Cushing’s syndrome due to ectopic ACTH production by (neuroendocrine) prostate carcinoma

Alwani, R A; Neggers, Sebastian J C M M; Klift, Marjolein van der; Baggen, M.G.A.; Leenders, Geert J.L.H. van; Aken, Maarten O. van; Lely, Aart-Jan van der; Herder, Wouter W. de; Feelders, Richard A

doi:10.1007/s11102-008-0100-z

Cited by 22 publications

(30 citation statements)

References 28 publications

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“…In the current case, given the severity of the hypercortisolaemia, bilateral adrenalectomy was discussed, but was initially declined by the patient and then deferred due to a rapid response to chemotherapy. Bilateral adrenalectomy has been shown to be a potentially lifesaving procedure in patients critically unwell with CS (10, 22), although in the three cases of SCPC treated with bilateral adrenalectomy, death occurred at four weeks, three months and three weeks postoperatively due to metastatic disease, sepsis and liver failure from extensive metastatic disease, respectively (23, 24, 25). …”

Section: Discussionmentioning

confidence: 99%

“…Of the reported cases of CS associated with SCPC most are due to ectopic ACTH production (24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34), but two cases of ectopic CRH production have also been reported (35, 36). As expected, based on the SCPC literature, in 14 of 25 cases, conventional prostate adenocarcinoma had been diagnosed a median of 23.5 months prior to the presentation with CS-associated SCPC (Table 2).…”

Section: Discussionmentioning

confidence: 99%

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Severe Cushing’s syndrome due to small cell prostate carcinoma: a case and review of literature

Elston

Crawford

Swarbrick

et al. 2017

Endocrine Connections

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Cushing’s syndrome (CS) due to ectopic adrenocorticotrophic hormone (ACTH) is associated with a variety of tumours most of which arise in the thorax or abdomen. Prostate carcinoma is a rare but important cause of rapidly progressive CS. To report a case of severe CS due to ACTH production from prostate neuroendocrine carcinoma and summarise previous published cases. A 71-year-old male presented with profound hypokalaemia, oedema and new onset hypertension. The patient reported two weeks of weight gain, muscle weakness, labile mood and insomnia. CS due to ectopic ACTH production was confirmed with failure to suppress cortisol levels following low- and high-dose dexamethasone suppression tests in the presence of a markedly elevated ACTH and a normal pituitary MRI. Computed tomography demonstrated an enlarged prostate with features of malignancy, confirmed by MRI. Subsequent prostatic biopsy confirmed neuroendocrine carcinoma of small cell type and conventional adenocarcinoma of the prostate. Adrenal steroidogenesis blockade was commenced using ketoconazole and metyrapone. Complete biochemical control of CS and evidence of disease regression on imaging occurred after four cycles of chemotherapy with carboplatin and etoposide. By the sixth cycle, the patient demonstrated radiological progression followed by recurrence of CS and died nine months after initial presentation. Prostate neuroendocrine carcinoma is a rare cause of CS that can be rapidly fatal, and early aggressive treatment of the CS is important. In CS where the cause of EAS is unable to be identified, a pelvic source should be considered and imaging of the pelvis carefully reviewed.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Severe Cushing’s syndrome due to small cell prostate carcinoma: a case and review of literature

Elston

Crawford

Swarbrick

et al. 2017

Endocrine Connections

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“…EAS is associated with a variety of malignancies, predominantly of (neuro-)endocrine origin (bronchial, thymic, or pancreatic neuroendocrine tumors (NETs)). Other tumors associated with EAS are small cell lung carcinoma (SCLC), pheochromocytoma, medullary thyroid carcinoma (MTC), and prostate carcinoma (2,5,6,7,8).…”

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confidence: 99%

Prevalence and clinical features of the ectopic ACTH syndrome in patients with gastroenteropancreatic and thoracic neuroendocrine tumors

Kamp¹,

Alwani²,

Korpershoek³

et al. 2016

European Journal of Endocrinology

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Objective: Several series report on the relative contribution of ectopic ACTH syndrome (EAS) in the spectrum of Cushing's syndrome. However, prevalence of EAS in patients with thoracic or gastroenteropancreatic neuroendocrine tumors (GEP-NETs) is currently unknown. Design: We assessed, in a tertiary referral center, the prevalence of EAS in a large cohort of thoracic and GEP-NET patients including clinical, biochemical, and radiological features; management; and treatment outcome. Methods: In total, 918 patients with thoracic or GEP-NETs were studied (1993)(1994)(1995)(1996)(1997)(1998)(1999)(2000)(2001)(2002)(2003)(2004)(2005)(2006)(2007)(2008)(2009)(2010)(2011)(2012). Multiple endocrine neoplasia type 1 and small cell lung carcinoma patients were excluded. Differentiation between synchronous, metachronous, and cyclic occurrence of EAS was made. Results: Out of the 918 patients with thoracic and GEP-NETs (469 males and 449 females; median age 58.7 years (range: 17.3-87.3)), 29 patients (3.2%) had EAS (ten males and 19 females; median age 48.1 years (range: 24.7-77.9)). EAS occurred synchronously in 23 patients (79%), metachronously in four patients (14%), and cyclical in two patients (7%) respectively. NETs causing EAS included lung/bronchus (nZ9), pancreatic (nZ9), and thymic (nZ4). In four patients, the cause of EAS was unknown (nZ4). Median overall survival (OS) of non-EAS thoracic and GEP-NET patients was 61.2 months (range: 0.6-249.4). Median OS of EAS patients was 41.4 months (range: 2.2-250.9). After comparison, only the first 5-year survival was significantly shorter (PZ0.013) in EAS patients. Conclusion: Prevalence of EAS in this large cohort of patients with thoracic and GEP-NETs was 3.2%. EAS was mostly caused by thoracic and pancreatic NETs. First 5-year survival of EAS patients was shorter compared with non-EAS patients.

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“…Activation of MC2R can also result in phosphorylation of MAPK and the MC2R accessory protein isoform β (MRAP-β) in cells stably expressing MC2R (29). Similarly, ectopic production of ACTH, the putative ligand for MC2R, has been reported in cases of prostate carcinoma associated with Cushing's syndrome (30).…”

Section: Introductionmentioning

confidence: 99%

Expression of melanocortin receptors in human prostate cancer cell lines: MC2R activation by ACTH increases prostate cancer cell proliferation

Hafiz¹,

Dennis²,

Schwartz³

et al. 2012

International Journal of Oncology

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The melanocortin receptors (MCRs 1-5) are G protein coupled-receptors (GPCRs) that regulate food intake, inflammation, skin pigmentation, sexual function and steroidogenesis. Their peptide ligands, the melanocortins, are α-, β- and γ-melanocyte-stimulating hormone and adrenocorticotropic hormone (ACTH) all of which are secreted from the anterior pituitary gland under hypothalamic control. MC2R binds ACTH but has no affinity for the other melanocortins and is, thereby, pharmacologically different from MCRs that bind those ligands. Evidence suggests that elevated GPCRs transactivate the androgen receptor (AR), the critical mediator of prostate cell growth, and consequently promote prostate cancer cell proliferation. It may be that reduced central melanocortin signaling is coincidental with reversal of prostate cancer cachexia, but no data are available on the expression of, or the role for, MCRs in prostate cancer. Here, we show that MCR (1-5) mRNAs are expressed in androgen-dependent LNCaP and androgen-independent PC3 and DU-145 human prostate cancer cell lines. Further, MC2R, the specific target of ACTH, is expressed in LNCaP, PC3 and DU-145 cells. Among the several synthetic MCR peptide ligands that we used, only ACTH promoted concentration-dependent cell proliferation in the three cell lines as shown by MTT cell proliferation assay. In LNCaP cells, the effect was additive with testosterone stimulation and was partially blunted with SHU9119, a non-selective MCR antagonist. In the same cells, ACTH induced cAMP production and increased AR nuclear labeling in immunocytochemical assays. Our observations suggest that MC2R is involved in prostate carcinogenesis and that targeting MC2R signaling may provide a novel avenue in prostate carcinoma treatment.

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Cushing’s syndrome due to ectopic ACTH production by (neuroendocrine) prostate carcinoma

Cited by 22 publications

References 28 publications

Severe Cushing’s syndrome due to small cell prostate carcinoma: a case and review of literature

Severe Cushing’s syndrome due to small cell prostate carcinoma: a case and review of literature

Prevalence and clinical features of the ectopic ACTH syndrome in patients with gastroenteropancreatic and thoracic neuroendocrine tumors

Expression of melanocortin receptors in human prostate cancer cell lines: MC2R activation by ACTH increases prostate cancer cell proliferation

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