Cushing's Syndrome is a hormonal disorder caused by prolonged exposure of the body's tissues to high levels of cortisol. The most common cause of hypercortisolism (80%) is a pituitary adenoma (Cushing's disease), which was excluded in our patient [11
]. Another possible cause is ectopic ACTH- and/or CRH-Syndrome caused by benign or malignant tumors originating outside the pituitary gland (10–15%). This condition is described as ectopic, paraneoplastic ACTH and/or CRH production and is mostly induced by lung tumors (50%). The most common forms of ACTH-producing tumors are oat cell or small cell lung cancer which accounts for about 25% of all lung cancer cases, and carcinoid tumors. In rare cases less common types of tumors which are described causing ectopic ACTH production are: pancreatic islet cell tumors, thymomas, very rarely abdominal carcinoids, liver-, prostate-, breast- or colon and medullary thyroid carcinomas. Paraneoplastic, ectopic hypersecretion of ACTH is a very rare occurrence in MTC, with only 50 cases reported.
MEN I can cause Cushing's Syndrome due to pituitary, ectopic or adrenal tumors, and has to be diagnosed by PCR genotype analysis when suspected. Other possible causes of CS are adrenal gland tumors which often lead to rapid development of clinical symptoms. Most of these cases involve adrenal adenomas. Adrenal cancers, primary or as metastasis are one of the least common causes of Cushing's Syndrome [12
Cushing's Syndrome and, much more frequently, patients receiving exogenous glucocorticoid therapy (after adrenalectomy for example), are especially at risk of infections. The same is true for patients with ectopic ACTH-production which potentially leads to extensive hypercortisolism as in our patient. This vulnerability is attributed to the complex dysregulation of immunity caused by glucocorticoids [13
]. The cytotoxic T-lymphocyte type 1: type 2 ratio is impaired which makes patients prone to serious opportunistic infections [14
In the author's point of view it is important to be aware of early clinical and laboratory signs of ectopic Cushing's Syndrome and further initiate laboratory and radiologic examinations determining the causes of excess levels of cortisol.
The diagnosis of paraneoplastic CS is based on hypercortisolism with normal or high levels of plasma ACTH and elevated lipotropic pituitary hormone (LPH), which is not suppressed by low-dose dexamethason suppression, and the absence of pituitary adenoma as seen in pituitary MRI. Both were the case in our patient. Uncommonly, the diagnosis is confirmed by immunohistochemical techniques or by proopiomelanocortin mRNA in situ hybridization of MTC tissue.
Therapy is either conservative or surgical. Somatostatin analogues, metyrapone, aminoglutethimide, etomidate and ketoconazol are among the medications described in the literature [15
]. The indication for bilateral adrenalectomy, however, should be discussed early in the disease. As in our patient a conservative form of therapy was ineffective and valuable time was lost before we made the diagnosis of an adrenal gland metastasis.
Surgical treatment of the patient's cancer may lead to cure. However, in patients with advanced disease and metastases, as was the case described, the early diagnosis of CS would be of strong value as specific treatment of hypercortisolism including bilateral adrenalectomy, can be initiated early, before the impact on the patient's immunity leads to serious complications.
Persistent diarrhea has been described as a symptom of MTC [17
]. This phenomenon is possibly linked to the involvement of calcitonin gene-related peptide (CGRP) which has been shown to induce colonic fluid secretion in the rat colon with an increased secretion of sodium, potassium, and chloride [18
]. The extent to which the latter observation can be valid for humans has yet to be investigated.