Chemodectoma (paraganglioma): Etiology, Pathogenesis, Classification, Diagnosis, Treatment methods

Carotid body paraganglioma (chemodectoma) is a rare, mostly benign tumor arising from the chemoreceptor cells of the carotid body located at the bifurcation of the common carotid artery.

Epidemiology

• Approximately 1-2 cases per 100,000 population.
• Women are affected more often than men.
• The average age of diagnosis is about 45 years old.
• The prevalence is high in Latin American countries, especially in Mexico, where women account for up to 90% of cases.
• Residents of high altitude areas have an increased risk of developing chemodectomas due to chronic hypoxia.

Etiology

Genetic mutations: Mutations in genes encoding subunits of the succinate dehydrogenase complex (SDH), which is involved in the mitochondrial respiratory chain and cellular metabolism, play a leading role. Major genes:

• SDHD is most commonly associated with multiple head and neck paragangliomas and is inherited paternally;
• SDHB is associated with more aggressive forms and an increased risk of malignant progression;
• SDHC, SDHA, SDHAF2 are less frequently involved but may also contribute to tumor development.

Syndromes associated with chemodectomas:

• Von Hippel-Lindau syndrome (VHL);
• Multiple endocrine neoplasia type 2 (MEN2);
• Neurofibromatosis type 1 (NF1).

Chronic hypoxia: living at > 2000 m above sea level, as well as conditions such as chronic obstructive pulmonary disease and congenital heart disease, can stimulate carotid body hyperplasia.

Family history: about 10% of cases are familial.

Pathogenesis

1. Hereditary mutations (SDHx)

Mutations of SDH (key enzyme of complex II of mitochondrial respiratory chain and Krebs cycle) → Accumulation of succinate (acts as “oncometabolite”) → Inactivation of prolyl hydroxylases (PHDs) enzymes, controlling degradation of HIF-1α (hypoxia-inducible factor) → Accumulation of HIF-1α → Pseudohypoxia → Activation of VEGF (angiogenesis)/ GLUT1 (glycolysis)/ PDGF (cell proliferation) → Neoplastic transformation of chemoreceptor cells and tumor formation.

2. Chronic hypoxia

Hypoxia (altitude, COPD) → Decreased pO₂ → Carotid receptor activation → Cell hyperplasia → HIF-1α accumulation → Angiogenesis and neoplasia.

As a result, the tumor gradually increases in size. As it grows, it can demonstrate a locally invasive nature, to the point of encircling or compressing nearby anatomical structures – such as the internal and external carotid arteries, vagus, hyoid and lingual nerves – which can cause associated neurologic and vascular symptoms.

Classification of paraganglioma

W.R. Shamblin proposed to divide paragangliomas of the carotid calf into three types:

• Type I: limited tumors up to 3.5 cm, loosely associated with arterial walls;
• Type II: 3.5-5 cm, partially cover the carotid arteries, have a denser fusion with the arterial walls;
• Type III: more than 5 cm, covering the carotid arteries and/or nearby vessels, nerves have a markedly dense fusion with these structures.

In addition, chemodectomas can be categorized by etiology: sporadic (up to 85%), familial (10-15%), and hyperplastic (1-5%).

Clinical manifestations

For long periods of time, symptoms may be absent. As the tumor grows, complaints may appear:

• Palpable tumor: slowly growing, painless, pulsating mass on the lateral surface of the neck (in the area of the sternoclavicular-papillary muscle);
• Neurologic symptoms: hoarseness of voice, dysphagia, numbness of tongue caused by compression of cranial nerves (IX-XII);
• Complaints related to catecholamine production (palpitations, attacks of arterial hypertension, sweating, headache, tremor);
• Rarely: dizziness, fainting with carotid sinus compression.

Diagnosis of paraganglioma

• Physical examination: dense, throbbing tumor on the neck, shifting horizontally but not vertically;
• Ultrasound with Doppler: a hypervascular tumor in the region of the carotid bifurcation;
• MRI with contrast: characteristic “salt-and-pepper” appearance on T1-weighted images;
• CT with contrast: determination of the degree of invasion into vessels, evaluation of Shamblin classification. Construction of a 3D model for planning surgery;
• Angiography: detection of the “lira sign” – divergence of the internal and external carotid arteries. Allows assessment of the need/ feasibility of embolization of the area as a step before surgical intervention;
• PET-CT with 68Ga-DOTATATE: if multiple or metastatic foci are suspected;
• Laboratory tests: plasma and urine levels of metanephrines and normetanephrines in suspected secreting tumor;
• Genetic testing for mutations in SDH genes in the presence of family history or multiple tumors.

Treatment

Treatment of carotid chemodectoma depends on tumor size, clinical symptomatology, risk of complications, functional activity, genetic profile, and Shamblin grade. The main treatment modalities are surgical excision, preoperative embolization, and in some cases radiotherapy or chemotherapy.

1. Preoperative embolization

Preoperative embolization to reduce tumor vascularization and intraoperative blood loss, and to facilitate tumor isolation during surgery.

Indications:

• Shamblin grade II-III tumors;
• Tumor diameter >3 cm;
• Presence of significant arterial blood flow (according to CT/angiography);
• Planned resection with vascular reconstruction.

Contraindications:

• Shamblin I tumors;
• Absence of an arterial component (low vascularization);
• Anastomoses with cerebral circulation – risk of cerebral embolization.

Methods: Selective angiography of the external carotid artery is performed. Embolizing agents are introduced through the microcatheter: polyvinylalcohol particles (PVA), microspheres, less commonly glue or spirals. Control angiography confirms blood flow reduction. Surgery is performed within 24-48 hours after embolization as long as the effect persists.

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2. Surgical treatment

Indications:

• Symptomatic tumors (pain, dysphagia, speech impairment);
• Rapid tumor growth;
• Tumors >2.5-3 cm (even asymptomatic);
• Confirmed activity by PET or biochemistry;
• Confirmed SDHB mutation (risk of malignancy);
• Age <60 years.

Types of surgical treatment:

• Extracapsular resection of the tumor. Standard for Shamblin I-II, vascular preservation, minimal risk;
• Carotid resection with reconstruction. More often at Shamblin III. After resection of the carotid artery site, a prosthesis (Dacron, PTFE) is performed;
• Neuromonitoring and microsurgery. It is used when close to cranial nerves (IX-XII).

Possible complications:

• Bleeding (especially with inadequate embolization);
• Damage to cranial nerves (IX-XII) – up to 30% in large tumors;
• Stroke (when collateral blood flow is impaired);
• Recurrence (rare, with incomplete resection).

3. Chemotherapy

It is not the standard treatment for carotid chemodectoma, as most tumors are slow growing and benign in nature. However, in rare cases of malignant course (rapid progression, metastatic lesions) or in inoperable metastatic forms, systemic therapy may be used.

4. Radionuclide therapy ¹⁷⁷Lu-DOTATATE (PRRT)

Prescribed in the presence of somatostatin receptor expression by PET with ⁶⁸⁸Ga-DOTATATE.