Bilateral pheochromocytoma: case series and review of treatment strategies based on genetic mutations

Background: Recent genetic analyses have revealed that bilateral pheochromocytoma (PCC) is more frequently associated with hereditary syndromes, such as von Hippel-Lindau (VHL) disease and multiple endocrine neoplasia type 2 (MEN2), than previously recognized. Although bilateral adrenalectomy has traditionally been considered the standard treatment for bilateral PCC, it inevitably results in permanent adrenal insufficiency, requiring lifelong steroid replacement and increasing the risk of adrenal crisis. As an alternative strategy, adrenal-sparing surgery has been proposed to preserve adrenal function; however, concerns remain regarding the risk of tumor recurrence in the remnant adrenal tissue. Case Description: We report four cases of bilateral PCC treated with adrenal-sparing surgery at The Jikei University Hospitals. Adrenal-sparing surgery was successfully attempted in all patients, and all avoided long-term steroid dependence. Genetic testing confirmed VHL disease in one patient in the overall cohort. Based on family history and clinical features, VHL disease was suspected in one additional patient, and MEN2 was suspected in two patients. Conclusions: Based on our experience and a review of the literature, adrenal-sparing surgery allows preservation of adrenal function and can eliminate the need for postoperative steroid replacement in many patients with bilateral PCC. Although the risk of recurrence in the residual adrenal gland may be higher than that after total adrenalectomy, recurrence at other sites and overall mortality appear comparable between the two surgical approaches. Therefore, adrenal-sparing surgery represents a valuable surgical option in carefully selected patients. Furthermore, recent studies have identified pathogenic mutations in several genes associated with bilateral PCC, with incidence and prognosis varying according to genetic background. Gene mutations are more likely in younger patients, those with tumors ≥5 cm, paragangliomas (PGLs), norepinephrine-secreting tumors lacking epinephrine production, and individuals with known hereditary syndromes, who also exhibit a higher risk of recurrence. Accordingly, current guidelines recommend lifelong surveillance and individualized management based on genetic and clinical factors.