Diagnosing Cushing's syndrome is challenging and is further hampered when investigations are performed in a patient with cyclic Cushing's syndrome. A subset of patients with Cushing's syndrome exhibit periods of abnormal cortisol secretion with interspersed normal secretion. Patients can have periods of clinical improvement during these quiescent phases or remain symptomatic. Initial diagnostic testing can be challenging because of the unpredictable durations of the peak and trough phases, and it is especially challenging when the diagnosis of cyclic Cushing's syndrome has not yet been determined. Here, the authors present the case of a patient with Cushing's disease with a pathology-proven adrenocorticotropic hormone (ACTH)–secreting pituitary adenoma and whose initial inferior petrosal sinus sampling (IPSS) results were deemed indeterminate; further studies elucidated the diagnosis of cyclic Cushing's syndrome. Repeat IPSS was diagnostic of a central source for ACTH secretion, and the patient was treated successfully with transsphenoidal resection. Literature concerning the diagnosis and management of cyclic Cushing's syndrome is also reviewed.
Vivien Bonert, Namrata Bose and John D. Carmichael
Gabriel Zada, John D. Carmichael and Warren R. Selman
John D. Carmichael, Gabriel Zada and Warren R. Selman
Justin Seltzer, Joshua Lucas, Deborah Commins, Olga Lerner, Alexander Lerner, John D. Carmichael and Gabriel Zada
Ectopic pituitary adenomas are exceedingly rare entities that are often misdiagnosed. The resulting delay in diagnosis may be particularly concerning in the case of Cushing syndrome caused by an ectopic adrenocorticotropic hormone (ACTH)–secreting pituitary adenoma. Although the total resection of ectopic adenomas results in rapid and durable remission, persistent Cushing syndrome is often associated with permanently damaging invasive procedures and significantly higher risk of mortality.
The authors report the case of a 48-year-old man with ACTH-dependent Cushing syndrome. On the morning before surgery, his serum cortisol measured 51 μg/dl, his ACTH level was 195.7 pg/ml, and his urinary free cortisol level was 2109 μg/day. Serum cortisol was not suppressed with the administration of high-dose dexamethasone. Imaging showed separate masses in both the sphenoid sinus and the pituitary gland, complicating the diagnostic process and requiring pathological assessment of both masses. No other abnormalities were found on thoracic, abdominal, or pelvic scans. Gross-total resection of both lesions was accomplished via an endoscopic endonasal transsphenoidal approach. Pathology confirmed an ectopic ACTH pituitary adenoma of the sphenoid sinus and a Crooke hyaline change of the pituitary gland. The patient achieved stable hormonal remission without significant postoperative complications, returned to full activity within 3 months, and remained disease free nearly 1 year after tumor resection.
In a systematic literature review, the authors identified 41 cases of ectopic ACTH-secreting pituitary adenomas, including 18 arising in the sphenoid sinus without direct involvement of the sella. Including the case described here, the total number of ectopic ACTH pituitary adenomas arising in the sphenoid sinus was 19, and the total number of ectopic ACTH pituitary adenomas without regard to location was 42. For the 19 patients with adenomas found in the sphenoid sinus, ages ranged from 16 to 76 years, and there were 15 women and 4 men. The mean and median diameters of the resected sphenoid masses were 13.9 and 8 mm, respectively, with a range of 3–55 mm. Seven were microadenomas (< 1 cm). Fifteen of the 19 cases reported serum ACTH and morning cortisol levels, the means of which were 106.7 pg/ml and 32.5 μg/dl, respectively. Gross-total tumor resection was achieved in all patients except one, and in all of them durable hormonal remission of Cushing syndrome was achieved (mean follow-up time 20 months).
Ectopic pituitary adenomas are rare but important causes of Cushing syndrome and related endocrinopathies, particularly because of the rapid onset and severity of symptoms with atypical presentation. Ectopic pituitary adenomas, especially those in the nasal cavity, nasopharynx, or paranasal sinuses, are easily misidentified. Any patient presenting with signs and symptoms of Cushing syndrome without any obvious pituitary adenoma or other sources of hypercortisolemia should be thoroughly screened for an ectopic adenoma. However, as with the case presented here, the coincident existence of a sellar mass should not preclude the possibility of an ectopic source. There should be a high degree of clinical suspicion for any mass in the general area surrounding the sella when evaluating Cushing syndrome.
Justin Seltzer, Charles E. Ashton, Thomas C. Scotton, Dhiraj Pangal, John D. Carmichael and Gabriel Zada
Functional corticotroph pituitary adenomas (PAs) secrete adrenocorticotropic hormone (ACTH) and are the cause of Cushing's disease, which accounts for 70% of all cases of Cushing's syndrome. Current classification systems for PAs rely primarily on laboratory hormone findings, tumor size and morphology, invasiveness, and immunohistochemical findings. Likewise, drug development for functional ACTH-secreting PAs (ACTH-PAs) is limited and has focused largely on blocking the production or downstream effects of excess cortisol. The authors aimed to summarize the findings from previous studies that explored gene and protein expression of ACTH-PAs to prioritize potential genetic and protein targets for improved molecular diagnosis and treatment of Cushing's disease.
A systematic literature review was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A PubMed search of select medical subject heading (MeSH) terms was performed to identify all studies that reported gene- and protein-expression findings in ACTH-PAs from January 1, 1990, to August 24, 2014, the day the search was performed. The inclusion criteria were studies on functional ACTH-PAs compared with normal pituitary glands, on human PA tissue only, with any method of analysis, and published in the English language. Studies using anything other than resected PA tissue, those that compared other adenoma types, those without baseline expression data, or those in which any pretreatment was delivered before analysis were excluded.
The primary search returned 1371 abstracts, of which 307 were found to be relevant. Of those, 178 were selected for secondary full-text analysis. Of these, 64 articles met the inclusion criteria and an additional 4 studies were identified from outside the search for a total of 68 included studies. Compared with the normal pituitary gland, significant gene overexpression in 43 genes and 22 proteins was reported, and gene underexpression in 58 genes and 15 proteins was reported. Immunohistochemistry was used in 39 of the studies, and reverse transcriptase polymerase chain reaction was used in 26 of the studies, primarily, and as validation for 4 others. Thirteen studies used both immunohistochemistry and reverse transcriptase polymerase chain reaction. Other methods used included microarray, in situ hybridization, Northern blot analysis, and Western blot analysis. Expression of prioritized genes emphasized in multiple studies were often validated on both the gene and protein levels. Genes/proteins found to be overexpressed in ACTH-PAs relative to the normal pituitary gland included hPTTG1/securin, NEUROD1/NeuroD1 (Beta2), HSD11B2/11β-hydroxysteroid dehydrogenase 2, AKT/Akt, protein kinase B, and CCND1/cyclin D1. Candidate genes/proteins found to be underexpressed in ACTH-PAs relative to the normal pituitary gland included CDKN1B/p27Kip1, CDKN2A/p16, KISS1/kisspeptin, ACTHR/ACTH-R, and miR-493.
On the basis of the authors' systematic review, many significant gene and protein targets that may contribute to tumorigenesis, invasion, and hormone production/secretion of ACTH have been identified and validated in ACTH-PAs. Many of these potential targets have not been fully analyzed for their therapeutic and diagnostic potential but may represent candidate molecular targets for biomarker development and drug targeting. This review may help catalyze additional research efforts using modern profiling and sequencing techniques and alteration of gene expression.
Justin Seltzer, Michelle A. Wedemeyer, Phillip A. Bonney, John D. Carmichael, Martin Weiss and Gabriel Zada
Incidental pituitary adenomas (IPAs) are commonly discovered during cranial imaging evaluations obtained for unrelated indications. The optimal management of IPA remains controversial. The authors investigated the outcomes and safety of the surgical treatment of IPAs at their institution.
Clinical outcome data for 1692 patients surgically treated for pituitary adenomas at the Keck Medical Center of USC/USC Pituitary Center over a 17-year period (1999–2016) were reviewed to identify all cases with surgically managed IPAs. Clinical characteristics reviewed in this retrospective analysis included patient demographics, endocrine laboratory data, visual field examinations, and MRI results. Intraoperative data reviewed included requirement for CSF leak repair, surgical complications, and estimated extent of resection. Postoperative data collected included pathology results, length of stay, postoperative complications, endocrine outcomes, readmission rates, and long-term outcomes, including extent of resection noted on postoperative imaging studies and tumor progression and/or recurrence.
Fifty-two patients (3.1% of all cases) underwent transsphenoidal surgery for IPA. The median age at surgery was 61 years (range 31–86 years). The most common reasons for neuroimaging included trauma (19%), stroke/transient ischemic attack (15%), and sinonasal disease (15%). Visual field deficits were present in 15% of bedside examinations, and among the 22 patients sent for formal testing, 54.5% were noted to have deficits. Preoperative endocrine function was normal in 69% of patients, which includes 3 patients (5.8%) having isolated hyperprolactinemia consistent with a stalk effect without other hormonal dysfunction. The average maximal tumor diameter was 20.9 mm (8–50 mm; data available in 35 patients). The most common primary indication for surgery was compression of the chiasm or vision loss (52%); other major considerations included tumor growth, a young patient age, and identified endocrine abnormalities. Intraoperative CSF leak repair was performed in 56% of patients, and 1 patient (2%) developed postoperative CSF rhinorrhea treated with lumbar drainage. The median hospital stay was 2 days. There were no deaths or major complications. Three patients (5.8%) developed transient diabetes insipidus. Over a mean follow-up of 61 months, 4 patients (50.0%) reported improved headaches and 6 (54.5%) reported improvement in their visual deficits. Four patients (25%) had improved endocrine function, including one with resumption of menstruation and another with remission of acromegaly. One patient (2.4%) reported new postoperative headache, and none experienced worsened vision. Four patients (10.5%) developed new single-axis hypopituitarism and 1 (2.6%) developed new panhypopituitarism. The overall recurrence/progression rate on neuroimaging was 9.6% at a mean of 80 months.
Transsphenoidal resection of IPAs, when appropriate, can be performed safely at experienced treatment centers. Incidental pituitary adenomas should be evaluated and treated as indicated, especially in younger patients at risk for endocrine or visual dysfunction.
Matthew S. Agam, Michelle A. Wedemeyer, Bozena Wrobel, Martin H. Weiss, John D. Carmichael and Gabriel Zada
Pituitary adenomas (PAs) are benign neoplasms that are frequently encountered during workup for endocrinopathy, headache, or visual loss. Transsphenoidal surgery remains the first-line approach for PA resection. The authors retrospectively assessed complication rates associated with transsphenoidal PA resection from an institutional database.
A retrospective analysis of 1153 consecutive transsphenoidal pituitary adenoma resections performed at the Keck Hospital of USC between November 1992 and March 2017 was conducted. Microscopic transsphenoidal resection was performed in 85.3% of cases, and endoscopic transsphenoidal resection was performed in 14.7%. Analysis of perioperative complications and patient and tumor risk factors was conducted.
The overall median hospital stay was 3 days. There was 1 perioperative death (0.1%). Surgical complications included postoperative cerebrospinal fluid leak (2.6%), epistaxis (1.1%), postoperative hematoma (1.1%), meningitis (1.0%), cranial nerve paresis (0.8%), hydrocephalus (0.8%), vision loss (0.6%), stroke (0.3%), abdominal hematoma or infection (0.2%), carotid artery injury (0.1%), and vegetative state (0.2%). Perioperative medical complications included bacteremia/sepsis (0.5%), pneumonia (0.3%), myocardial infarction (0.3%), and deep venous thrombosis/pulmonary embolism (0.1%). Endocrine complications were the most frequent, including transient diabetes insipidus (4.3%), symptomatic hyponatremia (4.2%), new hypopituitarism (any axis) (3.6%), permanent diabetes insipidus (0.3%), and adrenal insufficiency (0.2%). There were no significant differences between microscopic and endoscopic approaches with regard to surgical complications (6.4% vs 8.8%, p = 0.247) or endocrine complications (11.4 vs 11.8%, p = 0.888). Risk factors for surgical complications included prior transsphenoidal surgery (11.4% vs 6.8%, p = 0.025), preoperative vision loss (10.3% vs 6.8%, p = 0.002), and presence of PA invasion on MRI (8.5% vs 4.4%, p = 0.007).
In this single tertiary center study assessing complications associated with transsphenoidal PA resection, the rate of death or major disability was 0.26%. Risk factors for complications included prior surgical treatment and PA invasion. No differences in complication rates between endoscopic and microscopic surgery were observed. When performed at experienced pituitary centers, transsphenoidal surgery for PAs may be performed with a high degree of safety.
Daniel Wilson, Diana L. Jin, Timothy Wen, John D. Carmichael, Steven Cen, William J. Mack and Gabriel Zada
Cushing's disease (CD) is a potentially lethal neuroendocrinopathy that often requires specialized multidisciplinary treatment to achieve optimized outcomes. The authors analyzed data pertaining to patient, hospital, and admission characteristics as they relate to outcomes following transsphenoidal surgery (TSS) in more than 5500 patients treated for CD.
The Nationwide Inpatient Sample (NIS) database was used to identify all patients admitted with CD between 2002 and 2010. A variety of patient demographic data (e.g., age, sex, race, payer status), hospital variables (e.g., bed size, TSS volume, teaching status), and admission subtypes (e.g., elective, emergency) were tested for association with postoperative endocrine and nonendocrine complications, mortality, nonroutine discharge, length of stay, and total hospital charges. All tests were performed using univariate analysis followed by multivariate analysis, with 4 models tested via an additive methodology. Statistical significance was defined as a p value < 0.05 for all analyses.
From 2002 to 2010, 5527 individuals who were admitted for TSS (54 biopsies, 4254 partial resections, and 1271 total resections; 5579 total TSS procedures) were identified as patients with CD. There were 25 deaths following TSS, resulting in a mortality incidence rate of 0.45%. Nonendocrine and endocrine complications were reported in 22.4% and 11.1% of patients, respectively. The most common nonendocrine complications were postoperative neurological complications (6.98%) and mechanical ventilation (1.71%). Diabetes insipidus was reported in 14.79% of patients. In a multivariate analysis, patients with Medicare were at increased risk of nonendocrine complications (relative risk [RR] 2.24, 95% CI 1.15–4.38; p = 0.02). Patients with Medicare had increased risk of higher charges (RR 1.89, 95% CI 1.04–3.45; p = 0.04), as did those with Medicaid (RR 1.93, 95% CI 1.10–3.41; p = 0.02). Additionally, as compared with white patients, Hispanic patients had an increased rate of higher charges (RR 1.86, 95% CI 1.12–3.10; p = 0.02). Patients whose age was less than 40 years had a higher risk of developing diabetes insipidus (RR 1.39, 95% CI 1.0–1.93; p = 0.05). When compared with those in northeast hospitals, patients in western hospitals were more likely to experience nonendocrine complications (RR 1.85, 95% CI 0.99–3.46; p = 0.05) and endocrine complications (RR 1.98, 95% CI 1.28–3.07; p < 0.01). Patients treated in teaching hospitals were at significantly lower risk of incurring higher hospital charges (RR 0.49, 95% CI 0.28–0.85; p = 0.01). Patients with emergency admissions had a risk of higher hospital charges (RR 3.06, 95% CI 1.26–7.46; p = 0.01) and nonendocrine complications (RR 3.18, 95% CI 1.22–8.28; p = 0.02).
This review of NIS data in more than 5500 patients treated surgically for CD pointed to major outcome disparities predicted primarily by payer status, admission type, and hospital region. Identification and targeting of such barriers to quality health care in patients with CD may help optimize patient outcomes on a national level and present an opportunity to improve access of high-risk patient subgroups to specialty centers of excellence.
Wouter I. Schievink, Miriam Nuño, Todd D. Rozen, M. Marcel Maya, Adam N. Mamelak, John Carmichael and Vivien S. Bonert
Spontaneous intracranial hypotension is an increasingly recognized cause of headaches. Pituitary enlargement and brain sagging are common findings on MRI in patients with this disorder. The authors therefore investigated pituitary function in patients with spontaneous intracranial hypotension.
Pituitary hormones were measured in a group of 42 consecutive patients with spontaneous intracranial hypotension. For patients with hyperprolactinemia, prolactin levels also were measured following treatment. Magnetic resonance imaging was performed prior to and following treatment.
The study group consisted of 27 women and 15 men with a mean age at onset of symptoms of 52.2 ± 10.7 years (mean ± SD; range 17–72 years). Hyperprolactinemia was detected in 10 patients (24%), ranging from 16 ng/ml to 96.6 ng/ml in men (normal range 3–14.7 ng/ml) and from 31.3 ng/ml to 102.5 ng/ml in women (normal range 3.8–23.2 ng/ml). In a multivariate analysis, only brain sagging on MRI was associated with hyperprolactinemia. Brain sagging was present in 60% of patients with hyperprolactinemia and in 19% of patients with normal prolactin levels (p = 0.02). Following successful treatment of the spontaneous intracranial hypotension, hyperprolactinemia resolved, along with normalization of brain MRI findings in all 10 patients.
Spontaneous intracranial hypotension is a previously undescribed cause of hyperprolactinemia. Brain sagging causing distortion of the pituitary stalk (stalk effect) may be responsible for the hyperprolactinemia.