Chemodectoma (Paraganglioma): Etiology, Pathogenesis, Classification, Diagnosis, and 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 the genes encoding the subunits of the succinate dehydrogenase complex (SDH), involved in the mitochondrial respiratory chain and cellular metabolism, play a major role. Key genes:

• SDHD — most commonly associated with multiple head and neck paragangliomas; inherited paternally;
• SDHB — associated with more aggressive forms and an increased risk of malignancy;
• SDHC, SDHA, SDHAF2 — less frequently involved, but can 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 an altitude of more than 2000 m above sea level, as well as conditions such as chronic obstructive pulmonary disease and congenital heart defects, can stimulate carotid body hyperplasia.

Family history — about 10% of cases are familial.

Pathogenesis

1. Hereditary mutations (SDHx)

Mutations SDH (a key enzyme of complex II of the 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 → activation of carotid receptors → cell hyperplasia → accumulation of HIF-1α → angiogenesis and neoplasia.

As a result, the tumor gradually increases in size. As it grows, it may demonstrate locally invasive characteristics, to the extent of surrounding or compressing nearby anatomical structures such as the internal and external carotid arteries, vagus, hypoglossal, and glossopharyngeal nerves. This can cause accompanying neurological and vascular symptoms.

Classification of paraganglioma

William Shamblin proposed dividing carotid body paragangliomas into three types (Shamblin classification):

• Type I: limited tumors up to 3.5 cm, loosely connected to arterial walls;
• Type II: 3.5–5 cm, partially encompass carotid arteries, have a denser fusion with arterial walls;
• Type III: more than 5 cm, enclosing carotid arteries and/or adjacent vessels and nerves with a markedly dense connection to these structures.

Additionally, chemodectomas can be classified by etiology: sporadic (up to 85%), familial (10–15%), hyperplastic (1–5%).

Paraganglioma Type I

Paraganglioma Type III

Clinical manifestations

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

• Palpable tumor — slow-growing, painless, pulsating mass on the lateral surface of the neck (in the region of the sternocleidomastoid muscle);
• Neurological symptoms — hoarseness, dysphagia, tongue numbness due to compression of cranial nerves (IX–XII);
• Complaints related to catecholamine production — palpitations, episodes of hypertension, sweating, headache, tremor;
• Rare symptoms — dizziness, fainting due to carotid sinus compression.

Diagnosis of paraganglioma

• Physical examination: firm, pulsating tumor on the neck, moves horizontally but not vertically.
• Ultrasound with Doppler: hypervascular tumor at the carotid bifurcation.
• MRI with contrast: characteristic “salt-and-pepper” appearance on T1-weighted images.
• CT with contrast: determination of the degree of vessel invasion, evaluation of Shamblin classification. ​Construction of a 3D model for planning surgery.
• Angiography: identification of the “harp sign”—divergence of the internal and external carotid arteries. Allows for assessing the need/possibility of embolization in this area as a pre-surgery stage.
• PET-CT with ⁶⁸Ga-DOTATATE: if multiple or metastatic foci are suspected.
• Laboratory tests: determine plasma and urine levels of metanephrines and normetanephrines if a secreting tumor is suspected.
• Genetic testing for mutations in SDH genes in the presence of family history or multiple tumors.

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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 is performed to reduce tumor vascularization, decrease intraoperative blood loss, and facilitate tumor dissection 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.

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

2. Surgical Therapy

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.