552
0 1991 The Japanese
Case Reports
Society of Pathology
Giant Cell Fibroblastoma A Case Report and lmmunohistochemical Comparison with Ten Cases of Dermatofibrosa rcoma Protu berans
Yae Kanai', Makio Mukai2, Hitoshi Sugiura', Yoichi Tanaka2, Kiyoshi Mukai3, Etsushi U kiyama4, Jotaro Yokoyama4, Hisami lri2,and Yasuhiro Hosoda'
A 7 year-old boy with giant cell fibroblastoma (GCF) of the skin and subcutaneous tissue of the right chest wall is described. To date, the histogenesis of GCF has not been clarified. The reason for the diversity of immunohistochemical data among various authors may be because the specimens studied were from only part of the lesion, or reduction of antigenicity through the preparation process. However, our findings based on studies of many specimens from various parts of the tumor for accurate immunohistochemical evaluation suggest that GCF may be a myofibrohistiocytic tumor. Recently, the suggestion that GCF is a juvenile form of dermatofibrosarcoma protuberans (DFSP) has been reported. I n addition to the present case, we performed immunohistochemical examination of 10 cases of definitely diagnosed DFSP for comparison. The immunohistochemical characteristics of these two neoplasms were concordant. However, from clinical and morphological viewpoints, it seems premature to recognize GCF as a juvenile form of DFSP. Acta Pathol Jpn 41: 552-560,
1991. Key words : Giant cell fibroblastoma, Immunohistochemistrv. .,Dermatofibrosarcoma Drotuberans
dren. Shmookler and Enzinger were the first to describe this entity in 1 9 8 2 (1). Since then, 49 cases have been reported (1-9). This tumor is characterized by spindleshaped fibroblastic tumor cells, multinucleated giant cells and sinusoid-like tissue spaces which are diagnostic for the disease. Although local recurrences have been reported (2, 4, 6, 7), there has been no confirmation of its metastatic capability. The histogenesis has been disputed, with various authors favoring fibrous (2-9), histiocytic (3),myogenic (9), neural (3, 5) and vascular (4) origins. Shmookler et a/. (7) have regarded this neoplasm as a juvenile form of dermatofibrosarcoma protuberans (DFSP), but the definite histogenesis of GCF has not yet been clarified. The lack of familiarity with GCF has often led to its being seriously misdiagnosed as a malignant neoplasm (2, 4-8), occasionally leading to inappropriately aggressive therapy. Here we present the second report and the first electron-microscopic description of GCF in Japan. We also performed an immunohistochemical comparison with 10 definitely diagnosed cases of DFSP and clarified the histogenesis of GCF.
INTRODUCTION Giant cell fibroblastoma (GCF) is a benign mesenchymal neoplasm occurring almost exclusively in chilReceived February 7, 1991. Accepted for publication April 5, 1991. 'Department of Pathology, Keio University School of Medicine, Tokyo. 2Divisionof Surgical Pathology, Central Clinical Laboratories and 4Department of Surgery, Keio University Hospital, Tokyo. 3Pathology Division, National Cancer Center Research Institute, Tokyo. Mailing address : Yae Kanai, Department of Pathology, Keio University School of Medicine, 35 Shinanomachi, Shinjukuku, Tokyo 160, Japan.
CLINICAL SUMMARY A 7-year-old boy was first admitted to Keio University Hospital, Tokyo, in June 1990, with a painless nodule on the right anterior chest wall in the vicinity of the axilla. The m~dulehad first been noticed one year prior to admission. Three months before admission, the boy had sustained a minor trauma over the area and the tumor had begun to grow rapidly. OtheWise he had no significant medical history. Physical examination revealed a solitary, firm, nontender, skin-colored nodule, 5.2 x 6 . 5 cm in size, not fixed
553
Acta Pathologica Japonica 41 (7): 1991
Figure 1. Computed tomogram of the chest. A flat low-density mass without adipose tissue or calcification is evident on the right chest wall (arrow).
to the underlying tissue. There was no lymphadenopathy. Results of routine laboratory studies were within normal limits. Ultrasonic examination revealed a flat hypoechoic mass without a definite cystic structure. According to Doppler echography, no definite flow of fluid was observed in the lesion. Computed tomography revealed a flat, low-density mass without adipose tissue or calcification (Fig. 1). The enhancement effect was weak. The clinical data suggested that the lesion might be an atypical lymphangioma or hemangioma. The tumor was excised with adequate lateral and inferior margins, since it had no capsule and no clear margin. Further advanced therapy has not been performed. A t 7 months follow-up, the patient is doing well with no evidence of recurrence.
MATERIALS AND METHODS The specimen was fixed in 10% formalin and embed.
Table 1. Antibodies Used in lmmunohistochemical Studies Antibody anti-S-100 protein (poly.) anti-factor VIII-related antigen (mono.) anti-alpha-1-antitrypsin (poly.) anti-alpha-1-antichymotrypsin f DO IV.,1 anti-desmin (mono.) anti-vimentin (mono.) anti-muscle actin (mono.)
.,
Source Dakopatts Dakopatts
dilution 1: 300 1: 100
Dakopatts Dakopatts
1: 1:
400 300
ded in paraffin. Paraffin sections were stained routinely with hematoxylin and eosin (HE), alcian blue with and without hyaluronidase treatment, and elastica van Gieson. lmmunoperoxidase demonstration of various antigens (Table 1) was performed on paraffin sections by the avidin-biotin complex method. Omission of the primary antibodies and replacement with normal sera were done as negative controls. Sections were also examined for binding with the lectin Ulex europaeus I (UEAI) (Vector Laboratories, Burlingame, CA, 50 pg/ml) using biotinylated UEAI and avidin-biotin complex. Immunohistochemical examination of specimens from 10 cases of definitely diagnosed DFSP (patient age range: 24-33 y r ; 1 male, 9 female) was performed in the same manner for demonstration of alpha-1 -antitrypsin, alpha1-antichymotrypsin, and muscle actin. Electron microscopic examination of the present case was performed. Formalin-fixed tissue was washed with phosphate-buffered saline, re-fixed with 2.5% glutaraldehyde for 2 h, post-fixed with 1% osmium tetroxide for 1 h, dehydrated with a graded ethanol series and acetone, and embedded in epoxy resin. Ultrathin sections were cut and double-stained with uranyl acetate and lead nitrate, and examined with a JEOL lOOC electron microscope.
PATHOLOGICAL FINDINGS
I
Dakopatts 1: 50 Lipshaw 1: 2 Enzo Biochem 1 : 20,000
mono., monoclonal antibody ; poly., polyclonal antibody. Trypsin pre-treatment was performed before immunohisto. chemical demonstration of all antigens except for desmin and v imentin.
Macroscopically the tumor involved the dermis and subcutaneous tissue. It was irregularly shaped and non-enca psula ted with ill-def ined, infiltrative borders. In cut section, tan-yellow gelatinous tissue was revealed (Fig. 2)- There was no macroscopic evidence Of hemorrhage or necrosis.
554
Giant Cell Fibroblastoma (Kanai et a!.)
Figure 2. Macroscopic view of the excised tumor. Cut section reveals tan-yellow gelatinous tissue without hemorrhage or necrosis.
Figure 3. Microscopic view of the cellular area. Spindle-shaped fibroblastic tumor cells show a dense and rather haphazard arrangement in the densely collagenized stroma (HE).
Figure 4. The cutaneous adnexal structures are entrapped, but not obliterated, by the cellular component (HE).
Acta Pathologica Japonica 41 (7): 1991
555
Figure 5. In the hypocellular area, the stroma shows marked myxomatous changes (HE).
Figure 6. Floret giant cells are present in clusters (HE). They are characterized by a peripheral arrangement of the nuclei and central basophilic cytoplasm (inset).
Figure 7. Sinusoid-like spaces with irregular branching are rimmed by discontinuous layers of spindle-shaped cells and giant cells (HE).
556
Giant Cell Fibroblastoma (Kanai et a/.)
Histo logica I examination revealed an infiltrating neoplasm replacing the reticular dermis and subcutaneous adipose tissue. No capsule was present. The neoplasm was composed essentially of two populations of cells, spindle cells and giant cells, and had a collagenous or myxoid background with sinusoid-like tissue spaces. In the cellular area, wavy, oval o r dendritic spindle-shaped fibroblastic cells formed a dense, but rather haphazard arrangement in the densely collagenized stroma (Fig. 3). Mitotic figures, although few in number, were present. Sometimes a focal storiform pattern was observed. Well developed small capillaries were seen in the cellular component. A characteristic feature was the entrapment, not obliteration, of cutaneous adnexal structures by the cellular component (Fig. 4). The cellular area often transformed, rather abruptly, into a hypocellular area. In this area, the stroma showed marked myxomatous change, and the spindle-shaped cells were similar to those in the cellular area (Fig. 5). Alcian blue
staining with hyaluronidase revealed abundant hyaluronic acid deposition in the myxomatous stroma. In addition to the spindle cell population, multinucleated giant cells were scattered in both the cellular and hypocellular areas, and tended to occur in clusters (Fig. 6). The giant cells were of the floret type, characterized by a peripheral arrangement of the nuclei and central basophilic cytoplasm (Fig. 6). Irregularly shaped and branched sinusoid-like or slit-like tissue spaces, which resembled blood vessels or lymphatic vessels at first glance, were seen along the periphery of the tumor. They were rimmed by discontinuous layers of spindle-shaped cells or giant cells, but occasionally lacked any cellular lining (Fig. 7). lmmunohistochemical examination of the present case revealed strongly positive staining of the spindle-shaped cells and multinucleated giant cells with antibody against vimentin. Some spindle-shaped cells and a few multinucleated giant cells showed immunoreactivity for alpha-
Figure 8. lmmunohistochemical stain. (a) Some tumor cells are positive for alpha-1-anti. chymotrypsin, particularly in the cellular area. (b) Some tumor cells are positive for muscle actin, particularly in the vicinity of the sinusoid-like spaces. An actin-positive giant cell is evident (inset).
Acta Pathologica Japonica 41 (7) : 1991
55 7
Figure 9. Electron-microscopic view of a spindle-shaped cell with irregularly shaped cytoplasmic projections. Well developed rough endoplasmic reticulum and intracytoplasmic filaments are present ( x 23,000).
1-antitrypsin and alpha-l -antichymotrypsin (Fig. 8a), particularly in the cellular area. On the other hand, particularly in the hypocellular area and the vicinity of the sinusoid-like spaces, some spindle-shaped cells and a few multinucleated giant cells showed immunoreactivity for muscle actin (Fig. 8b). The reactions for desmin, S100 protein and factor VIII-related antigen were negative in all tumor cells. Lectin UEAl was also negative. Generally, all adjacent normal structures showed the usual staining patterns. lmmunohistochemical study of the 1 0 cases of DFSP revealed that the tumor cells were positive for alpha-lantitrypsin in 6 cases, alpha-1 -antichymotrypsin in 8 cases and muscle actin in 8 cases. Electron-microsco pic exa minat io n showed that the
spindle cells were variable in size and irregular in shape with several long cytoplasmic projections. They demonstrated well developed rough endoplasmic reticulum, a few oval mitochondria with a clear matrix, and intracytoplasmic filaments showing a haphazard arrangement. The nuclei were marginated with a dense rim of heterochromatin (Fig. 9). They had multiple invaginations and were often segmented. The giant cells did not differ much from the spindle-shaped cells, except for multinucleation and an increased amount of cytoplasm (Fig. 10). These tumor cells were suspended in a matrix rich in proteoglycan particles and collagen fibers. No distinct basement membrane was seen around the tumor cells.
558
Giant Cell Fibroblastoma (Kanai et a/.)
Figure 10. Electron-microscopic view of a giant cell. It does not differ much from the spindleshaped cells, except for multinucleation and an increased amount of cytoplasm ( x 30,000). lntracytoplasmic filaments showing a haphazard arrangement are also present (inset, ~ 8 0 , 0 0 0 ) .
DISCUSSION GCF is a rather new entity first recognized by Shmookler and Enzinger in 1982 (1). To date, there have been 49 cases reported in the literature (1-9). The present case, the 50th, was representative of the characteristic clinicopathological features of this tumor (Table 2). From the collective evidence, GCF is an asymptomatic, slow-growing neoplasm occurring in the dermal or sub cutaneous regions. Affected patients range in age from 4 months to 64 years, but 74% (37 cases) are in the first decade of life. The tumor occurs predominantly in infancy and childhood. There is a predilection for male children, accounting for 66% (33 cases) of reported tumors, compared with 34% (17 cases) in female children. These tumors occur in various sites, particularly in the chest wall (7cases), neck-clavicular region (7 cases), shoulder-axilla region (7 cases), and thigh-knee
region (7 cases). The lesions measure from 0.8 to 8 cm in diameter at the time of surgery, and 50% (21 cases) of 42 follow-up cases have shown local recurrence. However, there have been no reported cases of metas task, indicating that the biologic behavior of this tumor is benign rather than malignant. This tumor is recognized to be curable by adequate excision. However, unfamiliarity with this neoplasm has often led to serious misdiagnosis. Not a few cases of GCF were initially interpreted as malignant tumors such as liposarcoma and myxoid malignant fibrous hist iocytoma (2,4-8). This has occasionally resulted in unnecessarily aggres sive therapy, for instance, wider surgical re-excision or irradiation (2,7). It is important for pathologists t o be aware of this entity and its distinctive morphological features, which are scattered multinucleated giant cells and sinusoid-like tissue spaces, so as to avoid such diagnostic pitfalls.
559
Acta Pathologica Japonica 41 (7) : 1991 Table 2. Review of Giant Cell Fibroblastoma Reports -
Reference
Year
No. of cases
Shmookler et a/. (1, 7)
1982
28
Abdul-Karim et a/. ( 2 )
1985
3
Barr et a/. (3) Dymock et a/. (4)
1986
1
1987
7
Fletcher (5)
1988
Chou et a/. (6)
1989
2
Rosen et a/.
1989
1
1990 1991
&
1989
Patient Site Age Sex 4 mo 1 8 M Thigh 5, inguinal region 5, to chest wall 3, axilla 3. 55 yr 1OF back 3, clavicular region 2, abdominal wall 2, foot 2, neck 1, scrotum 1, hand 1 3 y r 4 m o 3 M Back 1, to perineum 1, 9yr6mo shoulder 1 34 y r 1F Chest wall 1
a
2 Yr to 18 y r 8 mo to 64 y r 8 Yr 10 y r
5M
Chest wall 2, thigh 1, axilla 1, neck 1, scrotum 1, hand 1 Neck 3, axilla 1, buttock 1, lower leg 1
Size
0.8cm 15/25 to (at 2 mo t o 2 v r 11 mo 8 c m after excision)+ 2.5 c m 3/3 to (at 1 mo t o 10 mo 6 c m after excision) 0/1 1.5 c m
3F 2M
Shoulder 1, hand 1
15 y r
1M
Abdominal wall 1
1cm to 5 cm 3 cm to 7 cm 2 cm to 3 cm 1cm
1
1yr4mo
IF
Knee 1
2 cm
1 50
7 y r 8 mo 4mo to 6 4 yr
1M 33M & 17F
6
& 2F 3M
&
Recurrence/follow-up
117
(at 7 mo after excision) 011 2/2 (at 1 yr and 2 yr after excision) 0/1 0/1
(8) Hirose et a/. (9) Present case Total
Chest wall 1 Chest wall 7, neck-clavicular region 7, axilla-shoulder 7, thigh-knee 7, back-buttock 5, inguinal region 5, perineum-scrotum 3, abdominal wall 3, hand 3. lower lea-foot 3
lmmunohistochemical studies of 2 1 cases have been reported, and the histogenesis of GCF has been disputed by various authors. The reason for the diversity of their immunohistochemical findings may be reduction of antigenicity as a result of the preparation process. However, the reaction for vimentin has been consistently positive (2-6, 8, 9), including the present case. Dymock et a/. (4) have suggested the possibility of a vascular origin, but reactions for factor VIII-related antigen and UEAl in cells in the vicinity of the sinusoidlike spaces have been constantly negative (2-6,8, 9), including the present case. These results appear to deny a vascular or lymphatic endothelial origin. Stromal hyalinization seems to cause progressive dilation of intercollagenous clefts, resulting in the formation of the diagnostic sinusoid-like spaces. Fletcher (5) has suggested a perineural fibroblastic origin based on the histological features. However, the reaction for S-100 protein has been constantly negative (3, 5, 6, 8, 9), including the present case. Hirose et a/. (9) have reported that epithelial membrane antigen (recently found to be a perineural cell marker) was not detected in one case. Barr et a/. (3) suggested a fibrohistiocytic origin based
6.5 c m 0/1 0.8 c m 2 1/42 to (at 1 mo to 2 y r 11 mo 8 cm after excision)
on a positive reaction for alpha-1 -antichymotrypsin in one case. However, no positive reactions have been observed in other studies (5, 6, 8, 9). Chou et a/. (6) reported a negative reaction for alpha-1 -antitrypsin in three cases, but no other reports on this antigen have been described. Therefore some have denied the possibility of histiocytic differentiation. Our study showed positivity for both alpha-1 -antitrypsin and alpha-1 -antichymotrypsin. The tumor cells showing immunoreactivity for both antigens tended to be localized in the cellular area. The reason why many authors have reported negative findings f o r both antigens may be because they studied specimens from only a part of the lesion. We believe that examination of many specimens from various parts of the tumor is important for accurate immunohistochemical evaluation. Shmookler et a/. (7) have stated that GCF is a juvenile form of DFSP, and have described that GCF and DFSP often share many clinical and morphological features except for their distinct difference in mean patient age. On the other hand, Chou et a/. (6) and Hirose et a/. (9) have reported that the tumor cells of GCF show immunoreactivity for muscle actin, whereas DFSP has been reported to be negative for muscle actin by Miettinen
5 60
Giant Cell Fibroblastoma (Kanai et a/.)
(10). Thus Hirose et a/. (9) have countered Shmookler's suggestion that GCF is a juvenile form of DFSP. However according to our immunohistochemical studies on 10 cases of DFSP, the tumor cells were positive for muscle actin. The present findings certainly indicate immunohistochemical similarity of GCF and DFSP, and thus they may share myofibroblastic and histiocytic differentiation. Shmookler et a/. (7) have also described the presence of sinusoid-like tissue spaces in some cases of DFSP as the most convincing basis for their suggestion. However, only a few other cases of DFSP with sinusoid-like spaces have been reported in spite of the rather high incidence of DFSP (11). Furthermore, DFSP metastasizes in approximately 1-3% of cases (12-14), whereas there have been no documented examples of metastatic GCF. In view of these points, we consider that it may be premature to recognize GCF as a juvenile form of DFSP. Electron-microscopically, multisegmented nuclei, well developed rough endoplasmic reticulum and cytoplasmic projections have been described as characteristic features of GCF (2, 4, 6-8). These have been interpreted as evidence of fibroblastic differentiation. In addition to these findings, we observed here int racy topla smic filaments showing a haphazard arrangement. However, bundles of thin filaments with dense patches indicative of myofibroblastic differentiation were not seen, and no findings suggesting histiocytic differentiation were obtained. There are some discrepancies between the above immunohistochemical data and the ultrastructural features. Since only a few specimens fro m part of the lesion can be studied electron-microscopically, we find it rather difficult to determine the origin of this neoplasm based on ultrastructural findings alone. In summary, the present immunohistochemical study suggests that GCF may be a myofibro-histiocytic tumor. The immunohistochemical features of GCF indicate its similarity to DFSP, since both are positive for alpha-lantitrypsin, alpha-1 -antichymotrypsin and muscle actin. However, from the clinical and morphological viewpoints, there are several differences between GCF and DFSP.
REFERENCES 1. Shmookler BM and Enzinger FM. Giant cell fibroblastoma. A peculiar childhood tumor. Lab Invest 46: 76A, 1982. 2. Abdul-Karim FW, Evans HL, and Silva EG. Giant cell fibroblastoma. A report of three cases. Am J Clin Pathol 83: 165-170, 1985. 3. Barr RJ, Young EM, and Liao S-Y. Giant cell fibroblastoma. An immunohistochemical study. J Cutan Pathol 13: 301-307, 1986. 4. Dymock RB, Allen PW, Stirling JW, et a/. Giant cell fibroblastoma. A distinctive, recurrent tumor of childhood. Am J Surg Pathol 11 : 263-271, 1987. 5. Fletcher CDM. Giant cell fibroblastoma of soft tissue. A clinicopathological and immunohistochemical study. Histopathology 13: 499-508, 1988. 6. Chou P, Gonzalez-Crussi F, and Mangkornkanok M. Giant cell fibroblastoma. Cancer 63 : 756-762, 1989. 7. Shmookler BM, Enzinger FM, and Weiss SW. Giant cell fibroblastoma. A juvenile form of dermatofibrosarcoma protuberans. Cancer 6 4 : 2154-2161, 1989. 8. Rosen LB, Amazon K, Weitzner J, and Resnick L. Giant cell fibroblastoma. A report of a case and review of the literature. Am J Dermatopathol 11: 242-247, 1989. 9. Hirose T, Sasaki M, and Shintaku M, et a/. Giant cell fibroblastoma. A case report. Acta Pathol Jpn 40: 540-544, 1990. 10. Miettinen M. Antibody specific to muscle actins in the diagnosis and classification of soft tissue tumors. Am J Pathol 130: 205-215, 1988. 11. Beham A and Fletcher CDM. Dermatofibrosarcoma protuberans with areas resembling giant cell fibroblastoma: Report of two cases. Histopathology 1 7 : 165- 167, 1990. 12. Pack GT and Tabah EJ. Dermatofibrosarcoma protuberans. Arch Surg 62: 391-411, 1951. 13. Taylor HB and Helwig EB. Dermatofibrosarcoma protuberans. A study of 115cases. Cancer 15: 717-725, 1962. 14. McPeak CJ, Cruz T, and Nicastri AD. Dermatofi brosarcoma prot u berans. Analysis of eighty -six cases, five with metastasis. Ann Surg 166: 803816, 1967.
0 1991 The Japanese
Case Reports
Society of Pathology
Giant Cell Fibroblastoma A Case Report and lmmunohistochemical Comparison with Ten Cases of Dermatofibrosa rcoma Protu berans
Yae Kanai', Makio Mukai2, Hitoshi Sugiura', Yoichi Tanaka2, Kiyoshi Mukai3, Etsushi U kiyama4, Jotaro Yokoyama4, Hisami lri2,and Yasuhiro Hosoda'
A 7 year-old boy with giant cell fibroblastoma (GCF) of the skin and subcutaneous tissue of the right chest wall is described. To date, the histogenesis of GCF has not been clarified. The reason for the diversity of immunohistochemical data among various authors may be because the specimens studied were from only part of the lesion, or reduction of antigenicity through the preparation process. However, our findings based on studies of many specimens from various parts of the tumor for accurate immunohistochemical evaluation suggest that GCF may be a myofibrohistiocytic tumor. Recently, the suggestion that GCF is a juvenile form of dermatofibrosarcoma protuberans (DFSP) has been reported. I n addition to the present case, we performed immunohistochemical examination of 10 cases of definitely diagnosed DFSP for comparison. The immunohistochemical characteristics of these two neoplasms were concordant. However, from clinical and morphological viewpoints, it seems premature to recognize GCF as a juvenile form of DFSP. Acta Pathol Jpn 41: 552-560,
1991. Key words : Giant cell fibroblastoma, Immunohistochemistrv. .,Dermatofibrosarcoma Drotuberans
dren. Shmookler and Enzinger were the first to describe this entity in 1 9 8 2 (1). Since then, 49 cases have been reported (1-9). This tumor is characterized by spindleshaped fibroblastic tumor cells, multinucleated giant cells and sinusoid-like tissue spaces which are diagnostic for the disease. Although local recurrences have been reported (2, 4, 6, 7), there has been no confirmation of its metastatic capability. The histogenesis has been disputed, with various authors favoring fibrous (2-9), histiocytic (3),myogenic (9), neural (3, 5) and vascular (4) origins. Shmookler et a/. (7) have regarded this neoplasm as a juvenile form of dermatofibrosarcoma protuberans (DFSP), but the definite histogenesis of GCF has not yet been clarified. The lack of familiarity with GCF has often led to its being seriously misdiagnosed as a malignant neoplasm (2, 4-8), occasionally leading to inappropriately aggressive therapy. Here we present the second report and the first electron-microscopic description of GCF in Japan. We also performed an immunohistochemical comparison with 10 definitely diagnosed cases of DFSP and clarified the histogenesis of GCF.
INTRODUCTION Giant cell fibroblastoma (GCF) is a benign mesenchymal neoplasm occurring almost exclusively in chilReceived February 7, 1991. Accepted for publication April 5, 1991. 'Department of Pathology, Keio University School of Medicine, Tokyo. 2Divisionof Surgical Pathology, Central Clinical Laboratories and 4Department of Surgery, Keio University Hospital, Tokyo. 3Pathology Division, National Cancer Center Research Institute, Tokyo. Mailing address : Yae Kanai, Department of Pathology, Keio University School of Medicine, 35 Shinanomachi, Shinjukuku, Tokyo 160, Japan.
CLINICAL SUMMARY A 7-year-old boy was first admitted to Keio University Hospital, Tokyo, in June 1990, with a painless nodule on the right anterior chest wall in the vicinity of the axilla. The m~dulehad first been noticed one year prior to admission. Three months before admission, the boy had sustained a minor trauma over the area and the tumor had begun to grow rapidly. OtheWise he had no significant medical history. Physical examination revealed a solitary, firm, nontender, skin-colored nodule, 5.2 x 6 . 5 cm in size, not fixed
553
Acta Pathologica Japonica 41 (7): 1991
Figure 1. Computed tomogram of the chest. A flat low-density mass without adipose tissue or calcification is evident on the right chest wall (arrow).
to the underlying tissue. There was no lymphadenopathy. Results of routine laboratory studies were within normal limits. Ultrasonic examination revealed a flat hypoechoic mass without a definite cystic structure. According to Doppler echography, no definite flow of fluid was observed in the lesion. Computed tomography revealed a flat, low-density mass without adipose tissue or calcification (Fig. 1). The enhancement effect was weak. The clinical data suggested that the lesion might be an atypical lymphangioma or hemangioma. The tumor was excised with adequate lateral and inferior margins, since it had no capsule and no clear margin. Further advanced therapy has not been performed. A t 7 months follow-up, the patient is doing well with no evidence of recurrence.
MATERIALS AND METHODS The specimen was fixed in 10% formalin and embed.
Table 1. Antibodies Used in lmmunohistochemical Studies Antibody anti-S-100 protein (poly.) anti-factor VIII-related antigen (mono.) anti-alpha-1-antitrypsin (poly.) anti-alpha-1-antichymotrypsin f DO IV.,1 anti-desmin (mono.) anti-vimentin (mono.) anti-muscle actin (mono.)
.,
Source Dakopatts Dakopatts
dilution 1: 300 1: 100
Dakopatts Dakopatts
1: 1:
400 300
ded in paraffin. Paraffin sections were stained routinely with hematoxylin and eosin (HE), alcian blue with and without hyaluronidase treatment, and elastica van Gieson. lmmunoperoxidase demonstration of various antigens (Table 1) was performed on paraffin sections by the avidin-biotin complex method. Omission of the primary antibodies and replacement with normal sera were done as negative controls. Sections were also examined for binding with the lectin Ulex europaeus I (UEAI) (Vector Laboratories, Burlingame, CA, 50 pg/ml) using biotinylated UEAI and avidin-biotin complex. Immunohistochemical examination of specimens from 10 cases of definitely diagnosed DFSP (patient age range: 24-33 y r ; 1 male, 9 female) was performed in the same manner for demonstration of alpha-1 -antitrypsin, alpha1-antichymotrypsin, and muscle actin. Electron microscopic examination of the present case was performed. Formalin-fixed tissue was washed with phosphate-buffered saline, re-fixed with 2.5% glutaraldehyde for 2 h, post-fixed with 1% osmium tetroxide for 1 h, dehydrated with a graded ethanol series and acetone, and embedded in epoxy resin. Ultrathin sections were cut and double-stained with uranyl acetate and lead nitrate, and examined with a JEOL lOOC electron microscope.
PATHOLOGICAL FINDINGS
I
Dakopatts 1: 50 Lipshaw 1: 2 Enzo Biochem 1 : 20,000
mono., monoclonal antibody ; poly., polyclonal antibody. Trypsin pre-treatment was performed before immunohisto. chemical demonstration of all antigens except for desmin and v imentin.
Macroscopically the tumor involved the dermis and subcutaneous tissue. It was irregularly shaped and non-enca psula ted with ill-def ined, infiltrative borders. In cut section, tan-yellow gelatinous tissue was revealed (Fig. 2)- There was no macroscopic evidence Of hemorrhage or necrosis.
554
Giant Cell Fibroblastoma (Kanai et a!.)
Figure 2. Macroscopic view of the excised tumor. Cut section reveals tan-yellow gelatinous tissue without hemorrhage or necrosis.
Figure 3. Microscopic view of the cellular area. Spindle-shaped fibroblastic tumor cells show a dense and rather haphazard arrangement in the densely collagenized stroma (HE).
Figure 4. The cutaneous adnexal structures are entrapped, but not obliterated, by the cellular component (HE).
Acta Pathologica Japonica 41 (7): 1991
555
Figure 5. In the hypocellular area, the stroma shows marked myxomatous changes (HE).
Figure 6. Floret giant cells are present in clusters (HE). They are characterized by a peripheral arrangement of the nuclei and central basophilic cytoplasm (inset).
Figure 7. Sinusoid-like spaces with irregular branching are rimmed by discontinuous layers of spindle-shaped cells and giant cells (HE).
556
Giant Cell Fibroblastoma (Kanai et a/.)
Histo logica I examination revealed an infiltrating neoplasm replacing the reticular dermis and subcutaneous adipose tissue. No capsule was present. The neoplasm was composed essentially of two populations of cells, spindle cells and giant cells, and had a collagenous or myxoid background with sinusoid-like tissue spaces. In the cellular area, wavy, oval o r dendritic spindle-shaped fibroblastic cells formed a dense, but rather haphazard arrangement in the densely collagenized stroma (Fig. 3). Mitotic figures, although few in number, were present. Sometimes a focal storiform pattern was observed. Well developed small capillaries were seen in the cellular component. A characteristic feature was the entrapment, not obliteration, of cutaneous adnexal structures by the cellular component (Fig. 4). The cellular area often transformed, rather abruptly, into a hypocellular area. In this area, the stroma showed marked myxomatous change, and the spindle-shaped cells were similar to those in the cellular area (Fig. 5). Alcian blue
staining with hyaluronidase revealed abundant hyaluronic acid deposition in the myxomatous stroma. In addition to the spindle cell population, multinucleated giant cells were scattered in both the cellular and hypocellular areas, and tended to occur in clusters (Fig. 6). The giant cells were of the floret type, characterized by a peripheral arrangement of the nuclei and central basophilic cytoplasm (Fig. 6). Irregularly shaped and branched sinusoid-like or slit-like tissue spaces, which resembled blood vessels or lymphatic vessels at first glance, were seen along the periphery of the tumor. They were rimmed by discontinuous layers of spindle-shaped cells or giant cells, but occasionally lacked any cellular lining (Fig. 7). lmmunohistochemical examination of the present case revealed strongly positive staining of the spindle-shaped cells and multinucleated giant cells with antibody against vimentin. Some spindle-shaped cells and a few multinucleated giant cells showed immunoreactivity for alpha-
Figure 8. lmmunohistochemical stain. (a) Some tumor cells are positive for alpha-1-anti. chymotrypsin, particularly in the cellular area. (b) Some tumor cells are positive for muscle actin, particularly in the vicinity of the sinusoid-like spaces. An actin-positive giant cell is evident (inset).
Acta Pathologica Japonica 41 (7) : 1991
55 7
Figure 9. Electron-microscopic view of a spindle-shaped cell with irregularly shaped cytoplasmic projections. Well developed rough endoplasmic reticulum and intracytoplasmic filaments are present ( x 23,000).
1-antitrypsin and alpha-l -antichymotrypsin (Fig. 8a), particularly in the cellular area. On the other hand, particularly in the hypocellular area and the vicinity of the sinusoid-like spaces, some spindle-shaped cells and a few multinucleated giant cells showed immunoreactivity for muscle actin (Fig. 8b). The reactions for desmin, S100 protein and factor VIII-related antigen were negative in all tumor cells. Lectin UEAl was also negative. Generally, all adjacent normal structures showed the usual staining patterns. lmmunohistochemical study of the 1 0 cases of DFSP revealed that the tumor cells were positive for alpha-lantitrypsin in 6 cases, alpha-1 -antichymotrypsin in 8 cases and muscle actin in 8 cases. Electron-microsco pic exa minat io n showed that the
spindle cells were variable in size and irregular in shape with several long cytoplasmic projections. They demonstrated well developed rough endoplasmic reticulum, a few oval mitochondria with a clear matrix, and intracytoplasmic filaments showing a haphazard arrangement. The nuclei were marginated with a dense rim of heterochromatin (Fig. 9). They had multiple invaginations and were often segmented. The giant cells did not differ much from the spindle-shaped cells, except for multinucleation and an increased amount of cytoplasm (Fig. 10). These tumor cells were suspended in a matrix rich in proteoglycan particles and collagen fibers. No distinct basement membrane was seen around the tumor cells.
558
Giant Cell Fibroblastoma (Kanai et a/.)
Figure 10. Electron-microscopic view of a giant cell. It does not differ much from the spindleshaped cells, except for multinucleation and an increased amount of cytoplasm ( x 30,000). lntracytoplasmic filaments showing a haphazard arrangement are also present (inset, ~ 8 0 , 0 0 0 ) .
DISCUSSION GCF is a rather new entity first recognized by Shmookler and Enzinger in 1982 (1). To date, there have been 49 cases reported in the literature (1-9). The present case, the 50th, was representative of the characteristic clinicopathological features of this tumor (Table 2). From the collective evidence, GCF is an asymptomatic, slow-growing neoplasm occurring in the dermal or sub cutaneous regions. Affected patients range in age from 4 months to 64 years, but 74% (37 cases) are in the first decade of life. The tumor occurs predominantly in infancy and childhood. There is a predilection for male children, accounting for 66% (33 cases) of reported tumors, compared with 34% (17 cases) in female children. These tumors occur in various sites, particularly in the chest wall (7cases), neck-clavicular region (7 cases), shoulder-axilla region (7 cases), and thigh-knee
region (7 cases). The lesions measure from 0.8 to 8 cm in diameter at the time of surgery, and 50% (21 cases) of 42 follow-up cases have shown local recurrence. However, there have been no reported cases of metas task, indicating that the biologic behavior of this tumor is benign rather than malignant. This tumor is recognized to be curable by adequate excision. However, unfamiliarity with this neoplasm has often led to serious misdiagnosis. Not a few cases of GCF were initially interpreted as malignant tumors such as liposarcoma and myxoid malignant fibrous hist iocytoma (2,4-8). This has occasionally resulted in unnecessarily aggres sive therapy, for instance, wider surgical re-excision or irradiation (2,7). It is important for pathologists t o be aware of this entity and its distinctive morphological features, which are scattered multinucleated giant cells and sinusoid-like tissue spaces, so as to avoid such diagnostic pitfalls.
559
Acta Pathologica Japonica 41 (7) : 1991 Table 2. Review of Giant Cell Fibroblastoma Reports -
Reference
Year
No. of cases
Shmookler et a/. (1, 7)
1982
28
Abdul-Karim et a/. ( 2 )
1985
3
Barr et a/. (3) Dymock et a/. (4)
1986
1
1987
7
Fletcher (5)
1988
Chou et a/. (6)
1989
2
Rosen et a/.
1989
1
1990 1991
&
1989
Patient Site Age Sex 4 mo 1 8 M Thigh 5, inguinal region 5, to chest wall 3, axilla 3. 55 yr 1OF back 3, clavicular region 2, abdominal wall 2, foot 2, neck 1, scrotum 1, hand 1 3 y r 4 m o 3 M Back 1, to perineum 1, 9yr6mo shoulder 1 34 y r 1F Chest wall 1
a
2 Yr to 18 y r 8 mo to 64 y r 8 Yr 10 y r
5M
Chest wall 2, thigh 1, axilla 1, neck 1, scrotum 1, hand 1 Neck 3, axilla 1, buttock 1, lower leg 1
Size
0.8cm 15/25 to (at 2 mo t o 2 v r 11 mo 8 c m after excision)+ 2.5 c m 3/3 to (at 1 mo t o 10 mo 6 c m after excision) 0/1 1.5 c m
3F 2M
Shoulder 1, hand 1
15 y r
1M
Abdominal wall 1
1cm to 5 cm 3 cm to 7 cm 2 cm to 3 cm 1cm
1
1yr4mo
IF
Knee 1
2 cm
1 50
7 y r 8 mo 4mo to 6 4 yr
1M 33M & 17F
6
& 2F 3M
&
Recurrence/follow-up
117
(at 7 mo after excision) 011 2/2 (at 1 yr and 2 yr after excision) 0/1 0/1
(8) Hirose et a/. (9) Present case Total
Chest wall 1 Chest wall 7, neck-clavicular region 7, axilla-shoulder 7, thigh-knee 7, back-buttock 5, inguinal region 5, perineum-scrotum 3, abdominal wall 3, hand 3. lower lea-foot 3
lmmunohistochemical studies of 2 1 cases have been reported, and the histogenesis of GCF has been disputed by various authors. The reason for the diversity of their immunohistochemical findings may be reduction of antigenicity as a result of the preparation process. However, the reaction for vimentin has been consistently positive (2-6, 8, 9), including the present case. Dymock et a/. (4) have suggested the possibility of a vascular origin, but reactions for factor VIII-related antigen and UEAl in cells in the vicinity of the sinusoidlike spaces have been constantly negative (2-6,8, 9), including the present case. These results appear to deny a vascular or lymphatic endothelial origin. Stromal hyalinization seems to cause progressive dilation of intercollagenous clefts, resulting in the formation of the diagnostic sinusoid-like spaces. Fletcher (5) has suggested a perineural fibroblastic origin based on the histological features. However, the reaction for S-100 protein has been constantly negative (3, 5, 6, 8, 9), including the present case. Hirose et a/. (9) have reported that epithelial membrane antigen (recently found to be a perineural cell marker) was not detected in one case. Barr et a/. (3) suggested a fibrohistiocytic origin based
6.5 c m 0/1 0.8 c m 2 1/42 to (at 1 mo to 2 y r 11 mo 8 cm after excision)
on a positive reaction for alpha-1 -antichymotrypsin in one case. However, no positive reactions have been observed in other studies (5, 6, 8, 9). Chou et a/. (6) reported a negative reaction for alpha-1 -antitrypsin in three cases, but no other reports on this antigen have been described. Therefore some have denied the possibility of histiocytic differentiation. Our study showed positivity for both alpha-1 -antitrypsin and alpha-1 -antichymotrypsin. The tumor cells showing immunoreactivity for both antigens tended to be localized in the cellular area. The reason why many authors have reported negative findings f o r both antigens may be because they studied specimens from only a part of the lesion. We believe that examination of many specimens from various parts of the tumor is important for accurate immunohistochemical evaluation. Shmookler et a/. (7) have stated that GCF is a juvenile form of DFSP, and have described that GCF and DFSP often share many clinical and morphological features except for their distinct difference in mean patient age. On the other hand, Chou et a/. (6) and Hirose et a/. (9) have reported that the tumor cells of GCF show immunoreactivity for muscle actin, whereas DFSP has been reported to be negative for muscle actin by Miettinen
5 60
Giant Cell Fibroblastoma (Kanai et a/.)
(10). Thus Hirose et a/. (9) have countered Shmookler's suggestion that GCF is a juvenile form of DFSP. However according to our immunohistochemical studies on 10 cases of DFSP, the tumor cells were positive for muscle actin. The present findings certainly indicate immunohistochemical similarity of GCF and DFSP, and thus they may share myofibroblastic and histiocytic differentiation. Shmookler et a/. (7) have also described the presence of sinusoid-like tissue spaces in some cases of DFSP as the most convincing basis for their suggestion. However, only a few other cases of DFSP with sinusoid-like spaces have been reported in spite of the rather high incidence of DFSP (11). Furthermore, DFSP metastasizes in approximately 1-3% of cases (12-14), whereas there have been no documented examples of metastatic GCF. In view of these points, we consider that it may be premature to recognize GCF as a juvenile form of DFSP. Electron-microscopically, multisegmented nuclei, well developed rough endoplasmic reticulum and cytoplasmic projections have been described as characteristic features of GCF (2, 4, 6-8). These have been interpreted as evidence of fibroblastic differentiation. In addition to these findings, we observed here int racy topla smic filaments showing a haphazard arrangement. However, bundles of thin filaments with dense patches indicative of myofibroblastic differentiation were not seen, and no findings suggesting histiocytic differentiation were obtained. There are some discrepancies between the above immunohistochemical data and the ultrastructural features. Since only a few specimens fro m part of the lesion can be studied electron-microscopically, we find it rather difficult to determine the origin of this neoplasm based on ultrastructural findings alone. In summary, the present immunohistochemical study suggests that GCF may be a myofibro-histiocytic tumor. The immunohistochemical features of GCF indicate its similarity to DFSP, since both are positive for alpha-lantitrypsin, alpha-1 -antichymotrypsin and muscle actin. However, from the clinical and morphological viewpoints, there are several differences between GCF and DFSP.
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