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Ann Thorac Surg 2002;74:285-293
© 2002 The Society of Thoracic Surgeons

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Review

Solitary fibrous tumors of the pleura

^a Division of Thoracic Surgery, Toronto General Hospital, University of Toronto, University Health Network, Toronto, Ontario, Canada
^b Division of Clinical Pathology, University Hospital of Geneva, Geneva, Switzerland

* Address reprint requests to Dr Keshavjee, Division of Thoracic Surgery, Toronto General Hospital, 200 Elizabeth St, EN 10-224, Toronto, Ontario M5G 2C4, Canada
e-mail: shaf.keshavjee{at}uhn.on.ca

	Abstract

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Solitary fibrous tumor of the pleura is a mesenchymal tumor that has been increasingly recognized over the past few years. The tumor was initially described in the pleura, but it has been reported in many other sites lately. Although the majority of these tumors have a benign course, the malignant form still remains enigmatic. Indeed, the behavior of these tumors is often unpredictable and does not always correlate with histologic findings. In addition, benign tumors may remain unproblematic for several years before changing into a malignant form. In order to define more precisely the clinical behavior of solitary fibrous tumors of the pleura, we reviewed the literature with particular attention to the clinical presentation, histopathologic characteristics, and cytogenetic differentiation of these tumors. A staging system and an algorithm for the management and follow-up of these patients are proposed.

	Introduction

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Primary tumors of the pleura are commonly divided into two major categories: diffuse and localized tumors. Whereas the diffuse pattern is known for its association with asbestos and its poor outcome, the localized pattern is rare and remains a subject of controversy. Lately, electron microscopy and immunohistochemistry have demonstrated that these tumors have a mesenchymal rather than a mesothelial origin [1–5]. Therefore, the term "localized mesothelioma" was abandoned, and these tumors are now called "solitary fibrous tumors of the pleura" (SFTP) [6].

Approximately 800 cases of SFTP have been reported in the literature. The majority of them are pedunculated masses with benign histologic features [7]. Although they may be relatively large, these tumors are usually treated by simple excision and do not recur if their resection is microscopically complete [8]. About 12% of SFTP, however, are malignant and eventually lead to death through local recurrence or metastatic disease [9]. The malignant form of SFTP still remains enigmatic. Indeed, the tumor’s behavior is often unpredictable and does not always correlate with histologic findings [7]. In addition, in some cases benign SFTP may remain unproblematic for several years before changing into the malignant type of the disease [10]. In order to define the clinical behavior of SFTP more precisely, we reviewed the clinical presentation, histopathologic characteristics, and cytogenetic differentiation of these tumors, noting that localized fibrous tumors have recently been reported in extrathoracic sites such as the meninges, nose, oral cavity, pharynx, epiglottis, salivary gland, thyroid, breast, kidney, bladder, and spinal cord [6, 11–13]. Finally, we proposed a classification scheme based on histologic and morphologic characteristics of the tumor that may be helpful for treatment plan and follow-up care of SFTP.

	Historical background

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The first report of a primary localized pleural tumor is attributed to Wagner [14] in 1870. However, it was only in 1931 that Klemperer and Rabin [15] published the first accurate pathologic description and classified mesothelioma as either "localized" or "diffuse." Because tissue culture [16] and ultrastructural analysis [17, 18] demonstrated the presence of epithelial-like cells in localized mesotheliomas, Stout and Murray [16] in 1942 claimed that localized mesothelioma had a mesothelial origin. However, other investigators showed that the mesothelial layer covering the tumor was intact, and they postulated that the epithelial cells seen could have been trapped within growing fibrous mesenchymal tumors [17, 19]. The controversy on the origin of these tumors persisted for several decades and is reflected by the variety of terms given to the neoplasm (Table 1).

	Clinical features

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Solitary fibrous tumors of the pleura have been described in all age groups from 5 to 87 years, but they peak in the sixth and seventh decades of life; they have an even distribution between men and women [7, 9, 25]. The majority of patients with malignant SFTP are symptomatic and present with large tumors [7, 10, 26, 27]. Symptoms usually include cough, chest pain, and dyspnea. More rarely, hemoptysis and obstructive pneumonitis are observed as a result of airway obstruction [7, 10]. Digital clubbing and hypertrophic pulmonary osteoarthropathy (Pierre-Marie-Bamberg syndrome) have been described in 10% to 20% of patients with either benign or malignant SFTP [7, 26, 28, 29]. These clinical features usually resolve within 2 to 5 months or sometimes longer after removal of the tumor, but they may reappear with recurrence of the tumor [7, 27–30]. The causes of digital clubbing and of hypertrophic pulmonary osteoarthropathy could be, respectively, an abnormal production of hepatocyte growth factor or an excessive release of hyaluronic acid by the tumor [31, 32]. In less than 5% of patients, SFTP can also secrete insulin-like growth factor II, which causes refractory hypoglycemia (Doege-Potter syndrome) [7, 9, 33]. A high serum level of insulin-like growth factor II is typically associated with low levels of insulin and insulin-like growth factor I, which return to normal values within 3 to 4 days after resection of the tumor [29, 30, 34, 35].

Recurrence after surgical resection is most often located in the same hemithorax and may occur up to 17 years after resection [28]. Intrathoracic recurrence may be fatal because of mediastinal compression and inferior vena cava obstruction [9, 36]. Metastases, if present, are usually blood borne and are located, by order of frequency, in the liver, central nervous system, spleen, peritoneum, adrenal gland, gastrointestinal tract, kidney, and bone [7].

	Radiologic features

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Benign and malignant SFTP usually appear as a well-defined, homogeneous, and rounded mass on the initial chest radiograph [7, 26–28]. Rarely, a pleural effusion is associated with malignant SFTP [7, 27, 28]. While small tumors arising from the parietal pleura classically form obtuse angles with the chest wall, large or pedunculated SFTP may form acute angles and be confused with intrapulmonary masses [37, 38]. Pedunculated SFTP have occasionally been reported to be moving on successive chest radiographs [39, 40].

Computed tomographic scan usually demonstrates a well-delineated, homogeneous, and occasionally lobulated mass of soft tissue attenuation [41]. Although no specific computed tomographic features have been described for the diagnosis of SFTP, the tumors typically appear in contact with the pleural surface and show displacement or invasion of the surrounding structures [27]. Heterogeneity may be observed with benign and malignant variants of SFTP because of myxoid degeneration, hemorrhage, or necrosis (Fig 1). Tumors arising in an interlobar fissure may be more difficult to differentiate from an intraparenchymal mass, because the lesion appears to be surrounded by lung parenchyma [42]. Calcifications may be observed in a few tumors, regardless of their benign or malignant histologic features [7, 10, 27], and can be difficult to distinguish from those in large bronchial carcinoids [43].

View larger version (103K): [in this window] [in a new window]   Fig 1. Computed tomographic scan showing a large solitary fibrous tumor of the pleura with heterogeneous zones due to hemorrhage and necrosis of the tumor. (Reprinted with permission from The Society of Thoracic Surgeons [Ann Thorac Surg 1999, 67, 1456–9] [10].)

View larger version (184K): [in this window] [in a new window]   Fig 2. Magnetic resonance imaging showing a large solitary fibrous tumor of the pleura situated on the left hemidiaphragm. Magnetic resonance imaging was helpful in determining the intrathoracic localization of the tumor.

	Histopathology

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Macroscopically, benign and malignant tumors appear as firm, smoothly lobulated masses. Most of them are encapsulated by a thin, translucent membrane, containing a reticulated vascular network. Firm adhesion without signs of invasion may be present between visceral and parietal pleura at the surface of the tumor. The cut surface appears gray-white to tan with a whorled pattern and may show areas of hemorrhage and necrosis [7, 52]. Hemorrhagic and necrotic areas may be present in benign tumors, but they usually predominate in the malignant form, most likely because of their larger size [7].

Microscopically, SFTP are characterized by a proliferation of uniform elongated spindle cells intimately intertwining with various amounts of connective tissue (Fig 3). Zones of hypercellularity may alternate with hypocellular or fibrous areas within the same tumor. Typically, fibroblasts and connective tissue are arranged in a so-called patternless pattern or storiform pattern that is characterized by a haphazard distribution of spindle cells and collagen fibrils [53, 54]. Occasionally, an increased amount of blood vessels within the tumor causes a hemangiopericytoma-like pattern [7, 53]. More rarely, other patterns, such as herringbone and neural palisading, are also observed inside the tumor [7].

View larger version (130K): [in this window] [in a new window]   Fig 3. Histologic presentation of a benign solitary fibrous tumor of the pleura. Small ovoid or spindle cells without nuclear atypia in a mixoid loose matrix. (Hematoxylin and eosin, x100.) (Reprinted with permission from The Society of Thoracic Surgeons [Ann Thorac Surg 1999, 67, 1456–9] [10].)

View larger version (159K): [in this window] [in a new window]   Fig 4. Histologic presentation of a malignant solitary fibrous tumor of the pleura. Highly cellular tumor with spindle cells arranged in a storiform pattern. (Hematoxylin and eosin; x100.) (Reprinted with permission from The Society of Thoracic Surgeons [Ann Thorac Surg 1999, 67, 1456–9] [10].)

	Differential diagnosis

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Immunohistochemistry has been an extremely useful tool to differentiate SFTP from mesotheliomas and other sarcomas over the last few years (Table 2). Indeed, SFTP by definition is vimentin positive and keratin negative. In addition, CD34 is positive in most benign and malignant SFTP, whereas it remains negative for most other pulmonary tumors. Hemangiopericytomas are CD34 positive tumors, and thus some authors have raised the possibility that both SFTP and hemangiopericytoma may represent a single entity [64]. However, recent genetic analyses have suggested that hemangiopericytomas are unrelated to SFTP [65]. In addition, the antiapoptotic proto-oncogene bcl-2 is strongly expressed in SFTP, whereas it is not expressed or is only poorly expressed by hemangiopericytomas [66].

Recently, some authors have demonstrated that O-13 (CD99) and factor XIIIa could be expressed by solitary fibrous tumors located in the pleura and in other locations [12, 67–69]. However, in contrast to CD34 and bcl-2, CD99 and factor XIIIa are not strongly expressed by SFTP and can also frequently be positive with other tumors such as synovial sarcomas or neural tumors and thus are less specific for the diagnosis of SFTP [43, 60, 65, 67–71].

	Cytogenetic analysis

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El-Naggar and coworkers [3] analyzed 14 histologically benign fibrous tumors by flow cytometry. Although they observed that all tumors presented a diploid DNA content, two of the recurrent tumors exhibited an elevated S-phase (mean 4% versus 2% in the primary tumors) and a higher number of mitoses (5 to 10 mitoses per 10 high-power fields versus 0 to 3 in primary tumors). Hence, the number of mitoses and corresponding S-phase may reflect rapidly growing lesions that exhibit locally aggressive behavior. In a more advanced stage of malignancy, SFTP may become partially aneuploid and be associated with a high mitotic index [72].

More recently, cytogenetic analyses have shown anomalies such as trisomy 8, trisomy 21, or more complex translocations in solitary fibrous tumors that may help to distinguish them from mesothelioma and other sarcomas [73–75]. Miettinen and coworkers [65] have shown by genomic hybridization that chromosomal anomalies were present mainly in tumors larger than 10 cm. Whereas only one tumor smaller than 10 cm showed chromosomal loss, seven out of eight tumors larger than 10 cm presented with changes in DNA copy numbers [65]. They also showed that the most common change, trisomy 8, was observed in four of eight tumors larger than 10 cm [65]. Hence, the relationship between size and chromosomal anomalies may suggest that genetic changes may promote tumor growth. Further analysis may help researchers to appreciate the types of genetic anomalies and the risk of recurrence of SFTP.

	Histopathogenesis

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Malignant SFTP may occur de novo or degenerate from benign tumor [52]. Indeed, some tumors consist entirely of highly atypical cells, whereas others contain benign areas within the tumor [52]. Possible malignant degeneration of SFTP is further emphasized by the fact that chromosomal anomalies and genetic mutations of the proapoptotic gene p53 are located only in some areas of the tumor, and that benign tumors may recur with histologic signs of malignancy several years after resection of a benign form [10, 52, 55, 65].

The antiapoptotic proto-oncogene bcl-2 is constitutively expressed by all benign and malignant SFTP, which suggests that these tumors may derive from a long-lived CD34-positive "fibroblastic" stem cell [67, 76, 77]. In further analyses, Yokoi and coworkers [52] showed that all malignant tumors were p53 positive ( 2% versus < 1% in the benign variants). In addition, they showed that the index of positive staining for Ki67, a marker of cellular proliferation, was greater in malignant than in benign tumors (1% to 44% versus 0% to 2%, respectively) and roughly paralleled the clinical outcome. Hanau and Miettinen [55] have shown similar results, with the numbers of Ki67-positive cells ranging from 0% to 2% in benign tumors and from 20% to 40% in malignant ones. Unfortunately, the cutoff between benign and malignant lesions is not always as clear, because Hasegawa and coworkers [76] showed that benign tumors could have a Ki67 index of up to 10%. The proliferating cell nuclear antigen, which is another index of cell proliferation, showed less striking differences between benign and malignant tumors, with an index of 1% to 21% in benign forms and 3% to 62% in malignant forms [52]. Hence, successive mutations in bcl-2 and p53 may lead to an excessive proliferation rate and to the malignant form of SFTP. Further analysis is required to determine if other proto-oncogenes are involved in the transformation of benign SFTP into a malignant form.

	Classification

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Although solitary fibrous tumors are now well recognized as a single entity in the pleura and in other sites, there are as yet no unifying criteria for classifying these tumors.

Morphologic and histologic indicators seem to be important predictors of outcome [6]. In 1981, Briselli and coworkers [9] presented eight new cases and reviewed 360 cases from the literature. Twelve percent of the tumors followed a malignant course and led to death. The authors observed that the growth pattern of the tumor was more important for prognosis than the histologic characteristics. More recently, England and coworkers [7] reported 223 cases from the files of the Armed Forced Institute of Pathology, of which 82 were described as histologically malignant. Whereas none of the patients with a histologically benign disease died, 55% of those with a malignant form died because of recurrences or metastases. The authors observed that among the malignant variants, complete resectability was the single most important predictor of outcome.

In order to stratify the risk of recurrence based on histologic and morphologic indicators and to develop a staging system, we reviewed all publications reporting adequate follow-up for patients with a diagnosis of SFTP proven by histology and immunohistochemistry [4, 10, 26, 27, 29, 31, 51, 52, 55, 59, 76, 78–81]. Among a total of 185 reported cases, 19 (10%) of the patients presented at least one recurrence of their tumor, and 16 (9%) died of the disease (Table 3). Of the 35 patients who presented a recurrence or died of the disease, 27 had a primary sessile tumor with histologic sign of malignancy, whereas 5 presented with a primary sessile histologically benign tumor and 2 with a primary pedunculated histologically malignant tumor. One patient with a pedunculated histologically benign tumor presented a recurrence (or a new primary tumor) and died 10 years after the initial resection [52]. Recurrence was thus observed in 63% of all the patients presenting with a malignant sessile tumor, in 14% of all the patients presenting with a malignant pedunculated tumor, in 8% or less of all the patients presenting with a benign sessile tumor, and in 2% or less of all the patients presenting with a benign pedunculated tumor. Recurrences were often associated with a progression in the degree of malignancy and seemed more aggressive in patients with malignant sessile tumors, because 10 patients in this group died of the disease within 24 months. These findings are consistent with the previous report from England and coworkers [7], who demonstrated that recurrence of SFTP occurred in 60% of sessile histologically malignant tumors, 19% of pedunculated histologically malignant tumors, and 2% of the benign tumors.

	Treatment

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Complete en bloc surgical resection is the mainstay of therapy for all benign and malignant SFTP. A distance of 1 to 2 cm from the tumor is usually recommended to be in healthy tissue. Whereas pedunculated tumors can be safely resected with a wedge resection of the lung, large sessile tumors can be difficult to resect because of extensive adhesions and may occasionally require a lobectomy or a pneumonectomy in order to achieve complete resection [31, 83]. Frozen section can be helpful to demonstrate that the resection margins are free of tumors, but this is not routinely required.

Tumors adherent to the parietal pleura require an extrapleural dissection [29, 31]. However, concomitant chest wall resection can be necessary if the tumor densely adheres to or invades the chest wall [26]. In 3% or less of the cases, the tumor can be "inverted" and grow inside the lung parenchyma [84]. These tumors may occasionally require a lobectomy or a sleeve lobectomy [31, 52, 80, 85]. In our experience, a sleeve lobectomy was required in one case for a solitary fibrous tumor growing from the left lower lobe bronchus inside the left main bronchus. Interestingly, the tumor was growing without invading the main bronchus and could be simply pulled back from the main bronchus (Fig 5).

View larger version (125K): [in this window] [in a new window]   Fig 5. Solitary fibrous tumor growing from the left lower lobe bronchus inside the left main bronchus. The tumor did not present any signs of invasion and could be simply pulled back from the main bronchus.

The role of adjuvant therapy in SFTP has not been systematically explored because of the limited number of patients [10, 31, 59]. However, some indices suggest that radiotherapy and chemotherapy could be beneficial in some patients. Suter and colleagues [26] have reported 1 patient who is alive with no evidence of disease more than 20 years after subtotal resection of the tumor followed by radiotherapy, and Veronesi and colleagues [87] have observed significant reduction of an inoperable recurrent SFTP with ifosfamide and adriamycin. Although neoadjuvant therapy could be helpful in large malignant tumors, its use is limited by the difficulty of obtaining a precise preoperative diagnosis even with an open biopsy [87]. Currently, we would recommend the administration of adjuvant therapy after resection of malignant sessile tumors, in particular if they are recurrent.

Additional therapies, such as brachytherapy and photodynamic therapy, have been developed for malignant mesothelioma and could be applied for other pleural tumors, in particular if they cannot be completely resected. However, their use in SFTP has rarely been reported, and their utility remains unproven [88, 89].

	Follow-up care

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The risk of recurrence is high after resection of a malignant sessile SFTP. However, most of the recurrences are initially located inside the pleural cavity, and distant metastasis seems to be a late event in the evolution of the disease. Some recurrences can be extremely aggressive locally, leading to patients’ death by local invasion and compression without evidence of distant metastasis [26, 52]. Our review of the literature has shown that the majority of the recurrences after resection of malignant sessile tumors occur within the first 24 months after the initial resection and that approximately half of the recurrences were the cause of death during that period (Table 3). Hence, half-yearly radiologic control with chest roentgenogram or computed tomographic scan during the initial 2 years after the resection and yearly thereafter seems warranted and may help to reduce the mortality from malignant SFTP. In case of recurrence, aggressive surgical resection remains the treatment of choice and may lead to long-term survival [27]. Adjuvant therapy should be considered if the tumor appears histologically malignant. An algorithm for the management of SFTP is proposed in Figure 6.

View larger version (25K): [in this window] [in a new window]   Fig 6. Treatment plan and follow-up according to the type of solitary fibrous tumor of the pleura (SFTP).

	Conclusions

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	References

Top Abstract Introduction Historical background Clinical features Radiologic features Histopathology Differential diagnosis Cytogenetic analysis Histopathogenesis Classification Treatment Follow-up care Conclusions References

 

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