Mini-symposium

CURRENT DIAGNOSTIC PATHOLOGY

Haemangiopericytoma- A dying breed? -Reappraisal of an 'entity' and its variants: a hypothesis

C. D. M. Fletcher

H a e m a n g i o p e r i c y t o m a has been genera l ly accep ted for ha l f a cen tu ry as a dist inctive histological

type of soft tissue t u m o u r . However , it has become a p p a r e n t tha t m a n y o t h e r types of t u m o u r m a y

closely mimic haemang iope r i cy toma , and tha t h a e m a n g i o p e r i c y t o m a itself shows, at best, only a

l imited morpholog ica l re la t ionship to n o rma l per icytes . T h e r e f o r e this ent i re diagnost ic

concep t has become con t rovers ia l and r equ i r e s reassessment : in p a r t i c u l a r t he re are no posi t ive

c r i t e r ia by which to m a k e this diagnosis, t h e r e b y br ing ing into doub t its ve ry existence.

With regard to the distinctive clinical and topographic subsets of haemangiopericytoma, there is good evidence that the infant i le (or congeni ta l ) type represen t s the same ent i ty as infant i le

myof ib romatos i s ; the s inonasal type, which is a lmost a lways benign, a p p e a r s to show evidence of

myoid d i f ferent ia t ion in some cases and m a y be mo re closely re la ted to g lomus t u m o u r ; the

meningea l type, which was f o r m e r l y misclassified as angioblas t ic men ing ioma , r ema ins as diff icult to

ca tegor ise as the mino r i t y of soft tissue h a e m a n g i o p e r i c y t o m a s which p resen t in adu l thood and which cannot easily be allocated to alternative diagnostic categories with more reproducible features.

Haemangiopericytoma was introduced as a diagnostic concept by Stout and Murray in 1942, ~ who asserted that this type of tumour was composed of the cells described as pericytes by Zimmerman, 2 which they believed to be modified smooth muscle ceils. Among Stout's cases (9 in the first study and a further 25 published in 1949) 3 there was notable clinical and pathological heterogene- ity. The marked variation in clinical behaviour within this group of lesions was noted repeatedly over the succeeding 30 years 4-6 and later authors emphasised that the histological appearances could not be used to predict prognosis reliably.

Although the majority of cases presented in adulthood, Kauffman and Stout 7 in-1960 described a significant subset of similar lesions in children and noted that those

C. D. M. Fletcher, MD MRCPath, Soft Tissue Tumour Unit, Department of tlistopathology, St Thomas's ttospital (UMDS), London, UK

arising in infants less than 3 years old most often were benign. In older children, clinicopathological variability was stressed once again. Subsequent authors have gone on to establish the concept of congenital or infantile haemangiopericytoma 8-1° as a distinct subgroup associ- ated with a benign clinical course, despite worrying histological features such as vascular invasion, necrosis and a high mitotic count.

With regard to adult cases, strenuous attempts were made in the 1970s to introduce histological criteria which would aid the prediction of clinical behaviour with a degree of success, 8,11.12 albeit it was necessary to retain a borderline category. Experience over the years has shown that the single most valuable indicator of malignancy in adult haemangiopericytoma is the pres- ence of 4 or more mitoses per 10 high power fields 8,t3 (using a ×40 objective). The recent application of more objective criteria (such as DNA flow cytometry and PCNA staining) has not been able to improve upon

Current Dtagnostic Pathology (994) 1, 19-23 © 1994 Longman Group Ltd 19

20 CURRENT DIAGNOSTICPATtlOLOGY

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Fig. 1--Monophasic synovial sarcoma showing a striking haemangiopericytoma-like vascular pattern. This tumour was EMA positive and showed typical ultrastructural features of synovial sacroma, including microvilli.

Fig. 2--An example of the typical pericellular reticulin pattern seen in haemangiopericytoma, which was formerly regarded as a valuable diagnostic adjunct. In fact this slide comes from a case of deep benign FH]

carefully applied morphological grading) 3 Overall it appears that no more than 25% of adult haemangio- pericytomas behave in a malignant fashion.

It has also become apparent that lesions with the ap- pearance of haemangiopericytoma may arise at a wide variety of sites, including the breast, ~4 lung, ~5 orbit ~6 and, more notably, the, sinonasal region and meninges. Sinonasal lesions have been a source of interest because of their usually benign clinical course, 17A8 irrespective of histology. Meningeal lesions have been the subject of considerable nosological discussion but essentially have replaced (and thereby abolished) the concept of angioblastic meningioma. 19-2~

In addition to these variants or subsets of haem- angiopericytoma, it is recognised widely that a very large number of other tumour types may closely mimic haemangiopericytoma, in that they may show prominent thin-walled branching (staghorn) vessels around which small or relatively undifferentiated tumour cells are arranged. Almost any type of sarcoma may show this pattern, 22 but the lesions in which it is an especially common or characteristic feature are synovial sarcoma (Fig. 1), mesenchymal chondrosarcoma, infantile fibro- sarcoma, solitary fibrous tumour, deep benign fibrous histiocytoma and infantile myofibromatosis. Therefore it has been important to try and define histological criteria by which these lesions may be separated from haemangiopericytoma. While, for example, the identifi- cation of glands or immunopositivity for epithelial anti- gens in synovial sarcoma and of islands of cartilage in mesenchymal chondrosarcoma aids this distinction, it has become evident that there are no positive means by which haemangiopericytoma may be recognised consist- ently. In other words it has become a 'difficult' diagnosis made only by exclusion - rarely, if ever, a secure basis for an entity, as witness the dissolution of so-called pleomorphic MFHfl 3

Normal pericytes, which vary somewhat in nature according to their location in the vascular tree, 24 are characterised at the ultrastructural level by the presence of elongated cell processes, covered usually by a con- tinuous external lamina, and within the cytoplasm by

variable numbers of microfilaments with focal densi- ties. These myoid features are reflected in the general immunopositivity of these cells for alpha-smooth muscle actin (SMA). 25 If one compares the features of adult haemangiopericytoma at most locations with those of normal pericytes, one finds, by contrast, that more than 50% of cases, even in the best defined ultrastructural series, 24 lack myoid features at the EM level. The situa- tion is even worse at the immunohistochemical level, since most, if not all, haemangiopericytomas in adulthood are entirely negative for actin, t9.20,24.26,27 which begs the question as to how many of these lesions show any degree of true pericytic differentiation. Furthermore, given that these ultrastructural features overlap significantly with those of myofibroblastic cells, it is unclear by what means one can reliably distinguish some cases of haemangiopericytoma from lesions such as infantile fibrosarcoma, solitary fibrous tumour and benign fibrous histiocytoma (FH), in all of which at least a limited myofibroblastic component is common. In this regard, even the presence of a consistently periceilular reticulin staining pattern is not reliably discriminatory (Fig. 2). The simple truth is that the diagnosis of haem- angiopericytoma in adulthood is made less often: for example, the presence of a storiform pattern, along with scattered giant or foamy cells, allows logical

,.recategorisation as deep FH, 2s while CD34 positivity in this context facilitates recognition of solitary fibrous tumours (Fletcher - unpublished observation).

Returning to haemangiopericytomas in early childhood, several features of these cases question the validity of their present classification. Firstly, from the clinical point of view, some patients have been said to develop multiple lesions 7 and, in some cases, spontaneous regres- sion has occurred. I° Secondly, at the light microscopic level, very many cases at least focally contain fascicles or nodules or eosinophilic (myoid) spindle cells, typical of myofibroblasts (Fig. 3). Thirdly, using immunohisto- chemistry, most of these infantile cases show at least focal actin positivity (Fig. 4). 29 Taking all these features together, it is clear that infantile haemangiopericytoma is, in fact, indistinguishable from infantile myofibro-

HAEMANGIOPERICYTOMA -A DYING BREED? 21

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Fig. 3 - - In the majori ty of otherwise typical cases of infantile haemangioper icytoma (A), one can find at least small foci with a more spindled, myoid appearance (B).

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Fig. 4 - - S M A posit iv i ty can be demonstrated in almost all cases of infantile haemangioper icytoma, underl ining their close relat ionship with infantile myof ibromatosis. (ABC method).

matosis and that the cases formerly classified as haem- angiopericytoma simply represent the more poorly differentiated end of a continuous spectrum. This recategorisation of infantile cases also accounts for the presence of necrosis and vascular invasion which, while theoretically worrying in the context of haem-

angiopericytoma, are commonplace in infantile myofibromatosis. 2%3~ It has been claimed in the litera- ture that these two entities may be separated by the distribution, or zonation, of the small cell and myoid areas, but personal experience suggests that this is not in the least reproducible or reliable.

What about the sinonasal group in adults which are distinguished by their generally benign clinical course? These lesions, which are most common in middle to late adulthood, consist of rather more spindle-shaped cells with more evident, somewhat eosinophilic, cytoplasm than most examples from their counterpart at other loca- tions (Fig. 5). Possibly a third of them are actin positive and, ultrastructurally, most cases examined show con- vincing myoid/pericytic differentiation, m.32 It is clear, therefore, that these lesions come closer to justifying their name than do their soft tissue counterparts, albeit this may simply reflect the fact that they appear better differentiated, thereby perhaps being more closely related to glomus tumours or myofibroblastic lesions. Regarding the meningeal subgroup, 19.2° which were formerly mistaken for meningiomas, their morphology, immunophenotype and ultrastructure most closely resembles that of the remaining few non-nasal

A B

Fig. 5- -Haemangioper icy tomas in the sinonasal region tend to have more eosinophil ic cytoplasm (A) and usually show more myoid cytological features (B) than haemangioper icytomas at other sites.

22 CURRENT DIAGNOSTIC PATHOLOGY

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Fig. 6--Meningeal haemangiopericytoma, formerly known Fig. 7--Unpublished data suggests that there is a as angioblastic meningioma, is morphologically distinctive, as yet undescribed group of indistinguishable from adult-type haemangiopericytoma in haemangiopericytoma-like lesions characterised by soft tissue, variation in cellularity and at least focal (sometimes

extensive) adipocytic differentiation.

haemangiopericytomas in adults (Fig. 6) (described above) which cannot be eased logically (or pushed!) into any other diagnostic category.

What can we conclude from these somewhat confus- ing data? Firstly, the types of lesion currently grouped under the heading haemangiopericytoma, in all probabil- ity, are not all truly related to one another, other than by the similarity of their vascular pattern. Secondly, only those tumours located in the sinonasal region show reasonably consistent features of convincing pericytic differentiation. Thirdly, the entity of infantile haem- angiopericytoma probably does not exist and such cases are better classified as infantile myofibromatosis. Fourthly, haemangiopericytomas in adulthood, as pres- ently diagnosed, represent a very heterogeneous group which have in common only their delicate branching vasculature: with care and the strict application of diagnostic criteria, this appellation need not often be used. Most cases show little or no evidence of pericytic differentiation and, on the basis of future findings, nomenclature may perhaps need to be revised.

Finally, what is the nature of those cases in soft tissue and the meninges which do not belong in other diagnos- tic categories and which do not show good evidence of pericytic differentiation? At present, their recognition and continued existence as an entity is endangered by the lack of any positive diagnostic criteria. Primitive perivascular mesenchymal cells, which underlie the development of fat lobules in embryogenesis, have been recognised for many years. 33 In some ways it would be tempting to invoke these as the progenitor cells in the residuum of haemangiopericytomas, especially since there exists a distinctive, as yet undocumented, subgroup of haemangiopericytoma-like lesions with a significant adipocytic component (Fig. 7) (Fletcher, Krausz & Nascimento - in.preparation). These fat-forming peri- vascular cells appear to differ considerably, at the ultrastructural level, from fetal pericytes in a suben- dothelial location, 24 since the latter are generally far less specialised. However, the prominent RER and Golgi apparatus seen in fat-forming mesenchymal cells are

absent in the cells of haemangiopericytoma, so as yet there is no convincing morphological similarity to support such a relationship.

Perhaps we are being deluded by thinking that these tumours arise from any type of perivascular cell. After all, we recognise that tumours of other quite different specialised types may produce an identi'cal pericytoma- like pattem. Other than the well-delineated glomus tu- mours, perhaps pericytic tumours do not exist in reality. Whether or not the recent cytogenetic data suggesting the consistent presence of abnormalities on the long-arm of chromosome 12 in these lesions 34 will shed light on their differentiation pattern remains to be seen, but this seems unlikely in view of the frequent involvement of the 12q13-15 region in a wide range of mesenchymal tumours.

R e f e r e n c e s

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33.