Expression of prohormone convertase, PC2, in adrenocorticotropin-producing thymic carcinoid with elevated plasma corticotropin-releasing hormone.

Abstract

An autopsy case of ACTH-producing thymic carcinoid with Cushing's syndrome is reported. The patient was a 63-yr-old man with multiple bone metastases from an undetermined primary site. Hyperpigmentation was observed at the terminal stage. The plasma levels of ACTH, cortisol, chromogranin A, and urinary 17-hydroxy-corticosteroids were extremely high, and ectopic ACTH-producing neuroendocrine tumor was diagnosed. In addition, plasma CRH was high. Autopsy revealed that the patient had primary thymic carcinoid with extensive metastases. Remarkable hyperplasia of the adrenal cortexes and Crooke's hyaline degeneration of the pituitary gland were consistent with Cushing's syndrome by ectopic ACTH production. There were multiple CRH-producing cells without degenerative changes in the hypothalamus. The tumor cells were immunoreactive to ACTH, CRH, and the cleavage enzyme PC2. POMC messenger ribonucleic acid and PC2 messenger ribonucleic acid were detected in the tumor cells by an in situ hybridization method. Expression of PC2 was considered to induce hyperpigmentation by producing alpha MSH. Despite hypercortisolism and ectopic production of CRH by the tumor cells, hypothalamic CRH cells were not atrophic. This case is a good example to demonstrate the correlation between CRH and the hypothalamo-pituitary-adrenal axis as well as hyperpigmentation in Cushing's syndrome.

Nelson's Syndrome: A Narrative Review

“…The current diagnostic standards for NS center on skin hyperpigmentation, an increasing pituitary tumor post-BLA, and rising plasma ACTH levels. A remnant's presence is insufficient evidence of pituitary tumor growth [8,22]. Skin pigmentation intensity and ACTH levels are unrelated; however, some individuals may only experience it when their ACTH levels are exceedingly high, which raises sensitivity concerns [23].…”

“…Barber et al [6] proposed the following diagnostic criteria for the diagnosis of NS. A patient must meet at least one of the following two requirements in addition to having previously undergone complete BLA for CD to be diagnosed with NS: (1) an increasing mass lesion in the pituitary after BLA surgery, as shown on an MRI or CT scan, as opposed to an MRI of the pituitary before BLA surgery and ( 2) an elevated level of ACTH to >500 ng/L from a single plasma sample taken at 08:00 h before steroid administration and post-BLA surgery as well as progressive elevations of ACTH levels from plasma samples taken on at least three consecutive occasions at different time-points post-BLA surgery or an increase of ACTH by 30% of the initial post-BLA sample [8,22,24].…”

“…Due to its link to tumor growth, high ACTH levels in the first year after BLA are the most reliable prognostic predictor. An ACTH cut-off value of more than 100 pg/mL increase in the first year following BLA has been proposed [22] as a predictor of corticotroph tumor progression.…”

“…The presence of pituitary adenoma before BLA has also been considered a risk factor. However, this is yet to be proven [10,22]. It has been proposed that prophylactic pituitary irradiation administered concurrently with BLA may play a preventive effect in lowering the likelihood of NS development or even postponing its onset [2,5,25].…”