Section 5 -

Solitary Fibrous Tumors (SFTs): A Comparison Of Intrathoracic And Extrathoracic SFTs Chrystal van de Belt, Sonja Klebe, Thomas J. Dodd, Philip W. Allen and Douglas W. Henderson Departments of Anatomical Pathology Flinders University and Flinders Medical Centre, and The Institute of Medical and Veterinary Science, Adelaide, South Australia

Solitary fibrous tumors (SFTs) are uncommon localized spindle-cell fibroblastoid neoplasms that most commonly arise in relation to the pleura, where they are thought to arise from submesothelial mesenchyme. [1] First described in 1931 by Klemperer and Rabin, [2] SFTs have been reported under a variety of different names, but solitary fibrous tumor is preferred at present: [3] the former expression fibrous mesothelioma is to be avoided, because: (i) characteristically, the spindle cells comprising these lesions show no evidence of a mesothelial phenotype; and (ii) the term fibrous mesothelioma invites confusion with conventional mesothelial tumors. Intrathoracic SFTs most often arise in relation to the visceral pleura (~80% of pleural SFTs [3]) or the parietal pleura, [1, 4, 5] but they can also arise within the mediastinum, [6] as intraparenchymal lung tumors [6] and in relation to the pericardium [7] and diaphragm. [8] Over recent years, extrathoracic SFTs have been recorded with increasing frequency, in a variety of sites [9, 10] such as the orbit, [11, 12, 13, 14] nasal cavity, [9, 15] paranasal sinuses [15] and nasopharynx, [16] soft tissues of the extremities, [9, 17] retroperitoneum, [18] kidney, urinary bladder, [9, 19] seminal vesicle and prostate, [9] spermatic cord, vagina, [20] parotid gland, [21] thyroid, [22] liver, [23] pancreas, omentum/mesentery, [24] and meninges. [13] SFTs have been recorded in patients within the age range of 5–87 years, but they are rare in patients under the age of 10 years, and the peak incidence is between the 4th and 6th decades of life. One review of 55 patients with pleural SFTs recorded an age range of 18–80 years, with a mean of 55 years; [25] a smaller series of 14 intrathoracic SFTs recorded an older age range of 44–73 years, with a mean of 60 years. [26] Extrathoracic SFTs have been reported within a similar age range: a series of SFTs affecting the nasal cavity and paranasal sinuses reported an age range of 30–71 years, with a mean of 52, [15] and SFTs affecting the soft tissues of the extremities have been recorded in patients aged 17–60 years. [27] Both intrathoracic and extrathoracic SFTs have been recorded rarely during childhood, for example, in an 8-year-old boy (intrapulmonary) [28] and an 11-year-old girl (parotid gland). [21] In several series of intrathoracic SFTs, the tumors occurred more often in females than males, but one larger study had a male predominance (32/55 cases). [25] Extrathoracic SFTs are less common than their intrathoracic counterparts, and it is more problematical to detect a male:female trend. Most commonly, SFTs are discovered incidentally on routine chest x-rays or CT scans in asymptomatic patients. [3, 29] When present, symptoms can be related to the size of the tumor and the presence of involvement, compression or intrusion into surrounding tissue. [29] In such circumstances, symptoms related to intrathoracic SFTs include non-specific symptoms such as fatigue, fever, night sweats and weight loss, whereas symptoms related to the intrathoracic location include cough, dyspnea, chest pain, digital clubbing, hypertrophic osteoarthropathy and, less commonly, hypoglycemia related to production of insulin-growth factor [30] (Doege-Potter syndrome [3]). In contrast, extrathoracic SFTs are more often symptomatic, related to the site of their occurrence. In a review of 79 cases of SFT [31] — 54 intrathoracic and 25 extrathoracic — 89% of the intrathoracic lesions were asymptomatic, whereas 83% of the extrathoracic SFTs were associated with symptoms, which varied according to the range of sites in which the tumors arose: meningeal SFTs have been recorded to present with headache, [32] and those arising in the urinary bladder with a sensation of heaviness, frequency of micturition, and difficulty in voiding. [19] All patients with nasal/paranasal SFTs in one series presented with symptoms of a nasal obstruction, and rhinorrhea and epistaxis can also occur. [15] In the case of SFTs affecting the somatic soft tissues, the lesions presented as a painless mass lesion. [27] Both intrathoracic and extrathoracic SFTs vary greatly in size: in one series of intrathoracic tumors, the SFTs ranged from 1.3 to 33 cm in greatest diameter. [26] In a study of 22 SFTs arising in the nasal cavity and paranasal sinuses, there was a smaller range in tumor size (2.8–8 cm). [15] A range of diameters has also been recorded for SFTs in other extrathoracic sites: 5–26 cm for the pelvis, [33] 1–13 cm in the meninges, [32] and 3.2–17 cm for SFTs arising from the urinary bladder wall. [19] Detection of SFTs within the thorax and other similar axial sites is characteristically based on radiological examination, which may give some inkling of the diagnosis (e.g., a smooth localised pleura-based tumor [3]), but definitive diagnosis requires histological examination of either a biopsy or surgical resection specimen. Characteristic of SFTs, irrespective of their site, is a histological picture ranging from the 'patternless pattern' of Stout to 'herringbone', cellular, short storiform, diffuse sclerosing, myxoid and hemangiopericytic or angiofibromatoid areas, and areas with neural-type palisading and, in some instances synovial sarcoma-like areas. [1, 3, 5] The bipolar spindle-shaped cells resemble fibroblasts, and they often show a distinctive localisation along and parallel to stromal collagen bundles. Multinucleated giant cells occur in some cases, and calcification, and ossification may be present: other changes include cystic degeneration, necrosis, and haemorrhage. It is characteristic of SFTs that several of these patterns coexist within the same tumour. Varying degrees of nuclear atypia and pleomorphism, and mitotic activity can be found, and the mitotic index in particular appears to be a probability marker for a diagnosis of malignant SFT (see following discussion). Entrapped alveolar epithelium may be present. [3] There appear to be no histological differences between intrathoracic and extrathoracic SFTs, and the latter are, in particular, recognised by their histological resemblance to their intrathoracic counterparts, including their immunophenotype. The differential diagnosis includes a variety of other spindle-cell fibroblastoid tumors that can arise in relation to the pleura, chest wall, mediastinum and other sites where both intrathoracic and extrathoracic SFTs have been recorded, including intrathoracic gastrointestinal stromal tumors (GISTs). In the case of pleural tumors, the major differential diagnoses include sarcomatoid and desmoplastic mesothelioma (which can occur as a localised tumor on occasions), fibroblastoid tumors arising in relation to the chest wall or ribs, monophasic synovial sarcoma, Schwannoma, inflammatory myofibroblastic tumor (inflammatory pseudotumor), calcifying fibrous (pseudo)tumor [29] and, perhaps, a spindle-cell carcinoma of lung with invasion of the pleura. In most instances, the histological findings can discriminate between the differential diagnoses at a reasonable order of confidence, but immunohistochemical studies are crucial if there is doubt. Characteristically, the fibroblastoid cells comprising benign SFTs are devoid of cytokeratin (CK) expression, and instead the cells show positive immunohistochemical staining for vimentin and CD34, [3] and less consistently for bcl-2 [34] and CD99. [9, 13, 35, 36] (However, in some malignant SFTs, the tumor may show no evidence of CD34 expression either throughout or over extensive areas; in addition, malignant SFTs may show a lobulated growth pattern, with incorporation of linear arrays of hyperplastic mesothelial cells into the tumor, but the background fibroblastoid cells are still devoid of CK expression.) Intrathoracic gastrointestinal stromal tumors (GISTs) can be excluded by the absence of staining for CD117 (c-kit), and Schwannomas by their positive labelling for S-100 proteins and other markers of Schwannian differentiation. Discrimination between benign versus malignant SFTs remains problematical. In their series of 223 SFTs, England et al [1] commented that there appeared to be no clearly defined histological discriminators between benign versus malignant tumors: as indicators of malignancy they invoked high cellularity, nuclear atypia and pleomorphism, and more than four mitotic figures per 10 high power fields (HPFs), among others. At the same time, about 45% of the cases so designated as malignant appeared to have been cured by surgical resection suggesting either that such tumors have a favourable prognosis or, alternatively, that the histological indicators of malignancy were not reliable. Other clear or probabilistic markers for malignancy in SFTs include metastasis, invasion of adjacent structures, sessile as opposed to pedunculated tumors, focal tumor necrosis and large size — by way of analogy with the criteria for malignancy in GISTs — and localization to the parietal pleura as opposed to the visceral pleura. [5] At present, it seems that assessment of malignancy is best based upon a multifactorial approach (one wonders whether a Bayesian method might yield discrimination at a higher order of confidence than the non-Bayesian approach used at present). Accordingly, it seems that a small pedunculated tumor arising from the visceral pleura is likely to have a 'benign' course following apparently complete surgical resection, irrespective of the cellularity and cytological atypia seen focally within such a lesion. On the other hand, a large sessile tumor arising on parietal pleura, with areas of tumor necrosis and obvious invasion of the pleura is likely to pursue a 'malignant' course, irrespective of the degree of nuclear pleomorphism and atypia: e.g., the authors have encountered a case of a massive malignant SFT that arose as a sessile lesion in relation to the parietal pleura, with invasion of the pleura and chest wall and which recurred with a fatal outcome within 10 months of incomplete surgical resection, although exhaustive histological sampling of the tumor revealed no evidence of excessive cellularity, nuclear atypia or pleomorphism, and only extremely rare mitoses could be found. Therefore, by extension of the criteria put forward by Churg, [37] it appears that the major discriminators in perhaps the following order of rank would favour assessment of a SFT as malignant as opposed to benign, in biopsy tissue or a surgical resection specimen: Invasion of adjacent structures (pleura, chest wall, lung). Areas of overtly sarcomatous tissue within an SFT, and not resembling SFT. Areas of tumor necrosis (as opposed to ischaemic-type necrosis possibly related to partial portion of the lesion). More than four mitotic figures per 10 high-power fields. High cellularity, with prominent nuclear atypia and pleomorphism. Occurrence on the parietal pleura. Sessile tumor. Large tumor size (>10 cm). Associated pleural effusion. Local tumor recurrence following surgical rescetion. With the exception of invasion (or metastasis), most of these markers may be regarded as probability indicators, and some are probably linked (non-independent) variables: assessment of the benign versus malignant status of an SFT is arguably best based upon a combination of findings. Depending on the above combination of findings, we report SFTs as benign (no histologic evidence of malignancy), SFTs with features of malignancy (e.g., SFT with invasion), and SFTs of uncertain malignant potential. From the literature, benign SFTs appear to predominate within the thorax: in one study of 36 cases, only two recurred locally [38] (see later discussion). Another series of 55 cases [25] revealed features of malignancy in four, but only case showed aggressive behaviour, with local recurrence. In another study, four out of 14 cases were assessed as malignant; [26] the malignant tumors were larger in diameter (>20 cm) and were soft and fleshy, and they showed high mitotic activity, with an average of about 7 mitoses per 10 HPF. Extrathoracic SFTs appear to be predominantly benign, although one case affecting the meninges recurred on four occasions with distant metastasis to the lung. [32] Wherever possible, management of SFT is by surgical resection. [3] It has been observed that incompletely resected pleural SFTs can recur locally, sometimes as multiple tumor nodules, even where there are no other indicators of malignancy. Therefore, we recommend that local resection of pleural SFTs should include a tumor-free margin of about 10 mm around the base of the pedicle or base of the tumor, whenever feasible. 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