Final Diagnosis
Pheochromocytoma
DISCUSSION
Pathophysiology
Pheochromocytomas have the highest degree of hereditary susceptibility of any human tumor, and up to 40% are hereditary. SDHx mutations are presented in 80% of familial pheochromocytomas, 30% of pediatric tumors and more than 40% of metastatic tumors. Germline mutations in the VHL/HIF family of genes are implicated in inheritable cases of pheochromocytomas.
Epidemiology
Most pheochromocytomas present in the 4th or 5th decades of life, with equal distribution. Presentation in children suggests hereditary susceptibility.
Clinical Presentation
Most patients with pheochromocytoma present with symptoms of catecholamine excess. Biochemical tests should be performed to aid in the diagnosis. Urinary metanephrine and normetanephrine are elevated in pheochromocytoma cases. In adults, solitary tumors represent sporadic disease. In children, tumors present as part of hereditary disease.
Microscopic Description
Characteristic histologic findings in pheochromocytoma include an alveolar pattern with a rich microvasculature and consists of cells that are large, with inconspicuous cell borders and round to oval nuclei with prominent pleomorphism. No necrosis or mitosis is usually seen. Neoplastic cells can contain small dark brown to black granules in the cytoplasm which are melanin-like. Several histologic variants are seen, including spindle cell, oncocytic, angiomatous and ganglioneuromatous.
On immunohistochemistry, neuroendocrine markers such as Synaptophysin and Chromogranin are positive. S100 highlights sustentacular cells. Immunostains for HMB-45 and cytokeratin are negative.
References
1. Santos P et al: Hereditary pheochromocytoma. Int J Surg Pathol. 22(5):393-400, 2014
2. DeLellis RA et al: Pathology & genetics: tumours of endocrine organs. World Health Organization Classification of Tumours. Lyon: IARC Press, 2004
3. Pacak K et al: Pheochromocytoma: recommendations for clinical practice from the First International Symposium. October 2005. Nat Clin Pract Endocrinol Metab. 3(2):92-102, 2007
4. Guido Bellezza, Michele Giansanti, Antonio Cavaliere, Angelo Sidoni; Pigmented “Black” Pheochromocytoma of the Adrenal Gland: A Case Report and Review of the Literature. Arch Pathol Lab Med 1 October 2004; 128 (10)
5. Peng S, Zhang J, Tan X, Huang Y, Xu J, Silk N, Zhang D, Liu Q, Jiang J. The VHL/HIF Axis in the Development and Treatment of Pheochromocytoma/Paraganglioma. Front Endocrinol (Lausanne). 2020 Nov 24;11:586857. doi: 10.3389/fendo.2020.586857. PMID: 33329393; PMCID: PMC7732471.