Pheochromocytomas and paragangliomas are rare neuroendocrine tumors that originate from chromaffin cells in the adrenal medulla or extra-adrenal sympathetic and parasympathetic tissues, respectively. They can be part of inherited syndromes characterized by specific genetic mutations. Frequently asked topic in FRCPath -Part 1 Histopathology exam.
Syndromes Associated with Pheochromocytomas and Paragangliomas :
Syndrome Gene Mutation (Function) Clinical Phenotype Pheochromocytoma Characteristics Lifetime Pheochromocytoma Risk
MEN 2A RET (proto-oncogene) Medullary thyroid cancer, primary hyperparathyroidism Benign, bilateral or multicentric, intra-adrenal 50%
MEN 2B RET (proto-oncogene) Medullary thyroid cancer, marfanoid habitus, mucosal neuromas Benign, bilateral or multicentric, intra-adrenal 50%
Neurofibromatosis Type 1 NF1 (negative regulator of Ras oncogene pathway) Neurofibromas, café-au-lait spots, optic gliomas 15% malignant; intra-adrenal 1-5%
Von Hippel-Lindau (VHL) VHL (tumor suppressor) Retinal angiomas, CNS hemangioblastomas, renal cancer, pancreatic cysts Benign, bilateral, younger age at diagnosis 10-20%
Familial Paraganglioma Syndrome SDHA, SDHB, SDHC, SDHD (mitochondrial enzymes) GIST; SDHB may be associated with renal cell cancer SDHB: 40-80% malignant; solitary 20-30%
Hereditary Pheochromocytoma (MAX) MAX (transcription regulator) Possibly other tumors Bilateral or multicentric; intra-adrenal; thoraco-abdominal PG Unknown
Hereditary Pheochromocytoma (TMEM127) TMEM127 (tumor suppressor) Possibly other tumors Benign; intra-adrenal Unknown
Hereditary Pheochromocytoma (HIF-2α) HIF-2α (transcription regulator) Polycythemia, thoraco-abdominal paragangliomas. Multicentric, extra-adrenal Unknown
PASS (Pheochromocytoma of the Adrenal gland Scaled Score) Pheochromocytoma of the adrenal gland scaled score
Histologic feature Score Periadrenal adipose invasion +2 > 3 mitoses/10 high power fields +2 Atypical mitoses +2 Necrosis +2 Cellular spindling +2 Marked nuclear pleomorphism +1 Cellular monotony +2 Large nests or diffuse growth +2 High cellularity +2 Capsular invasion +1 Vascular invasion +1 Hyperchromasia +1
Interpretation :
PASS < 4 : Low risk of malignancy.PASS ≥ 4 : Suggestive of potential malignancy, requiring closer clinical follow-up.
GAPP (Grading of Adrenal Pheochromocytoma and Paraganglioma) Grading system for adrenal pheochromocytoma and paraganglioma (GAPP)
Feature Score (well differentiated, 0 – 2; moderately differentiated, Histological pattern Zellballen, 0 Large and irregular cell nests, +1 Pseudorosette, +1 Cellularity (number of tumor cells in 10 mm x Low, < 150, 0 Moderate, 150 – 250, +1 High, > 250, +2 Comedonecrosis +2 Capsular / vascular invasion +1 Ki67 % < 1%, 0 1 – 3%, +1 > 3%, +2 Catecholamine type Nonfunctional, 0 Epinephrine or epinephrine + norepinephrine, 0 Norepinephrine or norepinephrine + dopamine , +1
Interpretation :
Score 0-2 : Well-differentiated, low risk of malignancy.Score 3-6 : Moderately differentiated, intermediate risk.Score 7-10 : Poorly differentiated, high risk of malignancy.
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References: WHO Classification of Tumors of Endocrine Organs, 5th Edition . Lyon: IARC Press, 2022.
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