Intraocular Schwannoma: Case Series of 28 Patients and Literature Review

Background: Intraocular schwannoma is a rare intraocular tumor, which is often misdiagnosed. We aimed to analyze the demographics and clinical characteristics of patients with intraocular schwannoma. Methods: Retrospective case series were collected from May 2005 to July 2021 in Beijing Tongren Hospital. Then a literature review was also performed. Results: A total of 28 patients were diagnosed with intraocular schwannoma histopathologically. The median age (range) of the included patients was 39 (12-64) years old, among whom half subjects were female. The most common symptom was visual loss (75.0%), followed by visual eld loss (10.7%). Intraocular schwannoma presented as nonpigmented mass, which occurred mainly in ciliary body (42.9%), followed by choroid (32.1%) and ciliochoroid (25.0%).16 patients (57.1%) were clinically misdiagnosed as uveal melanoma. Tumor excision was performed for all patients and increased light transmission was detected in half cases. In the consecutive follow-up (median: 6.0 years, range: 0.5-16.0 years), no recurrence or metastasis case was detected. Conclusions: Intraocular schwannoma is a rare benign intraocular tumor. It usually presents as nonpigmented mass, which is easily misdiagnosed as nonpigmented uveal melanoma.


Background
Schwannoma, also known as neurilemmoma or neurinoma, is a benign tumor that originates from the peripheral-nerve sheath [1]. Schwannoma is a rarely seen intraocular tumor that occurs in ciliary body, choroid, and occasionally in the iris [2][3]. They are rarely pigmented, while usually amelanotic or pseudo-pigmented when covered by retinal pigment epithelium. However, it is di cult to distinguish schwannoma from amelanotic malignant melanoma by clinical examination alone. To our knowledge, malignant transformation of an intraocular schwannoma has not yet been reported. Although this type of tumor is cytologically benign and not life threatening, appropriate treatment is required to prevent visual loss and its progressive enlargement. In this study, we reviewed our experience dealing with 28 intraocular schwannoma patients, which contains the largest sample size so far. We aimed to describe the clinical features, relevant histopathology, and treatment options of intraocular schwannoma.

Data collection
We retrospectively reviewed the clinical data and histopathological materials from all patients with documented intraocular schwannoma, who were diagnosed in Beijing Tongren Hospital from May 2005 to July 2021. Patients' age, sex, symptoms, systemic diseases, tumor locations, preoperative clinical diagnoses, and treatment procedures were all recorded. Hematoxylineosin-stained slides were available in all cases, as well as special stains such as periodic acid-Shiff (PAS) and Masson. Immunohistochemical studies were also performed based on formalin-xed and para n-embedded tissue. The monoclonal antibodies used were against Leu-7, Vimentin, S-100, smooth muscle actin (SMA), Melan-A, human melanoma black-45 (HMB-45), Ki-67, and neuron-speci c enolase (NSE). This study was approved by the Institutional Review Board of Beijing Tongren Hospital.

Literature review
A literature search was performed in electronic databases including PubMed, Embase, Web of Science, and Cochrane Library using the following terms: "schwannoma", "intraocular schwannoma", "neurilemmoma", "neurinoma", "uveal schwannoma", "choroidal schwannoma". The publications were limited for human studies and manuscripts written in English. The last search date was July 1st, 2021. All identi ed full-text references were reviewed by two authors (LD and HYL). After selection, references with relative information and available data were included in the literature review.

Results
The basic characteristics of the included patients were presented in Table 1. A total of 28 patients were histopathologically diagnosed as intraocular schwannoma. The median age (range) of all of the patients was 39 (12-64) years old, among whom half cases were female. Visual loss was the most common symptoms (75.0%), followed by visual eld loss (10.7%). Almost all intraocular schwannoma (27/28) presented as nonpigmented mass (Fig. 1), which occurred mainly in ciliary body (42.9%), followed by choroid (32.1%) and ciliochoroid (25.0%). An adjacent retinal detachment was common (Fig. 2). Fundus uorescein angiography and indocyanine green angiography revealed multiple hyper uorescent areas in the neoplasma in the early phase followed by its marked staining in the late phase (Fig. 3). In magnetic resonance imaging (MRI), intraocular schwannoma often showed equal signal intensity in T1-weighted images and low signal intensity in T2-weighted images (Fig. 4), while in ultrasonography the tumor usually presented as mushroom mass with relatively medium internal re ectivity (Fig. 5). For tumors located in anterior segment, ultrasonic biological microscopy always revealed a medium internal re ectivity in ciliary body, with iris and lens affected (Fig. 6). 16 patients (57.1%) had history of clinically misdiagnosis as uveal melanoma. Tumor excision was performed for all patients by senior author WBW, and increased light transmission of the tumor was detected in 50.0% cases during the surgery. Consecutive follow-up was conducted for all patients, with the median of 6.0 (0.5-16.0) years. No recurrence or metastasis case was found in any included patients. Immunohistochemical studies were performed in 26 cases. Most cases diffusely immunoreacted with antibodies to S-100 protein and Vimentin (Fig. 7). There was no immunoreactivity for muscle marker SMA or melanocytic markers (Melan-A and HMB45). Immunostaining with the proliferation marker Ki-67 labeled less than 1% of the neoplastic nuclei.
The literature search identi ed 36 references with 49 cases after removal of duplicates [2,. A brief summary of the main ndings in publications was presented in Table 2. The median age (range) was 33 (0.5-76) years old, and 32 patients (65.3%) were female. Visual loss was the most common symptom (67.3%). The neoplasma occurred mostly in choroid (53.1%), followed by ciliary body (28.6%), and ciliochoroid (18.4%).

Discussion
Intraocular schwannoma is a rare and benign peripheral nerve neoplasma that usually appears as solitary and amelanotic lesion in the ciliary body or choroid. So far, a total of 49 cases of intraocular schwannoma have been reported, and we have collected another 28 cases, which contains the largest sample size in a single center. Among all these 77 cases, intraocular schwannoma occurs more often in female than male with a ratio of 2:1. This trend is also consistent with schwannomas that occur in other parts of human bodies [39].
In our study, choroidal schwannoma was often clinically misdiagnosed as amelanotic melanoma, because of the similar shape and color. Even MRI and ultrasonography cannot provide distinguished characteristics exactly. However, we still considered they were more likely to be benign tumors such as schwannoma, neuro bromatosis, or hemangioma. Therefore, we chose to excise the mass with vitrectomy, and the histopathologic ndings con rmed our speculation.
Considering with the experience of previously reported cases, it is very di cult to differentiate intraocular schwannoma with amelanotic melanoma, hemangioma, and metastatic carcinoma. Clinical features, ultrasonography, and MRI ndings in schwannoma can only provide limited clues to identify those tumors. It is often impossible to make a de nite diagnosis before histopathologic examination, which makes it di cult to choose treatment strategies. Surgical excision or tissue biopsy may be a better choice when diagnosing an amelanotic neoplasma. For those cases with huge intraocular mass and severe vision loss, enucleation can also be considered. Immunohistochemistry based on histopathological slide is helpful in the diagnosis of intraocular schwannoma, especially in differentiating with uveal melanoma and neuro broma. Schwannoma diffusely immunoreacts with antibodies to S-100 protein and frequently expresses Vimentin and Leu-7 [40].
Generally, the prognosis of intraocular schwannoma is favorable. Malignant change of schwannoma is rare, so that it has not been reported in any intraocular location. Only one case was reported with recurrence after local excision [12].
In conclusion, intraocular schwannoma is a rare and benign tumor, which is often misdiagnosed as uveal melanoma. Therefore, cautions should be taken when diagnosing an amelanotic intraocular mass.

Conclusion
Intraocular schwannoma is a rare benign intraocular tumor. It usually presents as nonpigmented mass, which is easily misdiagnosed as nonpigmented uveal melanoma.

Declarations
Ethics approval and consent to participants Ethics approval and informed consent were not required for this study because of public accessibility to the data.

Consent for publication
Not applicable.

Availability of data
Not applicable.

Competing interest
The authors declared no potential con icts of interest with respect to the research, authorship, and/or publication of this article.
Funding Figure 1 Appearance of intraocular schwannoma of Case 10 (A), Case 20 (B), and Case 25 (C) that located in ciliary body. Blue arrow: tumor.

Figure 2
Page 12/14 Ultra-wide eld fundus image of intraocular schwannoma of Case 24, and an adjacent retinal detachment was also noted.  Magnetic resonance imaging (MRI) showed equal signal intensity in T1-weighted images and low signal intensity in T2weighted images of intraocular schwannoma of Case 27.

Figure 5
Ultrasonography showed a mushroom mass with relatively medium internal re ectivity of Case 21.

Figure 6
Ultrasonic biological microscopy of case 28 revealed a medium internal re ectivity in ciliary body, with iris and lens affected.