type, and prior treatment did not predict transplant-related mortality. Patients over the age of 30 had a higher rate of toxic mortality. Patients with recurrent medulloblastoma had a significant improvement in long-term survival (median: 34 months) as compared with historical reports; two patients with glioblastoma survive beyond four years without progression, but overall, a significant improvement in long-term survival could not be demonstrated for malignant gliomas.

Astroblastoma is a rare and controversial tumor about which little is known. We have made the diagnosis in seven patients since 1990 at Memorial Sloan-Kettering Cancer Center. Four patients had astroblastomas with anaplastic features, whereas three patients had tumors which were well-differentiated. All three patients with low grade lesions are alive and recurrence free after surgery alone (mean follow-up 29 months). All four patients with anaplastic astroblastoma were treated with surgery, radiotherapy and chemotherapy. One died of infection during induction chemotherapy. Two others died of tumor progression at 28 and 42 months. Radiographic response to chemotherapy was seen in one patient. The results of our series and other reports suggest that anaplastic histology is a prognostic factor in the setting of astroblastoma. More aggressive treatment is necessary for patients with anaplastic astroblastoma although the precise role of irradiation and chemotherapy cannot be defined at this time.

We report an unusual case of an intraparenchymal clear cell meningioma of the brainstem, occurring in a 22-month-old girl. She presented with bulbar dysfunction and a right hemiparesis due to an intrinsic tumor of the medulla, which was confirmed by radiologic imaging to be focal and with an exophytic component. At surgery, a partial resection was achieved and no dural attachment was found. Pathologic examination revealed a clear cell meningioma. In reviewing the literature, there have been fewer than 20 reported cases of clear cell meningioma, none of which were intraparenchymal, involved the brainstem or occurred in such a young patient. The pathologic findings, treatment options and present understanding of this tumor are discussed.

Patients with neuroendocrine-related tumors and paraneoplastic encephalomyelitis (PEM) or paraneoplastic sensory neuronopathy (PSN) develop high titers of antibodies, called anti-Hu, against neuronal proteins expressed in their tumors, usually small cell lung cancer (SCLC). These tumors appear to be more indolent than those not associated with anti-Hu antibodies. The aims of this study were to determine 1) if patients with neuroblastoma (NB) also have anti-Hu antibodies, 2) the correlation between antibody titer and survival, and 3) if coexpression of Hu antigens and major histocompatibility proteins (MHC) by the tumor correlates with the development of anti-Hu associated PEM/PSN:Using immunohistochemistry and Western blot analysis, the sera of 109 patients with NB whose neurologic condition was concealed at the time of the study were examined for the presence of anti-Hu antibodies. The expression of Hu antigens and MHC proteins in 50 nonselected NB and 26 SCLC (16 known to be from seropositive and 10 from seronegative patients) was examined using immunohistochemistry.Four Stage 4 NB patients were seropositive and had longer survival (median 86 months) than 71 seronegative patients in the same age group and with the same tumor stage (median survival, 28.5 months). Seventy-eight percent of NB and all SCLC expressed Hu antigens. Overall, 17 of 20 tumors from seropositive patients expressed both Hu and MHC Class I proteins, but only 4 of 30 tumors from seronegative patients expressed both proteins (P0.0001).1) Some patients with NB develop anti-Hu antibodies; a search for that type of tumor is indicated in seropositive children, 2) most NBs and SCLCs express Hu antigens but only a few are associated with anti-Hu antibodies, and 3) Class I MHC expressed by some Hu antigen-bearing tumors may play a role in the development of anti-Hu associated PEM/PSN

This report describes two autopsy-proven cases of a rare complication of infratentorial glioblastoma multiforme (GBM): metastatic seeding of the peritoneal cavity through ventriculoperitoneal (VP) shunts. Patient 1 was a 13-year-old boy with a pontine GBM, and Patient 2 was a 9-year-old girl with a thoracolumbar spinal cord GBM. Autopsy of both patients demonstrated leptomeningeal gliomatosis encasing the spinal cord and basal structures of the brain, in addition to peritoneal and omental metastases. The pattern of abdominal metastasis seen in these patients is typical of tumors that directly seed the peritoneal cavity and implicates the VP shunt as the vehicle of extraneural spread. Although a rare occurrence, extraneural metastases should be sought in patients with glioma with VP shunts who demonstrate increased abdominal girth, unexplained weight gain, or persistent abdominal pain.

The progress that has been made in the treatment of the patient with medulloblastoma is gratifying. Survival for those who fall into the lower risk category probably exceeds 75%. For this degree of success, however, patients and their families have had to pay a price in terms of suffering the deleterious late effects of treatment. With sophisticated neuroimaging techniques diagnoses are now being made in a timely fashion and surgical mortality has been reduced to almost zero in most major medical centers. Radiation therapy and chemotherapy regimens have been increasingly successful, and further refinements of treatment are to be expected with the completion of randomized cooperative group trials. It is time to focus on means of achieving similar, or even better results, with reduced doses of neuraxis radiation, whenever possible, especially in the younger patient.

Turcot's syndrome is a rare, genetically transmittable disease in which patients with colonic polyposis (possibly complicated by the progression to adenocarcinoma) have malignant central nervous system neoplasms. Dominant, recessive, and sporadic cases have been described. A 26-year-old man is reported with no relevant family history who had intermittent abdominal discomfort in 1986. Sigmoidoscopy revealed numerous polyps, several of which showed carcinomatous change. Dukes' Stage C colorectal carcinoma was diagnosed. Treatment consisted of total colectomy with construction of a Koch's pouch. He remained well for 3 years until onset of headache, nausea, and vomiting. Computed tomographic scan disclosed a large, circumscribed, enhancing, right frontoparietal mass. After craniotomy and partial resection, histologic review disclosed anaplastic astrocytoma. He received cranial radiation therapy, 6000 cGy, by parallel opposed ports to the tumor bed, and carmustine 200 mg/m2 intravenously every 8 weeks. Flow cytometric DNA analysis was done on the paraffin-embedded archival material from the patient's normal colon, colonic adenocarcinoma, and anaplastic astrocytoma. DNA histograms revealed diploid distributions in all three samples. The G2/M fraction of the astrocytoma was elevated at 16%, and the S-phase fraction of the colonic adenocarcinoma was 19.4%.

The cellular schwannoma is a variety of schwannoma with a predominantly cellular growth but no Verocay bodies. Because doubt has been raised about the original assessment of this tumor as benign, the clinical and pathologic characteristics of 58 cellular schwannomas from 57 patients were reviewed. The patients were most often middle aged (63% were female), and their tumors most commonly were painless masses with a predilection for the paravertebral region of the retroperitoneum, pelvis, and mediastinum. Most tumors were solitary and encapsulated, and an associated nerve was identified for 43% of the cases. Electron microscopic and immunohistochemistry studies confirmed the tumor's Schwann cell nature. Worrisome features such as bone erosion, hypercellularity, foci of necrosis (four tumors), hyperchromasia, nuclear pleomorphism, and the presence of mitotic figures led to a malignant diagnosis for 28% of the cases. Treatment in all but one case was surgical excision. Two patients also received radiation therapy and chemotherapy. Follow-up of from 1 year to 24 years, 7 months (median of 6 years and mean of 7 years) for 61% (35 cases) of the cases reveals three patients with a local recurrence but no cases in which the tumor metastasized or the patient died of the tumor. Awareness of this tumor type is important so that the surgeon will avoid unnecessary sacrifice of functionally important nerves attached to these tumors and so that needless adjuvant radiation and chemotherapy will not be instituted.

Thrombotic microangiopathic hemolytic anemia has been associated with several chemotherapeutic agents. The authors describe a patient who developed this syndrome while receiving carboplatin, an analog of cisplatin. The clinical course was marked by encephalopathy and multifocal neurologic deficits. Progressive brainstem dysfunction culminated in coma and respiratory arrest. Pathologic examination revealed widespread microvascular thrombosis, particularly severe in the heart, kidney, and brain. Although the pathogenesis of chemotherapy-related thrombotic microangiopathy remains unclear, an elevated von Willebrand factor antigen and pathologic evidence of endothelial hyperplasia in this patient suggest that an abnormality of the endothelium is related to the development of the clinical syndrome.

Pituitary morphology was studied in 49 autopsied patients with acquired immunodeficiency syndrome. Direct infectious involvement was noted in six adenohypophyses (12%), including five cases by cytomegalovirus and one by Pneumocystis carinii. Two cases with neurohypophysial lesions presumably caused by cytomegalovirus and one questionable case of Toxoplasma gondii were also observed. In all instances these changes were associated with generalized and/or cerebral infection by these same agents. Neither Kaposi's sarcoma nor malignant lymphoma was encountered in the pituitary glands. Acute necrotic foci, presumably due to infarction, were noted in four cases. Four pituitary microadenomas (8%) and four hyperplastic nodules were identified. The incidence of such noninfectious lesions, as well as the prevalence and distribution of the various immunoreactive adenohypophysial cell types, were similar to those seen in the pituitary glands of age-matched male control patients.

We have identified an autoantibody that reacts with a neuronal nucleoprotein in the serum of patients with small cell lung carcinoma (SCLC) and the paraneoplastic syndrome, subacute sensory neuronopathy (SSN). A similar antigen has been found in the tumor from one of these patients. To determine the distribution of this antigen, immunoblots of a homogenate from the SCLC of another patient with SSN, six SCLC cell lines from patients without SSN, five non-SCLC cell lines, and one ovarian carcinoma cell line were reacted with serum from five patients with SCLC and SSN. Control sera were obtained from two patients with SSN without cancer, two patients with SSN associated with tumors other than SCLC, two patients with paraneoplastic cerebellar degeneration, and five patients with SCLC but no SSN. The sera from all five patients with SCLC and SSN identified a Mr 35,000 to 40,000 antigen in neurons, in all of six SCLC cell lines and in the SCLC tumor homogenate. The antigen was not detected in other tumor cell lines. Control sera did not react with these bands, in either neurons or SCLC cell lines. Bound IgG was eluted from the blot of one SCLC cell line after reaction with SSN serum. Eluates from the Mr 35,000 to 40,000 area reacted with neuronal nuclei in the cerebral cortex by an immunoperoxidase technique; eluates from other areas of the blot were negative. These findings support the hypothesis that the autoantibody in SSN arises in reaction to an antigen shared between SCLC and neuronal nuclei.