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2015 Annual Meeting
Specialty Conference
Evening Specialty Conference - Neuropathology
(EC13-15) Evening Specialty Conference - Neuropathology - Fuller - materials -0
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Clinical History

A 38-year-old man presented with left facial numbness. MR imaging revealed a contrast-enhancing dura-based mass of the left middle cranial fossa. Subsequent craniotomy with gross total resection of the mass was performed.

Figure 1. Sagittal T1-weighted MR image with contrast. A highly vascular extra-axial, circumscribed, contrast-enhancing mass is seen in the left middle temporal fossa.
Figure 1. Sagittal T1-weighted MR image with contrast. A highly vascular extra-axial, circumscribed, contrast-enhancing mass is seen in the left middle temporal fossa.
Figure 2. Axial T1-weighted MR image with contrast. A highly vascular extra-axial, circumscribed, contrast-enhancing mass is seen in the left middle temporal fossa.
Figure 2. Axial T1-weighted MR image with contrast. A highly vascular extra-axial, circumscribed, contrast-enhancing mass is seen in the left middle temporal fossa.
Figure 3. Coronal T1-weighted MR image with contrast. A highly vascular extra-axial, circumscribed, contrast-enhancing mass is seen in the left middle temporal fossa.
Figure 3. Coronal T1-weighted MR image with contrast. A highly vascular extra-axial, circumscribed, contrast-enhancing mass is seen in the left middle temporal fossa.
Figure 4. H&E
Figure 4. H&E
Figure 5. H&E.
Figure 5. H&E.
Figure 6. H&E.
Figure 6. H&E.
Figure 7. H&E.
Figure 7. H&E.
Figure 8. H&E.
Figure 8. H&E.
Figure 9. H&E.
Figure 9. H&E.
Figure 10. Phosphohistone-H3.
Figure 10. Phosphohistone-H3.
Figure 11. Phophohistone-H3.
Figure 11. Phophohistone-H3.
Figure 12. Phosphohistone-H3.
Figure 12. Phosphohistone-H3.
Figure 13. Ki-67 antigen (MIB1).
Figure 13. Ki-67 antigen (MIB1).
Figure 14. Ki-67 antigen (MIB1).
Figure 14. Ki-67 antigen (MIB1).
Figure 15. Immunostain 1. Low-power.
Figure 15. Immunostain 1. Low-power.
Figure 16. Immunostain 1. High power.
Figure 16. Immunostain 1. High power.
Figure 17. Immunostain 2. Low power.
Figure 17. Immunostain 2. Low power.
Figure 18. Immunostain 2. Higher power.
Figure 18. Immunostain 2. Higher power.
Figure 19. Immunostain 2. Focal area of tumor. Low power
Figure 19. Immunostain 2. Focal area of tumor. Low power
Figure 20. Immunostain 2. Higher power.
Figure 20. Immunostain 2. Higher power.
Figure 21. Pertinent negative immunostains.
Figure 21. Pertinent negative immunostains.
Figure 22. Immunostain 3. Low power.
Figure 22. Immunostain 3. Low power.
Figure 23. Immunostain 3.
Figure 23. Immunostain 3.
Figure 24. Immunostain 3.
Figure 24. Immunostain 3.

Historical Perspective. “Hemangiopericytoma” is a term fraught with a long and colorful history. Originally described by Stout and Murray in 1942 as “Hemangiopericytoma: a vascular tumor featuring Zimmermann’s pericytes”, the earliest exclusively intracranial example was reported by Begg and Garret in 1954, setting the stage for healthy dispute and many heated discussions for the next 50 years regarding its validity or lack thereof as a bona fide unique entity sui generis or whether it was more properly subsumed under the rubric of “angioblastic meningioma” (a term itself coined by Bailey, Cushing and Eisenhardt in 1928). The latter viewpoint was espoused and defended by many prominent pathologists, including the late Drs. Dorothy Russell and Lucien Rubinstein, who wrote in the first edition of their legendary textbook under the subheading of angioblastic meningioma:

“In some examples the tumor appears less cellular: the blood spaces are then separated more widely and the stroma cells are collected about the vessels giving a peritheliomatous appearance, a feature which has recently led some observers to postulate the existence of meningeal “haemangiopericytomas”…. There are however, in our view no convincing grounds for separating such an entity from the group under discussion.”

 

And the entity of “Haemangiopericytic” meningioma was included in the first edition of the WHO “blue book” Histological Typing of Central Nervous System Tumours (Zulch, 1979), being defined as “A meningioma that is indistinguishable from the haemangiopericytoma that occurs elsewhere in the body.“  Dr. Rubinstein’s comment on the subject in the last edition of his textbook that he himself wrote (5th ed, 1989), influenced heavily by his experience with tumors that showed morphologic features of both hemangiopericytoma and meningioma in the same tumor specimen, was “In summary, the retention of the concept of angioblastic meningioma under which the variant of hemangiopericytoma is subsumed seems, at least for the time being, to be both valid and useful.”  By the 1990s, most investigators had accepted the separation of hemangiopericytoma as a distinct tumor from meningioma, based in part on evolving knowledge of the molecular alterations characteristic of meningioma but not found in hemangiopericytoma. Meanwhile, a tempest was brewing in the soft tissue world over the validity of “hemangiopericytoma”, with the view of it as only a pattern, which could be seen in a number of “valid” soft tissue tumors; moreover, the name itself was under siege as an egregious misnomer (the tumor exhibiting fibroblastic, rather than pericytic, features), with the proposal (which has been largely successful, save for the last holdouts, until recently, of the neuropathologists) to ditch the name and combine said tumors with their generally more indolent cousins under the rubric “extrapleural solitary fibrous tumor”.

 

Saved by the Translocation. Then, in 2013, refreshing clarity was brought to this half-century-old debate with the discovery that hemangiopericytomas and solitary fibrous tumors of both the soft tissues and of the central nervous system share a common molecular signature: the defining molecular alteration underlying the solitary fibrous tumor / hemangiopericytoma family spectrum is a NAB2-STAT6 fusion that results from an inversion within chromosome 12 (Chmielecki, 2013; Robinson, 2013; Schweizer, 2013). The resultant chimeric NAB2-STAT6 fusion protein promotes cell proliferation. Furthermore, because the NAB2 partner ensures protein localization in the nucleus, antibodies directed against STAT6, which normally is a cytoplasmic protein, can be used as diagnostic reagents, with the nuclear localization of expression signal indicating presence of the chimeric protein and, hence, the underlying fusion gene.

 

Current Perspective. Extrapleural solitary fibrous tumor comprises a spectrum of molecularly-defined mesenchymal neoplasm of fibroblastic lineage, ranging from indolent (classical SFT) to malignant (classical HPC), with a cohort of the family falling along the middle of the spectrum in terms of morphology, immunophenotype, and proliferative indices. The current WHO Classification of Soft Tissue Tumours (4th edition, 2013), recognizes extrapleural SFT (most showing indolent clinical behavior) and malignant SFT (most showing aggressive clinical behavior), with acknowledgement that intermediate forms exist and behavior cannot be predicted with absolute certainty, even for SFT at the benign end of the spectrum. The most reliable predictor of behavior is elevated mitotic activity, with SFT not typically exceeding 3 mitoses per 10 high power fields and malignant SFT general exhibiting 4 or more mitoses per 10 HPF. The current WHO Classification of Tumours of the Central Nervous System (4th edition, 2007) is outdated  (currently under revision) and describes SFT and HPC as separate entities, with grading of HPC according to the criteria of Mena et al. (1991)  into grade  II and grade III (anaplastic HPC), with the latter showing elevated mitotic activity (at least 5 mitoses per 10 HPF) and/or necrosis, plus at least two of three features, namely hemorrhage, moderate to marked nuclear atypia, and moderate to high cellularity. A more recent proposal for grading CNS SFT/HPC was provided by Bouvier C, et al. (2012), who stratified SFT/HPC into three grades (I, II, III; with the middle grade having two subdivisions, IIa, IIb) based on three features: hypercellularity, necrosis and mitotic count per 10 HPF, as follows:

 

Grade I: hypocellular (abundant collagen bundles present), no necrosis, 4 or fewer mitoses per 10HPF (classical SFT by morphology)

Grade IIa: high cellularity, no necrosis, 5 or fewer mitoses per 10 HPF

Grade IIb: high cellularity, no necrosis, more than 5 mitoses per 10 HPF

Grade III: high cellularity, necrosis, more than 5 mitoses per 10 HPF (classical HPC by morphology)

 

The importance of clinical prognostication is of paramount importance in that malignant solitary fibrous tumor (hemangiopericytoma) has an extremely high recurrence rate on the order of 85-90%, as well as a high rate of distant metastasis (bone, lungs, liver) and associated high mortality rate.

 

Future studies examining prognostic features will undoubtedly require known NAB2-STAT6 status for study entry. In addition, recent data suggest that different NAB2-STAT6 fusion variants hold promise for predicting clinical behavior (Barthelmeß S et al. 2013).

 

 References

Bailey P, Cushing H, Eisenhardt L. Angioblastic meningiomas.  Arch. Pathol. 6:953,1928.

Barthelmeß S et al. Solitary fibrous tumors (SFTs)/hemangiopericytomas (HPCs) with different variants of the NAB2-STAT6 gene fusion are characterized by specific histomorphology and distinct clinicopathological features. Am J Surg Pathol 184:1209-1218, 2014.

Begg CF, Garret R. Hemangiopericytoma occurring in the meninges. A case report. Cancer7:602-606, 1954.

Bouvier C, et al. Solitary fibrous tumors and hemangiopericytomas of the meninges: overlapping pathological features and common prognostic factors suggest the same spectrum of tumors. Brain Pathology 22:511-521, 2012.

Chmielecki J, et al. Whole-exome sequencing identifies a recurrent NAB2-STAT6 fusion in solitary fibrous tumors. Nature Genetics 45:131-132, 2013.

Fletcher CDM, et al. WHO Classification of Tumours of Soft Tissue and Bone. Lyon: IARC, 2013.

Louis DN, et al. WHO Classification of Tumours of the Central Nervous System. Lyon: IARC, 2007.

Mena H, et al. Hemangiopericytoma of the central nervous system: a review of 94 cases. Human Pathology 22:84-91, 1991.

Robinson DR, et al. Identification of recurrent NAB2-STAT6 gene fusions in solitary fibrous tumor by integrative sequencing. Nature Genetics 45:180-187, 2013.

Russell DS, Rubinstein LJ. Pathology of Tumors of the Nervous System. London:Edward Arnold, 1st edition, 1959; 5th edition, 1989.

Schweizer L, et al.  Meningeal hemangiopericytoma and solitary fibrous tumors carry the NAB2-STAT6 fusion and can be diagnosed by nuclear expression of STAT6 protein. Acta Neuropathol 125:651-658, 2013.

Stout AP, Murray MR. Hemangiopericytoma: a vascular tumor featuring Zimmermann's pericytes, Ann. Surg. 116:26, 1942.

Zulch KJ. Histological Typing of Tumours of the Central Nervous System. WHO: Geneva, 1979.