RESEARCHHUMANCLINICAL STUDIES

RESEARCHHUMANCLINICAL STUDIES

TOPIC

Cystic Glioblastoma: An Evaluation of IDH1 Status

and Prognosis
J. Manuel Sarmiento, BA
Miriam Nuno, PhD
Alicia Ortega, BA
Debraj Mukherjee, MD, MPH
Xuemo Fan, MD, PhD
Keith L. Black, MD
Chirag G. Patil, MD, MS
Center for Neurosurgical Outcomes
Research, Maxine Dunitz Neurosurgical
Institute, Department of Neurosurgery,
Cedars-Sinai Medical Center, Los Angeles,
California
Correspondence:
Chirag G. Patil, MD, MS,
Center for Neurosurgical Outcomes
Research,
Department of Neurosurgery,
Cedars-Sinai Medical Center,
Advanced Health Sciences Pavilion,
127 S San Vicente Blvd, Ste A6600,
Los Angeles, CA 90048.
E-mail: chirag.patil@cshs.org
Received, July 24, 2013.
Accepted, September 25, 2013.
Published Online, October 1, 2013.
Copyright 2013 by the
Congress of Neurological Surgeons

BACKGROUND: Controversy exists regarding the prognostic significance of cystic

features in newly diagnosed glioblastoma multiforme (GBM) and the pathological origin
of cystic GBMs.
OBJECTIVE: To determine whether cystic GBMs develop from low-grade gliomas by
evaluating IDH1 status and to evaluate the differences in overall survival between
patients with cystic and noncystic tumors.
METHODS: We retrospectively reviewed the records of 351 consecutive newly diagnosed adult GBM patients treated at our institution from October 1997 to November
2011; patients with .50% cystic tumor composition were further identified. IDH1
mutation was determined by immunohistochemical staining. Patient characteristics and
treatment were reported for cystic and noncystic tumors separately. Overall survival was
reported for cystic and noncystic cohorts by using the Kaplan-Meier estimates.
RESULTS: Of 351 patients, 27 (7.7%) had cystic tumors and 324 (92.3%) had noncystic
tumors. Tumor samples for patients with cystic GBMs were immunohistochemically
analyzed for IDH1 mutations. Two (7.4%) of the 27 tumor samples were documented as
having IDH1 mutations. Characteristics such as age, sex, perioperative Karnofsky Performance Status, tumor size, extent of resection, postsurgery radiation, and temozolomide therapy were comparable in the and noncystic cohorts. Patients in the cystic
cohort had a median overall survival of 15.0 months compared with 18.2 months for the
noncystic cohort (log-rank P = .77).
CONCLUSION: The low frequency of IDH1 mutation status in our cystic cohort strongly
suggests that most newly diagnosed cystic GBMs do not arise from malignant transformation of previously undiagnosed low-grade gliomas. Furthermore, there is no difference in overall survival between patients newly diagnosed with cystic and noncystic
GBMs.
KEY WORDS: Cystic glioblastoma, IDH1, Low-grade glioma, Overall survival
Neurosurgery 74:7176, 2014

DOI: 10.1227/NEU.0000000000000200

pproximately 8% to 10% of glioblastoma

multiforme (GBM) tumors have a significant cystic component.1 The origin and
prognostic significance of this cystic feature is not
known. There are conflicting reports in which
some studies show a longer survival for patients
with cystic GBMs,2 whereas others demonstrate
no significant difference in survival between
patients with cystic and noncystic GBMs.3 Some
studies have suggested an association between cyst
ABBREVIATIONS: CI, confidence interval; GBM,
glioblastoma multiforme; KPS, Karnofsky Performance Status; WHO, World Health Organization

NEUROSURGERY

www.neurosurgery-online.com

formation and low-grade gliomas,4-7 proposing

that newly diagnosed cystic GBMs may arise from
previously undiagnosed low-grade gliomas and
have a better prognosis.8,9
Isocitrate dehydrogenase 1 (IDH1) gene mutation is a favorable prognostic marker and is
associated with an increase in overall survival
among GBM patients.10 IDH1 mutations are
found very commonly in low-grade gliomas and
are a hallmark of secondary GBMs that arise from
the progression of lower-grade tumors.11 In fact,
the vast majority of secondary GBMs harbor an
IDH1 mutation.12,13 It is on the basis of this
observation that we sought to determine (1) if
newly diagnosed cystic GBMs indeed arise from

VOLUME 74 | NUMBER 1 | JANUARY 2014 | 71

Copyright Congress of Neurological Surgeons. Unauthorized reproduction of this article is prohibited.

Copyright Congress of Neurological Surgeons. Unauthorized reproduction of this article is prohibited.

SARMIENTO ET AL

previously undiagnosed lower-grade gliomas on the basis of IDH1

mutation and (2) whether patients with cystic GBM have a better
prognosis than patients with noncystic GBM.

PATIENTS AND METHODS

Patient Selection
We retrospectively identified 351 consecutive patients newly diagnosed
with GBM at our institution. These patients were all adult (age . 18)
GBM patients who were treated with biopsy or surgical resection at the
time of initial GBM diagnosis between October 1997 and November
2011. Among the 351 total patients, 27 patients had cystic GBMs and
324 patients had noncystic GBMs. We defined cystic tumors as those
with a large cyst cavity that constituted 50% or more of the total tumor
volume.3,8,9 A histological diagnosis of GBM according to the World
Health Organization (WHO) classification of brain tumors was
performed by 1 of 2 board-certified pathologists within our institutions
pathology department.

Variables
We performed a comprehensive retrospective chart review of medical
records and reviewed brain magnetic resonance images to ascertain the
cystic components within tumors and other key variables. The information collected included age at diagnosis, sex, tumor size, perioperative
Karnofsky Performance Status (KPS), the extent of resection at initial
surgery, and postoperative radiation and chemotherapy. All patients
underwent either surgery or biopsy at the time of diagnosis. Tumor size
was categorized as 1 to 4 cm, 4 to 6 cm, and .6 cm. Perioperative KPS was
identified for each patient on a scale ranging from 0 to 100. The extent of
resection at initial surgery was categorized as biopsy, partial, or near
gross/gross total resection. The outcome of interest in this study was
overall survival, which was defined as the time from initial surgery to the
date of death or last follow-up for those patients with censored date of
death. Date of death was confirmed by the California Cancer Registry.14

Statistical Analysis
Descriptive statistics were reported by subgroups of patients with cystic
and noncystic tumors. Continuous variables were described by using means
and medians, whereas categorical variables were reported by using
frequencies. The Kaplan-Meier estimation method was used to obtain
median survival times and survival probabilities. A multivariate survival
analysis that adjusted for multiple covariates including KPS by using the
Cox proportional hazards model was conducted. In a subanalysis, each cystic
patient was matched with a noncystic control from the 324 patient
noncystic GBM cohorts by using propensity score matching; matching
variables included age in years, extent of resection, and KPS. A P value of less
than .05 was considered to be statistically significant. All statistical analyses
were conducted in SAS 9.2 (SAS Institute, Cary, North Carolina).

RESULTS
Demographics
A total of 351 newly diagnosed GBM patients were identified. Of
these patients, 27 (7.7%) had cystic GBMs and 324 (92.3%) had
noncystic GBMs. The average age in years was 55.4 and 60.6 for
patients with cystic and noncystic tumors, respectively (Table 1).
Overall, 39% of patients were female and the majority of patients
with cystic and noncystic tumors had radiation (85.2% and
82.7%) and temozolomide (81.5% and 75.3%), respectively, as

TABLE 1. Characteristics of Newly Diagnosed GBM Patients

According to Cystic and Noncystic Statusa
Variables
Age at diagnosis, y
Mean (SD)
Median (IQR)
Sex, n (%)
Female
Male
KPS at diagnosis, n (%)
Mean (SD)
Median (IQR)
Tumor size, n (%)
1-4 cm
4-6 cm
$6 cm
Missing
Resection, n (%)
Biopsy
Partial
Near/gross total
Radiation, n (%)
Yes
No
Temozolomide, n (%)
Yes
No

Immunohistochemistry and Morphometric Analysis

of IDH1
One representative formalin-fixed paraffin-embedded tumor tissue
block was selected from each case. The total length of formalin fixation
varied from 4 to 12 hours. Subsequently, the tissue was paraffinembedded with the use of a PELORIS II automated tissue microprocessor
(Leica Microsystems, Buffalo Grove, Illinois). Isocitrate dehydrogenase 1
(IDH1) antibodies were used in this study in accordance with
manufacturers (Dianova) instructions and at 1:200 dilutions. Pathological slides were subsequently counterstained with Mayer hematoxylin.
Low pH heat antigen retrieval for IDH-1 was performed on the Dako PT
Link module (Carpinteria, California). IDH-1 staining was performed
on the Dako Autostainer Plus (Carpinteria, California) using Dako
Mouse Envision 1 detection. Detection was done with the use of
a Ventana Ultraview DAB Detection Kit, followed by counterstaining
with hematoxylin (Biocare Medical). A negative control was performed
by omitting the primary antibody and revealed no immunoreactivity.
The semiquantification for IDH-1 is straightforward, because positive
cases usually show rather diffuse intracytoplasmic stains in the majority
of tumor cells and negative cases are usually completely negative. We did
not observe any cases with very patchy or focal stains.

72 | VOLUME 74 | NUMBER 1 | JANUARY 2014

Cystic
Noncystic
(n = 27, 7.7%) (n = 324, 92.3%) P Value
.16
55.4 (14.6)
54 (42-66)

60.6 (14.2)
61 (52-77)

12 (44.4)
15 (55.6)

125 (38.9)
199 (61.4)

81.1 (12.8)
80 (70-90)

78.1 (14.2)
80 (70-90)

.55

.24

.63
3
15
7
2

(12.0)
(60.0)
(28.0)
(7.4)

44
159
53
68

(17.2)
(62.1)
(28.0)
(21.0)
.32

4 (14.8)
5 (18.5)
18 (66.7)

88 (27.2)
63 (19.4)
173 (53.4)

23 (85.2)
4 (14.8)

268 (82.7)
56 (17.3)

22 (81.5)
5 (18.5)

244 (75.3)
80 (24.7)

1.0

.47

GBM, glioblastoma multiforme; IQR, interquartile range; SD, standard deviation.

www.neurosurgery-online.com

Copyright Congress of Neurological Surgeons. Unauthorized reproduction of this article is prohibited.

Copyright Congress of Neurological Surgeons. Unauthorized reproduction of this article is prohibited.

CYSTIC GLIOBLASTOMA: IDH1 STATUS AND PROGNOSIS

part of the initial treatment for GBM. Both cohorts had an overall
median KPS of 80, with a range of 70 to 90, and near gross or gross
total resection was achieved in 66.7% of patients with cystic
tumors and 53.4% of patients with noncystic tumors at initial
surgery. Overall, there were no significant differences between the
2 cohorts with respect to age, sex, perioperative KPS, tumor size,
extent of resection, or radiation and temozolomide received
postoperatively (Table 1).
IDH1 Molecular Marker
Tumor samples from all 27 patients with cystic GBM were
analyzed for IDH1 mutations with immunohistochemistry. Two
(7.4%) of the 27 tumor samples were identified as IDH1 positive.

Overall Survival
The median overall survival in months for the cystic cohort was
15.0 (95% confidence interval [CI], 6.1-30.8) and 18.2 (95% CI,
15.6-20.1) for patients with noncystic GBMs (log-rank P = .77)
(Figure). The 12-, 24-, and 36-month survival estimates for the
cystic group were 63.0% (95% CI, 42.1-78.1), 38.6% (95% CI,
20.3-56.7), and 22.1% (95% CI, 7.6-41.3), respectively (Table 2).
The equivalent survival estimates for the noncystic cohort were
66.6% (95% CI, 61-71.5), 36.6% (95% CI, 31.0-42.2), and
22.3% (95% CI, 17.3-27.6). Although the matched-control
survival estimates are not presented in Table 2, our results support
the all-case analysis findings of no statistical difference between the
cystic and noncystic cohorts (P = .35).
Among all patients, younger patients (#65 years) survived an
average of 8.4 months longer than older patients (.65 years).
Higher functioning (KPS $80) patients survived 7.6 months
longer than patients with low functioning levels perioperatively.
Patients that underwent a near/gross total resection compared
with those who underwent a biopsy survived an average of 8.9
months longer (Table 3). Furthermore, patients with methylated O6-methylguanine-DNA methyltransferase (MGMT) status had significantly higher survival than unmethylated patients
(24.8 vs 15.0 months, P = .004).

FIGURE. Kaplan-Meier survival curve for 324 patients with noncystic GBM
and 27 patients with cystic GBM. GBM, glioblastoma multiforme; OS, overall
survival.

DISCUSSION
Glioblastomas (WHO grade IV gliomas) may develop de novo
(primary GBMs) or from malignant progression of WHO grade II
or WHO grade III gliomas (secondary GBMs). Patients with
primary GBMs often have a short clinical history, and the

TABLE 3. Median Overall Survival, 95% Confidence Intervals, and

Corresponding Log-Rank P Values for Each Variablea
Variables
Tumor type
Cystic
Noncystic
Age at diagnosis, y
#65
.65
KPS, postsurgery
,80
$80
Tumor size, cm
,6
$6
Extent of resection
Biopsy
Partial
Near/gross total
MGMT promoter methylation status
Methylated
Unmethylated

TABLE 2. Median Overall Survival, Survival Rates, and 95%

Confidence Intervalsa
Median OS (CI)b
Survival rates, % (CI)
6-mo
12-mo
18-mo
24-mo
36-mo
a
b

Cystic (n = 27)

Noncystic (n = 324)

15.0 (6.1-30.8)

18.2 (15.6-20.1)

70.4
63.0
47.2
38.6
22.1

(49.4-84.0)
(42.1-78.1)
(27.6-64.5)
(20.3-56.7)
(7.6-41.3)

OS, overall survival; CI, confidence interval.

Log-rank: P = .77.

NEUROSURGERY

81.3
66.6
50.6
36.6
22.3

All

(76.6-85.1)
(61.0-71.5)
(44.8-56.1)
(31.0-42.2)
(17.3-27.6)
a
b

P Value
.77

15.0 (6.1-30.8)
18.2 (6.1-30.8)
,.001
20.4 (18.8-23.4)
12.0 (9.2-15.6)
,.001
12.6 (9.7-14.9)
20.2 (18.8-23.2)
.56
13.2 (9.5-19.5)
19.0 (16.0-20.5)
,.001
12.0 (7.6-14.5)
15.8 (10.1-20.8)
20.9 (19.0-25.0)

.004b

24.8 (19.5-28.6)
15.0 (12.3-19.0)

KPS, Karnofsky Performance Status; MGMT, O6-methylguanine-DNA methyltransferase.

MGMT data only available for 237 (67.5%) of patients.

VOLUME 74 | NUMBER 1 | JANUARY 2014 | 73

Copyright Congress of Neurological Surgeons. Unauthorized reproduction of this article is prohibited.

Copyright Congress of Neurological Surgeons. Unauthorized reproduction of this article is prohibited.

SARMIENTO ET AL

diagnosis is confirmed based on the presence of the histological

features of GBM at first biopsy or resection. In contrast, diagnosis
of a secondary GBM requires radiographic or histological evidence
of evolution from a lower-grade tumor. Secondary GBMs make up
to 20% of all GBM cases4,15,16; they tend to occur in younger
patients, and they demonstrate a distinct genetic profile, with
most harboring the IDH1 mutation.11,13,17,18 Secondary GBM
patients carry a more favorable prognosis than their primary
GBM counterparts.18,19
IDH1 mutations have been reported in the majority of lowergrade gliomas and are a hallmark of secondary GBMs.12,13
Therefore, we evaluated IDH1 status for our cystic GBM
cohort to determine whether most newly diagnosed cystic
GBMs arose from undiagnosed lower-grade tumors with cystic
features. Previous studies have reported the absolute incidence
of cystic GBMs between 8% and 10%.1 In our study, 27
(7.7%) patients with cystic GBMs were identified among a pool
of 351 newly diagnosed GBMs. Of our 27 patients with cystic
GBM, only 2 (7.4%) showed IDH1 mutations, thereby
suggesting that most cystic GBMs do not develop from
malignant transformation of previously undiagnosed cystic
low-grade gliomas.
Some authors have postulated that cystic GBMs may develop
from malignant transformation of a previously undiagnosed cystic
low-grade glioma.8 This hypothesis is based on the findings of
similar clinical and pathological profiles of patients with cystic
GBMs and patients with secondary gliomas. Utsuki et al8
analyzed the different histological and clinical characteristics of
37 GBM tumors, of which 5 cases were classified as cystic GBMs
and 32 cases were noncystic GBMs. This study showed
a statistically significant difference (P , .05) in age between
the cystic GBM group (median, 44 years) and the noncystic
GBM group (median, 54 years). Furthermore, all of the cystic
GBM specimens (n = 5) had many small, irregularly shaped foci
of necrosis surrounded by groups of densely packed neoplastic
cells with their long axes pointing toward the necrotic focus
(known as pseudo palisading structures). These histological
features were proposed to be similar to those found in secondary
GBMs.9 Therefore, we sought to further investigate this
intriguing hypothesis by evaluating IDH1 status.
One of the newest and most significant GBM molecular markers
is the IDH1 mutation, which was first identified by Parsons et al10
in 12% of GBM patients in a 2008 report. In their landmark
study, Parsons et al10 discovered that IDH1 mutations occurred in
a large fraction of young patients (nearly 50% [9 of 19] of patients
under 35 years of age) and in most patients (5 of 6 patients, or
83%) with secondary GBMs, and they were associated with longer
overall survival. Other studies confirmed these results and
demonstrated that IDH1 mutations are frequently found in
secondary GBMs (.80%), but rarely in primary GBMs
(,5%).12,20 Until the identification of IDH1 mutation as
a molecular marker of secondary glioblastoma, the patterns of
genetic alterations did not allow an unequivocal separation of the 2
GBM subtypes.21 Pathologists now agree that IDH1 mutation is

74 | VOLUME 74 | NUMBER 1 | JANUARY 2014

a definitive diagnostic molecular marker of secondary glioblastomas and more reliable and objective than clinical and/or
pathological criteria.21 Of our 27 patients with cystic GBM,
only 2 (7.4%) showed IDH1 mutations, thereby suggesting that
most cystic GBMs do not develop from malignant transformation
of previously undiagnosed cystic low-grade glioma.
Prognosis of Patients With Cystic GBMs
A case-control study by Maldaun et al9 first demonstrated
a strong trend toward longer survival and a statistically significantly
longer time to recurrence for GBMs with large cysts ($50% of
tumor volume) compared with noncystic GBMs. The median
overall survival for patients with cystic and noncystic GBMs was
18.7 months and 14.4 months (P = .10 log-rank), respectively, and
the median time to recurrence was 7.6 months and 4.2 months
(P = .04 log-rank), respectively.9 Utsuki et al8 also reported
statistically significant longer survival in patients with cystic vs
noncystic GBMs. Patients with cystic GBMs had a median survival
of 19.8 months, whereas patients with noncystic GBMs had
a median survival of 12.8 months (P , .05 log-rank).8 Although
there are relatively few studies evaluating the prognostic significance of cystic GBMs,3,8,9,22-25 clinical outcomes from the largest
case series do not support the theory of most cystic GBMs
developing from low-grade gliomas and having a better prognosis.3,9 This study by Kaur et al3 comprised 37 patients with cystic
GBM and 317 patients with noncystic GBM, and did not show
a statistically significant difference in survival between the cystic
and noncystic GBM groups (17 vs 15.9 months, respectively, P =
.99). After controlling for known GBM prognostic factors, we did
not observe a statistically significant difference in survival between
cystic and noncystic GBMs (15 vs 18.2 months, log-rank P = .77).
Similar findings were confirmed in the matched-control cohort
analysis of 27 patients.
Limitations
It should be noted that, as with any retrospective study, our study
may be limited by selection bias that may distort the estimate of
association between risk factor and disease. Immunohistochemical
staining may not capture all IDH1 mutations, meaning our cystic
cohort may have had a slightly higher incidence of IDH1-positive
tumors than reported in our study. A small percentage of low-grade
gliomas may also be IDH1 negative, in which case it is possible that
a few cystic tumors in our cohort were a subset of cystic tumors
derived from low-grade, IDH1 negative de novo tumors. Whereas
genome sequencing may have provided a more definitive method
for determining IDH mutation status, this type of investigation
was unable to be performed owing in part to the limited size of
tissue samples available. Additionally, there is a gross discrepancy
between the number of patients in the cystic GBM cohort and the
number of patients in the noncystic GBM cohort because of the
uncommon nature of this disease. Despite these limitations, we
were unable to show any clinical evidence that supports the
hypothesis that cystic GBM develops from low-grade gliomas.

www.neurosurgery-online.com

Copyright Congress of Neurological Surgeons. Unauthorized reproduction of this article is prohibited.

Copyright Congress of Neurological Surgeons. Unauthorized reproduction of this article is prohibited.

CYSTIC GLIOBLASTOMA: IDH1 STATUS AND PROGNOSIS

Pathophysiology of Cyst Formation

The pathophysiology of cyst formation in GBM remains
unclear, although it seems that these processes take place during
the natural growth pattern of primary de novo GBMs.3 One
proposed mechanism of cyst formation cites rapidly progressing
tissue, liquefaction, necrosis, and subsequent fluid accumulation
as a primary driver of cystic formation.26 This cyst fluid is
believed to originate from the degeneration of tumor tissue and
plasma fluid leaking from local disruption of the blood-brain
barrier7,27 in tumor microvessels. Another theory explaining cyst
formation suggests that cysts may form secondary to intratumoral
hemorrhage that becomes encapsulated by gliosis.27,28 Water is
presumed to be osmotically drawn in to expand the cyst cavity as
the blood clot breaks down. These theories of cyst formation are
not mutually exclusive, and it is possible that both mechanisms
may contribute in the formation of cystic GBM tumors. These
mechanisms may occur as a result of the pseudopalisading
necrosis observed in all cystic GBM tumor samples by Utsuki
et al.8 Areas of pseudopalisading necrosis are a hallmark of
GBMs18 and are observed at a similar frequency in primary and
secondary GBMs.29

CONCLUSION
Molecular profiling evidence of IDH1 mutation status indicates
that most cystic GBMs do not develop from malignant transformation of a previously undiagnosed cystic low-grade glioma.
There is no difference in median age or survival between patients
with cystic and those with noncystic newly diagnosed GBM.
Disclosure
The authors have no personal, financial, or institutional interest in any of the
drugs, materials, or devices described in this article.

REFERENCES
1. Afra D, Norman D, Levin VA. Cysts in malignant gliomas. Identification by
computerized tomography. J Neurosurg. 1980;53(6):821-825.
2. Keles GE, Anderson B, Berger MS. The effect of extent of resection on time to
tumor progression and survival in patients with glioblastoma multiforme of the
cerebral hemisphere. Surg Neurol. 1999;52(4):371-379.
3. Kaur G, Bloch O, Jian BJ, et al. A critical evaluation of cystic features in primary
glioblastoma as a prognostic factor for survival. J Neurosurg. 2011;115(4):754-759.
4. Keles GE, Lamborn KR, Berger MS. Low-grade hemispheric gliomas in adults:
a critical review of extent of resection as a factor influencing outcome. J Neurosurg.
2001;95(5):735-745.
5. Laws ER, Taylor WF, Clifton MB, Okazaki H. Neurosurgical management
of low-grade astrocytoma of the cerebral hemispheres. J Neurosurg. 1984;61(4):
665-673.
6. Laws ER Jr, Taylor WF, Bergstralh EJ, Okazaki H, Clifton MB. The neurosurgical
management of low-grade astrocytoma. Clin Neurosurg. 1986;33:575-588.
7. Lohle PN, Verhagen IT, Teelken AW, Blaauw EH, Go KG. The pathogenesis of
cerebral gliomatous cysts. Neurosurgery. 1992;30(2):180-185.
8. Utsuki S, Oka H, Suzuki S, et al. Pathological and clinical features of cystic and
noncystic glioblastomas. Brain Tumor Pathol. 2006;23(1):29-34.
9. Maldaun MV, Suki D, Lang FF, et al. Cystic glioblastoma multiforme: survival
outcomes in 22 cases. J Neurosurg. 2004;100(1):61-67.
10. Parsons DW, Jones S, Zhang X, et al. An integrated genomic analysis of human
glioblastoma multiforme. Science. 2008;321(5897):1807-1812.

NEUROSURGERY

11. Masui K, Cloughesy TF, Mischel PS. Review: molecular pathology in adult highgrade gliomas: from molecular diagnostics to target therapies. Neuropathol Appl
Neurobiol. 2012;38(3):271-291.
12. Yan H, Parsons DW, Jin G, et al. IDH1 and IDH2 mutations in gliomas. N Engl J
Med. 2009;360(8):765-773.
13. Juratli TA, Kirsch M, Robel K, et al. IDH mutations as an early and consistent
marker in low-grade astrocytomas WHO grade II and their consecutive secondary
high-grade gliomas. J Neurooncol. 2012;108(3):403-410.
14. American Cancer Society CDPH, California Cancer Registry. California Cancer
facts and Figures. Oakland, CA: 2011.
15. Barker FG, Chang SM, Huhn SL, et al. Age and the risk of anaplasia in magnetic
resonance-nonenhancing supratentorial cerebral tumors. Cancer. 1997;80(5):
936-941.
16. Dropcho EJ, Soong SJ. The prognostic impact of prior low grade histology in patients
with anaplastic gliomas: a case-control study. Neurology. 1996;47(3):684-690.
17. Karcher S, Steiner HH, Ahmadi R, et al. Different angiogenic phenotypes in
primary and secondary glioblastomas. Int J Cancer. 2006;118(9):2182-2189.
18. Kleihues P, Ohgaki H. Primary and secondary glioblastomas: from concept to
clinical diagnosis. Neuro Oncol. 1999;1(1):44-51.
19. Scherer HJ. Cerebral astrocytomas and their derivatives. Am J Cancer. 1940;40:
159-198.
20. Nobusawa S, Watanabe T, Kleihues P, Ohgaki H. IDH1 mutations as molecular
signature and predictive factor of secondary glioblastomas. Clin Cancer Res. 2009;
15(19):6002-6007.
21. Ohgaki H, Kleihues P. The definition of primary and secondary glioblastoma. Clin
Cancer Res. 2013;19(4):764-772.
22. Choi CY, Yee GT, Lee CH, Joo M. Large cystic glioblastoma multiforme: patient
surviving over 7 years without progression. Clin Neuroradiol. 2013;23(2):145-147.
23. Hakan T, Aker FV. Case report on a patient with neurofibromatosis type 1 and
a frontal cystic glioblastoma. Neurol Neurochir Pol. 2008;42(4):362-365.
24. Kanai R, Tasaka M, Sejima H, et al. Brain stem glioblastoma with multiple large
cyst formation and leptomeningeal dissemination in a 4-year-old girl. Brain Dev.
2005;27(1):58-61.
25. Reiche W, Schuchardt V, Hagen T, Ilyasov KA, Billmann P, Weber J. Differential
diagnosis of intracranial ring enhancing cystic mass lesionsrole of diffusionweighted imaging (DWI) and diffusion-tensor imaging (DTI). Clin Neurol
Neurosurg. 2010;112(3):218-225.
26. Poisson M, Philippon J, van Effenterre R, Racadot J, Sichez JP. Cerebral
pseudocysts following chemotherapy of glioblastomas. Acta Neurochir (Wien).
1977;39(3-4):143-149.
27. Lohle PN, van Mameren H, Zwinderman KH, Teepen HL, Go KG, Wilmink JT.
On the pathogenesis of brain tumour cysts: a volumetric study of tumour, oedema
and cyst. Neuroradiology. 2000;42(9):639-642.
28. Kadota O, Kohno K, Ohue S, et al. Discrimination of brain abscess and cystic
tumor by in vivo proton magnetic resonance spectroscopy. Neurol Med Chir
(Tokyo). 2001;41(3):121-126.
29. Tohma Y, Gratas C, Van Meir EG, et al. Necrogenesis and Fas/APO-1 (CD95)
expression in primary (de novo) and secondary glioblastomas. J Neuropathol Exp
Neurol. 1998;57(3):239-245.

COMMENT

he authors have interrogated their 14-year institutional experience

with glioblastoma to test the hypothesis that cystic features on radiography are predictive of secondary tumors and have implications for
overall survival. To do so, they performed immunohistochemistry for
mutant IDH1 on 27 cystic tumors identified by retrospective review of
351 patients WITH newly diagnosed glioblastoma treated at their
institution from October 1997 to November 2011, and report the
overall survival for the cystic and noncystic cohorts BY using KaplanMeier estimates. Their findings failed to support their hypothesis. Two
of 27 (7.4%) cystic tumors were found to harbor IDH1 mutation,
compared with an expected rate of 6% in all glioblastomas.1 In addition,
patients with cystic tumors had an overall survival of 15.0 months
compared with 18.2 months in patients with noncystic tumors.

VOLUME 74 | NUMBER 1 | JANUARY 2014 | 75

Copyright Congress of Neurological Surgeons. Unauthorized reproduction of this article is prohibited.

Copyright Congress of Neurological Surgeons. Unauthorized reproduction of this article is prohibited.

SARMIENTO ET AL

The authors investigational methods are sound, although limited.

The small number of cystic tumors identified compromises any attempt
at statistical analysis. As they note in their discussion, the approach used
by the authors for determination of IDH1 status allows for the capture of
the tumors harboring the R132H mutation, but does not identify tumors that harbor other IDH1 mutations, or IDH2 mutation. In addition, the study period bridges both the CT/MRI era and pre-/posttemozolomide era, which could have confounded both their identification of cystic lesions and the outcomes of their cohorts.
Finally, the authors hypothesis rests on an assumption that cyst
formation is a common feature of low-grade gliomas. Discounting

76 | VOLUME 74 | NUMBER 1 | JANUARY 2014

pilocytic astrocytomas, it is not clear to me that this assumption is

supported by the literature. Regardless, the authors should be lauded for
disabusing the field of a prevalent but unsupported assumption.
Sunit Das
Toronto, Ontario

1. Ichimura K, Pearson DM, Kocialkowski S, et al. IDH1 mutations are present in the
majority of common adult gliomas but rare in primary glioblastomas. Neuro Oncol.
2009;11:341-347.

www.neurosurgery-online.com

Copyright Congress of Neurological Surgeons. Unauthorized reproduction of this article is prohibited.

Copyright Congress of Neurological Surgeons. Unauthorized reproduction of this article is prohibited.