Case Report: An Unusual Case of Ectopic ACTH Syndrome Caused by Mediastinal Paraganglioma

Ectopic adrenocorticotrophic hormone (ACTH) syndrome is not common, which is more unusual when caused by paraganglioma. We herein present a 40-year-old Chinese male who was diagnosed with ACTH-dependent Cushing’s syndrome. However, the localization of the ACTH source was troublesome due to the inconsistent results of the high-dose dexamethasone suppression test and the desmopressin stimulation test. Bilateral inferior petrosal sinus sampling was performed, and ectopic ACTH syndrome was diagnosed. After 68Ga-DOTATATE-PET/CT and 18F-FDG-PET/CT were performed, it was localized in the anterior mediastinum. Post-operation histopathology demonstrated an ACTH-secreting mediastinal paraganglioma. The patient obtained complete clinical remission after a mediastinal tumorectomy.

Glucocorticoid Receptor Antagonism Upregulates Somatostatin Receptor Subtype 2 Expression in ACTH-Producing Neuroendocrine Tumors: New Insight Based on the Selective Glucocorticoid Receptor Modulator Relacorilant

Somatostatin exhibits an inhibitory effect on pituitary hormone secretion, including inhibition of growth hormone and adrenocorticotropic hormone (ACTH), and it can have antisecretory and antitumor effects on neuroendocrine tumors (NETs) that express somatostatin receptors. Although the precise mechanism remains unclear, the finding that glucocorticoids downregulate somatostatin receptor subtype 2 (SSTR2) expression has been used to explain the lack of efficacy of traditional SSTR2-targeting analogs in patients with ACTH-secreting NETs. Glucocorticoid receptor (GR) antagonism with mifepristone has been shown to reverse the glucocorticoid-induced downregulation of SSTR2; however, the effects of GR modulation on SSTR2 expression in ACTH-secreting NETs, particularly corticotroph pituitary tumors, are not well known. The current study presents new insight from in vitro data using the highly selective GR modulator relacorilant, showing that GR modulation can overcome dexamethasone-induced suppression of SSTR2 in the murine At-T20 cell line. Additional data presented from clinical case observations in patients with ACTH-secreting NETs suggest that upregulation of SSTR2 via GR modulation may re-sensitize tumors to endogenous somatostatin and/or somatostatin analogs. Clinical, laboratory, and imaging findings from 4 patients [2 ACTH-secreting bronchial tumors and 2 ACTH-secreting pituitary tumors (Cushing disease)] who were treated with relacorilant as part of two clinical studies (NCT02804750 and NCT02762981) are described. In the patients with ectopic ACTH secretion, SSTR2-based imaging (Octreoscan and 68Ga-DOTATATE positron emission tomography) performed before and after treatment with relacorilant showed increased radiotracer uptake by the tumor following treatment with relacorilant without change in tumor size at computed tomography. In the patients with Cushing disease who received relacorilant prior to scheduled pituitary surgery, magnetic resonance imaging after a 3-month course of relacorilant showed a reduction in tumor size. Based on these findings, we propose that GR modulation in patients with ACTH-secreting NETs upregulates previously suppressed SSTR2s, resulting in tumor-specific antisecretory and anti-proliferative effects. The effect of relacorilant on pituitary corticotroph tumors is being investigated in an ongoing phase 3 study (NCT03697109; EudraCT 2018-003096-35).

Pituitary tumors and the risk of other malignancies- is the relationship coincidental or causal?

Pituitary adenomas are benign neoplasms of the pituitary. The most prevalent are prolactinomas and nonfunctioning pituitary adenomas, followed by growth hormone- and ACTH-secreting adenomas. Most pituitary adenomas seem to be sporadic and their persistent growth is very atypical. No molecular markers predict their behavior. The occurrence of pituitary adenomas and malignancies in the same patient can be either pure coincidence or caused by shared underlying genetic susceptibility involved in tumorigenesis. Detailed family history on cancers/tumors in the first, second and third generation of family members on each side of the family has been reported in a few studies. They found an association of pituitary tumors with positive family history for breast, lung and colorectal cancer. We have reported that in about 50% of patients with pituitary adenomas an association with positive family history for cancer has been found independent of secretory phenotype (acromegaly, prolactinoma, Cushingʼs disease or non-functioning pituitary adenomas). We also found earlier onset of pituitary tumors (younger age at diagnosis of pituitary tumors) in patients with strong family history of cancer. In our recent unpublished series of 1300 patients with pituitary adenomas, 6.8% of patients were diagnosed with malignancy. The latency period between the diagnosis of pituitary adenoma and cancer was variable and in 33% of patients was longer than 5 years. Besides the inherited trophic mechanisms (shared underlying genetic variants), the potential influence of shared complex epigenetic influences (environmental and behavioral factors -obesity, smoking, alcohol intake, insulin resistance) is discussed. Further studies are needed to better understand if patients with pituitary adenomas are at increased risk for cancer.

Use of 18F-FDG PET/CT to Differentiate Ectopic Adrenocorticotropic Hormone-Secreting Lung Tumors From Tumor-Like Pulmonary Infections in Patients With Ectopic Cushing Syndrome

BackgroundEctopic adrenocorticotropic hormone (ACTH)-secreting lung tumors represent the most common cause of ectopic Cushing syndrome (ECS). Pulmonary opportunistic infections are associated with ECS. The present study aimed to evaluate the usefulness of 18F-FDG PET/CT for differentiating ectopic ACTH-secreting lung tumors from tumor-like pulmonary infections in patients with ECS.MethodsWe retrospectively reviewed the imaging data of 24 patients with ECS who were suspected to have ACTH-secreting lung tumors and underwent 18F-FDG PET/CT between 2008 and 2019. Eleven patients with lung tumors and 4 with pulmonary infections also had additional somatostatin receptor imaging (99mTc-HYNIC-TOC SPECT/CT or 68Ga-DOTATATE PET/CT).ResultsIn total, 18 patients had lung tumors and six had pulmonary infections. The primary source of ECS remained occult in the six patients with pulmonary infections. The maximum standardized uptake value (SUVmax) for pulmonary infections was significantly higher than that for tumors (P = 0.008). Receiver operating characteristic analysis revealed that a cut-off SUVmax of 4.95 helped in differentiating ACTH-secreting lung tumors from infections with 75% sensitivity and 94.4% specificity. For the 11 patients with ACTH-lung tumors, somatostatin receptor imaging (SRI) was positive in 6; while for the 4 with pulmonary infections, SRI was positive in 2. The sensitivity and specificity of somatostatin receptor imaging (SRI) for detecting ACTH-secreting lung tumor was 54.5% and 50%.ConclusionsOur findings suggest that pulmonary infections exhibit significantly higher FDG uptake than ACTH-secreting lung tumors in 18F-FDG PET/CT. An SUVmax cut-off value of 4.95 may be useful for differentiating the two conditions. Our results also suggested that SRI may not be an effective tool for differentiating the two conditions given the relatively low specificity.

Gamma Knife Radiosurgery for Pituitary Tumors: A Systematic Review and Meta-Analysis

To describe and evaluate outcomes of Gamma Knife radiosurgery (GK) for the treatment of pituitary tumors over the past twenty years, a systematic review and meta-analysis according to PRISMA statement was performed. Articles counting more than 30 patients were included. A weighted random effects models was used to calculate pooled outcome estimates. From 459 abstract reviews, 52 retrospective studies were included. Among them, 18 reported on non-functioning pituitary adenomas (NFPA), 13 on growth hormone (GH)-secreting adenomas, six on adrenocorticotropic hormone (ACTH)-secreting adenomas, four on prolactin hormone (PRL)-secreting adenomas, and 11 on craniopharyngiomas. Overall tumor control and five-year progression free survival (PFS) estimate after one GK procedure for NFPA was 93% (95% CI 89–97%) and 95% (95% CI 91–99%), respectively. In case of secreting pituitary adenomas, overall remission (cure without need for medication) estimates were 45% (95% CI 35–54%) for GH-secreting adenomas, 64% (95% CI 0.52–0.75%) for ACTH-secreting adenomas and 34% (95% CI: 19–48%) for PRL-secreting adenomas. The pooled analysis for overall tumor control and five-year PFS estimate after GK for craniopharyngioma was 74% (95% CI 67–81%) and 70% (95% CI: 64–76%), respectively. This meta-analysis confirms and quantifies safety and effectiveness of GK for pituitary tumors.

The genomic profiling and MAMLD1 expression in human and canines with Cushing’s disease

Background Cushing’s disease (CD) is defined as hypercortisolemia caused by adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas (corticotroph PA) that afflicts humans and dogs. In order to map common aberrant genomic features of CD between humans and dogs, we performed genomic sequencing and immunostaining on corticotroph PA. Methods For inclusion, humans and dog were diagnosed with CD. Whole exome sequencing (WES) was conducted on 6 human corticotroph PA. Transcriptome RNA-Seq was performed on 6 human and 7 dog corticotroph PA. Immunohistochemistry (IHC) was complete on 31 human corticotroph PA. Corticotroph PA were compared with normal tissue and between species analysis were also performed. Results Eight genes (MAMLD1, MNX1, RASEF, TBX19, BIRC5, TK1, GLDC, FAM131B) were significantly (P < 0.05) overexpressed across human and canine corticotroph PA. IHC revealed MAMLD1 to be positively (3+) expressed in the nucleus of ACTH-secreting tumor cells of human corticotroph PA (22/31, 70.9%), but absent in healthy human pituitary glands. Conclusions In this small exploratory cohort, we provide the first preliminary insights into profiling the genomic characterizations of human and dog corticotroph PA with respect to MAMLD1 overexpression, a finding of potential direct impact to CD microadenoma diagnosis. Our study also offers a rationale for potential use of the canine model in development of precision therapeutics.

Cushing Syndrome is Associated with Increased Stage N2 Sleep and Decreased SWS Partially Reversible After Treatment

The aim of the present study was to evaluate the sleep parameters of patients with Cushing syndrome (CS) at the time of diagnosis and 12-months after treatment. Thirty four newly diagnosed patients with endogenous CS (17 with ACTH-secreting pituitary adenoma, 17 with adrenal CS) and 23 controls with similar age were included in the study. Two polysomnography (PSG) recordings were performed; one at the time of diagnosis and the other 12 months after resolution of hypercortisolemia. Control group had only baseline PSG. Based on the PSG findings, stage N2 sleep was found to be prolonged, stage N3 and REM sleep were shortened in patients with CS. Average heart rate and mean Apnea Hypopnea Index (AHI) score were higher in patients with CS than the control subjects. Sixteen (47.1%) patients with CS and 4 (17.4%) controls had obstructive sleep apnea (OSA; AHI ≥5). There were no significant differences in sleep parameters of patients according to the etiology of CS (adrenal vs. pituitary) patients. Following 12-months of treatment, a significant decrease in stage N2 sleep and a significant increase in stage N3 sleep were detected, but there was no change in terms of AHI. In conclusion, Cushing syndrome has disturbing effects on sleep structure and these effects are at least partially reversible after treatment. However, the increased risk of OSA was not reversed a year after treatment indicating the importance of early diagnosis and treatment of CS.