Adrenal & Pheochromocytoma / Paraganglioma

Quick Answer

Pheochromocytomas (adrenal medulla) and paragangliomas (extra-adrenal) are catecholamine-related neuroendocrine tumors localized with several complementary functional agents. Ga-68-DOTATATE PET has become the most sensitive modality — first-line for head-and-neck and metastatic paraganglioma and SDHx-related disease; I-123-MIBG confirms candidacy for I-131-MIBG therapy (the theranostic gate); F-18-FDOPA excels for sporadic adrenal pheo and many paragangliomas; and FDG is most useful in SDHB / dedifferentiated disease. Genotype strongly shapes which tracer performs best.

Definition

Pheochromocytomas and paragangliomas (collectively PPGL) are tumors of chromaffin cells. Pheochromocytoma arises in the adrenal medulla; paraganglioma arises in extra-adrenal paraganglia — sympathetic (paravertebral/para-aortic, usually catecholamine-secreting) or parasympathetic (head-and-neck, e.g. carotid-body/glomus, usually non-secreting). Diagnosis is biochemical; imaging localizes and stages.

Synonyms

Pheo; para; PPGL; chromaffin-cell tumor; head-and-neck paraganglioma (glomus/carotid-body tumor). Adrenal incidentaloma and adrenocortical carcinoma are separate adrenal entities addressed for contrast.

Epidemiology

PPGL are rare. They have the highest heritable fraction of any human tumor — a large minority (often cited around 40%) carry a germline driver mutation — so genetic testing is recommended in essentially all patients. The old "rule of 10s" (10% bilateral/extra-adrenal/malignant/familial) understates the hereditary and extra-adrenal proportions. Malignancy is defined by metastasis (there is no reliable histologic malignancy marker), and is substantially more common with SDHB.

Etiology & Genetics

Germline/somatic drivers fall into functional clusters that predict biochemical phenotype and imaging avidity:

SDHx disease favors DOTATATE/FDG over MIBG; kinase-cluster adrenal pheo is often FDOPA/MIBG-avid.

Pathophysiology

Chromaffin tumors synthesize and (in sympathetic disease) secrete catecholamines — driving paroxysmal hypertension, and, in excess, catecholamine cardiomyopathy and life-threatening crisis. Imaging exploits three cell properties: the norepinephrine transporter (uptake-1) — basis for MIBG; somatostatin-receptor (SSTR2) expression — basis for DOTATATE; and catecholamine-precursor uptake/decarboxylation — basis for FDOPA. Pseudohypoxia (SDHx) tumors upregulate glucose metabolism (Warburg-like), explaining their FDG avidity and lower MIBG uptake.

Histopathology

Nested ("Zellballen") architecture of chromaffin cells in a sustentacular framework; chromogranin A / synaptophysin positive. There is no single histologic malignancy criterion — metastasis defines malignant behavior — though composite scores (GAPP, PASS) and Ki-67 add risk information. SDHB immunohistochemistry loss flags SDHx disease.

Clinical Presentation

Classic triad of episodic headache, palpitations, and diaphoresis with hypertension (sustained or paroxysmal), plus pallor, anxiety, and tremor. Head-and-neck paragangliomas present as a painless neck mass, pulsatile tinnitus, or cranial-nerve deficits (usually non-secreting). Some are found as adrenal incidentalomas or during syndromic screening.

Laboratory Findings

• Plasma free metanephrines and normetanephrines (highest sensitivity) or 24-hour urinary fractionated metanephrines — the diagnostic tests.
• Chromogranin A as an adjunct.
• Genetic testing for the cluster genes above (recommended broadly) — it changes tracer choice, malignancy risk, and family screening.

Imaging Findings by Modality

• CT / MRI: anatomic localization; pheochromocytoma classically shows high T2 signal and does not follow the adenoma washout/chemical-shift pattern (a key incidentaloma discriminator).
• Ga-68-DOTATATE PET: most sensitive functional test, especially head-and-neck, metastatic, and SDHx disease.
• F-18-FDOPA PET: excellent for sporadic/adrenal pheo and many paragangliomas.
• I-123-MIBG SPECT: functional localization and the theranostic gate for I-131-MIBG therapy.
• FDG-PET: most useful in SDHB / dedifferentiated / metastatic disease.

Radiopharmaceutical Uptake Mechanisms

MIBG enters via the norepinephrine transporter (uptake-1) and is stored in catecholamine vesicles; many drugs (labetalol, tricyclics, sympathomimetics) block it. DOTATATE binds SSTR2. FDOPA uses the amino-acid transporter and aromatic-amino-acid decarboxylase. FDG reflects glucose metabolism, high in pseudohypoxia (SDHx) tumors.

Tracer Selection by Scenario

Typical PET / SPECT Tracers

Therapy Indications

• Surgery (adrenalectomy/resection) — with preoperative α-blockade first, then β-blockade (order is critical) and volume expansion to prevent intraoperative hypertensive crisis.
• I-131-MIBG (iobenguane) for MIBG-avid metastatic/inoperable disease (theranostic pair with I-123-MIBG).
• ¹⁷⁷Lu-DOTATATE (PRRT) for SSTR-avid metastatic disease.
• Systemic: chemotherapy (e.g. cyclophosphamide-vincristine-dacarbazine; temozolomide, especially SDHB), sunitinib; external-beam/ablation for local control.

Theranostics

Two image-and-treat pairs converge here: MIBG (I-123 image → I-131-MIBG treat) and DOTATATE (Ga-68 image → ¹⁷⁷Lu-DOTATATE treat). Tracer avidity selects the therapy — MIBG-avid disease for I-131-MIBG, SSTR-avid disease for PRRT — and SDHx/FDG-avid disease often escapes both, favoring chemotherapy.

Differential Diagnosis

• Adrenal incidentaloma / adenoma — separated from pheo by CT washout and chemical-shift MRI (adenoma washes out / loses signal; pheo does not).
• Adrenocortical carcinoma (large, heterogeneous, cortisol/androgen excess) and adrenal metastasis.
• Physiologic adrenal, brown-fat, and bowel uptake on functional imaging.

Reporting Checklist

• Localize adrenal vs extra-adrenal (sympathetic vs head-and-neck) disease and stage for metastasis.
• State the genotype-appropriate tracer used and functional avidity relevant to therapy (MIBG-avid → I-131-MIBG; SSTR-avid → PRRT).
• Note interfering medications (MIBG) and physiologic mimics.
• For incidentalomas, defer to CT/MRI washout/chemical-shift characterization.

Prognosis

Most PPGL are benign and cured by resection. SDHB mutation carries the highest malignant/metastatic risk and warrants lifelong surveillance. Metastatic disease is often slowly progressive; theranostic (MIBG/PRRT) and systemic options provide durable control in avid disease. Genotype drives both prognosis and family screening.

Board Pearls

PPGL are localized by complementary functional tracers, and the genotype shapes the choice: Ga-68-DOTATATE is now first-line for metastatic, head-and-neck, and SDHx disease; I-123-MIBG confirms candidacy for I-131-MIBG therapy (the theranostic gate); F-18-FDOPA excels for sporadic adrenal pheo; and FDG is most useful in SDHB/dedifferentiated disease.

Before surgery, block α first, then β (never β alone — unopposed α-stimulation can precipitate crisis) with volume expansion. Adrenal incidentaloma characterization stays primarily CT/MRI (washout, chemical shift); functional imaging is for confirmed or metastatic disease.

SDHB predicts malignancy and a pseudohypoxia phenotype that favors FDG/DOTATATE over MIBG — so a single tracer does not suffice, and genotype-driven, complementary imaging improves detection. Watch MIBG-blocking drugs (labetalol, tricyclics, sympathomimetics) and physiologic adrenal/brown-fat/bowel uptake.

Related Pages

• Tracers: I-123-MIBG, DOTATATE PET agents, FDG.
• Therapies: I-131-MIBG and ¹⁷⁷Lu-DOTATATE (PRRT).
• Related disease: Neuroendocrine tumors (SSTR biology), medullary thyroid carcinoma (MEN2 overlap).

Figure / Diagram Suggestions

• A genotype → cluster → tracer decision map (pseudohypoxia/kinase; DOTATATE/FDOPA/MIBG/FDG).
• The two theranostic pairs (MIBG→I-131-MIBG; DOTATATE→Lu-177-DOTATATE) side by side.
• Preoperative blockade sequence (α before β) safety graphic.

Common Pitfalls

• Physiologic uncinate-process (pancreatic-head) DOTATATE uptake is a classic mimic of a para-aortic paraganglioma — require a discrete CT correlate before calling it disease.
• Normal adrenal-medullary uptake on MIBG/FDOPA/DOTATATE is mild and roughly symmetric; only nodular, asymmetric, or intense uptake is meaningful — bilateral faint uptake alone is not bilateral pheochromocytoma.
• A negative I-123-MIBG scan does not exclude PPGL — both interfering drugs and intrinsically MIBG-poor SDHx/dedifferentiated tumors cause false negatives; escalate to DOTATATE or FDG rather than stopping.
• Urinary excretion of DOTATATE/FDOPA in the collecting system and ureters can obscure or mimic a para-aortic focus — correlate with SPECT/CT or CT.

Self-Check (Board-Style)