HISTORY AND PHYSICAL EXAMINATION
A 63 year-old man presented with a 7-year history of a slow-growing, painless mass arising in the midline thoracolumbar spine. He had no other complaints, especially none of the pelvis or lower extremities. Initial imaging studies included biplane conventional radiographs of the thorax and the thoracolumbar spine and computed tomography (CT) scans of the spine. The CT scans showed a circumscribed solid tumor with a diameter of 17 cm (Fig 1).The tumor was delineated by a partially calcified pseudocapsule and showed signs of invasion into surrounding structures, including the spinous process of T10 (Fig 1). Based on the clinical history and the CT scans, the lesion was judged to be a slow growing, benign lesion. A primary wide resection was performed. Histopathologic analysis of the resected specimen showed wide surgical margins and a benign-appearing mesenchymal tumor composed of spindle cells of varying cellularity. The findings were judged most consistent with a hemangiopericytoma (HPC). After an uneventful followup period of 1 year the patient was lost to followup.
Nine years later, the patient presented again and reported progressive low back and left hip pain that began 2 months prior. On clinical examination there was a large recurrent solid subcutaneous palpable mass 5 × 7 cm at the previous surgical site. Hip motions were painful and the left iliac wing was painful on palpation. Neurologic examination was normal. All laboratory values were in normal limits.
Imaging studies were obtained including plain radio- graphs (Fig 2), a CT scan (Fig 3), magnetic resonance imaging (MRI) (Figs 4, 5), and whole body technetium 99m-methylene diphosphonate scans. Based on the history, physical examination, and imaging studies, what is the differential diagnosis?
Anteroposterior (AP) plain radiographs of the thorax showed soft tissue calcifications at the level of the spinous processes of T10 and T11 (Fig 2A). In the left iliac bone, a large osteolytic lesion with a pathologic fracture at the most proximal part of the bone was seen (Fig 2B).
Computed tomography scans of the pelvis showed a 13 × 8-cm expansile, circumscribed, partly calcified mass displacing the surrounding muscles (Fig 3). The studies suggested ingrowth of the tumor into and around the left acetabulum and the hip (Fig 3B).
A T1-weighted gadolinium-enhanced MRI showed a 4 × 5-cm local recurrence with destruction of the spinous process of T11 and invasion of the laminae and surrounding tissues (Fig 4A). On T2-weighted images, the tumor showed only slightly higher signal intensity (Fig 4B). There was no invasion or compression of the spinal cord (Fig 4). The MRI of the pelvis also showed a large mass in the left iliac bone invading the acetabulum (Fig 5). Both tumor locations showed low signal intensity on T1- weighted MRI scans (Figs 4A, 5A) and a higher signal intensity on short tau inversion recovery (STIR) MRI (Fig 5B), with an area of central necrosis of the iliac mass (Fig 5A).
Whole body radionuclide imaging showed high uptake of radioactive tracer in the area of T9 and T11, the left part of the sacrum, and the left iliac bone. There were no suggestions of other lesions. Taken together, the radiologic findings combined with the clinical picture suggest a benign aggressive process.
Malignant fibrous histiocytoma
Ossifying fibromyxoid tumor
Malignant peripheral nerve sheath tumor
Percutaneous Yamshidi biopsies of both lesions were performed (Figs 6-8). Based on the history, physical examination, diagnostic images, and histologic appearance, what is the diagnosis and how should this patient be treated?
Gross inspection of the resected spinal specimen showed an elastic firm mass with gray or tan-white cut surfaces on serial sagittal sleeve resections. Histopathologic, immunohistopathologic, and ultrastructural analyses of the recurrence biopsies, the iliac biopsies, and of the old resection specimens were performed. All showed a spindle-cell proliferation with irregularly hyalinized bands of collagenous matrix between clusters of cells and collagen. There was marked vascularity with perivascular hyalinization. Immunohistochemistry showed tumor cells to be positive for vimentin, Factor XIIIa, CD117 (C-kit) and, focally, for S100. Other tumor markers (CD31, CD34, LCA, keratin, desmin, Bcl-2, SMA and ULEX) were negative. Ultra- structural analysis revealed the presence of lobulated nuclei, and the cytoplasm contained mitochondria and microfilament differentiation. The primary tumor characteristically showed an incomplete shell of lamellar bone at the periphery with a complete pseudocapsule (Fig 6). The recurrence and metastasis biopsies showed similar histopathologic and immunohistochemical features as the primary tumor, but no shell of peripheral lamellar bone (Figs 7, 8).
In contrast with the previous histopathologic diagnosis, the primary tumor, the local recurrent, and the metastasic lesion were most consistent with an ossifying fibromyxoid tumor of soft parts (OFMT) and not an HPC.
Ossifying fibromyxoid tumor
DISCUSSION AND TREATMENT
As treatment, wide en bloc resection of the recurrent spinal tumor was planned. Initially, an en bloc laminectomy of the levels T8 through T11, including part of the underlying dura, was performed. The dura-defect was reconstructed with a dura-patch, followed by a multilevel dorsal spinal stabilization. Frozen sections taken during surgery showed resection margins free of tumor. The tumor was fixed onto the part of resected dura without invasion of it. There were clear signs of invasion of surrounding muscular structures and invasion and destruction of bone (lamina and spinous process). Microscopically, the recurrent tumor was well circumscribed and surrounded by a pseudocapsule (Fig 7). Resection margins were free of tumor. The tumor showed a spindle-cell proliferation with irregularly hyalinized bands of collagenous matrix. There was no clear rim of lamellar bone (Fig 7). The mitotic activity index (MAI) was five mitoses per 10 high power fields. Immunohisto- chemically, the biopsy and specimens of the primary tumor showed similar findings.
At the top of our differential diagnosis was HPC; however, the negativity of the present tumor for CD34 and the morphology strongly suggests against HPC.9 Additionally, malignant fibrous histiocytoma is a high-grade sarcoma with frequent typical bizarre tumor giant cells.14 Hemangioendothelioma and angiosarcoma are vascular tumors, and the latter is a high-grade sarcoma. Both tumors are positive for CD34.14 Malignant peripheral nerve sheath tumor is also a high-grade sarcoma, frequently growing fascicles, with or without neurogenic differentiation.14 In all these tumors there typically is no shield of bone as seen in the current case. In high-grade sarcomas, high nucleus- to-cytoplasm (N/C) ratios with high mitotic activity indices are typical and therefore they were excluded.14
Two weeks postoperatively, embolization of the left iliac wing metastasis was performed, which unfortunately was complicated by the development of multiple lung emboli. Therefore, the intended surgical intervention of the left hemipelvis was postponed. Magnetic resonance and radionuclide imaging studies performed 3 months postoperatively showed an increase in size and extent of the tumor in the left hemipelvis, and a new process in the right iliac bone (Fig 9). Palliative radiotherapy with a total dose of 20 Gy was used on both masses in the pelvis, and an experimental chemotherapy regime consisting of intermitted imatinib mesylate infusions (Gleevec®, Novartis, Stein, Switzerland) was started for the duration of 12 months.
Four years later, the patient walked with a cane for short distances. Repeat staging studies showed no signs and symptoms of a local spinal recurrence or other metastases and the pelvic masses showed no increase in size. Surgical excision was not considered an option for this 78-year-old man.
An ossifying fibromyxoid tumor (OMFT) of soft parts is a rare soft tissue tumor first described by Enzinger et al in 1989.3 Generally, an OFMT occurs predominantly in adult men with a mean age of 47 years.3 However, a case of OFMT occurring in a 3-week-old boy has been reported and therefore, the tumor probably can occur at any age.1 The majority of these tumors present as a painless, slow- growing mass in subcutis or muscle.3,4 In order of frequency, the tumor is located on the upper and lower extremities, the trunk, head, and neck.4 Ossifying fibromyxoid tumor presenting on the back, as in our patient, is very rare, with less than five cases reported to date.7 On physical examination, the tumor often has a firm, hard rubbery consistency.3 Tumor size can vary from 1 to 17 cm in diameter.3,4
Little is known about the appearance of OFMT on radiologic imaging studies. Most findings reported in patients with OFMT are irregular calcifications on radio- graphs. Some cases also show focal destruction of the adjacent cortical bone.10 Because of the good vascularization, significant enhancement of the soft tissue on contrast- enhanced-CT scans can be seen. Additionally, CT scanning clearly shows the typical bone formation, present in 80% of the cases.10 In our patient, we also found peripheral bone formation in the primary lesion. However, CT scanning of the recurrent lesion showed a homogeneous, noncalcified mass with predominantly high attenuation and possible areas of necrosis on contrast-enhanced images. As described in the literature, on T1-weighted MRI scans, the tumor showed low signal intensity and high intensity on STIR. Additional features revealed by MRI are central necrosis and invasion of surrounding tissue.10
Macroscopic examination of OFMT usually reveals a well-circumscribed, spherical, multinodular or lobulated tumor covered by a thick fibrous membrane or pseudocapsule.3,4 In approximately 80% percent of the cases, an incomplete shell of lamellar bone is present in the periphery of the lesion.3,4 Most tumors arise from the deep subcutis and often are attached to underlying fascia, muscle, or tendon. In ⅓ of the cases, the tumor originates in the muscle.3,4 In our patient, the tumor, the recurrence, and metastases showed signs of invasion and destruction of surrounding structures (acetabulum, hip, lamina, and spinous process T9 -T10). These features only occasionally are described in literature.4 The exact behavior of local recurrences has not been described. The recurrent spinal lesion showed local invasion and destruction of bone and surrounding soft tissue. The tumor was attached to the dura without invasion. As in the presented case, OFMT is often a highly vascularized tumor, and frequently shows deposition of hyalinized collagen around the dilated vessels on histologic examination.2,3,13 Because of the rich vascularity, the tumor occasionally may have a rose-red appearance and show focal hemorrhage on cut sections instead of the typical white-tan appearance.3,5
On microscopic examination, the tumor usually shows small, round tumor cells that vary little in size and are separated by varying amounts of mucoid material, collagen, and osteoid.2,3 Tumor cells contain small amounts of eosinophilic cytoplasm and have eccentrically placed, round and oval, pale-staining vesicular nuclei with inconspicuous nucleoli.3,7,13 In some areas, tumor cells are aligned in a distinct cordlike or linear pattern separated by a fibromyxoid matrix, but most often they are arranged in a solid pattern.3,10,13 In some cases the tumor cells are distributed randomly or show transition toward a clear- cell or spindle-cell pattern and nuclear palisading.3 Intra- cellular vacuoles are often a prominent feature.3 Most cases of OFMT show a low mitotic rate.4,7 Because the tumor cells ultrastructurally show continuous basal lamina, long interdigitating cell processes, and microtubules and microfilaments in the cell processes, many investigators suspect a Schwannian origin.4,13
Although the thick fibrous membrane or pseudocapsule is a characteristic feature, close examination often shows small protrusions into surrounding tissue. Nests of tumor cells often are present in these protrusions and therefore may be the source of a local recurrence.2,13 Other features that occasionally can be present in OFMT include focal spindle cell areas, hyalinized and epitheloid areas, entrapped hyperplastic eccrine glands, cystic changes, and cartilage and bone localized in the tumor shells or septa or distributed randomly throughout the lesion.4,13 In our patient, instead of a complete shell of bone, metaplastic ossifications were found.
Immunohistochemical analysis shows (focal) positivity for S100 protein in about ⅔ of all cases.3,4,7 There seems to be a significant relation between tumor appearance and S100 protein expression; S100 expression is higher in typical cases than in atypical variants. In tumors that contain both banal and atypical foci, expression of S100 protein is often diminished in the atypical zones.4,10 About ½ of the tumors investigated are positive for vimentin.2,5 Our patient showed focal positivity for S100 protein and strong positivity for vimentin. While the exact origin of the tumor remains uncertain, the high expression of S100 protein and vimentin favors an origin as nerve sheet tumor, especially a schwannoma.2,4,5 Other markers that occasionally are positive in OFMT are desmin, cytokeratin, and collagen Type 2.4,13
Cytogenetic analyses of OFMT have been published in only two cases.8,11 One case revealed a loss of chromo- some 6 in the primary tumor, extra material attached to the long arm of chromosome 12, and an unbalanced translocation involving chromosomes 6 and 14.6 Interestingly, the authors conclude that these genetic changes imply an osteochondroid origin of OFMT and therefore seem to contradict the immunohistochemical findings; these preliminary genetic observations agree with the genetic changes that are commonly seen in chondroblastic tumors and osteosarcomas.4,11
There is currently no well-documented role for chemo- therapy or radiotherapy as primary or adjuvant therapy.4 Because of the progression of disease in the current case, in spite of radiotherapy, and because both metastases are not amenable to surgery, experimental imatinib mesylate therapy was started. Imatinib mesylate is a tyrosine-kinase inhibitor of the bcr-abl fusion protein, the stem-cell factor receptor C-kit (CD 117) and the platelet-derived-growth- factor receptor.6 Successful treatment with imatinib mesylate in chronic myeloid leukemia, gastrointestinal stroma- cell tumors, and dermatofibrosarcoma protuberans has been reported.6 It is currently being evaluated in treatment of other C-kit positive tumors; in the current case, the tumor stained positive for C-kit. Prechemotherapy and repeated postchemotherapy whole body positron emission tomography (PET) scanning studies and MRI studies of the pelvis did not show a significant increase in tumor activity, no new metastasis, and no progression of the metastatic lesions, respectively. Nonetheless, the role of imatinib mesylate as an adjuvant in keeping the metastasis in a more or less steady state is unclear. There is no evidence in the literature that substantiates the clinical course of similar cases and the use of this drug in OFMT.12
Ossifying fibromyxoid tumor is generally regarded as a benign tumor, though cases of recurrence, metastases and even death have been reported. Folpe and Weiss tried to define criteria that could predict the risk of metastasis in patients with OFMT. After studying 51 patients they found that high cellularity, high nuclear grade, and high mitotic activity (> 2 figures/50 HPF) were associated with the development of metastatic disease and local recurrence.4 They suggested the term malignant OFMT for these cases and recommended that these tumors should be regarded as sarcomas. Unfortunately, the remainder of tumors also possesses a risk of metastasizing and should be considered tumors of intermediate malignancy.4 Folpe and Weiss also noticed that tumors without typical components had an overall architectural arrangement that was highly similar to the typical OFMT, namely lobular corded and nested growth.4 Other features seen in atypical lesions are less intercellular matrix and frequent nuclear overlapping. Gradual transition from typical into malignant foci in OFMT is a well known feature.3,4,5 In our case, the primary tumor could be classified as a benign OFMT, while the local recurrence and the metastasis showed histologic features (eg, mitotic activity index [MAI], nuclear grade, cellularity) of a malignant OFMT.
Little is known about the natural course and prognosis of OFMT. In the original report of Enzinger et al,3 one case of metastasis occurred in a 47-year-old woman. The metastasis was discovered 20 years after the primary tumor; during these years she also developed three local recurrences. The metastasis had markedly increased cellularity and mitotic activity compared with the primary tumor. Unfortunately, she committed suicide shortly after the metastasis was found. Folpe and Weiss overall found 17% recurrence and 5% metastatic rates of typical OFMT.4 Finally, they found OFMT causing death in four patients (8%).
This report provides an example of a malignant variant of OFMT on a patient's back. Though some characteristics supported the diagnosis OFMT, such as the existence of a pseudocapsule, metaplastic bone-formation, and positivity for the markers S100 protein and vimentin, the diagnosis of HPC initially was preferred. Histopathologically, the recurrence and the metastases of the OFMT showed histomorphologic features of a higher grade of malignancy compared with the primary tumor. The primary tumor and the local recurrence and the bone metastases showed features of local aggressiveness, including invasion and destruction of bony structures, joints, and soft tissues. Treatment of choice is en bloc surgical resection aiming for wide surgical margins; long-term followup is mandatory.
STIR MRI = (short TI inversion recovery) an inversion recovery pulse sequence with specific timing so as to suppress the signal from fat.
Yamshidi = core needle biospy (also called ‘tru-cut’ biopsy)
Vimentin = intermediate filament typical for mesenchymal cells
MAI = mitotic activity index
CD117 (C-kit) = stem cell factor-receptor Factor XIIIa = blood clotting protein expressed by endotheilial cells.
S100 = protein related to neural differentiation CD31 = a transmembrane cell surface glycoprotein expressed by macrophages, granulocytes, B cells and eosinophils.
CD34 = a transmembrane cell surface glycoprotein expressed by hematopoietic progenitor cells, endothelium, and certain mesenchymal stromal cells in the dermis.
LCA = (CD45) a transmembrane cell surface glyco- protein expressed by leukocytes.
Keratin = protein expressed by keratinocytes. Desmin = an intermediate filament indicative of myogenic differentiation.
Bcl-2 = anti-apoptotic protein first described in follicular B-cell lymfomas, but also expressed in various epithelial and mesenchymal tissues.
SMA = smooth muscle auto-antigen
ULEX = glycoprotein expressed by cells with endothelial or epidermal differentiation
The authors thank The Dutch Soft Tissue Workgroup for reviewing the case and histology.
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