Giant Cell Fibroblastoma: An Entity or a Reactive Phenomenon?

PATHOLOGY

RESEARCH AND PRAGICE

© Urban & Fischer Verlag http://www.urbanfischer.de/journalslprp

Giant Cell Fibroblastoma: An Entity or a Reactive Phenomenon? Vasso Karabela-Bouropoulou', Georgia tiapi-Avqeri-, Helen Mahera'. V. Maqiassis-. D. Anaqnostopoulos-, Antonia Bourlr', Helen Kokka? and Sotiria Savva? 'Department of Pathology, 2Department of Internal Medicine and 3Neurosurgery Unit of Regional State General Hospital KAT, "Department of Pathology, "Ag. Anargyri" Oncological Hospital, and 'Department of Pathology, "Amalia Flemming," General Hospital, Attiki, Greece

Summary The histological and immunohistochemical features of four tumors displaying the characteristic pattern of Giant Cell Fibroblastoma (GCF) are presented. Three of them were found in association with classical and/or myxoid dermatofibrosarcoma protuberans, while the fourth tumor was a retroperitoneal malignant hemangiopericytoma where foci with features of GCF were found. Typical sinusoidal spaces and the bizarre mononuclear and multinucleated cells in close association to blood vessels presenting a wide spectrum of lesions of their walls are also described. These last changes led us to believe that GCF-like lesions might not always characterize an entity but could often represent a host reaction of the connective tissue to locally aggressive or malignant tumors. Key words: Soft tissue tumor - Dermatofibrosarcoma protuberans - Host reaction - Vascular lesions

Introduction Giant Cell Fibroblastoma (GCF) represents one of the few recently recognised entities in soft tissue tumour pathology. Its special interest is probably due to its usual misinterpretation as a sarcoma [26J as well as its relationship to other aggressive lesions [2,3,6, 7, 9, 23, 24, 27, 30J and its obscure nature [13, 27J. Although most of the 52 already published cases refer to Pathol. Res. Pract. 195: 413-420 (1999)

infants and children, occasional cases have also been described in adolescents and adults [1-3, 5-9, 15, 23, 24, 27,30J. Some authors suggest this tumor to be related to dermatofibrosarcoma protuberans (DFSP), considered to represent its juvenile form [2, 3, 7,23, 30J, while others believe that this entity is related to locally recurring fibroblastic proliferations in youth and childhood [6, 9J. Shmookler et al. who recognised the entity in 1982 and reported a larger series of such lesions in 1989 [26J, have also observed giant cell fibroblastoma like areas in the tumor-host interface of several classical adult DFSP. In view of the paucity of reports as well as the obscure nature of the lesion, we present four tumors with features of GCF, all of which have developed in adults. The results of our study on the histology and immunohistochemistry of the lesional tissue are reported, together with some suggestions concerning the possible nature of the lesion.

Material and Methods All four cases were encountered by the authors as routine surgical specimens or in consultation between 1990-1996. The surgical specimens were thoroughly sampled, fixed in buffered formalin and embedded in paraplast by the usual procedure.

Address for correspondence: Assoc. Prof. Vasso KarabelaBouropoulou, 22 Artemidos str., Ag. Stefanos, GR - 145 65 Attiki, Greece 0344-0338/99/195/6-413 $12.00/0

414 . V. Karabela-Bouropoulou et al. The histological study was based on H&E stained sections, while for histochemistry and immunohistochemistry 4 urn serial sections from representative blocks were cut and mounted on poly-l-lysine coated slides. Histochemical staining methods comprised Aldan Blue (pH 2.5) - PAS with and without diastase pretreatment, Gomori's reticulin stain, van Gieson stain and Toluidine blue stain. Immunohistochemistry was performed using monoclonal and polyclonal antibodies (Table 2). The immunoreactions were developed using Avidin-Streptavidin system-PAP and APAAP (Shandon-Lipsaw - U.S.A.). Pretreatment was administered with trypsin 0.01 % at 37°C for 18 minutes prior to the application of the monoclonal detecting CKI9, AEl/AE3, CD31 and CD68.

Results

striking feature was the presence of sinusoidal spaces either large and cystic with intracavity tufting, or small, compressed, and slit-like, either empty or partly filled with light blue amorphous material. A variable number of large, bizarre, multinucleated cells, many of them with angulated outline were found around these spaces or seemed to line them (Fig. 2a-d).The stroma around the spaces showed extensive myxoid changes and/or was partially collagenized. Many blood vessels in the tumor-host interface presented perivascular lymphocytic aggregates (Fig. 3a), while in others a moderate to marked subendothelial thickening due either to the deposition of myxoid substances or to hyalinization of the wall was observed (Fig. 3b). Finally a concentric fibroblastic proliferation resulted in a marked narrowing of the lumens of some vessels (Fig. 3c).

Clinical findings

Histochemical findings

All clinicopathologic data referring to the patients of our study appear in Table 1.

The stroma contained abundant glycosaminoglycans which stained light to moderate blue with AB (pH 2.5) PAS and blue with AB (pH 1.0) - AY (pH 2.5) staining reactions, pointing to the participation of sulphated glycosaminoglycans. The myxoid material content of the lumens of the sinusoidal spaces stained blue and green correspondingly, indicating the participation of hyaluronic acid. The granules of the mast cells stained deep blue with Alcian Blue and metachromatic ally with toluidine blue (Fig. 3d).

Pathological findings

All tumors were circumscribed but not encapsulated. In three of them the GCF pattern was observed in association with classical and/or myxoid DFSP, while in the fourth, areas with features similar to GCF were found in a malignant hemangiopericytoma (Fig. la, b). In case No.1 the GCF-like areas were noticed in the specimens of the third and the fourth recurrence, while in the other cases GCF-like lesions were present from the beginning. These lesions were observed either at the periphery of the neoplastic tissue, or in the fibrovascular septa separating the neoplastic nodules (Fig. Ic, d). The most

Immunohistochemical findings

The bizarre cells reacted strongly positive with vimentin and CD34. Some of them also displayed SMA positive reaction while the immunoreactions with CD3l

Table 1. Clinicopathological data of the presented cases Age

Sex

Location Size

25

F

groin

3.5 cm

2

37

M

groin

3

43

F

thigh

4

72

M

retroperi- 15xl3x7 em malignant toneum hemangiopericytoma with GCF-like areas

Case

Diagnosis

Therapy

Recurrence

Follow-up

initial = neurofibroma eXCISiOn revised = DFSP

Ist= DFSP 2nd=DFSP 3rd = with GCF 4th = with GCF

free of disease

4.0cm

initial = MFH revised = DFSP withGCF

excision

Ist= DFSP withGCF

free of disease

3.0cm

initial = sarcoma Revised = DFSP withGCF

wide excision

no recurrences

free of disease

excision

l st = high grade sarcoma

died with disseminated disease

Giant Cell Fibroblastoma . 415

a

l'

Fig. 1. Histological findings in H&E stained sections. a and b) GCF-like features in an otherwise malignant hemangiopericytoma. 100x. c) GCF-like pattern in the fibrovascular septa separating the neoplastic lobules of a DFSP, 20x. d) Higher magnification of the framed area, 100x.

and all other markers in Table 2 were negative. Vimentin and CD34 positivity was also expressed by the tumor cells of the DFSP nodules as well as by the tumor cells of the malignant hemangiopericytoma.

Discussion Giant cell fibroblastoma was first recognized by Shmookler, Enzinger and Weiss in 1989 [27J and until now 52 cases have been published either in large or small series, as well as in case reports [1-3, 6-9, 15,23,

Table 2. Antibodies used for immunohistochemical studies Antibody

Clone

Dilution

Source

vimentin desmin cytokeratin N.S.E S.M.A S-100

V9

33 AEl/AE3 N3 1A4 polycl.

1:1200 1:80 1:100 1:500 1:3000 1:3000

Biomakor BioGenex BioGenex Biomakor Biomakor Dako

CD31 CD34 CD68

JC/70A Qbend/lO PGM1

1:40 1:60 1:200

BioGenex BioGenex Dako

416 . V. Karabela-Bouropoulou et al.

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Fig. 2. Histological findings in GCE a) Large cystic space with intracavital tufting. H & E, 100x. b) Compresed, slit-like sinusoidal space. H & E, 100x. c) Large bizarre multinucleated cells lining the spaces and/or around them. H & E, 100x. d) Myxoid material stained blue-green in the filling the cavity of sinusoidal spaces. Alcian Blue (pH 1.0) - Alcia Yellow (pH 2.5) , 100x.

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Fig. 3. a) Moderate to dense perivascular lymphocytic infiltrate. H & E, IOOx. b) Subendothelial thickening of the vessel wall due either to the depo sition of myxoid substance or to hyalinization of the wall. H & E, IOOx. c) Periv ascular concentric fibroblastic proliferation in the GCF-like area s. H & E, lOOx. d) Significant number of mast cell s stained met achromatically with toluidine blue, lOOx.

418 . V. Karabela-Bouropoulou et aI.

24, 27, 30J. The largest series comprising 28 cases is from the AFIP and presents in detail the clinicopathological findings of this new entity. The authors also suggest the possibility of a close relationship between giant cell fibroblastoma and DFSP [26J. This relationship was based upon many cases which either recurred as DFSP or presented features of GCF in otherwise typical DFSP [2, 3, 7, 23, 24, 26, 30J. This was also the reason for considering GCF to be the juvenile form of DFSP [26J. Moreover a case of DFSP that recurred as GCF was also reported [7 J. Other authors, however, suggested that GCF is related rather to fibroblastic proliferations, since these lesions are more frequently encountered in infants, children and adolescents as does the majority of GCF cases reported so far. However, 8 cases, most of them associated to or recurring as DFSP have been identified in patients over 20 years of age (6 males and 2 females) [3, 7, 14, 26, 29J. Four more cases of GCF affecting adults are included in our series. Two of them were men and two women and their age ranged from 25 to 72 years. In Three of the cases the GCF was associated with DFSP, while in the fourth case the GCF-like areas were found in a malignant hemangiopericytoma. Most of the GCF already reported were subcutaneous tumors and showed a wide anatomic distribution with no predilection for any particular site, although the trunk and the extremities seem to present a higher incidence. Three out of the four tumors reported herein were subcutaneous, two in the groin and one in the thigh. The fourth case revealed areas with features similar to GCF in a huge retroperitoneal tumor. This fourth tumor presented many peculiarities which challenged us to include it in our study. The GCF-like areas were found in association to a frankly malignant tumor of the retroperitoneum, and the patient was the oldest adult patient reported so far (72 years old). GCF was initially considered to be a benign lesion [1, 3, 7, 8, 9J but its relationship to DFSP and the high recurrence rate of the tumor probably resulted in its classification in the group of tumors of intermediate malignancy or borderline [28 J. The histology of GCF as described and illustrated in detail by many authors presents no real diagnostic difficulties [13, 26, 28J. However, as the entity was unknown before 1989 there is a great possibility that some cases with the histology of GCF both in children and adults have been classified as either malignant tumors or other benign lesions. Our case No.1 was diagnosed as neurofibroma in both the initial tumor and the first recurrence, while the tumor in case No. 3 was firstly misdiagnosed as MFH. The characteristic features of GCF such as the bland spindle cells and the bizarre multinucleated cells in a myxoid stroma, as well as the so called sinusoidal spaces of variable size and shape lined partly by those cells [13, 26J were observed in all cases. These features were mainly encountered at the

peripheral parts of the neoplastic nodules of DFSP and/or within the fibrous septa separating the neoplastic tissue. They were also more pronounced and extensive in case No.2, both in the initial tumor and the recurrence with extensive myxoid changes of the stroma and great number of bizarre multinucleated giant cells resulting in the misinterpretation of the lesions as malignant fibrous histiocytoma. A common finding in all tumors of our series was the close relationship of GCF areas to preexisting blood vessels presenting severe lesions within their walls. These vascular changes need further analysis. They ranged from a moderate to dense perivascular lymphocytic infiltrate around some vessels, to a subendothelial myxoid thickening or perivascular concentric fibroblastic proliferation and/or collagenization resulting in a significant narrowing or partial obstruction of their lumens. A variable but usually large number of mast cells was also found at the GCF areas in contrast to the center of the tumor mass. The sinusoidal spaces, also designated by the term "angiectoid" [15 J probably because of their apparent resemblance to ectatic vessels, present no evidence supporting their blood vascular or lymphatic endothelial origin. Although both vimentin and CD34 were positively expressed by the cells lining these spaces, the immunoreaction with CD3l was negative. On the other hand the positive SMA expression points towards a myofibroblastic rather than endothelial differentiation [25, 26J, while the presence of abundant glycosaminoglycans into the lumens of the sinusoidal spaces seems ganglion cyst formation very similar. Similar, though not identical sinusoidal spaces have also been described in synovial metaplasia of the skin [12, 13]. It has been suggested that these structures, displaying to some degree the features of synovium, develop as the result of local mechanical disruption of the connective tissue in many conditions and that a "nidus" may serve as a starting point [9-l2J. In the case of GCF, the "nidus" may be a tumor or a tumor-like lesion, such as a DFSP or any other fibroblastic proliferation, and even more an area of previous surgery. Mast cells may play an important role in the appearance of the lesion, since it is generally accepted that mast cells promote fibroblastic proliferation [18J. Finally the atypical appearance of fibroblastic and/or myofibroblastic elements might be related to local ischemic conditions attributed to the vascular changes observed. Similar changes are frequently seen in lesions such as decubital fibroplasia [21J, reactive fibroplasia following radiation [27J and degenerating benign tumors [16J probably due to local ischemic conditions. Therefore, the question arising is whether GCF represents a benign entity, or if its relationship to DFSP coupled with its high recurrence rate justifies its classification among the tumors of intermediate malignancy [28 J. Furthermore, what is the meaning of lesions with features similar to GCF that are found adjacent to other

Giant Cell Fibroblastoma . 419

benign lesions and/or malignant tumors? Immunoreactivity of the bizarre fibroblastic cells with vimentin, CD34 and SMA could not be interpreted as favoring the relationship of GCF to DFSP, because similar reactions are also displayed by the cells of hemangiopericytoma denoting the participation of myofibroblasts, cells commonly encountered in reactive lesions [24, 25J. On the basis of our observations and of the pertinent data from the literature, we suggest that GCF might not always represent an entity, but often only the histologic pattern of connective tissue host reaction related to tumors or tumor-like lesions, either benign but locally aggressive or malignant. Therefore the diagnosis of GCF should not be easily rendered, unless an extensive study of the whole specimen rules out the possibility of an underlying tumor that probably needs special care.

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