Fibrosarcoma

Although inflammatory myofibroblastic tumors, originally described in the lung, have recently been recognized to occur in various sites, their origin in bone is exceptional. We present a case of inflammatory myofibroblastic tumor, so-called inflammatory fibrosarcoma, of the bone. The tumor occurred in the iliac bone of a 70-year-old woman. Standard radiographs and magnetic resonance imaging revealed a destructive bone tumor that expanded into the soft tissue. Although the patient underwent excision of the hemi-iliac bone, multiple pulmonary metastases were noted 1 year after the operation. On histologic examination, the tumor was found to be composed of a sarcoma-like cellular area and a hypocellular fibrous area. Inflammatory cell infiltration into the tumor was a distinctive feature and is analogous with that of conventional inflammatory myofibroblastic tumor or inflammatory fibrosarcoma of the soft tissue. This is the first report to our knowledge of an inflammatory myofibroblastic tumor of the bone with distant metastasis.

(Arch Pathol Lab Med. 2000;124:1514-1517)

Inflammatory myofibroblastic tumors (IMTs) are rather rare and were originally described in the lung by such names as pseudotumor,1 inflammatory pseudotumor,2 and plasma cell granuloma 34 They are characterized as solitary, well-demarcated fibrous tumors with numerous inflammatory cells, mainly lymphoid or plasma cells2-5 Subsequently, it was recognized that analogous tumors can occur in various sites other than the lung, including the mesentery, omentum, retroperitoneum,6,7 genitourinary tract,8-9 liver, gastrointestinal tract, and upper respiratory tract.6 Electron microscopic and immunohistochemical examinations clarified that the proliferating spindle cells in these tumors are myofibroblast-like,4-10 and, therefore, these distinctive tumors are now preferentially called IMTs.11 We report a case of a primary IMT with aggressive clinicopathologic features arising in the iliac bone, which gave rise to lung metastases 1 year after its extirpation. This is the first report to our knowledge of an IMT of bone with distant metastasis.

MATERIALS AND METHODS

Specimens were fixed in 20% formalin and embedded in paraffin wax. Sections 3 to 4 wm thick were cut and stained with hematoxylin-eosin. Immunohistochemical studies using the streptavidin-biotin-peroxidase complex method were performed on the nondecalcified paraffin-embedded sections. The primary antibodies and their final dilutions were high-molecular-weight caldesmon (1:50; Dako, Kyoto, Japan), desmin (1:50; Dako), alphasmooth muscle actin (1:200; Dako), muscle actin (1:8000; Enzo Diagnostics, New York, NY), AEi/3 (1:50; Dako), and CAM5.2 (prediluted: Becton Dickinson, San Jose, Calif, USA). Microwave pretreatment for 15 minutes was performed for high-molecularweight caldesmon, desmin, and AEl/3, and the slides were pretreated with 0.1% trypsin only when using CAM5.2. The sections were deparaffinized and then immersed in methanol containing 1% peroxidase to block endogenous peroxidase activity. After treatment with 5% skimmed milk (Yukijirushi, Sapporo, Japan) to avoid nonspecific protein adsorption, the sections were incubated in primary antibodies overnight at 4deg.C and then with both anti-rabbit and anti-mouse immunoglobulin conjugated with biotin (SAB kit; Dako) and streptavidin-peroxidase complex (SAB kit; Dako), respectively for 30 minutes at room temperature. The immunoreactive products were visualized by immersion in a solution of 20 mg of 3,3'-diaminobenzidine (Dojin Laboratories, Kumamoto, Japan) in 100 ml of 0.01 mol/L phosphate-buffered saline. Finally the slides were counterstained for nuclei with hematoxylin. Gastric wall tissues were immunostained as a control on the same procedure, and the specificity of each antibody was confirmed by positive staining on smooth muscle or epithelial cells. Mitotic figures in the tumors were counted using a x40 objective lens (SPlan Apo; Olympus, Japan).

REPORT OF A CASE

A 70-year-old woman was admitted to the hospital in March 1997 complaining of pain in her left gluteal region. A standard radiograph revealed a 7-cm osteolytic lesion with a rather irregular rim of sclerotic margin, suggesting slow growth in her left iliac bone (Figure l, A). Magnetic resonance imaging examination revealed that the tumor had destroyed the iliac bone and extended into the surrounding soft tissue (Figure 1, B). Clinically a metastatic bone tumor was suspected, but systemic examination of her whole body failed to reveal a primary tumor. In addition, she did not have a history of hysterectomy. The histologic findings of a needle biopsy suggested a malignant spindle cell tumor, and, subsequently, a wide excision of the iliac bone along with the gluteal muscles was performed in May 1997. On gross examination, the tumor was grayish to yellowish and expanded into the surrounding gluteal muscle. One year after the operation, multiple pulmonary nodules, suggesting metastasis, appeared (Figure 2). The nodules grew slowly and the patient died in September 1999.

HISTOPATHOLOGIC FINDINGS

Histologically the tumor was composed of a mixture of a cellrich fascicular area and a hypocellular fibrous area. In the former area, eosinophilic thin spindle cells were arranged in interlacing fascicle, mimicking a leiomyosarcoma (Figure 3, A). In addition, a weak storiform pattern was occasionally noted (Figure 3, B). The tumor cells nuclei were oval or elongated and showed mild pleomorphism, but the strong nuclear atypia was never seen (Figure 3, A and B). Although there were frequent mitotic figures (8 mitoses per 10 high-power fields), no abnormal mitoses were observed. Numerous inflammatory cells, mainly composed of small lymphocytes and plasma cells, infiltrated into the interstitium (Figure 3, A). In contrast, in the hypocellular fibrous area the spindle tumor cells were sparsely distributed in the collagenous or myxoid fibrous matrix (Figure 3, C). Storiform cellular arrangements were sometimes seen. The inflammatory cells were not very conspicuous but infiltrated to various degrees in this region.

Immunohistochemically the tumor showed intense and extensive immunoreactivities for vimentin, muscle actin, and ot-smooth muscle actin (Figure 4) but was negative for desmin and highmolecular-weight caldesmon. In addition, tumor cells were not labeled by antibodies against AE1/3 and CAM5.2.

COMMENT

Coffin et al6 observed 84 cases of extrapulmonary IMT and found that it affects infants and adults younger than 20 years, mainly females, and that it is less well circumscribed and not infrequently multinodular in contrast to pulmonary IMT. Although 5 patients had adverse outcomes because of tumor locations (2 mesentery and 1 cardiac case) and infection (2 cases), none develop distant metastasis. These authors described 3 histologic types of IMT The first is composed of myxoid granulation tissueor nodular fasciitis-like tissue; the second is characterized by a compact spindle cell proliferation that sometimes exhibits an interlacing fascicular arrangement or a storiform pattern; and the third is composed of sparsely cellular plate-like collagen that resembles a scar or desmoid fibromatosis. In all forms, an inflammatory background is a distinctive microscopic feature.6 The present case is also composed mainly of eosinophilic spindle cells arranged in fascicles with various degrees of inflammatory cells. The interlacing fascicles that mimic leiomyosarcoma and a partial storiform pattern in addition to scarlike fibrous features are characteristics of this tumor. These microscopic findings are analogous with those of extrapulmonary IMTs described by Coffin et al.6

To our knowledge, only 2 cases of IMT of the bone have been reported in the literature, both by Sciot et al,12 but the clinicopathologic features of those cases are considerably different from the present case. First, in the cases described by Sciot et al the tumors occurred in young and middle-aged men, whereas our case occurred in an elderly patient. Second, although the plain radiograph and magnetic resonance image examination showed metadiaphyseal well-delineated lytic lesions localized in the bone in the cases described by Sciot et al, the present case exhibited an aggressive expanding growth into the surrounding soft tissue. Third, their tumors were composed of a paucicellular dense collagenous tissue and lacked the spindle cell-rich sarcomatous area found in the present case. Finally, the prognoses of their cases were excellent, and neither metastasis nor local recurrence was seen after curettage alone.

Inflammatory fibrosarcoma (IFS) is a designation proposed by Meis and Enzinger7 for tumors that are locally aggressive or that can cause distant metastases. They described 38 cases of IFS in their original paper, and, in fact, 3 of the tumors metastasized to the lung or brain. Although there has been a controversy as to whether IMT and IFS are different tumors, it is currently recognized that IMT and IFS are interrelated neoplastic lesions. These lesions exhibit a range of morphologic atypia and a behavior characterized by local aggressiveness and rare metastasis.10,13-17 Recently, clonal chromosomal changes have been reported, providing additional evidence of a neoplastic origin. 12,18

Inflammatory myofibroblastic tumors of the bone should be histologically differentiated from other malignant spindle cell tumors. The tumors most likely to be confused with IMTs are malignant fibrous histiocytoma19,20 and leiomyosarcoma.21 Although IMTs occasionally show a weak storiform pattern and mild-to-moderate nuclear atypia, the strong pleomorphism characteristic of malignant fibrous histiocytoma is not seen in IMTs. In addition, IMTs lack the abnormal mitoses that are common in malignant fibrous histiocytoma. Malignant fibrous histiocytoma of inflammatory type is characterized by numerous inflammatory cells within the tumor, but composed inflammatory cells are predominantly neutrophils and histiocytic foamy cells distinct from IMTs. On the other hand, the differentiation between IMTs and leiomyosarcoma is more difficult, because IMTs may be composed of eosinophilic spindle cells arranged in interlacing fascicles. The intense immunoreactivity of IMTs for a-smooth muscle actin or muscle actin can lead to a misdiagnosis of leiomyosarcoma.6,7,22 The difficulty in differentiating both of these tumors has been pointed out in the soft tissue and the urogenital tract tumors.8,9 Recently, it was demonstrated that high-molecular-weight caldesmon, a protein that binds to actin and tropomyosin and regulates cellular contraction,23-25 is highly specific to smooth muscle cells and is not expressed in reactive myofibroblasts and myofibroblast-related tumors.26-29 Thus, the use of this antibody is thought to be extremely useful in differential diagnosis.27-29 In addition, inflammatory cells are usually less conspicuous in leiomyosarcoma than in IMTs. A desmoid tumor of the bone may be included in the differential diagnosis, because the present cases had, in part, a fibromatosis-like hypocellular region. In general, however, desmoid tumors are richer in collagen fibers and less cellular than IMTs, and, in addition, numerous inflammatory cells are unusual features in the desmoid tumors. Conventional fibrosarcoma is usually ruled out by its histologic characteristics, which include interlacing fascicles with a herringbone arrangement and lack of myofibroblastic dif ferentiation shown by immunohistochemistry. Finally, the distinction from low-grade myofibroblastic sarcoma recently reported by Mentzel et al30 in soft tissue is difficult, because those tumors also show myofibroblastic proliferation without pleomorphism. However, low-grade myofibroblastic sarcoma lacks inflammatory cells and myxoid stroma different from IMTs, yet both tumors may be intimately related.

In summary, a case of an IMT (IFS) of the bone is described. Standard radiograph and magnetic resonance imaging examinations revealed osteolytic masses that extended into the surrounding soft tissue. On histologic examination, the tumor was composed of a sarcoma-like cellular area and a fibromatosis-like hypocellular area. Various degrees of inflammatory cell infiltration were a distinctive feature. In addition, the tumor cells exhibited diffuse and intense immunoreactivity for a-smooth muscle actin and muscle actin. The tumor metastasized to the lung 1 year after it was extirpated. This is the first report to our knowledge of an IMT of the bone with distant metastasis.

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Kazuo Watanabe, MD; Takahiro Tajino, MD; Mihoko Sekiguchi, MD; Toshimitsu Suzuki, MD

Accepted for publication February 22, 2000.

From the Pathology Division (Drs Watanabe and Suzuki) and Department of Orthopedics (Drs Tajino and Sekiguchi), Fukushima Medical University School of Medicine Hospital, Fukushima City, Japan.

Reprints: K. Watanabe, MD, Pathology Division, Fukushima Medical University School of Medicine Hospital, 1 Hikariga-oka, Fukushima City, 960-1295, Japan (e-mail: w-kazuo@fmu.ac.jp).

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