Ectopic ACTH Secretion (EAS) Associated to a Well-Differentiated Peritoneal Mesothelioma

Case Report

Carmen F. Mendoza; Patricia Ontiveros; Daniel X. Xibillé; Manuel H. Rivera


BMC Endocr Disord. 2015;15(40) 

In This Article


It is known that non pituitary tumors have low cortisol suppression rates after high doses of dexamethasone, unlike those seen in pituitary adenomas; however, 10 % to 20 % of ectopic tumors can biochemically behave as Cushing's disease. While several authors agree on the high sensitivity of the urinary free cortisol, late-night salivary cortisol and LDDST determination for the diagnosis of endogenous hypercortisolism, there is controversy about the usefulness of HDDST in locating an ACTH-producing tumor. Some authors, such as Aaron et al., suggest that the high dose dexamethasone test should no longer be used. They studied 68 patients with Cushing's syndrome concluding that the accuracy of HDDST for differentiating between Cushing's disease and ectopic ACTH secretion ranges between 70 % and 80 %.[10] However, in a study of 87 patients[11] in which 74.71 % were diagnosed with Cushing's disease (CD), 8.05 % with EAS and 17.2 % with ACTH-independent Cushing's syndrome, the mean serum cortisol suppression with 8 mgs of dexamethasone in the first group was 83.6 %, 52.5 % for the second and 17 % for the third group, showing statistically significant differences only between patients with Cushing's disease and non-ACTH dependent Cushing's syndrome, but not between the first group and those with ectopic ACTH secretion. This study concluded that the specificity of the cortisol suppression with high-dose dexamethasone test (HDDST) for the diagnosis of Cushing's disease, with a percentage of suppression of more than 50 %, 60 % and 79 %, is 75 %, 88 % and 100 % respectively.[11] In the series published by Vilar et al., 74 cases of patients with endogenous hypercortisolism were analyzed; seven had EAS and of these 28.6 % had a suppression of >50 % of serum cortisol levels with HDDST, and the only patient who had a rate of suppression of >80 % had Cushing's disease, so these authors suggest that a percentage of suppression of >80 % in HDDST should be achieved to distinguish between Cushing's disease and EAS.[12] In another series published by Isidiri,[3] Doi,[4] Kakade[5] and Ejaz,[13] percentages of serum cortisol suppression using HDDST in patients with EAS were no greater than 50 %, with few exceptions. The gold standard to distinguish between Cushing's disease and ectopic ACTH secretion, in patients with discordant results (suppression of cortisol post-HDDST >60 % and normal IRM), is a bilateral inferior petrosal sinus sampling (BIPSS), a ratio of central to peripheral ACTH of more than 2 under baseline conditions or over 3 after CRH stimulation, which is consistent with Cushing's disease. If the diagnosis of Cushing's disease is excluded after BIPSS, the next step is to perform a CT scan or MRI of the neck, thorax, abdomen and pelvis to identify the non-pituitary ACTH-producing tumor;[14,15] however, it has been described that in up to 20 % of patients the site of ectopic ACTH secretion cannot be identified. Because most neuroendocrine tumors express receptors for somatostatin, some case reports have mentioned the use of somatostatin receptor scintigraphy (SRS) in order to identify the origin of the ectopic ACTH secretion; nonetheless, Tabarin et al., reviewed 20 cases of ectopic ACTH secretion published in the literature finding that in 18 of the 20 cases, the tumor was visible using more conventional methods (CT scans and MRI), as well as SRS. The same authors present a series of 12 patients with ectopic ACTH secretion who underwent serial CT or MRI scanning and SRS, with the latter resulting in findings in only four of the patients, but in two of them the tumor detected both by SRS as by conventional imaging, was not the origin of the ectopic ACTH secretion, with the primary tumor remaining unknown. Another patient dies before the tumor, identified using SRS, could be resected and, in the last case, the image seen as abnormal in SRS turned out to be a carcinoid metastasis from an unknown primary site, unidentified by conventional imaging.[16] In the series by Doi, et al., 50 % of tumors causing ectopic ACTH secretion were identified through CT or MRI, and 11 of the 16 cases presented underwent somatostatin receptor scintigraphy (SRS), four of which were positive (36 %), with only one (11.1 %) positive to [ 18 F] fluorodeoxyglucose-positron emission tomography (FDG-PET).[4] On the other hand, in the series of patients published by Ejaz, et al., CT or MRI identified the origin of the ectopic ACTH secretion in 67.5 %, failing to find it in four patients in spite of performing CT, MRI, octreoscan and FDG-PET.[13] In another series of 19 patients, the usefulness of SRS with In 111 octreotide and Ga 68 DOTATATE PET-CT was evaluated, being positive in only 7 of these patients, 4 of which had undergone a previous CT that had shown the sites of abnormal uptake, and another in which the MRI had also shown an abdominal tumor; one more who had already undergone resection of a mediastinal mass and lymph nodes without showing clinical improvement underwent SRS which showed lymph node and bone metastasis. The last one had a pulmonary tumor, diagnosed with Ga 68 DOTATATE and had previously undergone a CT that failed to reveal the tumor. The authors suggest that performing SPECT or SPECT/TC imaging would improve the sensitivity of diagnosis with the planar images of SRS and propose that the images with Ga 68 peptide may offer better results in localizing ectopic ACTH-producing tumors than those peformed with In 111 octreotide.[17] There are, to date, several case reports in which imaging with Ga 68 DOTATATE have identified the tumor secreting ectopic ACTH[18–20] but it must be remembered that case reports involve a selection bias per se in evaluating the sensitivity of a diagnostic tool. Most authors currently coincide that once the ectopic secretion of ACTH is confirmed through BIPSS, imaging techniques such as CT or MRI should be preferentially employed in an initial stage as most tumors will be shown by their use. In the case here presented, abdominal CT evidenced an intra-abdominal tumor and the possibility of a mesothelioma was considered as the most likely, leading to an exploratory laparotomy in the patient, without performing other imaging tests, as SRS or PET/CT are difficult to access in most of our country.

Finally, the histological diagnosis of peritoneal mesothelioma was performed on the basis of a positive staining for keratin markers such as calretinin and thrombomodulin, as well as negative staining using markers for adenocarcinoma such as carcinoembrionic antigen (CEA), CA-125 and CK 5/6. Calretinin is expressed in normal and neoplastic mesothelial cells, with some authors reporting positive staining for this protein in 80 % of mesotheliomas with a specificity close to 100 % while, for thrombomodulin, some studies have reported a positivity of 80 % in mesotheliomas and only 15 % in adenocarcinomas. The sensitivity also depends on whether mono or poyclonal antibodies are employed, as well as the tissue fixation in large specimens.[21–23]

A fact that stands out in the case we present is that the levels of plasma ACTH were on the lower limit of the normal range. Although most patients with ectopic ACTH secretion have plasma levels that are considerably greater than normal, there are also reports of cases with normal or mildly elevated ACTH; these cases generally have a gradual progression and are associated to poorly aggressive carcinoid tumors. Neary, et al, presented a series of 12 patients with ACTH-producing neuroendocrine thymic tumors where 2 cases had normal plasma ACTH in spite of having considerably high levels of free urinary cortisol.[24] On the other hand, in a series of 90 patients with EAS published by the National Institutes of Health, 30 % had normal baseline plasma ACTH, one of them with an ACTH of 12.7 pg/mL,[25] leading to the conclusion that levels of plasma ACTH per se do not rule out a suspicion of ectopic secretion of ACTH.