Journal of Neuropathology and Experimental Neurology
Copyright q 2002 by the American Association of Neuropathologists
Vol. 61, No. 1
January, 2002
pp. 58 63
Histopathological-Molecular Genetic Correlations in Referral Pathologist-Diagnosed
Low-Grade ‘‘Oligodendroglioma’’
HIKARU SASAKI, MD, MAGDALENA C. ZLATESCU, MD, REBECCA A. BETENSKY, PHD, LOKI B. JOHNK,
ANDREA N. CUTONE, J. GREGORY CAIRNCROSS, MD, AND DAVID N. LOUIS, MD
Abstract. Allelic loss of chromosome 1p predicts increased chemosensitivity and better survival in oligodendroglial tumors.
Clinical testing for 1p loss in oligodendroglial tumors at our hospital has allowed us to postulate that certain histological
appearances are associated with 1p allelic status. Forty-four cases received for genetic testing were diagnosed by referring
pathologists as pure low-grade oligodendroglioma. Central neuropathological review divided the series equally into 22 cases
with classical oligodendroglioma histology and 22 with more astrocytic features. Molecular genetic analyses demonstrated 1p
loss in 19 of 22 classic oligodendrogliomas (86%) and maintenance of both 1p alleles in 16 of 22 gliomas with astrocytic
features (73%). No glial fibrillary acidic protein-positive cell type (gliofibrillary oligodendrocyte, minigemistocyte, cellular
processes) was associated with 1p allelic status. Fourteen of the 44 cases were treated with chemotherapy at tumor progression:
3 ‘‘astrocytic’’ gliomas with 1p loss responded to PCV chemotherapy and 2 classic oligodendrogliomas that maintained both
1p alleles included a responder and a non-responder. These results suggest that histological appearance correctly predicts
genotype in approximately 80% of low-grade gliomas, but that tumor genotype more closely predicts chemosensitivity. As a
result, such objective molecular genetic analyses should be incorporated into patient management and into clinical trials of
low-grade diffuse gliomas.
Key Words:
Astrocytoma; Chromosome 1p; Chromosome 19q; GFAP; Histopathology; Oligodendroglioma.
INTRODUCTION
have as favorable prognoses as more traditionally defined
oligodendrogliomas.
Oligodendrogliomas are genetically characterized by
frequent allelic losses of chromosome 1p and 19q. Allelic
loss of chromosome 1p in anaplastic oligodendroglioma
is a predictor of far greater likelihood of chemotherapeutic response to procarbazine, lomustine (CCNU), and vincristine (PCV regimen). In addition, combined losses of
1p and 19q are powerful predictors of longer survival in
anaplastic oligodendroglioma (1). Patients with lowgrade oligodendrogliomas that have allelic loss of chromosome 1p and 19q also show a trend toward better survival (3). Thus, clinical testing for allelic loss of 1p and
19q provides relevant clinical data and, as a result, has
begun to be incorporated in the clinical armamentarium.
Massachusetts General Hospital (MGH) began offering
clinical testing for 1p loss in oligodendroglial tumors
about two and a half years ago and has received approximately 1 case per week from hospitals around the United
States and Canada. While the majority of cases have been
anaplastic oligodendrogliomas, tumors diagnosed as lower-grade oligodendrogliomas have also been received for
genetic evaluation. Such clinical testing has allowed our
supervising neuropathologists to hypothesize that certain
histological appearances of diffuse low-grade gliomas
could be associated with 1p allelic status. Although all
of these tumors arrived from outside hospitals with a diagnosis of ‘‘oligodendroglioma,’’ their appearances varied considerably, most likely reflecting the loosened criteria mentioned above. The presence of this population
of referral pathologist-diagnosed oligodendrogliomas allowed us to inquire how oligodendrogliomas were being
diagnosed in the referring community, relative to our
For a number of reasons, oligodendrogliomas have
been of great interest to the neuro-oncology community
over the past decade. Among the malignant gliomas, oligodendrogliomas remain the only subtype that commonly
responds to chemotherapy (1). Oligodendrogliomas also
have, in general, more favorable prognoses than diffuse
astrocytic tumors (2). Thus, neuro-oncologists and patients have become alert to the importance of recognizing
oligodendroglial tumors, since the diagnosis affects both
therapeutic decisions and estimation of prognosis. At the
same time, the emphasis on the importance of oligodendroglioma diagnosis has been a substantial challenge to
pathologists, since the criteria used to recognize these
lesions are subjective and no reliable immunohistochemical markers exist. As a result, pathologists, rather than
risk missing this clinically important diagnosis, have generally loosened their criteria for oligodendroglioma over
the past few years and make the diagnosis more frequently than in the past. Importantly, it is possible that such
loosened criteria may not yield groups of ‘‘oligodendrogliomas’’ that respond as frequently to chemotherapy and
From the Molecular Neuro-Oncology Laboratory (HS, LBJ, ANC,
DNL), Department of Pathology and Neurosurgical Service, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Department of Oncology (MCZ, JGC), University of Western Ontario and London Regional Cancer Centre, London, Ontario, Canada;
Department of Biostatistics (RAB), Harvard School of Public Health,
Boston, Massachusetts.
Correspondence to: David N. Louis, MD, Molecular Neuro-Oncology
Laboratory, Massachusetts General Hospital, 149 13th St., Charlestown,
MA 02129.
Supported by NIH CA57683 and MRC-MOP-37849.
58
HISTOLOGICAL-GENETIC CORRELATION IN OLIGODENDROGLIOMA
59
practice and relative to objective parameters such as genetic status and therapeutic response. Using this population, we therefore sought to determine how closely standard hematoxylin and eosin (H&E) staining as well as
glial fibrillary acidic protein (GFAP) immunohistochemistry reflected 1p status, and if histological appearance or
1p status correlated better with therapeutic parameters.
(GFO), minigemistocytes, and tapering GFAP-positive cytoplasmic processes (reminiscent of those seen in small reactive
astrocytes). By definition, GFO and minigemistocytes did not
have such GFAP-positive processes. Each GFAP-positive feature was scored as 2, not obvious; 1, present in ,10% of
tumor cells; or 11, present in .10% of tumor cells.
MATERIALS AND METHODS
Tumor DNA was extracted from formalin-fixed, paraffin-embedded sections of histologically verified cellular tumor (6), and
constitutional DNA was extracted from blood leukocytes according to standard protocols. Allelic losses of chromosomes
1p and 19q were assessed in loss of heterozygosity assays using
microsatellite markers on 1p36 (D1S2734, D1S199, D1S508)
and 19q13.3 (D19S219, D19S112, D19S412), as previously described (6).
Tissues and Clinical Parameters
Forty-four low-grade gliomas were referred for clinical 1p
testing. The cases originated from 16 different institutions
across the United States and Canada. All 44 tumors were diagnosed as pure low-grade oligodendroglioma (WHO grade II)
by the referring pathologists (4). Central histological review by
one of us (DNL) confirmed that none of the tumors were classical biphasic oligoastrocytomas; in addition, while some had
worrisome histological features such as mitotic activity, none
met criteria for anaplastic oligodendroglioma, WHO grade III
(4). Of the 44 tumors, 42 had no prior adjuvant therapy (radiation or chemotherapy), whereas information about prior treatment was not available for 2 cases. PCV chemotherapy was
given to 14 of the 44 tumors at tumor progression, with a median interval of 47 months from surgery to chemotherapy
(range: 2 months to 11 yr and 3 months). Eleven of the 14
PCV-treated tumors showed neuroradiological responses, defined by a decrease in tumor size of 50% or greater (5).
Assessment of Histopathological Features
Each case was assessed, using H&E stains and GFAP immunohistochemistry, by a single neuropathologist (DNL) blinded to the molecular genetic findings. Over the past 2 yr, it had
been our impression that oligodendrogliomas with classical features more frequently demonstrated loss of 1p. Special attention
was therefore paid to classical oligodendroglioma features, such
as uniform and rounded nuclei, often with small nucleoli, surrounded by perinuclear halos, and in an even tissue distribution
(Fig. 1). Cases with such features were designated as classic
oligodendroglioma. Such tumors sometimes had other histological findings such as calcifications and ‘‘chickenwire’’ vasculature, but these were not considered necessary for designation
as classic oligodendroglioma. Cases were also assessed for histopathological features commonly found in astrocytic tumors,
such as irregular distribution of mildly pleomorphic, more hyperchromatic nuclei, often with tapering eosinophilic cell processes (Fig. 1). Such tumors were considered to have a more
astrocytic histological appearance and, in our hospital practice,
would be diagnosed as diffuse astrocytoma (4). These cases did
not contain significant numbers of reactive-appearing astrocytes.
GFAP immunohistochemistry was performed on formalinfixed, paraffin-embedded sections with monoclonal anti-human
GFAP antibody (DAKO USA, Carpinteria, CA; 1:1,000 dilution) and visualized by the avidin-biotin complex technique
with 3, 39-diaminobenzidine tetrahydrochloride/H2O2 solution.
The presence or absence of the following GFAP-positive features was carefully assessed: gliofibrillary oligodendrocytes
Loss of Heterozygosity Studies
Statistical Analysis
The Fisher exact test was used to test for associations among
genotype, histology, and GFAP immunohistochemistry.
RESULTS
Histopathological-Molecular Genetic Correlation
Central neuropathological review of H&E stains divided the series into 2 even groups: 22 tumors with classical
oligodendroglioma histopathology (classic oligodendroglioma) and 22 tumors with more astrocytic histopathological features. Those with classical oligodendroglioma
appearances were predicted to have allelic loss of chromosome 1p, whereas those with more astrocytic features
were predicted to have maintenance of both 1p alleles.
Molecular genetic analyses demonstrated 1p loss in 19 of
22 tumors (86%) with classical oligodendroglioma histopathology, and maintenance of both 1p alleles in 16 of
22 lesions (73%) with more astrocytic features (Fig. 1;
Table 1). Histopathological grouping based on H&E
stains and 1p status were significantly associated with one
another (p , 0.001). Nonetheless, 9 tumors had discrepant histopathology and 1p status; these tumors were all
adult-onset, hemispheric gliomas except for 1 classic oligodendroglioma lacking 1p loss that arose in a 17-yr-old
girl. Twenty-four of the 25 tumors with 1p loss also had
allelic loss of chromosome 19q, and the sole tumor with
1p loss that maintained both 19q alleles had classical oligodendroglioma histopathology in the sampled tissue
(Table 1). One of the 19 tumors without 1p loss had 19q
loss; this was one of the 22 tumors with more astrocytic
features (Table 1). GFAP immunohistochemistry was performed on 36 tumors for which extra tissue sections were
available. Twenty-four of the 36 tumors had GFO, 14 had
minigemistocytes, and 26 had GFAP-positive cellular
processes (Fig. 1). There was no significant association
between 1p allelic status and the presence of any of these
GFAP-positive cell types (Table 2), although the presence
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J Neuropathol Exp Neurol, Vol 61, January, 2002
SASAKI ET AL
61
HISTOLOGICAL-GENETIC CORRELATION IN OLIGODENDROGLIOMA
TABLE 1
Histopathological-Molecular Genetic Correlations
(n 5 44)1,2
of GFAP-positive cytoplasmic processes was, not surprisingly, associated with astrocytic histopathology (Table 3, p 5 0.03).
1p LOH
1p intact
19 (18)
6 (6)
3 (0)
16 (1)
Chemotherapeutic Response
Chemotherapeutic response was evaluated in 13 of the
14 tumors treated with PCV chemotherapy at conversion
to more aggressive lesions. Eleven tumors responded and
2 did not respond. Ten of the 11 tumors that responded
to chemotherapy had allelic loss of chromosome 1p, and
both of the 2 tumors that lacked response to chemotherapy maintained both alleles of 1p. Five of the 13 tumors
with known response status had histopathological-molecular genetic discrepancies and thus provided a small
group to sample the possible predictive power of histopathological appearance versus 1p status. Strikingly, 3
tumors with more astrocytic histopathology but with 1p
loss responded to PCV chemotherapy. One of the 2 tumors with classic oligodendroglioma pathology that
maintained both 1p alleles did not respond to chemotherapy, but the other tumor responded.
DISCUSSION
The present study, comparing molecular genetic and
histopathological features in a referral pathologist-based
series of non-anaplastic diffuse gliomas, suggests that the
diagnosis of ‘‘oligodendroglioma’’ is being made more
frequently in the community of pathologists currently referring these tumors to MGH for molecular diagnosis
than in our laboratory at central review. In this series,
only half of 44 tumors diagnosed as ‘‘oligodendroglioma’’ in the United States and Canada were considered
classic oligodendrogliomas on central neuropathological
review. Importantly, these diagnoses were compared with
objective molecular genetic parameters: allelic losses of
chromosomes 1p and 19q. Central review diagnosis of
oligodendroglioma correlated closely with allelic status
of 1p and 19q, with 86% of such tumors harboring 1p
loss. In contrast, only 57% of referral pathologist-diagnosed ‘‘oligodendrogliomas’’ had 1p loss. The present
figure of 86% of our central neuropathologist-diagnosed
oligodendrogliomas with 1p loss also contrasts with a
Classic oligodendroglioma
Glioma with astrocytic features
Number of tumors with 19q LOH in parentheses.
Histopathological grouping and 1p status were significantly
associated (p , 0.001).
1
2
figure of 73% 1p loss in a predominantly low-grade collection of oligodendrogliomas diagnosed by consensus of
3 experienced neuropathologists (7). The comparison figures demonstrate that pathologists can be educated to recognize histopathological patterns that reflect specific tumorigenic events.
In our experience, the overwhelming majority (86%) of
diffuse, non-anaplastic gliomas with classical oligodendroglioma histology have allelic loss of chromosome 1p. These
tumors have relatively evenly distributed, uniform and
rounded nuclei and frequent perinuclear halos. Such tumors
are not controversial diagnoses and resemble the typical
depictions of oligodendroglioma in standard textbooks. In
common parlance, these cases are ‘‘first year pathology resident’’ diagnoses. Other histological features, such as delicate branching vasculature and calcifications, may be present but are not essential to the diagnosis. On the other
hand, the diffuse gliomas with more astrocytic histological
appearances, which would have been diagnosed by us as
‘‘diffuse astrocytoma,’’ have irregularly distributed, mildly
pleomorphic and irregular, hyperchromatic nuclei, often
with tapering eosinophilic cytoplasmic processes that can
be highlighted with GFAP immunohistochemistry. Notably,
these cases did not simply represent the infiltrating edge of
an otherwise classical oligodendroglioma, and copious reactive astrocytes were not present. Presumably, the presence
of some rounded nuclei and some perinuclear halos in such
cases suggested a diagnosis of ‘‘oligodendroglioma’’ to the
referring pathologists. More than 70% of such cases maintained both 1p alleles. Thus, although it is perhaps premature to suggest that such cases are not oligodendrogliomas,
these tumors clearly differ from classic oligodendrogliomas
←
Fig. 1. Low-grade ‘‘oligodendrogliomas’’ referred for genetic testing. Case 1 (1A, H&E; 1B, GFAP): classic oligodendroglioma with 1p loss showing rounded nuclei with perinuclear halos and microcalcification (1A). Reactive GFAP-positive astrocytes
among predominantly GFAP-negative tumor cells (1B). Case 2 (2A, H&E; 2B, GFAP): classic oligodendroglioma with 1p loss
showing even distribution of tumor cells with rounded, monotonous nuclei (2A). Minigemistocytes with GFAP-positive cytoplasm
(2B). Case 3 (3A, H&E; 3B, GFAP): glioma with astrocytic features, without 1p loss. Irregularly distributed tumor cells with
mild nuclear pleomorphism and occasional cellular processes (3A). Tumor cells with tapering cytoplasmic processes are highlighted with GFAP staining (3B, arrows). Case 4 (H&E): glioma with astrocytic features that has 1p loss, showing nuclear
pleomorphism, irregular clustering of cells and some visible cellular processes. Case 5 (H&E): glioma with astrocytic features
that has 1p loss. Cytoplasmic cellular processes are readily detectable in many tumor cells. This tumor showed 90% response to
PCV chemotherapy at the time of progression. Original magnification: 3400 with enlargement in 4, 5.
J Neuropathol Exp Neurol, Vol 61, January, 2002
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SASAKI ET AL
TABLE 2
GFAP Immunohistochemistry vs 1p Status (n 5 36)1,2
A
1p LOH
1p intact
Gilofibrillary oligodendrocyte
2
1
11
6
6
12
10
2
0
B
1p LOH
1p intact
C
1p LOH
1p intact
Minigemistocyte
2
1
11
13
9
5
5
2
2
GFAP-positive cytoplasmic processes
2
1
11
7
3
10
7
3
6
1
2, not obvious; 1, present in ,10% of tumor cells; 11,
present in .10% of tumor cells.
2
None of the GFAP positive cell types was significantly associated with 1p allelic status.
at a genetic level. Nonetheless, the classic oligodendrogliomas lacking 1p loss did not appear histologically different
from those with 1p loss, nor did the tumors with more
astrocytic appearance that had 1p loss appear histologically
different from those lacking 1p loss.
In the present study, none of the various GFAP-positive cell types was significantly associated with 1p allelic
status, consistent with the previous report that presence
of minigemistocytes and/or GFO does not correlate with
patient survival (8). The presence of GFAP-positive cell
processes correlated with the central review impression
of astrocytic features, but in nearly all cases the processes
were clearly visible on H&E stains. Therefore, GFAP patterns are not likely to predict 1p allelic status in lowgrade diffuse gliomas directly, although GFAP staining
can confirm astrocytic histological features such as cell
processes, which in turn correlate with maintenance of
both 1p alleles.
The present findings raise the questions of how one
defines an oligodendroglioma, and whether a particular
genetic signature can define a neuropathological entity.
In the fields of hematological and soft tissue malignancies, various translocations and other genetic events indeed define diagnostic entities (9, 10). In neuro-oncology,
there is certainly increasing evidence that tumor genotyping can stratify gliomas into clinically relevant groups (1,
3, 11, 12). This evidence is largely derived from studies
of oligodendrogliomas, particularly anaplastic oligodendrogliomas. In these tumors, as noted earlier, there are
strong associations between allelic status and both therapeutic response and survival. Allelic status of chromosomes 1p and 19q has become an important determinant
J Neuropathol Exp Neurol, Vol 61, January, 2002
TABLE 3
GFAP Immunohistochemistry vs ‘‘Trained’’ H&E
Histological Classification (n 5 36)1
A
Classic oligodendroglioma
Glioma with astrocytic
features
Gliofibrillary oligodendrocyte
2
1
11
7
5
9
13
1
1
B
Classic oligodendroglioma
Glioma with astrocytic
features
C
Classic oligodendroglioma
Glioma with astrocytic
features
Minigemistocyte
2
1
11
10
12
4
6
3
1
GFAP-positive cytoplasmic
processes2
2
1
11
7
3
9
8
1
8
1
2, not obvious; 1, present in ,10% of tumor cells; 11,
present in .10% of tumor cells.
2
GFAP-positive cytoplasmic processes were significantly associated with histological classification (p 5 0.03).
in oligodendroglioma patient management, not only to
encourage chemotherapy in some patients, but to minimize the toxicity of ineffective therapies in other patients
(11). Such tailored approaches to patient treatment promise to improve the likelihood of response of individual
patients to therapies and reduce unnecessary toxicities,
thus maximizing patient quality of life.
The association of 1p and 19q loss with well-differentiated oligodendroglioma histology has been suggested
from single institution studies (13), but it has not been
determined whether histological appearance or genetic
status is more relevant to clinical course. The present
series enabled us to identify discrepant cases in which
pathological appearance and actual allelic status did not
match, that is, classical oligodendrogliomas maintaining
both 1p alleles and more astrocytic tumors with 1p loss.
Since prognostic studies of low-grade diffuse gliomas require long follow-up times, the present series of relatively
recent cases cannot adequately evaluate differences in
prognosis; the literature, however, suggests that 1p loss
does confer better prognosis in series of consensus-diagnosed low-grade oligodendrogliomas (3). Importantly,
we were able to assess therapeutic response in those patients who received chemotherapy at recurrence or progression. Strikingly, of the 5 tumors discrepant for genotype-phenotype that were treated with PCV therapy at
tumor progression, all 3 tumors with 1p loss that were
HISTOLOGICAL-GENETIC CORRELATION IN OLIGODENDROGLIOMA
centrally diagnosed as having astrocytic features indeed
responded to chemotherapy. The 2 tumors with classic
oligodendroglioma histology that maintained both 1p alleles included 1 responder and 1 non-responder. Thus, the
outcomes of 4 of 5 discordant cases were predicted by
their genotype rather than their phenotype. Although
these are small numbers of cases and although these chromosomal changes do not currently define oligodendroglioma, the data raise the testable hypothesis that 1p allelic status is a more clinically relevant predictor than
histopathological diagnosis in diffuse low-grade gliomas
(14).
A caveat to some of the molecular-histological comparisons relates to possible sampling error, a common
problem in neuropathological diagnosis of brain tumor
biopsies. Two of the 3 tumors in this series with classic
oligodendroglioma histology that maintained both 1p alleles were represented by only small biopsy specimens,
and it is possible that other regions of the tumor appeared
astrocytic. Nonetheless, such possibilities again indicate
a role for molecular genetic testing, especially since studies on glial neoplasms to date have shown greater homogeneity in genotype than in phenotype. For instance,
microdissection of oligodendroglioma from astrocytoma
components in oligoastrocytomas has revealed allelic
losses of 1p and 19q in the astrocytic regions if present
in the oligodendroglial areas (15). And in gliosarcomas,
the glioblastomatous and sarcomatous regions typically
have the same genetic alterations (16, 17). Such data argue strongly that molecular genetic testing can add objectivity sorely needed to overcome diagnostic problems
such as phenotypic heterogeneity and tissue sampling biases.
Finally, it is important to emphasize that even neuropathologists ‘‘trained’’ to recognize particular histopathological appearances do not achieve 100% accuracy in
predicting tumor genotype in low-grade diffuse gliomas.
Rather, the correct prediction rate was only 80% for these
non-anaplastic diffuse gliomas (35 of 44 cases; 76% of
1p-deleted and 84% of 1p-intact tumors). Moreover, for
those cases with discrepant findings, tumor genotype
seems more promising than histological appearance in
predicting possible response to chemotherapy. While
such results clearly need to be confirmed in larger and
prospective series, the present findings encourage the use
of molecular analyses in clinical trials that evaluate novel
therapies, not only in oligodendroglioma studies but also
in investigations of low-grade diffuse gliomas in general.
63
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Received June 22, 2001
Revision received September 17, 2001
Accepted September 20, 2001
J Neuropathol Exp Neurol, Vol 61, January, 2002