Orbital Granular Cell Tumor

Key points at a glance

Key facts about this disease

• Orbital granular cell tumor is an extremely rare benign soft tissue tumor, accounting for about 3% of all granular cell tumors occurring in the orbit.
• It is derived from Schwann cells (peripheral nerve sheath cells) and most often arises in the extraocular muscles, especially the inferior rectus muscle.
• The main symptoms are slowly progressive proptosis, double vision, and limited eye movement.
• On MRI, its low to isointense T2 signal is an important clue for distinguishing it from typical benign orbital tumors, which are usually T2 hyperintense.
• Malignant transformation occurs in fewer than 7% of cases, but histopathologic confirmation is essential to establish the diagnosis.
• Complete surgical excision is the first-line treatment, and margins can be difficult to secure because of infiltrative growth.
• There have been reports of tumor regression with proton beam therapy in cases of incomplete resection.

1. What is an orbital granular cell tumor?

An orbital granular cell tumor (granular cell tumor, GCT) is a rare soft tissue tumor that originates from Schwann cells (peripheral nerve sheath cells). It is made up of polygonal cells with abundant eosinophilic granular cytoplasm, and this granular cytoplasm reflects intracellular inclusions rich in lysosomes. It is now classified as a peripheral nerve sheath tumor with neuroectodermal differentiation, and the former term “granular cell myoblastoma” is no longer used.

This tumor was first reported by Abrikossoff in 1926. Most granular cell tumors occur in the head and neck region, especially the tongue, and orbital cases make up only about 3% of all cases. It is most common in adults aged 30 to 60 years, and cases in children are extremely rare. There is a slight female predominance, and a somewhat higher rate has been reported in African Americans, but the data are limited.

In the orbit, it tends to occur in the extraocular muscles (especially the inferior rectus muscle), and a literature review reported extraocular muscle involvement in about 67% to 70% of cases, with inferior rectus involvement accounting for about 40% (Li et al., 2016)[2]. Malignant transformation is reported in fewer than 7% of cases.

Q How rare is an orbital granular cell tumor?

A

About 3% of all granular cell tumors occur in the orbit. It is also among the very rare orbital tumors, and it is most common in adults aged 30 to 60 years. Cases in children are extremely rare.

2. Main symptoms and clinical findings

Subjective symptoms

• Proptosis: Reflects a slowly growing unilateral orbital mass. One of the most common first symptoms.
• Diplopia: Caused by tumor invasion into the extraocular muscles. It often persists after surgery.
• Restricted eye movement: Movement is limited in the direction of the affected extraocular muscle.
• Eyelid swelling and ptosis: More likely with tumors located more anteriorly.
• Reduced vision and visual field loss: Occurs when the optic nerve is compressed.
• Pain: Not common in general, but can occur with tumors located at the orbital apex or posterior orbit.

Q Is there pain in orbital granular cell tumor?

A

Pain is not typically common. However, pain can occur when the tumor is located at the orbital apex or posterior orbit. Painless, slowly progressive eye bulging and double vision are the typical initial symptoms.

Clinical findings (findings confirmed by the doctor during examination)

• Eye bulging: Usually axial and mild. Non-axial bulging may be seen with anterior tumors.
• Eyelid findings: Anterior tumors may appear as eyelid swelling, a palpable nodule, or drooping of the eyelid.
• Conjunctival findings: Large lesions can cause conjunctival redness and swelling.
• Eye movement: Limited in the direction of the involved muscle. A positive forced duction test suggests mechanical restriction. In cases of inferior rectus GCT, a characteristic sign has been reported in which visual acuity that was 20/20 in primary gaze decreased markedly in upgaze (Che et al., 2018) [6].
• Pupil: Usually normal. A relative afferent pupillary defect (RAPD) appears when the optic nerve is compressed. Rarely, tonic pupil may occur because of involvement of the ciliary ganglion.
• Visual acuity and color vision: Preserved early on, but reduced when the optic nerve is involved.
• Visual field: Arcuate scotomas or central scotomas may be seen.
• Fundus: Usually normal. In advanced cases, optic disc pallor and swelling are seen. Posterior masses show choroidal folds and scleral indentation.

3. Causes and risk factors

Orbital granular cell tumor arises from Schwann cells and occurs sporadically along peripheral nerves in the orbit or along the orbital branches that innervate the extraocular muscles. It was formerly thought to be muscle-derived (old name: granular cell myoblastoma), but it is now classified as a neuroectodermal tumor with Schwann cell differentiation.

Abnormal lysosomal accumulation within the tumor cells and dysfunction of the V-ATPase pathway are known to be involved in its development. Recurrent somatic loss-of-function mutations in ATP6AP1 and ATP6AP2 are found in about 72% of sporadic granular cell tumors and are considered pathognomonic (Pareja et al., 2018)[1]. Silencing these genes in Schwann cells in vitro induces lysosomal accumulation and a shift to a tumor-like phenotype.

No environmental, behavioral, or genetic risk factors have been established. It occurs most often in adults aged 30 to 60 years, with a slight female predominance.

Special note

ATP6AP1 and ATP6AP2 are endosomal pH regulators in the V-ATPase proton pump complex. These mutations impair endosomal acidification, leading to lysosomal accumulation and a change to granular cell morphology.

4. Diagnosis and tests

Imaging

For imaging of orbital tumors, it is essential to obtain axial and coronal slices with a slice thickness of 3 mm or less, and fat-suppressed STIR images are useful.

• CT: A well-defined, homogeneous soft tissue mass that is isodense to slightly hyperdense compared with muscle. Changes in adjacent bone are rare. It shows moderate, homogeneous contrast enhancement.
• MRI T1-weighted image: Isointense to gray matter (Ahdoot & Rodgers, 2005)[4].
• T2-weighted MRI: low to isointense. This is an important distinguishing point from the T2 hyperintensity usually seen in benign orbital tumors.
• Gadolinium-enhanced MRI: shows slight to marked enhancement, and strong peripheral enhancement may be seen.
• Diffusion-weighted imaging: diffusion restriction is generally absent. In Qi et al.’s study of 8 cases of extraocular muscle GCT, functional MRI findings including DWI and dynamic contrast-enhanced MRI were reported systematically for the first time, suggesting the possibility of benign/malignant differentiation by apparent diffusion coefficient [3].

Histopathology and immunohistochemistry

Definitive diagnosis is made by histopathological and immunohistochemical examination of a biopsy.

• Histopathology: polygonal cells with abundant granular eosinophilic cytoplasm and small, uniform nuclei arranged in sheets or nests.
• Periodic acid–Schiff (PAS) stain: PAS-positive and diastase-resistant (a diagnostic hallmark).
• Ultrastructure: membrane-bound electron-dense lysosomes and myelin figures (mesaxon) are seen.

The immunohistochemical profile is shown below.

Stain	Result
S-100, SOX10, CD68	Positive
neuron-specific enolase, vimentin, calretinin, inhibin alpha	Positive
cytokeratin, desmin, smooth muscle actin	Negative
myogenin, HMB-45, Melan-A	Negative

Cytologic features suggestive of malignant granular cell tumor: increased cellularity, nuclear pleomorphism, spindle-shaped cell morphology, vesicular nuclei with prominent nucleoli, necrosis, and increased mitotic figures.

Differential diagnosis

The main diseases that require differentiation are listed below. In orbital imaging, idiopathic orbital inflammation (formerly orbital inflammatory pseudotumor) makes inflammatory lesions relatively easy to identify on MRI, while thyroid eye disease often shows enlargement of the inferior rectus muscle, which overlaps with the common site of GCT, so care is needed in the differential diagnosis.

Schwannoma

Common point: S-100 positive.

Differences: High T2 signal (granular cell tumor is low to iso signal on T2). No granular cytoplasm. CD68 negative.

Rhabdomyosarcoma

Features: More common in children. Rapidly progressive. Desmin positive. T2 hyperintense.

Differences: Granular cell tumor occurs in adults, progresses slowly, and is desmin negative.

Alveolar soft part sarcoma

Features: S-100/SOX10 negative. Strong nuclear TFE3 expression. ASPL-TFE3 gene fusion.

Differences: Granular cell tumor is S-100/SOX10 positive. No gene fusion.

Thyroid eye disease and idiopathic orbital inflammation

Common point: Enlargement of the inferior rectus muscle (the inferior rectus is also the most commonly involved muscle in thyroid eye disease).

Differences: These show diffuse involvement of muscles and fat, and do not form a discrete mass.

Q What MRI finding suggests orbital granular cell tumor?

A

A characteristic clue is low to isointense signal on T2-weighted images. Ordinary benign orbital tumors (such as schwannoma) show high T2 signal, whereas granular cell tumors show low to isointense T2 signal. It is important to suspect this diagnosis by combining this finding with localization to an extraocular muscle, especially the inferior rectus muscle.

5. Standard treatment

Surgical excision (first-line treatment)

Complete surgical excision is the first-line treatment. The goal is wide local excision with clear margins. Complete removal of a benign tumor usually leads to cure.

However, because the tumor shows an infiltrative growth pattern without a true capsule, interdigitation with normal muscle and nerve fibers can occur at the tumor border, making it difficult to secure clean margins. If diplopia is present before surgery, it is likely to persist afterward.

Main postoperative complications: infection, bleeding, subcutaneous hemorrhage, vision loss, diplopia, and the need for reoperation.

Observation

Observation is justified if all of the following are met.

• No evidence of malignancy on biopsy
• No compressive optic neuropathy
• Surgical excision is judged likely to cause high morbidity

During observation, continue regular imaging surveillance and ophthalmologic examinations.

Radiation therapy / proton beam therapy

Conventional radiation therapy has been suggested to be ineffective for granular cell tumors, and there are reports of cases that did not respond and required orbital exenteration.

Proton beam therapy has been reported to produce marked tumor shrinkage and symptom relief in cases of incomplete resection. Barrantes et al. reported that proton beam therapy resulted in significant reduction of residual tumor and symptom improvement in an incompletely resected orbital apex lesion adjacent to the optic nerve [5]. It has the advantage of enabling focused dose delivery and protecting sensitive tissues around the orbit.

Medical treatment

Chemotherapy, targeted anti-angiogenic therapy, and immunotherapy have been tried for malignant granular cell tumors and metastatic disease, but no proven effectiveness has been shown so far.

Important points in treatment

• Even when the tumor can be completely removed, preoperative double vision is likely to persist after surgery. Adequate informed consent before surgery is necessary.
• Conventional radiation therapy is considered to have little effect on granular cell tumors.
• The effectiveness of medical treatment, such as chemotherapy, has not been established, and malignant granular cell tumors and metastatic cases require individual evaluation.

Q What happens if the tumor cannot be completely removed during surgery?

A

Because of the infiltrative growth pattern, it may be difficult to secure clean margins. There have been rare reports of spontaneous shrinkage after incomplete resection, and involvement of an immune-mediated process has been proposed as a hypothesis. Observation and proton beam therapy are also options.

6. Pathophysiology and detailed pathogenesis

Orbital granular cell tumors arise along peripheral nerves in the orbital fat or along the motor branches that supply the extraocular muscles. The inferior rectus muscle is the most common site, accounting for about 42%, followed by the medial rectus and superior rectus muscles.

The tumor lacks a true capsule and shows an infiltrative growth pattern. At the tumor border, interdigitation with normal muscle and nerve fibers occurs. This makes it difficult to secure clean margins during surgical removal.

Main chain of disease processes:

• Extraocular muscle involvement: If the tumor invades the extraocular muscles, movement restriction and double vision can occur. These may persist after surgery.
• Optic nerve and orbital apex involvement: Compression of the optic nerve can cause compressive optic neuropathy, leading to decreased vision and visual field loss.
• Ciliary ganglion involvement: Rarely, it can cause tonic pupil.

The tumor grows slowly, enlarging over several years. Spontaneous regression after incomplete resection has occasionally been reported, and an immune-mediated process has been proposed, but the mechanism remains unclear.

At the molecular level, somatic loss-of-function mutations in ATP6AP1 and ATP6AP2 (about 70% of sporadic granular cell tumors) impair endosomal acidification. This causes material to accumulate in lysosomes and changes the cells into the characteristic granular cell morphology.

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7. Latest research and future prospects (research-stage reports)

For patients: Please read

The following content is still at the research stage or under clinical trial and is not standard treatment available at ordinary hospitals. It is specialist reference information about future medical developments.

Understanding molecular pathology: ATP6AP1/ATP6AP2 mutations

Somatic mutations in ATP6AP1 and ATP6AP2 (endosomal pH regulators of the V-ATPase proton pump complex) have been identified in about 70% of sporadic granular cell tumors and are considered pathognomonic. Silencing of ATP6AP1/2 in Schwann cells in vitro has been shown to induce lysosomal accumulation and a tumor-forming phenotype, and these mutations are drawing attention as candidate molecular targets for granular cell tumor therapy.

Exploratory Use of Proton Beam Therapy

There are reports of tumor shrinkage and preservation of visual function with proton beam therapy in incompletely resected cases, especially those adjacent to the optic nerve. These findings suggest that proton beam therapy may be effective for granular cell tumors that do not respond to conventional radiation, but the number of cases is limited and its role as a standard treatment has not been established.

Attempts at Systemic Therapy for Malignant Granular Cell Tumors

For malignant granular cell tumors and metastatic disease, chemotherapy, targeted anti-angiogenic therapy, and immunotherapy have been tried. However, none have proven efficacy at present, and their use remains limited to experimental treatment in individual cases.

Hypothesis of Spontaneous Regression and an Immune-Mediated Mechanism in Benign Granular Cell Tumors

There are rare case reports of tumors spontaneously regressing after incomplete resection. An immune-mediated process has been proposed as a possible factor, but the mechanism remains unclear and reproducibility is unknown.

Research on Benign/Malignant Differentiation Using the Apparent Diffusion Coefficient

The possibility of distinguishing benign from malignant lesions using apparent diffusion coefficient (ADC) values calculated from diffusion-weighted imaging is being studied. At present, diagnostic usefulness has not been established.

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8. References

1. Pareja F, Brandes AH, Basili T, et al. Loss-of-function mutations in ATP6AP1 and ATP6AP2 in granular cell tumors. Nat Commun. 2018;9(1):3533. PMID: 30166553. doi:10.1038/s41467-018-05886-y
2. Li XF, Qian J, Yuan YF, Bi YW, Zhang R. Orbital granular cell tumours: clinical and pathologic characteristics of six cases and literature review. Eye (Lond). 2016;30(4):529-537. PMID: 26742863. doi:10.1038/eye.2015.268
3. Qi M, Zhang F, Pan Y, Chen Y, Ren J, Sha Y. CT and MRI features of extraocular muscle granular cell tumour: preliminary experience in eight cases. Clin Radiol. 2022;77(4):e312-e318. PMID: 34980459. doi:10.1016/j.crad.2021.12.007
4. Ahdoot M, Rodgers IR. Granular cell tumor of the orbit: magnetic resonance imaging characteristics. Ophthalmic Plast Reconstr Surg. 2005;21(5):395-397. PMID: 16234712. doi:10.1097/01.iop.0000173193.56711.e2
5. Barrantes PC, Zhou P, MacDonald SM, Ioakeim-Ioannidou M, Lee NG. Granular Cell Tumor of the Orbit: Review of the Literature and a Proposed Treatment Modality. Ophthalmic Plast Reconstr Surg. 2022;38(2):122-131. doi:10.1097/IOP.0000000000002038. PMID:34406152.
6. Che L, He P, Fan B, Li GY. Case report: an intriguing sign in a patient with an inferior rectus muscle granular cell tumor. Medicine (Baltimore). 2018;97(50):e13624. PMID: 30558046. doi:10.1097/MD.0000000000013624