Metastatic Malignant Glomus Jugulare Tumor: A Rare Case Report with Clinical Manifestations and Treatment Approach

Background

Paragangliomas are neuroendocrine neoplasms derived from paraganglia of the sympathetic and parasympathetic nervous systems [1]. They can occur along the paraganglia’s pathway from the base of the skull to the pelvic floor due to embryologic migration [2].

Parasympathetic ganglia-derived tumors, also called non-chromaffin, are located almost exclusively in the neck and skull base and are usually non-secretory and inactive. Less than 5% of parasympathetic paragangliomas secrete catecholamines and become symptomatic [3], but sympathetic ganglia-derived tumors (chromaffin-secreting) are highly active and symptomatic. They mainly secrete norepinephrine and can arise anywhere from the skull base, along the sympathetic chain, to the pelvis, and 80–85% of all paragangliomas are located in the abdomen [4].

Paragangliomas are most commonly identified in the head and neck region, and most commonly in the carotid body, followed by jugulotympanic paraganglia, vagal nerve, and ganglion nodosum, as well as laryngeal paraganglia [1,5]. The fact that carotid body tumors are far more common than other head and neck paragangliomas (HNPs) is probably due to a higher mass of normal paraganglionic tissue in this area [6]. Carotid body tumors and vagal paragangliomas can be grouped clinically as cervical paraganglioma [7].

Tympanojugular paragangliomas arise in the layer of adventitia of the jugular bulb or along the pathway of the Jacobson nerve (the tympanic branch of the glossopharyngeal nerve) or the Arnold nerve (the auricular branch of the vagus nerve). The term tympanicum has been applied to those paragangliomas arising on the promontory and limited to the middle ear and mastoid, with preserved jugular plate and jugular bulb. Jugular paragangliomas are described as those arising from within the jugular bulb and extending into the jugular foramen [8,9]. Paragangliomas can arise from structures in the temporal bone canaliculi, the jugular fossa, and the middle ear cleft, and the close association of these structures to each other often makes it difficult to pinpoint the exact site of origin. They were classified anatomically into Fisch types A to D [10]. Vagal paragangliomas occur in the nodose ganglia in almost all cases. Carotid body tumors arise from the carotid body tissue at the carotid bifurcation [9].

Jugular-tympanic paraganglioma can be diagnosed early due to classic symptoms of pulsatile tinnitus with or without conductive hearing loss. It can also involve lower cranial nerves, which causes paralysis of the affected nerve. Vagal paraganglioma is rare and its clinical symptoms range from hoarseness and mass effect to painless neck mass [2,7].

Although most paragangliomas are sporadic, certain familial cases have been reported, with 25% to 35% associated with recognized genetic defects such as succinate dehydrogenase (SDH) -mutations, Carney-Stratakis dyad, neurofibromatosis type 1, Von Hippel Lindau, and multiple endocrine neoplasia types 2A and 2B [2,11,12].

Almost 90% of all hereditary HNPs are associated with paraganglioma syndromes (PGL) types 1, 3, and 4. PGL-1 is associated with mutations in the gene encoding succinate dehydrogenase subunit D (SDHD). Genetic mutations in SDHC and SDHB can lead to PGL-3 and PGL-4, respectively. Patients with paraganglioma syndromes usually develop tumors at a young age. Most SDHC mutation patients develop benign, single paraganglioma, whereas SDHD mutation patients have multiple HNPs. However, patients with SDHB mutations have a significantly increased risk of developing malignant paraganglial tumors [2,11].

Malignant paraganglioma is rare, and malignant jugular paraganglioma is extremely rare as the origin of the tumor helps in anticipating the malignancy potential [10]. Diagnostic criteria by histopathology or immunohistochemical staining have not been established [2]. Therefore, it can only be diagnosed when metastases to non-neuroendocrine tissues are present [2]. Malignant head and neck paragangliomas tend to metastasize to regional cervical lymph nodes [10].

A case of malignant glomus jugulare with a metastatic cervical lymph node is described here.

Case Report

A 24-year-old woman, not known to have any medical illness, was referred to an otolaryngology clinic for a concern of voice change for 1 month, which was associated with right progressive hearing loss, pulsating tinnitus, and right facial weakness. There was no history of headache, palpitations, or sweating and no family history of a similar condition. A clinical examination revealed a reddish mass in the right ear behind an intact tympanic membrane, and a healthy external auditory canal. Right facial weakness of House-Brackmann grade VI was noted. A bedside flexible nasopharyngoscopy revealed an im-mobile right vocal fold. Apart from the right VIIth and Xth nerve palsies, the rest of the cranial nerves and neck examination were unremarkable. The audiological assessment revealed profound right ear sensorineural hearing loss.

A computed tomography scan (CT) of the brain revealed a destructive lesion within the right jugular foramen that extended superiorly to the infra-temporal fossa, destroying the temporal bone, and widening of the jugular foramen (Figure 1A).

Magnetic resonance imaging (MRI) revealed an enhanced soft-tissue mass lesion within the right jugular foramen extending to the infra-temporal fossa, causing destruction and widening of the jugular foramen as well as mass effect on the right internal carotid artery, jugular vein, and right cerebellopontine angle. The mass was heterogeneous on T1-weighted images (Figure 1B) and hyperintense with small low-signal flow voids (salt and paper appearance) on T2-weighted images (Figure 1C). The mass measured 35×34×49 mm and was invading the middle ear cleft. There was no cervical lymphadenopathy or suspicious lymph nodes on imaging. A nuclear medicine whole-body I-123/131 MIBG (metaiodobenzylguanidine) and positron emission tomography (PET/CT) scan showed an uptake within the right jugular foramen with no signs of tracer avid distance metastatic lesions. Plasma and urine normetanephrine levels were elevated, as well as vanillylmandelic acid (VMA) (urine normetanephrine, 1081; serum normetanephrine, 893; and VMA/creatinine, 9.9), for which she was referred to endocrinology for hormonal control preoperatively.

The patient underwent embolization then glomus tumor resection via infra-temporal fossa approach – Fisch type A approach, which involves transmastoid and transcervical incisions that provide exposure of the jugular vein, carotid artery, and the lower cranial nerves at the lateral skull base and neck levels. During neck dissection, there was a suspicious ipsilateral lateral neck lymph node discovered intraoperatively and both the tumor and lymph node were submitted for pathology review.

Pathology revealed that the tumor was an infiltrative epithelioid tumor with a spindle and nesting pattern separated by fibrovascular stroma (Figure 2A). The tumor cells had central round/oval chief cells with eosinophilic granular nuclei and dispersed chromatin. There was a very low mitotic count of 1/10 high-power fields. The tumor had infiltrated the surrounding soft tissue and bone trabeculae (Figure 2B). Moreover, there was angioinvasion present and no necrosis present. The immunohistochemistry stains showed that the tumor cells were positive for chromogranin and synaptophysin but negative for keratin and GATA3. The sustentacular cells were highlighted by S100. Based on 113 proliferative cells in 1039 counted tumor cells, the Ki67 proliferative index was 10.8%. The submitted lateral neck lymph node revealed a metastatic tumor nest, which was highlighted by diffuse positivity for synaptophysin stain (Figure 2C, 2D).

The patient was referred to a radiation oncology team and was treated with radiotherapy. A heterozygous, likely pathogenic, variant in the SDH-C gene was discovered, confirming the genetic diagnosis of autosomal dominant hereditary paraganglioma pheochromocytoma syndrome, as well as CENTOGEN variant likely pathogenic (Class 2) and an SDHC variant c.405+1G>A.

The patient tolerated the procedure without complications, with only mild dysphagia followed by speech-language pathology. During her 3-month follow-up, a head and neck MRI was done, showing a residual tumor in the right petrous apex, cerebellopontine cistern, and infra-temporal fossa. Therefore, she was referred to radiation oncology for adjuvant radio-therapy, where she received external beam radiation therapy (EBRT) of 66 Grey/30 fraction to the residual tumor site. During her 10-month follow-up, her imaging showed stable residual disease. She also underwent a whole-body MIBG scan and whole-body PET/CT, which showed no evidence of distant metastasis. Surveillance consisted of a 3-month interval head and neck MRI, brain to pelvis MRI every 6 months, and yearly plasma-free metanephrines. The patient and her family had a genetic counseling session and her family members will be genetically screened.

Discussion

Rosenwasser published the first report of a glomus jugulare tumor in 1945 [13]. While the sex ratio is equal for carotid body tumors, tympanojugular paragangliomas are 4–6 times more common in females than males [3], but males are more commonly affected in the familial type. All of the head and neck paraganglioma subtypes show a peak age of onset in the fourth and fifth decades of life, with rare incidence in the pediatric age group. The familial type appears at a significantly younger age [3,14].

The clinical presentation varies with tumor location, degree of tumor burden, and secretory functionality. Functional paragangliomas secrete excessive catecholamines, resulting in a clinical presentation of paroxysmal hypertension, headache, sweating, and palpitations [11], but it is an extremely rare presentation for head and neck paragangliomas (HNPs). In non-functional paragangliomas, the clinical presentation is a result of a compressive mass effect on adjacent structures [4,11].

Because of their generally slow growth and initial absence of symptoms, tympanojugular paragangliomas are often not detected until they are large [15]. Hearing loss, tinnitus, vertigo, otalgia, otorrhea, hemorrhage, headache, and other symptoms may be present depending on the local structures involved, in addition to lower cranial nerves palsy. The most common presenting symptom in non-metastatic tumors is decreased hearing, while otalgia is the most common presentation in patients with metastatic tumors [6]. The pain is mostly attributed to the invasive nature of malignant tumor, while patients with hearing loss present earlier, before any metastasis. Tinnitus, otorrhea, and facial nerve paralysis are more common in metastatic tumors than in non-metastatic tumors [6,15].

The most common finding on examination is the presence of a middle-ear vascular mass, whether they originate in the middle ear or from within the canaliculi or bulb. Blanching of the middle ear mass, which is classically described as Brown’s sign, is present in 20% [7]. Tumors that invade the tympanic bone through the jugular fossa can show the classic “rising sun” sign. The tympanic membrane may be intact, red, and bulging, or normal. Paraganglioma is the most common cause of retrotympanic vascular masses, but other pathologies should be considered. Apparently, unless the margins of the mass are completely visible, the vascular mass seen on otoscopy involves the jugular bulb until proven otherwise. About 10% of such patients present with silent lower cranial nerve palsies [15].

The incidence of metastases from glomus jugulare tumors is estimated to be 1–4% [6]. Local invasion is common, and it is possible for it to spread intracranially or into the neck structures [14]. The most common sites of metastasis are the bones and lungs. Other sites include lymph nodes, the liver, pancreas, pleura, and others. The cervical lymph nodes are the most common site of lymph node metastasis. Other locations of metastasis have been reported, such as the parotid, mediastinal, and hilar lymph nodes. The majority of metastatic cases will have persistent or recurrent disease. Within 6 years, the death rate from metastatic disease is around 68%, and it is 10% from non-metastatic disease [6].

Due to the rarity of malignant head and neck paragangliomas, there is no TNM staging system to date apart from the anatomical staging of the paraganglioma as previously discussed [16]. In general, the management options of either benign or malignant head and neck paragangliomas include surgery, radiotherapy, or a follow up policy [17]. In the majority of these lesions, surgery remains the mainstay of treatment. Total removal leads to a complete cure in most cases [15]. Cervical lymph node metastasis is usually removed surgically, which is the standard of management. Selective level II and III neck dissection should be carried out [7], which aid in the histological confirmation of such metastases [18]. Adjuvant radio-therapy is required for large, residual, metastatic, or unresectable tumors [10,19].

Paragangliomas have histological appearances that are typically composed of polygonal neoplastic chief cells organized into nests (zellballen) surrounded by a capillary network. Nuclei exhibit significant atypia and secondary changes such as stromal fibrosis and hemorrhage. According to some studies, certain characteristics such as large zellballen, pleomorphic mitotic cells, and focal necrosis indicate malignant behavior. The presence of metastases is currently used to diagnose cancer. The role of histopathology and immunohistochemical stains is mainly to confirm the presence of metastatic paraganglioma [12].

The American College of Medical Genetics and Genomics (ACMG) classified CENTOGEN variants as pathogenic (Class 1), likely pathogenic (Class 2), variant of uncertain significance (Class 3), likely benign (Class 4), and benign (Class 5). The SDHC variant c.405+1G>A is predicted to disrupt the highly conserved donor splice site. According to the recommendations of CENTOGEN and ACMG, it is classified as likely pathogenic [20]. Although the present case had SDHC variant, which carry less risk of malignancy in comparison with SDHB variant, it is crucial to perform genetic testing and follow such patients to assess and predict the growth of other tumors [10].

Patients with head and neck paraganglioma should undergo a thorough evaluation by history-taking, clinical examination, and contrast head and neck CT and MRI. A whole-body scan is also recommended to rule out metastatic disease, and is the preferred modality. Moreover, baseline plasma metanephrine levels should be obtained to identify patients with a secretory type that mandates endocrinology follow-up. Finally, genetic testing and counseling are required in all patients, even those with a negative family history [10]. Metastatic cervical lymph nodes are usually discovered clinically or radiologically [18]. In the present case, however, it was discovered intraoperatively, similar to the case reported by Brewis et al [21].

Such cases require long-term follow-up, and those with genetic mutations need close follow-up. Initially, a 3-month follow-up with MRI is necessary during the first year, followed by annual MRI and assessment of plasma metanephrine levels during the next 3 years. For patients with genetic mutations, whole-body MRI every 2 years is recommended for early detection and monitoring for recurrence [10]. In a study done to assess the surveil-lance duration in SDHB mutation, the average duration of surveillance was 2.3–11.3 years, with a median of 3.7 years [22].

Conclusions

Glomus jugulare tumors are uncommon paragangliomas, and malignant behavior with metastasis is extremely rare. Patients with metastatic tumors are prone to have facial and vagal nerves palsy. There are no histological features that distinguish malignant glomus jugulare tumors. Malignant neoplasms are characterized by the presence of metastases. The lungs, bones, and cervical lymph nodes are the most common sites of metastasis. Tumors of the glomus jugulare that are malignant are treated with surgery, radiotherapy, or both. However, the literature revealed no clear guidelines given the scarcity of cases. Moreover, the presence of metastasis increases the risk of death.