Adrenal gland & paraganglia

• Approximately 30% are hereditary and include the following autosomal dominant disorders:
  • Von Hippel-Lindau syndrome
  • Multiple endocrine neoplasia type 2 (MEN2)
  • Neurofibromatosis type 1 (NF1)
  • Familial paraganglioma (Cancer Genet 2012;205:1, J Clin Endocrinol Metab 2017;102:3296, Am J Surg Pathol 2021;45:1155)
• Suspect hereditary etiology when:
  • Family history or symptoms of a syndrome
  • Bilateral tumors
  • Presentation of tumor < 45 years of age
  • Paraganglioma concurrent with pheochromocytoma

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• No specific histologic or molecular markers to differentiate benign from malignant
  • See Table 2 for clinical and pathologic features associated with malignancy
• There is a TNM staging system for which pT is based on tumor size (≤ 5 cm or > 5 cm) and depth of invasion
• Worse prognosis associated with (Am J Surg Pathol 2021;45:1155)
  • Hispanic ethnicity
  • Larger (metastatic mean diameter ~7 - 9 cm) tumors
  • Heavier (metastatic mean 280 g) tumors
  • Metastasis
• Better prognosis associated with (Am J Surg Pathol 2021;45:1155)
  • Family history
  • Younger age
  • Lack of symptoms / incidental finding
  • Bilaterality
• Presence of metastases defines malignancy: most commonly to lymph nodes, bone, liver and lung (Endocr Relat Cancer 2007;14:569)
• ~10% of pheochromocytomas are metastatic (Endocr Relat Cancer 2007;14:569, J Surg Oncol 2015;112:815)
• 5 year and 10 year survival ~65% and 35%, respectively (J Surg Oncol 2015;112:815)
• 6 - 9% of excised tumors have local recurrence (Surgery 2014;156:1523)
  • Median time to recurrence ~35 months (Surgery 2014;156:1523)
  • 25% of recurrences do not demonstrate metanephrine elevation so surveillance should include annual CT imaging (Surgery 2014;156:1523)

Table 2. Clinical and pathologic features of pheochromocytoma associated with malignancy

Clinical features	Younger age
	Secretion of norepinephrine
Gross features	Tumor size
	Tumor weight
Histologic features	Periadrenal adipose tissue invasion
	Mitotic rate
	Atypical mitoses
	Necrosis
	Cellular spindling
	Marked nuclear pleomorphism
	Cellular monotony
	Large nests or diffuse growth
	High cellularity
	Capsular invasion
	Vascular invasion
	Hyperchromasia
Ancillary studies	Higher Ki67
	SDHB, VHL, RET mutations

• 3 year old boy with malignant hypertension, seizures and electrolyte derangements (Case #489)
• 22 year old woman with type IIb von Hippel-Lindau (Med Princ Pract 2016;25:196)
• 30 year old man with diabetic ketoacidosis (BMJ Case Rep 2016;2016:bcr2016216961)
• 35 year old man with NF1 and asymptomatic pheochromocytoma (Korean J Intern Med 2018;33:214)
• 44 year old man with suspected myocardial infarction (BMJ Case Rep 2015;2015:bcr2015211472)
• 45 year old man with severe hyperglycemia after glucocorticoid administration (J Med Case Rep 2019;13:3)
• 64 year old man with intermittent abdominal pain (Am J Case Rep 2017;18:826)
• 69 year old man with classic symptoms (J Med Case Rep 2016;10:279)

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Contributed by Debra L. Zynger, M.D. (Case #319)

Contributed by Debra L. Zynger, M.D.

• Nested (zellballen), trabecular or solid arrangement
  • Nests outlined with sustentacular cells best visualized with S100 immunostain
• Cells: large, polygonal, uniform or extensively vacuolated
• Cytoplasm: abundant fine, granular red-purple cytoplasm
  • Pigmented granules containing hemosiderin, melanin, neuromelanin and lipofuscin may be seen
• Nuclei: may be uniform or exhibit extensive variation in size, round to oval nuclei, nucleoli prominent
• Pheochromocytoma of the adrenal gland scaled score (PASS) and grading system for adrenal pheochromocytoma and paraganglioma (GAPP) can be used to assess for malignant potential (see Table 3 and Table 4)
• Composite pheochromocytoma: pheochromocytoma with ganglioneuroma, ganglioneuroblastoma, neuroblastoma or peripheral nerve sheath tumors

Table 3. Pheochromocytoma of the adrenal gland scaled score (Am J Surg Pathol 2002;26:551)

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

Table 4. Grading system for adrenal pheochromocytoma and paraganglioma (GAPP) (Endocr Relat Cancer 2014;21:405)

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

Contributed by Debra L. Zynger, M.D. (Case #319), Brian Werstein, M.D. and Nicole K. Andeen, M.D. (Case #489)

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Contributed by Debra L. Zynger, M.D.

Contributed by Debra L. Zynger, M.D. and Edward Calomeni, B.S.


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• Genetic testing is recommended for all patients with pheochromocytoma
• Germline mutations include:
  • Von Hippel-Lindau syndrome: autosomal dominant truncation, deletion or missense mutation of VHL tumor suppressor gene on 3p25-26
    • Pheochromocytoma in 10 - 20%
    • Also hemangioblastomas of the central nervous system, renal cysts, clear cell renal cell carcinoma, pancreatic cysts and pancreatic neuroendocrine tumors, endolymphatic sac tumors and epididymal cystadenomas (Cancer Genet 2012;205:1)
  • Multiple endocrine neoplasia type 2 (MEN 2): autosomal dominant activating mutations in RET proto oncogene on 10q11.2
    • Pheochromocytoma in 50%
    • Also medullary thyroid carcinoma (Endocr Relat Cancer 2018;25:T15)
    • MEN 2a: may also present with hyperparathyroidism
    • MEN 2b: may also present with Marfanoid habitus and multiple mucosal ganglioneuromas
  • Neurofibromatosis type 1 (NF1): autosomal dominant inactivating mutations in NF1 tumor suppressor gene on 17q11.2 (J Clin Oncol 2005;23:8812)
    • Pheochromocytoma in 5 - 7%
    • Also café au lait spots, iris hamartomas, axillary or inguinal freckling, osseous dysplasia and optic pathway glioma (Cancer Genet 2012;205:1)
  • Familial paraganglioma: inactivating mutations in succinate dehydrogenase tumor suppressor gene
    • Associated with pheochromocytoma in 3 - 5%
    • Also paraganglioma, gastrointestinal stromal tumors, breast carcinoma and papillary thyroid carcinoma (Cancer Genet 2012;205:1)
    • SDHB and SDHD mutations most closely associated with pheochromocytoma (J Clin Oncol 2005;23:8812)
    • SDHB mutation may increase risk of malignancy (Cancers (Basel) 2019;11. pii: E1121)
    • Identifiable with immunohistochemistry staining: SDHB staining negative or weak in SDHB and SDHD mutations, respectively (Hum Pathol 2010;41:805)
  • Others: mutations in TMEM127 and MYC associated factor X (MAX) (familial), HRAS (somatic) (Cancer Genet 2012;205:1, Genes Chromosomes Cancer 2016;55:452)

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A 38 year old woman presents to clinic complaining of intermittent episodes of headaches and sweating. Her family history is significant for VHL gene mutation in her father. On exam, she has mild hypertension and elevated plasma metanephrines. A noncontrast CT of the abdomen reveals an attenuating 8 cm tumor in the adrenal medulla. An adrenalectomy was done and is shown in the photo. Which immunostains should be expressed?


1. AE1 / AE3, CK7, TTF1
2. AE1 / AE3, CK7, ER
3. MelanA, inhibin A, calretinin
4. PAX8, PAX2, CAIX
5. Synaptophysin, chromogranin, S100

E. Synaptophysin, chromogranin, S100. The clinical presentation and image are diagnostic of a pheochromocytoma. Synaptophysin, chromogranin and S100 are positive in pheochromocytoma. AE1 / AE3, CK7 and TTF1 are consistent with metastatic lung adenocarcinoma. AE1 / AE3, CK7 and ER are consistent with metastatic breast carcinoma. MelanA, inhibin A are calretinin are seen in adrenal cortical adenoma / carcinoma. PAX8, PAX2 and CAIX are associated with renal cell carcinoma, clear cell type.

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Reference: Pheochromocytoma

A 65 year old man presents with acute worsening of previously well controlled hypertension. Further investigation reveals elevated plasma metanephrines and a right sided adrenal mass. Adrenalectomy reveals a 3 cm, 120 g pheochromocytoma with large, uniform, polygonal cells and 4 mitotic figures per 10 high power fields (HPF). It is positive for chromogranin and synaptophysin. Which of the following features is associated with a more aggressive course?

1. > 3 mitoses per HPF
2. Age of diagnosis ≥ 45 years
3. Positive for synaptophysin
4. Tumor size < 5 cm
5. Tumor weight < 130 g

A. > 3 mitoses per HPF. > 3 mitoses per HPF increases risk for malignant pheochromocytoma. It is part of the pheochromocytoma of the adrenal gland scaled score (PASS). A score of ≥ 4 is concerning for malignancy, and scores are based on the presence of the following features: periadrenal adipose invasion (+2), > 3 mitosis per 10 high powered 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). Age of diagnosis < 45 years is associated with more aggressive disease, rather than older age. Staining with synaptophysin is a characteristic feature of pheochromocytoma and does not predict a more aggressive disease course. Larger and heavier tumors are associated with more aggressive disease, rather than smaller and lighter tumors.

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Reference: Pheochromocytoma

The adrenal tumor shown above was found to express chromogranin and GATA3 and was negative for AE1 / AE3. Which is the correct diagnosis?

1. Adrenal cortical adenoma
2. Adrenal cortical carcinoma
3. Lung adenocarcinoma
4. Pheochromocytoma
5. Urothelial carcinoma

D. Pheochromocytoma

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Reference: Pheochromocytoma