Granular cell tumors (GCTs) are soft-tissue tumors, possibly derived from the nervous system, that primarily affect the skin, tongue, and breasts [1,2]. GCTs are generally benign, with an incidence of 0.01-0.03% of all tumors, a female prevalence of 2:1, and occurring primarily in middle age. Malignant GCTs are rare, accounting for less than 2% of GCTs, and are aggressive and associated with a poor prognosis [2]. GCTs have rarely been reported to originate from the spine. In such cases, most GCTs commonly arise within the dura mater of the thoracic or lumbar spine as intradural and extramedullary (IDEM) tumors. [1,3,4]. GCTs share radiological similarities with meningiomas and neurofibromas, necessitating histological confirmation for their diagnosis [3]. Complete excision is the primary treatment for GCTs, with radiotherapy considered for recurrent tumors or incomplete resections [1,2].

This report presents a case of a 40-year-old woman with ill-defined thoracic and axillary pain, caused by a malignant epidural GCT extending from T1 to T4 spinal levels, accompanied by a literature review. This report was approved by the Institutional Review Board of our hospital (SNU IRB No. 2310-056-1474).

A 40-year-old woman presented to a pain clinic at the tertiary university-based hospital with an aching sensation and paresthesia in the right axillary area, which had begun six months prior. She had previously undergone a total thyroidectomy followed by neck dissection for thyroid cancer (malignant papillary carcinoma). The malignancy had been in complete remission for ten years with regular medical check-ups. She had been taking thyroxine since the surgery. A recent ultrasonographic examination of her neck, performed ten months prior to consult, did not reveal any recurrent lesions.

The aching sensation in the right axilla, spread to the posterior scapular and anterior chest areas, distributing in the right T1-2 dermatome. The pain was suspected to be neuropathic, with a sharp stabbing and burning pattern, with an 11-pointed numerical rating scale (NRS) pain score of 5-7/10, aggravated during daily activity and relieved by rest. The patient’s motor function in her right arm was normal.

She had undergone upper extremity magnetic resonance imaging (MRI) and electromyography (EMG) examination at another hospital right before visiting the pain center. The radiologist and neurologist reported no significant abnormalities in the MRI and EMG readings, respectively. She also underwent cervical epidural steroid injections three times in the same hospital, which did not provide pain relief. Additive blood and chest imaging tests at the first visit to the pain center showed nothing specific. She denied any skin lesions, such as those of herpes zoster, along the pain dermatome.

Initially, the pain was suspected to be caused by zoster sine herpete, intercostal neuralgia, breast or lung diseases, or pain originating from the cervical spine. However, subsequent physical examinations and further imaging tests, such as upper extremity infrared thermography, chest X-ray, and breast and neck ultrasonography, did not identify any significant findings or lesions to explain the pain.

Under suspicion of intercostal neuralgia as the initial diagnosis, the patient underwent a series of interventional procedures, including subcutaneous botulinum toxin injection, ultrasound-guided intercostal nerve block, serratus plane block, pectoralis block II, thoracic paravertebral block, and brachial plexus block. She also received oral medications, including acetaminophen, a non-steroidal anti-inflammatory drug, an anticonvulsant (pregabalin), and an antidepressant (nortriptyline), with the application of 5% lidocaine patches. She reported that subcutaneous injection with botulinum toxin slightly reduced her pain. However, despite the aforementioned interventional procedures with oral and topical medications for six months, the patient’s pain severely aggravated, with an NRS pain score of 7-9/10. She also experienced sleep disturbance and newly developed symptoms in her right eye (mild ptosis, pupil constriction, fixation, and light blur in vision), anhidrosis on the right side of the face, decreased sensation in the right C8-T3 dermatomal areas, and intermittent muscle weakness in her right fourth and fifth fingers.

Her former imaging studies (an upper extremity MRI taken eight months ago) were reviewed by a radiologist. Further, she underwent a T-spine MRI and EMG-nerve conduction velocity (NCV) study, focusing on the disease from the right brachial plexus and the upper thoracic spine, with a request to focus on diseases from the right-sided brachial plexus and upper thoracic spine. In the EMG-NCV study, there was electrophysiologic evidence of right cervical plexopolyradiculopathy (C8-T1) with the possibility of right brachial lower trunk plexopathy. In her old upper extremity MRI, the radiologist found a paravertebral elongated enhancing soft tissue mass at the T1-3 vertebral levels, abutting the T1 and T2 nerve roots, which could not be excluded from a neurogenic tumor (Fig. 1). In her new T-spine MRI images, an 8.0 cm-sized enhancing mass lesion at her right paravertebral region at the T1-4 vertebral levels was detected, which had grown into the spinal canal at the T2-3 vertebra levels without definite bone destruction but involving paraspinal muscles (Fig. 2). In a sagittal MRI image, an 8.0 cm-sized enhancing mass lesion at the right T1-4 paravertebral region was identified, which showed an aggressive interval increase in axial diameter compared to the previous upper extremity MRI.

Figure 1. Coronal (A) and axial (B) T2-weighted magnetic resonance images of the upper extremity. They were taken before visiting the pain center and the paravertebral elongated enhancing soft tissue mass at the T1-3 vertebral level (arrows) was missed at the initial radiologist’s reading.

Figure 2. Sagittal (A) and axial (B) T1-weighted magnetic resonance images of the thoracic spine. They were taken 8 months later from the former upper extremity magnetic resonance images. An 8.0 cm-sized enhancing mass lesion at the right T1-4 paravertebral region was identified (arrows).

A computed tomography-guided biopsy of the paravertebral region mass was done for histopathological examination. The biopsy was performed by a radiologist, and confirmed the presence of a malignant GCT. Surgical excision was the recommended treatment for the tumor. The patient was referred to the Departments of Neurosurgery and Thoracic Surgery. In addition to her oral medications, she was prescribed tapentadol analgesics for pain management. The patient was scheduled to undergo a combined tumor removal surgery by a neurosurgeon and a thoracic surgeon, followed by radiation therapy by a radiation oncologist. She would also continue to receive cancer pain management at our pain center.

During the surgical operation, the paravertebral mass, visceral pleural mass, parietal pleural mass, and intradural mass were all successfully removed through radical resection. The procedure involved a laminectomy for the removal of the IDEM tumor and video-assisted thoracic surgery. First, the patient was placed in a prone position under general anesthesia. The neurosurgeon performed a T1-3 laminotomy and en-block resection of the IDEM tumor, which was embedded around the right T2-3 intervertebral foramen. Screws were then inserted into the T2 and T3 pedicles. Next, the patient was re-positioned in a lateral decubitus position. The thoracic surgeon then approached the second, fourth, and fifth intercostal spaces for video-assisted thoracic surgery. After identifying the yellow and irregular mass with hypervascularity originating from sympathetic nerves and invading the second and third intercostal nerves, a massive mass dissection was conducted.

The tumor consisted of a main paravertebral mass (2.2 × 1.5 × 0.8 cm), multiple pleural metastases (visceral pleural mass: 0.3 × 0.3 × 0.3 cm and parietal pleural mass: 0.8 × 0.6 × 0.5 cm), and an intradural tumor (1.1 × 0.7 × 0.4 cm), all of which exhibited infiltrative patterns. At the same time, a mediastinal mass was identified while conducting the video-assisted thoracic surgery, which was also excised. Postoperative pathological examination confirmed that the paravertebral and intradural masses were GCTs with epithelioid cell proliferative lesions and abundant eosinophilic granular cytoplasm. Specific tumor markers (Ki-67, S-100, and CD56) were used for the histopathological examination, and all were positive in this patient (positive in 9.6%; diffuse positive; positive, respectively). Additionally, the mediastinal mass excised during the surgery was confirmed to be metastatic thyroid papillary cancer.

At the postoperative one-month visit, the patient’s pain was significantly relieved, with an NRS score of 3-5/10. She only needed to take acetaminophen twice daily, eliminating the need for strong opioid analgesics. Post-surgical radiation therapy was administered to prevent any recurrence or metastasis of the malignant GCTs. Continuous follow-up was planned to monitor for any acute and chronic complications associated with the surgical excision and tumor itself. A positron emission tomography scan was taken at the postoperative three-month follow-up, which revealed negative findings for metastasis-related to both GCTs and papillary thyroid cancer.

GCTs are rare soft tissue tumors typically originating from the nerve sheath, such as Schwann cells [1]. They can affect any part of the body, but they are most commonly found in the skin, tongue, ovaries, brain, and breast tissues [1,2,5]. Due to the heterogeneous origin of GCTs, a few reports have suggested that they could arise from smooth-muscle cells [5,6]. However, electron microscopy and immunoenzymatic reactions with neurogenic markers (S100 protein and NSE) support a Schwann cell origin [5,7]. Most GCTs are benign, with only 2% of all GCTS being malignant [2]. Spinal cord GCTs are extremely rare [2,3]. Although GCTs most frequently occur in middle-aged females, the mean age of the spinal cord GCTs is likely younger, around 23 years, with a typical age range of 13 to 49 years, and they predominantly affect females [2,4]. Clinical symptoms of GCTs originating from the spine include slowly progressive neurologic manifestations that vary depending on the tumor location, such as back pain, neuromuscular symptoms, weakness, paresthesia, erectile dysfunction, gait disturbance, bowel and bladder function, and upper and lower motor nerve dysfunction [4]. However, malignant GCT lesions are aggressive and have a poor prognosis, with a high rate of metastasis and recurrence, and a mortality rate of 40% [2,7-9]. Therefore, differentiating malignancy from benign GCTs is crucial.

In the present case report, the patient initially reported neuropathy-like pain with severe intensity. Over time, she experienced progressive deterioration of symptoms, along with motor and autonomic dysfunction. Notably, her pain responded poorly to conservative management. Although her initial upper extremity MRI provided a clue to the presence of GCTs, with a paravertebral elongated enhancing soft tissue mass at the T1-3 vertebral levels, this finding was missed in a previous radiologist’s reading and failed to be identified at her initial visit, resulting in an incorrect diagnosis of intercostal neuralgia [10] and delayed confirmation of the malignancy. Additionally, given her history of remission from malignant thyroid cancer, any recurrence of this malignancy should be considered. This patient’s case highlights that if symptoms worsen despite active pain management, it is crucial to consider the possibility of a space-occupying lesion or malignancy to prevent catastrophic progression.

Given the rarity of GCTs and the low specificity of their clinical findings, diagnosis typically relies on histopathology following extensive evaluation, including cervical-thoracic-abdomen CT and MRI [5]. MRI tissue characteristics are non-specific, and similar changes can be observed in other spinal canal tumors, including schwannomas, meningiomas, paragangliomas, ependymomas, or metastatic tumors [3,5]. Therefore, histopathologists play a primary role in the confirmatory diagnosis of GCTs [6]. The histological origin of GCT has been a subject of debate, leading to a variety of names for the tumor, such as Abrikossoff’s tumor, myoblastoma, and myoblastic myoma [6,7,9]. Histologically, GCTs are typically characterized by large polygonal cells with finely granular eosinophilic cytoplasm, a consequence of lysosomal granule accumulation [7]. Immunohistochemistry is recommended to distinguish these lesions from other more common neoplasms such as schwannomas, neurofibromas, or inflammatory processes, and vasculitis [1,7].

Malignant GCTs are diagnosed based on a combination of histological findings, including cellular pleomorphism, necrosis, elevated mitotic activity, and clinical malignant behavior. Clinical suspicion of malignant GCTs should be raised when there is evidence of a large, rapidly growing, or widely disseminated lesion [4]. In this patient, specific tumor markers revealed positivity for Ki-67 (a cellular marker of proliferation), S-100 (a marker for cells of neural crest cell origin), and CD56 (a homophilic binding glycoprotein expressed on the surface of neurons, glia, and skeletal muscle) at histopathologic examination. Although not observed in the present patient, nuclear pleomorphism and necrosis have been reported in approximately 20% of the GCTs, along with intratumoral hemorrhage [7].

The treatment of choice for GCTs is surgical removal with a wide-margin resection [1-4]. These tumors may not have well-defined margins and can infiltrate surrounding tissues, necessitating complete excision with extensive resection extending to areas without infiltration [2]. To reduce the risk of local (30%) or metastatic (50-60%) recurrent, a margin of 2-3 cm should maintain for malignant forms [5,9]. Radiation and chemotherapy have been used in patients with a history of malignancies or large-margin tumors that cannot be resected, but their efficacy remains unproven. GCTs are generally not sensitive to radiotherapy or chemotherapy [6]. However, there is a case report where radiotherapy successfully stabilized recurrent and residual disease in a patient with spinal GCT [6]. While spinal GCTs have been classified as IDEM tumors and are histologically benign, the anatomical limitations of the spinal canal can lead to severe morbidity if not diagnosed and treated correctly [4]. In this patient, the GCT masses were scattered, and the margins of GCT were unclear. Additionally, critical structures were located near the malignant GCTs, making it impossible to secure a sufficient safety margin. Nevertheless, all malignant tissues were aggressively removed via radical resection, including the main paravertebral mass, multiple pleural metastases, and the IDEM tumor. A three-month follow-up positron emission tomography scan revealed no evidence of metastasis from these malignancies. However, a longer follow-up is mandatory due to the infiltrative patterns of GCT and the potential for recurrence of papillary thyroid cancer.

In conclusion, while GCTs are rarely associated with malignancy, malignant GCTs are highly aggressive, and characterized by a high metastasis and recurrence rate, leading to a poor prognosis [2]. Furthermore, differentiating spinal GCTs from other spine-origin tumors or peripheral nerve diseases, based on clinical symptoms, is challenging [8]. In the case above, the patient experienced severe developing thoracic pain that remained unresponsive to multiple injections and medications. Crucially, the patient’s early MRI failed to provide any indication of the paraspinal mass, which resulted in a delayed diagnosis of her malignancy. This case highlights the importance for physicians to consider the possibility of a space-occupying lesion or malignancy when a patient’s symptoms worsen rapidly, even with active pain management. This case emphasizes that vigilant caution is crucial for physicians to prevent catastrophic progression and safeguard their patients.

No potential conflict of interest relevant to this article was reported.