Metastatic paraganglioma

Abstract

A man in his 70s, with a history of a glomus jugulare paraganglioma diagnosed 18 years ago, presented with an unprovoked deep vein thrombosis (DVT). The paraganglioma had been treated by radiotherapy, and yearly scans had not shown any progression since treatment. A sclerotic focus in L4 vertebral body was reported on a CT scan of the neck and trunk which was done to exclude a neoplastic process being the precipitating factor for the DVT. Nuclear imaging showed multiple areas of bony uptake, suggestive of metastases. A bone biopsy of the left femur resulted positive for metastatic paraganglioma. A monthly intramuscular injection of octreotide 30 mg was prescribed.

Background

While paragangliomas are not common tumours, we felt that most physicians are not completely knowledgeable about this condition. Even though most paragangliomas remain localised, some can metastasise, even many years after diagnosis. There are no reliable markers that can predict the neoplastic potential of a paraganglioma. This requires the need for lifelong monitoring of such patients. Genetic syndromes can contribute to the development of paragangliomas and so need to be tested for. Some genetic syndromes can even increase the risk of malignancy. It is also of utmost importance to ascertain whether a paraganglioma is secretory due to the risk of catecholamine crisis on any handling of these tumours. Complete resection remains the treatment of choice for paragangliomas and should as well be considered for metastatic paragangliomas.

Case presentation

A man in his 70s was admitted to the hospital with pain and swelling affecting his left calf. A deep vein thrombosis affecting the medial gastrocnemius vein was diagnosed via ultrasonography. The patient denied any provoking factors for the thrombosis. His medical history included hypertension, hyperlipidaemia, gastro-oesophageal reflux disease, a pontine stroke and a glomus jugulare paraganglioma which had been diagnosed 18 years ago, after presenting with right-sided tinnitus, sensorineural hearing loss and bloody otorrhoea. He had undergone radiotherapy and was still being followed up by the oncologists with yearly head CT scans showing no signs of progression.

In view of the risk of intracranial haemorrhage secondary to the paraganglioma, the thrombosis was treated with subcutaneous enoxaparin 1 mg/kg for a total of 3 months. Further investigations were carried out in order to exclude a malignant cause for the thrombosis. A CT scan of the neck and trunk revealed the known glomus jugulare paraganglioma which was unchanged from previous scans and a sclerotic focus in L4 vertebral body, among other ancillary findings (figure 1). Liver function tests and prostate-specific antigen were normal, while alpha-fetoprotein and CA19.9 were slightly elevated (table 1).

Figure 1.

Sclerotic focus on CT scan of the trunk.

Table 1.

Relevant blood investigations

Parameter	Result	Normal range
Bilirubin	8.1 µmol/L	0–21 µmol/L
Alkaline phosphatase	62 U/L	40–129 U/L
Gamma glutamyl transferase	20 U/L	8–61 U/L
Alanine aminotransferase	13 U/L	5–41 U/L
Prostate-specific antigen	0.88 ng/mL	0–4 ng/mL
CA19.9	50.2 U/mL	0–33 U/mL
Alpha-fetoprotein	8.30 U/mL	0–6.64 U/mL
Chromogranin A	162 ng/L	<102 ng/L
Metanephrines	<50 ng/L	<70 ng/L
Normetanephrines	107 ng/L	<120 ng/L
3-methoxytyramine	<15 ng/L	<18 ng/L

A whole-body bone scan showed abnormal tracer uptake in several areas, including L4 vertebra (figure 2). This raised the suspicion of osteoblastic bone lesions. Given the history of a paraganglioma, a DOTATATE positron emission tomography (PET)-CT scan was done, showing intense tracer uptake by the paraganglioma and several DOTATATE-avid pathological skeletal lesions, some of which were also FDG-avid (figures 3–5).

Figure 2.

Whole-body bone scan showing abnormal tracer uptake in L4 vertebra, left posterior 11th rib and left frontal bone, with less intense uptake in the right temporal bone.

Figure 3.

Positron emission tomography CT scan showing the L4 vertebral lesion.

Figure 4.

Positron emission tomography CT scan showing the left femur lesion which was biopsied.

Figure 5.

Positron emission tomography CT scan showing the pancreatic paraganglioma.

Histology from a CT-guided biopsy of the left proximal femur was consistent with a metastatic paraganglioma (figures 6 and 7), while an MRI scan of the pancreas revealed a 1.8 cm × 1.6 cm lesion in the posterior aspect of the pancreatic head, with imaging features suggestive of a paraganglioma, with the main differential diagnosis being of a neuroendocrine tumour. Metanephrines and normetanephrines were normal, while chromogranin A was elevated. The latter was likely secondary to the patient’s long-term omeprazole treatment.

Figure 6.

Metastatic paraganglioma to bone showing a nested arrangement of tumour cells, ×100 magnification.

Figure 7.

Metastatic paraganglioma to bone showing a nested arrangement of tumour cells, ×200 magnification.

Given the diagnosis of a metastatic paraganglioma, a monthly intramuscular injection of 30 mg octreotide was prescribed.

Investigations

Radiology

A CT scan of the neck and trunk revealed the known glomus jugulare paraganglioma which was unchanged from previous scans, a 6 mm left lower lung nodule and scattered sub-5 mm bilateral lung nodules, a slightly prominent proximal common bile duct measuring 8 mm and a sclerotic focus in L4 vertebral body (figure 1).

A whole-body bone scan showed abnormal tracer uptake in L4 vertebra, left posterior 11th rib and left frontal bone, with less intense uptake in the right temporal bone, likely due to the known locally invasive paraganglioma (figure 2).

A DOTATATE PET-CT scan revealed intense tracer uptake by the paraganglioma and several DOTATATE-avid pathological skeletal lesions in the left frontal bone, proximal femora, left iliac bone, posterior left 10th rib, and C3, T5, T7, T10, T11 and L4 vertebrae (figure 3).

An FDG-PET-CT scan showed low-grade uptake by the paraganglioma, hypermetabolic L4 vertebra (figure 3), left iliac bone and left proximal femur (figure 4) and also intense uptake at the pancreatic-duodenal region (figure 5).

An MRI scan of the pancreas revealed a 1.8 cm × 1.6 cm lesion in the posterior aspect of the pancreatic head, with imaging features suggestive of a paraganglioma, with the main differential diagnosis being of a neuroendocrine tumour.

Histology

On examining the left proximal femur bone biopsy, a metastatic tumour consisting of small nests of mildly pleomorphic tumour cells with round to oval non-descript nuclei with indistinct nucleoli and set in an abundant amphophilic cytoplasm was seen. Tumour nests are variably surrounded by flattened cells which stain with S100, consistent with sustentacular cells. The lesional cells stain with synaptophysin, neuron-specific enolase and GATA 3 (figures 6 and 7).

This was consistent with a metastatic paraganglioma.

Differential diagnosis

Given the patient’s history of a paraganglioma that had been diagnosed 18 years ago, metastatic spread from this tumour was the main differential diagnosis. Other differential diagnoses that were considered were osteoblastic metastases from other primary tumours, such as prostate cancer.

Treatment

Given the now metastatic nature of the paraganglioma, medical treatment was opted for. This involved a monthly intramuscular injection of 30 mg octreotide.

Outcome and follow-up

The patient was referred to a hepatobiliary surgeon in view of the paraganglioma affecting the head of the pancreas, and oncological follow-up was continued. It was planned for the patient to eventually undergo follow-up scans to look for any progression, if any, of the paraganglioma and its metastases and the response to medical treatment.

Discussion

Paragangliomas are rare neuroendocrine neoplasms that originate from the extra-adrenal autonomic paraganglia, at an incidence of 1 per 300 000.¹ The average age at diagnosis is 30–50 years old, with head and neck paragangliomas usually presenting at an older age.² Similar neoplasms affecting the adrenal medulla are known as phaeochromocytomas. This is based on the WHO Tumour Classification.³ Sympathetic paragangliomas are usually found in the thorax, abdomen or pelvis and are often catecholamine secreting, with similar clinical features, such as headaches, diaphoresis, palpitations and hypertension to phaeochromocytomas. On the other hand, parasympathetic paragangliomas are commonly non-secretory and are usually located in the head and neck, presenting with a mass effect on adjacent structures, such as the cranial nerves.

Around one-third of paragangliomas appear to be part of a hereditary syndrome, such as multiple endocrine neoplasia types 2A and 2B, neurofibromatosis type 1 and von Hippel Lindau.⁴ A younger age at diagnosis and bilateral or multifocal disease suggest the presence of a hereditary syndrome.⁵ Hereditary paragangliomas show no gender disparity, while sporadic ones are commoner in females.⁶ Since the 2017 WHO Classification of neuroendocrine tumours, paragangliomas have no longer been classified into malignant or benign types, but rather metastatic or non-metastatic. There are no reliable features that can determine the metastatic potential of a lesion, and even non-metastatic paragangliomas can have an effect on a patient’s morbidity or mortality through compression or invasion of adjacent structures.⁷ Metastatic disease is defined as the discovery of deposits, at sites where chromaffin cells are not normally seen.⁸ Of note, 15%–35% of extra-adrenal paragangliomas and 10% of phaeochromocytomas can have metastatic potential.⁹ Head and neck paragangliomas are commonly non-metastatic, especially jugulotympanic tumours with a 2%–4% risk of metastatic disease.¹⁰ Mutations in the gene encoding SDH subunit B (SDHB) can lead to metastatic disease in around 40% of patients with paragangliomas and usually account for multiple paragangliomas.^{11 12} This is why the Endocrine Society recommends genetic testing in all patients diagnosed with a paraganglioma in its guideline.¹³ Recent published data has refuted the previously taught ‘Rule of 10%’, that is that 10% of paragangliomas/phaeochromocytomas are bilateral or multifocal, hereditary, extra-adrenal and malignant.

All patients with a suspected or diagnosed paraganglioma should have measurements of plasma-free metanephrines (in the supine position for at least 30 min, ideally) or urinary unfractionated metanephrines. This should be followed by imaging to locate the tumour, with contrast CT, MRI, radioisotope imaging using metaiodobenzylguanidine (MIBG) and PET all being viable options.¹³ While laboratory testing and imaging provide a provisional diagnosis, definite diagnosis is based on tissue histopathology, obtained by a biopsy or on surgical resection of the tumour. It is imperative that testing for catecholamine secretion is done prior to such procedures due to the risk of a catecholamine crisis in functioning paragangliomas.

Determining whether a paraganglioma has metastatic potential, prior to the development of metastatic disease, remains a challenge. There is often a long interval between diagnosis of the initial paraganglioma and metastatic spread, sometimes even up to 20 years. Identifying such metastatic potential would prompt more aggressive treatment of the paraganglioma, with potentially better outcomes.¹⁴ There are no reliable features on histology that would be diagnostic of a paraganglioma with metastatic potential, so it is recommended that all patients with paragangliomas are routinely screened for metastatic disease.¹⁵ The size of the tumour (if more than 5 cm) might be a characteristic suggesting the potential for metastatic spread,¹⁶ as well as, thoracoabdominal sympathetic paragangliomas.⁸ Patients with metastatic disease have an approximate 5-year survival rate of 50%.¹⁷

Prior to the development of metastases, surgical resection of paragangliomas should be the treatment of choice and is highly effective and potentially curable.¹⁶ However, the development of metastatic disease is not a contraindication to surgery. Local interventions, such as tumour debulking, might lead to a relief of mass-effect symptoms or symptoms secondary to catecholamine release, as well as, a better response to subsequent therapeutic modalities.¹⁸ If surgery is not an option, other forms of therapy, such as chemotherapy with cyclophosphamide, vincristine and dacarbazine, radiotherapy, cryoablation, radiofrequency ablation, therapeutic iobenguane I-131 (recently approved by the FDA if MIBG-scan is positive)¹⁹ or peptide receptor radionuclide therapy may be tried.²⁰ However, these treatments can all have a negative impact on a patient’s quality of life, so active surveillance is another option for patients with metastatic disease who are asymptomatic.¹⁹ Treatment with the somatostatin analogue, octreotide (as in our patient), has shown mixed results in the few small studies that have been done. A few case reports have shown a benefit in metastatic paragangliomas treated with octreotide, especially for inoperable head and neck tumours.^21–23

Learning points.

• Paragangliomas are rare tumours with possible harmful and even devastating complications, such as uncontrolled hypertension and cardiovascular ill-effects from catecholamine secretion, mass effects on adjacent tissues and organs, and even metastatic potential. Thus, it is of vital importance that one suspects, investigates and manages this condition accordingly.

• Testing for catecholamine secretion should be done in all patients, especially prior to biopsy or resection of paragangliomas, due to the risk of catecholamine crisis in the case of functioning tumours.

• Genetic testing should be done for all patients with a paraganglioma. Detection of a paraganglioma secondary to a hereditary syndrome may lead to earlier diagnosis and management of affected family members. Also, diagnosis of a hereditary syndrome may prompt one to look for other features of such syndrome.

• All patients with a paraganglioma should be followed up lifelong with full-body imaging to diagnose early metastatic disease.

• Surgical resection, if possible, should be the initial mode of management for non-metastatic paragangliomas.

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