In a retrospective study 118 patients with Cushing's syndrome (CS) [102 Cushing's disease (CD), 10 adrenal CS and 6 ectopic adrenocorticotropic syndrome (EAS)]. Thyroid functions [thyroid-stimulation hormone (TSH), T3, free T3 (FT3), T4, and free T4 (FT4)] were measured in all CS at the time of diagnosis and in all CD 3 months after transsphenoidal pituitary tumor resection. Postoperative hormone monitoring within 3 months was conducted in 9 CD patients completing remission. 28 remitted CD patients experienced hormone and antithyroid antibody evaluation preoperatively and on the 3rd, 6th, and 12th month after surgery.
TSH, T3, and FT3 were below the reference range in 31%, 69% and 44% of the 118 CS patients. Remitted CD patients (81/102) had significantly higher TSH (P=0.000), T3 (P=0.000), and FT3 (P=0.000) than those in the non-remission group (21/102). After remission of CD, TSH, T3, and FT3 showed a significant increase, with a few cases above the reference range. By 12 months, most CD patients' thyroid functions returned to normal. Thyroid hormones (including TSH, T3, and FT3) were negatively associated with serum cortisol levels both before and after surgery. No significant changes of antithyroid autoantibodies were observed.
TSH, T3, and FT3 are suppressed in endogenous hypercortisolemia. After remission of CD, TSH, T3, and FT3 increased significantly, even above the reference range, but returned to normal one year after surgery in most cases. Antithyroid antibodies didn't change significantly after remission of CD 1).
A descriptive retrospective study included all patients admitted to the Endocrinology and Nutrition Department of the University Hospital Virgen del Rocío, Seville, Spain, from January 1980 to May 2016. All patients had a definitive diagnosis of CD.
Total sample included 119 patients; 100 (84%) were female. Median age at diagnosis was 37.97 years (interquartile range [IQR]: 25.89-45.07 years). Median follow-up was 88 months (IQR: 45.50-157.00 months). Most tumors were microadenomas (62/95) (5.1 mm [IQR: 4.0-7.0 mm]) without sinus invasion. Surgical procedures were conventional transsphenoidal surgery (CTSS) (101/108; cured 70 after first attempt) and expanded endoscopic transsphenoidal surgery (EETSS) (7/108; cured 5 after first attempt); 11 patients did not receive surgical treatment. Fourteen patients received radiotherapy after a first surgery and 5 patients after a second surgical removal attempt. In 13 patients (12.04%), CD relapse was demonstrated after initial CTSS (median disease-free period 65 months [IQR: 45-120 months]). Ten patients developed panhypopituitarism owing to the surgical procedure (CTSS); 8 patients developed panhypopituitarism after adjuvant radiotherapy.
They observed slightly inferior cure rate after first surgery compared with moderately better relapse rates and time to relapse. Radiotherapy after surgery failure seemed to be more effective than CTSS; however, EETSS may be a valid alternative. Postoperative panhypopituitarism rate after first surgery was lower than expected; after radiotherapy, our results were comparable to other series 2).
Among 50 cases of pituitary Corticotroph adenoma, 31 were vasopressin receptor 2 positive, 38 were vasopressin receptor 3 positive, and 24 were both vasopressin receptor 2 and 3 positive. Two patients with ectopic ACTH syndrome were vasopressin receptor 3 positive, and one was also vasopressin receptor 2 positive. In 12 patients who underwent bilateral inferior petrosal sinus sampling before surgery, the central ACTH increment ratio after desmopressin stimulation was correlated with vasopressin receptor 2 but not with vasopressin receptor 3 staining intensity. In an in vitro study, the expression of both vasopressin receptor 2 and 3 on AtT20 cells was confirmed. The vasopressin receptor 2 antagonist Tolvaptan inhibited desmopressin-induced ACTH secretion in a dose-dependent manner.
Both vasopressin receptor 2 and 3 are expressed in ACTH-secreting tumors. Vasopressin receptor 2 rather than vasopressin receptor 3 is the primary receptor that seems to mediate the ACTH response in corticotrophin tumors. A vasopressin receptor 2 antagonist can inhibit ACTH secretion induced by desmopressin in AtT-20 cells 3).
Qiao et al., analyzed the clinical presentation and treatment outcomes in 45 CD patients older than 60 years, in comparison to 90 CD patients younger than 60, and a control group of 45 older patients with nonfunctioning pituitary adenomas. We reviewed preoperative clinical characteristics, medical comorbidities, imaging findings and endocrine testing as well as surgical and endocrine outcomes.
Older CD patients had significantly lower body mass index (BMI) (p = 0.031), were more likely to have muscle wasting (p = 0.006) and women were less likely to have hirsutism (p = 0.033). Older patients with CD had more medical comorbidities than younger patients, which correlated with a higher ASA grade (p < 0.001), but the surgical complication rates were similar in both groups. Surgical remission was achieved in 38/45 (84.4%) older patients and 78/90 (86.7%) younger patients (p = NS). Recurrent disease was more frequent in younger patients (19.2%) in comparison to older patients (2.6%, p = 0.019).
Older patients with CD appear to have a distinct phenotype with a more catabolic picture, including a lower BMI and greater prevalence of muscle wasting. Surgical outcomes are similar without a significant age-related increase in complications 4).
Feng et al. retrospectively analyzed 91 patients with Cushing's syndrome who had either negative findings on Dynamic contrast enhanced MR imaging of the pituitary gland or non-suppressed high dose dexamethasone suppression tests (HDDST). Thin-slice thoracoabdominal computed tomography (CT) and octreotide scan were also negative to rule out ectopic adrenocorticotropin hormone (ACTH) syndrome. All patients went through inferior petrosal sinus sampling (IPSS) with desmopressin. Afterwards, transsphenoidal pituitary surgery, light microscope pathology and immunohistological staining for ACTH were performed in all patients.
1. Diagnosis of Cushing's disease (CD). Among the 91 patients included, 90 were confirmed with CD, of whom 89 had positive IPSS findings, therefore the sensitivity was 98.9%. The one patient who was negative for CD also had negative IPSS findings, therefore the specificity was 100%. 2. Tumour lateralization. Among the 51 patients who were ultimately diagnosed with CD and whose lateralization by IPSS and surgery was either left or right, 37 had IPSS lateralization in concordance with surgery, therefore the concordance rate was 72.5%. Patients in the concordant group had a higher frequency of right lateralization by surgery.
IPSS with desmopressin is a sensitive approach in the diagnosis of CD and has moderate accuracy in tumour lateralization, making it an alternative choice to IPSS with CRH 5).
Liu et al. retrospectively enrolled 92 consecutive patients with confirmed diagnosis of Cushing's disease. A voxel-based analysis was performed to investigate the association between cerebral 18F positron emission tomography uptake and serum cortisol level. Relatively impaired metabolism of specific brain regions correlated with serum cortisol level was found. Specifically, notable correlations were found in the hippocampus, amygdala, and cerebellum, regions considered to be involved in the regulation and central action of glucocorticoids. Moreover, some hormone-associated regions were found in the frontal and occipital cortex, possibly mediating the cognitive decline seen in Cushing's disease. The findings link patterns of perturbed brain metabolism relates to individual hormone level, thus presenting a substrate for cognitive disturbances seen in Cushing's disease patients, as well as in other conditions with abnormal cortisol levels 6).
Sarkar et al studied 64 consecutive patients who underwent 69 endoscopic transsphenoidal procedures. Radiological evaluation comprised detailed examination of preoperative magnetic resonance images (MRI), including positron emission tomography (PET) for select cases. Inferior petrosal sinus sampling (IPSS) was not performed for any patient. Remission was defined by the presence of hypocortisolemia with requirement for steroid replacement therapy or eucortisolemia with suppression to <1.8 μg/dl after 1 mg dexamethasone on evaluation at least 3 months after surgery.
Preoperative MRI was abnormal in 87.5 % of cases and included 11 macroadenomas (17.2 %). PET was used to localize the adenoma in four cases. For microadenomas, operative procedures executed were as follows: selective adenomectomy (n = 15), enlarged adenomectomy (n = 21) and subtotal/hemihypophysectomy (n = 17). Overall, pathological confirmation of an adenoma was possible in 58 patients (90.6 %). Forty-nine patients (76.6 %) developed hypocortisolemia (<5 μg/dl) in the early postoperative period. Mean follow-up was 20 months (range 6-18 months). Remission was confirmed in 79.7 % of the 59 cases followed up for >3 months and was superior for microadenomas (86.4 %) versus macroadenomas (55.6 %) and equivocal MRI adenomas (66.7 %). Postoperative CSF rhinorrhea occurred in five patients, and new endocrine deficits were noted in 17.1 % patients. A nadir postoperative cortisol <2 μg/dl in the 1st week after surgery was highly predictive of remission (p = 0.001).
ETS allows for enhanced intrasellar identification of adenomatous tissue, providing remission rates that are comparable to traditional microsurgery for CD. The best predictor of remission remains induction of profound hypocortisolemia in the early postoperative period 7).
Retrospective analysis of the records of 96 patients with Cushing disease from 1997 to 2012.
There were 73 females and 23 males, with a mean follow-up of 44 months (range, 3-13 years). The sex ratio was significantly different in children and teenagers versus adults. Magnetic resonance imaging showed microadenoma, macroadenoma, and no adenoma in 66, 18, and 12 patients, respectively. There was no surgical mortality. Early remission (normal 24-hour urinary free cortisol and basal serum cortisol <5 μg/dL) was achieved in 94.8%. Regression analysis showed that only tumor size, cavernous sinus extension, and tumor consistency influenced remission. Recurrence was seen in 21.9%. Regression analysis showed that age, preoperative basal cortisol levels, and follow-up duration influenced recurrence. Correlation analysis showed that there was a significant negative correlation between patient age and the follow-up period. After detection of recurrence, 17 patients underwent repeat transsphenoidal surgery that resulted in remission in 12 patients (70.6%). The other 5 patients were referred for gamma knife radiosurgery or bilateral adrenalectomy.
Transsphenoidal surgery is a safe and highly efficient procedure in the treatment of Cushing disease. Macroadenomas, cavernous sinus invasion, and harder tumor consistencies, however, are associated with lower remission rates (higher disease persistence) and younger age, higher preoperative cortisol levels, and longer follow-up periods are associated with higher recurrence 8).
A retrospective study of 33 patients with CD undergoing transsphenoidal surgery from January 2007 to February 2014 (27 females and 6 males, median age 38 years, range 18-71 years). The diagnosis of Cushing's syndrome was established on the basis of the patient's history, characteristic clinical features, and laboratory data including an elevated 24-h urinary free cortisol level, lack of serum cortisol suppression after dexamethasone suppression tests and an elevated midnight cortisol level. In 28/33 patients, the tumor was visualized on MR of the sellar region, while in 5 it was diagnosed using an inferior petrosal sinus sampling. Out of the 33 patients, 10 had macroadenoma and the remaining 23 had microadenoma. Twenty-one patients (63.6 %) had hypertension, 17 (51.5 %) dyslipidemia, and 7 (21.2 %) had type 2 diabetes or impaired glucose tolerance. The median follow-up period was 28 months. Remission after transsphenoidal surgery was achieved in 78.8 % of patients, while 7 patients failed to achieve disease remission. Those patients were treated with second-line treatment modalities (second operation, radiotherapy, bilateral adrenalectomy, and/or ketoconazole). One patient rejected all the treatment modalities after surgery. Cumulative remission after all the treatment modalities was achieved in 87.9 % patients. Patients with Cushing's disease should be managed in centers with much experience due to high patient load. In our Center, the remission of the disease has been achieved in 78.8 % of the patients following transsphenoidal surgery. Multimodal treatment which included radiotherapy and medical treatment led to biochemical remission of the disease in 87.9 % of patients 9).
Forty consecutive CD patients, with an average age of 41.0 years, were analyzed with a mean follow-up of 40.2 ± 29.6 months. These included 22 patients with microadenoma and 18 with macroadenoma, including 9 cavernous invasions. The overall remission rate of CD after ETS was 72.5% throughout the entire follow-up. Patients with microadenoma or noninvasive macroadenoma had a higher remission rate than those who had macroadenoma with cavernous sinus invasion (81.8% or 77.8% vs. 44.4%, P = 0.02). After ETS, the patients who had adrenocorticotropic hormone-positive adenoma had a higher remission rate than those who had not (76.5% vs. 50%, P = 0.03). In the 11 patients who had persistent/recurrent CD after the first ETS, 1 underwent secondary ETS, 8 received gamma-knife radiosurgery (GKRS), and 2 underwent both. At the study end point, two (5%) of these CD patients had persistent CD and were under the medication of ketoconazole.
For MRI-positive CD patients, primary (i.e., the first) ETS yielded an overall remission rate of 72.5%. Adjuvant therapies, including secondary ETS, GKRS, or both, yielded an ultimate remission rate of 95% 10).
Clinical, endocrine, imaging, and histologic data from 252 patients undergoing pituitary surgery at Toranomon Hospital through the end of 2012 were entered into a database and statistically analyzed. In 22 of these patients (8.7%; positive venous sampling in 15 and negative venous sampling in 7 patients), tumors were invisible on magnetic resonance imaging (MRI) and 42.9% of them achieved remission. In the remaining 230 patients, 93.5% of those with microadenomas (n=154) and 71.1% of those with macroadenomas (n=76) achieved early postoperative remission, with recurrence rates of 2.7% and 14.8%, respectively, during a 72.5-month median follow-up. In multivariate analyses, cavernous sinus invasion (CSI; odds ratio [OR], 13.0), type of surgery (OR, 4.0), and tumor size (OR, 2.7) were significant preoperative factors affecting early postoperative results, whereas peak cortisol levels ≥9.4 μg/dL in response to corticotropin-releasing hormone (CRH) and CSI were significant factors predicting recurrence. Tumor recurrence was more common in patients with non-densely granulated adenomas than in patients with densely granulated adenomas. We propose that the higher remission and lower recurrence rates in this series are due to our surgical strategies, including extracapsular tumor removal, aggressive resection of tumors with CSI, extended transsphenoidal surgery (TSS), or a combined approach for large/giant adenomas. Appropriate multimodal treatments, including radiotherapy, medication, and repeated surgery in patients with persistent or recurrent CD, could result in better overall outcomes than previously achieved 11).