Clinicopathological Characteristics of Three Cases with Recurrent Orbital Solitary Fibrous Tumors: A Retrospective Study and Literature Review


 Purpose Solitary fibrous tumor (SFT) is a spindle cell neoplasm that rarely occurs in orbit. This study aimed to report clinical, imaging, and pathological features of three patients with recurrent orbital SFTs.Methods Clinical, imaging, and pathological data of the three patients were retrospectively reviewed, and the results were compared with those of previously reported cases with recurrent orbital SFT. Results One female and two male patients (mean age, 54 years old) were included in this study. The present cases and literature review showed that the average time to recurrence in patients who aged under 50 years old was shorter than that in those who aged over 50 years old. The most common site for recurrent orbital SFT was the retrobulbar area of the orbit (23.8%). Imaging examinations showed consistent intensity of MRI signals before and after recurrence. Immunohistochemical results of all cases revealed the expressions of CD34. The mitotic rate increased in 4/8 cases, and the percentage of Ki-67-positive cells was elevated in 5/16 cases. Conclusion These results suggested that young patients were more likely subjected to recurrent orbital SFT. The postoperative pathological diagnosis revealed that patients with recurrent orbital SFT had more nuclear abnormalities and mitotic activity, as well as a higher percentage of Ki-67-positive cells, indicating that orbital recurrent SFT tended to be malignant according to both morphological features and immunohistochemistry results.


Introduction
Solitary brous tumor (SFT) is a spindle cell neoplasm that was rst presented in 1931 by Klemperer and Rabin, who reported it as a primary neoplasm of the visceral pleura [1,2]. SFT demonstrates a different cellular proliferation of bland spindle-shaped cells lacking any pattern of growth, with associated 'ropey' keloidal collagen bundles and characteristic 'staghorn' blood vessels [3]. The hemosiderotic brolipomatous tumor is histologically characterized by the presence of mature adipose tissue and spindle cell component accompanied by hemosiderin pigment deposition within macrophages, in the cytoplasm of some of the spindle cells and also within the extracellular stroma. The spindle cell component of these lesions is generally positive for CD34 and negative for CD68, S100, SMA and desmin [4,5]. The biological course of SFT tends to be benign in nature, while some cases with recurrent SFT and its malignant transformation have been reported in recent years.
SFT of orbit is uncommon and recurrent orbital SFT is even less. To date, no large sample-sized controlled trial on the pathological features of recurrent orbital SFT has been conducted. In the present research, clinical data of 3 patients with recurrent orbital SFT, who were con rmed by pathology, were retrospectively analyzed. The clinical, imaging, and pathological data of patients with two or more episodes were compared. To increase our understanding about the recurrent orbital SFT, literature review of the clinicopathological manifestations of cases with recurrent orbital SFT, including tumor necrosis, mitotic rate, and the percentage of Ki-67-positive cells, was carried out via the PubMed database.
Besides, all participants signed the written informed consent form prior to commencing the study.

Clinical Features
Two male patients and one female patient were included in the current study. The median age at the time of their rst diagnosis was 54 (range, 48-60) years old. Their clinical manifestations included exophthalmos (n = 3), ptosis (n = 2), incomplete closure of the eyelids (n = 2), abnormal eye position (n = 1), and blurred vision (n = 2). On the results of physical examination revealed that the three patients involved in the present study exhibited a huge and incompressible mass behind the eyeball, making the eyeball protruded forward, with the protrusion degree of 22-23 mm compared with the degree of 15 mm for the other eye. The best corrected visual acuity (BCVA) was reduced to 1/20 in Case #1 and 2/20 in Case #2. The dilated conjunctival blood vessels of the involved eye were apparent (n = 3), while on fundus examination, the optic disc edema was raised with an unclear boundary and dilated blood vessels (n = 2), and bleeding could be observed around the optic disc (n = 1). The recurrence time after the rst surgery ranged from 9 to 120 months. Two patients did not relapse during a follow-up period of 2 years after the second surgery. Case #3 had 6 relapses in total, he underwent surgery for 4 relapses, and in 2015, he received gamma knife radiosurgery for three times, however, the tumor recurred again in 2016. The patient died of systemic metastasis one year later.  There were 18 male and 19 female patients, except one case whose sex could not be determined, and no signi cant difference (P = 0.33) was noted between male and female patients. The position of the lesion included superolateral or lacrimal gland fossa (n = 3), superomedial or upper eyelid (n = 4), inferotemporal (n = 3), medial canthal region or lacrimal sac (n = 3), postero-lateral (n = 2), retrobulbar (n = 5), and entire orbit (n = 1). Meanwhile, the duration of recurrence after initial surgery ranged from 2 to 240 months. The average time to recurrence after the rst surgery for patients who aged ≤ 50 and 50 years old was 34.4 and 57.1 months, respectively, which showed no signi cant difference (P = 0.19) between the two groups. In addition, 7 (21.2%) patients with SFT had multiple recurrences, and 4 (12.9%) patients had distant metastasis.

Radiology
Orbital MRI of Case #1 before and after recurrence revealed that there was a mass above the optic nerve in the posterior muscular cone of the left orbit, which was indistinguishable from the optic nerve. The internal signal was uneven, in which a slightly lower value of signal intensity was noted in T1-weighted image (T1WI) (Fig. 1a), a slightly higher value of signal intensity was found in T2-weighted image (T2WI) ( Fig. 1b), and an irregular enhancement could be observed after intravenous gadolinium administration (Fig. 1c). These results were consistent after recurrence (Figs. 1d-f).
In Case #2, the MRI revealed a huge heterogeneous multi-cystic mass occupied the entire posterior orbit, with a size of about 3.4 cm * 3.2 cm. In T1WIs, the intensity of signals was almost equal, while in T2WIs, the intensity of signals was slightly higher. The signals were diffusely and unevenly enhanced on contrast-enhanced MR images. These results were consistent with those observed 9 years before her admission to our hospital.
Besides, Case #3 underwent CT scan for two times in our hospital, and in 2016, the secondary CT scan showed soft tissue masses in the right-sided orbit, maxillary sinus, ethmoid sinus, and frontal sinus.

Pathological Characteristics
Gross pathology showed that the specimens were gray-white or gray-red oval-shaped tissues. Cystic cavities with different sizes were found inside the tumor in Case #2 before and after relapse, and the cystic uid was yellow green.
Histopathology, in all cases before relapse, revealed that well-arranged spindle cells with oval-to-spindle nuclei and eosinophilic cytoplasm (Fig. 2a) were distributed in the dense collagen bers with a great number of blood vessels in the background. Blood vessels occasionally showed a staghorn appearance (Fig. 2b). No obvious mitotic activity or necrotic areas were found. After relapse, the spindle cells were arranged irregularly with a higher frequency of chromosomal heteromorphism (Fig. 2c). The number of mitotic gures was > 4/10 high-power elds (HPFs) in the three cases (Fig. 2d). Besides, tumor necrosis was found after recurrence in Case #3.
The pathological manifestations of 5 previously conducted researches and the present study with recurrent orbital SFT before and after recurrence, including tumor necrosis, mitotic rate, and the percentage of Ki-67-positive cells are shown in Table 2. The mitotic rate decreased in only one case, while it remained stable in 3 cases and increased in 4 cases; besides, the percentage of Ki-67-positive cells slightly decreased after recurrence in only one case, while it stably maintained in 10 patients and increased in 5 patients. Tumor necrosis was found in 1 case after recurrence.

Clinical Manifestations
SFT was originally thought to occur exclusively in the intrathoracic region, while it has been recently described in extrapleural sites (e.g., orbit). SFT of the orbit is a rare lesion, which can be misdiagnosed as hemangioendothelioma, brous histiocytoma, meningioma, or neuro broma. Its main clinical manifestations are painless protrusion of the eyeball, ptosis, diplopia, and limited eye movement. Painless, non-pulsating, incompressible masses can be touched by physical examination [24]. The patients involved in the current study had a mean age of 54 years old, and their clinical manifestations included exophthalmos, ptosis, abnormal eye position, and blurred vision, which were consistent with those reported previously [24][25][26][27].
Recurrence time was also counted through literature analysis and the current cases (see Table 1), although the duration of recurrence after the rst surgery for patients who aged ≤ 50 and 50 years old showed no signi cant difference (P = 0.19). The average time to recurrence in patients who aged under 50 years old was shorter than that in those who aged over 50 years old, suggesting that young patients were more likely subjected to recurrent orbital SFT. Moreover, 21.2% of patients with SFT had multiple recurrences, including Case #3 presented herein and those reported previously. A number of scholars have shown that the failure of radical resection is a high risk-factor for tumor recurrence [19]. The tumors of 3 patients reported in the current study were located in the posterior muscular cone of eyeball, which caused di culty in their surgical removal. After reviewing the literatures, we found that orbital SFT can originate from any part of the orbit, mainly from the superomedial orbital quadrant (20%), medial orbit (15%), and superotemporal area (13%). Lacrimal sac area and inferotemporal area also account for 9.5% and 7%, respectively [3,28]. However, after comparing the clinical characteristics of the previously conducted researches and the cases herein presented (Table 1.), the most common site for recurrent orbital SFT was the retrobulbar area of the orbit (23.8%). This site is the most di cult area of orbital surgery, and the surgical approach, surgical method and surgical eld exposure may all affect the prognosis [29]. The fact that the tumor was in almost the same place before and after recurrence suggested that the failure of the rst surgery to completely remove the tumor, which left residual tumor, could be responsible for the recurrence. In addition to the local recurrence, orbital SFT is also associated with distant metastasis. In the present research, among the 4 cases, only Case #3 had a history of multiple recurrences. As distant metastases scarcely occur, further study needs to be conducted.

Imaging Manifestations
The MRI ndings of orbital SFT showed that lesions had equal density with the gray matter on T1WI, and values of signal intensity on T2WIs were controversial [30][31][32][33]. Previous studies reported that orbital SFT is rich in brous matrix and T2WI should be dominated by a low signal intensity, however, in several reported cases of malignant orbital SFT, cystic degeneration could be detected with a high signal intensity, suggesting that cystic degeneration could be related to malignant transformation [4,34]. In addition, the contrast-enhanced MRI showed enhanced SFT, while the enhancement can be uniform or uneven, and it may be associated with the distribution of blood vessels and capillary permeability [35][36][37]. In the current research, 2 patients underwent MRI of the orbit, and the values of signal intensity on T1WI and T2WI before and after the recurrence of SFT were consistent, indicating that MRI signals did not signi cantly change before and after recurrence. Changes in cystic lesion were both observed before and after recurrence in Case #2. According to the results of IHC, the patient was diagnosed as benign orbital SFT before recurrence and malignant SFT after recurrence, demonstrating that change in cystic lesion may not be the speci c marker for differentiating benign SFT from malignant SFT.

Pathological Manifestations
Orbital SFTs are largely benign tumors with few instances of recurrence. Grossly, they could be round-or long oval-shaped specimens. The masses of three cases in the current study were elliptical, all of which were behind the eyeball and con ned by the orbital wall. Yang et al pointed out that although a tumor is mainly benign, it may involve the orbital bone and occasionally penetrate the orbital wall and invade the intracranial structure [23]. During the second surgery on Case #1 and Case #2, surgeons found an adhesion between the masses and the orbital bone. In Case #3, the tumor not only involved the rightsided orbit, but also maxillary sinus, ethmoid sinus, and frontal sinus. However, after recurrence, the tumor may inevitably adhere to the bone wall due to the previous surgery, thus, destruction of the tumor on orbital bony ssure before and after recurrence still needs further observation and veri cation.
In the review of subjects of previous studies, it was found that SFTs shared a histopathologic morphology, which was recognized for spindle cells, remarkably characteristic 'staghorn' blood vessels, and matrix with numbers of collagen bundles [24]. The results of IHC showed that CD34 is a useful marker in the diagnosis of SFT. Previous studies reported that SFT expressed CD34 in 90% of cases, CD99 in 70% of cases, and Bcl-2 in only 30% of cases [26,37]. In 2016, the World Health Organization (WHO) classi ed tumors with a classic SFT phenotype as grade I, tumors with intermediate or HPC phenotype as grade II, and tumors with ve or more mitoses (× 10 HPFs) as grade III [38]. A number of scholars demonstrated that the presence of mitosis is a poor prognostic indicator, and, Sagiv et al.
emphasized that the number of mitotic gures higher than 4/10 HPFs can be a predictor of malignant SFT [4]. In addition, nuclear atypia, cell proliferation, and necrosis were also considered as manifestations of malignant SFT [35]. It has been reported that the percentage of Ki-67-positive cells tends to increase correspondingly in SFT with an invasive tendency, which is clinically signi cant for the selection of postoperative treatment plan and assessment of tumor prognosis [37,[39][40][41]. In three cases reported herein, tumor cells were spindle-shaped and densely distributed in collagen bers. The nuclei were oval, round or spindle-shaped, the cytoplasm was pale and eosinophilic, and branched or antlers-shaped blood vessels could be observed. IHC showed CD34 positive, while S-100 and CK negative, which were consistent with the diagnosis of orbital SFT. In cases #1 and #2, nuclear abnormalities were found for the rst time after recurrence, and those cases were diagnosed as malignant SFT with mitotic activity of ≥ 4/10 HPFs. To date, few reports have concentrated on the recurrent orbital SFT, and there is currently no large sample-sized controlled trial related to the pathological manifestations of recurrent orbital SFT before and after recurrence. In the present study, we compared the pathological manifestations of 24 orbital SFT patients before and after recurrence, including tumor necrosis, mitotic rate, and the percentage of Ki-67-positive cells. As shown in Table 2, the rate of SFT mitosis was elevated in the relapsed eyes, and the proportion of Ki-67 positive cells remained stable in some cases, while it increased in a large proportion after recurrence, indicating that recurrent orbital SFTs tend to increase in malignancy in terms of both morphological features and IHC results. In addition, the pathology testing of Case #3 after repeated recurrences revealed new occurred necrosis, and the percentage of Ki-67-positive cells was about 50%, suggesting that the degree of malignancy may be higher after several recurrences, while the above mentioned results should be veri ed by further case-control studies with a larger sample size.
In conclusion, the time to recurrence of orbital SFT in the reported patients ranged from 3 months to 20 years, and the average time to recurrence in patients who aged under 50 years old was shorter than that in those who aged over 50 years old. In the current report, 2 patients underwent MRI of the orbit, and the values of signal intensity on T1WI and T2WI before and after recurrence of SFT were consistent, indicating that MRI signals did not signi cantly change before and after recurrence. Morphological features and IHC results indicated that recurrent orbital SFTs tend to be malignant. The degree of malignancy may increase with the frequency of recurrence. Therefore, orbital SFT requires radical resection to avoid tumor recurrence and change of malignant tendency.

Declarations
Findings: The work was supported by the National Natural Science Foundation of China (Grant No:81800868), the Health and Family planning Commission of Zhejiang Province, China (Grant No:2018KY057).

Data availability
All data and materials support our published claims and comply with eld standards.

Con icts of interest
There are no con icts of interest.
Authors' contributions CJL, WXW, LY and CHG gathered the clinical information and drafted the manuscript. WXW and ZMM collected the clinical data and revised the draft.

Statement:
That the manuscript has been read and approved by all the authors. Each author believes that the manuscript represents honest work.
Ethical Approval: The current study was approved by the Ethics Committee of the First A liated Hospital of Zhejiang University School of Medicine, and was performed in accordance with the Declaration of Helsinki.
Besides, all participants signed the written informed consent form prior to commencing the study.

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