Solitary fibrous tumor

INTRODUCTION — Solitary fibrous tumor (SFT) comprises a histologic spectrum of rarely metastasizing fibroblastic mesenchymal neoplasms that includes tumors formerly classified as hemangiopericytoma [1,2]. Although they are commonly thought of as intrathoracic tumors, 50 to 70 percent of SFTs arise outside the thorax, including the central nervous system (CNS). The clinical manifestations, diagnosis, management, and prognosis of SFT at sites other than the CNS are reviewed here.

Data on the presentation, clinical features, and natural history of SFT are nearly exclusively derived from retrospective series and case reports. The rarity of SFT, historical bias in subclassifying tumors by body site (pleural versus extrapleural) and histology (SFT versus hemangiopericytoma), as well as changes in diagnostic terminology over the years have resulted in a fragmented, unsystematic approach to this neoplasm.

SFTs/hemangiopericytomas arising within the CNS are discussed elsewhere. (See "Uncommon brain tumors", section on 'Solitary fibrous tumor'.)

PRIOR NOMENCLATURE — The discovery of a shared, recurrent, and thus far unique gene fusion in solitary fibrous tumor (SFT) and tumors previously histologically identified as hemangiopericytoma has confirmed the identical nature of these tumors. SFT is the preferred terminology, and the use of the term "hemangiopericytoma" is considered obsolete across all anatomic sites [1-3].

SFT was first described in the pleura in 1931 and historically recognized by several names (eg, benign mesothelioma, localized mesothelioma, solitary fibrous mesothelioma, pleural fibroma, submesothelial fibroma, subserosal fibroma, and localized fibrous tumor) [4]. However, SFT can occur anywhere in the body, including soft tissue and viscera, albeit with a peculiar predilection for body cavity sites, including pleura, peritoneum, and meninges.

Hemangiopericytomas were first described in 1942 and initially thought to be a vascular neoplasm related to smooth muscle perivascular cells known as pericytes [5]. However, the diagnosis was largely descriptive, based upon a nonspecific, albeit characteristic, staghorn vascular pattern, and the term became a "wastebasket" diagnosis, which included a variety of unrelated benign and malignant entities. With the advent of diagnostic immunohistochemistry (IHC) and cytogenetic analysis, pathologists were able to exclude histologic mimics, and hemangiopericytoma became more accepted as a distinct entity, although largely a diagnosis of exclusion, until the recognition of phenotypic and behavioral overlap with SFT led pathologists to consider the two as one tumor type.

Sinonasal glomangiopericytoma, sometimes also called "sinonasal hemangiopericytoma," is a clinically, morphologically, and biologically distinct entity that differs from SFT and should not be confused with it [6].

EPIDEMIOLOGY AND RISK FACTORS — In one nationwide study, SFT accounted for 3.7 percent of all soft tissue sarcomas and mesenchymal tumors of intermediate malignancy presenting over a four-year period (2013 to 2016), with an estimated annual incidence of 0.35 per 100,000 individuals [7]. In smaller series, SFTs arising from the pleura have been estimated to occur with a frequency of 2.8 per 100,000 individuals [8-10]. Pleural SFTs account for less than 5 percent of all tumors arising from the pleura [9,11,12].

SFTs are most common in the fifth to seventh decades and may arise at any age. Meningeal tumors arise in slightly younger patients (fourth decade), while pleural SFTs often present in older patients (sixth to seventh decade, median age at diagnosis 56 to 60) compared with SFTs arising intraabdominally or in soft tissue [1,2,13]. Males and females are affected with SFT at equal frequencies.

There is no known association with environmental exposure to radiation, tobacco, asbestos, or other toxicants, and no known inherited, predisposing risk factors.

ANATOMIC DISTRIBUTION — SFTs preferentially arise in serosal membranes, the dura of the meninges, and deep soft tissues. In contemporary series, approximately 30 percent of cases arise in the thoracic cavity (including pleura, lungs, and mediastinum). Intrathoracic SFTs may arise in the pleura, mediastinum, or lung parenchyma.

Another 30 percent arise in the peritoneal cavity, retroperitoneal soft tissue, or pelvis (including visceral sites). Intraabdominal SFTs in the peritoneum, retroperitoneum, and pelvis constitute the largest site-related group in most series of extrapleural SFTs [14]. The retroperitoneum is the most common intraabdominal site, followed by the pelvic soft tissues. Visceral involvement, particularly of the liver [15] and genitourinary tract (bladder, prostate, seminal vesicle, kidney) may also occur. In large tumors involving multiple subsites (eg, pelvic soft tissue and urogenital tract), it may not be possible to accurately determine the site of primary origin [14]; this distinction has no biologic significance, but may impact the initial formulation of a differential diagnosis.

Approximately 20 percent of SFTs occur in the head and neck (including the meninges) [16-23]. SFTs of the extracranial head and neck most often arise in the sinonasal tract, oral cavity, and deep soft tissues, including orbit.

The remaining cases involve deep soft tissues of the trunk and extremities, or occasionally may arise in bone. It is extremely rare for SFTs to primarily involve superficial soft tissues (eg, dermis), and care must be taken to exclude histologic mimics, such as benign fibrous histiocytoma or dermatofibrosarcoma protuberans, before making the diagnosis in superficial sites [24]. (See 'Histologic variants' below and "Dermatofibrosarcoma protuberans: Epidemiology, pathogenesis, clinical presentation, diagnosis, and staging".)

CLINICAL PRESENTATION

Pleuropulmonary SFT — At presentation, approximately 40 to 60 percent of patients have nonspecific pulmonary symptoms, typically cough, shortness of breath, or chest pain [10,13,14,25-27]. Rarely, hemoptysis and obstructive pneumonitis may occur as a result of airway obstruction [13,28]. In other cases, an intrathoracic mass is incidentally detected in asymptomatic individuals at the time of chest imaging carried out for an unrelated reason.

Pleural SFTs can reach an enormous size while remaining asymptomatic. Large tumors that are not discovered incidentally can cause symptoms as a result of mechanical compression (eg, of the inferior vena cava, causing lower extremity edema, or of the heart).

Pleuropulmonary SFT cases may rarely be associated with digital clubbing and hypertrophic pulmonary osteoarthropathy (HPO; Pierre-Marie-Bamberger syndrome). (See 'Paraneoplastic syndromes' below.)

Two-thirds of pleural SFTs occur in the visceral pleura, where the tumor is often attached to the lung by a narrow pedicle, and one-third occur in the parietal pleura, where the tumors are often larger, with a broad-based attachment. Sometimes, imaging may not be able to determine whether the mass is arising from the pleura or from the mediastinum, and the actual site of origin may not be evident until surgery. (See 'Imaging findings' below.)

Intraabdominal SFT — A palpable abdominal mass is the most common presentation of an intraabdominal SFT, followed by pain and weight loss. Urinary symptoms including dysuria, urinary retention, hydronephrosis, nocturia, and gastrointestinal symptoms such as constipation, incontinence, or vomiting have also been reported. Because small tumors are typically asymptomatic, intraabdominal SFTs may attain large sizes (>20 cm) prior to presentation.

Meningeal SFT — Within the central nervous system (CNS), SFT are typically intracranial and originate from the dura. Clinically resembling meningiomas, these tumors cause symptoms by means of a slow increase in size, either by compressing adjacent structures or by increasing intracranial pressure. The clinical presentation of SFT arising in the brain is discussed in detail elsewhere. (See "Uncommon brain tumors", section on 'Solitary fibrous tumor'.)

Extracranial SFT of the head and neck — SFTs arising in the extracranial head account for approximately 10 percent of cases and typically present early as small, symptomatic tumors, most commonly involving the sinonasal tract and orbit [29,30]. In the orbit, the clinical presentation may include an expanding mass in the eyelid or orbit, epiphora (excess tearing), or proptosis.

In the oral cavity, SFTs can occur beneath the buccal mucosa, tongue, and lower lip [14]. In the sinonasal tract, SFTs often present with sinus/nasal obstruction and a painless mass. Tumors arising in the deep soft tissue of the cheek or neck most commonly present as a painless mass. Local recurrence is common (up to 40 percent) when tumors arise in difficult-to-access sites of the orbit or sinonasal tract, where complete, en bloc resection cannot be assured. While most tumors behave in a benign fashion, malignant behavior has been reported. (See 'Prognosis, recurrence risk, and assessing malignant potential' below.)

Soft tissue SFT — Approximately 10 percent of SFTs arise from deep tissues of the extremities, abdominal wall, and other sites, including the bones and diaphragm [14,31]. As with SFTs at other sites, the most common presenting symptom is a painless mass [14,22]. Paresthesias or other nerve symptoms may be present if the tumor impinges upon a nerve. SFTs are frequently slow-growing and the mass may be long-standing, gradually enlarging over several years, if not decades. Soft tissue SFTs tend to be smaller at presentation than pleural or intraabdominal SFTs, likely due to the relative ease of detection earlier in the course of disease.

Paraneoplastic syndromes — Uncommonly, patients come to clinical attention because of a paraneoplastic syndrome, most commonly hypoglycemia. Paraneoplastic syndromes may occur in patients with SFT arising in all sites.

Refractory hypoglycemia (Doege-Potter syndrome) occurs in <5 percent of cases and is primarily seen in large peritoneal/pleural tumors [32-34]. It is caused by tumor secretion of large insulin-like growth factor 2 (IGF-2) [35-37]. (See "Nonislet cell tumor hypoglycemia".)

Rarely, pleuropulmonary SFT may be associated with hypertrophic pulmonary osteoarthropathy (HPO) [38-40]. Originally described in 1935 by Bamberger and Pierre Marie and occasionally referred to as Pierre-Marie-Bamberger syndrome, HPO is characterized by clubbing of the fingers, periostitis, and synovial effusions. Although the precise mechanism underlying HPO is unclear, chronic hypoxia and tumoral secretion of hyaluronic acid or cytokines have all been proposed as effectors. (See "Malignancy and rheumatic disorders", section on 'Hypertrophic osteoarthropathy'.)

DIAGNOSIS — The diagnosis of SFT may be suspected based upon imaging and clinical features. However, a definitive diagnosis requires histologic confirmation.

Imaging findings

General features — Radiographic findings of a SFT on cross-sectional imaging (computed tomography [CT], magnetic resonance imaging [MRI]) are similar to those of other soft tissue tumors, and there are no pathognomonic features that are specific for this tumor type. Regardless of site, SFTs usually appear as a well-circumscribed soft tissue mass, which may be lobulated. Tumors are often homogenous in appearance, although cystic areas, calcifications, myxoid degeneration, or hemorrhage may be apparent, particularly in large tumors (image 1). SFTs tend to displace rather than invade surrounding tissues, and infiltrative borders may only rarely be appreciated in aggressive disease. The tumors enhance after contrast administration, and the enhancement may be homogeneous or heterogeneous.

On MRI, SFTs typically display low T1 signal intensity and variable T2 signal. Densely collagenized hypocellular tumors typically have low signal on T2-weighted images, while hypercellular tumors, highly vascular edematous tumors, or those with necrosis or myxoid degenerative changes demonstrate high signal intensity [41-43]. SFTs enhance intensely after intravenous gadolinium administration [8].

Thorax — On chest radiograph, pleuropulmonary SFTs usually appear as a well-defined, rounded, homogeneous mass (image 2).

On CT, SFT of the pleura typically appears as a well-delineated and occasionally lobulated mass of soft tissue attenuation arising from the pleura (image 3) [11,44]. Large tumors may attain a diameter greater than 20 cm. The tumors typically appear in contact with the pleural surface and show displacement or, less frequently, invasion of the surrounding structures. A pedicle is present in 40 percent of cases, resulting in marked tumor mobility, change in shape, or change in location in sequential images (image 4) [45,46]. A pleural effusion may be present [47-49].

Occasionally, SFTs may simulate mediastinal, paravertebral, or intrapulmonary masses, depending upon their exact location within the pleural cavity (image 5 and image 6). Uncommonly, a tumor arising from the parietal pleura can be "inverted" and appear to grow within the lung parenchyma [50,51].

MRI imaging is of limited utility for the assessment of pleural tumors. However, the morphology and relationship of SFT to adjacent mediastinal or major vascular structures, or the presence and extent of vertebral/foraminal involvement for large posterior chest tumors may be better appreciated with MRI than with CT [26]. Furthermore, MRI may be helpful in confirming intrathoracic localization when the tumor abuts the diaphragm [41].

Abdominopelvic tumors — The imaging appearance of SFT arising in the abdominopelvic cavity is similar to that arising in the thorax. The margins are well defined, the mass may be lobulated, and there is generally a lack of gross infiltration into adjacent tissues (image 7) [31,52].

SFTs arising in visceral sites such as the liver or kidney typically manifest as a large well-defined heterogeneously enhancing mass with or without areas of necrosis. A capsule may be evident (image 8 and image 9) [31].

Extracranial head and neck — On CT, extracranial SFTs of the head and neck appear as a solitary well-circumscribed mass that may be isointense to muscle on non-contrast studies [53-57]. The most common radiographic osseous finding is regressive remodeling of adjacent bone due to the long-standing pressure effects of the slow-growing mass [54]. Radiographic evidence of bone destruction may be seen, and this does not necessarily correlate with histologic features of malignancy [53].

The clinical presentation of intracranial (CNS) SFT/hemangiopericytoma is presented elsewhere. (See "Uncommon brain tumors", section on 'Solitary fibrous tumor'.)

Histopathology — Diagnosis of SFT requires histologic examination of an adequate tissue sample and is based upon recognition of typical morphologic features in conjunction with a characteristic immunophenotype.

Complete resection is required for full histopathologic evaluation. Fine needle aspiration biopsies are often inadequately cellular and are not recommended for diagnosis. In most cases, core biopsy will provide diagnostic material to establish a diagnosis of SFT, but the limited sampling provided by core biopsy may not accurately demonstrate the histologic evidence indicative of high risk of aggressive behavior.

Grossly, SFTs range from <1 cm to over 40 cm in diameter. Tumors are usually well circumscribed, with a fibrous pseudocapsule or serosal lining. Pleural tumors are frequently pedunculated; the pedicle typically contains large feeder vessels for the tumor. The cut surface of SFT ranges from firm and white for more fibrous tumors to tan and fleshy for cellular variants. Hemorrhage, necrosis, or calcification may be present, particularly in larger tumors [47].

Histologically, SFTs comprise a spectrum, with classic fibrous pleural SFTs representing the hypocellular phenotype and meningeal hemangiopericytomas typifying the hypercellular variant. Hypocellular SFTs are characterized by a dense collagenous background, often with hyalinized or thick collagen bands (picture 1). Variably atypical spindled cells are arrayed haphazardly within this stroma, in a storiform configuration or in randomly oriented fascicles, characteristically referred to as the so-called "patternless pattern." Less and more cellular areas alternate. Thin-walled, branching capillaries are always present but may not be prominent.

On the hypercellular end of the tumor spectrum, collagen fibers are scant or entirely absent (picture 2). Instead, tumors are composed of solid nests of neoplastic cells interspersed with very prominent branching and anastomosing "staghorn" capillaries. In cellular SFT, tumor cells may lose their spindled morphology and become more ovoid to rounded. Hemorrhage is common in cellular tumors, and necrosis may be present.

SFTs have a spectrum of biologic behavior, with the majority of tumors behaving in an indolent fashion with low risk of local recurrence or metastasis. (See 'Prognosis, recurrence risk, and assessing malignant potential' below.)

Histologic variants — Anaplasia or so-called "dedifferentiation" occurs in less than 1 percent of SFTs [58]. Anaplastic SFTs demonstrate marked nuclear atypia and pleomorphism in conjunction with a markedly elevated mitotic rate and may take the form of an undifferentiated spindle cell or pleomorphic sarcoma (picture 3). Heterologous elements, including osteosarcoma and rhabdomyosarcoma, have been reported, as well as diffuse keratin expression [59-61]. Anaplasia may be very focal or may overgrow the more typical areas to comprise the majority of the tumor. Extensive anaplasia in SFT is associated with a high rate of recurrence and a poor prognosis.

Several histologic variants (fat-forming "lipomatous" SFT; myxoid SFT; and giant cell rich SFT [formerly "giant cell angiofibroma"]) have no prognostic significance but are important due to their differential diagnoses.

●Fat-forming "lipomatous" SFT is a rare variant containing variable quantities of mature adipocytes [62]. The majority of fat-forming SFTs are benign, although malignant tumors are described, which may have an immature fatty (lipoblastic) component [63]. (See 'Histologic' below.)

●Focal myxoid change in SFT is common, likely resulting from increased connective tissue mucin production by neoplastic cells. Rarely, myxoid areas predominate in SFT, resulting in a very hypocellular, bland histologic appearance. (See 'Histologic' below.)

Ancillary diagnostic studies

Immunohistochemistry — Immunohistochemistry (IHC) is an extremely useful tool to differentiate SFT from other tumors, such as mesotheliomas and other sarcomas [64]. Entities in the differential diagnosis for SFT for which there are specific diagnostic IHC markers are summarized in the table (table 1). The histologic differential diagnosis for SFT is discussed in more detail below. (See 'Differential diagnosis' below.)

Conventional IHC markers of SFT include expression of CD34, Bcl2, CD99, and vimentin in the absence of actin, desmin, S100 protein, or epithelial markers (epithelial membrane antigen [EMA], low molecular weight cytokeratins). Although these markers have been historically useful to distinguish SFT from histologic mimics, they are not specific for SFT. Furthermore, they may be inconsistently expressed, leading to some difficulties in establishing the diagnosis in cases with non-classical histology.

IHC demonstration of strong nuclear expression of the C-terminal part of STAT6 (signal transducer and activator of transcription 6) has been shown to be a highly sensitive and specific marker for SFT, with aggregate sensitivity of 98 percent and specificity of greater than 85 percent [65-69]. STAT6 positivity alone may not be sufficient to distinguish some cases of SFT from its histologic mimic well-differentiated/dedifferentiated liposarcoma, as these tumors also rarely overexpress full-length STAT6 [70]. However, SFT lacks expression of MDM2 and CDK4, while well-differentiated and dedifferentiated liposarcoma will be positive for these markers. Moreover, STAT6 in SFT is typically confined to the nucleus, while well- and dedifferentiated liposarcoma express STAT6 in both the nucleus and cytoplasm.

STAT6 has also been reported to be expressed in a pathologic entity with GLI1 (GLI family zinc finger 1) gene alterations [71]. These GLI1-amplified or rearranged tumors predominantly arise on the tongue; have a multinodular growth pattern with distinctive nested architecture and small monotonous ovoid cells; and are histologically very distinct from SFT. STAT6 expression in these tumors is a result of co-amplification with GLI1.

Several additional markers have been identified through gene expression profiling as specific diagnostic markers of SFT relative to important histologic mimics. GRIA2 (glutamate receptor, ionotropic, AMPA 2) is reported to have 80 to 93 percent sensitivity for SFT [72], while cytoplasmic ALDH1 (aldehyde dehydrogenase 1) was reported to have an 84 percent sensitivity and 99 percent specificity for SFT versus meningioma and synovial sarcoma [73]. Subsequent studies have shown that ALDH sensitivity for SFT ranges from 76 to 97 percent, while GRIA2 sensitivity ranges from 64 to 84 percent with worse specificity than either ALDH1 or STAT6 against histologic mimics [74-76].

Molecular pathogenesis and molecular diagnostics — SFTs of all sites, including meningeal tumors, are characterized by a recurrent inversion of the long arm of chromosome 12 (12q13). This inversion results in fusion of two genes, NAB2 (NGFI-A binding protein 2) and STAT6 [65,77-79]. The NAB2 gene encodes a member of the family of NGFI-A (Nerve Growth Factor Inducible A gene) binding (NAB) proteins, which function in the nucleus to repress transcription induced by some members of the EGR (early growth response) family of transactivators, which are involved in cellular differentiation and proliferation. The product of the STAT6 gene is an inflammatory signaling intermediary that acts as a transcriptional transactivator. (See 'Ancillary diagnostic studies' above.)

The fusion of NAB2 and STAT6 creates a chimeric transcription factor in which the NAB2 repressor domain is substituted by a carboxy-terminal STAT6 transactivation domain or near-full-length STAT6. The NAB2-STAT6 chimeric transcription factor constitutively localizes to the nucleus, where it is thought to serve as a driver of tumorigenesis by constitutively activating NAB2 target genes [77].

The NAB2-STAT6 fusion gene is a distinct molecular feature of SFT, present in up to 100 percent of cases, which has not been detected in other tumors [77-80]. Other molecular abnormalities that drive tumorigenesis in SFT are extremely rare, although mutations in the platelet-derived growth factor beta (PDGFRB) gene have been reported in isolated instances of pleural SFT [81].

RT-PCR may be used to confirm the presence of the NAB2-STAT6 fusion gene, and this may assist in the diagnosis, but this is much less sensitive than IHC for STAT6 due to the diversity of possible fusion types [77-80]. The small size of the inverted sequence precludes the use of fluorescence in situ hybridization (FISH) for 12q13 rearrangement as a diagnostic modality. RNA-seq fusion assays identify most NAB2-STAT6 fusion products but can miss the rare intronic fusions.

At present, there are no distinct molecular features clearly separating benign from malignant tumors. All tumors likely possess some degree of metastatic potential. While an early study suggested that specific NAB2-STAT6 fusion variants may be associated with higher risk of aggressive behavior [80], this finding has not been confirmed by others [82,83]. Telomerase reverse transcriptase (TERT) promoter mutations resulting in overexpression of TERT have been reported in 20 to 30 percent of all SFT sites [84-89]. These mutations might have prognostic significance. Some observational series report shorter disease-free survival for patients with tumors that contain TERT promoter mutations compared with those that do not [84,88]. Other studies report a higher frequency of TERT promoter mutations in aggressive tumors, although this has not held true in all series [90-93]. TP53 mutations have also been found in high risk and anaplastic (dedifferentiated) SFT, and may contribute to aggressive phenotypes [88,91,94]. (See 'Prognosis, recurrence risk, and assessing malignant potential' below.)

Of note, IGF2, which is implicated in the pathogenesis of Doege-Potter syndrome (paraneoplastic hypoglycemia associated with SFT), is among the EGR target genes that are thought to be dysregulated by the NAB2-STAT6 chimeric transcription factor [77], possibly accounting for the frequency of this paraneoplastic syndrome in SFT. (See 'Paraneoplastic syndromes' above.)

DIFFERENTIAL DIAGNOSIS

Radiographic — The radiographic differential diagnosis for a pleural SFT includes focal tumor-like conditions such as posttraumatic thoracic splenosis or extrapleural hematoma and loculated pleural effusions causing a pleural pseudotumor in the interlobar fissures [95]. In addition, pleural metastases, sarcomatoid mesothelioma, and lymphoma should be considered [8]. For intrapulmonary SFT, the differential includes carcinoid, hamartomas, and pulmonary carcinoma.

For SFTs of the mediastinum, the differential diagnosis includes a thymic epithelial neoplasm, pericardial mesothelioma, sarcoma, lymph node mass, or a peripheral nerve sheath tumor.

The radiographic differential diagnosis for intraabdominal SFTs arising in the retroperitoneum or mesentery includes predominately malignant mesenchymal tumors such as synovial sarcoma, dedifferentiated liposarcoma, mesenteric fibromatosis, leiomyosarcoma, or gastrointestinal stromal tumor (GIST), among others. In the pelvis, other tumors with a primarily fibrous component that can mimic SFTs include mesothelioma, ovarian Brenner tumor, fibroma or fibrothecoma, as well as uterine leiomyoma.

The differential diagnosis for SFTs arising in visceral sites such as the liver or kidney includes more common hypervascular hepatic or renal masses such as focal nodular hyperplasia, hepatocellular adenoma, hepatocellular carcinoma, and fibrolamellar carcinoma (for liver tumors) or renal cell carcinoma, oncocytoma, and metastases (for renal tumors). Differentiation on the basis of imaging alone is often not possible. (See "Approach to the adult patient with an incidental solid liver lesion" and "Clinical features and diagnosis of hepatocellular carcinoma", section on 'Evaluation after HCC Diagnosis' and "Epidemiology, clinical manifestations, diagnosis, and treatment of fibrolamellar carcinoma".)

Histologic — The histologic differential diagnosis for SFT varies based on the site and histologic appearance of the tumor with more cellular cases having a slightly different differential than hypocellular tumors.

●In the pleura, the primary histologic differential diagnosis for more cellular SFT includes synovial sarcoma and sarcomatoid mesothelioma, while in abdominopelvic sites, dedifferentiated liposarcoma and GIST must be included [64]. Smaller soft tissue tumors may be mistaken for spindle cell lipoma, cellular angiofibroma, or deep benign fibrous histiocytoma. For less cellular soft tissue tumors, the differential may include fibromatosis, low-grade fibromyxoid sarcoma, or dermatofibrosarcoma protuberans. The emerging entity, PRXX-NCOA1/2 rearranged fibroblastic tumor, is a particularly close mimic for hypocellular soft tissue SFT [96]. On small biopsy specimens, the differential for highly cellular tumors may sometimes also include malignant peripheral nerve sheath tumor, adult-type fibrosarcoma, or mesenchymal chondrosarcoma.

●It is extremely rare for SFTs to primarily involve superficial soft tissues (eg, dermis), and care must be taken to exclude histologic mimics such as benign fibrous histiocytoma or dermatofibrosarcoma protuberans before making the diagnosis in superficial sites. (See 'Soft tissue SFT' above.)

●Fat-forming SFTs, particularly those arising in intraabdominal and retroperitoneal sites, and those containing lipoblasts, must be distinguished from well-differentiated/dedifferentiated liposarcomas, which they may closely mimic. Fat-forming SFT may also mimic the histologically similar but genetically distinct benign tumors spindle cell lipoma and mammary-type myofibroblastoma. (See 'Histologic variants' above.)

●Particularly on small biopsy specimens, myxoid SFT may be easily confused with other myxoid sarcomas, including low-grade fibromyxoid sarcoma, myxofibrosarcoma, myxoid liposarcoma, soft tissue angiofibroma, or malignant peripheral nerve sheath tumor, among others [97]. (See 'Histologic variants' above.)

Ancillary diagnostic studies may help in establishing the histologic diagnosis. Entities in the differential diagnosis of SFT for which there are specific diagnostic immunohistochemical and/or molecular markers are outlined in the table (table 1). (See 'Histologic variants' above.)

PROGNOSIS, RECURRENCE RISK, AND ASSESSING MALIGNANT POTENTIAL — The majority of SFTs behave in an indolent fashion and do not recur locally or distantly. However, 10 to 25 percent of tumors recur, and reported 10-year disease-specific survival rates for both pleural and extrapleural SFTs are between 73 and 100 percent [16,17,19,98-100].

In large series, 10 to 25 percent of pleural SFTs recur by 10 years [47,64,81,101]. Reported recurrence rates of extrapleural, non-central nervous system (CNS) SFT are similar in many reports [16,17,19,99-103], although others report a higher risk for recurrence compared with pleuropulmonary SFT [98,104]. In general, meningeal hemangiopericytomas behave more aggressively than SFTs of other sites, with frequent, rapid local recurrence, intrameningeal seeding, and early distant metastasis to bone. Outcomes after surgery for pleural and specific non-CNS extrapleural sites are discussed below. (See 'Surgery' below.)

As yet, the underlying reason for the more aggressive behavior of some tumors is not known. The prognostic value of molecular biomarkers (eg, NAB2-STAT6 [NGFI-A binding protein 2-signal transducer and activator of transcription 6] fusion type, secondary genetic alterations, mutations in the telomerase reverse transcriptase [TERT] gene promoter) is under study in patients with SFTs, but none is ready for clinical use, either alone or in conjunction with scores that are based on clinicopathologic features [27,80,81,84,88]. (See 'Molecular pathogenesis and molecular diagnostics' above.)

The utility of conventional staging systems, such as the tumor, node, metastasis (TNM) staging system of the combined American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC), to predict prognosis for SFTs is unclear. While the most recent version of the AJCC/UICC TNM staging system (eighth edition, 2017) recommends that "malignant" SFT be staged according to the guidelines for other soft tissue sarcomas (table 2 and table 3 and table 4 and table 5), there are no data stratifying outcomes according to TNM stage or prognostic stage groupings (which are only available for soft tissue sarcomas arising in the retroperitoneum, trunk, and extremities). Under the updated AJCC/UICC guidelines, malignant SFT of the pleura are recommended to be staged using the retroperitoneal staging criteria, as no site-specific system exists for sarcomas arising in the pleura. Unfortunately, no guidance is provided on how to classify SFTs as "malignant," and in the fifth edition of the World Health Organization (WHO) Classification of Tumours series, using "benign/malignant" terminology in reference to SFT is not recommended. (See 'Risk assessment' below.)

Recurrence in SFT may be due to incomplete resection [47,105], tumor seeding within the pleura, peritoneum or meninges, or distant hematogenous spread. For pleuropulmonary tumors, recurrences are most often located in the ipsilateral hemithorax. The most common sites of distant metastasis in SFT at all sites are lung, liver, bone, and brain [106].

Prolonged survival after an SFT recurrence is possible, particularly for those who are amenable to reresection [26,105]. Patients with multiple synchronous metastases that are not amenable to surgical intervention have a uniformly poor prognosis [47,48,64,99]. (See 'Advanced and metastatic disease' below.)

Late relapse, even for tumors initially classified as histologically "benign," is common. Among tumors classified as malignant, 10 to 40 percent of those destined to metastasize will do so after five years, and they can recur up to 20 years after initial presentation [48,103,105,107-109]. This underscores the need for continued long-term follow-up, particularly for high-risk individuals. (See 'Posttreatment surveillance' below.)

Risk assessment — Historical criteria for assigning SFT to "benign" or "malignant" categories were poorly reproducible and inconsistently applied. Moreover, it was increasingly recognized that SFT encompasses a spectrum of behavior, rather than a strict "benign or malignant" dichotomy. In addition, with the merging of SFT and "hemangiopericytoma" under one disease umbrella, the classic malignancy risk criteria specific to SFT (eg, tumor cellularity) became muddied. As a resulted, there was a widely held belief that the behavior of SFT was unpredictable. Anaplastic (dedifferentiated) SFT is the exception to this rule, representing a clearly malignant tumor with aggressive behavior and rapid progression [16,19,58,98,110,111].

Subsequent studies have shown that the behavior of SFT can, in general, be predicted by a variety of risk stratification models. Confusion continues to arise, however, from the variety of published models, their sometimes poor consensus on risk when applied to the same case, and their applicability to different anatomic sites.

The main point of contention in determining the behavior of SFT, is that no single risk factor is a great predictor of outcome when used in isolation, and studies disagree on which are most relevant. These factors may be influenced by patient population (eg, primary or tertiary care center), site of disease (thoracic, soft tissue, head and neck, etc), interobserver variability, and the subjective nature of features like cellularity, as well as study size.

Objectively, the most well-validated risk criteria for recurrence/metastasis in SFT of any site are incomplete surgical resection [17,20], metastatic disease at presentation, tumor size >10 cm, high mitotic rate, and the presence of tumor necrosis [13,20,64,110,112-116]. Other large series have reported that tumor location (extremity, visceral, pleural, or intraabdominal/retroperitoneal) has varying associations with local recurrence or metastasis [101,103,116]. Different clinicopathologic risk assessment models combine these and other identified criteria in various combinations to predict SFT behavior.

Risk stratification models — To date, there remain two separate schools of thought on risk stratification models for SFT: those who regard pleural tumors separately from other extrameningeal SFT and those who include SFT of all extrameningeal sites in the model. The Demicco model (table 6) is the most widely used in clinical practice because it is applicable to SFT of all extrameningeal sites and is recommended over the pleural-specific models for its simplicity [115].

Pleural tumors — Pleural SFT-specific risk assessment models are distinct in that they alone utilize criteria related to pedunculation or origin from parietal or visceral pleura; four models have been developed (table 7) [27,47,64]:

●The England criteria was derived from 233 cases of pleural SFT from the Armed Forces Institute of Pathology (AFIP), of which 82 were described as histologically malignant. The histologic criteria for malignancy for this system are outlined in the table (table 7) [47]. Whereas none of the patients with histologically benign disease died, 55 percent of those with malignant SFT died because of recurrence or metastases. Among the malignant variants, complete resectability was the single most important predictor of outcome.

●The de Perrot classification (table 7) was derived from 185 reported cases of pleural SFT in the literature that had adequate follow-up; 19 (10 percent) had at least one recurrence, and 16 (9 percent) died of their disease [64]. Histologically benign pedunculated tumors comprised 35 percent of the total and only recurred 2 percent of the time, while sessile, histologically malignant pleural SFT, accounting for 23 percent of the total, recurred in up to 63 percent of cases. The authors used the absence/presence of pleural pedunculation with histologic features of malignancy and the presence of metastasis to create a five-tiered staging system, which correlated with risk of local recurrence (table 8).

The de Perrot classification was validated in another series of 88 SFTs, in which de Perrot stage 0 to I tumors accounted for 67 percent, stage II for 18 percent, and stage III to IV for 15 percent of cases. Stage significantly correlated with disease-specific survival and overall survival [81]. Local recurrence was documented in 16 cases (18 percent of the total), but the authors did not provide a stratification of recurrence rate according to de Perrot stage.

●The Tapias classification (table 7) is a refinement on the England and de Perrot criteria. It uses a point-based system (one point each for high mitotic activity, hypercellularity, necrosis/hemorrhage, size >10 cm, sessile [as compared with pedunculated] growth, and parietal pleural origin) to assess risk in pleural SFTs [13,27]. A recurrence score cutoff of three points or more was used to define high risk for recurrence, and this system was proposed to outperform the England criteria and the de Perrot classification:

•In the initial series of 59 patients, >3 points predicted disease recurrence with a sensitivity of 100 percent and a specificity of 92 percent [27]. Low-risk patients, comprising 80 percent of cases, had a zero risk of recurrence at 15 years compared with 77 percent for those classified as high risk. There was no significant difference in overall survival when comparing patients classified as high or low risk for recurrence.

•The follow-up validation study of 113 pleural SFTs demonstrated less impressive prognostic stratification for recurrence using this same cutoff, with sensitivity of only 78 percent, specificity of 74 percent, and both positive and negative likelihood ratios of 0.3 [13]. Low-risk patients, comprising 70 percent of cases, had only 3.5 percent risk of recurrence at 15 years, compared with 27.9 percent for high-risk patients. High-risk patients also experienced worse long-term survival (overall survival rates at 5, 10, and 15 years were 76, 73, and 66 percent, respectively, compared with 96, 91, and 89 percent, respectively, for those with low-risk [less than points] tumors). An analysis of cancer-specific survival could not be performed. When directly compared, the recurrence score outperformed both the England and de Perrot classifiers, as assessed by the area under the Receiver Operating Characteristic Curve (AUC-ROC), which was 0.7730; the AUC-ROC for the England criteria (0.697) and the de Perrot classifier (0.524) were both significantly inferior.

•Further validation in an independent series of 147 pleuropulmonary SFTs showed that the Tapias model predicted overall survival and progression-free survival, and performed similarly to the Demicco model in this cohort [115].

●The Diebold classification (table 7) is predicated on the theory that mitotic count may not the best indicator of tumor proliferation, and incorporates immunohistochemistry for Ki-67 (MIB-1) into its model [117]. Although it was developed in pleural SFT samples, it does not take thorax-specific anatomic features (pedunculation, origin on parietal versus visceral pleura) into account. One point each is given for mitotic figures at least 4 per 10 high-power fields, tumor size at least 10 cm, presence of necrosis, and MIB-1 proliferation index >10 percent.

•In the initial multicenter series of 78 patients, a score of 1 was associated with adverse outcome with a sensitivity of 88 percent and specificity of 48 percent, while a score of 4 had 22 percent sensitivity, but 100 percent specificity. A score of 2 performed best at identifying patients at risk of recurrence or death. This model was reported to outperform the Tapias score in this patient population but has not yet been validated.

Extrameningeal tumors at all sites — Three risk assessment models have been published for extrameningeal SFT of all sites, including pleural tumors (table 6). Two of these models were externally validated using independent cohorts:

●The Demicco model (also referred to as "D-score" or "MDACC score") (table 6) is based upon an analysis of patients treated at a tertiary sarcoma center in the United States. This model used patient age at presentation, tumor size, and mitotic count to stratify patients into low-, moderate-, and high-risk groups for development of metastases [17]. Points were assigned as follows: one point for age ≥55 years, one point for size between 5 and 9.9 cm, two points for size 10 to 14.9 cm, three points for size ≥15 cm, one point for one to three mitoses/10 HPF, and two points for ≥4 mitoses/10 HPF. Total scores were tabulated, with a score <3 considered low risk and ≥5 high risk.

In the initial series of 82 SFTs, this model was successfully able to identify a population of low risk tumors, comprising 34 percent of cases, of which none metastasized or died of disease, and a highly aggressive population, comprising 28 percent of cases, with an 85 percent five-year risk of metastasis and a 60 percent five-year disease-specific survival rate. In the intermediate-risk group, there was a 33 percent risk of metastases at five years, and the five-year disease-specific survival rate was 93 percent. This risk prognostication system was subsequently validated by the original investigators and in several independent studies, including a multinational series wherein the Demicco score provided prognostic discrimination of overall survival among the subset of 309 extremity, trunk, and head and neck SFT and 131 retroperitoneal tumors [115,116,118-121].

A further refinement of this model was proposed incorporating necrosis as a fourth prognostic feature, the inclusion of which increased the number of cases identified as being at minimal risk of metastasis (table 6) [118]. The advantage of this model is that it relies less on subjective histologic criteria (pleomorphism and cellularity) that are not reported routinely in pathologic reports, and more on ostensibly reproducible objective criteria, which allow for increased ease in clinical application outside of referral centers. However, it may underscore risk on small biopsy specimens due to potential undersampling of mitoses and necrosis, and it may also be inaccurate in previously irradiated tumors.

●A large series comprising 214 SFT from the French Sarcoma Group has also been used to develop a risk calculator (actually three separate calculators (table 6), also sometimes referred to as the Salas models) for prediction of overall survival, and local and metastatic recurrence in extrameningeal SFTs [101]. Four prognostic groups for local recurrence or distant metastasis were defined based upon the number of unfavorable prognostic factors (age <60, visceral localization, and no radiation therapy for local recurrence and age >60, mitotic count >4 mitoses/10 HPF, and limb location for metastasis). A three-tiered score was derived for stratifying overall survival based on mitotic activity and patient age. The investigators also performed both internal and external validation on the models, with reported C-indices of 0.58 and 0.72 for local recurrence and metastatic risk, respectively, using an external dataset.

Notably, this model found no prognostic significance for size above/below the median of 9 cm, in contrast to another large series using a similar median cutoff of 8 cm [103]. This model has the advantages of incorporating whether local therapy was administered in the prediction of local recurrence, and its relative ease of use, with only one variable requiring pathologic interpretation.

●One major limitation of the above models is that the median follow-up was less than five years, whereas SFTs are known to be prone to late recurrences. One series with extended median follow-up (84 months) for recurrence-free interval demonstrated that the Demicco and Salas models accurately predicted recurrences in high-risk patients but failed to predict late recurrences in some low-risk patients [109]. The investigators proposed a risk score ("G-score") based on mitotic count (2 points for 4 or more mitoses/10 high-power fields), tumor necrosis (1 point for <50 percent tumor necrosis, 2 points for 50 percent or more tumor necrosis) and male sex (1 point) [109]. A sum of 0 was considered low risk and sum 3 to 5 was considered high risk. This "G-score" correlated well with outcomes in the study population but has not yet been validated in an independent cohort.

●To date, only one risk stratification model has been developed solely for extrameningeal, extrapleural SFT (the Pasquali score). These investigators analyzed 243 SFTs from four European sarcoma referral centers and found that only high mitotic rate (>4 mitoses/10 HPF), nuclear pleomorphism, and hypercellularity were predictive of disease-free survival in multivariate analysis [102]. Their model assigned points for each of these risk factors, resulting in a four-tiered model for risk of any recurrence, either distant or local (table 6). This model is most similar to traditional conceptions of atypical and "malignant" SFT.

●In one comparative study, the Demicco model and the French Sarcoma Group models for metastasis and overall survival outperformed the Pasquali model in predicting metastatic risk in extrameningeal SFT of all sites [121]. It was also independently shown to perform well in pleural SFT [115].

TREATMENT — Management of SFTs at all sites should be discussed in a multidisciplinary tumor board with sarcoma specialists who have experience with this disease.

Localized disease — Complete en bloc surgical resection is the mainstay of therapy for all localized SFTs [11]. Although risk stratification analyses as detailed above can categorize some SFTs as potentially more malignant, the standard of care is complete surgical resection to negative margins (R0 resection) even for tumors classified as high-risk, given the low overall metastatic potential and the lack of effective adjuvant therapy. (See 'Risk assessment' above.)

Surgery

Pleural tumors — Pedunculated tumors can generally be resected with a wedge resection, but large sessile tumors and those with ipsilateral intrapleural metastases may occasionally require a lobectomy, pneumonectomy, or a chest wall or diaphragm resection to achieve negative (R0) margins [26,38,122]. (See "Overview of pulmonary resection" and "Surgical management of chest wall tumors".)

Outcomes from surgery for pleural SFTs are illustrated in the following reports:

●In a retrospective series, 157 patients with a pleural SFT underwent complete en bloc resection, which required wedge resection in 122, lobectomy of one or more lobes in 19, pneumonectomy in four, chest wall resection in 8, diaphragm resection in 3, and multilevel hemivertebrectomy in 1 [26]. Despite R0 resection, 15 (10 percent) recurred at a median of 29 months. Ten recurred locally, while five recurred at distant sites. In 9 of the 10 cases with a local recurrence, disease control was achieved with reresection. Recurrences were more common in patients with malignant histology (19 versus 1.3 percent). At a median follow-up of 14 years, the overall 5- and 10-year survival rates for the entire cohort were 86 and 77 percent; long-term survival was significantly better in those with a histologically benign SFT as compared with those with malignant features (at five years, 96 versus 68 percent, respectively).

●Another multi-institutional study focused on 50 malignant pleural SFTs treated over a 10-year period at one of four institutions [25]. Complete resection was achieved in 46 cases (92 percent) and required extended resection in 15. At a median follow-up of 52 months, the overall survival rates at 5 and 10 years were 81 and 67 percent, and the disease-free survival rates at 5 and 10 years were 72 and 61 percent. Even patients with an England score of 4 had an 80 percent long-term survival rate. (See 'Risk assessment' above.)

Disease recurred in 15 cases (mean time to recurrence 34 months, range 2 to 128 months), and it was localized in 6 and diffuse in 9. Four of the patients with localized recurrences were successfully managed with reresection.

Extrapleural tumors — Smaller series have examined the results of treatment at anatomical locations outside of the thorax. The surgical procedures have generally paralleled those used for treatment of sarcomas at different body sites. As with pleuropulmonary SFTs, complete surgical resection is the primary approach. (See "Surgical resection of retroperitoneal sarcoma" and "Overview of multimodality treatment for primary soft tissue sarcoma of the extremities and superficial trunk".)

●One multicenter retrospective cohort analysis evaluated 81 patients treated with surgery for curative intent [20]. Seventy percent of the patients in the study had SFTs outside the thorax with 27 percent in the head and neck area. With a median long-term follow-up of 45 months, the metastatic rate was 34 percent and mortality rate was 16 percent.

●A second study of 83 patients included 59 extrathoracic SFTs, 22 with visceral/abdominal locations and 24 with neurologic locations [104]. Fourteen patients experienced a recurrence, and multivariate analysis indicated that extrathoracic location significantly increased the likelihood of a local recurrence. However, only 4 of the 83 patients died of their disease.

●A third single-institutional study retrospectively reviewed 33 cases of extrathoracic SFTs [98]. Fifteen patients presented with abdominal/retroperitoneal disease and 18 with extremity/truncal disease. Although the study reported a higher proportion of malignant versus benign tumors than in most series of pleuropulmonary tumors (18 versus 15 cases), and intraabdominal cases had a significantly higher risk of local recurrence, the overall survival after five years was approximately 80 percent.

●A fourth series reported that the five-year survival rate was 79 percent for patients undergoing R0 resection compared with 50 percent in those with a partial resection or biopsy only [18,123].

Radiation therapy — The aim of radiation therapy (RT) is local control of disease at high risk for recurrence. In general, our approach for most patients is to proceed with surgery directly, with evaluation of adjuvant (ie, postoperative) RT on a case-by-case basis. However, some clinicians may offer neoadjuvant (ie, preoperative) RT when adjuvant RT would be challenging to deliver. The use of RT is best decided in the context of a multidisciplinary discussion.

Adjuvant radiation therapy — Our approach to adjuvant RT is as follows:

●For patients with complete (ie, R0) resection and no high-risk histologic features, we offer observation rather than adjuvant RT or chemotherapy.

●For patients with resected intermediate- to high-risk SFT and positive margins who are eligible for resection with minimal morbidity, we offer re-resection rather than adjuvant RT.

●For patients with resected intermediate- to high-risk SFT and positive margins who are ineligible for further resection, we suggest adjuvant RT rather than observation or chemotherapy. As an example, candidates for adjuvant RT include those with positive surgical margins (ie, R1/R2 resection) and an inability to achieve R0 resection with repeat surgery due to anatomic constraints (eg, in the pleura or mediastinum). However, as there are limited prospective data for this approach, some experts may reasonably omit adjuvant RT for these patients. Optimal management is best determined in a multidisciplinary setting, and risk stratification models may be helpful in the decision to offer adjuvant RT. (See 'Prognosis, recurrence risk, and assessing malignant potential' above.)

●For patients with locally recurrent SFT, we offer re-resection followed by adjuvant RT, as such patients likely had disease not initially controlled with surgery alone.

For patients with resected SFT and certain higher risk features (eg, positive surgical margins, high mitotic count), the use of adjuvant RT may prevent local recurrences, although an overall survival benefit has not been established in observational studies [20,53,64,103,104,116,124-127]. As these patients may still have a favorable long-term outcome, surgeons may be able to offer surgery that is less morbid and preserves function if RT can be safely and effectively offered postoperatively [116]. Because there are limited prospective data validating the use of adjuvant RT, patients should continue to receive multidisciplinary discussion evaluating its use on a case-by-case basis. Select risk stratification models may also be helpful in the multidisciplinary decision to offer adjuvant RT.

As an example, in one retrospective study, 549 patients with extrameningeal, primary localized SFT were treated with surgical resection alone or in combination with RT [116]. Among the 121 patients treated with surgery and RT, 48 percent (58 patients) received adjuvant RT. Only two patients in whom R0 resection was achieved received adjuvant RT. At median follow-up of 52 months, the addition of RT to surgery was associated with a decreased risk of local disease progression, when adjusted for margin status (R1 or R2 resection) and mitotic count (local relapse rate 6.1 versus 7.2 percent, hazard ratio [HR] 0.19, 95% CI 0.04-0.84). No overall survival benefit was noted. Among those treated with surgery followed by adjuvant RT, five-year local control and overall survival rates were 96 and 67 percent, respectively. The local control and overall survival results from this study are consistent with prior observational studies utilizing radiation in SFT with higher risk features [20,103,126,127].

Adjuvant RT is typically indicated following resection of a WHO grade 3 SFT of the central nervous system (CNS), which has a high risk for local recurrence. This use of adjuvant RT in such patients is discussed separately. (See "Uncommon brain tumors", section on 'Solitary fibrous tumor'.)

Neoadjuvant radiation therapy — The use of neoadjuvant RT is decided on a case-by-case basis in patients with SFTs. Neoadjuvant RT may be offered to patients with tumors in anatomic regions that may be difficult to initially resect (eg, pelvis and retroperitoneum) and where adjuvant RT would be challenging to deliver due to the presence of bowel or other radiosensitive structures in the RT field.

The addition of preoperative (neoadjuvant) RT (50.4 Gy) to surgery was evaluated in a randomized European Organisation for Research and Treatment of Cancer (EORTC) phase III trial (STRASS) in patients with primary localized retroperitoneal sarcoma. However, there were too few patients with SFT histology to inform management with RT for all patients with this disease [128,129]. Further details on the STRASS trial in the entire sarcoma population are discussed separately. (See "Surgical resection of retroperitoneal sarcoma", section on 'Consideration of nonsurgical therapies' and "Clinical presentation and diagnosis of retroperitoneal soft tissue sarcoma".)

Adjuvant chemotherapy — We suggest not pursuing adjuvant chemotherapy for patients with completely resected SFT, given the lack of data supporting benefit and the favorable outcomes from surgery in most cases. The discussion and decisions about adjuvant chemotherapy for patients with margin-positive or recurrent SFTs should be decided on a case-by-case basis but only take place within the context of a multidisciplinary discussion for patients who have a good performance status.

The role of adjuvant chemotherapy for resected SFT is unknown. Given the rarity of this tumor, comprehensive trials studying the use of adjuvant chemotherapy for resectable tumors have not been possible. However, even for high-grade, large extremity sarcomas, which have a worse outcome than do malignant SFTs, the benefit of adjuvant chemotherapy is controversial, and data from individual trials and meta-analyses suggest that a survival benefit, if it exists, is small.(See "Adjuvant and neoadjuvant chemotherapy for soft tissue sarcoma of the extremities" and "Head and neck sarcomas", section on 'Other adult soft tissue sarcomas'.)

Advanced and metastatic disease — The optimal management for locally advanced unresectable or metastatic SFT is not established. While some chemotherapy agents have efficacy in this disease, definitive therapy should not reflexively follow usual paradigms for the treatment of soft tissue sarcoma with traditional chemotherapy agents (ie, anthracycline, ifosfamide). Objective responses with these agents are uncommon, and duration of benefit is short. (See "Overview of the initial treatment of metastatic soft tissue sarcoma".)

Targeted therapies utilizing antiangiogenic agents are also effective and well tolerated in this disease [130-134]. There are limited data for the efficacy of other agents (ie, immunotherapy). Where available, eligible patients should be encouraged to participate in clinical trials.

RT can provide local tumor control in some patients with unresected tumors, as well as palliation in the setting of metastatic disease [135].

Our approach to systemic therapy is as follows:

●Treatment-naïve disease – For patients with metastatic and locally advanced unresectable tumors, we suggest initial therapy with dacarbazine as a single agent or in combination with doxorubicin. (See 'Dacarbazine with or without doxorubicin' below.)

•For patients with a good Eastern Cooperative Oncology Group (ECOG) performance status (table 9) and no contraindications to anthracyclines, we suggest the combination of dacarbazine and doxorubicin.

•For patients with a poor ECOG performance status and/or contraindications to anthracyclines, we offer single agent dacarbazine.

●Progressive disease – For patients with progressive disease on chemotherapy, we suggest antiangiogenic therapy as subsequent therapy rather than further lines of chemotherapy. Options include pazopanib, sunitinib, or bevacizumab in combination with temozolomide. (See 'Progressive disease' below.)

For patients previously treated with dacarbazine (with or without doxorubicin), we prefer pazopanib. Notably, we do not offer bevacizumab and temozolomide in such patients, as dacarbazine and temozolomide are both alkylating agents and have similar structure, function, and chemotherapeutic mechanisms of action. (See 'Pazopanib' below.)

Treatment-naive disease

Dacarbazine with or without doxorubicin — Dacarbazine alone or in combination with doxorubicin has efficacy in patients with advanced or metastatic SFT. As an example, one study evaluated single-agent dacarbazine and then tested a combination of doxorubicin and dacarbazine in 12 patients [136]. Six patients had Response Evaluation Criteria in Solid Tumors (RECIST) responses (50 percent), with one exhibiting stable disease. In this small series, 80 percent of patients with a dedifferentiated SFT phenotype responded, compared with only 30 percent of the patients with non-dedifferentiated tumors. Progression-free survival (PFS) was six months, and 20 percent of patients were without progression at one year.

Progressive disease — Data suggest efficacy for agents targeting the vascular endothelial growth factor (VEGF) and other tyrosine kinase signaling pathways in patients with advanced SFT with progression on prior therapy.

Criteria to assess response on targeted agents — In patients treated with these agents, we prefer assessment of treatment response using the Choi criteria. An important point is that antitumor efficacy by conventional RECIST criteria can be difficult to demonstrate with antiangiogenic agents. Agents such as these may cause tumor devascularization that is detectable on contrast-enhanced scans, without much size change in tumor masses. Further details on RECIST versus Choi criteria are discussed separately. (See "Tyrosine kinase inhibitor therapy for advanced gastrointestinal stromal tumors", section on 'RECIST versus Choi criteria'.)

Pazopanib — Pazopanib is a tyrosine kinase inhibitor (TKIs) that targets VEGFR1, VEGFR2, VEGFR3, and platelet-derived growth factor receptor (PDGFR) family members. In several phase II studies, response rates for pazopanib exceed 50 percent (table 10) [131-133,137-140]:

●High-risk or dedifferentiated SFT – In an open-label, phase II trial of pazopanib in 36 patients with malignant or dedifferentiated (anaplastic) SFT with progression on prior therapies, there were 18 Choi criteria partial responses (51 percent), and nine had stable disease (26 percent) [133]. At a median follow-up of 27 months, median survival was not reached, and 73 percent were still alive at 24 months.

This response rate is higher than what has previously been reported in earlier small trials of pazopanib [131]. This discrepancy may be attributed to earlier studies using RECIST criteria, which is generally considered a suboptimal measure of response to TKIs compared with the Choi criteria. In this phase II trial, the corresponding response rate with use of RECIST criteria was just 6 percent (2 responses). The authors concluded that pazopanib is an active agent in SFT and that Choi criteria provide a more accurate assessment of response than RECIST.

●Typical SFT – In a subsequent phase II trial, 40 patients with metastatic or unresectable typical SFT (approximately 80 percent with progression on prior therapies) were treated with pazopanib [132]. At a median follow-up of 18 months, partial responses were seen in 18 of 31 patients (58 percent), according to Choi criteria. Median PFS and overall survival were 10 and 50 months respectively.

Further randomized clinical trials are needed to confirm the efficacy of pazopanib in patients with advanced and metastatic SFT.

Alternative options

●Sunitinib – Sunitinib, which inhibits multiple receptor tyrosine kinase pathways including those involving platelet-derived growth factor receptor (PDGFR) and VEGF receptor (VEGFR), appears to have some activity [134,141,142]:

•In a retrospective series of 31 patients with advanced SFT who received sunitinib (37.5 mg daily), two (6.5 percent) achieved a PR according to standard RECIST, 58 percent exhibited stable disease, and 36.5 percent progressed [141]. Median PFS was six months. However, when the Choi criteria for response (which take into account both changes in tumor size and density [vascularity] [139]) were applied, 48 percent of patients met criteria for a partial response, indicating that this agent has effects on the vasculature in the tumors.

•In another phase II study of sunitinib (37.5 mg daily) in non-GIST advanced soft tissue sarcomas, durable disease control was achieved in two of three patients with SFT/hemangiopericytoma (stable disease for 24 to 58+ weeks) [134].

●Bevacizumab and temozolomide – We do not offer bevacizumab and temozolomide in patients who have previously received dacarbazine, because dacarbazine and temozolomide are both alkylating agents and have similar structure, function, and chemotherapeutic mechanisms of action.

By virtue of their use in gliomas, the combination of bevacizumab (VEGFa inhibitor) and temozolomide was evaluated in 14 patients with SFT with progression on previous chemotherapy and was shown to have evidence of activity [130]. Median PFS in this group of locally advanced, unresectable, or metastatic patients was 10 months. The partial response (PR) rate was 14 percent with 76 percent stable disease. Interestingly, when non-dimensional Choi criteria (which invoke change in density and tumor size in a response criterion [139]) were used instead of RECIST, 79 percent of the patients exhibited a PR. Some of the patients involved in this single-institution study were converted to resectable disease.

Less preferred options

●Chemotherapy agents – Experience with other chemotherapy agents (eg, anthracyclines with or without ifosfamide [106,143,144], gemcitabine-based regimens [144], carboplatin plus paclitaxel [145], trabectedin [106,136]) demonstrates limited efficacy in patients with advanced or metastatic SFT. Data come exclusively from small case series and retrospective reviews, as there are no prospective trials:

•A retrospective review included 30 patients with advanced SFT derived from the European rare cancer database who were treated with traditional sarcoma chemotherapy [143]. At three months, among those treated with an anthracycline-based regimen (single-agent anthracyclines [n = 7] or a combination of anthracyclines plus ifosfamide [n = 23]), there were six (20 percent) partial responses, and eight (27 percent) had stable disease. However, the median progression-free survival (PFS) was only four months, and only six (20 percent) remained progression free at six months. Analysis of 19 patients in the group who received single-agent high-dose ifosfamide revealed that 10 percent had a partial response, 26 percent had stable disease; the median PFS was only four months.

•Single-institutional retrospective reviews of conventional chemotherapy also reinforce the limited value of conventional chemotherapy:

-One report included 24 patients with locally advanced unresectable or metastatic SFT, 20 of whom received systemic cytotoxic chemotherapy (17 anthracycline-based, 2 temozolomide plus bevacizumab, and 1 trabectedin) [106]. Three others received axitinib. There was one objective partial response, and 20 patients with stable disease. Median PFS in the entire cohort was 4.2 months.

-A second single-institutional retrospective review of experience with cytotoxic chemotherapy in 21 patients with advanced SFT who received a doxorubicin-based (n = 15) or gemcitabine-based regimen (n = 5) or paclitaxel (n = 1) revealed no objective responses according to Response Evaluation Criteria in Solid Tumors (RECIST) (table 11) [144]. However, 16 (89 percent) had stable disease, 28 percent for greater than six months; median PFS was 4.6 months.

-In another retrospective review of 23 patients receiving chemotherapy for advanced SFT (19 receiving anthracycline-based therapy, the others received vinorelbine, paclitaxel alone or with carboplatin, or brostallicin [145]), there were 2 partial responses (both in patients receiving a doxorubicin-based regimen) and 13 others (57 percent) had stable disease; median PFS was 5.2 months. [136]

-Although there are no published data in patients, given the activity of trabectedin observed in xenograft models [136], a study of trabectedin versus a combination of doxorubicin plus dacarbazine is planned (NCT03023124).

●Antiangiogenic therapy

•Sorafenib – Sorafenib, a tyrosine kinase inhibitor that targets VEGF, also appears to have antitumor efficacy [142,146,147] in advanced SFT. As an example, in a subgroup analysis of a larger phase II trial of sorafenib in advanced soft tissue sarcomas, two of five patients with SFT (40 percent) had stable disease for nine months [146].

•Axitinib – The activity of axitinib is unclear but appears to have limited activity in dedifferentiated SFT [106,148]. In a phase II study of axitinib, 17 patients with advanced SFT (nine with prior exposure to other antiangiogenics) were evaluated by Choi criteria with overall response rate as the primary endpoint [148]. Partial responses were seen in seven patients (41 percent); none of the four patients with a dedifferentiated phenotype responded to axitinib. Median PFS was approximately five months.

POSTTREATMENT SURVEILLANCE — There are no studies addressing the types of studies and optimal frequency of posttreatment surveillance, and no widely accepted guidelines. Continued long-term follow-up is needed for high-risk individuals because of the indolent natural history and possibility of late recurrence up to 20 years after initial treatment [101]. A suggested posttreatment surveillance schedule for pleural SFT that is based upon the risk for malignant behavior is shown in the algorithm (algorithm 1) [64]. It is difficult to extrapolate this algorithmic approach to posttreatment surveillance to extrapleural SFTs, as risk assessment has not focused so much on sessile versus pedunculated appearance, but more on pathologic characteristics. (See 'Risk assessment' above.)

For patients with pleural SFT and patients with extrapleural SFT, we largely follow posttreatment surveillance guidelines for soft tissue sarcoma from the National Comprehensive Cancer Network (NCCN) [149] stratified by estimated risk, as follows:

●For very low-risk and low-risk individuals (table 6), we image the local tumor site every six months for three years, then yearly through year 5. For intermediate- and high-risk tumors, we image the primary tumor site every three to four months for the first two years, then every six months through year 5. We do not typically repeat local imaging after five years, as local recurrence at that point would be unusual.

●For chest imaging in very low-risk and low-risk patients, we would typically image them with computed tomography (CT) or chest radiograph every six months for three years, then yearly through year 10. In these patients, we utilize chest radiographs more often than chest CT. For intermediate- and high-risk patients, we perform chest CT every three to four months for two years, then every six months for three years, then annually through year 20.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Soft tissue sarcoma".)

SUMMARY AND RECOMMENDATIONS

●Molecular characteristics of solitary fibrous tumor (SFT) – SFT comprises a histologic spectrum of fibroblastic soft tissue neoplasms including tumors formerly recognized as hemangiopericytoma. SFTs are characterized by a recurrent inversion of the long arm of chromosome 12 (12q13), which results in fusion of two genes, NAB2 (NGFI-A binding protein 2) and STAT6 (signal transducer and activator of transcription 6). (See 'Introduction' above and 'Molecular pathogenesis and molecular diagnostics' above.)

●Anatomic distribution – SFTs preferentially arise in serosal membranes, the dura of the meninges, and deep soft tissues. Although they are commonly described as predominantly intrathoracic tumors, approximately 50 to 70 percent are localized outside of the thorax. (See 'Anatomic distribution' above.)

●Clinical presentation – Pleuropulmonary SFTs typically present with pulmonary symptoms (cough, shortness of breath, chest pain), although approximately one-third of cases are found incidentally during chest imaging. SFTs in other locations can present as a painless mass. (See 'Clinical presentation' above.)

The majority of SFTs have indolent behavior with a very low risk of recurrence or metastasis. However, 10 to 25 percent of tumors recur, including anaplastic ("dedifferentiated") SFT, which show aggressive behavior and rapid progression.

SFTs infrequently have been associated with paraneoplastic syndromes, most commonly non-islet cell tumor hypoglycemia (Doege-Potter syndrome) or hypertrophic pulmonary osteoarthropathy (Pierre-Marie-Bamberger syndrome). (See 'Paraneoplastic syndromes' above.)

●Diagnosis – The diagnosis of SFTs is based on the following clinical findings:

•Imaging studies – Radiographic findings on cross-sectional imaging (computed tomography [CT], magnetic resonance imaging [MRI]) are characteristic but not pathognomonic. Regardless of site, SFTs present as well-circumscribed soft tissue masses with a homogenous appearance, although cystic areas as well as calcifications and hemorrhage may be apparent. Tumors enhance after contrast administration, but this may be homogeneous or heterogeneous. (See 'Imaging findings' above.)

•Histologic and molecular findings – Diagnosis of SFT requires histologic examination of an adequate tissue sample and is based upon recognition of typical morphologic features in conjunction with a characteristic immunophenotype. Strong nuclear expression of STAT6 is a highly sensitive and specific immunohistochemical marker for SFT. (See 'Ancillary diagnostic studies' above.)

●Risk stratification models – Risk stratification models have replaced the use of nomenclature like "benign SFT" and "malignant SFT", and these terms should be avoided. (See 'Prognosis, recurrence risk, and assessing malignant potential' above.)

Risk stratification models are based on differing combinations of clinical, pathologic, and/or anatomic criteria (table 7 and table 6). In direct comparisons, models incorporating at least mitotic activity and patient age outperformed a model based on histologic criteria alone. (See 'Risk stratification models' above.)

●Localized disease – Management of SFT should be discussed in a multidisciplinary tumor board with sarcoma specialists who have experience with the disease. Complete en bloc surgical resection with negative margins (an R0 resection) is the mainstay of therapy for all localized SFTs, even for tumors classified as high risk, given the low overall metastatic potential. (See 'Surgery' above.)

●Indications for radiation therapy in resected disease – The use of radiation therapy (RT), either in the adjuvant (ie, postoperative) or neoadjuvant (ie, preoperative) setting for resected SFT is best decided in the context of multidisciplinary discussion, and on a case-by-case basis in patients with SFTs. (See 'Radiation therapy' above.)

•For patients with complete resection and no high-risk histologic features, we offer observation rather than adjuvant RT or chemotherapy.

•For patients with resected intermediate- to high-risk SFT and positive margins who are eligible for resection with minimal morbidity, we offer re-resection rather than adjuvant RT.

•For patients with intermediate- to high-risk resected SFT and positive surgical margins who are ineligible for further resection, we suggest adjuvant RT rather than observation or chemotherapy (Grade 2C). However, prospective data are limited for this approach and some experts may reasonably omit adjuvant RT for these patients. Management of such patients is best determined in a multidisciplinary setting. Risk stratification models may be helpful with the decision of when to offer adjuvant RT. (See 'Adjuvant radiation therapy' above.)

•Neoadjuvant RT may be offered to patients with tumors in anatomic regions that may be difficult to initially resect (eg, pelvis and retroperitoneum) and where adjuvant RT would be challenging to deliver due to the presence of bowel or other radiosensitive structures in the RT field. (See 'Neoadjuvant radiation therapy' above.)

●Posttreatment surveillance – Treatment should be followed by careful long-term postoperative surveillance. SFTs can recur locally, and such recurrences can often be managed successfully with reresection. The frequency of posttreatment surveillance may be tailored to the risk of recurrence. (See 'Posttreatment surveillance' above.)

●Advanced and metastatic disease – For patients with metastatic and locally advanced unresectable tumors, our approach is as follows (see 'Advanced and metastatic disease' above):

•Initial therapy – For patients with treatment-naïve disease, we suggest initial therapy with dacarbazine and doxorubicin rather than other regimens (Grade 2C); however, for patients with a poor ECOG performance status and/or contraindications to anthracyclines, we offer single agent dacarbazine. (See 'Treatment-naive disease' above.)

•Progressive disease – For patients with progressive disease on chemotherapy, we suggest antiangiogenic therapy rather than further lines of chemotherapy (Grade 2C). (See 'Progressive disease' above.). However, participation in clinical trials is encouraged.

RT can provide local tumor control in some patients with unresected SFTs and palliation in the setting of metastatic disease.

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Thomas F DeLaney, MD, who contributed to an earlier version of this topic review.