Challenging Case of Ectopic ACTH Secretion from Prostate Adenocarcinoma

Abstract

Cushing’s syndrome (CS) secondary to ectopic adrenocorticotrophic hormone (ACTH)-producing prostate cancer is rare with less than 50 cases reported. The diagnosis can be challenging due to atypical and variable clinical presentations of this uncommon source of ectopic ACTH secretion. We report a case of Cushing’s syndrome secondary to prostate adenocarcinoma who presented with symptoms of severe hypercortisolism with recurrent hypokalaemia, limb oedema, limb weakness, and sepsis. He presented with severe hypokalaemia and metabolic alkalosis (potassium 2.5 mmol/L and bicarbonate 36 mmol/L), with elevated 8 am cortisol 1229 nmol/L. ACTH-dependent Cushing’s syndrome was diagnosed with inappropriately normal ACTH 57.4 ng/L, significantly elevated 24-hour urine free cortisol and unsuppressed cortisol after 1 mg low-dose, 2-day low-dose, and 8 mg high-dose dexamethasone suppression tests. 68Ga-DOTANOC PET/CT showed an increase in DOTANOC avidity in the prostate gland, and his prostate biopsy specimen was stained positive for ACTH and markers for neuroendocrine differentiation. He was started on ketoconazole, which was switched to IV octreotide in view of liver dysfunction from hepatic metastases. He eventually succumbed to the disease after 3 months of his diagnosis. It is imperative to recognize prostate carcinoma as a source of ectopic ACTH secretion as it is associated with poor clinical outcomes, and the diagnosis can be missed due to atypical clinical presentations.

Paraneoplastic Syndromes in Neuroendocrine Prostate Cancer: A Systematic Review

“…Prostate-specific antigen (PSA) values are usually normal in men with small cell cancer [ 31 ]. This was also the case in our review (as shown in Table 2 ), except for patients with a previous history of adenocarcinoma, who had elevated PSA levels [ 10 , 16 , 18 , 20 , 21 ]. The reviewed cases emphasize the concept that negative immunohistochemical staining for PSA or ACTH should not exclude an ectopic ACTH-secreting prostate neuroendocrine tumor as this subtype of PCa usually loses or partially expresses PSA, as it is reported that up to 30% of ACTH-secreting tumors stain negative for ACTH [ 10 , 17 , 19 , 20 , 21 , 27 , 33 , 34 ].…”

“…There were several presentations, but hypokalemia, resistant hypertension, and fluid overload were documented frequently. Furthermore, 7 out of 11 patients with paraneoplastic CS had a previous history of prostate adenocarcinoma, for which they were treated with ADT before developing neuroendocrine differentiation and CS [ 10 , 16 , 17 , 18 , 19 , 20 , 21 ]. Small cell carcinoma was the predominant histological subtype, with one case having a large cell NEPC [ 14 , 15 , 19 , 20 , 21 , 22 , 23 ].…”

“…Small cell carcinoma was the predominant histological subtype, with one case having a large cell NEPC [ 14 , 15 , 19 , 20 , 21 , 22 , 23 ]. In addition, Prostate Specific Antigen (PSA) levels were high in patients who reported a previous history of prostate adenocarcinoma [ 10 , 16 , 18 , 20 , 21 ] but were normal in patients who developed prostate neuroendocrine cancer de novo [ 14 , 15 , 23 ]. The management of paraneoplastic CS was mostly based on Ketoconazole, Metyrapone, Spironolactone, and Potassium supplementation, along with treating hyperglycemia and hypertension.…”

“…As demonstrated in Table 2 , we found that CS is the most frequently reported PNS associated with NEPC. Patients presented in a variety of ways, including fluid overload, hypokalemia, resistant hypertension, metabolic alkalosis, easy bruising, fatigue, and generalized weakness [ 10 , 14 , 15 , 16 , 17 , 18 , 20 , 21 , 22 , 23 ]. On physical examination, many of the reviewed cases [ 14 , 15 , 16 , 17 , 18 , 20 , 21 ] had proximal weakness and edema, although the classical features of CS are usually absent in malignancy [ 30 ].…”