Clinical and survival covariates of eight classes of childhood supratentorial neuroglial tumors

Authors

  • Floyd H. Gilles M.D.,

    Corresponding author
    1. Division of Neuropathology, Department of Pathology and Laboratory Medicine, Childrens Hospital Los Angeles and University of Southern California School of Medicine, Los Angeles, California
    • Division of Neuropathology, Childrens Hospital Los Angeles, 4650 Sunset Blvd., MS #43, Los Angeles, CA 90027
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    • Fax: (323) 669-4553

  • Alan Leviton M.D., S.M.,

    1. Division of Neuroepidemiology, Children's Hospital and Harvard Medical School, Boston, Massachusetts
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  • C. Jane Tavaré M.S.,

    1. Division of Neuropathology, Department of Pathology and Laboratory Medicine, Childrens Hospital Los Angeles and University of Southern California School of Medicine, Los Angeles, California
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  • Lester Adelman M.D.,

    1. Neuropathology Laboratory, New England Medical Center Hospital and Tufts University, Boston, Massachusetts
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  • Lucy B. Rorke M.D.,

    1. Division of Neuropathology, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, Pennsylvania
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  • Eugene L. Sobel Ph.D.,

    1. Division of Biostatistics, Department of Preventive Medicine, University of Southern California School of Medicine, Los Angeles, California
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  • E. Tessa Hedley-Whyte M.D.,

    1. Division of Neuropathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
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  • Richard L. Davis M.D.,

    1. Department of Pathology, University of California San Francisco, School of Medicine, San Francisco, California
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  • The Childhood Brain Tumor Consortium

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    • The Childhood Brain Tumor Consortium (Floyd H. Gilles, principal investigator) is comprised of the following institutions: Barnes and St. Louis Children's Hospital, St. Louis, MO (William F. Blank and Keith H. Fulling); Cardinal Glennon Memorial Hospital, St. Louis, MO (John D. Blair [deceased] and Daphne DeMello); Children's Hospital, Boston, MA (Floyd H. Gilles and Ana Sotrel); Children's Hospital of Denver, Denver, CO (Edmund N. Orsini, Jr.); Childrens Hospital of Los Angeles, Los Angeles, CA (Hart Isaacs); Children's Hospital of Philadelphia, Philadelphia, PA (Lucy B. Rorke); Children's Hospital of Pittsburgh, Pittsburgh, PA (Yoshie Hashida, Robert A. Price, Eduardo J. Yunis, and Barbara W. Zaias); Hospital for Sick Children, Toronto, Ontario, Canada (Larry E. Becker); Los Angeles County-University of Southern California Medical Center, Los Angeles, CA (Richard L. Davis); and St. Christopher's Hospital for Children, Philadelphia, PA (Guillermo A. de Leon, Dale Huff, Gladys Mestre, and Massoud Shamszadeh). The following are slide readers for the Childhood Brain Tumor Consortium: Lester S. Adelman (Tufts University Medical School, Boston, MA); R. Damon Averill, Jr. (University of Michigan Medical School, Ann Arbor, MI); Richard L. Davis (University of California-San Francisco, San Francisco, CA); Umberto DeGirolami (University of Massachusetts Medical School, Boston, MA); E. Tessa Hedley-Whyte (Harvard Medical School, Boston, MA); George M. Kleinman (Yale Medical School, University of Connecticut Medical School, New Haven, CT); James H. Morris (Harvard Medical School, Boston, MA); E. P. Richardson, Jr. (deceased) (Harvard Medical School, Boston, MA); Lucy B. Rorke (University of Pennsylvania Medical School, Philadelphia, PA); William C. Schoene (Harvard Medical School, Boston, MA); Thomas W. Smith (University of Massachusetts Medical School, Boston, MA); and Raymond A. Sobel (Harvard Medical School, Boston, MA). Administrative/data collection staff: Carol Kenney and Donna Morelli. Editorial/Data Analysis Committee: Floyd H. Gilles, E. Tessa Hedley-Whyte, Alan Leviton, Eugene Sobel, and C. Jane Tavaré.


Abstract

BACKGROUND

In the current study, the authors investigated clinical, surgical, and histologic characteristics (covariates) and their interactions in eight previously identified classes of childhood supratentorial neuroglial tumors. The classes resulted from 5 factor score profiles on 703 supratentorial neuroglial tumors in the Childhood Brain Tumor Consortium database.

METHODS

The Cox proportional models were used to identify class survival covariates.

RESULTS

Age was found to be a survival covariate only in Class 1, in which older age increased the 5-year survival rate 73% from the first year (0.49) to the tenth year (0.85). A greater amount of tumor removed improved survival in Classes 2 and 4 only. Rosenthal fibers improved survival in Class 2 and overrode the negative effects of high Proliferative factor scores and pleomorphic nuclei. Survival for Class 3 children with high Proliferative factor scores improved from 0.60 to 0.95 as the Spongy factor scores increased. Survival in Class 4 increased from 0.17 to 0.39 with total tumor removal. Irregular nuclei and glomeruloid capillaries improved survival in Class 5 patients. Class 6 survival improved with low cell density. Macrocysts in tumors in Classes 1 and 5 were found to improve survival.

CONCLUSIONS

As a result of the current study, the authors conclude that survival covariates differ with tumor class and may modify prognosis considerably. Cancer 2002;95:1302–10. © 2002 American Cancer Society.

DOI 10.1002/cncr.10815

It generally is accepted that survival is improved by certain covariates, such as greater amounts of tumor removed, older patient age, and the abscence of pleomorphic nuclei, regardless of tumor type. The objectives of the current study were to investigate this assump-tion by identifying survival covariates within homogeneous tumor classes and to examine their interactions on survival.

Childhood neuroglial tumors are comprised of a large number of differing microscopic features. Various patterns of histologic features differentiate these tumors one from another. Although each tumor type (astrocytoma, anaplastic astrocytoma, and glioblastoma) has broad survival expectations, other characteristics also modify survival expectation such as tumor location, amount of tumor removed, age of the patient, etc. Relatively histologically homogenous groups of tumors are essential to identify and compare survival covariates. However, childhood neuroglial tumors of the same World Health Organization (WHO) diagnostic name or Daumas-Duport grade do not capture all the histologic information available in a tumor. They contain histologic subsets that differ markedly in survival expectation.1, 2 These observations reflect the histologic heterogeneity within each diagnosis or grade. Previously, we have used methods for assessing extended childhood brain tumor histology that statistically minimize histologic variance, (the variation in histologic features from tumor to tumor) and provide eight classes of supratentorial neuroglial tumors3 with relative histologic homogeneity. These procedures can quantitatively fine-tune the diagnostic groups provided by the WHO classificaiton, by identifying the subsets within broad diagnostic categories with different survival expectations.

Our alternative strategy for grouping children's neuroglial tumors was based on 26 histologic features identified as reliably ascertained in childhood supratentorial neuroglial tumors.4 We used factor analysis to identify significant histologic feature associations (factors)and to quantify their relationships. Five factors requiring only 17 of the 26 features were identified.5 The factor names of Jumbo, Fibrillary, Proliferative, Spongy, and Oligo reflected the histologic features important to each factor (Table 1). The group of histologic features important for one factor is not correlated with the group of histologic features important for another factor. A tumor's score on a factor is a weighted linear combination of the absence or presence of the 17 histologic features. We calculated a score on each of the 5 factors for each of the 703 tumors. The five scores characterize and summarize the histology of the tumor. Mixed tumors have high scores on more than one factor. Approximately 67% of childhood supratentorial neuroglial tumors are mixed when evaluated in this fashion. We used these 703 tumor factor score profiles in cluster analyses to form 8 relatively histologically homogeneous classes of tumors.3 Each class had a distinct pattern of high or low factor score profiles that reflect its unique histology (Table 2). The factor score profile and class assignment calculations are available as worksheets that are easily programmable. The calculations of the five factor scores and class allocation for each tumor are rigorous and completely without bias or subjectivity, once the absence or presence of the reliable histologic features are known, following strict definitions.4 This reproducibility contrasts with the poor intraobserver reliability of the diagnoses in the WHO classification6 when used for childhood brain tumors.

Table 1. Factors and Their Defining Histologic Features
FactorDefining histologic features
JumboNuclei; large nucleoli; prominent cells; multinucleated; (giant) nuclei; intermediate abnormal neurons
FibrillaryAstrocytes; stroma elongated nuclei; low-cell density
ProliferativeMitosis; necrosis; very high-cell density
SpongyVacuoles; microcysts; spongy and compact pattern
OligoCalcification; parenchymal; oligodendroglial foci
Table 2. Tumor Classes and Their Factor Score Profiles: Mean Factor Scores Compared with High/Low Cutpoints
FactorClass
12345678
  1. Mean score (–) not significantly different from score cutpoint; H: mean score significantly (P < 0.05) higher than score cutpoint; L: mean score significantly (P < 0.05) lower than score cutpoint.

JumboHH
FibrillaryLL
ProliferativeHH
SpongyHH
OligoHHH

The eight classes had significantly different survival distributions (Table 3) and many WHO diagnoses contained subsets that fell into two or more classes (Table 4), reflecting the different distributions of histologic features in the subsets. For example, Class 4 had high mean factor scores on the Jumbo and Proliferative factors (reflecting the presence in these tumors of large numbers of large cells and mitosis, necrosis, and very high cell density) whereas Class 2 did not. Classes 2 and 4 contained the two subsets of ‘anaplastic astrocytomas’ and had significantly different survival distributions. The anaplastic astrocytomas in Class 2 had a much higher estimated 5-year survival probability than those in Class 4 (0.70 vs. 0.17). Two of the 3 classes that contained subependymal giant cell astrocytomas had similar survival probabilities (Classes 1 and 6 with estimated 5-year survival probabilities of 0.80), whereas the third had a significantly lower estimated 5-year survival probability of 0.17 (Class 4). There were no significant differences with regard to the survival distributions for classes containing the majority of pilocytic astrocytomas (Classes 1 and 2 with estimated 5-year survival probabilities of 0.79 and 0.70), the other astrocytomas (also included in Classes 1 and 2), oligodendrogliomas (Classes 3 and 8 with estimated 5-year survival probabilities of 0.81 and 0.62), or ‘ependymomas’ (Classes 5 and 7 with estimated 5-year survival probabilities of 0.32 and 0.55). Of the unclassifiable tumors (cases in which the team of 2 readers agreed they could not make any WHO diagnosis, 17.9% fell into Class 2, 16.1% into Class 4, and 46.4% into Class 5). Of the ambiguous tumors (cases in which the team of 2 readers disagreed on a WHO diagnosis), 14% fell into Class 1, 43% into Class 2, and 23.7% into Class 5. Classes 1 and 2 had similar survival distributions; Class 5 was significantly worse, and Class 4 had the worst survival distribution among all supratentorial neuroglial tumors.

Table 3. Estimated Survival Probability
SurvivalClass
31628754
  1. Groups of underlined Classes were found to have nonsignificant differences in estimated survival distributions. Classes 3, 1, 6, and 2 had significantly different survival distributions than Classes 7, 5 and 4, and Classes 7 and 5 had significantly different survival distributions than Class 4 (P < 0.01). Class 8 had a survival distribution that was significantly different than Classes 5 and 4. Children who survived < 1 month were deleted from the survival analyses.

1 year0.940.930.880.880.890.780.570.46
5 years0.810.790.800.700.620.550.320.17
   
   
Table 4. Distribution of WHO Diagnoses by Class
DiagnosisClass Row-percent
12345678Total
  1. WHO: World Health Organization; PNET: primitive neuroectodermal tumor. The cutoff for a diagnosis to be included with a Class percent was a frequency of at least 10.

Pilocytic astrocytoma44.446.0      124
Subependymal giant cell “astrocytoma”13.3  17.9 60.7  28
Anaplastic astrocytoma 24.5 49.0    102
Other astrocytoma29.653.76.61.51.53.72.21.5136
Oligodendroglioma  35.6    28.945
Ependymoma    45.2 25.8 62
Ganglioglioma     76.2  21
Glioblastoma   71.414.314.3  7
Giant cell glioblastoma   78.6    14
Medulloblastoma (PNET)    73.3   15
Unclassifiable 17.9 16.146.4   56
Ambiguous14.043.0  23.7   93
Total no. of cases128218459399584022703

MATERIALS AND METHODS

The Childhood Brain Tumor Consortium (CBTC) database, which was presented in detail elsewhere,7 contains the CBTC WHO diagnosis as well as clinical, surgical, tumor histology, treatment, and survival information for 3291 unselected children. To be included in the database, we required enough surgical material to make a diagnosis. The number of slides reviewed per case ranged from 1 to 22 slides, with a median of 2.2 slides. Four teams of two neuropathologists reached consensus regarding the presence or absence of a large number of histologic features in the microscopic slides of each case. Another team came to consensus regarding the appropriate WHO diagnosis. The teams reviewed cases without clinical information, primary diagnosis, or knowledge of whether the case had been reviewed by them previously. The reliability judgments regarding individual histologic features or tumor diagnosis were based on the 25% of cases reread by the same team.4, 6, 7 With a brain tumor incidence of approximately 3 per 100,000 children per year, our sample represents approximately 100,000,000 children-years of observation.8, 9 The sample for the current study was comprised of 703 children with tumors confined to the supratentorial compartment with complete information concerning 26 reliably identified histologic features. We defined the caudal anatomic limit of the supratentorial compartment as the junction between the third ventricle and the aqueduct. We excluded from this analysis tumors that involved both the infratentorial and supratentorial compartments (n = 120 tumors) or all three compartments (n = 14 tumors) because of differences in associated clinical and histologic characteristics.10 Because the reliable histologic features in the infratentorial and supratentorial compartments differed, the tumor factors, classes, and survival covariates apply only to neuroglial tumors in the supratentorial compartment. The operational definitions of each of the histologic features were presented in Appendix 1 in our previous publication.4 The majority of the survival covariates are self-explanatory; the estimation of the amount of tumor removed was the surgeon's estimate at the time of surgery. Because magnetic resonance imaging (MRI) shows the amount of proton density (or contrast enhancement) and not the full extent of these often infiltrating tumors, we used the surgeon's estimate.

In the current study, we used the chi-square and analysis of variance tests to evaluate whether the tumor class differences with regard to clinical, surgical, and histologic characteristics achieved nominal statistical significance. We used Cox proportional hazards models to identify tumor class survival covariates. For each class, we allowed the factor scores and the seven reliable histologic features unnecessary for the factors into the model as covariates after first accounting for associations with survival of the clinical features of radiotherapy or rudimentary chemotherapy, amount of tumor removed, patient age, decade of surgery, location, and gender. Apart from the amount of tumor removed, we did not include surgical observations in our final model of survival expectation. This was because we made the assumption during data analysis that if a surgical observation was absent from the medical record it was not present in the tumor, which may be incorrect, and because some classes were small relative to the number of possible covariates. In all survival analyses we excluded children who died within 1 month of surgery to avoid including deaths from surgical complications. All reported significant differences between clinical and histologic variables and survival distributions were based on a P value of ≤ 0.01. A P value of ≤ 0.05 was used to identify covariates with a significant association with survival estimation.

RESULTS

There were no significant differences with regard to male to female gender ratios among the classes (Table 5). Patients in two classes (Classes 3 and 6) were less likely to have received auxiliary radiation therapy or chemotherapy (33% and 29%, respectively), and those in Class 5 were more likely to have received auxiliary radiation therapy (72%). Approximately 40–55% of the patients in the remaining classes received auxiliary radiation therapy. Children in Class 3 were significantly older and children in Class 6 were significantly younger. The surgeon's estimate of “total removal” of tumor was more likely in Classes 6 and 8, but nevertheless, it was reported to occur in only 30–40% of the cases in each class. Total tumor removal was less likely in Classes 2 and 4. There were no significant differences with regard to prevalence among classes in tumor colors gray/white (range, 19–41%) or purple/red (range, 17–38%) or the surgeon's ability to distinguish margins (range, 12–27%); whether the tumors were firm (range, 18–33%), vascular (range, 2–29%), friable (range, 3–10%), or contained trabeculae (range, 3–6%); or whether there was a ventricular attachment (range, 11–29%). Class 2 tumors tended to be located superficially and the tumors in Classes 3 and 8 tended to be located deep in the brain. Leptomeningeal deposits were found at the time of surgery in < 10% of cases in all classes.

Table 5. Prevalence of Clinical and Surgeon Assessment Variables
VariableClass
12345678P value
  1. NS: not significant; P-value: significance of overall difference; SD: standard deviation.

  2. The arrows indicate a significantly (P < 0.05) increased (↑) or decreased (↓) finding for the class.

Location         
 Superficial8489↑69↓7677838068↓0.003
Radiation and/or chemotherapy464933↓6372↑29↓43550.001
Gender:         
 Male4852365553536055NS
Age (yrs)         
 Mean7.77.010.6↑8.36.49.96.1↓8.30.0001
 (SD)(4.5)(4.8)(4.9)(4.9)(4.2)(4.9)(4.2)(5.1) 
 Median7.65.710.38.45.510.65.87.9 
Surgeon's assessment         
Amount removed         
 Biopsy2035↑12↓182015↓16↓5↓ 
 Partial63515969565353580.001
 Total1714↓2913↓2433↑3237↑ 

In six of the eight classes, additional clinical, surgical, or histologic characteristics changed survival expectancy from the average for the class (Table 6). The survival covariates varied from class to class, had opposite effects in some classes, and interacted in occasionally surprising ways.

Table 6. Influence of Selected Covariate Values on Estimated Survival
ClassCovariatesEstimated survival
   Age (yrs)1 yr5 yrs
  1. SD: standard deviation: −, negative; +, positive.

1   < 10.810.49
    50.910.71
    100.950.85
2Amount removedProliferative scoreRosenthal fibersPleomorphic nuclei  
 BiopsyMean0.830.62
 PartialMean − SD0.920.81
 PartialMean0.900.76
 PartialMean + SD0.870.70
 TotalMean0.940.86
 BiopsyMean+0.770.53
 PartialMean + SD++0.940.85
3  Proliferative scoreSpongy score  
   Mean + SDMean − SD0.840.60
   Mean + SDMean + SD0.980.95
4  Amount removedProliferative score  
   BiopsyMean0.180.01
   TotalMean0.740.39
   TotalMean − SD0.850.61
5  Irregular nucleiGlomeruloid capillaries  
   0.750.48
   +0.890.75
   +0.490.17
   ++0.750.49
6   Very low cell density  
    0.750.60
    +0.970.94

Class 1 was the only class in which the age of the child made a significant difference (P = 0.0006) to the survival of the child. The overall 5-year survival expectation for children with a Class 1 tumor was 0.81. If the child was in the first year of life (0 years), the 5-year expected survival was 0.49 compared with a child age 10 years with the same tumor, in whom the survival expectancy was 0.85 (Table 6) (Fig. 1). These tumors had significantly higher percentages of macrocysts (53%) and were macroscopically yellow or tan in color (39%). Classes 1 and 2 contained the majority of pilocytic astrocytomas (approximately 45% in each class) (those in Class 1 containing regions of spongy and compact pattern; those in Class 2 without this histologic feature). Class 1 also included approximately 15% of the subependymal giant cell astrocytomas and 30% of the grouped other astrocytomas.

Figure 1.

Class 1 survival by patient age at the time of first surgery. This is the only class in which the age of the child was a covariate. If the child was in the first year of life, the 5-year survival expectancy was 0.49 (lowest curve); for the same tumor type, the 5-year survival expectancy for a child age 10 years was 0.85 (upper curve).

Class 2 tumors were astroglial tumors without significantly high or low factor scores for any factor. In addition to the pilocytic astrocytomas, Class 2 also contained 25% of the anaplastic astrocytomas, > 50% of the “other” astrocytomas, and nearly 20% of the unclassifiable tumors. For children with Class 2 tumors, there were four survival covariates. Increased amounts of tumor removed and Rosenthal fibers were reported to improve survival. The overall 5-year survival expectancy for this class was 0.70. If these tumors had been biopsied only and had the class mean Proliferative score with neither Rosenthal fibers nor pleomorphic nuclei present, the 5-year survival expectation was 0.62 (Table 6). If the surgeon believed the same tumor had been partially removed, the 5-year survival improved to 0.76, and if the surgeon believed the tumor had been removed totally, the 5-year survival was 0.86. Higher scores on the Proliferative factor (P = 0.0163) and the presence of pleomorphic nuclei (P = 0.0467) worsened survival expectancy. Adding pleomorphic nuclei to the original tumor reduced the 5-year survival expectancy to 0.53. Holding the amount of tumor removed at partial removal and both histologic features absent, increasing scores on the Proliferative factor from the class mean Proliferative score less 1 standard deviation to the class mean score plus 1 standard deviation reduced the 5-year survival expectancy from 0.81 to 0.70. Surprisingly, the presence of Rosenthal fibers, even with high Proliferative scores and pleomorphic nuclei, overrode the negative effects of the latter on survival expectancy and elevated survival expectation to ≥ 0.85. This phenomenon demonstrates the interaction of survival covariates and the importance of recognizing the presence of individual covariates (in this case, histologic features) within a tumor class or group. Only approximately 25% of Class 2 tumors were found to contain macrocysts at the time of surgery.

Many of the tumors in Class 3 were oligodendrogliomas, and high scores on the Oligo and Proliferative factors characterized these tumors. The class 5-year survival estimate was 0.81. In this class, higher scores on the Spongy factor (P = 0.0133) improved survival expectancy whereas high Proliferative factor scores (P = 0.0495) worsened survival. For instance, the 5-year survival expectancy for Class 3 children with high scores on the Proliferative factor improved from 0.60 to 0.95 as the score on the Spongy factor increased (Fig. 2). They also were more frequently yellow or tan in color (42%) and gritty or calcified (20%).

Figure 2.

Class 3 survival by Proliferative and Spongy factor scores. The overall class 5-year survival estimate was 0.81. In this class, higher Spongy factor scores improved survival expectancy whereas higher Proliferative factor scores worsened survival expectancy. However, if the Proliferative factor scores were held at the mean for the class plus 1 standard deviation (SD), the 5-year survival expectancy increased significantly as the Spongy factor scores increased. Interactions among covariates, such as in this example, are important in estimating survival expectancy using quantitative histologic methods.

The overall 5-year survival expectancy for children with Class 4 tumors was 0.17. Class 4 tumors, characterized by high scores for the Jumbo and Proliferative factors, included approximately 50% of the anaplastic astrocytomas and all the glioblastomas. More tumor removed, low Proliferative factor scores, and the absence of pleomorphic nuclei increased survival (P values of 0.0037, 0.0001, and 0.0009, respectively). For example, holding the Proliferative factor score at the Class 4 mean, the 5-year survival probability increased from 0.01 for biopsy only to 0.39 for children in whom the surgeon believed that the tumor was removed totally. Conversely, for any amount of tumor removed, as the score for the Proliferative factor increased, survival probability decreased. In fact, for tumors believed to be removed totally, if the score for Proliferative factor was low, the 5-year survival probability was 0.61 (Fig. 3). Class 4 tumors had a higher percentage of soft tumors (39%).

Figure 3.

Class 4 survival by amount of tumor removed and Proliferative score. The overall class 5-year survival estimate was 0.17. In the lower two curves, the score for the Proliferative factor was held at the mean for the class and illustrates the influence of biopsy (lower curve) and total tumor removal (middle curve) on survival expectancy (5-year survival estimates of 0.01 and 0.39, respectively). The upper curve demonstrates the effect on survival of the combination of an estimated total tumor removal and a low Proliferative factor score (5-year survival expectancy of 0.61). SD: standard deviation.

The overall 5-year survival expectancy for children with Class 5 tumors was 0.32. Low scores on the Fibrillary factor characterized this tumor class. Large proportions of the ependymomas and unclassifiable tumors as well as the majority of the primitive neuroectodermal tumors (medulloblastomas) fell into this class. Irregular nuclei (P = 0.00029) and glomeruloid capillaries (P = 0.0234) were found to be associated significantly with survival. If neither irregular nuclei nor glomeruloid capillaries were present in the tumor, the 5-year survival expectancy improved to 0.48. If just irregular nuclei were present without glomeruloid capillaries, then survival expectancy fell to 0.17. If just glomeruloid capillaries were present, then survival expectancy improved to 0.75. If both histologic features were present, the glomeruloid capillaries balanced the survival effect of irregular nuclei and the 5-year survival expectancy returned to 0.49. Class 5 tumors had a significantly lower percent of gritty or calcified tumors (2%).

The overall 5-year survival expectancy of children with Class 6 tumors was 0.80. Class 6 tumors included the majority of the subependymal giant cell astrocytomas and gangliogliomas. High scores on the Jumbo factor characterized this class. Very low cell density was identified as a covariate (P = 0.0083). The 5-year survival expectancy improved to 0.94 if very low cell density was present (Fig. 4).

Figure 4.

Class 6 survival by low cell density. The overall class 5-year survival estimate was 0.80. If the histologic feature of low cell density was absent in a tumor in this class, the survival expectancy decreased significantly (lower curve) to 0.60. If the same histologic feature was present, the survival expectancy increased to 0.94 (upper curve).

Classes 7 and 8 had no survival covariates in the final model. Class 7 tumors had high mean scores on Proliferative and Oligo factors, occurred in younger children, and were less likely to have been biopsied only. The overall 5-year survival expectancy for Class 7 tumors was 0.55. Class 8 tumors differed from Class 3 tumors by having a lower mean score on the Fibrillary factor and an average score of zero on the Spongy factor. Similar to Class 3 tumors, tumors in Class 8 were more likely to be gritty or calcified (18%). A tumor with oligodendroglial foci, parenchymal calcification, astrocytes, and stroma would be assigned to Class 8. If this tumor had the additional features of necrosis, intermediate-size nuclei, and mitosis, it would fall into Class 7. Class 8 tumors were less likely than other tumors to have been located superficially, and were more likely to have been totally removed. Approximately 29% of oligodendrogliomas fell into Class 8.

DISCUSSION

The results of the current study demonstrate that generalizations regarding survival covariates of childhood neuroglial tumors (e.g., a greater amount of tumor removed improves survival, older patient age improves survival, or the presence of pleomorphic nuclei in a tumor worsens survival) do not apply to all statistically identified classes of supratentorial neuroglial tumors. The classes resulted from clustering each tumor's extended histologic profile quantitatively represented in five uncorrelated factor scores. The calculation of the factor scores and class allocation incorporate the information concerning all reliable features in a reproducible and unbiased manner using easily programmable worksheets3 or an automated spreadsheet.

Age, a frequently cited survival covariate for adult neuroglial tumors (e.g., in studies by Kowalczuk et al. and Levin et al.11, 12) and for children,13 was found to apply only to Class 1 tumors, approximately 50% of the pilocytic astrocytomas (those with spongy and compact regions), and approximately 25% of the anaplastic astrocytomas. Older age at surgery in children with Class 1 neuroglial tumors resulted in a 73% increase in survival expectancy at 5 years after first surgery from the first to the tenth year. Conversely, older age at surgery was not found to be a survival covariate for the remainder of the pilocytic astrocytomas (those without spongy and compact regions), remaining anaplastic astrocytomas, or other supratentorial tumors in the remaining seven classes (specifically, the glioblastomas or the primitive neuroectodermal tumors [medulloblastomas]).

Another survival covariate that is cited frequently is the amount of tumor removed (e.g., in studies by Levin et al., Hess, and Groves et al.14–16). In children with supratentorial neuroglial tumors, the amount of tumor removed was found to be an important covariate in only two classes, Classes 2 and 4 (but not in Class 1) (Table 6). This observation demonstrates that the probability of survival for the two varieties of pilocytic astrocytomas found in Classes 1 and 2 is improved by greater tumor removal for only the second variety. Greater removal of supratentorial “juvenile” pilocytic astrocytomas (those with alternating spongy and compact regions found in Class 1) did not appear to improve survival probability but greater removal of the other variety of pilocytic astrocytomas (those without alternating spongy and compact regions in Class 2) did appear to improve survival probability. Thus, only for the class containing the more malignant tumors (Class 4) and another class containing some of the more benign tumors (Class 2) was additional tumor removal found to be a significant factor. The amount of tumor removed is, of course, a surgical and clinical decision depending on many considerations, including tumor location and surgical findings. These findings do not, of course, assist the surgeon in any way in deciding at the time of surgery whether to attempt to remove additional tumor. That decision is dictated by the biology of the tumor as revealed at the time of surgery. Furthermore, the histologic factoring and grouping of the tumors into classes requires permanent sections, not the intraoperative frozen sections.

Individual factors and individual histologic features also had an effect on survival. Higher scores on Proliferative factor were associated with decreased survival probability in Classes 2, 3, and 4, whereas higher scores on Spongy factor increased the survival probability in Class 3. Individual reliable histologic features, not represented in the factors, were important in survival probability models of several classes; the presence of Rosenthal fibers in Class 2, pleomorphic nuclei in Class 4, glomeruloid capillaries in Class 5, and very low cell density in Class 6 were associated with improved survival probability. Pleomorphic nuclei in Class 2 and irregular nuclei in Class 5 were associated with worsened survival. The presence of pleomorphic nuclei had opposite effects in two classes (improved survival probability in Class 4 and decreased survival probability in Class 2). Deep or superficial location within the hemisphere, treatment with radiation therapy or rudimentary chemotherapy, decade of surgery, and gender were not found to be associated with changes in survival probability.

These observations appear to extend the usefulness of the WHO definitions. They emphasize the importance of regarding neuroglial neoplastic processes as containing many different histologic patterns, some of which occur commonly in different kinds of childhood brain tumors. Only by quantifying the full histologic content of brain tumors and using the measured relations among their histologic features can we recognize groupings of histologic features that are important for prognosis and identify associated survival covariates. We have shown that there are two or more varieties of many of the supratentorial neuroglial tumors, and that for these varieties of tumor, different covariates are associated with survival, (e.g., that maximal tumor removal of some pilocytic astrocytomas improves survival expectation, but not all). We also have shown that the same histologic features may have opposite effects on survival expectation in the varieties of anaplastic astrocytoma that fall into different classes.

The reasons why tumors of the same name, but different classes, often differ with regard to survival covariates are complex. They are in different classes because they differ with regard to their extended histologic content (used in the current series of studies) that is not reflected in the conventional diagnosis.2 Differing extended histologic content among tumors of the same name is important to measure because it can result in the assignment to classes that may differ with regard to estimated survival distributions and survival covariates. For instance, the “anaplastic” astrocytomas fell into two different classes with markedly different survival expectations (0.17 in Class 4 and 0.70 in Class 2 at 5 years after first surgery). The results of the current study demonstrate that neuroglial tumors of the same name in the supratentorial compartment in children are not histologically or biologically homogeneous, but often are divisible into subclasses. Conversely, tumors with different WHO diagnoses may fall into the same class because they contain common patterns of histologic features other than the few features used for naming the tumor type.

Histology and tumor locations remain the dominant variables influencing survival.17, 18 After the supratentorial neuroglial tumors in the current study were histologically grouped statistically based on a relatively large number of reliable features, only a few covariates remained significant. The most important observations are that the covariates were important for only some of the classes, had opposite effects in some of the classes, and interacted in surprising ways in some of the classes. We suggest that these tumor classes, identified by factor and cluster analyses on a relatively large number of reliable features, provide the researcher with an improved method for comparing therapies in clinical trials of childhood tumors in the supratentorial compartment.

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