Case 3 -

Hemangiopericytoma (HPC) Tarik Tihan The University of California San Francisco, CA

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Discussion: The significance of this case is probably not in the difficulty it poses (or does not pose) in diagnosis, but in understanding what the diagnosis implies. There is increasing diversity in opinion on the definition of hemangiopericytoma (HPC), and the implications of that diagnosis in soft tissues versus the CNS. This discussion begins with a brief review of current terminology and historical perspective. Case 3 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 3 - Figure 1 - Pre-operative axial MR images (T2-weighted, FAIR and T1-weighted post-gadolinium sequences) showing a 5 x 5 x 3 cm right parietal parasagittal mass accompanied by significant vasogenic edema and right-to-left midline shift. Case 3 - Figure 2 - Pre-operative coronal MR images (FAIR and T1-weighted post-gadolinium sequences) showing the mass. Case 3 - Figure 3 - Nerve sheath tumor (T7-8). The morphologic features are characteristic of hemangiopericytoma. (low-power, H&E) Case 3 - Figure 4 - Nerve sheath tumor (T7-8). The morphologic features are characteristic of hemangiopericytoma. (high-power, H&E) Case 3 - Figure 5 - Intracranial tumor. Hemangiopericytoma. (low-power, H&E) Case 3 - Figure 6 - Intracranial tumor. Hemangiopericytoma. (high-power, H&E) Case 3 - Figure 7 - Intracranial tumor. Hemangiopericytoma. The tumor is negative for S-100 protein. (S-100 immunostain) Case 3 - Figure 8 - Intracranial tumor. Hemangiopericytoma. Tumor cells exhibit positivity for neuron-specific enolase (NSE immunostain). Case 3 - Figure 9 - Intracranial tumor. Hemangiopericytoma. Strong positivity for CD 34 is seen in endothelium, with patchy focal reactivity in the tumor cells. (CD34 immunostain) Case 3 - Figure 10 - Intracranial tumor. Hemangiopericytoma. Tumor cells are positive for Bcl-2. (Bcl-2 immunostain) Case 3 - Figure 11 - Intracranial tumor. Hemangiopericytoma. Strong positivity for Collagen type IV is seen. (Collagen type IV immunostain) The current WHO Classification of Tumours of Soft Tissue and Bone discusses the two neoplastic entities Extrapleural Solitary Fibrous Tumor and HPC in the same chapter and gives the following definition for HPC [1]: "The residual group of lesions (!), previously combined under the term hemangiopericytoma, which closely resemble cellular areas of solitary fibrous tumor (SFT) and which appear fibroblastic in type. It has a range of clinical behavior and is closely related to, if not synonymous with, SFT." Whereas, the new WHO Classification of Tumours of the Nervous System identifies HPC as a distinct neoplasm, gives it a chapter of its own outside the mesenchymal, non-meningothelial tumor group, and proposes the following definition for HPC: "A highly cellular and vascularized mesenchymal tumour, exhibiting a characteristic monotonous low-power appearance and a well-developed, variably thick-walled, branching "staghorn" vasculature; almost always attached to the dura and having a high tendency to recur and to metastasize outside the CNS." In this upcoming edition of the WHO classification of tumors of the CNS, there seems to be no attempt to provide a unifying concept for HPC and SFT as is seen in the WHO classification on soft tissues published in 2002 [2]. Historical Perspective: Hemangiopericytoma (HPC), was described by Stout and Murray 1942 [3], in a study of nine tumors, which they believed to originate from the "pericyte" described earlier by Zimmermann [4]. The pericyte, described by Zimmermann was a cell that lined the capillaries at the point of their transition from arterioles. Zimmermann contended that the pericyte resembled smooth muscle cells and a transition between the two could be observed [4]. The original report by Stout & Murray acknowledged the variations in cell size and shape, in the amount of connective tissue, etc. Thus, most features were not defining of an entity except for the so-called "stag-horn" shaped, branching and elaborate vascular infrastructure. In time, the presence of the so-called "HPC-like vessels has increasingly become less typical of hemangiopericytomas, and are now recognized in an array of soft tissue neoplasms. According to a recent review, up to 15% of all soft tissue neoplasms show HPC-like vascular features [5]. Over the last decade, more and more tumors within the HPC category have been redefined as other entities [5, 6]. Stout published a series of 25 HPCs a few years after his initial manuscript with Murray that also included one tumor arising in the meninges [7]. This report has introduced the entity to the neuropathology literature. Subsequently, tumors that were originally recognized as angioblastic meningioma were reclassified as meningeal hemangiopericytomas, and the justification was documented in many studies [8]. To date, the largest published series on meningeal HPCs is that of Mena et al. (from the soon-to-be-dissolved AFIP Neuropathology Division) [9]. This study segregated HPCs into "differentiated" and "anaplastic" groups. Anaplastic HPC was characterized by the presence of necrosis and/or greater than 5 mitoses per 10 HPF (400x microscopic fields), and at least two of the following microscopic features: hemorrhage, moderate-to-high nuclear atypia, and moderate-to-high cellularity. For those patients known to be dead, median survival time was 144 months for differentiated HPC and 62 months for anaplastic HPC. Regardless of grade, the authors reported 60.6% recurrence during the follow-up period, and a 23.4% metastasis rate. Bone, liver, lung, and abdominal cavity were the most common sites of extracranial metastasis. The authors also suggested that adjuvant therapy increased patient survival time. Many subsequent studies have utilized the grading criteria proposed by Mena et al. and have reported similar findings. A more recent study of 38 patients by Ecker et al. used the same histological criteria suggested by Mena et al. [10] The results showed a 63% rate of progression on follow-up images. The authors did not report the length of the follow-up period, but were able to demonstrate extraneural metastases in 29% of patients. They also concluded that high-grade tumors recurred 6.7 years earlier than low-grade HPCs. Many studies have also emphasized the importance of complete resection in terms of prolonging progression-free and overall survival [11, 12]. Some studies contend that radiotherapy is "helpful" in the management of hemangiopericytoma; however, many studies report limited or no impact of radiation on overall survival. Pathological Features: Pathological features of HPCs in soft tissues and in the CNS seem to be quite similar. The reports on histological and immunohistochemical features of HPCs in the CNS focus primarily on distinguishing these neoplasms from meningioma, and, more recently, SFT. Microscopically, most tumors resemble each other with high cellularity and numerous blood vessels with the classical "stag-horn" or delicate, slit-like, branching appearance. The cytoplasm is often sparse with a variable degree of nuclear hyperchromasia. The so-called "jumbled-up" pattern implies no specific architecture but gives an impression of tumor cells organizing in haphazard, loose clusters. Epithelioid features, whorls, and psammomatous calcifications, which are typical of meningioma, are distinctly absent. Many tumors harbor areas of paucicellularity, giving the tumor a vague biphasic appearance. One of the most striking features of tumors classified as HPC is the presence of an abundant and elaborate reticulin network that usually appeares as delicate filaments wrapping around individual or small groups of cells. This feature can be demonstrated by a special stain for reticulin as well as by immunohistochemical staining for Collagen type IV. The immunohistochemical profile of HPC can partly overlap that of meningioma and heavily overlap that of SFT. Typically, tumors recognized as HPC show negative staining with antibodies against EMA, S-100 protein and GFAP, which is useful is excluding meningioma as well as schwannoma [13]. Even though rare cells in HPC may show EMA positivity, this is neither strong nor diffuse. Staining is often strong and diffuse for antibodies against vimentin, Bcl-2, CD99, and Factor XIIIa. While the latter three may be useful in distinguishing HPC from meningioma, they cannot segregate HPC from SFT. Other stains that may show focal positivity in some HPCs include cytokeratin cocktail, desmin and Leu-7. Staining for CD34 is markedly variable, although most HPCs demonstrate some positive-staining tumor cells in addition to staining of the elaborate vascular network. Other tumors, on the other hand, may demonstrate diffuse strong staining in almost all of the tumor cells. In such cases, a diagnosis of SFT is favored by most investigators, since the operational definition of SFT involves diffuse strong staining by this antibody. The proliferation index as determined by MIB-1 antibody (Ki-67 antigen) has been studied for prognostic value, but does not provide added information because of the considerable overlap between low- and high-grade tumors [14]. Ultrastructurally, basal lamina-like material, cytoplasmic processes, cytoplasmic filaments, and poorly formed intercellular junctions are the most frequently noted features of tumor cells in HPC, whether in the CNS or soft tissues [15] Distinguishing HPC from SFT, and the validity of such a distinction, warrants additional consideration. After the establishment of existence of the SFT in the CNS, the challenge of segregating these two entities became more pronounced [16]. While CD34 staining was the main staple for diagnosis of SFT, the extensive reticulin network highlighted by reticulin stains became the critical feature for HPC. Earlier series of SFTs in the CNS also presented evidence that tumors considered in this category had a much lower tendency to recur and disseminate compared to typical HPC [17]. Additional studies made the same observation with the caveat that the overall experience was quite limited with "malignancy" in SFT [13]. This suggestion is confirmed by case reports highlighting aggressive behavior and metastases observed in tumors that were classified as SFT [18]. Thus, more data is needed to document whether SFTs with malignant phenotype can be clearly defined, reliably distinguished from HPC, and demonstrated to be as aggressive as HPC. Until such data are available, the current consensus favors a more indolent behavior for CNS tumors that are considered to be in the SFT category. On the other hand, the overwhelming majority of studies focusing on HPC in the CNS consistently report a tumor that has a very high rate of recurrence, even after decades, and possibly the highest rate of extracranial metastases among all primary intracranial neoplasms. This biological behavior is observed in both "differentiated" and "anaplastic" examples. The limited experience with SFTs in the CNS does not appear to indicate a similar grave outcome, at least not up to the present time. It may be quite plausible to consider the suggestion of some soft tissue pathology experts who consider both entities to fall along the same spectrum, with SFT representing the benign or low-grade end, and anaplastic-type HPC representing the malignant or high-grade end [5]. Evidence of morphologic "transformation" of tumors with classical HPC features into tumors with classical SFT features upon recurrence [17] or treatment is an additional argument for considering these tumors within the same "family of neoplasms". One unique feature of the case presented in this conference is the spread of a spinal cord primary neoplasm to the supratentorial space. Most tumors with HPC morphology in the CNS tend to occur intracranially, and may spread to the spinal cord or to extracranial sites. Extension of a primary spinal cord neoplasm to the supratentorial space is distinctly unusual, and raises the possibility that the spread may have occurred via CSF dissemination, although a hematogenous spread is also possible. References Guillou L, Fletcher JA, Fletcher CDM, Mandahl N. Extrapleural solitary fibrous tumor and haemangiopericytoma. In: Fletcher CDM, Unni KK, Mertens F, eds. Pathology and Genetics of Tumours of Soft Tissue and Bone. 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