Characterization of Human Corticotrophin‐releasing Hormone and Pro‐opiomelanocortin‐related Peptides in a Thymic Carcinoid Tumour Responsible for Cushing's Syndrome

Abstract

Severe Cushing's syndrome developed in a man of 35 years. Plasma ACTH and lipotrophin hormone levels were supranormal, and dexamethasone failed to stop their production. An ACTH-producing thymic carcinoid tumour was found to be responsible for the Cushing's syndrome. The tumour tissue contained pro-opiomelanocortin (POMC)-mRNA and POMC-related peptides. In addition, human corticotrophin-releasing hormone (h-CRH) (0.25 ng/mg wet tissue) was identified in the tumour extract. Among a series of extracts from two normal and three tumoral (Nelson's syndrome) pituitary glands, six non-pituitary POMC-producing tumours and five normal thymuses examined, only the extract from the thymic tumour of our patient contained h-CRH. The molecule isolated had the same properties as synthetic h-CRH (dilution, Sephadex G 50 chromatography). Circulating h-CRH levels, however, were normal. The possible involvement of such ectopic CRH production in the aetiology of Cushing's syndrome remains uncertain.

Ectopic ACTH Syndrome: Discrepancy between Somatostatin Receptor Status in vivo and ex vivo, and between Immunostaining and Gene Transcription for POMC and CRH

“…The undetectable plasma CRH concentration is of limited value since it was sampled when the patient was in clinical remission. Normal circulating CRH levels in a patient with a CRH- and ACTH-producing thymic carcinoid has been published, and it was suggested that CRH acted in an autocrine or paracine manner [8]. It has been reported that ectopic tumors containing CRH and CRH mRNA respond with a significant ACTH increase following CRH stimulation [9], which is in contrast to our case.…”

Ectopic Adrenocorticotropic Hormone Syndrome

“…The plasma CRH was above the normal range in all patients in which it was measured, except in the case of the thymic carcinoid reported by Raux Demay et al (200), which had normal circulating hCRH levels. In this case, the tumor tissue was demonstrated to contain POMC mRNA and POMC-related peptides such as 1-39 ACTH in addition to hCRH (200).…”

“…In those tumors that may be slow growing or "occult" such as carcinoid tumors, a relatively low dose of 4 g/day of mitotane can be used with remission of the Cushing's syndrome after a few months of therapy, as reported by DeStephano et al (199). Raux Demay et al (200) reported a patient with thymic carcinoid treated with 12 g/day of mitotane for 3 months in preparation for open chest surgery.…”

“…Inability of immunocytochemistry to stain peptides in tumors that briskly secrete those peptides has been reported (220) and is more pronounced in highly malignant tumors, such as the SCLCs. Table 11 summarizes 12 cases of ectopic CRH-ACTH syndrome described in the literature (73,97,200,208,209,228,(234)(235)(236)(237)(238) and one from our series (58). Thus, negative staining for ACTH in a tumor is insufficient evidence to rule out ACTH biosynthesis.…”

Two Cases of Ectopic Adrenocorticotropic Hormone Syndrome with Olfactory Neuroblastoma and Literature Review

“…Interestingly, one report of an adrenal neuroblastoma producing increased levels of POMC did not show any increased ACTH level [22]. In addition, by Raux Demay et al, an ACTH-producing thymic carcinoid tumor was found to be responsible for the Cushing's syndrome [23]. In this case, human CRH, POMC-mRNA and POMC-related peptides were identified in the tumor extract.…”