A pitfall of bilateral inferior petrosal sinus sampling in cyclic Cushing’s syndrome

Abstract

BackgroundClinical care of patients with cyclic Cushing’s syndrome (CS) is challenging. Classical pitfalls include incorrect subtyping, unnecessary surgical procedures and delayed definite treatment.Case presentationA 43-year-old female suffered from a rapidly cycling ectopic CS. She experienced six cycles of severe hypercortisolism within a 2 year period (maximum plasma cortisol 5316 nmol/L, normal range 124.2–662.4 nmol/L; maximum urinary free cortisol 79,469 nmol/24 h, normal range < 414 nmol/24 h) lasting 2–9 weeks. The episodes were associated with pronounced hypokalemia (lowest K+ value recorded 2.4 mmol/l) and progressive signs and symptoms of CS. A bilateral inferior petrosal sinus sampling (BIPSS) performed during a trough phase was false positive for pituitary ACTH overproduction resulting in unnecessary transsphenoidal surgery while a second BIPSS performed during an active phase was indicative for ectopic CS. The 18F-DOPA PET/CT showed a pancreatic lesion, which was subsequently partially removed. Surprisingly, the histopathology was conclusive for ACTH-positive lymph node metastasis located in the retro-duodenal tissue of an occult neuroendocrine tumor WHO grade II. The primary tumor has not been identified so far and, because of the persistent hypercortisolism, the patient underwent bilateral adrenalectomy. Two years later, ACTH levels started to increase progressively. Percutaneous biopsy of a newly identified suspected lesion in the fifth thoracic vertebra revealed a metastasis with positive staining for ACTH, synaptophysin and chromogranin A. Therapy with carboplatin and etoposide was started and, since then, the patient underwent 12 cycles of chemotherapy.ConclusionsWe report the challenging case of a rapidly cycling CS secondary to ACTH-secreting neuroendocrine intestinal tumor of unknown primary. We highlight the importance of performing diagnostic tests only during the phases of active cortisol secretion and as soon as first symptoms appear to avoid pitfalls.

Revalidation of inferior petrosal sinus sampling: the latest results from a single-center experience

“…In contrast, false positive results are problematic precisely because patients may end up undergoing unnecessary surgery. One of the possible causes of false-positive and false-negative results is cyclic Cushing's syndrome (CS) [17,18]. Meinardi et al assessed the causes underlying cyclic CS and reported that 54% of the cases were caused by ACTH-producing pituitary adenomas, 26% by ectopic ACTH production, and 11% due to ACTH-independent causes [19].…”

“…For cyclic ACTH-producing pituitary adenomas, IPSS performed during a trough phase can theoretically lead to false-negative results given the lack of a gradient at baseline and after CRH administration [17]. In contrast, IPSS performed during a trough phase of cyclic ectopic ACTH-producing tumors may lead to false positive results [18]. An ectopic tumor that cyclically secretes ACTH could partially suppress the secretory activity of normal corticotrophic cells, resulting in the persistence of the IPS/P ratio, which could consequently raise the IPS/P ratio above the threshold upon CRH stimulation [18].…”

Cyclic Cushing’s Syndrome – A Diagnostic Challenge

“…If intermittent hypercortisolemia is suspected, the procedure should be performed during active phase of the disease. Otherwise, the results might come back negative with the patient unnecessarily exposed to an invasive procedure ( 1 , 19 ).…”

“…Cyclic Cushing's syndrome (also known as intermittent or periodic) is a disease characterized by periods of transient hypercortisolemia shifting into periods of normo-and/or hypocortisolemia. Just as classic Cushing's syndrome, cyclic hypercortisolemia may arise from hormonal activity of corticotropinoma (approximately 80% of all cases), ectopic adrenocorticotropic hormone (ACTH; corticotropin) release, or ACTH-independent causes (1)(2)(3)(4)(5)(6)(7)(8)(9). Retrospective analysis of 201 patients with Cushing's syndrome showed that 15% of them met the diagnostic criteria of intermittent hypercortisolemia and up to 70% showed evidence of cyclicity before the diagnosis (10).…”

Persistent Cushing’s Disease after Transsphenoidal Surgery: Challenges and Solutions

“…Misdiagnosis may also be a pitfall since CD diagnosis is very challenging. Cortisol levels alternating between periods of hypercortisolism and spontaneous remission as seen in cyclic Cushing's syndrome impede the proper diagnosis [32][33][34]. Several conditions, such as depression, chronic alcohol consume, polycystic ovary syndrome (PCOS) and obesity may muddle the diagnosis leading to activation of the hypothalamus-pituitary-adrenal axis [35].…”