The new WHO classification of tumors of the nervous system 2000. Pathology and genetics

New developments in neuro-oncology have prompted an update of the World Health Organization (WHO) classification of tumors of the nervous system. Major changes include the addition of new entities and the refinement of criteria for the diagnosis and grading of various neoplasms, in particular the meningiomas. As novel clinico-pathological entities, the chordoid glioma of the third ventricle, the atypical teratoid/rhabdoid tumor (AT/RT), the solitary fibrous tumor, and the perineurioma have been listed. The former lipomatous medulloblastoma of the cerebellum, previously incorporated in the family of embryonal tumors, is now classified as cerebellar liponeurocytoma. The term mixed pineocytoma/pineoblastoma has been replaced by pineal parenchymal tumor of intermediate differentiation. Furthermore, the large cell medulloblastoma and the tanycytic ependymoma were established as novel tumor variants. A separate chapter on the peripheral neuroblastic tumors has now been included in the classification. Substantial revisions were introduced in the meningioma chapter. For both atypical meningioma WHO grade II and anaplastic meningioma WHO grade III, histopathological criteria are now precisely defined. An important new addition to the WHO 2000 classification of nervous system tumors is the inclusion of molecular pathology findings. With this combination of pathology and genetics it has set the stage for a new format of the WHO tumor classification series.     

The histopathological spectrum of human meningiomas

Histopathological examination and grading of meningiomas gives valuable prognostic information, although the method is subject for interobserver variability. The aim of this study was to review a large series of human meningiomas in order to examine the frequency of benign (grade I), atypical (grade II), and anaplastic (grade III) forms depending on various WHO classification schemes. In addition, we wanted to describe the frequency of various histopathological features and their mutual correlations. Sections from 196 consecutively treated primary human meningioma patients were revised retrospectively. The established criteria to grade meningiomas, which are also known to be associated with tumorigenesis, were shown to correlate significantly. The number of grade II meningiomas increased when using the WHO 2007 classification (30%) compared with previous editions, mainly due to the definition of brain infiltrating meningiomas as atypical (grade II). bimodal frequency distribution among age groups of females was observed. Continuous revision of histopathological classification systems is required to improve the diagnostic accuracy.     

Expression of extracellular matrix-degrading proteins in classic, atypical, and anaplastic meningiomas

Although the majority of meningiomas, commonly benign tumors (WHO I), are amenable to surgical resection, a percentage of up to 3% will recur as higher-grade meningiomas with potential brain invasion. Our study aims at the in situ identification of proteolytic, extracellular matrix-degrading enzymes in a broad spectrum of meningiomas. We examined 80 meningiomas (50 classic meningiomas WHO I, 19 meningiomas WHO II, including atypical, chordoid, and clear cell types, as well as 11 anaplastic meningiomas WHO III) for the immunohistochemical expression patterns of cathepsin D and metalloproteinases MMP-2 and MMP-9. Meningiomas of all types and grades revealed a distinct expression of MMP-9 and cathepsin D, while MMP-2 was found predominantly in WHO II and III meningiomas. There was a significant increase in positive tumor cells from WHO grade I to II and III for MMP-2 (p<0.001), but not for cathepsin D (p=0.099). MMP-9 displayed an increased number of positive tumor cells from WHO grade I to II, but a decrease in WHO III meningiomas (p<0.002). Routine screening for the expression of metalloproteinases and cathepsin D will not reveal any new diagnostically or prognostically relevant information. However, these factors may represent a potential target for pharmacological blocking as an anti-invasive therapy.     

Atypical,aplastic, and unusual meningiomas. Morphology and incidence in 300 consecutive cases

We morphologically studied 300 consecutive and primitive meningiomas surgically treated between march 1997 and april 2002 in order to evaluate the incidence of atypical, anaplastic, and morphologically unusual meningiomas. Two hundred and fifty-five meningiomas (85%) were WHO I, 33 (11%) were WHO II, 9 (3%) were WHO III; the remaining 3 meningiomas (1%) showed clear and diffuse oncocytic differentiation without cytologic or architectural atypia (oncocytic meningiomas). Forty-five of 255 WHO I meningiomas (18%) were infrequent histological subtypes: 18 (7%) psammomatous, 9 (4%) metaplastic, 9 (4%) secretory, 6 (2%) angiomatous, and 3 (1%) microcystic. Thirty of 33 WHO II meningiomas (91%) were atypical, 2 (6%) were clear cell meningiomas, and 1 (3%) was chordoid meningioma. Seven of 9 WHO III meningiomas (78%) were anaplastic and 2 (22%) were papillary. We evidenced the high morphological variability and the discrete occurrence of WHO I and WHO II meningiomas.     

Genetic alterations associated with adult diffuse astrocytic tumors

Astrocytic tumors make up a wide range of neoplasms that differ in their location in the central nervous system, morphologic features, progressive and invasive behaviors, and the age and gender of people they affect. This report reviews the cytogenetic, molecular cytogenetic, and molecular genetic abnormalities associated with diffuse infiltrating astrocytomas in adults. This group of tumors is subdivided into low-grade astrocytomas (WHO grade II), anaplastic astrocytomas (WHO grade III), and glioblastoma multiforme (WHO grade IV).     

Allelic gain and amplification on the long arm of chromosome 17 in anaplastic meningiomas

Using comparative genomic hybridization (CGH) we have previously identified amplification at 17q21-qter as a common aberration in anaplastic meningiomas but not in atypical or benign meningiomas (19). To define the amplified genomic region, we analyzed 44 meningeal tumors, including 7 benign meningiomas of World Health Organization (WHO) grade 1,19 atypical meningiomas (WHO grade II) and 18 anaplastic meningiomas (WHO grade III) at 46 chromosome 17 loci (including 42 17q loci). In line with the CGH data we found evidence of increased numbers of alleles on 17q. The incidence rose with malignancy grade, culminating at 61% (11 of 18 cases) in the anaplastic meningioma group. The majority of cases showing increased allele numbers had, on average, low-level allelic gains (relative increase in allele dosage of 2- to 5-fold). Amplification of alleles (defined here as an average relative increase in allele dosage of more than 5 times) was detected in 2 anaplastic meningiomas. The amplification patterns in these tumors defined a number of common regions of amplification/increased allele copy number, the best defined include one between D17S790 and D17S1607 and one between D17S1160 and PS6K. Real-time PCR analysis of the PS6K candidate gene revealed no high-level amplification despite this affecting adjacent loci. Our findings are fundamental for the identification of the gene(s) in 17q22-q23 that is (are) the target(s) for increased copy number in anaplastic meningiomas and possibly other tumor types.     

A conceptual shift in the grading of meningiomas

Grading schemes for meningiomas have traditionally designated tumors as "meningioma," "atypical meningioma," or "anaplastic (malignant) meningioma," depending upon the presence of histopathologic features thought to indicate aggressive behavior. In the past, most systems have considered brain invasion by tumor as the best evidence of malignancy. Perry et al. have recently investigated the significance brain invasion as a prognostic feature in meningiomas. The authors studied a series of 116 patients who had been diagnosed previously with "malignant meningioma" due to the presence of brain invasion, histologic anaplasia, or metastasis. On the basis of a multivariate analysis of histopathologic features and their relationship to tumor recurrence and patient survival, the authors concluded that brain invasion should be considered one of the diagnostic features of atypical meningioma. Accordingly, the diagnosis of malignant meningioma should be reserved for those tumors that are frankly anaplastic and/or contain (> = 20 mitoses per 10 high-power fields (HPF). Due in large part to the strength of evidence in this study, the World Health Organization (WHO) has adopted a grading scheme for meningiomas that incorporates many of the authors' proposals. New diagnostic criteria will result in improved reproducibility with fewer diagnoses of malignant meningioma (WHO grade III).     

Atypical meningioma: morphometric analysis of nuclear pleomorphism

The revised edition of the WHO classification of brain tumours now includes the "atypical" meningioma (grade II) which should be placed between the common type (grade I) and anaplastic type (grade III) according to histomorphological features and prognosis. However, diagnostic criteria for atypical meningioma are vague and the significance of brain invasion in the determination of malignancy is controversial. Nuclear pleomorphism and mitoses are usually considered the most important parameters to distinguish atypical and malignant meningiomas. According to WHO classification we selected eight cases of meningioma diagnosed as atypical (3 cases) and malignant (5 cases). All the tumours were supratentorially located. Nine cases of benign meningiomas were also studied as a control group. Morphometrical analysis was carried out by S.A.M. (Shape Analytical Morphometry) system. S.A.M. logical architecture assumes that each irregular shape contains elements of two distinct logical domains: gross distortions that interest the contour and its local perturbations. These features were investigated separately by analytical procedures to acquire independent parameters both on the logical and the numerical level. The results, statistically evaluated, show that nuclear pleomorphism is not a satisfactory criterion, if used alone, to distinguish atypical from malignant meningioma (Discriminant Analysis: 19% of minimum error).     

Hypermethylation and Transcriptional Downregulation of the TIMP3 Gene is Associated with Allelic Loss on 22q12.3 and Malignancy in Meningiomas

The gene for the tissue inhibitor of metalloproteinase 3 (TIMP3) on 22q12.3 had been reported to be inactivated by promoter methylation in various types of cancers, with controversial findings in meningiomas. We performed direct sodium bisulfite sequencing in a series of 50 meningiomas, including 27 benign meningiomas [World Health Organization (WHO) grade I], 11 atypical meningiomas (WHO grade II) and 12 anaplastic meningiomas (WHO grade III), and found hypermethylation of TIMP3 in 67% of anaplastic meningiomas, but only 22% of atypical and 17% of benign meningiomas. Moreover, TIMP3 methylation scores were significantly inversely correlated with TIMP3 mRNA expression levels (P = 0.0123), and treatment of the meningioma cell line Ben‐Men‐1 with demethylating agents induced an increased TIMP3 mRNA expression. TIMP3 is located in the chromosomal band 22q12, the allelic loss of which occurs early in meningioma tumorigenesis and preferentially targets the NF2 tumor suppressor gene. In our tumor panel, all meningiomas with TIMP3 hypermethylation—except for a single case—exhibited allelic losses on 22q12.3. Thus, TIMP3 inactivation by methylation seems fairly exclusive to meningiomas with allelic losses on 22q12 but—in contrast to NF2 mutation—appears to be involved in meningioma progression as it is associated with a more aggressive, high‐grade meningioma phenotype.     

Osteopontin predicts the behaviour of atypical meningioma

Lin C‐K, Tsai W‐C, Lin Y‐C & Hueng D‐Y
(2012) Histopathology  60, 320–325
Osteopontin predicts the behaviour of atypical meningioma Aim: Although the World Health Organization (WHO) histological criteria distinguishing benign from atypical and malignant meningioma are clear, discerning benign from atypical meningioma is still somewhat difficult, leading to interobserver diagnostic variability. Osteopontin (OPN) and cortactin play important roles in tumorigenesis, invasion and metastasis of several human cancers. The aim of this study was to evaluate the usefulness of OPN and cortactin immunohistochemistry for distinguishing between benign, atypical and malignant meningioma and predicting their recurrence. Methods and results: Seventy‐five specimens (48 benign, 17 atypical and 10 malignant meningiomas) were investigated immunohistochemically. The mean immunohistochemical scoreimmunohistochemical score ± SE of the mean of both OPN and cortactin were significantly higher in grade II or grade III meningiomas than in grade I meningioma. Discriminant analysis of immunohistochemical OPN expression showed correct classification of 97.7% of WHO grade I meningiomas and 88.2% of WHO grade II meningiomas (95.4% accuracy). However, the same analysis of cortactin expression showed correct classification of 95.8% of WHO grade I meningiomas and only 23.5% of WHO grade II meningiomas (76.9% accuracy). A cut‐off for predicting grades I and II meningioma recurrence was determined for OPN (3.0) but not for cortactin. Finally, logistic regression identified both this cut‐off (P < 0.05) and WHO grade (P < 0.05) as independent risk factors for recurrence. Conclusions: OPN expression is a valuable marker for diagnosis of atypical meningioma and prediction of grades I and II meningioma recurrence.     

Emergence of a high-grade sarcoma in a recurrent meningioma: malignant progression or collision tumor?

Anaplastic meningiomas that resemble sarcomas often reveal clues to their meningothelial differentiation or develop in a plausible setting that confirms their meningothelial origin. Malignant mesenchymal neoplasms without obvious evidence of meningothelial differentiation or origin are more likely to be true primary or metastatic sarcomas. Because of their clinical and biological differences, it is important to distinguish anaplastic meningioma from a sarcoma. We present a 67-year-old woman with multiple meningiomas, who developed a high-grade spindle cell tumor 6 months after the resection of a World Health Organization grade I meningioma. It was not clear whether this tumor represented a malignant transformation of meningioma or a primary sarcoma. Malignant transformation of a meningioma is exceptional within this short period and a coexisting sarcoma and meningioma are equally uncommon. Even though these malignant neoplasms are rare in general, they appear to be more prevalent in patients with multiple meningiomas including those with neurofibromatosis type 2.     

Smear preparation of intracranial lesions: a retrospective study of 306 cases

A cytohistological correlation with determination of accuracy rate of smear preparation result was done in a retrospective study of 306 cases of intracranial tumors. Cytomorphology of few new entities of CNS tumors are described. The cytological features and WHO grading of the tumors were described on smear preparation. The cases with discrepancy in cytological and histological diagnosis were reviewed again and a final possible diagnosis on smear preparation which should have been given is discussed. The clinical details like the age, sex, and site of the tumors were analyzed. The age range of the patients was from 3 years to 63 years with male:female ratio of 1.5:1. Of the total 306 cases, a cytohistological correlation was seen in 93% cases. Twenty-two (7.3%) cases showed discrepancy between the crush preparation diagnosis and final histopathological diagnosis. Majority of the tumors were located in the cerebral hemisphere (56%) and the most frequently diagnosed tumor was astrocytoma, in particular, pilocytic astrocytoma (18.5%) followed by meningioma (11.9%), medulloblastoma (7.3%), anaplastic oligodendroglioma (5%), ependymoma (4.3%), pituitary adenoma (3.3%), schwannoma (3.3%), etc. A few rarer tumors, in central nervous system like differentiating neuroblastoma, pineocytoma, atypical choroid plexus papilloma, piloxmyxoid astrocytoma, rosette forming glioneuronal tumor, etc. are also described, Smear/crush preparation is a very effective, simple, rapid and reliable technique for the diagnosis and WHO grading of central nervous system tumors. Diagnostic accuracy of cytology with final histopathological report is established with accuracy rate of 93%.     

Immunohistochemical expression of SPARC is correlated with recurrence,survival and malignant potential in meningiomas

Meningioma is a common neoplasm that constitutes almost 30% of all primary central nervous system tumors and is associated with inconsistent clinical outcomes. The extracellular matrix proteins play a crucial role in meningioma cell biology and are important in tumor cell invasion and in progression to malignancy. SPARC (secreted protein, acidic and rich in cysteine) (osteonectin) is a matricellular glycoprotein that regulates cell function by interacting with different extracellular matrix proteins. The aim of this study was to evaluate the expression of SPARC with proliferation index, p53 reactivity in WHO grade 1 (benign), grade 2 (atypical) and grade 3 (anaplastic) meningiomas and correlate with clinical features of the patients, including location of the tumor, recurrence of the tumor and survival of patients. We studied 111 meningiomas, 69 being benign, 34 being atypical and eight being anaplastic meningiomas of various histological types. Using immunohistochemical analysis, we evaluated the expression of SPARC, Ki‐67 (MIB‐1) and p53 in meningiomas. Immunohistochemical scores of SPARC were determined as the sum of frequency (0–3) and intensity (0–3) of immunolabeling of the tumor cells. A high immunohistochemical score (4–6) for SPARC was more frequent in atypical and in anaplastic meningiomas than in benign meningiomas (p < 0.01). MIB‐1 proliferation index showed significant association between tumor grades in meningiomas (p < 0.01). At the end of a follow‐up period of 47.53 ± 25.04 months, 30 tumors recurred. A high SPARC expression was significantly associated with tumor recurrence (p = 0.02). The immunoreactivity of p53 protein and MIB‐1 score were significantly higher in recurrent meningiomas than in non‐recurrent meningiomas. The cumulative survival of patients with high SPARC expression was significantly lower than patients with low SPARC expression. The high SPARC expression scores were predominantly identified in meningothelial, fibrous and chordoid meningiomas; low SPARC expression scores were mostly spotted in secretory and psammomatous meningiomas. Evaluating SPARC expression might help assessing recurrence risk and survival estimation in meningiomas.     

A collision tumor of solitary fibrous tumor/hemangiopericytoma and meningioma: A case report with literature review

An intracranial collision tumor is a rare lesion composed of two histologically different neoplasms in the same anatomic location. Even more rare is the collision tumor of a solitary fibrous tumor/hemangiopericytoma (SFT/HPC) and meningioma. The patient was a 46-year-old woman who had a 40 × 35 × 30-mm mass in the vermis of the cerebellum. Histologically, the mass consisted of two different components. One component showed the morphology of meningioma (World Health Organization (WHO) grade I), and the other component exhibited small round cell proliferation with hypercellular density, which was revealed to be SFT/HPC (WHO grade III) based on STAT6 immunohistochemistry. STAT6 showed completely different immunohistochemistry results in these two components (nuclear-negative in meningioma and nuclear-positive in SFT/HPC). Since these two neoplasms are associated with different prognoses, they should be distinguished from each other. When meningioma and an SFT/HPC-like lesion are identified morphologically, it is important to recognize the presence of such a collision tumor composed of meningioma and SFT/HPC, and identify the SFT/HPC component by employing STAT6 immunohistochemistry.     

Multiple meningioma with different grades of malignancy: case report with genetic analysis applying single-nucleotide polymorphism array and classical cytogenetics

Multiple meningiomas with synchronous tumor lesions represent only 1-9% of all meningiomas and usually show a uniform histology. The simultaneous occurrence of different grades of malignancy in these nodules is observed in only one third of multiple meningiomas. We report a case of a sporadic multiple meningioma presenting with different histopathological grades (WHO I and II). The tumor genome of both nodules was analyzed by GTG-banding, spectral karyotyping (SKY), locus-specific FISH, and single nucleotide polymorphism array (SNP-A) karyotyping. GTG-banding and SKY revealed 25 structural and 33 numerical aberrations with a slightly increased aberration frequency in the WHO grade II nodule. We could confirm terminal deletions on chromosomes 1p [ish del(1)(p36)(p58-,pter-) 16.5% WHO grade I and 20.9% WHO grade II], partial deletions on 22q, and/or monosomy 22 (monosomy 22 14% WHO grade I and 34% WHO grade II) as the most frequent aberrations in both meningioma nodules. In the meningioma WHO grade II, in addition, a de novo paracentric inversion within chromosomal band 1p36 was detectable. Furthermore, for meningiomas de novo, dicentric chromosomes 4 could be identified in both tumor nodules. We also detected previously published segmental uniparental disomy regions 1p31.1, 6q14.1, 10q21.1, and 14q23.3 in normal control DNA of the patient and in both tumor nodules. Taken together, we describe a very rare case of multiple meningioma with overlapping but also distinct genetic aberration patterns in two nodules of different WHO grades of malignancy.     

Molecular Classification of Human Diffuse Gliomas by Multidimensional Scaling Analysis of Gene Expression Profiles Parallels Morphology-Based Classification, Correlates with Survival, and Reveals Clinically-Relevant Novel Glioma Subsets

There are several currently employed classification systems for diffuse gliomas that sort tumors based on histological features. Contemporary molecular techniques, however, offer the promise of improved tumor classification and resultant patient stratification for treatment and prognosis. In particular, gene expression profiling has shown exceptional promise for providing an alternative and more objective molecular approach to glioma classification. In this study, we used cDNA array technology to profile the gene expression of 30 primary human glioma tissue samples comprising 4 different glioma subtypes as defined by current World Health Organization (WHO 2000) criteria: glioblastoma (GM, WHO grade IV), anaplastic astrocytoma (AA, WHO grade III), anaplastic oligodendroglioma (AO, WHO grade III), and oligodendroglioma (OL, WHO grade II). Gene expression data alone were used to group the tumors using multidimensional scaling, which is an unsupervised statistical method. Results show that impressive separation of the 4 glioma subtypes can be achieved solely on the basis of molecular data. In addition, a subcluster of 3 glioblastomas was identified as distinct from other GMs and from the oligodendroglial tumors. These 3 patients have shown extended survival compared to other GMs in the study. Survival analysis of the full data set revealed a good correlation with the molecular classification. Results of this proof-of-principle study demonstrate that molecular profiling alone can recapitulate conventional histologic classification and grading with high fidelity. In addition, results show that the molecular approach to tumor classification can generate clinically meaningful patient stratification, and, more importantly, is an efficient class-discovery tool for human gliomas, permitting the identification of previously unrecognized, clinically relevant tumor subsets.     

Clear cell meningioma with anaplastic features: Case report and review of literature

Clear cell meningioma (CCM) is an uncommon variant of meningioma, corresponding to WHO grade II. We present two cases of CCMs with anaplastic features in the intracranial and intraspinal region. The first case is a 65-year-old male who gradually developed changes in behavior over a period of 1 year. The second case is a 35-year-old female who presented with a 7-month history of posterior cervicothoracic pain and dysuria for 1 week. Magnetic resonance imaging revealed an intracranial lesion in the right frontal lobe in the male patient, and an intradural extramedullary lesion at C7 in the female patient. On histological examination, both tumors partly exhibited unusual anaplastic appearances with nuclear pleomorphism, high mitotic activity and necrosis, distinct from classical CCMs. Tumor cells were immunoreactive to epithelial membrane antigen (EMA) and vimentin, with a high MIB-1 index up to 40%. Total excision was performed. The male patient was found to have developed local recurrence and lateral ventricle metastasis 3 months after surgery. A diagnosis of CCM with anaplastic features was made (WHO grade III). Based on its aggressive behavior, we recommend postoperative adjuvant radiotherapy or chemotherapy even if total excision of the tumor has been performed, and MRI scans every 3–6 months during the first period of follow-up.     

Supratentorial Pilocytic Astrocytomas, Astrocytomas, Anaplastic Astrocytomas and Glioblastomas are Characterized by a Differential Expression of S100 Proteins

The levels of expression of the S100A1, S100A2, S100A3, S100A4, S100A5, S100A6 and S100B proteins were immunohistochemically assayed and quantitatively determined in a series of 95 astrocytic tumors including 26 World Health Organization (WHO) grade I (pilocytic astrocytomas), 23 WHO grade II (astrocytomas), 25 WHO grade III (anaplastic astrocytomas) and 21 WHO grade IV (glioblastomas) cases. The level of the immunohistochemical expression of the S100 proteins was quantitatively determined in the solid tumor tissue (tumor mass). In addition twenty blood vessel walls and their corresponding perivascular tumor astrocytes were also immunohistochemically assayed for 10 cases chosen at random from each of the four histopathological groups. The data showed modifications in the level of S100A3 protein expression; these modifications clearly identified the pilocytic astrocytomas from WHO grade II-IV astrocytic tumors as a distinct biological group. Modifications in the level of S100A6 protein expression enabled a clear distinction to be made between low (WHO grade I and II) and high (WHO grade III and IV) grade astrocytic tumors. Very significant modifications occurred in the level of S100A1 protein expression (and, to a lesser extent, in their of the S100A4 and S100B proteins) in relation to the increasing levels of malignancy. While the S100A5 protein was significantly expressed in all the astrocytic tumors (but without any significant modifications in the levels of malignancy), the S100A2 protein was never expressed in these tumors. These data thus indicate that several S100 proteins play major biological roles in human astrocytic tumors.     

Cytopathologic features of orbital intraosseous chordoid meningioma: Report of a case and distinction from other myxoid/mucoid tumors

Chordoid meningioma (CM) is characterized by a striking histologic resemblance to chordoma and propensity for aggressive behavior or recurrence (WHO grade II designation). Orbital intraosseous CM is extremely uncommon and only one case report has been documented. A case is presented here in which squash smears of a left orbital tumor in a 53‐year‐old male revealed small clusters or cord‐like structures of bland tumor cells embedded in a myxoid or mucinous background. Whorl‐like structures were also identified. The tumor cells possessed uniformly round nuclei with a smooth nuclear outline, fine granular chromatin, and small nucleoli. Occasional intranuclear inclusions, coarse collageneous cytoplasmic filaments were observed. Many spindle‐shaped cells with similar nuclear findings were also seen. A cytologic diagnosis of a chordoid meningioma was suggested and histochemical and immunohistochemical studies were conducted on formalin‐fixed, paraffin‐embedded material. Immunohistochemically, the tumor cells showed diffuse and strong membranous and cytoplasmic staining for vimentin, epithelial membrane antigen (EMA) and faintly reactive with S‐100 protein but negative for pan‐neuroendocrine markers (i.e., NSE, chromogranin A, synaptophysin), cytokeratin AE1/AE3, smooth muscle actin, D2‐40, brachyury or class III beta‐tubulin. The proliferative index with MIB‐1 was less than 1%. The diagnosis of orbital intraosseous CM was confirmed based on cytopathologic, histopathological, immunohistochemical results, location of the tumor, and the lack connection to the duramater. We demonstrated here for the first time the cytopathological features of intraosseous CM with emphasis on differential diagnostic considerations. Diagn. Cytopathol. 2010; 38:818–821. © 2010 Wiley‐Liss, Inc.