Introduction

Solitary fibrous tumor (SFT) is an uncommon fusion gene-associated neoplasm composed of spindled fibroblastic cells set within a branching vasculature. The tumor may occur in any anatomic site, with approximately 5–27% of SFTs arising in the head and neck region [1,2,3,4,5,6,7,8,9]. Within this anatomic region, preferred sites of involvement include the oral cavity and orbit [2, 10, 11]. In contrast, SFT infrequently affects the sinonasal tract (SNT). Due to its relative rarity and variable morphologic appearance, SNT SFT may be difficult to distinguish from other mesenchymal lesions that are more commonly recognized at this site. While the majority of SFTs behave in a benign fashion a small subset will recur or metastasize [12,13,14]. Whether SFTs of the SNT exhibit a similarly wide spectrum of biologic behavior remains unclear. A limited number of SNT SFTs have been reported, comprised mostly of isolated case reports, small series, and partial descriptions of small numbers of cases included among larger series of SFTs involving the head and neck or encompassing all anatomic sites [1, 2, 10, 11, 15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66]. In this study, six new cases of SFT of the SNT were evaluated in conjunction with a comprehensive literature review in order to further characterize the clinicopathologic features of this uncommon sinonasal neoplasm.

Materials and Methods

Six cases of SFT involving the nasal cavity and/or paranasal sinuses were identified from the files of the departments of pathology within Southern California Permanente Medical Group between 2007 and 2017, representing 0.021% of the 28,026 SNT specimens submitted during this period. Hematoxylin and eosin stained slides from all cases were reviewed, with a range of 1–9 slides (mean 4 slides) per case available for analysis. In addition, previously performed immunohistochemical stains from each case were reviewed, which included CD34 (n = 6), pan-cytokeratin (n = 4), desmin (n = 2), smooth muscle actin (SMA) (n = 6), bcl-2 (n = 3), muscle specific actin (MSA) (n = 3), CD31 (n = 2), and S-100 protein (n = 3). Additional immunohistochemical studies were performed on all cases using a monoclonal antibody directed against STAT6 (clone EP325; Cell Marque; Rocklin, California) utilizing standard techniques.

Clinical data, treatment, and follow up information were obtained from electronic medical records augmented by the surgical pathology reports. This clinical investigation was conducted in accordance and compliance with all statutes, directives, and guidelines of an Internal Review Board authorization (#5968) performed under the direction of Southern California Permanente Medical Group.

A review of the English literature based on a MEDLINE search from 1966 to 2017 was performed and all cases of SNT SFT were reviewed, with specific attention to the clinical series and those which included immunohistochemistry information.

Results

The patients included five males and one female who ranged in age from 33 to 72 years, with a mean age at presentation of 52 years (Table 1). Patients most frequently presented with nasal obstruction. Other symptoms included nasal discharge and epistaxis. The duration of symptoms ranged from 0.25 to 24 months, with an average of 9.9 months.

Table 1 Clinicopathologic features of six cases of sinonasal tract solitary fibrous tumor
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The tumors ranged from 0.4 up to 6.2 cm in greatest dimension with an average size of 3.8 cm. Three tumors involved the nasal cavity alone, one tumor was confined to the paranasal sinuses (ethmoid and sphenoid), and two involved both the nasal cavity and paranasal sinuses. Four tumors were centered on the left side and two on the right side. The tumors were submitted as multiple irregular fragments of tissue, described as white to pale tan with a firm consistency.

The tumors were situated beneath an intact surface respiratory epithelium and/or metaplastic squamous mucosa. Surface ulceration was noted in four cases, perhaps due to the size of the polypoid mass as it was subjected to trauma within the SNT. The tumors showed a moderately cellular proliferation of spindle cells dispersed within a collagenous stroma (Fig. 1). Entrapment of minor mucoserous glands was observed in three cases (Fig. 2). All tumors were characterized by variable cellularity with hypocellular areas admixed with areas of increased cellularity (Fig. 3). Paucicellular areas of the tumor were dominated by sclerotic to hyalinized stroma with rare interspersed spindle cells (Fig. 4). In the more cellular regions of the tumors, the spindle cells had a vaguely storiform or fascicular arrangement or were randomly distributed with no consistent architectural pattern of growth (Fig. 5). The neoplastic spindle cells were cytologically bland, with uniform fusiform to ovoid nuclei with fine chromatin, inconspicuous nucleoli and scant eosinophilic cytoplasm (Fig. 6). The spindle cells lacked atypical features and no pleomorphic cells were observed. All tumors were characterized at least focally, by the presence of a prominent vascular component ranging from small to medium sized thin-walled, dilated vessels to larger, thick-walled vessels with perivascular hyalinization (Fig. 7). Areas of cellular dyshesion, resulting in a pseudovascular appearance, similar to what has been described in giant cell angiofibroma, was observed in one case, though no stromal giant cells were identified (Fig. 8). Mitotic figures were present, ranging from 0 to 2 with a mean of 1.2 per 10 high power fields. No atypical mitotic figures were identified. Tumor necrosis was absent in all cases, although if surface ulceration was present, associated degenerative changes were noted.

Fig. 1
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SNT SFT below an intact respiratory epithelium

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Fig. 2
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Entrapment of normal mucoserous glands at the edge of the tumor

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Fig. 3
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Intratumoral variation in cellularity with transition between hyper- and hypo-cellular areas

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Fig. 4
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Paucicellular area of SFT with few scattered spindle cells in a collagen rich stroma

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Fig. 5
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More cellular focus in SFT

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Fig. 6
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Cytologically bland spindle cells lacking nuclear atypia

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Fig. 7
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SFT with prominent branching vessels

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Fig. 8
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Pseudovascular spaces in SFT

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All six SNT SFTs showed strong and diffuse nuclear expression of STAT6 (Fig. 9). CD34 had been performed at the time of initial diagnosis and was also positive in all cases. All three cases tested were positive for bcl-2. The tumors were negative for SMA (0/6), MSA (0/2), desmin (0/2), CD31 (0/2), pan-cytokeratin (0/4), and S-100 protein (0/3).

Fig. 9
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Strong, diffuse, nuclear STAT6 expression in SFT

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All of the tumors were removed by endoscopic surgical excision only without additional treatment. Clinical follow up was available for all patients with a mean duration of 72 months (range 32–102 months). None of the patients developed local recurrence or metastasis and all were alive with no evidence of disease at last follow-up.

Discussion

Clinical Presentation

SFTs are well described in the head and neck region, but rarely involve the nasal cavity and paranasal sinuses. Review of the English literature yielded 86 cases of SFT arising in the SNT, most of which were represented by single case reports [1, 2, 10, 11, 15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66]. Table 2 summarizes the published clinicopathologic characteristics of SNT SFTs combined with this clinical series. While the present series of SNT SFTs was comprised predominantly of men, overall, males and females are affected equally, similar to the sex distribution observed when SFTs of all anatomic sites are considered [13]. There is a wide age range at presentation (18–79 years) with a mean of 49.0 years. Most patients presented clinically with nasal obstruction and/or epistaxis, with symptoms present for an average of 18.5 months. A minority of patients reported proptosis, epiphora, and visual field changes, which correlated with orbital involvement by the tumor [17, 27, 42, 51, 54, 62]. The majority of tumors were unilateral with a mean size of 4.7 cm, and involved the nasal cavity alone followed by combined involvement of the nasal cavity and paranasal sinuses. Rarely, tumors were observed to extend beyond the confines of the SNT at presentation, involving the skull base, orbit, or nasopharynx [17, 20, 27, 37, 39, 42, 44, 49,50,51, 54,55,56, 59, 62].

Table 2 Literature summary and current cases of sinonasal tract solitary fibrous tumor
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Pathologic Features

SNT SFTs display histologic features identical to those occurring in other anatomic sites. The tumor is characteristically composed of cytologically bland spindle cells set in a collagenous stroma. Variation in cellularity is a typical finding, with both hyper- and hypo-cellular areas identified. The spindle cells may be haphazardly arranged or exhibit a fascicular or storiform pattern of growth. The presence of a prominent vascular network is another characteristic feature, with dilated, branching, stellate, or staghorn shaped vessels. Histologic variants include mature adipose tissue within SFT (previously designated as lipomatous hemangiopericytoma) or pseudovascular spaces lined with multinucleated stromal giant cells (previously designated as giant cell angiofibroma). While well recognized at other soft tissue sites, only rare examples of fat-containing or giant cell rich SFTs affecting the SNT have been reported [2, 47].

Molecular Genetics and Immunohistochemistry

A recurrent NAB2–STAT6 gene fusion resulting from a paracentric inversion in chromosome 12q13 has been consistently and specifically associated with SFT irrespective of anatomic site [67,68,69]. Several different fusion variants have been identified, but in the SNT SFTs evaluated, the majority have harbored a NAB2–STAT6 gene fusion with the breakpoint between NAB2 exon 4 and STAT6 exon 2, which is the most common fusion variant detected when tumors of all sites are considered [2, 65].

By immunohistochemistry, SFTs consistently express CD34, as well as bcl-2 and CD99 [12,13,14, 70]. None of these markers, however, are entirely specific for SFT, as immunoreactivity can be seen in a variety of other mesenchymal neoplasms. SFTs are generally negative for cytokeratins, actins, desmin, and S-100 protein [70]. Recently, STAT6 has emerged as a more reliable marker for establishing a diagnosis of SFT. Nuclear expression of STAT6 protein is thought to reflect the presence of a NAB2–STAT6 gene fusion characteristic of these tumors. The sensitivity of STAT6 for a diagnosis of SFT exceeds 95% when strong and diffuse nuclear expression is considered positive [1, 2, 71,72,73,74,75,76]. STAT6 nuclear expression seems highly specific for SFT with only occasional (~ 2%) non SFT mesenchymal neoplasms (such as fibrous histiocytoma, desmoid tumor, and dedifferentiated liposarcoma) exhibiting both nuclear and cytoplasmic positivity [72,73,74,75,76], rather than just nuclear reactivity seen in SFT.

Differential Diagnosis

The histologic differential diagnosis for SFT in the SNT is quite broad, as many mesenchymal lesions affecting this region have a similar appearance characterized by spindled-shaped cells accompanied by a variably prominent background vascular network.

Sinonasal glomangiopericytoma, similar to SFT, is composed of uniform, cytologically bland spindle cells separated by numerous, ectatic, branching vessels [77]. Glomangiopericytoma, however, lacks the variable cellularity and dense hyalinized collagen, typical of SFT. The characteristic peritheliomatous hyalinization, extravasated erythrocytes and mast cells are not features of SFT. By immunohistochemistry, unlike SFT, glomangiopericytoma exhibits a myoid phenotype with diffuse positivity for smooth muscle and muscle specific actins, and lacks expression of CD34 and STAT6 [65, 72, 76, 77]. While nuclear accumulation of β-catenin is consistently present in glomangiopericytoma secondary to the presence of CTNNB1 mutations [78], it should be noted that this finding is not unique to glomangiopericytoma, as nuclear β-catenin expression has also been frequently observed in SNT SFT [79].

Nasopharyngeal angiofibroma has a distinctive clinical presentation, affecting only males, while SNT SFT typically occur in middle age adults. Nasopharyngeal angiofibroma is characterized by a fibrocollagenous stroma containing numerous variably sized, irregularly shaped vessels imparting an appearance that may resemble SFT. These neoplasms are, however, overall less cellular than SFTs, with the constituent stromal cells lacking CD34 and STAT6 immunoreactivity [2, 72, 76, 80]. The presence of androgen receptor positivity also helps to support a diagnosis of nasopharyngeal angiofibroma, as SFTs are typically negative for this marker [81].

Leiomyoma and angioleiomyoma are rare sinonasal tumors composed of intersecting fascicles of spindled tumor cells, the latter also associated with a prominent vascular component [82, 83]. Unlike SFT, the constituent spindle cells of angioleiomyoma are intimately associated with the vascular component of the tumor, encasing or merging with thick walled vascular channels. Immunohistochemically, in contrast with SFT, the spindle cells of leiomyoma and angioleiomyoma are positive for SMA, MSA, h-caldesmon and desmin, while negative for CD34 and STAT6 [2, 72, 74, 82].

Nerve sheath tumors such as schwannoma and neurofibroma occasionally involve the SNT and can be potentially confused with SFT [84, 85]. Schwannoma in particular shares several features with SFT including hypercellular and hypocellular areas as well as the presence of hyalinized blood vessels. Neural tumors can be readily distinguished from SFT by strong expression of S-100 protein and SOX10. Although neurofibromas contain some CD34 immunoreactive cells, both schwannoma and neurofibroma lack STAT6 positivity [2, 71,72,73,74,75,76, 84].

Synovial sarcoma, similar to SFT, is composed of uniform spindle cells and can exhibit collagen bands or a branching vascular pattern in a subset of cases [86, 87]. Synovial sarcoma typically has a more densely cellular appearance with alternating light and dark-staining areas (marbling) and unlike SFT, shows variable keratin and EMA expression, but is negative for both CD34 and STAT6 [2, 71,72,73,74,75,76]. TLE1 is often used as a biomarker for distinguishing synovial sarcoma from other soft tissue neoplasms, however weak nuclear expression has been observed in a minority of SFTs [88].

Although commonly regarded as a small round cell neoplasm, mesenchymal chondrosarcoma is also included among the differential diagnostic considerations of SNT SFT due to the occasional spindle shaped morphology of the nuclei and characteristic peritheliomatous arrangement of the lesional cells around sinusoidal vascular spaces [89]. Mesenchymal chondrosarcoma is readily distinguished from SFT by the presence of foci of cartilaginous tissue. In addition, these tumors do not express CD34 or STAT6, but are CD99 and Sox9 reactive [71, 74, 76].

Biphenotypic sinonasal sarcoma is a low grade spindle cell neoplasm unique to the SNT, which bears some morphologic resemblance to SFT [90]. Although biphenotypic sinonasal sarcoma is comprised of cytologically low grade spindle cells and frequently displays branching staghorn type vessels, the tumor is uniformly hypercellular and lacks the collagenous stroma of SFT. The presence of entrapped invaginations of hyperplastic surface respiratory epithelium is another distinguishing feature. The immunohistochemical features of biphenotypic sinonasal sarcoma are distinctive, with tumors exhibiting immunoreactivity for S-100 protein and actins indicative of neural and myogenic differentiation. Furthermore, frequent nuclear β-catenin expression, although often focal and of weak to moderate intensity, along with a negative SOX10 are characteristic of this tumor [91]. Although CD34 expression may occur in a subset of biphenotypic sinonasal sarcomas, it is typically focal in nature, in contrast with the diffuse positivity typical of SFT. In addition, biphenotypic sinonasal sarcomas have been shown to lack STAT6 expression [2].

Treatment and Prognosis

Surgery is the preferred treatment for SNT SFTs. Complete surgical removal of the tumor is optimal, however pathologic evaluation of margins is often difficult as endoscopic surgical approaches are frequently employed in this anatomic region, with tumors resected in a piecemeal fashion. It is thus often left to the surgeon to determine whether adequate excision of the tumor has been performed. Additional therapy beyond surgical resection is generally not required for the majority of SNT SFTs, although radiation and chemotherapy have been employed to manage locally advanced or recurrent disease in individual cases [11, 48, 51].

When all anatomic sites are considered, most SFTs follow an indolent clinical course, with disease progression in the form of local recurrence or metastasis only observed in a small minority of cases [3, 6,7,8,9]. Histologic criteria for malignancy are not well defined, though the World Health Organization categorizes SFT as malignant based on the presence of hypercellularity, increased mitoses (> 4 mitoses per 10 high power fields), cytological atypia, tumor necrosis, and/or infiltrative margins [92]. Many of these parameters have been shown to be significantly associated with a higher risk of recurrence and decreased survival [3, 6,7,8,9]. SFTs exhibiting a high grade sarcomatous component (dedifferentiated SFT) are also considered malignant [93]. Histology is an imperfect predictor of clinical behavior, however, as occasional tumors classified as malignant based on morphologic parameters will behave in a benign manner [6, 94, 95], while conversely, recurrence and metastases are well documented in SFTs lacking atypical histologic features [5, 6, 8, 95, 96]. In addition to histology, patient age (≥ 55 years), tumor size (> 10 or ≥ 15 cm), and margin status have also demonstrated utility in predicting clinical outcome [6, 7, 9]. Various risk stratification models based on combinations of patient age, tumor size, and mitotic index [7], or mitotic rate, cellularity, and pleomorphism [3] have been proposed as a method of more accurately predicting behavior of SFTs.

SNT SFTs also appear to show variable biologic behavior, though overall prognosis is considered favorable. Among 72 reported cases of SNT SFT with available follow-up data, there were no instances of metastasis or death due to disease. Five patients developed local recurrence at 3–69 months after resection [43, 51,52,53,54]. None of these tumors exhibited any atypical morphologic features at the time of presentation, though an increased mitotic rate was observed in the recurrences of two cases [51, 54]. Among all anatomic sites, the incidence rate of histologically malignant SFT is approximately 10–20% [6, 9, 95, 97]. Malignant examples of SFT of the SNT are rare, with eight cases reported to date [1, 2, 11, 48, 50, 62, 63]. Seven were classified as such based on the presence of increased mitotic rate (> 4 mitoses per 10 high power fields) with or without hypercellularity, nuclear atypia, and necrosis [1, 2, 11, 48, 62, 63], while the remaining tumor was a histologically dedifferentiated SFT [50]. Follow up of a relatively short duration was reported in six of the cases; four patients were alive with no evidence of disease at 10, 12, 16 and 23 months, respectively [2, 11, 63], one patient died from postoperative complications related to colon cancer 5 weeks after resection of the SFT [62], and one patient was alive with disease at 54 months [48]. As with other anatomic sites, it is difficult to reliably predict prognosis of SNT SFTs. Although most will behave in a benign fashion, it should be recognized that a small potential for recurrence exists, even for those tumors lacking worrisome histologic features. While evidence from other anatomic regions has shown the presence of atypical morphologic features in SFTs to usually correlate with adverse outcomes [5,6,7,8, 95] the low number of malignant cases and relatively short reported follow up duration precludes meaningful analysis of the prognostic impact of malignant histology in SNT SFTs.

Conclusion

SFTs rarely originate within the SNT. Patients are typically middle aged with males and females equally affected. The most common presenting symptoms are nasal obstruction and epistaxis. The variable histologic appearance of SFT may lead to difficulties in identifying these neoplasms based on morphologic features alone, though nuclear expression of STAT6 allows distinction from other sinonasal spindle cell tumors in the differential diagnosis. The tumors are managed by complete surgical excision. The present series combined with prior reported cases suggests that SNT SFTs are indolent neoplasms associated with a good prognosis. Clinically malignant behavior is rare, and is not necessarily predicted by morphologic features. There is a low potential for disease recurrence, necessitating close clinical surveillance.