Solitary Fibrous Tumors

Etiology

While the exact etiology of SFTs remains unclear, data supports these tumors arising from mesenchymal origin cells.[7] Research suggests that genetic alterations, particularly the recurrent fusion of the NAB2 and STAT6 genes located at chromosomal region 12q13, play a crucial role in their pathogenesis.[3] To date, no environmental factors have been identified that increase the risk of SFT; other factors that may contribute to the development of SFTs include hormonal influences and potential genetic predispositions.[7] However, further research is needed to elucidate the precise mechanisms involved in their etiology.

Epidemiology

SFTs have been reported at almost every anatomic site.[8] SFTs have an age-adjusted incidence rate of 0.61 and 0.37 per million persons per year for extra meningeal and meningeal cases, respectively; in other words, we can assume an age-adjusted yearly incidence of 1 new case per million people.[8] The pleura is the most common site, accounting for approximately 30% of cases. Pleural SFTs represent less than 5% of all pleural tumors, with an estimated incidence of 2.8 per 100,000 people.[9] Other frequently involved sites include meninges (27%), abdominal cavity (20%), trunk (10%), extremities (8%), and the head and neck (5%). Intracranial SFTs constitute 2.5% of meningeal neoplasms and less than 1% of all intracranial tumors.[10]

SFTs typically occur in adults between 20 and 70, with a peak incidence in the 5th and 6th decades.[7] These tumors are rare in children and adolescents.[3] Pleural SFTs present at a somewhat older age (mean = 60.2 years) compared to meningeal (mean = 50.6 years) and extrapleural SFTs (mean = 50.3 years).[3] They tend to occur equally in men and women.[2][11] 

Pathophysiology

The pathophysiology of SFTs remains incompletely understood, although research suggests they arise from mesenchymal cells. These tumors typically harbor a recurrent fusion of the NAB2 and STAT6 genes located at chromosomal region 12q13, considered a molecular hallmark.[3] This fusion gene results in aberrant activation of STAT6 signaling pathways, contributing to tumor development and progression. However, the exact mechanisms underlying the initiation and growth of SFTs are not fully elucidated. 

SFTs, while often considered benign, can exhibit malignant behavior in a subset of cases. The malignant potential of SFTs is typically associated with specific clinical and histological features. These include older age, larger tumor size, increased cellularity, elevated mitotic activity (>4/10 high-power fields or >2 mitoses/2 mm²), nuclear pleomorphism, tumor necrosis, and infiltrative borders.[12] Tumors with such features are known to recur and metastasize. Importantly, no particular tumor location or imaging characteristics except tumor size, patient, environmental, or dietary factors have been implicated in the occurrence or malignant behavior of SFTs thus far.[13] Tumors lacking malignant histological features initially may acquire them at recurrence or metastasis.[14] In extrapleural and extra meningeal tumors, hypercellularity, increased mitotic rate, and nuclear pleomorphism are associated with recurrence and reduced overall survival. Additionally, patient age, tumor size, mitotic rate, and necrosis predict the time to metastasis and tumor-related death. 

SFTs commonly metastasize through hematogenous dissemination, most frequently to the lungs, followed by the intrabdominal organs.[15] Lymphatic spread is rare. Metastatic disease, mainly spread to the lungs, is often the primary cause of mortality associated with SFTs. Extrathoracic SFTs seem to have a higher propensity for metastasis than thoracic SFTs.[15] The 2020 World Health Organization (WHO) classification of soft-tissue tumors categorizes SFT as an intermediate tumor, acknowledging its potential for metastasis, albeit rarely. This classification underscores the importance of vigilant monitoring and comprehensive management strategies for patients diagnosed with SFT.

Despite tumor size often being considered a negative prognostic factor, SFTs can grow large without exhibiting aggressive behavior. They also tend to manifest as well-defined masses, with primary pleural tumors often presenting silently compared to those at extrapleural sites.[8] Furthermore, TP53 immunohistochemical expression and TERT promoter mutations have been linked to recurrence and metastasis, while dedifferentiation and specific anatomical locations are associated with poor prognosis. Recent risk stratification models incorporate factors like patient age, mitotic rate, tumor size, and percentage of tumor necrosis to more accurately predict prognosis and guide clinical management.[8] Therefore, while most SFTs are benign, a subset demonstrates malignant potential, necessitating careful histological evaluation and risk stratification to inform clinical decision-making.

Paraneoplastic syndromes, although rare in SFTs, can present significant clinical challenges.[16][17] Hypertrophic osteoarthropathy (HOA), also called Pierre-Marie Bamberg syndrome, is observed in less than 10% of cases (usually pleural) and often manifests as finger clubbing, hypertrophic skin changes, arthralgia, and increased periosteal activity.[18] Clubbing may be asymptomatic or associated with pain, typically affecting distal phalanges. Diagnosis relies on the combination of clubbing and increased periosteal activity on x-ray, suggesting systemic vascularization alterations induced by overexpression of vascular endothelial growth factor and platelet-derived growth factor. HOA is distinct from another syndrome characterized by hypoglycemia known as Doege-Potter syndrome, occurring in less than 5% of SFT cases and linked to overproduction of insulin-like growth factor II. The effects of these syndromes typically diminish once the causative tumor is surgically removed. These paraneoplastic syndromes show the diverse systemic effects of SFTs and the importance of thorough clinical evaluation in diagnosis and management.[8]

Histopathology

The pathological diagnosis of SFT is confirmed based on histological characteristics and immunohistochemistry (IHC). Histologically, SFTs exhibit a spectrum of morphological features characterized by ovoid to spindled cells with patternless growth against a collagenous stroma.[3][13] Notably, prominent "staghorn"-shaped blood vessels and medium-sized vessels with perivascular fibrosis are common features.[19] The background stroma may display focal or diffuse myxoid changes.

Classic fibrous SFTs are paucicellular and feature spindle-shaped cells within a prominent fibrous stroma. Cellular SFTs, conversely, are more densely cellular, with perivascular fibrosis and gaping blood vessels at the periphery. Markedly, cellular tumors resembling hemangiopericytomas consist of sheets of primitive-appearing rounded cells. Meningeal SFTs tend to be more cellular and display hemangiopericytoma-like morphology. Some SFT variants include the fat-forming variant, characterized by abundant mature adipocytes, and the giant cell-rich variant, featuring multinucleated stromal giant cells. Additionally, dedifferentiation can occur in SFTs, leading to an abrupt transition to low- or high-grade sarcoma, often with spindle cell or undifferentiated pleomorphic sarcoma components. Squamous and neuroendocrine differentiation may also be observed in rare cases of SFTs.[3]

Features suggesting the malignant nature of the mass, as reported from various case series, are moderate to severe atypia, high cell density, mitotic activity with more than 4 mitoses per high-powered field, margin infiltration, tumor size 10 cm or larger, varying degrees of pleomorphism, hemorrhage, and necrosis.[13][20] While these features are useful in predicting malignant potential, SFTs often exhibit unpredictable histologic behaviors.[21] The tumor immunophenotype can be characterized by CD34 and smooth-muscle-actin positivity and by S100 protein, creatine kinase pool, and desmin negativity.[22] 

IHC markers play a crucial role in diagnosing SFTs. CD34 and STAT6 strongly support the diagnosis of SFT, with CD99 and Bcl-2 also commonly used.[3][12] However, their utility is limited due to their expression in other neoplasms that mimic SFT histologically. Notably, CD34 expression is observed in 81% to 95% of SFTs but is often lost in malignant and dedifferentiated tumors. CD99 (about 75%) and Bcl-2 (over 90%) are sensitive to SFTs but lack specificity.[23]

STAT6 IHC stain has emerged as a valuable surrogate marker for NAB2-STAT6 gene fusion, exhibiting excellent sensitivity and specificity. Per previous IHC features, the new 5th edition of the WHO Central Nervous System (CNS) tumors classification reported that STFs show NAB2 and STAT6 gene fusion and STAT6 overexpression.[24] However, STAT6 expression can also occur in other soft tissue neoplasms, necessitating careful interpretation.

Additionally, gene expression profiling studies have identified overexpression of the GRIA2 gene and aberrant expression of GRIA2 protein in SFT, further aiding in diagnosis. Aldehyde dehydrogenase 1 has also shown promise as a marker for SFT, particularly in conjunction with STAT6 expression. Other markers, such as cytokeratins and epithelial membrane antigens, may exhibit multifocal expression in some SFT cases, adding to the diagnostic complexity.[3]

History and Physical

When evaluating a patient suspected of having an SFT, a comprehensive history and physical examination are crucial to the diagnostic process. Clinically, presenting symptoms of SFTs are specific to their site of origin but broadly include pain, a palpable mass, and typically neurologic or vascular symptoms. Urinary retention and bowel obstruction may be the presenting symptoms in patients with tumors of the abdomen or pelvis.[6] Therefore, the history-taking should include inquiries about the patient's presenting symptoms, such as pain, swelling, or changes in bowel or bladder habits, which may suggest the presence of a mass. The patient should also be asked about symptoms of hypoglycemia and joint pain that could correlate to paraneoplastic syndrome.[6] Any relevant medical history, including surgeries or radiation exposure, should be elicited. 

During the physical examination, attention should be paid to the location of the suspected tumor and any associated findings. Palpation of the area may reveal a firm, non-tender mass, although this can vary depending on the size and location of the tumor. Other signs to look for include skin changes overlying the mass, such as erythema or ulceration, and any signs of neurovascular compromise if the tumor is in a critical anatomical location. 

In addition to the local examination, a thorough systemic evaluation should be performed to assess for signs of metastatic disease or paraneoplastic syndromes associated with SFTs. This includes a comprehensive neurological examination, assessment of respiratory function, inspection of nails to look for clubbing, and evaluation for symptoms suggestive of endocrine dysfunction. Overall, a detailed history and physical examination are essential for identifying potential signs and symptoms associated with SFTs, guiding further diagnostic workup, and determining appropriate management strategies.

Evaluation

Radiological Studies

Obtaining radiologic imaging is usually the first step in diagnosing these tumors. Imaging studies such as computed tomography (CT) scans or magnetic resonance imaging (MRI) are essential for localizing the tumor, assessing its size, extent, and potential involvement of adjacent structures, and identifying locoregional and distant metastases.[6] At times, other imaging, such as 2-deoxy-2-[fluorine-18]fluoro-D-glucose positron emission testing integrated with CT (18F-FDG PET/CT) and ultrasound (US), may be of some utility.

• CT
  • CT is the preferred initial diagnostic method for identifying SFTs. On CT scans, SFTs exhibit notable vascularity, with approximately 65% of cases demonstrating avid contrast enhancement. Enhancement is most conspicuous in the arterial and early portal venous phases, with a contrast washout in the delayed phase. However, if fibrous elements are predominant, contrast enhancement also becomes marked in the delayed phases.[25] Interestingly, about 35% of cases show large collateral feeding vessels. Heterogeneity in enhancement is more common in aggressive SFTs compared to indolent ones, seen in 76.5% versus 40.0% of cases, respectively. SFTs typically demonstrate intermediate to high attenuation on unenhanced CT scans due to dense collagen fibers and a rich capillary network. Heterogeneous attenuation is observed in approximately 88% of cases. Regions of low attenuation on unenhanced scans, seen in up to 86% of cases, correspond to gross necrosis, hemorrhage, or cystic changes within the tumor. These radiological findings aid in assessing tumor aggressiveness and guiding treatment decisions.[6]
  • On CTs, intrabdominal and retroperitoneal SFTs typically appear as well-defined, predominantly hypervascular masses with varying degrees of cystic change and necrosis. SFTs are generally isodense to adjacent muscles on unenhanced images and typically demonstrate avid yet heterogeneous enhancement following intravenous contrast administration. In certain tumors, central areas that do not enhance or enhance less could indicate necrosis or cyst formation. Although rare, calcifications may appear in larger benign or malignant tumors.[26][27]  
  • While no pathognomonic imaging characteristics are associated with SFTs of the pleura, they typically present as well-circumscribed, homogenous masses originating from the pleural surface, occasionally with lobulated features.[28][29] Enhanced CT scans often show increased vascularity within the tumor, leading to enhancement. Areas of cystic or myxoid degeneration within the tumor may appear hypoattenuated on contrast-enhanced CT.[28] SFTs of the pleura commonly displace or invade surrounding structures and may exhibit changes in position or shape during respiration, particularly if pedunculated.[30] Associated pleural effusion may be observed on CT imaging.[31][32] Certain radiographic features, such as large size, pleural effusion, and necrosis, indicate malignant SFTs of the pleura. In some cases, calcifications may also be identified on CT scans.[26][27] 
• MRI
  • SFTs present a diverse appearance on MRI, characterized by a mixture of solid and cystic components. On T1-weighted images, the solid areas of SFTs typically appear isointense relative to skeletal muscle, reflecting their fibrous composition. However, there can be variability in signal intensity, with some solid areas appearing hypointense.[8][25]
  • Similarly, on T2-weighted images, the solid components of SFTs exhibit variable signal intensity, ranging from isointense to hypointense relative to skeletal muscle. Cystic areas within the tumor typically appear hyperintense on T2-weighted sequences, reflecting their fluid-filled nature.[8][25]
  • SFTs typically demonstrate strong enhancement upon contrast administration, consistent with their vascularity. This enhancement pattern is similar to that observed on CT imaging and aids in distinguishing SFTs from other soft tissue masses. MRI may also be useful in showing necrosis, hemorrhage, and cystic changes if present.[25] 
• 18F-FDG PET/CT 
  • There are few descriptions in the literature regarding the 18F-FDG PET/CT manifestations of SFT. Results from one study found that benign SFT exhibit low-grade activity and malignant SFT tend to be strongly hypermetabolic and homogeneous.[33] Another study of 17 patients with confirmed SFT didn't show 18F-FDG PET/CT to be a determinant in distinguishing indolent SFT (the old-fashioned typical SFT) from aggressive SFT (the old-fashioned malignant SFT). Still, it did conclude that 18F-FDG PET/CT may have a limited role in diagnosing malignant SFTP in suspected patients.[34]
  • In cases where there is suspicion of metastasis or recurrence, 18F-FDG PET/CT scans can be valuable for detecting distant sites of disease involvement. Metastatic SFTs may demonstrate increased FDG uptake in affected lymph nodes, bones, or distant soft tissues, helping to guide treatment decisions and assess prognosis.
  • Additionally, 18F-FDG PET/CT scans can help monitor treatment response in patients undergoing chemotherapy, radiation therapy, or targeted therapies for SFTs. Changes in FDG uptake over time can provide valuable information about the effectiveness of treatment and guide further management strategies.
• Ultrasound
  • US can be used in specific instances of SFT based on its location. In a patient case report of a breast SFT in a 73-year-old man with a 12-month history of a palpable breast mass, the only associated clinical symptom was bilateral gynecomastia. A US examination revealed an oval, well-circumscribed, and hypoechoic mass with hypervascularity in this case.[13] 

Invasive Procedures

SFT may be suspected based on imaging and clinical features. However, a definitive diagnosis requires histologic confirmation.

• Core-needle biopsy
  • A pretreatment biopsy to diagnose and grade the mass is ideal. This biopsy should be performed by an individual experienced in soft tissue mass biopsy techniques. Fine-needle aspiration biopsies rarely provide adequate tissue samples to make a diagnosis. Core biopsies may be sufficient to establish the diagnosis of SFT but are commonly limited in showing histologic features indicative of an aggressive tumor. Repeat biopsy can be considered if the initial biopsy is inadequate or fails to make the diagnosis. Depending on location, radiologic guided biopsy may be helpful.[7]
• Open incisional or excisional biopsy
  • Open incisional or excisional biopsy plays a crucial role in the definitive diagnosis and workup of SFTs. When imaging studies suggest the presence of a soft tissue mass consistent with SFT, biopsy is typically recommended to obtain tissue samples for histopathological examination and IHC analysis.
  • Incisional biopsy involves the removal of a small portion of the tumor tissue for examination, while excisional biopsy involves the complete removal of the tumor. The choice between incisional and excisional biopsy depends on various factors, including the size and location of the tumor, its proximity to vital structures, and the suspicion of malignancy. Some examples from case reports include:
    • A patient presented with a suspected SFT in the pancreas and underwent a total pancreatectomy. The diagnosis of SFT was confirmed.[12]
    • A patient presented with obstructive gastrointestinal symptoms, and imaging showed a left abdominal mass consistent with a soft tissue mass. Surgical exploration revealed a firm mass in the left abdominal region originating from the mesojejunum and enclosed by omental adhesions. Therefore, complete tumor resection and partial omentectomy were performed to ensure safe surgical margins. The diagnosis was confirmed as mesenteric SFT.[25]
    • A patient presented with a large soft tissue mass of the penis and underwent en bloc excision of the mass with consent for possible total penectomy and perineal urethrostomy. The diagnosis was confirmed to be penile SFT.[35]
    • A patient was found to have a retroperitoneal mass on imaging. The patient subsequently underwent successful radical resection of the retroperitoneal mass, right nephrectomy, right adrenalectomy, and partial hepatectomy. The subsequent diagnosis was retroperitoneal SFT.[6]

Histopathology

The excised tissue sample is sent to a pathology laboratory for histopathological examination by a pathologist. This examination involves analyzing the tissue under a microscope to evaluate its cellular composition, architecture, and other features characteristic of SFTs. Histopathological examination confirms the diagnosis of SFT based on characteristic morphological features such as spindle-shaped cells, patternless growth, and branching "staghorn" blood vessels. IHC staining may also be performed to detect specific markers associated with SFTs, such as CD34, STAT6, and Bcl-2, in the absence of other markers like desmin, S100 protein, epithelial membrane antigen, and low molecular weight cytokeratins is characteristic of SFTs.[36] Molecular testing may also detect the characteristic NAB2-STAT6 gene fusion, providing further diagnostic confirmation. In addition to confirming the diagnosis, histopathological examination may provide insights into the subtype and grade of the SFT, which can influence treatment decisions and prognosis. 

In summary, the evaluation and workup of an SFT involves a multidisciplinary approach, including clinical assessment, imaging studies, biopsy for histopathological evaluation, and molecular testing to confirm the diagnosis and assess the extent of disease spread. This comprehensive approach is essential for guiding treatment decisions and optimizing patient outcomes.

Treatment / Management

Due to their rarity and lack of randomized control trials, there is no global consensus on treating SFTs. At present, the most effective therapeutic modality for SFTs is surgical resection. The role of other treatment modalities in the management of SFTs is unclear. Some reports in the literature have demonstrated radiotherapy's effectiveness in controlling SFTs. Chemotherapeutic drugs and novel targeted drugs seem to exert some activity on SFTs. However, a consensus has not been achieved concerning the effectiveness of radiotherapy and chemotherapy against SFTs. Close multidisciplinary collaboration is essential for optimal management and outcomes in patients with SFTs.[3][8][25](B3)

Surgery

Surgical resection, ideally achieving an R0 resection, is the primary treatment modality for localized SFTs and in cases of oligometastatic disease. The approach to surgery varies depending on the location of the tumor:

• Thoracic SFTs
  • These tumors are commonly attached to the visceral pleura and are often pedunculated. Surgical resection typically involves excision of the pulmonary edge. Other procedures, such as isolated parietal pleural resection, chest wall resections, or pulmonary wedge resections, may be performed for SFTs arising from the parietal pleura or lungs.[20][37] Video-assisted thoracic surgery is increasingly utilized, particularly for smaller tumors (<10 cm).[38] In cases of pedunculated thoracic SFTs, preoperative angiography may be performed to identify feeding vessels, facilitating preoperative embolization or thoracoscopic ligation of vessels. For sessile SFTs, embolization is effective in reducing intraoperative bleeding.[39]
• Abdominal SFTs
  • SFTs in the abdominal cavity are most commonly located in the retroperitoneal space, with the pelvic area involved less frequently. Surgical resection aims to achieve wide excision while sparing adjacent organs unless they are encased, adherent, or invaded by the tumor.[8] En bloc or piecemeal resections are performed, with some studies suggesting no significant difference in prognosis between the 2 approaches.[40]
• Meningeal SFTs
  • These tumors are typically attached to the dura mater, with common locations including the tentorium cerebelli, frontal convexity, cerebellopontine angle, ventricles, falx cerebri, and posterior fossa. Complete surgical resection is associated with a better prognosis, although microscopical margins are challenging to define due to tumor fragmentation during resection. Meningeal SFTs may require adjuvant radiotherapy for better local control.
• Extremity SFTs
  • Surgical resection for SFTs of the extremities follows standard principles similar to other soft tissue sarcomas. The thigh is the most common site; tumors typically present as well-circumscribed masses related to fascial tissue.
(B2)

Notably, preoperative embolization should also be considered in all cases, given the highly vascular nature of SFTs. In 1 case report of retroperitoneal SFT, approximately 17 L of blood loss was reported during the successful resection, highlighting the potential advantage of mass embolization preoperatively.[6](B3)

Radiation

No prospective data supports neoadjuvant or adjuvant radiotherapy after surgical resection. The role of adjuvant radiation therapy is local control, especially in tumors at high risk for recurrence.[6] Patients with tumors with high-risk histologic features and positive surgical margins are likely to benefit from adjuvant radiation therapy.[3][41] In locally recurrent SFTs of the pleura, adjuvant radiation therapy may be employed after reresection. Adjuvant radiotherapy has also been recommended in meningeal SFT, and even though no prospective study has been addressed, retrospective analysis suggests a clear trend toward significantly better local control if radiation therapy is added in the adjuvant setting.[42] Neoadjuvant radiotherapy may have a role as upfront therapy in patients with tumors that are large and difficult to resect. Radiation therapy can be offered for palliation in patients with metastatic disease.[43] Due to the lack of data on the use of radiotherapy, a highly individualized treatment plan should be made by a multidisciplinary team.(B2)

Chemotherapy

Chemotherapy has traditionally been utilized in managing advanced or metastatic SFTs, although prospective evidence regarding its efficacy is limited. Clinical trials specifically addressing the role of chemotherapy in SFTs are lacking, leading to uncertainties regarding its optimal use. However, retrospective studies and preclinical research have provided insights into the potential activity of various cytotoxic agents in different subtypes of SFTs.

Anthracycline-based regimens have been the most extensively studied chemotherapy approach in SFTs. Often combined with ifosfamide, these regimens have shown modest response rates (10.5%–20%) and progression-free survival (PFS) ranging from 3 to 5 months. Patients with dedifferentiated SFTs (DD-SFT) have exhibited longer PFS with anthracycline-based regimens than those with malignant SFTs.[8]

Other cytotoxic agents, such as dacarbazine (DTIC) and temozolomide, have demonstrated promising activity in preclinical and clinical studies. DTIC, particularly combined with doxorubicin, has shown substantial activity, with response rates ranging from 38% to 50% and a median PFS exceeding 6 months. Temozolomide, often combined with bevacizumab, has also shown positive results in retrospective studies.[44][45] Trabectedin, an approved drug for pretreated metastatic soft tissue sarcomas, has shown activity in SFTs, particularly in translocation-related sarcomas like SFTs. Preclinical studies in SFT patient-derived xenograft models have demonstrated activity, and retrospective clinical data have reported variable but notable PFS outcomes.[44](B2)

Eribulin, a microtubule inhibitor approved for liposarcomas, has exhibited preclinical activity in SFT patient-derived xenograft models and has shown some responses in phase II trials on advanced soft tissue sarcoma. Clinical trials are currently underway to further evaluate its efficacy in SFTs.[46] While chemotherapy may be considered in managing advanced or metastatic SFTs, its efficacy varies among different subtypes of SFTs. Anthracycline-based regimens remain a standard approach, especially in DD-SFT, while other agents like DTIC, temozolomide, trabectedin, and eribulin show promise and are being evaluated in ongoing clinical trials. Further research and clinical data are needed to establish the optimal chemotherapy regimens and their role in managing SFTs.

Antiangiogenics

The treatment landscape for SFTs has evolved with the introduction of targeted therapies, particularly antiangiogenic agents. Here's a summary of some notable findings regarding the use of various agents in the management of SFTs:

• Temozolomide and bevacizumab
  • This combination therapy targeting VEGF showed promising results in a retrospective study. A high response rate (79%) was observed, with a median PFS of 9.7 months. However, the study's limitations, including a small sample size and variable radiological assessments, warrant a cautious interpretation of these findings.[47]
• Sunitinib
  • A multityrosine kinase inhibitor with activity against the VEGF receptor,platelet-derived growth factor (PDGF) receptor, and other targets, sunitinib demonstrated efficacy in a retrospective series of unfavorable SFT patients. Notably, DD-SFT cases showed less sensitivity compared to malignant SFT cases.[48]
• Sorafenib
  • Another multikinase inhibitor, sorafenib, showed activity in a small cohort of advanced and progressive SFT patients, with a median PFS of 5.9 months.[49]
• Pazopanib
  • This multitargeted receptor tyrosine kinase inhibitor exhibited activity in retrospective and prospective studies. Response rates ranged from 46% to 58%, with median PFS ranging from 4.7 to 9.8 months. The GEIS-32 trial showed favorable outcomes with pazopanib in aggressive and low-aggressive SFT cohorts.[50]
• Axitinib
  • An oral multityrosine kinase inhibitor, axitinib, demonstrated activity in a single-center trial, with a response rate of 41.2%. Notably, partial responses were observed even in patients previously treated with antiangiogenics, highlighting the potential for sequential therapy.[8]
(B3)

Antiangiogenic agents have emerged as promising therapeutic options for non-DD-SFT, showing superior activity to traditional chemotherapy. With its favorable toxicity profile and efficacy demonstrated in clinical trials, pazopanib is recommended as a first-line treatment. Sequential use of antiangiogenics and consideration of other agents like trabectedin or dacarbazine-based chemotherapy upon progression are reasonable strategies in managing SFTs. However, further research, including prospective studies and clinical trials, is needed to validate these findings and optimize treatment approaches. Patients should be encouraged to participate in ongoing clinical trials when appropriate.[6](B3)

Differential Diagnosis

Due to the wide range of histological patterns seen in SFTs, they have been dubbed "the great simulator" of soft tissue tumors by Machado et al.[19] These tumors frequently present diagnostic challenges, requiring the incorporation of clinical, histomorphological, immunohistochemical, and molecular characteristics to diagnose them accurately. The following are some differential diagnoses to consider when evaluating a suspected SFT:

• Gastrointestinal stroma tumor
• Leiomyosarcoma [25]
• Schwannoma
• Fibromyxoid sarcoma [12]
• Myofibroblastoma
• Angiofibroma
• Fibroblastic spindle cell tumor
• Spindle cell lipoma
• Fibroma
• Pseudoangiomatous stromal proliferation
• Synovial sarcoma [26]
• Malignant mesothelioma
• Sarcomatoid mesothelioma 
• Desmoid tumor
• Neurogenic tumors
• Lymphoma
• Soft tissue sarcoma
• Deep fibrous histiocytoma 
• Dedifferentiated liposarcoma 
• Malignant peripheral nerve sheath tumor 
• Dermatofibrosarcoma protuberans
• Metastases [3]

Staging

The 2013 WHO classification of soft tissue sarcomas marked a significant advancement in differentiating various sarcomas, categorizing SFT as a fibroblastic/myofibroblastic tumor. Consequently, the staging of SFTs adheres to the general principles applied to soft tissue sarcomas. The primary staging system utilized for soft tissue sarcomas is the American Joint Committee on Cancer's TNM (primary tumor [T], lymph nodes [N], distant metastasis [M]) staging system. Nonetheless, it's crucial to acknowledge that SFTs possess unique characteristics that may not always align perfectly with conventional staging frameworks.[7]

TNM staging

• T, Primary tumor
  • This staging system component describes the primary tumor's size and extent. Factors such as tumor size, invasion depth, and adjacent structures' involvement are considered. SFTs can vary widely in size and may involve nearby tissues or organs, influencing their T stage.
• N, Lymph nodes
  • SFTs typically do not metastasize to regional lymph nodes. Lymph node involvement is rare in SFTs, so nodal staging is usually not applicable in most cases.
• M, Distant metastasis
  • Metastasis refers to the spread of cancer to distant sites in the body. SFTs can potentially metastasize, commonly to the lungs, liver, bones, or other soft tissues. The presence or absence of metastases determines the M stage.

Grade

• While not officially part of the TNM staging system, tumor grade is an important prognostic factor for SFTs. Based on histological features such as cellularity, mitotic rate, necrosis, and degree of differentiation, SFTs are typically classified as benign or malignant.[7] Malignant SFTs have a higher risk of recurrence and metastasis compared to benign tumors.

Risk stratification

• In addition to TNM staging, risk stratification systems have been proposed for SFTs to help guide management and predict prognosis. These systems often incorporate tumor size, location, histological features, and patient characteristics to classify tumors into low-, intermediate-, or high-risk categories.

Clinical presentation

• The clinical presentation of SFTs, including symptoms, tumor location, and patient factors, also influences the overall stage and management approach.

Overall, staging SFTs involves a multidisciplinary approach, with input from pathologists, radiologists, oncologists, and surgeons to assess tumor characteristics, determine the extent of disease spread, and develop individualized treatment plans.

Prognosis

SFTs exhibit a spectrum of biological behaviors, with the majority displaying benign but potentially locally aggressive behavior, while a subset demonstrates malignant behavior. Predicting the behavior of individual SFTs is challenging, as histologically benign tumors may exhibit aggressive recurrence. Nonetheless, the overall prognosis for SFT is generally favorable compared to many adenocarcinomas, with 5-year survival rates ranging from 59% to 100% and 10-year survival rates between 40% and 89%. The tumor's location significantly influences prognosis. Tumors found outside the thoracic region, such as those in the meninges, pelvis, retroperitoneum, and mediastinum, are linked to higher recurrence risks and potentially poorer prognoses than thoracic tumors. Meningeal SFTs, in particular, often display increased cellularity and higher mitotic counts, contributing to a worse prognosis than SFTs outside the meninges.[8]

Several factors have been associated with prognosis in SFTs. Studies have identified recurrent tumors, positive resection margins (macro or microscopically), tumor size larger than 10 cm, presence of more than 4 mitoses per 10 high-power fields, increased nuclear pleomorphism, higher cellularity, and the presence of malignant components as poor prognostic indicators. Other factors such as tumor necrosis or hemorrhage, increased cellularity, and pleomorphism have also been linked to malignant behavior and worse prognosis. Demicco et al proposed a risk stratification model based on patient age, tumor size, and mitotic figures per 10 per high-powered fields to classify patients into low-, intermediate-, and high-risk categories.[8] This model provides a framework for assessing prognosis and guiding treatment decisions in patients with SFTs. A comprehensive evaluation of these prognostic factors is essential for risk stratification and optimizing management.[7]

Complications

 SFTs can lead to various complications depending on size, location, and aggressiveness. Some of the common complications associated with SFTs include:

• Local invasion
  • SFTs may infiltrate nearby tissues and organs, causing compression, displacement, or invasion. This invasion can lead to symptoms such as pain, obstruction, or dysfunction of affected structures.
• Compression symptoms
  • Depending on their location and size, SFTs can compress adjacent structures, nerves, or blood vessels, leading to symptoms such as pain, neurological deficits, or vascular compromise.
• Hemorrhage or necrosis
  • Larger SFTs may outgrow their blood supply, leading to hemorrhage or necrosis within the tumor, possibly causing acute symptoms such as pain, hemodynamic instability, or signs of organ dysfunction.
• Functional impairment
  • SFTs located in critical anatomical sites, such as the central nervous system or major blood vessels, can impair organ function or cause neurological deficits. For example, meningeal SFTs can lead to neurological symptoms due to compression of the brain or spinal cord.
• Obstructive symptoms
  • SFTs located in the abdomen, pelvis, or retroperitoneum may obstruct the gastrointestinal tract, urinary system, or bile ducts, leading to symptoms such as abdominal pain, vomiting, or jaundice.
• Paraneoplastic syndromes
  • In rare cases, SFTs may produce hormones or cytokines that result in paraneoplastic syndromes, such as hypoglycemia (Doege-Potter syndrome) or hypertrophic osteoarthropathy (Pierre-Marie Bamberger syndrome).
• Complications of treatment
  • Surgical resection, radiation therapy, or systemic therapies for SFTs can also lead to complications such as wound infections, radiation dermatitis, or chemotherapy-related side effects.
• Recurrence
  • Despite complete surgical resection, SFTs have the potential to recur locally. The risk of recurrence is higher with larger tumors, positive surgical margins, and tumors exhibiting malignant features.
• Metastasis
  • Malignant SFTs can metastasize to distant organs such as the lungs, liver, bone, or soft tissues. Metastatic spread may result in the development of secondary tumors at these sites, leading to additional complications and worsening prognosis.
• Psychological impact
  • Coping with a diagnosis of SFT, especially if malignant or recurrent, can have psychological implications for patients and their families, including anxiety, depression, or emotional distress.

Overall, the complications associated with SFTs can vary widely and depend on multiple factors, including tumor characteristics, anatomical location, and individual patient factors. Early detection, comprehensive evaluation, and multidisciplinary management are essential to minimize complications and optimize outcomes for patients with SFTs.