Pheochromocytoma (PHC)

Overview

Pheochromocytoma (PHC) is a neuroendocrine tumor arising from chromaffin cells of the adrenal medulla that secretes catecholamines (epinephrine, norepinephrine). It is classified within the PCPG (pheochromocytoma and paraganglioma) family. At least 40% of PCCs are hereditary, driven by germline mutations in SDHB, SDHD, SDHC, SDHAF2, VHL, RET, NF1, MAX, TMEM127, EGLN1, or FH. Approximately 10–15% are malignant (defined by metastasis). The TCGA PCPG analysis defined four molecular subtypes with distinct molecular drivers and clinical behavior.

Cohorts in the corpus

Recurrent alterations

  • TCGA PCPG cohort (n=173 total PCC/PGL): 95% of tumors had a driver identified; 46/173 (27%) had pathogenic germline mutations in 8 susceptibility genes — highest rates: SDHB (9%), RET (6%), VHL (4%), NF1 (3%); somatic drivers: HRAS Q61 hotspot (kinase signaling subtype), EPAS1 hotspots A530/P531/Y532 (pseudohypoxia subtype), RET M918 somatic (vs germline C634), CSDE1 truncating/splice-site mutations (novel driver, Wnt-altered subtype); recurrent fusions: UBTF-MAML3 and TCF4-MAML3 (10 tumors, all Wnt-altered subtype), RUNDC1-BRAF (5.2-fold BRAF overexpression) PMID:28162975.
  • Mean somatic mutation rate 0.67/Mb — among the lowest of TCGA tumor types PMID:28162975.
  • MAML3 fusions, SDHB germline mutations, SETD2/ATRX somatic mutations, Wnt-altered and pseudohypoxia subtypes, and hypermethylated DNA-methylation subtype all independently associated with poor aggressive-disease-free survival PMID:28162975.

Subtypes

  • Kinase signaling subtype: predominantly PCC; NF1, RET, TMEM127, HRAS mutations; highest epinephrine production; BRAF/NGFR fusions; best prognosis.
  • Pseudohypoxia subtype: SDHB/SDHD/VHL/EPAS1 mutations; genome-doubled; hypermethylated; miR-210 overexpression; highest metastatic risk.
  • Wnt-altered subtype: MAML3 fusions + CSDE1 mutations; sporadic adrenal PCCs; highest CHGA; poor prognosis; no germline susceptibility-gene mutations.
  • Cortical admixture subtype: adrenal cortex marker overexpression; MAX germline mutations; elevated leukocyte infiltration.

Therapeutic landscape

  • Surgical resection is curative for localized disease.
  • Malignant PHC: sunitinib (VHL/kinase-pathway), temozolomide + DTIC (SDHB-mutant, high MGMT methylation), PRRT with Lu-DOTATATE (somatostatin-receptor expressing).
  • MAML3 fusion/Wnt-altered: Wnt-pathway antagonists (beta-catenin inhibitors, STAT3 inhibitors) proposed PMID:28162975.
  • SDH-mutant: glutaminase inhibitors under investigation PMID:28162975.

Sources

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

This page was processed by crosslinker on 2026-05-14.