Paraganglioma (PGNG)

Overview

Paraganglioma (PGL) is a neuroendocrine tumor arising from extra-adrenal paraganglia of the autonomic nervous system — either sympathetic (abdominal/thoracic, typically catecholamine-secreting) or parasympathetic (head and neck, typically non-secreting). Together with pheochromocytoma (PHC), they form the PCPG family. PGLs share the same germline susceptibility gene spectrum as PHC (SDH subunits, VHL, RET, NF1, MAX, TMEM127, EGLN1). SDHB-germline PGLs carry the highest risk of malignant behavior. The TCGA PCPG study, which excluded head and neck PGLs, provides the most comprehensive molecular characterization to date.

Cohorts in the corpus

Recurrent alterations

  • TCGA PCPG cohort (n=173 total; mixed PCC/PGL, 57% female, 43% male, mean age 47): 95% of tumors had a driver identified; SDHB germline mutations most common single driver (9%); EPAS1 somatic hotspot mutations specific to pseudohypoxia PGLs; MAML3 fusions and CSDE1 mutations define the Wnt-altered subtype (predominantly adrenal PCCs, but methodology applies to PGLs); ATRX somatic mutations co-occurring with SDHB germline in 3 tumors linked to alternative lengthening of telomeres PMID:28162975.
  • 11/173 (6%) had distant metastases; 16/173 (9%) had aggressive disease (distant metastases, positive regional nodes, or local recurrence) at study enrollment PMID:28162975.

Subtypes

  • Kinase signaling: predominantly PCCs; NF1/RET/HRAS-driven.
  • Pseudohypoxia: SDH-mutant, VHL-mutant, EPAS1-mutant; mixed PCC 57%/PGL 43%; highest metastatic risk.
  • Wnt-altered: predominantly adrenal PCCs in this cohort; MAML3 fusions.
  • Cortical admixture: MAX germline; adrenal cortex marker expression.

Therapeutic landscape

  • Surgery for localized disease.
  • Malignant/metastatic PGL: Lu-DOTATATE PRRT for somatostatin-receptor-positive tumors; temozolomide + DTIC for SDHB-mutant disease; sunitinib evaluated.
  • SDH-mutant PGL: glutaminase inhibitors under investigation PMID:28162975.

Sources

  • PMID:28162975 — TCGA PCPG Analysis Working Group, multi-platform profiling of 173 PCC/PGL tumors.

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