Poster Presentation ESA-SRB-APEG-NZSE 2022

Ectopic ACTH and CRH secretion as a rare cause of ACTH dependent Cushing’s (#332)

Annabel Jones 1 , Luisa Rosi 1 , Anthony Russell 1 2 , Duncan Topliss 1 3 , Catriona McLean 4 , Leon Bach 1 3
  1. Department of Endocrinology and Diabetes, Alfred, Melbourne, Victoria, Australia
  2. School of Public Health and Preventative Medicine, Monash University, Melbourne, VIC, Australia
  3. Department of Medicine (Alfred), Monash University, Melbourne, Victoria , Australia
  4. Department of Anatomical Pathology, Alfred Health, Melbourne , Victoria, Australia

A 29-year-old male is referred with persistent biochemical and clinical ACTH-dependent hypercortisolaemia after transsphenoidal resection of a presumed right middle fossa pituitary tumour with no adenoma identified on histology. He describes a one-year history of progressive Cushingoid symptoms.

Further investigation is undertaken to localise the ACTH source. IPSS is consistent with a pituitary source (Table 1). However, Dotatate-PET identifies four pancreatic NETs without concomitant hormonal secretion (Table 2). He proceeds to hypophysectomy given the impression of Cushing’s disease. Unfortunately, post-operative cortisol and ACTH remained elevated: morning cortisol 487 nmol/L, ACTH 37-45 ng/L, and 24 hr urinary cortisol 1045 nmol/day.

Subsequently, CRH serum measurement is obtained and is significantly elevated at 12.4 pg/mL (<2 pg/mL). This, in combination with evidence of persistent ACTH and cortisol excess after total hypophysectomy, was thought to be in keeping with ectopic dual secretion of CRH and ACTH from pancreatic neuroendocrine tumours. Surgical opinion is that the risk  of pancreatic biopsy is too high to pursue tissue diagnosis. Medical management is trialled but is unsuccessful, and he proceeds to bilateral adrenalectomy with biochemical and clinical remission post operatively (cortisol 29 nmol/L) (Image 1).

Cases of dual secreting CRH and ACTH neuroendocrine tumours (NETs) are exceedingly rare with only 5 adult cases in the literature (1-5) and 2 associated with primary localised pancreatic lesions (3,5). Differentiation of central and ectopic cortisol secretion can be challenging given that pituitary production of ACTH is maintained and even stimulated by CRH on petrosal sinus sampling (2). Additionally, the CRH assay is not widely available in Australia.

Ectopic dual secretion of CRH and ACTH is a rare cause of Cushing’s syndrome which should be considered in cases where clinical, hormonal and imaging findings and treatment response are not consistent with a more common cause of hypercortisolism.

 

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  2. Young J, Deneux C, Grino M, Oliver C, Chanson P, Schaison G. Pitfall of petrosal sinus sampling in a Cushing's syndrome secondary to ectopic adrenocorticotropin-corticotropin releasing hormone (ACTH-CRH) secretion. J Clin Endocrinol Metab. 1998 Feb;83(2):305-8. doi: 10.1210/jcem.83.2.4549. PMID: 9467532.
  3. Fountas A, Giotaki Z, Ligkros N, Tsakiridou ED, Tigas S, Saeger W, Tsatsoulis A. Cushing's Syndrome Due to CRH and ACTH Co-secreting Pancreatic Tumor--Presentation of a New Case Focusing on Diagnostic Pitfalls. Endocr Pathol. 2015 Sep;26(3):239-42. doi: 10.1007/s12022-015-9384-5. PMID: 26202047
  4. Park SY, Rhee Y, Youn JC, Park YN, Lee S, Kim DM, Song SY, Lim SK. Ectopic Cushing's syndrome due to concurrent corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) secreted by malignant gastrinoma. Exp Clin Endocrinol Diabetes. 2007 Jan;115(1):13-6. doi: 10.1055/s-2007-948212. PMID: 17286228.
  5. Sauer N, zur Wiesch CS, Flitsch J, Saeger W, Klutmann S, Zustin J, Luebke A, Aberle J. Cushing's syndrome due to a corticotropin-releasing hormone- and adrenocorticotrophic hormone-producing neuroendocrine pancreatic tumor. Endocr Pract. 2014 Apr;20(4):e53-7. doi: 10.4158/EP13001.CR. PMID: 24325992.