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Surgical management of primary central nervous system germ cell tumors

Proceedings from the Second International Symposium on Central Nervous System Germ Cell Tumors 

Mark M. Souweidane, Mark D. Krieger, Howard L. Weiner, and Jonathan L. Finlay

The successful treatment of children with a primary CNS germ cell tumor can be greatly influenced by the neurosurgeon involved in the diagnostic and therapeutic care of these children. Variability in surgical philosophies no doubt exists due to the relatively infrequent incidence of these tumors, a lack of consensus regarding diagnostic and therapeutic approaches, and the advent of recent surgical innovations. Many of these issues were discussed at the Second International Symposium on Central Nervous System Germ Cell Tumors through presented abstracts and invited presentations. The neurosurgical aspects of these proceedings are summarized here in an effort to present the agreed-upon and debated issues that may confront the pediatric neurosurgeon.

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Thomas E. Merchant, Toni Haida, Ming-Hsien Wang, Jonathan L. Finlay, and Steven A. Leibel

✓ The authors conducted a retrospective review of the clinical and treatment characteristics and outcomes in 28 pediatric patients with anaplastic ependymoma treated with radiation therapy since the advent of computerized tomography (CT) (1978–1994). Twelve patients received craniospinal irradiation followed by a boost to the primary site, two received whole-brain radiation therapy followed by a boost to the primary site, and the remaining 14 were treated with focal radiation therapy. The mean dose to the primary site was 5486 cGy. With a median follow-up period of 86 months for the 14 surviving patients (range 31–201 months), the median disease-free survival, measured from the date of diagnosis to the time of recurrence after radiation therapy, was 40 months. The median disease-free survival measured from the start of radiation therapy was 32 months. The median overall survival rate has not been reached and the actuarial estimates of overall survival rates at 5 and 10 years were 56% and 38%, respectively. According to univariate analysis, the disease-free survival rate was significantly improved (p < 0.01) in patients who underwent a gross-total resection at diagnosis. Overall survival rates were negatively influenced by treatment with craniospinal and whole-brain irradiation. As calculated by multivariate analysis, increasing dosage to the primary site (p < 0.05), infratentorial location (p < 0.01), and gross-total resections (p < 0.02) resulted in the longest disease-free survival times. All 19 patients in whom treatment failed after radiation therapy suffered a recurrence at the primary site. In addition, one of these patients experienced subarachnoid dissemination. Radiation treatment recommendations for patients with ependymoma have been based on the tumor's location, perceived risk for dissemination, and malignant propensity. The significance of anaplastic histological classification is controversial. Differences in the disease-free and overall survival rates have been demonstrated between ependymomas and anaplastic ependymomas treated in the pre—CT era. The results of this study show that there is no benefit from craniospinal irradiation in this group of patients.

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Editorial

Germ cell tumors

Frederick A. Boop

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Gary K. Steinberg, Richard H. Britt, Dieter R. Enzmann, Jonathan L. Finlay, and Ann M. Arvin

✓ The common soil fungus, Fusarium, is rarely pathogenic in man but occasionally causes serious disease, particularly in immunocompromised hosts. A case is reported of Fusarium brain abscess and meningitis occurring in a patient with chronic infectious mononucleosis syndrome and immunodeficiency. The patient died despite aspiration of the abscess and treatment with amphotericin B. This case demonstrates the importance of identifying the offending pathological organism through abscess aspiration in immunocompromised patients.

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Ramin J. Javahery, Laurence Davidson, Jason Fangusaro, Jonathan L. Finlay, Ignacio Gonzalez-Gomez, and J. Gordon McComb

Papillary glioneuronal tumors are a newly recognized type of brain neoplasm characterized by prominent pseudopapillary structures and glioneuronal elements. All prior cases have shown that these tumors have an indolent course. The authors present 2 patients with an aggressive variant of the tumor. The first patient had dissemination of her tumor and the second had local spreading. Therefore, the authors conclude that papillary glioneuronal tumors do not always behave in a strictly benign fashion.

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Ian F. Pollack, Ronald L. Hamilton, C. David James, Sydney D. Finkelstein, Judith Burnham, Allan J. Yates, Emiko J. Holmes, Tianni Zhou, Jonathan L. Finlay, and Group for the Children’s Oncology

Object

In reporting on molecular studies involving malignant gliomas in adults, authors have noted that deletions of PTEN and amplification of EGFR are common and may contribute to tumor development, providing a rationale for a number of therapies aimed at these molecular targets. The frequency of comparable abnormalities has not been defined in a sizable pediatric cohort. To address this issue, we examined tumor samples from the Children’s Cancer Group 945 study, a large randomized trial of treatment for childhood malignant gliomas.

Methods

Tissue sections in 62 evaluable cases were examined, and the tumors were isolated by microdissection. Polymerase chain reaction amplification was used to detect PTEN mutations. Deletions of PTEN were also assessed by fluorescence in situ hybridization (FISH) in 27 cases and loss of heterozygosity analysis in 54; EGFR was assessed using immunohistochemistry to identify areas with maximal EGFR expression, followed by FISH to determine EGFR amplification.

Alteration of the PTEN sequence was detected in just one of 62 tumors, in conjunction with loss of chromosome 10; PTEN deletions without mutation were evident in seven additional tumors. The PTEN alterations were more common in glioblastoma multiforme (seven of 25 tumors) than other tumor subgroups (one of 37 tumors) (p = 0.0056). Although 14 of 38 evaluable tumors had increased EGFR expression compared to normal tissue, only one tumor exhibited amplification of EGFR.

Conclusions

Alterations in PTEN and amplification of EGFR are uncommon in pediatric malignant gliomas, in contrast to adult malignant gliomas. From this one can infer that the pediatric and adult tumors involve distinct molecular causes. The results of this study have important implications for the adaptation of glioma therapies aimed at molecular targets in adults to the treatment of childhood gliomas, and highlight the need for investigations of therapies specifically directed toward childhood tumors.

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Eric Bouffet, Jeffrey C. Allen, James M. Boyett, Allen Yates, Floyd Gilles, Peter C. Burger, Richard L. Davis, Laurence E. Becker, Ian F. Pollack, and Jonathan L. Finlay

OBJECT

The impact of central pathology review on outcome has been described in pediatric patients with high-grade glioma (HGG). The objective of this report was to analyze the impact of the central pathology review on outcome in the subgroup of patients with institutional diagnosis of HGG of the spinal cord enrolled in the Children's Cancer Group 945 cooperative study.

METHODS

Five neuropathologists centrally reviewed the pathology of the 18 patients with HGG of the spinal cord who were enrolled in the study. These reviews were independent, and reviewers were blinded to clinical history and outcomes. A consensus diagnosis was established for each patient, based on the outcome of the review.

RESULTS

Of 18 patients, only 10 were confirmed to have HGG on central review. At a median follow-up of 12 years, event-free and overall survival for all 18 patients was 43.2% ± 13.3% and 50% ± 13.4%, respectively. After central review, 10-year event-free and overall survival for confirmed HGGs and discordant diagnoses was 30% ± 12.5% versus 58.3% ± 18.8% (p = 0.108) and 30% ± 12.5% versus 75% ± 14.2% (p = 0.0757), respectively.

CONCLUSIONS

The level of discordant diagnoses in children and adolescents with institutional diagnosis of HGG of the spinal cord was 44% in this experience. However, there was no significant difference in outcome between patients with confirmed and discordant diagnosis. This group of tumor deserves a specific attention in future trials.

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Jeffrey C. Allen, Shraga Aviner, Allan J. Yates, James M. Boyett, Joel M. Cherlow, Patrick A. Turski, Fred Epstein, Jonathan L. Finlay, and Children's Cancer Group

Object. The purpose of this study was to devise an improved method of treating high-grade gliomas of the spinal cord in children who have a dismal prognosis following conventional treatment.

Methods. Eighteen children with newly diagnosed high-grade astrocytomas arising in the spinal cord were enrolled in the Children's Cancer Group (CCG) protocol 945. Following surgery, they were all assigned to receive two cycles of “8-drugs-in-1-day” (8-in-1) chemotherapy prior to radiotherapy and eight additional cycles thereafter. A centralized neuropathology review was used to confirm the diagnosis of high-grade astrocytoma in 13 of the 18 children: anaplastic astrocytoma (eight patients), glioblastoma multiforme (four patients), and mixed malignant glioma (one patient). Diagnoses were discordant in five patients. There were eight boys and five girls in the group with confirmed diagnoses, with a median age of 7 years (range 1–15 years). The extent of resection was confirmed by computerized tomography or magnetic resonance (MR) evaluation in five of 13 patients. There were six gross-total or near-total resections (> 90%), four partial or subtotal resections (10–90%), and three biopsies. Six patients showed evidence of leptomeningeal metastases at diagnosis based on staging MR examinations. Eight of the 13 patients completed at least eight of the prescribed 10 cycles of chemotherapy; five received craniospinal radiotherapy and five spinal radiotherapy.

Conclusions. The 5-year progression-free and total survival rates for the 13 children were 46 ± 14% and 54 ± 14%, respectively. Seven patients suffered a relapse at the primary site, four of whom also had leptomeningeal metastases. Seven of the 13 patients (54%) remain alive at the time of this report at a median of 76 months (range 51–93 months) from study entry. Six patients died between 8 and 38 months after diagnosis, all with active disease. Intensification of therapy may further improve outcome in this high-risk population.

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Jeffrey C. Allen, Shraga Aviner, Allan J. Yates, James M. Boyett, Joel M. Cherlow, Patrick A. Turski, Fred Epstein, Jonathan L. Finlay, and the Children's Cancer Group

The purpose of this study was to devise an improved method of treating high-grade gliomas of the spinal cord in children who have a dismal prognosis following conventional treatment. Eighteen children with newly diagnosed high-grade astrocytomas arising in the spinal cord were enrolled in the Children's Cancer Group (CCG) protocol 945. Following surgery, they were all assigned to receive two courses of “8-drugs-in-1-day” (8-in-1) chemotherapy prior to radiotherapy and eight additional courses thereafter. A centralized neuropathology review was used to confirm the diagnosis of high-grade astrocytoma in 13 of the 18 children: anaplastic astrocytoma, (eight patients), glioblastoma multiforme (four patients), and mixed malignant glioma (one patient). Diagnoses were discordant in five patients. There were eight boys and five girls in the group with confirmed diagnoses, with a median age of 7 years (range 1-15 years). The extent of resection was confirmed by computerized tomography or magnetic resonance (MR) evaluation in five of 13 patients. There were six gross-total or near-total resections (>90%), four partial or subtotal resections (10-90%), and three biopsies. Six patients showed evidence of leptomeningeal metastases at diagnosis based on staging MR examinations. Eight of the 13 patients completed at least eight of the prescribed 10 courses of chemotherapy; five received craniospinal radiotherapy and five spinal radiotherapy. The 5-year progression-free and total survival rates for the 13 children were 46 ± 14% and 54 ± 14%, respectively. Seven patients suffered a relapse at the primary site, four of whom also had leptomeningeal metastases. Seven of the 13 patients (54%) remain alive at the time of this report at a median of 76 months (range 51-93 months) from study entry. Six patients died between 8 and 38 months after diagnosis, all with active disease. Intensification of therapy may further improve outcome in this high-risk population.

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Patricia L. Robertson, Paul M. Zeltzer, James M. Boyett, Lucy B. Rorke, Jeffrey C. Allen, J. Russell Geyer, Philip Stanley, Hao Li, A. Leland Albright, Patricia McGuire-Cullen, Jonathan L. Finlay, Kenneth R. Stevens Jr., Jerrold M. Milstein, Roger J. Packer, Jeffrey Wisoff, and Children's Cancer Group

Object. Ependymomas in children continue to generate controversy regarding their histological diagnosis and grading, optimal management, and possible prognostic factors. To increase our knowledge of these tumors the authors addressed these issues in a cohort of children with prospectively staged ependymomas treated with radiotherapy and chemotherapy.

Methods. Children between the ages of 2 and 17.3 years harboring an intracranial ependymoma confirmed by a central review of the tumor's pathological characteristics were treated according to Children's Cancer Group Protocol 921 from 1986 to 1992. Treatment following surgery and postoperative tumor staging (including brain computerized tomography or magnetic resonance [MR] imaging, spinal MR imaging or myelography, and cerebrospinal fluid cytological investigation) included craniospinal irradiation with a local boost to the primary tumor and patient randomization to receive adjuvant chemotherapy with either 1) CCNU, vincristine, and prednisone, or 2) the eight-drugs-in-1-day regimen. Centralized review of the tumor pathological characteristics revealed 20 ependymomas and 12 anaplastic ependymomas in the 32 children included in the study. Diagnoses made at the individual institutions included anaplastic (malignant) ependymoma (15 patients), ependymoma (four patients), ependymoblastoma (nine patients), ependymoastrocytoma (one patient), and primitive neuroectodermal tumor (three patients), which were discordant with the centralized review diagnosis in 22 of 32 cases. Only three of the 32 patients had metastatic disease (two with M1 and one with M3 stages). At surgery, 47% of tumors were estimated to be totally resected. Among the 14 of 17 patients who suffered a relapse and were evaluated for site of relapse, 10 (71%) had an isolated local relapse, three (21%) had concurrent local and metastatic relapse, and only one (7%) had an isolated metastatic relapse. Kaplan—Meier estimates of 5-year progression-free survival (PFS) and overall survival rates were 50 ± 10% and 64 ± 9%, respectively.

Conclusions. Predictors of PFS duration included an estimate of the extent of resection made at surgery (total compared with less than total, p = 0.0001) and the amount of residual tumor on postoperative imaging as verified by centralized radiological review (≤ 1.5 cm2 compared with > 1.5 cm2, p < 0.0001). No other factors, including centrally reviewed tumor histopathological type, location, metastasis and tumor (M and T) stages, patient age, race, gender, or chemotherapy treatment regimen significantly correlated with PFS duration. The pattern of predominantly local relapse and the important influence of residual tumor or the extent of resection on PFS duration confirms a prevailing impression that local disease control is the major factor in the prediction of outcome of ependymoma. Survival rates were comparable with those reported by other investigators who have treated patients with similar doses of radiation and no chemotherapy.