Primary intracranial atypical teratoid/rhabdoid tumors of infancy and childhood: MRI features and patient outcomes.

BACKGROUND AND PURPOSE: Primary atypical teratoid/rhabdoid tumors (AT/RTs) are rare malignant intracranial neoplasms, usually occurring in young children. The objectives of this study were to characterize the MR imaging features and locations of primary intracranial AT/RTs, to determine the frequency of disseminated disease in the central nervous system (CNS) at diagnosis and postoperatively, and to assess patient outcomes. METHODS: The preoperative cranial MR images of 13 patients with AT/RTs were retrospectively reviewed for evaluation of lesion location, size, MR signal intensity and enhancement characteristics, and the presence of disseminated intracranial tumor. Postoperative MR images of the head and spine for 17 patients were reviewed for the presence of locally recurrent or residual tumor and disseminated neoplasm. Imaging data were correlated with patient outcomes. RESULTS: Patients ranged in age from 4 months to 15 years (median age, 2.9 years). Primary AT/RTs were intra-axial in 94% of patients. The single primary extra-axial lesion was located in the cerebellopontine angle cistern. AT/RTs were infratentorial in 47%, supratentorial in 41%, and both infra- and supratentorial in 12%. A germ-line mutation of the hSNF5/INI1 tumor-suppressor gene was responsible for the simultaneous occurrence of an intracranial AT/RT and a malignant renal rhabdoid tumor in a 4-month-old patient. Mean tumor sizes were 3.6 x 3.8 x 3.9 cm. On short TR images, AT/RTs typically had heterogeneous intermediate signal intensity, as well as zones of low (54%), high (8%), or both low and high (31%) signal intensity from cystic and/or necrotic regions, hemorrhage, or both, respectively. On long TR/long TE images, solid portions of AT/RTs typically had heterogeneous intermediate-to-slightly-high signal intensity with additional zones of high (54%) or both high and low signal intensity (38%), secondary to cystic and/or necrotic regions, edema, prior hemorrhage, and/or calcifications. AT/RT had isointense and/or slightly hyperintense signal intensity relative to gray matter on fluid-attenuated inversion-recovery (FLAIR) and long TR/long TE images, and showed restricted diffusion. All except 1 AT/RT showed contrast enhancement. The fraction of tumor volume showing enhancement was greater than two thirds in 58%, between one third and two thirds in 33%, and less than one third in 9%. Disseminated tumor in the leptomeninges was seen with MR imaging in 24% of patients at diagnosis/initial staging and occurred in another 35% from 4 months to 2.8 years (mean, 1.1 years) after surgery and earlier imaging examinations with negative findings. The overall 1-year and 5-year survival probabilities were 71% and 28%, respectively. Patients with MR imaging evidence of disseminated leptomeningeal tumor had a median survival rate of 16 months compared with 149 months for those without disseminated tumor (P < .004, logrank test). CONCLUSION: AT/RTs are typically intra-axial lesions, which can be infra- and/or supratentorial. The unenhanced and enhanced MR imaging features of AT/RT are often variable secondary to cystic/necrotic changes, hemorrhage, and/or calcifications. Poor prognosis is associated with MR imaging evidence of disseminated leptomeningeal tumor.

The role of surveillance magnetic resonance imaging (MRI) scanning in detecting recurrent brain tumors in asymptomatic children.

BACKGROUND: There is controversy regarding the utility of routine surveillance scanning for asymptomatic children with brain tumors. Although the role of CT or magnetic resonance imaging (MRI) scanning in this setting has been examined in several studies, none have focused on children followed exclusively by MRI. The purpose of this study was to determine how often recurrent brain tumors are detected by routine MRI surveillance in asymptomatic children. METHODS: The medical records of all children with brain tumors treated at Children's Hospital at Strong from 1990-1999 were reviewed. Recurrence was defined as an increase in size of the tumor on MRI scan. Astrocytomas and gangliogliomas were classified as low-grade tumors; high-grade astrocytomas, medulloblastomas, and ependymomas were classified as high-grade tumors. RESULTS: Of the 112 evaluable children with brain tumors during this time period, 46 (41%) suffered an MRI-documented recurrence. Of these 46 patients, 13 (28%) had low-grade tumors and 33 (72%) had high-grade tumors. Twenty-seven of the 46 recurrences (59%) occurred in asymptomatic children. Ten of the 13 children (77%) with recurrent low-grade tumors were asymptomatic compared to 17 of 33 children (52%) with recurrent high-grade tumors (p = 0.18). The median survival from time of recurrence for the symptomatic children was seven months, while the median survival from time of recurrence for the asymptomatic children has not yet been reached (p = 0.025). When the analysis was confined to children with high-grade tumors, there was no difference in median survival from the time of recurrence for symptomatic versus asymptomatic children (5 mo. versus 7 mo.) (p = 0.25). The frequency of detection of recurrences by surveillance scanning in asymptomatic children was 4.2% (one recurrence detected per 24 surveillence MRI scans). CONCLUSION: The majority of recurrent brain tumors are detected by MRI surveillence in asymptomatic children. However, asymptomatic recurrences were detected in only a small proportion of surveillance scans and had no impact on survival in children with high-grade tumors.

WBC-reduced blood transfusions and clinical outcome in children with acute lymphoid leukemia.

BACKGROUND: WBC reduction offers a variety of benefits to patients requiring multiple transfusions during induction therapy for childhood acute lymphoid leukemia (ALL), including reductions in febrile transfusion reactions, HLA alloimmunization, and CMV transmission. One potential benefit is a reduction in the deleterious effects of transfusion immunomodulation. In the surgical setting, transfusion immunomodulation has been linked to increases in postoperative infections and decreases in host cellular immunity that are mitigated by WBC reduction of transfused blood. STUDY DESIGN AND METHODS: A retrospective review was conducted of the medical records of 68 consecutive children undergoing induction therapy for newly diagnosed ALL from 1988 through 1995, a period whose midpoint is 1991, the year WBC reduction was introduced in this hospital. RESULTS: WBC reduction of platelet and RBC transfusions was associated with fewer days with fever (mean, 5.7 days [no WBC reduction] and 2.1 days [WBC reduction]; p = 0.012) and days with positive microbial cultures (mean, 1.5 [no WBC reduction] and 0.71 [WBC reduction]; p = 0.0055). There were more high-risk ALL patients in the group receiving WBC-reduced transfusions. CONCLUSION: Allogeneic WBCs in transfused blood may cause impairment of host defenses against microbial infection during induction therapy for childhood ALL.

"Liver function tests" are not always tests of liver function.

A child with Wilm's tumor and a child with immune thrombocytopenic purpura (ITP) were each noted to have persistent elevations of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH). Both children underwent thorough evaluation for liver disease and, as a result, experienced delays in treatment of the Wilm's tumor and ITP. Eventually both children were found to have extremely elevated serum creatine kinase (CK). Muscle biopsy confirmed diagnoses of Duchenne's muscular dystrophy in one child, and Becker's muscular dystrophy in the second. Hematologists/oncologists should consider obtaining a serum CK to rule out muscle disease in patients with unexplained elevations of AST, ALT, and LDH.

Postoperative evaluation for disseminated medulloblastoma involving the spine: contrast-enhanced MR findings, CSF cytologic analysis, timing of disease occurrence, and patient outcomes.

BACKGROUND AND PURPOSE: Postoperative MR imaging is routinely performed for staging of medulloblastoma because of frequent tumor dissemination along CSF pathways. The goals of this study were to: 1) determine the timing of disease occurrence and contrast-enhanced MR imaging features of disseminated medulloblastoma involving the spine and their relationship to patient outcomes; and 2) compare the diagnostic accuracy of MR imaging findings with CSF cytologic analysis. METHODS: Medical records, pathologic reports, and unenhanced and contrast-enhanced postoperative MR images of the spine and head from 112 patients who had resection of medulloblastoma were retrospectively reviewed. MR images of the spine were evaluated for abnormal contrast enhancement in the meninges and vertebral bone marrow. MR images of the head were evaluated for recurrent or residual intracranial tumor. Imaging data were correlated with available CSF cytologic results and patient outcomes. RESULTS: Twelve patients (11%) had tumor within the spinal leptomeninges depicted on MR images at the time of diagnosis. Twenty-five patients (22%) had disseminated disease in the spine (leptomeninges, n = 22; vertebral marrow, n = 1; or both locations, n = 2) on MR images 2 months to 5.5 years (mean, 2 years) after initial surgery and earlier negative imaging examinations. Eleven other patients (10%) had recurrent intracranial medulloblastoma without spinal involvement seen with MR imaging. Spinal MR imaging had a sensitivity of 83% in the detection of disseminated tumor, whereas contemporaneous CSF cytologic analysis had a sensitivity of 60%. The sensitivity of CSF cytologic analysis increased to 78% with acquisition of multiple subsequent samples, although diagnosis would have been delayed by more than 6 months compared with diagnosis by spinal MR imaging in six patients. Spinal MR imaging was found to have greater overall diagnostic accuracy than CSF cytologic analysis in the early detection of disseminated tumor (P = .03). Spinal MR imaging confirmed disseminated tumor when contemporaneous CSF cytologic findings were negative in 13 patients, whereas the opposite situation occurred in only two patients. False-positive results for spinal MR imaging and CSF cytologic analysis occurred when these examinations were obtained earlier than 2 weeks after surgery. The 5-year survival probability for patients with spinal tumor was 0.24 +/- 0.08 versus 0.68 +/- 0.05 for the entire study group. CONCLUSION: Spinal MR imaging was found to have greater diagnostic accuracy than CSF cytologic analysis in the early detection of disseminated medulloblastoma. CSF cytologic analysis infrequently confirmed disseminated tumor when spinal MR imaging results were negative. Delaying spinal MR imaging and CSF cytologic analysis by more than 2 weeks after surgery can reduce false-positive results for both methods. The presence of disseminated medulloblastoma in the spine seen with MR imaging is associated with a poor prognosis.

Swimming and central venous catheter-related infections in the child with cancer.

Although there have been many studies evaluating risk factors for catheter-related infections in children with cancer, none have examined whether swimming presents such a risk. Families of children with cancer were asked about specific swimming practices and central line care to determine whether there is an association between swimming and infection. Parents completed a self-report questionnaire and medical records were reviewed to document catheter-related intraluminal, tunnel, and exit-site infections. Ninety-one children with a total of 101 tunneled catheters participated in the study. Forty-nine children with a total of 50 catheters were swimmers; 46 children with 51 catheters were nonswimmers (four children had two catheters and swam with one catheter but not the other, therefore, these children were counted twice). There were no statistically significant differences in rates of catheter-related infections between the two groups (0.04/catheter-month in swimmers versus 0.25/in non-swimmers, relative risk; RR = 1.6, p = .16). When the analysis was confined to summertime infections per summertime catheter month, there were no significant differences in the rates of infections per summer month (0.06 for swimmers vs. 0.05 for non-swimmers, RR = 1.4; p = .50). When the analyses were performed to compare frequent swimmers with infrequent/non-swimmers, once again there were no differences found in rates of catheter-related infections between the two groups. These results suggest that swimming does not increase the risk of catheter-related infections in children with tunneled catheters.

Malignant ependymomas in a patient with Turcot's syndrome: case report and management guidelines.

BACKGROUND: Turcot's Syndrome is the association of multiple adenomatous polyps of the colon with a primary tumor of the central nervous system. We present the first reported case of Turcot's Syndrome in a patient with malignant ependymomas. Recent advances in the elucidation of the genetic basis for the hereditary forms of colon cancer have provided a clearer understanding of the etiology of Turcot's Syndrome. This new information is relevant to the neurosurgical community and provides updated guidelines in the diagnosis and management of patients with this complex disease process. RESULTS: Turcot's Syndrome is related to two distinct genetic errors. The first involves a germ-line mutation in the adenomatous polyposis coli (APC) gene, which is postulated to act as a tumor suppressor gene. The second is a germ-line defect in one of a group of genes responsible for DNA nucleotide mismatch repair. CONCLUSION: The elucidation of the gene defects responsible for the hereditary forms of colon cancer has provided a clearer understanding of the molecular basis of Turcot's Syndrome. Patients with hereditary forms of colon cancer and neurologic symptoms require immediate and thorough investigation because of their significantly increased risk of developing CNS tumors. Previously healthy patients diagnosed with a CNS tumor with a family history of adenomatous polyposis coli should undergo screening and surveillance colonoscopy as the CNS lesion may precede colonic symptoms. CNS screening guidelines for asymptomatic patients with adenomatous polyposis coli requires further risk analysis studies. All patients diagnosed with Turcot's Syndrome should be tested for the gene defect, including the CNS tumor tissue to provide further data on the genetic relationship between Turcot's Syndrome and the hereditary forms of colon cancer.

Phase II study of carboplatin (CBDCA) in progressive low-grade gliomas.

In this study, the authors sought to investigate the response rate and toxicity of carboplatin in patients with progressive low-grade glioma (LGG). Thirty-two patients with progressive LGG were treated with carboplatin at a dosage of 560 mg/m(2). Treatment was given at 4-week intervals and continued until the disease progressed, unacceptable toxicity supervened, or for 12 additional courses after achieving maximal response. Patients with stable disease were treated with a total of 12 cycles. All patients were treated as outpatients. Patients were evaluated for response to treatment and toxicity. All patients received a minimum of two cycles of carboplatin, and were examined for response. A partial response was achieved in nine patients (28%) and a minimal response in two (6%), for an overall response rate of 34% (11 of 32 patients). Eighteen patients (56%) had stable disease. A partial response was achieved in the nine patients after a median of six cycles (range 4-11 cycles), a minimal response was achieved in the two patients after five cycles. Glioma progression was noted in three patients after three, five, and five cycles, respectively. The 11 patients in whom some response was achieved had either an optic pathway tumor or a juvenile pilocytic astrocytoma. Twenty-six of the 32 patients had those characteristics, making the response rate in that group 42% (11 of 26 patients). Thirty-two patients received a total of 387 cycles of chemotherapy. Hematological toxicity was moderate. Twenty-one patients developed thrombocytopenia (platelet count < 50,000/microl); three patients required one platelet transfusion each. Nine patients developed neutropenia (absolute neutrophil count < 500/microl); one developed fever and required administration of antibiotic agents. One dose adjustment in each of the patients prevented further thrombocytopenia and neutropenia. Two patients with stable disease died of respiratory complications. One patient developed Grade III ototoxicity after receiving five cycles, one patient developed hypersensitivity to carboplatin, and none developed nephrotoxicity. Carboplatin given at a dosage of 560 mg/m(2) every 4 weeks has activity in patients with progressive LGG. This drug regimen is relatively simple and well tolerated. Further investigation and longer follow-up study are warranted.

Lack of relation of granulocyte antibodies (antineutrophil antibodies) to neutropenia in children with human immunodeficiency virus infection.

BACKGROUND: Neutropenia in children and adults with HIV infection is frequently observed, perhaps as a result of impaired myelopoiesis, drug myelotoxicity, immune destruction or opportunistic infection. The presence of antineutrophil antibodies (granulocyte antibodies) has been associated with severe neutropenia in some reports but not in others, and such antibody assays can be confounded by the presence of immune complexes and HLA antibodies. METHODS: To determine both the prevalence of granulocyte antibodies in children with HIV infection and whether such antibodies were related to neutropenia, we screened the sera of 30 HIV-infected children by performing granulocyte immunofluorescence, granulocyte agglutination and lymphocytotoxic anti-HLA antibody assays. Reactivity was graded by a standard numeric score calculated per number of reactive cells. RESULTS: Of 26 evaluable sera, 16 (62%) had granulocyte antibodies, 6 (23%) had HLA antibodies and 4 (15%) had neither. There was no correlation between presence of granulocyte antibodies and degree of neutropenia. CONCLUSIONS: We conclude that granulocyte antibodies are highly prevalent in children with HIV infection but do not correlate with the degree of neutropenia. Antineutrophil antibody determination as currently performed does not appear to be useful in the evaluation of the HIV-infected neutropenic child.

Routine chest radiography of children with cancer hospitalized for fever and neutropenia: is it really necessary?

BACKGROUND: Although there have been two reports suggesting that it is not necessary to obtain chest radiographs of all children with cancer who are hospitalized for fever and neutropenia, this practice continues. METHODS: Fifty-four children with cancer who were hospitalized for 108 episodes of fever and neutropenia were followed prospectively. Data on their respiratory signs and symptoms were collected on admission and throughout their hospital course. Chest radiographs were obtained at the discretion of the pediatric oncology attending physician and were interpreted by a pediatric radiologist. RESULTS: Pneumonia was documented by chest radiograph in 4 of the 108 episodes (3.7%) of fever and neutropenia. In 10 of the 108 episodes, the children had abnormal respiratory findings; this group included the 4 children with pneumonia documented by chest X-ray examination. None of the children with normal respiratory findings hospitalized for the remaining 98 episodes had pneumonia. Chest radiographs were not obtained for 40 of the 108 episodes of fever and neutropenia. None of the children with these 40 episodes had respiratory abnormalities and all recovered without a problem. Chest radiographs were obtained for the remaining 68 episodes of fever and neutropenia. Of the four children in this group with pneumonia documented by chest X-ray, two were diagnosed on admission, and another two whose initial radiographs were normal developed pneumonia later in their hospital course. There were no differences in age, absolute neutrophil count, temperature at presentation, or type of malignancy between the children who had chest radiographs and the children who did not. CONCLUSIONS: Pneumonia is an uncommon cause of infection in children with cancer hospitalized for fever and neutropenia. Therefore, the authors believe it is not necessary to obtain a chest radiograph in children with no respiratory abnormalities who are hospitalized for fever and neutropenia. [See editorial on pages 1009-10, this issue.]

Multiple ependymomas in a patient with Turcot's syndrome.

A 21-year-old woman was diagnosed with Turcot's syndrome (TS) at age 16 years. She had two ependymomas, one was located in the left middle cerebellar peduncle and the other in the low sacral spinal canal. Her mother and brother both had colectomies for colonic polyposis. Her maternal uncle and grandfather also had this disease and both died from cancer of the colon in their fourth decade of life. The patient was found to have hyperpigmented spots in the retina, skull osteomas and normal neurological examinations. The bone scan and CSF were normal and she had a germline mutation in the segment 3 of the adenomatous polyposis coli (APC) gene. Following partial resection of the two ependymomas, she was treated with radiation and chemotherapy. One year after surgery, paraspinal desmoid tumors were found and removed. She is presently 42 months postsurgical resection of the neural tumors and has remained central nervous system tumor-free. The occurrence of multiple ependymoma in TS has not been reported, and the control of this patient's ependymomas is consistent with other reports of long-term survival with TS and glial tumors.

Primary leptomeningeal histiocytic lymphoma in a young child.

A 20-month-old boy had an 8-week history of vomiting, lethargy, generalized muscle weakness, and seizures. There was no history or clinical signs of an underlying systemic disease or an immunodeficiency. Cerebrospinal fluid (CSF) had 99 nucleated cells/cu mm, malignant cells, high protein and normal glucose. CT and MRI scans showed diffuse meningeal enhancement around the brain and spinal cord, but no parenchymal involvement. Biopsy of the leptomeninges showed malignant cells with marked nuclear pleomorphism and prominent clear to eosinophilic cytoplasm. The immunohistochemical studies were positive for histiocyte-macrophage markers and were negative with T and B cells, Ki-1, neural and glial cell antibodies. Multiple tests revealed no other site of disease. The patient died 3 months after onset of treatment despite intensive i.v. and intrathecal chemotherapy. We have not found any other reported case of primary histiocytic leptomeningeal lymphoma in a young child.

Right atrial thrombi in children with cancer and indwelling catheters.

OBJECTIVE: To determine the prevalence of right atrial thrombi in children with cancer and indwelling catheters. STUDY DESIGN: We systematically examined 156 children with cancer and indwelling catheters for the presence of a right atrial thrombus when they underwent routine screening of cardiac function by two-dimensional echocardiography. RESULTS: Thirteen children (8.8%) had right atrial thrombi. Of the 13 children, 6 had thrombi adherent to the right atrial wall, and in 5 of these 6 children the clots were considered large enough to require intervention: 2 children with obstruction of venous or tricuspid valve inflow underwent right atriotomy and thrombus removal; they recovered and remained well. The other 3 children had moderate-sized thrombi and were treated with oral anticoagulants; their clots stabilized (2 children) or regressed (1 child). The remaining 7 children had thrombus on the tip of the catheter: 5 of these children were observed; the thrombi spontaneously resolved in 2 of them and did not change in size in the other 3. In the sixth child, the catheter malfunctioned 2 weeks after discovery of the clot and the catheter was removed. The seventh child was treated with warfarin and the clot decreased in size. Thrombi were detected in a greater proportion of children with catheter tips in the right atrium versus the superior vena cava, and in a greater proportion of children with acute lymphoblastic leukemia versus other diagnoses. There was no association between the presence of a clot and duration of time the catheter was in place, the number of catheters placed, treatment with asparaginase, or treatment with total parenteral nutrition. CONCLUSION: The incidence of right atrial thrombi in children with indwelling catheters may be higher than was previously appreciated.

Treatment of alloimmune neonatal neutropenia with granulocyte colony-stimulating factor.

Despite numerous attempts to increase the neutrophil count of infants with alloimmune neonatal neutropenia, no therapy has been consistently effective. We describe two infants with alloimmune neutropenia who had a rapid and prolonged increase in neutrophil number after treatment with granulocyte colony-stimulating factor (G-CSF). Patient 1 had antibody directed against the neutrophil antigen NA2. He received three daily doses of G-CSF, and within 2 days his neutrophil count increased from 0.350 x 10(9) to 3.584 x 10(9)/L (350 to 3584/mm3). Despite cessation of treatment the neutrophil count remained in the normal range. Patient 2 had antibody to the neutrophil antigen NA1, and received six daily doses of G-CSF. Within 4 days his neutrophil count increased from 0.477 x 10(9) to 4.320 x 10(9)/L (477 to 4320/mm3) and remained in the normal range for 11 days after the last dose of G-CSF. We recommend that treatment with G-CSF be considered for selected infants with alloimmune neutropenia.

Occult pneumococcal bacteremia: what happens to the child who appears well at reevaluation?

There is little information on the outcome of occult pneumococcal bacteremia in children who appear well at the time of first reevaluation. To determine the outcome of such children we reviewed the medical records of 364 children with blood cultures positive for Streptococcus pneumoniae managed at 2 hospitals in New Haven from 1973 to 1987. One hundred eighty of the 364 children were initially managed as outpatients; 111 of the 180 (62%) were afebrile and appeared well at the first reevaluation. Twenty-two of these 111 children (20%) were hospitalized and treated with intravenously administered antimicrobials at the first reevaluation visit; 2 of these 22 were still bacteremic, although no focal infection was found. Seventy-eight children (70%) were sent home after the first reevaluation visit with orally administered antimicrobials; 1 of these 78 children was still bacteremic and another subsequently was found to have meningitis that had been present at the first visit (culture of the cerebrospinal fluid obtained at the first visit subsequently grew S. pneumoniae). Eleven children (10%) were sent home from the reevaluation visit without antimicrobial treatment and none had persistent or recurrent pneumococcal infection. We conclude that the child who is afebrile and appears well at reevaluation for a blood culture positive for S. pneumoniae is unlikely to develop serious sequelae. Outpatient management with careful follow-up is essential for such children.