Paragangliomas (PGL) are neuroendocrine neoplasms, derived from paraganglia of the sympathetic and parasympathetic nervous systems. Paragangliomas are usually hypervascular and originate from neural crest cells arising within the autonomic nervous system. The distribution of paragangliomas is widespread. They are most commonly seen in the head and neck region being most frequent in the carotid body. Abdominal sites include the well-known urinary bladder tumors that originate in the Organ of Zuckerkandl. However, other unusual sites of origin include peri-adrenal, para-aortic, inter-aortocaval, and paracaval, retroperitoneal sites. The paraganglioma in the adrenal medulla is called pheochromocytoma.
Paragangliomas of the head and neck region (HN) are rare, comprising 0.6% of HN tumors and 0.03% of all neoplasms. These are found primarily at the bifurcation of the common carotid artery, in the middle ear temporal bone, along the course of the vagus nerve. Much less common presenting sites are the ciliary ganglion, nasal cavity, larynx, trachea, para-aortic region, and fallopian canal. Paragangliomas more often arise in female patients, usually in the 4th and 5th decades of life.
Paragangliomas are very hypervascular tumors and mostly benign and slow-growing. These tumors are often very symptomatic, and may cause fight-or-flight sympathetic symptoms like dry mouth, flushing of the face, racing heart, dilated pupils, fidgetiness (a state of nervousness), constipation, fatigue, profuse sweating, headache, tremors, panic-like symptoms and generalized weakness due to exhaustion. It may also present with blurry vision, light-headedness, weight loss, excessive thirst or hunger, mood disturbances, high blood sugar levels, and weight loss. Other possible symptoms include anxiety attacks, fever, extreme paleness in the face, shortness of breath, tremors or shakiness, nausea, vomiting, clammy skin, constipation, tingling fingers, vision disturbances, and chest or stomach pain. However, the most classical presentation has the triad of headache, palpitations, and profuse sweating. Paragangliomas usually grow extremely slowly and the primary cause of morbidity in patients with paragangliomas is cranial nerve impairment caused by compression or infiltration of the nerves.
In diagnosis, the first and foremost is the correlation of clinical symptoms with pathology and the provision of biomarkers for tumor surveillance. There is a strong genotype-phenotype correlation with respect to the tumor catecholamine profile, anatomic location, and risk of metastatic spread in PGLs. The diagnosis is based on laboratory investigations which include blood and urine tests, biochemical assessment, radiological evaluation, functional tests, as well as genetic tests. Laboratory investigations are the first step in the diagnosis of paragangliomas to validate the excessive production of catecholamines and then followed by anatomical identification of the tumor.
Radiological evaluation is the next step with imaging modalities such as Computed tomography (CT) scanning or Magnetic resonance imaging (MRI). Imaging studies depict the location and extent of tumor involvement, help determine the surgical approach, and predict operative morbidity (rate of disease in a population) and mortality (death rate).
Functional Tests are extremely sensitive in identifying any hidden paragangliomas. Genetic tests are done as multiple paragangliomas are commonly associated with mutations of the succinate dehydrogenase subunit genes. Different studies have demonstrated that approximately one-third of head and neck paragangliomas are caused by a germline mutation in SDH genes.
The treatment of paraganglioma has historically been controversial. The therapeutic strategy for paragangliomas is preferred to be discussed by a multidisciplinary team of experts based on the patient characteristics. Treatment options include wait and watch strategies for indolent tumors, followed by surgical resection, radiotherapy, chemotherapy, targeted therapy (i.e., antiangiogenic tyrosine kinase inhibitors), and chemotherapy.
A “wait and see” is watchful waiting and observation approach in certain situations, such as if the paraganglioma is slow growing and isn't causing signs and symptoms, may be recommended against immediate treatment and periodic monitoring is required during regular follow-up appointments.
Surgical resection is the cornerstone of therapy for most localized PGLs, as it is the only potentially curative therapeutic modality. The goal of surgery is to achieve complete tumor resection without rupture, including en bloc resection of adjacent infiltrated organs if needed.
Radiotherapy is the treatment of choice for paragangliomas that present in anatomic areas with difficult surgical access, involve critical structures, or present over a large geographic area. Multifraction traditional radiotherapy has demonstrated local control rates equal to, or surpassing that of surgery. Stereotactic radiosurgery (SRS) and stereotactic radiotherapy seem to play an increasingly important role in the treatment of these tumors due to the higher capability of sparing adjacent normal tissues than more conventional radiotherapy techniques.
If paragangliomas spread, chemotherapy may be recommended to help shrink the tumors. Also, in cases where the tumor produces excess hormones, medications to control the hormone levels are prescribed before undergoing chemotherapy.
Currently, human VEGF-A monoclonal antibodies and tyrosine kinase inhibitors are used as angiogenic therapies. Also, targeted therapy and immunotherapy are under clinical trials.
The emergence of new therapies challenges the traditional paradigm for the management of head and neck paragangliomas. Therefore, further research will provide new avenues for better management which in turn will help improve the quality of life of patients with paragangliomas.