Gemistocytic astrocytomas: a reappraisal

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✓ Although gemistocytic astrocytomas are considered slow-growing astrocytomas, they often behave aggressively. To clarify the biological and clinical behavior of these rare tumors, the authors retrospectively identified 59 patients with gemistocytic astrocytoma whose tumors were diagnosed and treated between June, 1976, and July, 1989. Three patients who were lost to follow-up review were excluded, as were two whose original slides could not be obtained and three whose tumors were diagnosed at recurrence or at autopsy. The pathological material of the remaining 51 patients was reviewed using two sets of histological criteria.

Thirteen patients (Group A) had “pure” gemistocytic astrocytoma, defined as a glial tumor with more than 60% gemistocytes/high-power field and a background of fibrillary astrocytes. Fifteen patients (Group B) had “mixed” gemistocytic astrocytoma, defined as a glial tumor with 20% to 60% gemistocytes/high-power field and a background of anaplastic astrocytes. Twenty-three tumors did not meet these criteria and were excluded from analysis. The median age of the patients was 48.5 years in Group A and 38.3 years in Group B (p < 0.05). In both groups, the median Kamofsky Performance Scale score was greater than 90%. All patients underwent surgical procedures (four total and 19 partial resections, and five biopsies) and postoperative radiation therapy. The majority also had interstitial brachytherapy, chemotherapy, or both. Ten patients had one reoperation for tumor recurrence and one had two reoperations; other treatments for recurrence included brachytherapy, chemotherapy, and repeat irradiation. All four patients who originally underwent gross total resection are still alive; all five who had a biopsy have died. There was no significant difference in median survival times between groups: 136.5 weeks in Group A (range 10 to 310+ weeks) and 135.6 weeks in Group B (range 31 to 460+ weeks). Analysis of all 28 patients showed a better prognosis for patients less than 50 years of age (185 vs. 36 weeks survival time; p < 0.001), patients with preoperative symptoms lasting for more than 6 months (228.1 vs. 110.2 weeks survival time; p < 0.05), and patients with seizures as the first symptom (185.7 vs. 80 weeks survival time; p < 0.01). Survival time did not correlate with the presence of perivascular lymphocytic infiltration.

The authors conclude that the presence of at least 20% gemistocytes in a glial neoplasm is a poor prognostic sign, irrespective of the pathological background. It is proposed that gemistocytic astrocytomas be classified with anaplastic astrocytomas and treated accordingly.

Abstract

✓ Although gemistocytic astrocytomas are considered slow-growing astrocytomas, they often behave aggressively. To clarify the biological and clinical behavior of these rare tumors, the authors retrospectively identified 59 patients with gemistocytic astrocytoma whose tumors were diagnosed and treated between June, 1976, and July, 1989. Three patients who were lost to follow-up review were excluded, as were two whose original slides could not be obtained and three whose tumors were diagnosed at recurrence or at autopsy. The pathological material of the remaining 51 patients was reviewed using two sets of histological criteria.

Thirteen patients (Group A) had “pure” gemistocytic astrocytoma, defined as a glial tumor with more than 60% gemistocytes/high-power field and a background of fibrillary astrocytes. Fifteen patients (Group B) had “mixed” gemistocytic astrocytoma, defined as a glial tumor with 20% to 60% gemistocytes/high-power field and a background of anaplastic astrocytes. Twenty-three tumors did not meet these criteria and were excluded from analysis. The median age of the patients was 48.5 years in Group A and 38.3 years in Group B (p < 0.05). In both groups, the median Kamofsky Performance Scale score was greater than 90%. All patients underwent surgical procedures (four total and 19 partial resections, and five biopsies) and postoperative radiation therapy. The majority also had interstitial brachytherapy, chemotherapy, or both. Ten patients had one reoperation for tumor recurrence and one had two reoperations; other treatments for recurrence included brachytherapy, chemotherapy, and repeat irradiation. All four patients who originally underwent gross total resection are still alive; all five who had a biopsy have died. There was no significant difference in median survival times between groups: 136.5 weeks in Group A (range 10 to 310+ weeks) and 135.6 weeks in Group B (range 31 to 460+ weeks). Analysis of all 28 patients showed a better prognosis for patients less than 50 years of age (185 vs. 36 weeks survival time; p < 0.001), patients with preoperative symptoms lasting for more than 6 months (228.1 vs. 110.2 weeks survival time; p < 0.05), and patients with seizures as the first symptom (185.7 vs. 80 weeks survival time; p < 0.01). Survival time did not correlate with the presence of perivascular lymphocytic infiltration.

The authors conclude that the presence of at least 20% gemistocytes in a glial neoplasm is a poor prognostic sign, irrespective of the pathological background. It is proposed that gemistocytic astrocytomas be classified with anaplastic astrocytomas and treated accordingly.

Gemistocytic astrocytomas are rare tumors, accounting for 21.4%11 and 24%28 of all astrocytomas in the earliest studies and 9% to 19% in more recent surveys.16,22,25,48 The wide variation in incidence seems to reflect differences in the histological definition. The most specific definition of gemistocytic astrocytoma is given in the classification published by the World Health Organization (WHO):56 “a tumour composed predominantly of large, plump astrocytes with abundant eosinophilic cytoplasm and one or more, usually eccentric, nuclei.” Although gemistocytic astrocytomas are considered Grade 2 astrocytomas in the Kernohan-Sayre system,23 they show a propensity for anaplastic transformation.38 Data on their biological and clinical behavior are scarce but generally seem to support this observation.10,11,16,25,28,48 In an autoradiographic study of gliomas exposed to tritiated thymidine, however, Hoshino, et al.,20 showed that gemistocytic astrocytes themselves have very little, if any, proliferative potential.

These conflicting data led us to review all patients diagnosed with gemistocytic astrocytoma between June, 1976, and July, 1989. The purpose of this retrospective study was to reconsider the definition of these tumors and to correlate the clinical and histopathological findings with survival.

Clinical Material and Methods

A review of the data base of the Neuro-Oncology Service, University of California at San Francisco (UCSF), identified 59 patients with an initial diagnosis of gemistocytic astrocytoma made between June, 1976, and July, 1989. Eight patients were excluded: three who were lost to follow-up review, two whose tumors were diagnosed at recurrence, one whose tumor was found at autopsy, and two whose original slides could not be obtained. The slides of tumor specimens from the initial operation of the remaining 51 patients were reviewed by two of us (H.G.J.K. and R.L.D.) using strictly applied criteria.

“Pure” gemistocytic astrocytoma was defined as a glial neoplasm with more than 60% gemistocytes in all high-power fields and a background of fibrillary astrocytes (Fig. 1). “Mixed” gemistocytic astrocytoma was defined as a glial neoplasm with 20% to 60% gemistocytes and a background of anaplastic astrocytes (moderately increased cellularity, at least focally; a high nuclear/cytoplasmic ratio; coarse nuclear chromatin; increased mitotic activity; and nuclear or cytoplasmic pleomorphism) (Fig. 2). Patients whose tumors did not meet these criteria were excluded from the analysis.

Fig. 1.
Fig. 1.

Photomicrographs of a paraffin-embedded specimen of “pure” gemistocytic astrocytoma from Case 11, Group A. Left: Section composed of sheets of gemistocytes (clearly > 60% of the tumor cells). There is a moderately dense lymphocytic infiltrate around a local small vessel. H & E, original magnification × 40. Right: Plastic-embedded specimen from the same tumor. Plump, round cytoplasmic masses are evident and fine processes can be seen in the background. H & E, original magnification × 100.

Fig. 2.
Fig. 2.

Photomicrographs of a paraffin-embedded specimen of “mixed” gemistocytic astrocytoma from Case 2, Group B. Upper Left: Section showing an area of gemistocytic astrocytes. H & E, original magnification x 25. Upper Right: Area of anaplastic astrocytes in the same tumor. H & E, original magnification × 250. Lower: Paraffin-embedded specimen of recurrent tumor from the same patient shows high cellularity and necrosis. This tumor was therefore reclassified as glioblastoma multiforme. H & E, original magnification × 10.

The pathological material was also reviewed to identify perivascular lymphocytic infiltration. Lymphocytes were defined as small cells with round, dark-staining nuclei and little or no visible cytoplasm. No attempt was made to classify the degree of perivascular lymphocytic infiltration, and infiltrates near areas of necrosis were not taken into account. In addition, all slides of material obtained during subsequent operations for recurrent tumor were reviewed with special attention to features indicating malignant transformation.

The patients were further analyzed regarding age, Karnofsky Performance Scale score, duration and type of preoperative signs and symptoms, extent of surgery, adjuvant therapy, treatment at recurrence, and duration of survival after the initial operation. If available, the bromodeoxyuridine labeling index was considered an indicator of proliferative potential.17–19

Tumor recurrence was assessed by neurological examination and contrast-enhanced computerized tomography.26 Survival curves were calculated using the method of Kaplan and Meier.21 Statistical comparison between groups was performed using the Wilcoxon-Gehan test.14

Summary of Cases
Histopathology

During the 13 years encompassed by this study, several pathologists made the diagnosis of gemistocytic astrocytoma in the total series of 59 patients, almost certainly using various definitions. Therefore, the diagnosis of gemistocytic astrocytoma was confirmed in only 28 patients: 13 with “pure” gemistocytic astrocytoma (Group A) and 15 with “mixed” gemistocytic astrocytoma (Group B). These 28 patients represent approximately 1.3% of all patients seen at the Neuro-Oncology Service since 1976. According to histological criteria currently used to classify malignant gliomas at UCSF (Table 1), 14 of the remaining 23 tumors were glioblastomas multiforme and seven were highly anaplastic astrocytomas. One tumor was reclassified as a subependymal giant-cell astrocytoma and one as a mixed protoplasmic/fibrillary astrocytoma. These 23 tumors were excluded from further analysis.

TABLE 1

Histological criteria for diagnosis of glioblastoma multiforme and highly anaplastic astrocytoma

glioblastoma multiforme
 a glial neoplasm that is at least focally highly cellular
 nuclear pleomorphism
 cytoplasmic pleomorphism
 vascular endothelial proliferation
highly anaplastic astrocytoma
 not a glioblastoma multiforme
 at least focally moderately to highly cellular
 presence of at least two of the following characteristics:
  high nuclear/cytoplasmic ratio
  coarse nuclear chromatin
  much mitotic activity
  nuclear pleomorphism
  cytoplasmic pleomorphism

Perivascular lymphocytic infiltration was identified in 15 (54%) of 28 tumors. The bromodeoxyuridine labeling index was available for one patient in Group A (< 1%) and three patients in Group B (1.1%, 6.5%, and 7.0%). All labeled cells were anaplastic astrocytes. No labeling of gemistocytes was seen.

Only one tumor showed malignant transformation to glioblastoma multiforme at reoperation (Fig. 2 lower). In this tumor, originally a “mixed” gemistocytic astrocytoma, all of the histological features we consider essential for the diagnosis of glioblastoma multiforme (Table 1) were unequivocally present, and necrosis was seen as well. The other recurrent tumors showed the typical histological features of astrocytomas after radiation therapy or chemotherapy: focal necrosis, astrocytes with bizarre nuclei, and mural vascular hyalinization. At least focally, some malignant features were also retained (increased cellularity, a high nuclear/cytoplasmic ratio, coarse nuclear chromatin, and mitoses). In six patients, focally prominent gemistocytes were still present.

Clinical Characteristics

The clinical characteristics are summarized in Table 2. The male:female ratio was 3:1. The median age was significantly higher in Group A than in Group B (48.5 vs. 38.3 years; p < 0.05). The median score on the Karnofsky Performance Scale at presentation was 95% (range 70% to 100%). All tumors were supratentorial and evenly distributed between the left and right hemispheres; 50% of the tumors were frontal and 32% were parietal. The median duration of preoperative symptoms was 21.9 weeks.

TABLE 2

Clinical characteristics in 28 patients with GA*

CharacteristicsGroup A (“pure” GA)Group B (“mixed” GA)Total Cases
sex (M:F)12:1 9:6 21:7 
age (yrs)
 median48.5 38.3 42.4 
 range28–69 21–73 21–73 
KPS (%)
 median94 98 95 
 range70–100 70–100 70–100 
duration of preop
  symptoms (wks)   
 median16.3 8.9 21.9 
 range1–204 0–297 0–297 
tumor location
  rt hemisphere8 7 15 
  lt hemisphere5 8 13 
  frontal4 10 14 
  frontotemporal1 1 2 
  temporal1 1 2 
  parietal6 3 9 
  occipital1  1 

GA = gemistocytic astrocytoma; KPS = Karnofsky Performance Scale score.

The initial signs and symptoms are summarized in Table 3. The majority of the patients in both groups presented with seizures. Headache, personality changes, and disturbances of speech, reading, or writing were also observed.

TABLE 3

Presenting signs and symptoms in 28 patients with GA*

SymptomGroup A (“pure” GA)Group B Total (“mixed” GA) CasesTotal Cases
headache7613
nausea/vomiting213
visual disturbances314
personality changes (confusion,538
 memory loss, apraxia)
epileptic seizures (grand mal,91120
 focal motor or sensory,
 partial complex)
weakness336
paresthesias112
speech/reading/ writing difficulties448

GA = gemistocytic astrocytoma.

Initial Treatment

The initial treatment is summarized in Tables 4 and 5. All 28 patients underwent surgery followed by radiation therapy. Four patients underwent gross total resection of their tumors as determined from the operative report; 19 had subtotal resection, and five had biopsy only. Ten patients received whole-brain radiation therapy (four also received a tumor radiation boost) and 18 received focal irradiation to the tumor plus a 2- to 3-cm margin. High-activity 125I seeds were implanted in the tumor in five patients after external irradiation. The median dose of whole-brain radiation therapy was 50.4 Gy (range 44 to 60 Gy) and that of focal irradiation was 60.6 Gy (range 50.8 to 61.2 Gy). The dose of interstitial brachytherapy ranged from 49 to 60 Gy.

TABLE 4

Treatment and survival of 13 patients with “pure” GA (Group A)*

Case No.Age (yrs), SexInitial Operation (resection)Initial TreatmentTreatment at Recurrence (resection, drugs) Survival (wks)
155, MbiopsyRT, BUdR-PCV 10
269, MsubtotalRT, HU 22
356, MsubtotalRT, BUdR-PCVsubtotal 192
449, MsubtotalRT, HU 60
543, MbiopsyRT, BUdR-PCV 48
637, MsubtotalRT, 125I-PCVsubtotal (×2) 142
754, MbiopsyRT, 125I-PCVsubtotal 53
828, FsubtotalRTsubtotal; NU; Proc 308
961, MsubtotalRTsubtotal, NU; AZQ 110
1043, MbiopsyRT, 125I-PCVsubtotal 158
1137, MsubtotalRT, HU, PCVIFNB 103
1240, Mgross totalRT, BUdR-PCV 310
1331, MsubtotalRT, BCNUNU; RT, NU; subtotal, NU, Proc 252

GA = gemistocytic astrocytoma; subtotal = subtotal resection; gross total = gross total resection; RT = radiation therapy; BCNU = carmustine; BUdR-PCV = bromodeoxyuridine as a parenterally administered radiosensitizer, followed by lomustine (CCNU), procarbazine, and vincristine; 125I-PCV = interstitial brachytherapy with 125I, followed by CCNU, procarbazine, and vincristine; HU = hydroxyurea; NU = nitrosourea-based chemotherapy; Proc = procarbazine; AZQ = aziridinylbenzoquinone; IFNB = interferon B; PCV = procarbazine, CCNU, and vincristine.

Died of pulmonary embolism.

Alive at time of analysis.

Nineteen patients were diagnosed and treated at UCSF according to protocols used at the time of presentation (Tables 4 and 5). The remaining nine patients were initially treated elsewhere and were managed at UCSF for tumor recurrence. All nine patients underwent radiation therapy, and two subsequently received adjuvant chemotherapy (lomustine (CCNU) in one and carmustine (BCNU) in the other).

TABLE 5

Treatment and survival of 15 patients with “mixed” GA (Group B)*

Case No.Age (yrs), SexInitial Operation (resection)Initial TreatmentTreatment at Recurrence (resection, drugs)Survival (wks)
146, Fgross totalRT, BUdR-PCV 231
238, MsubtotalRT, BUdR-PCVsubtotal, IFNB; NU 121
329, MsubtotalRTsubtotal, 125I; 138
NU 
473, MsubtotalRTAZQ 41
559, MsubtotalRT, HU, PCV 31
621, Mgross totalRT, BUdR-PCV 117
725, MsubtotalRTsubtotal, NU; RT 269
840, Mgross totalRT, HU, Miso, 460
 BCNU, 5-FU, 
 & Proc-VCR 
alternating 
924, MsubtotalRT, BUdR-PCV 129
1030, FsubtotalRTNU 274
1144, FsubtotalRT, 125I-PCVsubtotal 109
1239, MbiopsyRTNU 80
1328, FsubtotalRT, BUdR-PCVNU 155
1430, MsubtotalRT, CCNUAZQ, 6-TG 105
1541, FsubtotalRT, 125I-PCVAZQ 106

GA = gemistocytic astrocytoma; subtotal = subtotal resection; RT = radiation therapy; VCR = vincristine; BCNU = carmustine; CCNU = lomustine; BUdR-PCV = bromodeoxyuridine as a parenterally administered radiosensitizer, followed by CCNU, procarbazine, and VCR; 125I-PCV = interstitial brachytherapy with 125I, followed by CCNU, procarbazine, and VCR; HU = hydroxyurea; Miso = misonidazole; 5-FU = 5-fluorouracil; Proc = procarbazine; IFNB = interferon B; NU = nitrosourea-based chemotherapy; 125I = interstitial brachytherapy; AZQ = aziridinylbenzoquinone; 6-TG = 6-thioguanine.

Alive at time of analysis.

Treatment at Recurrence

Eighteen patients had recurrent tumors. Nine had one recurrence, seven had two recurrences, and two had three recurrences. All 29 recurrences were local; in three patients, a new adjacent lesion developed. Ten patients had one reoperation for tumor recurrence and one had two reoperations; this was followed by 125I interstitial brachytherapy in one patient and chemotherapy in four others. Chemotherapy alone was given in 13 instances of recurrence, and external reirradiation was administered in two patients (concurrently with BCNU in one). Two patients refused therapy for their second recurrence.

Survival Time

The median survival duration was 136.5 weeks in Group A, 135.6 weeks in Group B, and 140.7 weeks overall. (The slightly higher overall median survival is a mathematical artifact resulting from the linear extrapolation used to calculate median survival.) Kaplan-Meier21 survival curves for all 28 patients and for Groups A and B separately are shown in Fig. 3. Patients who received multimodality therapy postoperatively survived longer than those who received radiation therapy only (144 vs. 124 weeks), but the difference was not statistically significant. Fifteen of the 18 patients with recurrent tumors have died. The median duration of survival after the first recurrence was 26 weeks. Excluding six patients with insufficient follow-up time and one patient who died of pulmonary embolism, the 5-year survival rate was 23.8% overall (five of 21), 18.2% in Group A (two of 11, with one patient still alive at 310+ weeks), and 30% in Group B (three of 10, with one patient still alive at 460+ weeks).

Fig. 3.
Fig. 3.

Kaplan-Meier survival curves for all 28 patients and for those in Group A (“pure” gemistocytic astrocytoma) and Group B (“mixed” gemistocytic astrocytoma). Numbers in parentheses represent the ratio of survivors (and one censored patient) to the total number of patients in each group.

Age correlated inversely with period of survival. Median survival time was longer in patients younger than 50 years of age at diagnosis than in older patients (185 vs. 36 weeks; p < 0.001). Patients with preoperative symptoms for more than 6 months survived longer than those with a shorter duration of symptoms (median 228.1 vs. 110.2 weeks; p < 0.05). Seizures as the first symptom were associated with a longer median survival time (185.7 vs. 80 weeks, p < 0.01). There were no significant differences in median survival time between patients with and those without perivascular lymphocytic infiltration (135 vs. 139 weeks). One patient in Group A with a bromodeoxyuridine labeling index of less than 1% survived 60 weeks. Three patients in Group B with labeling indices of 1.1%, 6.5%, and 7.0% survived for 31, 41, and 106 weeks, respectively.

The extent of resection also influenced outcome. The four patients who underwent gross total resection were still alive at the time of analysis, 117, 231, 310, and 460 weeks postoperatively. Of the five patients who had a biopsy only, four died after 10, 53, 80, and 153 weeks, and the remaining patient died of a pulmonary embolism after 48 weeks. All patients who underwent gross total resection had frontal tumors; more eloquent areas were affected in the biopsied patients (four with a parietal and one with an occipital tumor).

Discussion
Histopathological Considerations

In 1935, Elvidge, et al.,12 introduced gemistocytic astrocytomas as a subtype of astrocytoma, defining them as tumors consisting of “an almost pure culture of gemistocytes” (gemistocytic astrocytes). The term gemistocyte (from the Greek word gemistos, meaning “filled up”) describes a large (15- to 40-µm), round-to-oval cell with abundant cytoplasm.20 Gemistocytic astrocytes are not found in normal brain but generally result from pathological conditions affecting brain tissue, including infiltration by neoplastic astrocytomas.12

The origin and significance of these cells are uncertain. In an autoradiographic study of gliomas, Hoshino, et al.,20 found no labeled gemistocytes in biopsy specimens and only small foci of labeled gemistocytes in autopsy specimens. They concluded that gemistocytic astrocytes cannot synthesize deoxyribonucleic acid (DNA), but occasionally incorporate tritiated thymidine in their original state as fibrillary or protoplasmic astrocytes, thereafter undergoing transformation into gemistocytic astrocytes and entering the nonproliferating pool. According to these authors, gemistocytes merely reflect the intense proliferative activity of surrounding cells but are relatively inert themselves. This hypothesis, however, does not explain the frequent observation of aggressive growth in these tumors consisting predominantly of gemistocytes.20,38

The histopathological features of gemistocytic astrocytomas have not been well defined. Indeed, Kernohan and Sayre23 included these tumors in Grade 1 (gemistocytic astrocytoma) as well as in Grade 2 (gemästete cell astrocytoma) of their classification system.23 The WHO56 defines gemistocytic astrocytoma as a tumor composed “predominantly” of gemistocytic astrocytes; no further description is offered of the gemistocytic component or, surprisingly, of the astrocytic component. Glanzmann, et al.,16 attempted to explain the differences in survival times between patients with gemistocytic astrocytoma by distinguishing between “well-differentiated” and “anaplastic” gemistocytic astrocytomas, but their criteria were not clearly defined.

Foci of gemistocytes may be found in any type of astrocytoma, especially diffuse fibrillary astrocytomas and glioblastomas multiforme.12,38,41 This makes sampling errors a crucial issue in the pathological diagnosis of brain tumors. Consequently, the diagnosis of “pure” gemistocytic astrocytoma in four biopsy specimens is debatable and might reflect foci of gemistocytes within a glioblastoma multiforme, for which the prognosis is accordingly worse. Owing to the lack of autopsy data, we cannot evaluate this possibility; however, exclusion of these four patients from the “pure” gemistocytic astrocytoma group did not significantly alter the median survival time (136.5 vs. 149 weeks for the remaining nine patients) and they were therefore included in the final analysis.

Perivascular lymphocyte infiltration has been reported in 30% to 89% of gliomas.2,3,34–36,39 An especially strong association has been noted between this feature and gemistocytic astrocytoma. Takeuchi and Barnard50 identified perivascular lymphocytic infiltration in 31 (28%) of 111 supratentorial astrocytomas and in 21 (62%) of 34 gemistocytic astrocytomas; however, their criteria for diagnosing gemistocytic astrocytomas were less strict than ours. Perivascular lymphocytic infiltration was present in 15 (54%) of 28 tumors in our series. Lymphocytic infiltration, especially perivascular lymphocytic infiltration, in gliomas has variously been found to improve the duration of survival,3,4,9,29,33 exert no influence on survival time,6,7,37,43 and reduce the survival period.39,51 In our series, there was no significant difference in median survival times between patients with and those without perivascular lymphocytic infiltration (135 vs. 139 weeks, respectively).

Malignant transformation of lower-grade astrocytomas is reportedly frequent,5,24,30,41,42,53 occurring in as many as 65% of patients.30 Russell and Rubinstein38 noted conversion to glioblastoma multiforme in 80% of their cases of gemistocytic astrocytoma. In our series, however, only one of 12 recurrent tumors showed malignant transformation. This discrepancy may be explained by our lack of autopsy data and by our strict histopathological criteria for diagnosing glioblastoma multiforme, according to which the mere presence of necrosis after irradiation or chemotherapy does not necessarily indicate malignant transformation.

In this study, the bromodeoxyuridine labeling index was obtained in only four tumors. In contrast to recent conclusions of Hoshino, et al.,18 prognostic implications cannot be inferred from the results of labeling studies in these few cases. One patient whose “pure” gemistocytic astrocytoma had a bromodeoxyuridine labeling index of less than 1% survived 60 weeks, while three patients whose “mixed” gemistocytic astrocytomas had labeling indices of 1.1%, 6.5%, and 7.0% survived 31, 41, and 106 weeks, respectively. All of the labeled cells were anaplastic astrocytes. The absence of bromodeoxyuridine-labeled gemistocytes in these specimens seems to support previous findings that the proliferative potential of gemistocytes is extremely low.15,20 The discrepancy between the behavior of individual gemistocytes and the frequently aggressive growth of gemistocytic astrocytomas is therefore still unexplained.

Clinical Considerations

Clinical data on patients with gemistocytic astrocytomas are scarce.10,11,28 Elvidge, et al.,12 noted the exclusively supratentorial occurrence of gemistocytic astrocytomas which we also found in our series. In other series,11,28 the male-to-female ratio was approximately 3:2, which corresponds to the ratio for all astrocytomas.45 In our series, males predominated by a ratio of 3:1 overall and by 12:1 among patients with “pure” gemistocytic astrocytoma. The median age at diagnosis (42.4 years) was similar to that reported by other authors (38.2 years11 and 40 years28). The median age of our patients with “pure” gemistocytic astrocytomas, however, was 48.5 years.

Elvidge and Martinez-Coll11 reported 18 patients with gemistocytic astrocytoma, presumably diagnosed according to the criteria of Elvidge, et al.12 Their mean survival time was 42.7 months; eight patients survived 4 years or longer and one lived 10 years 4 months. In the series of Levy and Elvidge,28 the mean survival time was 31 months in 18 patients who had incomplete resection and 46 months in those who had complete resection. The mean survival time was 26 months for the 19 patients who died and 70 months for the five patients who were still alive. These data are difficult to interpret because postoperative radiation therapy was not used routinely.

In a report on the role of radiation therapy in the treatment of astrocytomas, Leibel, et al.,25 found only one of 11 patients with gemistocytic astrocytoma who survived more than 5 years. In a similar report of 77 patients, Glanzmann, et al.,16 described six “well-differentiated” and nine “anaplastic” gemistocytic astrocytomas. Three of the patients with well-differentiated gemistocytic astrocytomas lived 5 years and one lived 10 years; in contrast, no patient with anaplastic gemistocytic astrocytoma lived longer than 6 years. Several authors1,38,41,44 have mentioned the unfavorable clinical course of gemistocytic astrocytoma without providing specific survival data or numbers of patients. In a recent report of radiation therapy for low-grade supratentorial astrocytomas, Shaw, et al.,48 described 17 patients with gemistocytic astrocytoma, as defined by the WHO.56 They found the gemistocytic subtype to be associated with shorter survival times but did not present survival data for this subgroup.

Our efforts to clarify the biological and clinical behavior of gemistocytic astrocytomas are based on histopathological criteria that differentiate between “pure” gemistocytic astrocytoma (> 60% gemistocytes with a background of fibrillary astrocytes) and “mixed” gemistocytic astrocytoma (20% to 60% gemistocytes with a background of anaplastic astrocytes). Although both groups received similar treatment, there was little difference in median survival time (136.5 vs. 135.6 weeks); this was less than in patients with anaplastic astrocytomas treated with postoperative radiation therapy and adjuvant chemotherapy with CCNU, procarbazine, and vincristine (157 weeks)27 and was similar to that in patients with atypical and anaplastic astrocytomas (28 and 36 months, respectively).31,32 Moreover, the 5-year survival rate in our series was considerably less than in recent studies of patients with low-grade astrocytomas treated with postoperative radiation therapy (23.8% vs. 50% to 60%).13,48,49 The only significant difference in prognostically important variables between groups was the somewhat younger median age of patients with “mixed” gemistocytic astrocytomas which, if anything, would have a favorable influence on prognosis. Thus, despite its nonanaplastic morphology and the non-proliferative character of its predominant cellular component, “pure” gemistocytic astrocytomas in our series were as aggressive clinically as “mixed” gemistocytic astrocytomas, which have more anaplastic astrocytic features.

The prognostic importance of age, duration of preoperative symptoms, and seizures at presentation among patients with gliomas has been well documented.7,46,52 Our study confirms the favorable impact on survival time of the following features: age less than 50 years, preoperative symptoms lasting more than 6 months, and the occurrence of seizures as the initial symptom. Our findings also support the importance of the extent of surgical resection as a prognostic variable in glioma patients.8,40,47,54,55

Conclusions

Our findings suggest that the presence of at least 20% gemistocytes in a glial neoplasm is an unfavorable prognostic sign, regardless of whether the surrounding background has more fibrillary or more anaplastic astrocytic components. We propose that such tumors be classified as anaplastic astrocytomas and be considered “high-grade” rather than “low-grade” astrocytomas. These tumors should be resected as extensively as feasible and be treated postoperatively with focal radiation therapy followed by nitrosourea-based chemotherapy.

Acknowledgments

We thank Susan Owen and Cheryl Christensen for manuscript preparation and Stephen Ordway for editorial assistance.

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    Elvidge ARMartinez-Coll A: Long-term follow-up of 106 cases of astrocytoma, 1928–1939. J Neurosurg 13:3183311956J Neurosurg 13:

  • 12.

    Elvidge ARPenfield WCone W: The gliomas of the central nervous system. A study of two hundred and ten verified cases. Proc Assoc Res Nerv Ment Dis 16:1071811935Proc Assoc Res Nerv Ment Dis 16:

  • 13.

    Garcia DMFulling KHMarks JE: The value of radiation therapy in addition to surgery for astrocytomas of the adult cerebrum. Cancer 55:9199271985Cancer 55:

  • 14.

    Gehan EA: A generalized Wilcoxon test for comparing arbitrarily singly-censored data. Biometrika 52:2032231965Gehan EA: A generalized Wilcoxon test for comparing arbitrarily singly-censored data. Biometrika 52:

  • 15.

    Germano IMIto MCho KGet al: Correlation of histopathological features and proliferative potential of gliomas. J Neurosurg 70:7017061989J Neurosurg 70:

  • 16.

    Glanzmann CHPeters JHorst Wet al: Indikationen und Ergebnisse der Radiotherapie in der Behandlung von Astrozytomen. Strahlentherapie 156:3823871980Strahlentherapie 156:

  • 17.

    Hoshino TNagashima TMurovic JAet al: In situ cell kinetics studies on human neuroectodermal tumors with bromodeoxvuridine labeling. J Neurosurg 64:4534591986In situ cell kinetics studies on human neuroectodermal tumors with bromodeoxvuridine labeling. J Neurosurg 64:

  • 18.

    Hoshino TPrados MWilson CBet al: Prognostic implications of the bromodeoxyuridine labeling index of human gliomas. J Neurosurg 71:3353411989J Neurosurg 71:

  • 19.

    Hoshino TRodriguez LACho KGet al: Prognostic implications of the proliferative potential of low-grade astrocytomas. J Neurosurg 69:8398421988J Neurosurg 69:

  • 20.

    Hoshino TWilson CBEllis WG: Gemistocytic astrocytes in gliomas: an autoradiographic study. J Neuropathol Exp Neurol 34:2632811975J Neuropathol Exp Neurol 34:

  • 21.

    Kaplan ELMeier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:4574811958J Am Stat Assoc 53:

  • 22.

    Katakura RYoshimoto T: Epidemiology and statistical analysis of gliomasSuzuki J (ed): Treatment of Glioma. Tokyo: Springer-Verlag1988316Treatment of Glioma.

  • 23.

    Kernohan JWSayre GP: Tumors of the central nervous system Washington, DC: Armed Forces Institute of Pathology1952

  • 24.

    Laws ERTaylor WFClifton MBet al: Neurosurgical management of low-grade astrocytoma of the cerebral hemispheres. J Neurosurg 61:6656731984J Neurosurg 61:

  • 25.

    Leibel SASheline GEWara WMet al: The role of radiation therapy in the treatment of astrocytomas. Cancer 35:155115571975Cancer 35:

  • 26.

    Levin VACrafts DCNorman DMet al: Criteria for evaluating patients undergoing chemotherapy for malignant brain tumors. J Neurosurg 47:3293351977J Neurosurg 47:

  • 27.

    Levin VASilver PHannigan Jet al: Superiority of postradiotherapy adjuvant chemotherapy with CCNU, procarbazine, and vincristine (PCV) over BCNU for anaplastic gliomas: NCOG 6G61 final report. Int J Radiat Oncol Biol Phys 18:3213241990Int J Radiat Oncol Biol Phys 18:

  • 28.

    Levy LFElvidge AR: Astrocytoma of the brain and spinal cord. A review of 176 cases, 1940–1949. J Neurosurg 13:4134431956J Neurosurg 13:

  • 29.

    Manoury RVedrenne CConstans JP: Infiltrations lymphocytaires dans les gliomes humains. Neurochirurgie 21:2132221975Neurochirurgie 21:

  • 30.

    Müller WÁfra DSchröder R: Supratentorial recurrences of gliomas. Morphological studies in relation to time intervals with astrocytomas. Acta Neurochir 37:75911977Acta Neurochir 37:

  • 31.

    Nelson DFNelson JSDavis DRet al: Survival and prognosis of patients with astrocytoma with atypical or anaplastic features. J Neurooncol 3:991031985J Neurooncol 3:

  • 32.

    Nelson JSTsukada YSchoenfeld Det al: Necrosis as a prognostic criterion in malignant supratentorial, astrocytic gliomas. Cancer 52:5505541983Cancer 52:

  • 33.

    Palma LDi Lorenzo NGuidetti B: Lymphocytic infiltrates in primary glioblastomas and recidivous gliomas. Incidence, fate, and relevance to prognosis in 228 operated cases. J Neurosurg 49:8548611978J Neurosurg 49:

  • 34.

    Ridley ACavanagh JB: Lymphocytic infiltration in gliomas: evidence of possible host resistance. Brain 94:1171241971Brain 94:

  • 35.

    Rossi MLCruz-Sanchez FHughes JTet al: Mononuclear cell infiltrate and HLA-DR expression in low grade astrocytomas: an immunohistological study of 23 cases. Acta Neuropathol 76:2812861988Acta Neuropathol 76:

  • 36.

    Rossi MLHughes JTEsiri MMet al: Immuno-histological study of mononuclear cell infiltrate in malignant gliomas. Acta Neuropathol 74:2692771987Acta Neuropathol 74:

  • 37.

    Rossi MLJones NRCandy Eet al: The mononuclear cell infiltrate compared with survival in high-grade astrocytomas. Acta Neuropathol 78:1891931989Acta Neuropathol 78:

  • 38.

    Russell DSRubinstein LJ: Pathology of Tumours of the Nervous Systemed 5. London: Williams & Wilkins1989

  • 39.

    Safdari HHochberg FHRichardson EP: Prognostic value of round cell (lymphocyte) infiltration in malignant gliomas. Surg Neurol 23:2212261985Surg Neurol 23:

  • 40.

    Salcman M: Supratentorial gliomas: clinical features and surgical therapyWilkins RHRengachary SS (eds): Neurosurgery. New York: McGraw-Hill19851579590Neurosurgery.

  • 41.

    Scherer HJ: Cerebral astrocytomas and their derivatives. Am J Cancer 40:1591981940Scherer HJ: Cerebral astrocytomas and their derivatives. Am J Cancer 40:

  • 42.

    Scherer HJ: The forms of growth in gliomas and their practical significance. Brain 63:1351940Scherer HJ: The forms of growth in gliomas and their practical significance. Brain 63:

  • 43.

    Schiffer DCavicchioli DGiordana MTet al: Analysis of some factors affecting survival in malignant gliomas. Tumori 65:1191251979Tumori 65:

  • 44.

    Schiffer DChio AGiordana MTet al: Prognostic value of histologic factors in adult cerebral astrocytoma. Cancer 61:138613931988Cancer 61:

  • 45.

    Schoenberg BS: The epidemiology of central nervous system tumorsWalker MD (ed): Oncology of the Nervous System. Boston: Martinus Nijhoff1983129Oncology of the Nervous System.

  • 46.

    Scott GMGibberd FB: Epilepsy and other factors in the prognosis of gliomas. Acta Neurol Scand 61:2272391980Acta Neurol Scand 61:

  • 47.

    Shapiro WRGreen SBBurger PCet al: Randomized trial of three chemotherapy regimens and two radiotherapy regimens in postoperative treatment of malignant glioma. Brain Tumor Cooperative Group Trial 8001. J Neurosurg 71:191989J Neurosurg 71:

  • 48.

    Shaw EGDaumas-Duport CScheithauer BWet al: Radiation therapy in the management of low-grade supratentorial astrocytomas. J Neurosurg 70:8538611989J Neurosurg 70:

  • 49.

    Shaw EGScheithauer BWGilbertson DTet al: Postoperative radiotherapy of supratentorial low-grade astrocytomas. Int J Radiat Oncol Biol Phys 16:6636681989Int J Radiat Oncol Biol Phys 16:

  • 50.

    Takeuchi JBarnard RO: Perivascular lymphocytic cuffing in astrocytomas. Acta Neuropathol 35:2652711976Acta Neuropathol 35:

  • 51.

    Vaquero JCoca SOya Set al: Presence and significance of NK cells in glioblastomas. J Neurosurg 70:7287311989J Neurosurg 70:

  • 52.

    Walker MDGreen SBByar DPet al: Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery. N Engl J Med 303:132313291980N Engl J Med 303:

  • 53.

    Wilson CB: Reoperation for primary tumors. Semin Oncol 2:19201975Wilson CB: Reoperation for primary tumors. Semin Oncol 2:

  • 54.

    Winger MJMacdonald DRCairncross JG: Supratentorial anaplastic gliomas in adults. The prognostic importance of extent of resection and prior low-grade glioma. J Neurosurg 71:4874931989J Neurosurg 71:

  • 55.

    Wood JRGreen SBShapiro WR: The prognostic importance of tumor size in malignant gliomas: a computed tomographic scan study by the Brain Tumor Cooperative Group. J Clin Oncol 6:3383431988J Clin Oncol 6:

  • 56.

    Zülch KJ: Geneva: World Health Organization19794344Zülch KJ:

This work was supported in part by Grant CA-13525 from the National Institutes of Health.

Article Information

Address reprint requests to: Michael Prados, M.D., Department of Neurological Surgery, c/o The Editorial Office, 1360 Ninth Avenue, Suite 210, San Francisco, California 94122.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Photomicrographs of a paraffin-embedded specimen of “pure” gemistocytic astrocytoma from Case 11, Group A. Left: Section composed of sheets of gemistocytes (clearly > 60% of the tumor cells). There is a moderately dense lymphocytic infiltrate around a local small vessel. H & E, original magnification × 40. Right: Plastic-embedded specimen from the same tumor. Plump, round cytoplasmic masses are evident and fine processes can be seen in the background. H & E, original magnification × 100.

  • View in gallery

    Photomicrographs of a paraffin-embedded specimen of “mixed” gemistocytic astrocytoma from Case 2, Group B. Upper Left: Section showing an area of gemistocytic astrocytes. H & E, original magnification x 25. Upper Right: Area of anaplastic astrocytes in the same tumor. H & E, original magnification × 250. Lower: Paraffin-embedded specimen of recurrent tumor from the same patient shows high cellularity and necrosis. This tumor was therefore reclassified as glioblastoma multiforme. H & E, original magnification × 10.

  • View in gallery

    Kaplan-Meier survival curves for all 28 patients and for those in Group A (“pure” gemistocytic astrocytoma) and Group B (“mixed” gemistocytic astrocytoma). Numbers in parentheses represent the ratio of survivors (and one censored patient) to the total number of patients in each group.

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Elvidge AR: Long-term survival in the astrocytoma series. J Neurosurg 28:3994041968Elvidge AR: Long-term survival in the astrocytoma series. J Neurosurg 28:

11.

Elvidge ARMartinez-Coll A: Long-term follow-up of 106 cases of astrocytoma, 1928–1939. J Neurosurg 13:3183311956J Neurosurg 13:

12.

Elvidge ARPenfield WCone W: The gliomas of the central nervous system. A study of two hundred and ten verified cases. Proc Assoc Res Nerv Ment Dis 16:1071811935Proc Assoc Res Nerv Ment Dis 16:

13.

Garcia DMFulling KHMarks JE: The value of radiation therapy in addition to surgery for astrocytomas of the adult cerebrum. Cancer 55:9199271985Cancer 55:

14.

Gehan EA: A generalized Wilcoxon test for comparing arbitrarily singly-censored data. Biometrika 52:2032231965Gehan EA: A generalized Wilcoxon test for comparing arbitrarily singly-censored data. Biometrika 52:

15.

Germano IMIto MCho KGet al: Correlation of histopathological features and proliferative potential of gliomas. J Neurosurg 70:7017061989J Neurosurg 70:

16.

Glanzmann CHPeters JHorst Wet al: Indikationen und Ergebnisse der Radiotherapie in der Behandlung von Astrozytomen. Strahlentherapie 156:3823871980Strahlentherapie 156:

17.

Hoshino TNagashima TMurovic JAet al: In situ cell kinetics studies on human neuroectodermal tumors with bromodeoxvuridine labeling. J Neurosurg 64:4534591986In situ cell kinetics studies on human neuroectodermal tumors with bromodeoxvuridine labeling. J Neurosurg 64:

18.

Hoshino TPrados MWilson CBet al: Prognostic implications of the bromodeoxyuridine labeling index of human gliomas. J Neurosurg 71:3353411989J Neurosurg 71:

19.

Hoshino TRodriguez LACho KGet al: Prognostic implications of the proliferative potential of low-grade astrocytomas. J Neurosurg 69:8398421988J Neurosurg 69:

20.

Hoshino TWilson CBEllis WG: Gemistocytic astrocytes in gliomas: an autoradiographic study. J Neuropathol Exp Neurol 34:2632811975J Neuropathol Exp Neurol 34:

21.

Kaplan ELMeier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:4574811958J Am Stat Assoc 53:

22.

Katakura RYoshimoto T: Epidemiology and statistical analysis of gliomasSuzuki J (ed): Treatment of Glioma. Tokyo: Springer-Verlag1988316Treatment of Glioma.

23.

Kernohan JWSayre GP: Tumors of the central nervous system Washington, DC: Armed Forces Institute of Pathology1952

24.

Laws ERTaylor WFClifton MBet al: Neurosurgical management of low-grade astrocytoma of the cerebral hemispheres. J Neurosurg 61:6656731984J Neurosurg 61:

25.

Leibel SASheline GEWara WMet al: The role of radiation therapy in the treatment of astrocytomas. Cancer 35:155115571975Cancer 35:

26.

Levin VACrafts DCNorman DMet al: Criteria for evaluating patients undergoing chemotherapy for malignant brain tumors. J Neurosurg 47:3293351977J Neurosurg 47:

27.

Levin VASilver PHannigan Jet al: Superiority of postradiotherapy adjuvant chemotherapy with CCNU, procarbazine, and vincristine (PCV) over BCNU for anaplastic gliomas: NCOG 6G61 final report. Int J Radiat Oncol Biol Phys 18:3213241990Int J Radiat Oncol Biol Phys 18:

28.

Levy LFElvidge AR: Astrocytoma of the brain and spinal cord. A review of 176 cases, 1940–1949. J Neurosurg 13:4134431956J Neurosurg 13:

29.

Manoury RVedrenne CConstans JP: Infiltrations lymphocytaires dans les gliomes humains. Neurochirurgie 21:2132221975Neurochirurgie 21:

30.

Müller WÁfra DSchröder R: Supratentorial recurrences of gliomas. Morphological studies in relation to time intervals with astrocytomas. Acta Neurochir 37:75911977Acta Neurochir 37:

31.

Nelson DFNelson JSDavis DRet al: Survival and prognosis of patients with astrocytoma with atypical or anaplastic features. J Neurooncol 3:991031985J Neurooncol 3:

32.

Nelson JSTsukada YSchoenfeld Det al: Necrosis as a prognostic criterion in malignant supratentorial, astrocytic gliomas. Cancer 52:5505541983Cancer 52:

33.

Palma LDi Lorenzo NGuidetti B: Lymphocytic infiltrates in primary glioblastomas and recidivous gliomas. Incidence, fate, and relevance to prognosis in 228 operated cases. J Neurosurg 49:8548611978J Neurosurg 49:

34.

Ridley ACavanagh JB: Lymphocytic infiltration in gliomas: evidence of possible host resistance. Brain 94:1171241971Brain 94:

35.

Rossi MLCruz-Sanchez FHughes JTet al: Mononuclear cell infiltrate and HLA-DR expression in low grade astrocytomas: an immunohistological study of 23 cases. Acta Neuropathol 76:2812861988Acta Neuropathol 76:

36.

Rossi MLHughes JTEsiri MMet al: Immuno-histological study of mononuclear cell infiltrate in malignant gliomas. Acta Neuropathol 74:2692771987Acta Neuropathol 74:

37.

Rossi MLJones NRCandy Eet al: The mononuclear cell infiltrate compared with survival in high-grade astrocytomas. Acta Neuropathol 78:1891931989Acta Neuropathol 78:

38.

Russell DSRubinstein LJ: Pathology of Tumours of the Nervous Systemed 5. London: Williams & Wilkins1989

39.

Safdari HHochberg FHRichardson EP: Prognostic value of round cell (lymphocyte) infiltration in malignant gliomas. Surg Neurol 23:2212261985Surg Neurol 23:

40.

Salcman M: Supratentorial gliomas: clinical features and surgical therapyWilkins RHRengachary SS (eds): Neurosurgery. New York: McGraw-Hill19851579590Neurosurgery.

41.

Scherer HJ: Cerebral astrocytomas and their derivatives. Am J Cancer 40:1591981940Scherer HJ: Cerebral astrocytomas and their derivatives. Am J Cancer 40:

42.

Scherer HJ: The forms of growth in gliomas and their practical significance. Brain 63:1351940Scherer HJ: The forms of growth in gliomas and their practical significance. Brain 63:

43.

Schiffer DCavicchioli DGiordana MTet al: Analysis of some factors affecting survival in malignant gliomas. Tumori 65:1191251979Tumori 65:

44.

Schiffer DChio AGiordana MTet al: Prognostic value of histologic factors in adult cerebral astrocytoma. Cancer 61:138613931988Cancer 61:

45.

Schoenberg BS: The epidemiology of central nervous system tumorsWalker MD (ed): Oncology of the Nervous System. Boston: Martinus Nijhoff1983129Oncology of the Nervous System.

46.

Scott GMGibberd FB: Epilepsy and other factors in the prognosis of gliomas. Acta Neurol Scand 61:2272391980Acta Neurol Scand 61:

47.

Shapiro WRGreen SBBurger PCet al: Randomized trial of three chemotherapy regimens and two radiotherapy regimens in postoperative treatment of malignant glioma. Brain Tumor Cooperative Group Trial 8001. J Neurosurg 71:191989J Neurosurg 71:

48.

Shaw EGDaumas-Duport CScheithauer BWet al: Radiation therapy in the management of low-grade supratentorial astrocytomas. J Neurosurg 70:8538611989J Neurosurg 70:

49.

Shaw EGScheithauer BWGilbertson DTet al: Postoperative radiotherapy of supratentorial low-grade astrocytomas. Int J Radiat Oncol Biol Phys 16:6636681989Int J Radiat Oncol Biol Phys 16:

50.

Takeuchi JBarnard RO: Perivascular lymphocytic cuffing in astrocytomas. Acta Neuropathol 35:2652711976Acta Neuropathol 35:

51.

Vaquero JCoca SOya Set al: Presence and significance of NK cells in glioblastomas. J Neurosurg 70:7287311989J Neurosurg 70:

52.

Walker MDGreen SBByar DPet al: Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery. N Engl J Med 303:132313291980N Engl J Med 303:

53.

Wilson CB: Reoperation for primary tumors. Semin Oncol 2:19201975Wilson CB: Reoperation for primary tumors. Semin Oncol 2:

54.

Winger MJMacdonald DRCairncross JG: Supratentorial anaplastic gliomas in adults. The prognostic importance of extent of resection and prior low-grade glioma. J Neurosurg 71:4874931989J Neurosurg 71:

55.

Wood JRGreen SBShapiro WR: The prognostic importance of tumor size in malignant gliomas: a computed tomographic scan study by the Brain Tumor Cooperative Group. J Clin Oncol 6:3383431988J Clin Oncol 6:

56.

Zülch KJ: Geneva: World Health Organization19794344Zülch KJ:

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