Extra-thoracic solitary fibrous tumour, malignant Dr. Françoise Collin Dijon, France

Case History: A 32-year-old man presented with urine retention. CT-scan and MRI were performed. They revealed a large pelvic mass with well-defined margins, located in the pre-sacral area. The rectum was displaced laterally, and the bladder was pushed forward. Sacral bone was uninvolved. A well circumscribed and partly encapsulated tumor measuring 14 x 10 x 6 cm was resected. On cut section, it was made of a white-grey, fibrous-appearing focally nodular tissue, with a firm consistency. There were scattered hemorragic changes. Three years later, the tumor recurred as a 6.5 cm mass in the retroperitoneum. Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Pathologic Findings The neoplasm was limited by a fibrocollagenous capsule. It was composed of bland round to spindle cells with variably abundant pale to eosinophilic cytoplasm. The nuclei were oval, uniform in size, slightly hyperchromatic, with small nucleoli and occasional folds. Pleomorphism was minimal. No giant cell was identified. The lesion was hypercellular, without any remarkable architectural features. Cells were closely packed, there was no bundle formation or storiform arrangement. Mitotic activity was moderate, not exceeding 3 mitoses per 10 high-power fields. The most salient histologic feature was the presence of numerous dilated branching vessels. Large vessels usually had a thin wall, or were unfrequently hyalinized. Smaller vessels also had very thin walls. There were no hyalinized or myxoid areas. Collagen deposition was only present in the form of sparse dense thick fibers, and a few stellate structures suggesting amianthoid fibers. Patchy areas of necrosis represented no more than 5 per cent of the tumour. Immunohistochemistry showed frank but focal staining for CD34 and CD99. There was no staining for bcl2, cytokeratins, smooth muscle actin, desmin, h-caldesmon, CD117, S-100 protein, synaptophysin, chromogranin A, or neurofilaments. Proliferation marker Ki67 stained no more than 5 per cent of tumour cell nuclei. Positive cells were unevenly distributed. Additionally, as an hypothesis of a gastro-intestinal stromal tumour (GIST) had been raised, a study of mutations of KIT (4 exons) and PDGFRA (3 exons) was performed , detecting no mutation. Diagnosis : Extra-thoracic solitary fibrous tumour, malignant. Extended clinical history Three years later, a recurrent 6.5 x 5.5 cm mass was removed in the retroperitoneum. It was well circumscribed and partly encapsulated. Microscopic and immunohistochemical findings were very similar to those of the primary tumour. High cellularity, monomorphism and patches of necrosis were found. Mitotic activity did not exceed 3 for 10 high-power fields. Ki67 proliferation marker expression was found in about 20 % of the tumour cell nuclei. A 50 gy radiation therapy course was given. Two years later, liver metastases were found. A biopsy showed a poorly differentiated neoplasm made of round/ovoid cells with CD34 staining. The patient was treated with a chemotherapy regimen including doxorubicin, ifosfamide and DTIC. He died of disease 6 months later. Discussion Solitary fibrous tumour (SFT) was first described by Klemperer and Rabin [1] who were studying primary pleural neoplasms, and divided them into diffuse and localized subtypes. Most of their localized tumours originated in the visceral pleura. They were well-demarcated and often pedunculated. They pursued a rather indolent course, though there were a few recurrent cases, and very rare metastasizing tumours. Conversely, diffuse neoplasms of the pleura portended a dismal prognosis. The mesothelial or fibroblastic nature of localized tumours remained disputed for years in many studies involving electron microscopy and immunohistochemistry [2, 3, 4] Since 1990, peritoneal, then non-serosal tumours were reported bearing the same clinicopathologic features, until 1996 which was according to Chan [5] the "year of the solitary fibrous tumour". This diagnosis became very popular in a wide variety of tumour sites, while malignant fibrous histiocytoma and hemangiopericytoma were waning [6, 7]. A large number of cases have been reported to date, comprising both thoracic and extra-thoracic neoplasms [2, 3, 4, 9, 10, 11, 12, 13, 14]. To summarize, SFT is a rare tumour which occurs in adults of all ages (mean 50 years) with no sex predilection. Extra-thoracic tumours are located in subcutaneous tissues in 40% of cases, and deep in other cases. Apart from thoracic sites (pleural, but also mediastinal, pericardial, thymic) which are the more frequently reported, a wide variety of locations have been described, either related to serosal cavities (peritoneum, omentum, retroperitoneum) or not : soft tissues of head and neck and especially orbit, extremities, pelvis, and many organs such as kidney, thyroid, salivary glands and meninges. Clinical symptoms are more likely to occur in patients with extra-thoracic locations. Hypoglycemia has been reported in a few cases. Gross examination reveals a fairly well demarcated tumour made of a white or tan tissue with a firm consistency and a whorled cut surface. Larger tumours may show areas of myxoid or hemorrhagic degeneration. The tumours range in size from 1 to 25 cm. Microscopic examination discloses a proliferation of spindled or rounded cells with no particular arrangement ("patternless pattern"). Cytoplasms are scanty and nuclei usually show very mild pleomorphism and rare mitotic figures. Multinuclear cells are occasionally found. Numerous dilated branching vessels of staghorn type are one of the hallmarks of this lesion, unfortunately shared by a number of other entities. Typically, SFT comprises alternating hyper- and hypocellular areas with abundant hyalinized collagen deposition. Immunohistochemical findings include diffuse and strong positivity for CD34 in most cases, and frequent expression of CD99 and bcl-2 protein. Focal staining for cytokeratins, muscle-specific actin, alpha-smooth actin, desmin or S100 protein has occasionally been reported. The mean number of MIB-1 positive nuclei was low (3,9%) in one study [12], in primary tumours or metastatic lesions. Electron microscopy performed in many studies showed that these tumours mostly comprised fibroblastic cells, with focal or prominent myofibroblastic differentiation [10, 12]. However others would call the same cells pericytes [15]. Molecular genetics yielded heterogeneous data. Up to now various techniques have failed to demonstrate recurrent abnormalities. DNA copy number changes were reported in SFTs larger than 10 cm [16]. All these morphologic features have been extensively reported. Two issues currently remain controversial : malignancy in SFT, and differential diagnosis including hemangiopericytoma. Malignancy in SFTs Increased recognition of SFT led to a large number of published cases with clinicopathologic reviews of pleural [2, 3, 13] or extra-thoracic diseases [8, 9, 10, 11, 12] or both [13]. Thoracic and extrathoracic SFTs basically show very similar features, as reported by Gold [13]. In his series, thoracic neoplasms were twice as frequent as extrathoracic (including visceral) ones. Among 75 patients who were treated by surgical excision in the same hospital, 5 had local recurrences and 4 developed distant metastases. Most series show a range of 10 to 20% of recurring and/or metastasizing tumours, but many of these neoplasms will have a very protracted course, and the outcome will not necessarily be fatal. The main sites of metastases are lungs, liver and abdominal cavity. Location is an important factor of prognosis. Among thoracic tumors of the series of England [3], pleural and pedunculated tumours had a better outcome than infiltrating or parietal or mediastinal ones, perhaps due to a better resectability. Other studies showed that tumours presenting with some clinicopathologic features were more likely to develop local recurrences and/or distant metastases : large size (10 cm and above), infiltration, high cellularity, more than 4 mitoses per 10 high-power fields, presence of a frankly sarcomatous component (sometimes called dedifferentiation), and necrosis. When analyzed separately [11], tumours exhibiting at least one of these features very often recurred or metastasized, but not all patients had a fatal outcome. Conversely, tumours devoid of adverse prognostic features sometimes recurred. However their recurrences could often be cured by simple excision. In spite of a better knowledge of their clinicopathologic features, SFTs of thoracic or extra-thoracic location remain neoplasms with an essentially unpredictable prognosis, though most of the patient will not die of their diseases. For these reasons, they have been classified into the intermediate (rarely metastasizing] category [16].They need a long-term follow-up, still more careful after resection of a recurrent tumour [11]. Our patient, with a tumour showing 3 adverse prognostic factors (size, high cellularity, necrosis), was at risk for an unfavourable outcome. Differential diagnosis including hemangiopericytoma To distinguish SFT from morphologically related neoplasms raises many issues. As stated by Chan [5], some diagnoses are raised more in keeping with the tumour location than on the ground of pathologic features. For example, serosal-based SFTs have to be distinguished at first from mesothelial proliferations, which show a cytokeratin+, calretinin+, CD34– immunoprofile. Immunohistochemistry also allows a careful evaluation of intra-abdominal SFTs, to distinguish them from gastro-intestinal stromal tumours, the latter expressing not only CD34, but also CD117 in most cases. The most crucial problems in differential diagnosis deal with hemangiopericytoma (HPC), an old entity which appears nowadays largely overlapping with SFT. However the last WHO classification [16] retained two different names for these tumours. Since its description in 1942 by Stout [17], who first collected 9 cases, then published 25 additional cases in 1949 [18], HPC was characterized by poorly differentiated cells associated with a prominent vascular component made of "staghorn" dilated branching vessels, and a largely unpredictable outcome. Its putative origin in Zimmermann's pericytes was never confirmed by electron microscopy or immunohistochemistry. A critical reappraisal was performed by Enzinger in 1976 [19], based on clinical and morphological observations. He drew pathologists' attention to the fact that some close mimickers of HPC were true sarcomas, while others, especially in children, were benign lesions. Since that time, the relation between HPC and SFT remained a controversial issue. Thus far, nobody could demonstrate that any of these lesions derived from pericytes. Most cases show a prominent component of fibroblastic cells, together with a variable proportion of myofibroblasts which may be reactive cells [20, 21, 22]. In recent studies [23, 24], the concept of HPC was reassessed. The authors retained the more basic fact that a hemangiopericytomatous pattern of growth could be met in three categories of tumours. The first category comprises several types of true sarcomas which must be ruled out at once. Poorly differentiated or spindle cell monophasic synovial sarcomas are the most frequently found. Positivity for cytokeratins is of great help for their diagnosis, molecular genetics still more if available. Additional sampling, immunohistochemistry and cytogenetics will help diagnose other sarcomas including fibrosarcomas, mesenchymal chondrosarcomas, or the so-called malignant fibrous histiocytoma. The second category of tumours is made up of SFT and its variants. They show CD34 positivity, but are devoid of muscular markers. The lesion called lipomatous HPC [25] is a kind of SFT including areas of mature adipocytes. It affects deep soft tissues, retroperitoneum and thigh being its most common locations. Similarly, giant cell angiofibroma [26] is a variant of SFT which harbors multinucleated tumour cells, some of which are lining pseudo-vascular spaces. Head and neck of adult people are mostly affected. The two latter neoplasms usually behave in a benign fashion. The tumours in the third category are benign neoplasms with myoid differentiation. They are related with smooth muscle neoplasms and glomus tumours. Immunohistochemical findings include positivity for muscle-specific actin and alpha-smooth actin, variable expression of h-caldesmon, very rare positivity for desmin, and negative CD34. Among those neoplasms, myopericytoma [27] is a cutaneous or subcutaneous nodule of the extremities in adult patients. It comprises a perivascular proliferation of myoid cells. Infantile myofibroma and myofibromatosis [28] are solitary or multiple similar lesions overlapping with infantile HPC. They may show substantial mitotic activity, vascular invasion, and necrosis. They are often present at birth, and may become life-threatening through possible visceral locations, though the lesion is intrinsically benign. Sinonasal hemangiopericytoma was also recognized many years ago as a benign lesion which rarely recurs. In most cases, tumour cells show immunohistochemical and ultrastructural features consistent with myoid differentiation, though a small subset of these tumours are probably true SFTs. Finally, meninges are the last site in which the controversial diagnoses, SFT or HPC, are still under debate. Though SFTs have been identified [29], the WHO classification retained the HPC diagnosis for these tumours [30]. However, they look like cellular SFTs, but they bear an ominous prognosis with high rates of local recurrences and extracranial metastases. 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