Morphology and etiology of pheochromocytoma

Abstract

Pheochromocytoma, a potentially lifethreateningtumor,washistologicallyfirst described byMax Schottelius in 1886 [1]. He used Müller’s chromate-containing solution thatmacroscopically transforms the surface of the tumor to dark-brown. To date, these tumors are classified as chromaffin. The term “pheochromocytoma” goes back to Ludwig Pick in 1912. Modern skills for clinical diagnosis and treatment have contributed to tremendous improvements in the outcome of patients. Still, the major step is to consider this tumor in patients with unexplained symptoms, such as paroxysms of tachycardia, headaches, and episodes of profuse sweating. While endocrinologists prefer the biochemical pathway, radiological imaging is equally important for diagnosis. Plasma normetanephrine and abdominal magnetic resonance imaging are the key diagnostic methods. Nuclear medicine imaging is essential in the detection of multiple and metastatic pheochromocytoma, today mainly performed with 68-Gallium-DOTATOC-PET-CT. Minimally invasive surgery is the current standard for treatment and the method of choice [2]. Histopathologically, the tumor typically shows a “zellballen” pattern with chief cells and sustentacular cells. Chief cells are stained by chromogranin and synaptophysin; sustentacular cells with S-100. Histological and cytological scoring systems (the so-called PASS and GAPP scores) have been suggested, but these are not generally accepted for prediction of malignant pheochromocytoma. Undoubtedly, only lymph node or distant metastases provide the proof, and the 2019 WHO Classification of Endocrine Tumours has replaced the term “malignant” with “metastatic” pheochromocytoma. Patients who are younger than 30 years, with multiple tumors, extra-adrenal tumors, and/or metastatic tumors must be evaluated as carriers of germline mutations of one of the genes RET, VHL, NF1, SDHA, SDHB, SDHC, SDHD, SDHAF2, MAX, or TMEM127 and must be considered thus to have manifestation of multiple endocrine neoplasia type 2, von Hippel–Lindau disease, neurofibromatosis type 1, paraganglioma syndromes type 1–5 or, other familial pheochromocytoma syndromes, respectively. Immunohistochemistry has been extended toward staining of the normal protein components, for example, by anti-SDHB. Patients with negative staining are likely to carry germline mutations in the respective susceptibility gene. Such patients should be advised to have genetic counseling followed by molecular genetic mutation screening. Detection of mutations opens avenues for preventive medicine with special management and in-time detection of chromaffintumorsandother tumorsoutside this system. This includes clinical screening for other pheochromocytomas that may be located in the skull base and neck region, the thorax, or the pelvis in patients with mutations of SDHA, SDHB, SDHC, and SDHD. Patients with RET mutations must be screened for medullary thyroid cancer, and such with VHL mutations for retinal and CNS hemangioblastomas, renal clear cell carcinoma, pancreatic neuroendocrine tumors, epididymal cystadenomas, and endolymphatic sac tumors of the inner ear. Once an index patient has been