Brain Pathology 3: 255268 (1993)

The New WHO Classification of Brain Tumours

Paul Kleihues 1, Peter C. Burger 2 and (CNS) neoplasms and, particularly, their histogenesis.
Bernd W. Scheithauer 3 Considering that immunohistochemistry was not
yet available, the task was enormous. However, the
result of the collaborative effort was quite successful
1 Institute of Neuropathology, Department of Pathology, as the "Blue Book rapidly gained popularity world-
University Hospital, CH-8091 Zurich, Switzerland
wide. Preparation of the second edition, just pub-
2 Department of Pathology, The Johns Hopkins Hospital,
Baltimore, MD 21287, U S A .
lished, was initiated during a consensus meeting
3 Department of Laboratory Medicine and Pathology, Mayo held in Houston, Texas, in 1988 (2). The "Blue Book"
Clinic, Rochester, MN 55905, U.S.A. still has the same scope, i.e., to propose a uniform
nomenclature for CNS neoplasms that can be used
internationally and which serves as a reliable guide-
line in day-to-day surgical pathology and as a unify-
The new edition of the World Health Organization ing basis for the evaluation of brain tumour therapy
(WHO) book on 'Histological Typing of Tumours of trials. In this article, the major alterations and
the Central Nervous System' reflects the progress in amendments are briefly reviewed, some with com-
brain tumour classification which has been achieved ments on the opinions expressed by participants of
since publication of the first edition in 1979. Several the WHO working group.
new tumour entities have been added, including
the pleomorphic xanthoastrocytoma, central neuro- Astrocytic Tumours a n d Glioma Progression
cytoma, the infantile desmoplastic astrocytoma /
ganglioglioma, and the dysembryoplastic neuro- The working group unanimously proposed that a
epithelial tumour. The list of histological variants clear line be drawn between the more circumscribed
has also been expanded. In line with recent mor- lesions (e.g., the pilocytic astrocytoma, the pleo-
phological and molecular data on glioma progres- morphic xanthoastrocytoma and the subependymal
sion, the glioblastoma is n o w grouped together giant cell astrocytomas associated with tuberous
with astrocytic tumours. The classification of child- sclerosis) on the one hand and diffusely infiltrating
hood tumours has been largely retained, the diag- astrocytomas typically located in the cerebral hemi-
nosis primitive neuroectodermal tumour (PNETI spheres on the other. Only the latter group shows an
only being recommended as a generic term for inherent tendency for progression to anaplastic
cerebellar medulloblastomas and neoplasms that astrocytoma and, ultimately, to glioblastoma multi-
are histologically indistinguishable from medullo- forme. Most participants, though not all, therefore
blastoma but located in t h e CNS at sites other voted to classify the glioblastoma as an astrocytic
than the cerebellum. The WHO grading scheme was tumour while in the first edition, it was grouped
revised and adapted t o n e w entities but its use, together with 'poorly differentiated and embryonal
as before. remains optional. tumours' (1).Although some participants contended
that anaplastic oligodendrogliomas and even epen-
Compiling the first edition of the World Health dymomas may, during advanced malignant progres-
Organization's consensus book on brain tumour clas- sion, turn into a tumour that fulfilIs the criteria for
sification (1) took almost a decade. At that time, diagnosis as glioblastoma, these neoplasms usually
pathologists had wide-ranging and often conflicting also show evidence of astrocytic differentiation.
views on the terminology of central nervous system The view adopted by the WHO working group,
i.e., that the glioblastoma is essentially an astro-
Corresponding author: cytic neoplasm, is supported by recent molecular
Or. I? Kleihues, Institute of Neuropathology, Department of genetic studies on the evolution of human gliomas
Pathology, University Hospital, CH-8091 Zurich, Switzerland (Table 1).It appears that in low grade astrocytomas
Tel. +41 (1) 255 2107; Fax +41 (1) 255 4402 (WHO Grade II), mutations of the p53 tumour Sup-
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256 P. Kleihues et al: WHO classification of brain tumours

Table 1 Comparison of the World Health Organization (WHO) and St. Anne / Mayo grading system for astrocytomas

WHO WHO St. Anne / Mayo Associated

Grade Designation Designation Histological Criteria Genetic Alterations

I Pilocytic
astrocytoma

II Astrocytoma Astrocytoma Grade 1 Zero criterion

(Low grade) Astrocytoma Grade 2 One criterion, usually p53 mutation & LOH 17p
nuclear atypia

111 Anaplastic Astrocytoma Grade 3 Two criteria, usually p53 mutation & LOH 17p,
astrocytoma nuclear atypia and LOH 19q
mitotic activity

IV Glioblastoma Astrocytoma Grade 4 Three criteria, usually p53 mutation & LOH 17p.
multiforme nuclear atypia, mitoses, LOH 19q & LOH 10,
endothelial proliferation EGF-R amplification
and/or necrosis

Abbreviations: LOH, loss of heterozygosity; EGF-R, epidermal growth factor receptor.

pressor gene with or without loss of heterozygosity than 70Oh of glioblastoma multiforme have loss of
on chromosome 17p occur in approximately 30% of chromosome 10 (11,12). In contrast to low grade
cases and constitute the earliest detectable genetic and anaplastic astrocytomas, glioblastomas contain,
alteration in diffusely infiltrating astrocytomas (3,4), in approximately one third of cases, amplification of
although isolated cases with loss of heterozygosity the epidermal growth factor receptor gene (EGF-R),
on chromosomes 13 and 22 have been reported (5). sometimes in a truncated form (11,13,14). Although
Anaplastic astrocytomas (WHO Grade 111) often the scheme shown in Table 1 is undoubtedly far from
develop over a course of several years from low grade complete, there is increasing evidence that in human
astrocytomas but may also arise de novo, i.e., with- astrocytomas genetic events may occur in a typical
out clinical or histopathological evidence of a pre- sequence which parallels histopathologically defined
ceding low grade glioma and contain p53 mutations stages of malignant progression. In contrast to dif-
at a similar incidence of 29 to 36% (3,6). In addition, fusely infiltrating astrocytomas, non-astrocytic brain
more than 4Ooh of anaplastic astrocytomas show tumours and pilocytic astrocytomas do not or very
loss of heterozygosity on chromosome 19q (7). Glio- rarely contain p53 mutations, thus suggesting a dif-
blastomas frequently develop from low grade or ferent genetic basis for these CNS neoplasms (4,15).
anaplastic astrocytomas ('secondary glioblastoma')
but may also primarily arise after a short clinical Pleomorphic Xanthoastrocytoma (PXA)
history, with no evidence of a less malignant pre- The participants unanimously accepted the pleo-
cursor lesion ('primary glioblastoma'). In three inde- morphic xanthoastrocytoma as a clinicopathologic
pendent studies, pS3 mutations were identified in entity. Details on the nosologic evolution of this
approximately one third of glioblastomas (6,8,9). tumour entity are provided by J. Kepes, elsewhere in
The observation of a similar overall incidence of this issue (16). In brief, the lesion is defined as a
p53 mutations in low grade astrocytomas, anaplastic generally superficial, compact neoplasm, with abun-
astrocytomas and glioblastoma multiforme may indi- dant reticulin and, frequently, perivascular chronic
cate that this gene is involved during a rather early inflammatory cells. Marked cellular pleomorphism is
stage of neoplastic transformation. One study sug- a consistent finding. Lipidization of the neoplastic
gests that the progression to glioblastoma is char- cells is variable, being scant in some cases and overt
acterized by a clonal expansion of cells carrying a in others (17). The classic lesion is noted for the
pS3 mutation, presumably due to a selective growth absence of mitotic figures, vascular proliferation and
advantage (10). In addition to p53 mutations, more necrosis, but it is increasingly recognized that other-
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P. Kleihues et al: WHO classification of brain turnours 257

wise typical lesions with mitoses are encountered. and a mucinous matrix within which neurons appear
The histogenesis of the lesion remains controversial, to 'float'. Such neurons vary from small to large and
but a glial origin was accepted by the Working Group from uni- to occasionally multinucleate. Surround-
in light of the immunohistochemical, histological, ing cortical dysplasia is also a common feature. A
and ultrastructural features. Some cells are usually detailed morphological description of DNTs is pro-
positive for glial fibrillary acidic protein. The resem- vided by C. Daumas-Duport in this issue, together
blance of some cases to malignant fibrous histio- with a proposal to distinguish between simple and
cytomas has, to some observers, raised the possibility complex forms of the lesion (25).
of a histiocytic origin (18). This is supported in part Since the original report (22), few additional cases
by immunohistochemical studies but the lack of have been reported (26,27). Despite incomplete or
specificity of these markers for histiocytes is widely subtotal removal of nearly half of reported lesions,
recognized and immunoreactivity in a PXA by no long-term follow-up reveals neither clinical nor
means excludes a glial origin for this lesion (19). radiological evidence of recurrence. Not only has no
Although there was consensus on the status of the benefit of radiotherapy been noted, but recognition
PXA as an entity, questions remained regarding the of DNT as a clinicopathologic entity is of impor-
biological behavior and grading of this lesion. Some tance since aggressive therapy must be avoided.
PXAs, for example, have an infiltrating component
the significance of which is not clear. In regard to Desmoplastic Infantile Ganglioglioma (DIG)
the issue of grading, the original supposition that This is a relatively recent recognized entity noted
these were only low grade tumours is contradicted for its early age of onset, superficial position, and
from time to time in practice, in the face of mito- frequent association with a large cyst (28). Histologi-
tically active neoplasms discussed above. In addi- cally, multiple tissue patterns have been encoun-
tion, some typical PXAs undergo anaplastic change tered, but the most distinctive is paucicellular des-
(20,21). At this point, grading of this lesion remains moplastic tissue in which astrocytes and neurons
controversial as does the tumour's relation to the are inconspicuous unless immunohistochemistry
giant cell glioblastoma. for neuronal and glial markers (GFAP) is applied.
An associated tissue pattern in some cases is a cellu-
Dysembryoplastic Neuroepithelial Tumour lar and, sometimes mitotically active, component
This recently described (22) morphologically unique which can prompt the diagnosis of a malignant
and surgically curable lesion, dysembryoplastic neu- neoplasm such as malignant glioma or gliosarcoma.
ropeithelial tumour (DNT), has also been included Experience with DIG is limited and the clinical
in the new WHO classification (23). It is typically behavior of this lesion remains to be defined. Never-
associated with medically intractable seizures of theless, the cases that have been followed have sug-
partial complex type. To date, neither neurologic gested that this is a low grade process, despite mito-
deficit nor an association with a phakomatosis or tic activity and occasional small cell component.
mental retardation have been reported. In most Many patients appear to be cured by simple excision.
cases, the patient's age at onset of symptoms is less Although this lesion has generally been encountered
than 20 years. Most affect the temporal or frontal in the first year of life, cases in adults have been
lobe; parietal, and particularly occipital involve- recognized (29). In one case studied postmortem, a
ment is infrequent. All DNTs are supratentorial and DIG was associated with a more conventional gang-
intracortical. Computer tomagraphy (CT) scans show lioglioma, raising the question as to how distinct this
DNTs to be well-defined, with little or no accom- entity is from the traditional classic ganglion cell
panying edema. Mass effect and effacement of corti- neoplasms (30).
cal architecture is subtle in small lesions, but their Desmoplastic cerebral astrocytoma of infancy. Ever
inherent nodularity may be appreciated on magnetic since the initial report by Taratuto et al., in 1984,
resonance (MR) scans. Focal contrast enhancement, (31) it has become increasingly evident that there
calcification, or cystic change is present in a small is a group of infantile desmoplastic tumours with
minority. Deformity of the overlying calvarium neoplastic astrocytes but which lack the neuro-
is common, attesting to their long-standing nature. nal component of the DIG (32-34). Since their clini-
A t low-power, multinodularity is a key feature. The cal behaviour is similarly benign (35), it has been
constituent cells include primarily oligodendrocytes proposed to use the generic term 'desmoplastic
and, to a lesser extent, astrocytes often of pilocytic supratentorial neuroepithelial tumours of infancy'
type. A recent detailed immunochemical and ultra- for these lesions (36).
structural study indicated that in a minority of cases
the oligodendroglia-like cells demonstrate astrocytic Central Neurocytoma
or early neuronal differentiation (24). The surround- The participants of the WHO working group unani-
ing extranodular cortex exhibits the so-called 'speci- mously voted to include this new entity, defined by
fic component' of DNT, one rich in oligodendrocytes J. Hassoun in 1982 (37), in the new classification.
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258 P. Kleihues et al: WHO classification of brain turnours

Over the past decade, this lesion has become a well- and anaplastic astrocytomas, and in the glioblastoma
established clinico-pathological entity with more multiforme. Thus, foci of astroblastic differentiation
than 125 documented and published cases. Its clini- in otherwise ordinary gliomas do not qualify for the
cal and morphologic characteristics are summarized designation as astroblastoma.
elsewhere in this issue (38). Briefly, this often calci- Polar spongioblastoma. The histopathological fea-
fied tumour is characterized by its manifestation ture of this neoplasm is quite unique as it is com-
in young adults, and by its typical supratentorial posed of unipolar or bipolar glial cells, the tumour
location in the lateral ventricles in the region of nuclei being arranged in parallel, forming a typical
the foramen of Monro. Histologically, the lesion is palisading pattern. The presence of this pattern can
moderately cellular and consists of isomorphous be focally observed in a variety of glial neoplasms,
round cells which alternate with patchy islands of a particularly during tumour progression, most notably
fibrillar 'neuropil' matrix. Central neurocytomas in oligodendrogliomas, pilocytic astrocytomas and
consistently show evidence of neuronal differentia- cerebellar medulloblastomas. Nevertheless, some
tion which can easily be assessed by immunohisto- members of the Working Group maintained the
chemistry (synaptophysin) and electron microscopy view that there is a 'true' polar spongioblastoma,
(EM) wherein of synapses and dense-core vesicles are which occurs usually in children and young adults
seen. Differential dignoses are oligodendroglioma, and in which the spongioblastic pattern is typically
ependymoma and cerebral neuroblastoma. Follow- present throughout the neoplasms (40,41). Sporadic
ing surgical resection, the clinical outcome is usu- cases of polar spongioblastoma continue to be pub-
ally favourable although recurrencies have been lished (42-44). In a recent study of 16 neoplasms
reported. Although some neurocytomas show sig- with spongioblastic differentiation, Schiffer et al. (45)
nificant mitotic activity, occasional necrosis and found only two tumours that showed this pattern
vascular proliferation, reported follow-up studies so throughout, but there were features of ependymal
far do not support the concept of a frankly malig- differentiation in one case and neuroblastic differen-
nant variant. tiation in the other. The authors concluded that in
embryonal tumours of the CNS the characteristic
Neuroepithelial Tumours of Uncertain Origin palisading pattern may dominate the entire surgical
In this category, three lesions were grouped together: specimen. In their view, a true polar spongioblas-
the astroblastoma, the polar spongioblastoma and toma does not exist. This view is, in part, supported
gliomatosis cerebri. Although undoubtedly of neu- by a report in which spongioblastic differentiation
roepithelial origin, their histogenesis has to date was observed in a medulloepithelioma (46).
remained enigmatic. This is particularly true for Gliomatosis cerebri. The term gliomatosis cerebri
astroblastoma and polar spongioblastoma; some engendered considerable discussion as to the origin
participants of the WHO working group considered of this lesion and its entitlement to the status of a
them sufficiently defined clinico-pathological enti- clinicopathologic entity. There was general consen-
ties while others regard them merely as a typical sus that the lesion is a glioma but little agreement as
but unspecific growth pattern which may occur in to cytogenesis. There was also disagreement whether
several of the more ordinary gliomas. gliomatosis was a non-specific pattern of infiltration
Astroblastoma. For some members of the Working or was sufficiently distinctive to be discussed sepa-
Group, the controversy as to whether this highly rately. The Working Group opted for the latter but
characteristic pattern of glial neoplasia represents with the qualification that the 'entity' was con-
a clinicopathologic entity or simply a focal morpho- troversial. Although the lesion is often felt to repre-
logic expression has been settled in favor of the sent an infiltrating astrocytic tumour, lesions with
former by the report by Bonnin and Rubinstein (39). oligodendrocyte phenotype have also been reported
Nonetheless, the nature of astroblastoma remains (47,423). The general consensus was that this lesion
an issue of contention. A tumour of the young, most is a clinical and radiographic entity as much as
are well-defined contrast-enhancing masses involv- a pathologically defined process. The term "glioma-
ing the cerebral hemispheres. Some, but not all, tosis" was not felt to be appropriate unless large
are periventricular in location. Despite obvious simi- areas (at least two, usually three lobes) of the brain
larities to ependymoma, broad rather than nar- are involved.
row tapering cell processes comprise astroblastoma Histologically, the features, which are shared by
pseudorosettes, as does lack of PTAH-positive cyto- a diverse group of infiltrating gliomas include a
plasmic fibrils despite strong GFAP reactivity. Con- diffusion of small, usually elongated cells (47-51).
spicuous vascular hyalinization may also distinguish Secondary structures in the cerebral cortex such
astroblastoma. A similarity to ependymoma is also as perivascular accumulation, perineuronal satel-
evident at the ultrastructural level. In the new litosis, and subpial aggregation are common. Dif-
classification, astroblastoma is defined on the basis fuse neoplasms with a markedly cellular, centrally
of the typical histologic pattern but it is also stated necrotic epicenter would generally be considered
that astroblastic features may be present in low grade glioblastoma rather than gliomatosis.
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P. Kleihues et al: WHO classification of brain turnours 259

Primitive Neuroectodermal Turnours (PNET) central portions of cranial and spinal nerves. New-
The nomenclature of embryonal CNS tumours was comers to the spectrum of schwannoma (neurilem-
among the most fervently discussed issues of the moma, neurinoma) include the cellular and mela-
Working Group. Origin of the dispute is the still notic variants.
unresolved histogenesis of the cerebellar medullo- Cellular schwannoma. This variant of schwannoma
blastoma. There appears t o be general agreement consists largely of cellular, Antoni A tissue exhibiting
that this tumour is embryonal, i.e., derived from variable mitotic activity. As such, it mimics malig-
an immature precursor cell which was initially pro- nant peripheral nerve sheath tumour (MPNST).
posed to be the embryonal medulloblast. This pre- Small, non-representative biopsies are particularly
cursor cell was never identified in the human CNS troublesome since the distinction of cellular schwan-
although a recent experimental study suggests that noma from MPNST requires attention to archi-
a cerebellar stem cell with potential for neuronal, tectural as well as cytologic and immunochemical
glial and muscle cell differentiation may exist (52). features. Distinguishing features of schwannoma
Pathologists have been intrigued by the observation include encapsulation, vascular hyalinization, peri-
that occasionally, medulloblastoma-like tumours vascular hemosiderin deposition, occasional foci of
occur in the cerebral hemispheres and it was pro- Antoni B pattern, strong generalized S-100 protein
posed by Hart and Earle in 1973 (53), that this immunoreactivity and frequent, albeit patchy stain-
group of embryonal neoplasms should be named ing for Leu-7, myelin-basic protein and glial fibrillary
primitive neuroectodermal tumours (PNETs). In acidic protein. Electron microscopy shows highly
1983, L. Rorke suggested that this term be applied developed schwann cell features including extensive
to a large variety of embryonal CNS tumours, includ- basal lamina formation and, in the minority of cases,
ing medulloblastoma, ependymoblastoma, neuro- long-spacing collagen.
blastoma and the pineoblastoma. The conceptual Since its original description (58), several series have
basis for this nomenclature was the assumption that confirmed the essentially benign nature of this lesion
PNETs share a common progenitor cell population, (59-62). Although approximately one-third of intra-
believed to be the subependymal matrix layer and cranial and intraspinal tumours recur (62), a figure
that their neoplastic transformation at various levels considerably higher than in peripheral nerves (SYo),
of the CNS leads to tumours with similar morpho- none have been reported to metastasize. No asso-
logy and biology (54). Whether and to what extent ciation with neurofibromatosis has been noted.
this concept holds true is still a matter of controversy Pigmented schwannoma. Unlike ordinary schwan-
although most authors now acknowledge that the nomas, the clinical behavior of melanotic schwan-
cerebellar medulloblastoma arises from the external nomas is variable. Approximately one-third are para-
granular layer which is the matrix zone for granular axial in location and nearly 109'0 arise within the
neurons but not for glial cells. Extensive immuno- CNS. N o association with neurofibromatosis has
histochemical studies have indeed shown that been noted. Fully 20940 are histologically malignant
medulloblastomas consistently express neuronal and of these, nearly one-third metastasize (63,64).
marker proteins (55,56) and often develop a mor- A subset of melanotic schwannomas demonstrate
phological phenotype resembling immature or fully psammomatous calcifications. Of these, one-half
developed ganglion cells. Astrocytic differentiation are associated with a clinical syndrome (Carney's
is less common, focal and usually restricted to a Complex) of spotty pigmentation, myxomas, and
small rim of GFAP immunoreactivity i n the peri- endocrine overactivity, usually Cushing's disease
karyon (57). Further, although supratentorial PNETs (65).
are now subjected to a therapy protocol similar to
that of the cerebellar medulloblastoma, their clinical Meningioma Variants
course appears to be less favourable; the results of Of tumours derived from components of the
prospective therapy trials are still pending. meninges, only those composed of or differenti-
Most members of the Working Group held the view ating toward arachnoidal cells are included in the
that the WHO classification should avoid this con- present classification of meningiomas. As a result,
troversy and voted t o largely retain the classification non-meningothelial tumours, other mesenchymal
of 'embryonal childhood tumours' and recommend- neoplasms, and those of uncertain. histogenesis
ed to use the diagnosis 'primitive neuroectodermal are separately grouped under benign and maljg-
tumour' (PNET) restrictively as a generic term for nant mesenchymal neoplasms as well as tumours
cerebellar medulloblastomas and for neoplasms of uncertain origin. In addition t o meningothelial
morphologically indistinguishable from the medullo- (syncytial), fibrous, transitional, psammomatous,
blastomas but located at other sites in the CNS. and metaplastic variants, a number of new variants
have been included i n the new WHO classification
Cranial Nerve Tumours
(66).
The spectrum of nerve sheath tumours encountered Secretory meningioma. This variant exhibits glan-
in the peripheral nerve system are also noted in dular metaplasia as evidenced by intracytoplasmic
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260 P. Kleihues et al: WHO classification of brain turnours

lumen formation. Such gland-like spaces contain epithelial membrane antigen and cytokeratin, and
a conspicuous PAS-positive secretion (67). Cells often (50Y0)show widespread S-100 staining. Chor-
surrounding such 'pseudopsammoma bodies' show doid meningiomas usually show only scant reac-
clear evidence of epithelial differentiation. Immuno- tivity for these antigens. Several examples have been
stains demonstrate keratin, carcinoembryonic anti- associated with a Castleman-like syndrome (78).
gen (CEA), and secretory component staining (68,
69). At the ultrastructural level, the intracytoplas- Atypical and Malignant Meningiomas
mic lumina contain microvilli and amorphous secre- In the previous WHO classification (l),the anaplastic
tions (70). The clinical behavior of secretory menin- (malignant) form of meningioma was recognized.
giomas resembles that of more ordinary variants. During the past decade, there was, however, increas-
The demonstration of obvious meningothelial or ing evidence of the presence of a meningioma with
transitional features in other portions of most intermediate biologic behaviour, i.e., the atypical
tumours prevents their confusion with metastatic meningioma. Although the definition of atypical
carcinoma. meningioma varied somewhat between the parti-
Microcystic meningioma. This unusual form of cipants of the Working Group, its inclusion in the
meningioma, once termed "humid" (71), differs new WHO classification was readily adopted.
from more ordinary meningiomas in displaying a Atypical meningioma. Although the biologic behav-
less pronounced female sex predilection (72,73). ior of meningiomas is affected by radiographic and
Occasionally grossly cystic, it is characterized by operative features, e.g., invasiveness, multifocality,
a wet, glistening cut surface. Microscopically, the and extent of resection, histologic studies demon-
distinctive microcystic pattern results from accumu- strate an association of recurrence with brisk mitotic
lation of extracellular fluid between attenuated pro- activity, hypercellularity, high nuclear cytoplasmic
cesses of neoplastic cells. Meningothelial cytology, ratio, nuclear atypia and nucleolar prominence,
including nuclear-cytoplasmic inclusions, is often uninterrupted patternless growth ('sheeting') and the
noted but whorl formation is inconspicuous. presence of zonal necrosis (79-86). Tumours exhibit-
Clear cell meningioma. This distinctive variant of ing these features, but lacking frank anaplasia, are
meningioma is characterized by sheet-like proli- termed "atypical meningiomas". In a retrospective
feration of clear, polygonal cells, the cytoplasm of clinico-pathological review of 1,799 meningiomas,
which contains abundant glycogen. Meningothelial Maier et al. (87) confirmed the intermediate clinical
features are inapparent and at most consist of behaviour of atypical meningioma but defined the
vague whorl formation. Coarse, blocky, stromal and lesion more narrowly. In their view, increased cellu-
perivascular collagen deposition is a conspicuous larity and brisk mitotic activity (at least five mito-
degenerative feature in tumours of long-standing. In tic figures in ten high-power fields) are sufficient to
view of its high content of glycogen, this form of allow the diagnosis of atypical meningioma.
meningioma must be distinguished from metastatic Malignant meningioma. With the exclusion of
renal cell carcinoma, a tumour with stronger, more hemangiopericytoma, considered sarcoma in the
uniform keratin and epithelial membrane antigen new WHO classification, the proportion of truly
immunoreactivity as well as lack of S-100 protein malignant meningiomas is significantly reduced.
staining. Clear cell meningiomas may recur or seed. Such tumours are either anaplastic from their onset
Lymphoplasmacyte-rich meningioma. This uncom- or occur in transition from ordinary or atypical
mon tumour is characterized by a prominent lym- meningiomas. It is notewothy that not all clini-
phoplasmacytoid reaction superimposed upon a cally malignant tumours, i.e. those exhibiting brain
more ordinary, often meningothelial or transitional invasion or distant metastasis, are frankly anaplastic.
meningioma (74,75). Germinal centers, Russell body- Papillary meningioma. The histologic appearance of
containing plasma cells, and even amyloid may be clinically or histologically malignant meningiomas
noted. Lymphoplasmacytoid meningiomas have covers the spectrum of morphologic variants, but
been associated with polyclonal hypergammaglo- papillary meningioma deserves special mention.
bulinemia which remits with resection and reappears This aggressive form of meningioma has long been
with tumour recurrence. This variant of meningioma considered 'malignant by definition' (88). A recent
must be distinguished from plasma cell granuloma review of the literature found not only a high fre-
(76) and meningeal plasmacytoma (77). quency of brain or local invasion, recurrence, and
Chordoid rneningioma. Due to their lobular, low- metastasis but a 50% likelihood death of disease
power architecture and production of stromal muco- (89). The papillary pattern predominates in only a
substances, chordoid meningiomas mimic chor- minority of cases and most tumours demonstrate a
doma. Neuroradiologic and immunochemical studies clearly recognizable meningioma pattern.
aid in the differential diagnosis. In contrast to chor-
doid meningiomas, chordomas affect the midline Deletion
skull base, are permeative of bone, lack a hypero- The monstrocelluiar sarcoma is no longer contained
stotic reaction, are strongly immunoreactive for in the WHO classification since immunohistoche-
 17503639, 1993, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1750-3639.1993.tb00752.x by INASP/HINARI - PAKISTAN, Wiley Online Library on [01/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
P. Kleihues et al: WHO classificationof brain tumours 261

Table 2 World Health Organization (WHO)grading system (malignancy scale) of CNS tumours.

Turnour Group Turnour Type Grade I Grade 11 Grade 111 Grade IV

Astrocytic tumours Subependymal giant cell

Pilocytic 0

Low grade
Pleomorphic xanthoastrocytoma 0

Anaplastic 0

Glioblastoma

Oligodendrogliomas Low grade

Anaplastic

Oligo-astrocytomas Low grade

Anaplastic

Ependymal turnours Subependymoma 0

Myxopapillary
Low grade 0

Anaolastic

Choroid plexus tumours Papilloma

Carcinoma 0

Neuronal / glial tumours Gangliocytoma

Gangliogiioma
Desmoplastic infantile ganglioglioma
Dysembryoplastic neuroepithelial tumour
Central neurocytorna

Pineal tumours Pineocytoma 0

Pineocytoma / pineoblastoma
Pineoblastoma

Embryonal tumours Medulloblastoma

Other PNETs
Medulloepithelioma
Neuroblastoma
Ependymoblastoma

Cranial & spinal nerve tumours Schwannoma

Malignant peripheral nerve sheath tumour 0

Meningeal tumours Meningioma

Atypical meningioma
Papillary meningioma 0

Hemangiopericytoma 0

Anaplastic rneningioma
 17503639, 1993, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1750-3639.1993.tb00752.x by INASP/HINARI - PAKISTAN, Wiley Online Library on [01/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
262 P. Kleihues et at: WHO classification of brain turnours

mica1 studies clearly showed that tumour cells con- Comparison of Grading System for Astrocytic
sistently express GFAP (90). Thus, this neoplasm Tumours
has to be regarded as a variant of the glioblastoma, Significant indicators of anaplasia in astrocytic
i.e., a giant cell glioblastoma with sarcomatous tumours are generally agreed upon and include cyto-
component. logic atypia, mitotic atypia, high cellularity, vascular
proliferation, and necrosis with or without pseudo-
WHO Grading of CNS Tumours palisading. Of these, all but cellularity readily lend
Although the difficulties in tissue sampling are recog- themselves to quantification. Several histologic grad-
nized, the participants were committed to the con- ing systems are in use for the division of astrocytic
cept that many gliomas, particularly the astrocytic tumours into prognostically meaningful groups.
tumours, require stratification into levels of differing Kernohan grading. Both three-tiered and four-tiered
histological 'malignancy'. The process of grading, grading schemes have been introduced. Of the lat-
as applied to diffuse or fibrillary astrocytic tumours, ter, the best known is the Kernohan method (93),
is plagued by variation of grade within a given neo- an outgrowth of the still popular four-tiered Broder's
plasm as well as the decided tendency for such classification (94) applied successfully to a variety
tumours to undergo anaplastic transformation over of systemic tumours. Like most methods, that of
time, thus providing an essentially 'moving target'. Kernohan shows correlation between patient age,
As expected, there were disagreements as to how this tumour grade, and length of postoperative survival.
stratification should be accomplished, e.g., which Significant detractions of the system are its 'lumping'
numbers or verbal descriptions, or both, were pre- of fibrillary and pilocytic astrocytoma as well as the
ferable. The numbers of steps or grades were also equation of the term "glioblastoma" with tumours
a point of discussion. In regard to the astrocytic of both grades 3 and 4. Rather than distinguishing
tumours, the group elected to retain a three-tiered four separate survival curves, however, tumours tend
system similar to that of the previous WHO volume to fall into low grade (l-Z)-and high grade (3-4)
(1) and similar to that proposed by Ringertz in 1951 groups. Furthermore, the individual criteria of the
(91). This system is also similar to the St. Anne/ Kernohan method are verbally expressed in such
Mayo classification published by Daumas-Duport et a way as to foster subjectivity and inter-observer
al. (92) discussed below (Table 1) since astrocytomas variation.
entitled to the grade I designation by the latter classi- Ringertz system. Currently used three-tier schemes,
fication are very uncommon (92). ones based upon the Ringertz system (91), designate
The group retained the general approach utilized tumours of differing grade by name rather than
in the prior edition of the WHO "Blue Book", which number. The Ringertz method, as well as modifica-
established a malignancy scale based on the histo- tions thereof (95-98), is limited in its application
logic features (Table 2). Grade I lesions, exemplified to astrocytoma, anaplastic astrocytoma, and glioblas-
by the pilocytic astrocytoma, generally included toma. Pilocytic and other special variants of astro-
tumours with a low proliferative potential, a fre- cytoma are not graded by these methods. Further-
quently discrete nature, and the possibility of cure more, they apply the designation "glioblastoma"
following surgical resection alone. Lesions desig- only to tumours of grade 4. As a rule, these schemes
nated grade I1 are generally infiltrating and low consider the well-differentiated lesion (grade 2, or
in mitotic activity, but recur. Some tumour types astrocytoma) to show atypia but only rare mitoses
tend to progress to lesions with higher grades and no vascular proliferation or necrosis, the inter-
of malignancy. The well differentiated astrocyto- mediate lesion (grade 3, or anaplastic astrocytoma)
mas, oligodendrogliomas and ependymomas are to be a more cellular, mitotically active lesion with
typical examples of grade I1 tumours. The desig- little if any vascular proliferation and no necrosis,
nation grade I11 was reserved for lesions with his- and the least differentiated (grade 4, or glioblastoma)
tologic evidence of malignancy, generally in the to be cellular, pleomorphic, and mitotically active
form of mitotic activity, clearly expressed infiltrative with neovascularization and necrosis. Significant
capabilities and anaplasia. The designation grade IV differences in survival are noted in each grade. Like
was assigned to mitotically active, necrosis-prone the Kernohan scheme, subjectivity and inter-observer
neoplasms, generally associated with a rapid pre- variation may pose a significant problem.
and postoperative evolution of the disease. Examples W HO grading. The previous WHO classification also
include most of the embryonal neoplasms, the glio- employs a three-tier system similar to the Ringertz
blastoma multiforme and occasional highly malig- scheme (1).Feature definitions are verbal, subjec-
nant choroid plexus carcinomas. Although not a tive, and thus permit considerable inter-observer
diagnostic criteria for a grade IV tumour, infiltra- variation. Astrocytic tumours of the diffuse or fib-
tion of adjacent tissue, and propensity for dissemi- rillary type are considered grade I1 (astrocytoma),
nation within the central nervous system in some grade I11 (anaplastic astrocytoma) and grade IV
cases, is a common feature of grade IV neoplasms. (glioblastoma), respectively. Tumours of grade I
 17503639, 1993, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1750-3639.1993.tb00752.x by INASP/HINARI - PAKISTAN, Wiley Online Library on [01/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
P.Kleihues et al: WHO classification of brain tumours 263

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266 P. Kleihues et al: WHO classification of brain tumours

95. Rubinstein LJ (1982) Tumours of the Central Nervous

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Martinus Nijhoff Publishers: Dordrecht
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P. Kleihues et al: WHO classification of brain turnours 267

JVHO Histological Typing of CNS Tumours 1.7.2 Dysplastic gangliocytoma of

cerebellum (Lhermitte-Duclos)
1 Tumours of Neuroepithelial Tissue 1.7.3 Desmoplastic infantile
ganglioglioma
1.1 Astrocytic tumours 1.7.4 Dysembryoplastic neuroepithelial
1.1.1 Astrocytoma tumour
1.1.1.1 Variants: Fibrillary 1.7.5 Ganglioglioma
1.1.1.2 Protoplasmic 1.7.6 Anaplastic (malignant)
1.1.1.3 Gemistocytic ganglioglioma
1.1.2 Anaplastic (malignant) astrocytoma 1.7.7 Central neurocytoma
1.1.3 Glioblastoma 1.7.8 Paraganglioma of the
1.1.3.1 Variants: Giant cell glioblastoma filum terminale
1.1.3.2 Gliosarcoma 1.7.9 Olfactory neuroblastoma
1.1.4 Pilocytic astrocytoma (Aesthesioneuroblastoma)
1.1.5 Pleomorphic xanthoastrocytoma 1.7.9.1 Variant: Olfactory neuro-
1.1.6 Subependymal giant cell astrocytoma epithelioma
(Tuberous sclerosis)
1.8 Pineal parenchymal tumours
1.2 Oligodendroglial tumours 1.8.1 Pineocytoma
1.2.1 Oligodendroglioma 1.8.2 Pineoblastoma
1.2.2 Anaplastic (malignant) 1.8.3 Mixed / transitional pineal tumours

oligodendroglioma 1.9 Embryonal tumours

1.9.1 Medulloepithelioma
1.3 Ependymal tumours 1.9.2 Neuroblastoma
1.3.1 Ependymoma 1.9.2.1 Variant: Ganglioneuroblastoma
1.3.1.1 Variants: Cellular 1.9.3 Ependymoblastoma
1.3.1.2 Papillary 1.9.4 Primitive neuroectodermal
1.3.1.3 Clear cell tumours (PNETs)
1.3.2 Anaplastic (malignant) ependymoma 1.9.4.1 Medulloblastoma
1.3.3 Myxopapillary ependymoma 1.!2.4.1.1 Variants: Desmoplastic
1.3.4 Subependymoma medulloblastoma
1.9.4.1.2 Medullomyoblastoma
1.4 Mixed gliomas 1.9.4.1.3 Melanotic medulloblastoma
1.4.1 Oligo-astrocytoma
1.4.2 Anaplastic (malignant)
oligo-astrocytoma
2 Tumours of Cranial and
Spinal Nerves
1.4.3 Others
2.1 Schwannoma
1.5 Choroid plexus tumours (Neurilemmoma, Neurinoma)
1.5.1 Choroid plexus papilloma 2.1.1 Variants: Cellular
1.5.2 Choroid plexus carcinoma 2.1.2 Plexiform
2.1.3 Melanotic
1.6 Neuroepithelial turnours of
uncertain origin
2.2 Neurofibroma
1.6.1 Astroblastoma 2.2.1 Circumscribed (solitary)
1.6.2 Polar spongioblastoma 2.2.2 Plexiform
1.6.3 Gliomatosis cerebri
2.3 Malignant peripheral nerve
1.7 Neuronal and mixed sheath tumour (MPNST) (Neuro-
neuronal-glial tumours genic sarcoma, Anaplastic neuro-
1.7.1 Gangliocytoma fibroma, "Malignantschwannoma")
2.3.1 Variants: Epithelioid
Reproduced from: P. Kleihues. P.C. Burger, B.W. Scheithauer 2.3.2 MPNST with divergent
(1993) Histological Typing of Turnours of the Central Nervous mesenchymal and/or
System, World Health Organization, International Histological epithelial differentiation
Classification of Tumours, Springer-Verlag: Berlin, Heidelberg 2r.3.3 Melanotic
 17503639, 1993, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/j.1750-3639.1993.tb00752.x by INASP/HINARI - PAKISTAN, Wiley Online Library on [01/05/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
268 P. Kleihues et al: WHO classification of brain turnours

3 Tumours of the Meninges 5 Germ Cell Tumours

3.1 Tumours of meningothelial cells 5.1 Germinoma

3.1.1 Meningioma 5.2 Embryonal carcinoma
3.1.1.1 Variants: Meningothelial 5.3 Yolk sac tumour
3.1.1.2 Fibrous (fibroblastic) (Endodermal sinus tumour)
3.1.1.3 Transitional (mixed) 5.4 Choriocarcinoma
3.1.1.4 Psammomatous 5.5 Teratoma
3.1.1.5 Angiomatous 5.5.1 Immature
3.1.1.6 Microcystic 5.5.2 Mature
3.1.1.7 Secretory 5.5.3 Teratoma with malignant
3.1.1.8 Clear cell transformation
3.1.1.9 Chordoid 5.6 Mixed germ cell tumours
3.1 .l.10 Lymphoplasmacyte-rich
3.1.1.11 Metaplastic
3.1.2 Atypical meningioma 6 Cysts and Tumour-like Lesions
3.1.3 Papillary meningioma
3.1.4 Anaplastic (malignant) 6.1 Rathke cleft cyst
men in gioma 6.2 Epidermoid cyst
6.3 Dermoid cyst
3.2 Mesenchymal, non-meningothelial 6.4 Colloid cyst of the third ventricle
turnours 6.5 Enterogenous cyst
Benign neoplasms 6.6 Neuroglial cyst
3.2.1 Osteocartilaginous tumours 6.7 Granular cell tumour
3.2.2 Lipoma (Choristoma, Pituicytoma)
3.2.3 Fibrous histiocytoma 6.8 Hypothalamic neuronal
Others hamartoma
3.2.4
6.9 Nasal glial heterotopia
Malignant neoplasms 6.10 Plasma cell granuloma
3.2.5 Hemangiopericytoma
3.2.6 Chondrosarcoma
3.2.6.1 Variant: Mesenchymal 7 Tumours of the Sellar Region
chondrosarcoma
3.2.7 Malignant fibrous histiocytoma 7.1 Pituitary adenoma
3.2.8 Rhabdomyosarcoma 7.2 Pituitary carcinoma
3.2.9 Meningeal sarcomatosis 7.3 Craniopharyngioma
3.2.10 Others 7.3.1 Variants: Adamantinomatous
7.3.2 Papi11ary
3.3. Primary melanocytic lesions
3.3.1 Diffuse melanosis
3.3.2 Melanocytoma 8 Local Extensions from
3.3.3 Malignant melanoma Regional Tumours
3.3.3.1 Variant: Meningeal
melanomatosis 8.1 Paraganglioma (Chemodectoma)
8.2 Chordoma
3.4 Turnours of uncertain histogenesis 8.3 Chondroma
3.4.1 Haemangioblastoma Chondrosarcoma
(Capillary haemangioblastoma) 8.4 Carcinoma

4 Lymphomas and 9 Metastatic Tumours

Haemopoietic Neoplasms

4.1 Malignant lymphomas 10 Unclassified Tumours

4.2 Plasmacytoma
4.3 Granulocytic sarcoma
4.4 Others