9530/3 - Anaplastic (malignant) meningioma
C70, C71 and C72 - Tumours of the central nervous system


Definition

Anaplastic meningioma is a highly aggressive and often fatal variant that may be encountered in patients either de novo or from the malignant progression of lower grade meningiomas of any subtype. Histologically, it is defined by overt cellular anaplasia and/or excessive mitotic activity, including: 1) ≥ 20 mitoses per 10 HPF and/or 2) overtly malignant sarcoma-, carcinoma-, or melanoma-like cytology 1 . These features may be encountered focally or diffusely and in the latter case, a firm diagnosis of meningioma requires additional supporting evidence, such as:
1) History of prior meningioma at the same site (often better differentiated)
2) Immunohistochemical features of meningioma
- Strong diffuse vimentin positivity
- Patchy EMA expression
3) Ultrastructural features of meningioma
- Imbricating cellular processes
- Intercellular junctions, including desmosomes
4) Genetic features of high-grade meningioma

Spread

As with other forms of meningioma, local spread is more common than metastasis, although both are possible 2 . Most anaplastic meningiomas grow rapidly and are highly invasive into surrouding tissues, including brain. This growth pattern likely accounts for the high recurrence rates encountered with these tumors, even after seemingly gross total resection. Little data has been published on the incidence of metastasis for anaplastic meningiomas using modern grading criteria. Nonetheless, it likely occurs in <10% of cases, with patterns of spread including both CSF dissemination and extracranial metastasis to lung, pleura, bone, liver, lymph nodes (especially cervical), and kidney 3 4 .

Macroscopy

As with other meningiomas, the gross appearance of anaplastic meningiomas is highly variable. Nonetheless, more cellular portions of the tumor tend to be soft and fleshy, often with large zones of necrosis evident on cut surface. These tumors are also commonly large and invasive of surrounding structures, such as bone, soft tissue, and brain.

Note the soft, gelatinous consistency on cut surface, as well as the large yellow zone of necrosis on the right.Note the irregular borders and highly invasive growth pattern on post-contrast T1-weighted MRI.The superior sagittal sinus is occluded with tumor.The inner surface of the skull is moth eaten from extensive bone invasion by the adjacent meningioma.

Histopathology

As described in the definition, anaplastic meningiomas must fulfill at least one of the following two criteria: 1) ≥ 20 mitoses per 10 HPF or 2) overtly malignant sarcoma-, carcinoma-, or melanoma-like cytology 5 . Other common features in anaplastic meningiomas include extensive zones of geographic necrosis, brain invasion, atypical mitotic figures, and Ki-67 labeling indices >20%. Examples with predominantly spindled cytology should not be confused with true meningeal sarcomas and thus, the older term "sarcomatous meningioma" should be avoided. Nevertheless, there are rare anaplastic meningiomas with either compelling carcinoma-like (e.g., malignant glands) or sarcoma-like (e.g., rhabdomyoblastic, myofibroblastic) foci of metaplasia.

Sheet-like growth with large epithelioid cells, abundant cytoplasm, and prominent nucleoli.Eight mitotic figures are seen in this one high-powered field (HPF).Atypical mitotic figure and prominent nucleoli.
Spindled morphology, increased matrix deposition, and poorly differentiated cytology.

Immunoprofile

The immunohistochemical features of anaplastic meningiomas are those of meningiomas in general (see meningioma, NOS section), although the majority are either completely negative for progesterone receptor or show only focal staining. A Ki-67 labeling index >20% provides additional supportive evidence for an anaplastic designation (i.e. WHO grade III). Furthermore, they are more commonly positive for cytokeratin and occasionally display aberrant expression of non-meningothelial markers.

Although not terribly specific, even the most poorly differentiated meningiomas are typically strongly and diffusely positive for vimentin. This can be particularly helpful in the differential diagnosis with metastatic carcinomas, where most of the latter are negative or only focally positive.EMA positivity is typically patchy in meningiomas of all grades. Unfortunately, about 10-20% are negative, so that lack of EMA staining does not entirely exclude the diagnosis.Strong positivity for CK7 (and other cytokeratins) in this anaplastic meningioma represented a diagnostic pitfall with metastatic carcinoma. However, other morphologic, immunohistochemical, and genetic features were characteristic of meningothelial origin.
Rare nuclei are positive for PR.

Origin

As with other meningiomas, the cell of origin is currently presumed to be the arachnoidal cap cell.

Grading

Anaplastic meningiomas are considered WHO grade III by definition 6 .

Genetic profile

The genetic profile of meningiomas is covered in greater detail in the meningioma, NOS section and in published reviews 7 . In addition to the common alterations seen in benign and atypical meningiomas, the anaplastic meningiomas commonly delete the 9p21 region, which includes CDKN2A, CDKN2B, and p14ARF 8 9 . The roughly two-thirds of anaplastic tumors with 9p21 are associated with a highly aggressive biology and short survival times. In contrast, those lacking these deletions often do surprisingly well, with clinical behavior often overlapping with that of the atypical meningiomas. Other alterations that are seen mostly in the anaplastic meningiomas include NDRG2 gene inactivation by deletion and promoter region methylation 10 and involvement by a chromosome 17q23 amplicon 11 12 .

Most tumor nuclei display 2 green centromere 9 signals, but only 1 red 9p21 (p16 or CDKN2A) signal.

Prognosis

In contrast to atypical meningiomas where the main risk is for recurrence, patients with anaplastic meningiomas are also at high risk of death from disease. The average survival in such cases is under 2 years 13 , although the clinical behavior is nonetheless, quite variable in this group. In addition to routine histologic grading, predictive factors include extent of surgical resection, proliferative indices, and genetic variables, such as chromosome 9p21 status (see genetic profile section).


1Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (Eds.), WHO Classification of Tumours of the Central Nervous System., 4th Edition, International Agency for Research on Cancer, Lyon 2007
2Perry A, Scheithauer BW, Stafford SL, Lohse CM, Wollan PC (1999) "Malignancy" in meningiomas: a clinicopathologic study of 116 patients, with grading implications. Cancer 85: 2046-56
3Adlakha A, Rao K, Adlakha H, Perry A, Crotty TB, Scheithauer BW, Ryu JH (1999) Meningioma metastatic to the lung. Mayo Clin Proc 74: 1129-33
4Yang SY, Park CK, Park SH, Kim DG, Chung YS, Jung HW (2008) Atypical and anaplastic meningiomas: prognostic implications of clinicopathological features. J Neurol Neurosurg Psychiatry 79: 574-80
5Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (Eds.), WHO Classification of Tumours of the Central Nervous System., 4th Edition, International Agency for Research on Cancer, Lyon 2007
6Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (Eds.), WHO Classification of Tumours of the Central Nervous System., 4th Edition, International Agency for Research on Cancer, Lyon 2007
7Riemenschneider MJ, Perry A, Reifenberger G (2006) Histological classification and molecular genetics of meningiomas. Lancet Neurol 5: 1045-54
8Boström J, Meyer-Puttlitz B, Wolter M, Blaschke B, Weber RG, Lichter P, Ichimura K, Collins VP, Reifenberger G (2001) Alterations of the tumor suppressor genes CDKN2A (p16(INK4a)), p14(ARF), CDKN2B (p15(INK4b)), and CDKN2C (p18(INK4c)) in atypical and anaplastic meningiomas. Am J Pathol 159: 661-9
9Perry A, Banerjee R, Lohse CM, Kleinschmidt-DeMasters BK, Scheithauer BW (2002) A role for chromosome 9p21 deletions in the malignant progression of meningiomas and the prognosis of anaplastic meningiomas. Brain Pathol 12: 183-90
10Lusis EA, Watson MA, Chicoine MR, Lyman M, Roerig P, Reifenberger G, Gutmann DH, Perry A (2005) Integrative genomic analysis identifies NDRG2 as a candidate tumor suppressor gene frequently inactivated in clinically aggressive meningioma. Cancer Res 65: 7121-6
11Cai DX, James CD, Scheithauer BW, Couch FJ, Perry A (2001) PS6K amplification characterizes a small subset of anaplastic meningiomas. Am J Clin Pathol 115: 213-8
12Büschges R, Ichimura K, Weber RG, Reifenberger G, Collins VP (2002) Allelic gain and amplification on the long arm of chromosome 17 in anaplastic meningiomas. Brain Pathol 12: 145-53
13Perry A, Scheithauer BW, Stafford SL, Lohse CM, Wollan PC (1999) "Malignancy" in meningiomas: a clinicopathologic study of 116 patients, with grading implications. Cancer 85: 2046-56