Macroprolactinoma with secondary resistance to dopamine agonists: a case report and review of the literature.

BACKGROUND: Resistance to dopamine agonists is not uncommonly seen in prolactinomas. However, development of resistance to dopamine agonists after an initial period of robust treatment response is rare, and only 39 cases have been reported in the past four decades. We describe a Chinese man with this rare condition and explored the postulated mechanisms that may explain this phenomenon. We compiled similar cases that were previously reported and compared their etiology, progress, and response to treatment. On the basis of these cases, we derived a list of differential diagnoses to consider in patients with secondary resistance to dopamine agonists. CASE PRESENTATION: A 63-year-old Chinese man presented with blurred vision and was subsequently diagnosed with a macroprolactinoma. He had initial response to cabergoline but developed secondary resistance to it after 5 years. The prolactinoma continued to grow, and his serum prolactin remained markedly elevated despite adherence to escalating dosages of cabergoline up to 6 mg/week. The patient finally underwent transsphenoidal surgery and was found to have a sparsely granulated lactotroph tumor with Ki-67 index of 5%. Postoperatively, there was improvement in his serum prolactin level, although he still required treatment with cabergoline at 6 mg/week. CONCLUSIONS: Surgery can facilitate disease control in patients with prolactinomas that develop secondary resistance to dopamine agonists. Malignant prolactinoma is an important differential diagnosis in this group of patients, especially when serum prolactin remains markedly elevated despite resolution or stability of the primary pituitary lesion, suggesting a metastatic source of prolactin secretion.

11C-Metomidate PET-CT versus adrenal vein sampling to subtype primary aldosteronism: a prospective clinical trial.

OBJECTIVE: Adrenal vein sampling (AVS) is recommended to subtype primary aldosteronism, but it is technically challenging. We compared 11C-Metomidate-PET-computed tomography (PET-CT) and AVS for subtyping of primary aldosteronism. METHODS: Patients with confirmed primary aldosteronism underwent both AVS and 11C-Metomidate PET-CT (post-dexamethasone). All results were reviewed at a multidisciplinary meeting to decide on final subtype diagnosis. Primary outcome was accuracy of PET versus AVS to diagnosis of unilateral primary aldosteronism based on post-surgical biochemical cure. Secondary outcome was accuracy of both tests to final subtype diagnosis. RESULTS: All 25 patients recruited underwent PET and successful AVS (100%). Final diagnosis was unilateral in 22 patients, bilateral in two and indeterminate in one due to discordant lateralization. Twenty patients with unilateral primary aldosteronism underwent surgery, with 100% complete biochemical success, and 75% complete/partial clinical success. For the primary outcome, sensitivity of PET was 80% [95% confidence interval (95% CI): 56.3-94.3] and AVS was 75% (95% CI: 50.9-91.3). For the secondary outcome, sensitivity and specificity of PET was 81.9% (95% CI: 59.7-94.8) and 100% (95% CI: 15.8-100), and AVS was 68.2% (95% CI: 45.1-86.1) and 100% (95% CI: 15.8-100), respectively. Twelve out of 20 (60%) patients had both PET and AVS lateralization, four (20%) PET-only, three (15%) AVS-only, while one patient did not lateralize on PET or AVS. Post-surgery outcomes did not differ between patients identified by either test. CONCLUSION: In our pilot study, 11C-Metomidate PET-CT performed comparably to AVS, and this should be validated in larger studies. PET identified patients with unilateral primary aldosteronism missed on AVS, and these tests could be used together to identify more patients with unilateral primary aldosteronism. VIDEO ABSTRACT: http://links.lww.com/HJH/B918.

Physiological and Pathological Roles in Human Adrenal of the Glomeruli-Defining Matrix Protein NPNT (Nephronectin).

Primary aldosteronism is a common cause of hypertension, which becomes refractory if undiagnosed, but potentially curable when caused by an aldosterone-producing adenoma (APA). The discovery of somatic mutations and differences in clinical presentations led to recognition of small but common zona glomerulosa (ZG)-like adenomas, distinct from classical large zona fasciculata-like adenomas. The inverse correlation between APA size and aldosterone synthase expression prompted us to undertake a systematic study of genotype-phenotype relationships. After a microarray comparing tumor subtypes, in which NPNT (nephronectin) was the most highly (>12-fold) upregulated gene in ZG-like APAs, we aimed to determine its role in physiological and pathological aldosterone production. NPNT was identified by immunohistochemistry as a secreted matrix protein expressed exclusively around aldosterone-producing glomeruli in normal adrenal ZG and in aldosterone-dense ZG-like APAs; the highest expression was in ZG-like APAs with gain-of-function CTNNB1 mutations, whose removal cured hypertension in our patients. NPNT was absent from normal zona fasciculata, zona fasciculata-like APAs, and ZG adjacent to an APA. NPNT production was regulated by canonical Wnt pathway, and NPNT overexpression or silencing increased or reduced aldosterone, respectively. NPNT was proadhesive in primary adrenal and APA cells but antiadhesive and antiapoptotic in immortalized adrenocortical cells. The discovery of NPNT in the adrenal helped recognition of a common subtype of APAs and a pathway by which Wnt regulates aldosterone production. We propose that this arises through NPNT's binding to cell-surface integrins, stimulating cell-cell contact within glomeruli, which define ZG. Therefore, NPNT or its cognate integrin could present a novel therapeutic target.