Anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) therapies represent a novel approach to cancer treatment via disruption of immune tolerance to antigens located on tumor cells. Disruption of immune tolerance, however, may occur at a cost. A host of immune related adverse events (IRAEs) are associated with anti-CTLA-4 therapy. Autoimmune hypophysitis has been reported in up to 17% of patients with melanoma and renal cell carcinoma treated with this therapy. Familiarity with the spectrum of IRAEs connected to these therapies is paramount for endocrinologists, oncologists and those involved in the care of these subjects. We review here key aspects of diagnosis and treatment of anti-CTLA-4 antibody therapy resultant IRAEs. We describe the first two cases of hypopituitarism in prostate cancer subjects undergoing experimental therapy with ipilimumab. The clinical evidence strongly suggests that the prostate cancer subjects developed autoimmune hypophysitis as a consequence of anti-CTLA-4 treatment. High dose glucocorticoid treatment resulted in markedly improved symptoms, and resolution of focal symptoms and diabetes insipidus. One subject recovered pituitary-thyroid axis function after 9 months; however, both continue to require GC replacement. These cases highlight the importance of early screening and treatment for hypopituitarism in all subjects undergoing treatment with anti-CTLA-4 therapy to prevent a potentially fatal outcome from secondary adrenal insufficiency, a readily treatable disease. We recommend mandatory long term follow-up to monitor the development of other hormonal deficits.

Acromegaly is associated with serious morbidity and mortality, if not well controlled. Approved somatostatin receptor ligands (SRLs) are a mainstay of medical therapy and exhibit preferential affinity for somatostatin receptor (SSTR) subtype 2. Our objective was to assess whether characteristic features of individual growth hormone (GH)-secreting adenomas at diagnosis, correlated with SRL sensitivity, using defined tumor markers. A retrospective review of 86 consecutive acromegaly surgeries (70 patients) performed between January 2006 and December 2011 was undertaken. Patients with any preoperative medical treatment were excluded. Response to SRL therapy was defined as normalization of insulin-like growth factor 1 (IGF1) and random GH < 1.0 ng/dl. Immunohistochemical staining pattern: sparsely granulated, densely granulated, mixed growth hormone-prolactin (GH/PRL) and SSRT2 positivity (+) were correlated with clinicopathologic features, adenoma recurrence, and SRL treatment response. Two-tailed t test, univariate ANOVA, Kruskal-Wallis and bivariate correlation were performed using PAWS 18. The cohort eligible for analysis comprised 59 patients (41 female and 18 male). Based on pre-surgery adenoma imaging dimensions, 81.3% (48) were macroadenomas and average maximum tumor diameter was 18.1 ± 9.9 mm. Patients on SRLs were followed for 13.4 ± 15.8 (mean ± SD) months. Sparsely granulated adenomas were significantly larger at diagnosis, exhibited lower SSTR2 positivity and had a lower rate of biochemical normalization to SRLs. Densely granulated adenomas were highly responsive to SRLs. Overall, patients with SSTR2A+ adenomas responded more favorably to SRL treatment than those with SSTR2A- adenomas. Eighty-one percent of patients with SSTR2A+ adenomas were biochemically controlled (both GH and IGF1) on SRL treatment, e.g. a much higher normalization rate than that reported in the unselected acromegaly population (20-30%). Detailed knowledge of adenoma GH granularity and the immunohistochemical SSTR2A+ status is a predictor of SRL response. These immunoreactive markers should be assessed routinely on surgical specimens to assess subsequent SRL responsiveness and potential need for adjunctive therapy after surgery.

Postoperative serum cortisol is used as an indicator of Cushing's disease (CD) remission following transsphenoidal surgery (TSS) and guides (controversially) the need for immediate adjuvant treatment for CD. We investigated postoperative cortisol and adrenocorticotropic hormone (ACTH) levels as predictors of remission/recurrence in CD in a large retrospective cohort of patients with pathologically confirmed CD, over 6 years at a single institution. Midnight and morning cortisol, and ACTH at 24-48 h postoperatively (>24 h after last hydrocortisone dose) were measured. Remission was defined as normal 24-h urine free cortisol, normal midnight salivary cortisol, a normal dexamethasone-corticotropin releasing hormone (CRH) test or continued need for hydrocortisone, assessed periodically. Statistical analysis was performed using PASW 18. Follow up data was available for 52 patients (38 females and 14 males), median follow up was 16.5 month (range 2-143 months), median age was 45 years (range 21-72 years), 28 tumors were microadenomas and 16 were macroadenomas, and in eight cases no tumor was observed on magnetic resonance imaging. No patient with postoperative cortisol levels >10 mcg/dl were found to be in remission. Ten of the 52 patients with cortisol >10 mcg/dl by postoperative day 1-2 underwent a second TSS within 7 days. Forty-three patients (82.7%) achieved CD remission (36 after one TSS and 7 after a second early TSS) and six patients suffered disease recurrence (mean 39.2 ± 52.4 months). An immediate second TSS induced additional hormonal deficiencies (diabetes insipidus) in three patients with no surgical complications. Persistent disease was noted in nine patients despite three patients having an immediate second TSS. Positive predictive value for remission of cortisol <2 mcg/dl and ACTH <5 pg/ml was 100%. Cortisol and ACTH levels (at all postoperative time points and at 2 months) were correlated (r = 0.37, P < 0.001). Nadir serum cortisol of ≤2 mcg/dl and ACTH <5 pg/ml predicted remission (P < 0.005), but no level predicted lack of recurrence. Immediate postoperative ACTH/cortisol did not predict length of remission. No patients with postoperative cortisol >10 mcg/dl were observed to have delayed remission; all required additional treatment. There was no significant difference in age, body mass index, tumor size and length of follow-up between postoperative cortisol groups: cortisol ≤2 mcg/dl, cortisol >5 mcg/dl and cortisol >10 mcg/dl. Immediate postoperative cortisol levels should routinely be obtained in CD patients post TSS, until better tools to identify early remission are available. Immediate repeat TSS could be beneficial in patients with cortisol >10 mcg/dl and positive CD pathology: our combined (micro- and macroadenomas) remission rate with this approach was 82.7%. ACTH measurements correlate well with cortisol. However, because no single cortisol or ACTH cutoff value excludes all recurrences, patients require long-term clinical and biochemical follow-up. Further research is needed in this area.