USP8 and TP53 Drivers are Associated with CNV in a Corticotroph Adenoma Cohort Enriched for Aggressive Tumors.

CONTEXT: Pituitary corticotroph adenomas are rare tumors that can be associated with excess adrenocorticotropin (ACTH) and adrenal cortisol production, resulting in the clinically debilitating endocrine condition Cushing disease. A subset of corticotroph tumors behave aggressively, and genomic drivers behind the development of these tumors are largely unknown. OBJECTIVE: To investigate genomic drivers of corticotroph tumors at risk for aggressive behavior. DESIGN: Whole-exome sequencing of patient-matched corticotroph tumor and normal deoxyribonucleic acid (DNA) from a patient cohort enriched for tumors at risk for aggressive behavior. SETTING: Tertiary care center. PATIENTS: Twenty-seven corticotroph tumors from 22 patients were analyzed. Twelve tumors were macroadenomas, of which 6 were silent ACTH tumors, 2 were Crooke's cell tumors, and 1 was a corticotroph carcinoma. INTERVENTION: Whole-exome sequencing. MAIN OUTCOME MEASURE: Somatic mutation genomic biomarkers. RESULTS: We found recurrent somatic mutations in USP8 and TP53 genes, both with higher allelic fractions than other somatic mutations. These mutations were mutually exclusive, with TP53 mutations occurring only in USP8 wildtype (WT) tumors, indicating they may be independent driver genes. USP8-WT tumors were characterized by extensive somatic copy number variation compared with USP8-mutated tumors. Independent of molecular driver status, we found an association between invasiveness, macroadenomas, and aneuploidy. CONCLUSIONS: Our data suggest that corticotroph tumors may be categorized into a USP8-mutated, genome-stable subtype versus a USP8-WT, genome-disrupted subtype, the latter of which has a TP53-mutated subtype with high level of chromosome instability. These findings could help identify high risk corticotroph tumors, namely those with widespread CNV, that may need closer monitoring and more aggressive treatment.

RECURRENT PITUITARY APOPLEXY IN AN ADENOMA WITH SWITCHING PHENOTYPES.

OBJECTIVE: To describe an unusual presentation of a patient with recurrent pituitary apoplexy of an adenoma that switched phenotypes from a nonfunctioning, or silent gonadotroph adenoma (SGA), to a silent corticotroph adenoma (SCA). We discuss the potential etiologies of both recurrent pituitary apoplexy and phenotype switching of pituitary tumors. METHODS: The presented case includes clinical and biochemical findings, surgical outcomes, and pathologic reports related to the treatment of our patient who presented with recurrent pituitary apoplexy. RESULTS: A 56-year-old man presented for evaluation of decreased libido and was found to have a low testosterone level. A pituitary magnetic resonance image demonstrated an 8-mm pituitary adenoma. He underwent transsphenoidal surgery (TSS) to remove the tumor and pathology demonstrated an SGA immunopositive for luteinizing hormone and follicle-stimulating hormone with evidence of apoplexy. Eight years later, the patient underwent another TSS after developing acute-onset headache, vomiting, and a cranial nerve palsy. Pathology at this time showed a necrotic tumor consistent with apoplexy with negative immunostains for all pituitary tumors. Three years after this, the tumor recurred and after another TSS the tumor stained positive for adrenocorticotropic hormone but was negative for luteinizing hormone and follicle-stimulating hormone with hemorrhage consistent with apoplexy. A few years afterward, he again developed acute-onset headache and cranial nerve palsies and had another TSS. On pathology, the tumor demonstrated extensive necrosis consistent with apoplexy and again stained positive for adrenocorticotropic hormone. The patient was then referred for radiation therapy and was subsequently lost to follow up. CONCLUSION: Recurrent pituitary apoplexy in the same patient has only been described 3 times in the literature. There have been no case reports of a pituitary adenoma that switched phenotypes from an SGA to SCA. We suggest that pituitary apoplexy may recur multiple times due to a tumor with particularly fragile vessel walls and increased vascularization. We review the literature that suggests clinical and molecular similarities between SGAs and SCAs. Further studies are needed to determine the etiologies of recurrent apoplexy and pituitary adenomas with switching phenotypes.

Identification of a novel RASD1 somatic mutation in a USP8-mutated corticotroph adenoma.

Cushing's disease (CD) is caused by pituitary corticotroph adenomas that secrete excess adrenocorticotropic hormone (ACTH). In these tumors, somatic mutations in the gene USP8 have been identified as recurrent and pathogenic and are the sole known molecular driver for CD. Although other somatic mutations were reported in these studies, their contribution to the pathogenesis of CD remains unexplored. No molecular drivers have been established for a large proportion of CD cases and tumor heterogeneity has not yet been investigated using genomics methods. Also, even in USP8-mutant tumors, a possibility may exist of additional contributing mutations, following a paradigm from other neoplasm types where multiple somatic alterations contribute to neoplastic transformation. The current study utilizes whole-exome discovery sequencing on the Illumina platform, followed by targeted amplicon-validation sequencing on the Pacific Biosciences platform, to interrogate the somatic mutation landscape in a corticotroph adenoma resected from a CD patient. In this USP8-mutated tumor, we identified an interesting somatic mutation in the gene RASD1, which is a component of the corticotropin-releasing hormone receptor signaling system. This finding may provide insight into a novel mechanism involving loss of feedback control to the corticotropin-releasing hormone receptor and subsequent deregulation of ACTH production in corticotroph tumors.

PREVELENCE OF PRIMARY ALDOSTERONISM IN AN URBAN HYPERTENSIVE POPULATION.

OBJECTIVE: To determine the prevalence of primary aldosteronism (PA) in hypertensive patients presenting to the primary care clinic at The Mount Sinai Hospital, regardless of the degree of hypertension and to identify clinical criteria that should prompt screening for PA. METHODS: An aldosterone:renin ratio (ARR, cutoff ≥20, with plasma aldosterone concentration [PAC] ≥10 and suppressed renin) was used to prospectively screen 296 hypertensive patients (blood pressure [BP] ≥140/90) over the age of 18 from August 2012 through May 2013. Subjects who screened positive then underwent confirmatory oral salt load testing (OSLT). RESULTS: Of the 296 patients, 14 screened positive for PA, an overall prevalence of 4.7%. Six of the 14 cases underwent confirmatory OSLT, upon which 2 were confirmed positive, for a prevalence of 0.7%. Overall, patients with confirmed PA were more likely to have resistant hypertension (42.9% vs. 18.1% (P = .0334)) and require more antihypertensive agents (2.8 ± 1.2 agents vs. 2.1 ± 1.1 agents, P = .0213). There was a trend toward lower potassium values in the cases. CONCLUSION: The prevalence of PA in our clinic is much lower than in reports from certain "at-risk" populations. PA screening is indicated in patients with resistant hypertension, regardless of serum potassium levels. ABBREVIATIONS: ARR = aldosterone:renin ratio ACTH = adrenocorticotropic hormone AVS = adrenal venous sampling BP = blood pressure MRA = mineralocorticoid receptor antagonist OSLT = oral salt load confirmatory test PA = primary aldosteronism PAC = plasma aldosterone concentration PCP = primary care provider PRA = plasma renin activity.

Primary aldosteronism: emerging trends.

Primary aldosteronism (PA) is the most common etiology of endocrine hypertension (HTN), and recent prevalence studies suggest that it may be under-diagnosed. Indications for screening have been expanded with recognition that many patients with PA do not have hypokalemia and that the disease may be familial. The aldosterone:renin ratio (ARR) is the preferred screening test for PA. The ARR can be interpreted in patients on most anti-hypertensive agents, and can be used to guide medical therapy of HTN even in patients without PA. Once PA is confirmed, adrenal venous sampling (AVS) should be performed to determine if PA is due to bilateral disease or a unilateral adenoma, if surgery is being considered. Targeted medical or surgical therapy improves patient outcomes.