Pheochromocytoma and Paraganglioma Syndromes

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 (total ≥ 4 is concerning for malignancy)
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,   3 - 6; poorly differentiated, 7 - 10)
Histological pattern	Zellballen, 0
	Large and irregular cell nests, +1
	Pseudorosette, +1
Cellularity (number of tumor cells in 10 mm x   10 mm square at high power magnification)	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.

Try to answer these MCQs

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References: WHO Classification of Tumors of Endocrine Organs, 5th Edition. Lyon: IARC Press, 2022.

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