Autoimmune Disorders Associated With Surgical Remission of Cushing's Disease : A Cohort Study.

BACKGROUND: Glucocorticoids suppress inflammation. Autoimmune disease may occur after remission of Cushing's disease (CD). However, the development of autoimmune disease in this context is not well described. OBJECTIVE: To determine 1) the incidence of autoimmune disease in patients with CD after surgical remission compared with patients with nonfunctioning pituitary adenomas (NFPAs) and 2) the clinical presentation of and risk factors for development of autoimmune disease in CD after remission. DESIGN: Retrospective matched cohort analysis. SETTING: Academic medical center/pituitary center. PATIENTS: Patients with CD with surgical remission and surgically treated NFPA. MEASUREMENTS: Cumulative incidence of new-onset autoimmune disease at 3 years after surgery. Assessment for hypercortisolemia included late-night salivary cortisol levels, 24-hour urine free cortisol (UFC) ratio (UFC value divided by the upper limit of the normal range for the assay), and dexamethasone suppression tests. RESULTS: Cumulative incidence of new-onset autoimmune disease at 3 years after surgery was higher in patients with CD (10.4% [95% CI, 5.7% to 15.1%]) than in those with NFPAs (1.6% [CI, 0% to 4.6%]) (hazard ratio, 7.80 [CI, 2.88 to 21.10]). Patients with CD showed higher prevalence of postoperative adrenal insufficiency (93.8% vs. 16.5%) and lower postoperative nadir serum cortisol levels (63.8 vs. 282.3 nmol/L) than patients with NFPAs. Compared with patients with CD without autoimmune disease, those who developed autoimmune disease had a lower preoperative 24-hour UFC ratio (2.7 vs. 6.3) and a higher prevalence of family history of autoimmune disease (41.2% vs. 20.9%). LIMITATION: The small sample of patients with autoimmune disease limited identification of independent risk factors. CONCLUSION: Patients achieving surgical remission of CD have higher incidence of autoimmune disease than age- and sex-matched patients with NFPAs. Family history of autoimmune disease is a potential risk factor. Adrenal insufficiency may be a trigger. PRIMARY FUNDING SOURCE: Recordati Rare Diseases Inc.

Health-related quality of life analyses in nonfunctioning pituitary macroadenoma patients identifies at-risk populations.

PURPOSE: The quality of life (QoL) impact of multidisciplinary treatment for patients with nonfunctioning pituitary macroadenomas (NFPMA) is unclear. We sought to investigate associations between patient factors, clinical data, and patient-reported QoL in patients with NFPMA. METHODS: Patients with treated NFPMA and > 1 year of follow up after transsphenoidal surgery (TSS) and with no evidence of progressive disease were evaluated utilizing the following patient-reported outcome measures: RAND-36-Item Health Survey, Multidimensional Fatigue Inventory, Cognitive Failures Questionnaire. RESULTS: 229 eligible patients completed QoL questionnaires a median of 7.7 years after initial transsphenoidal surgery (TSS). 25% of participants received radiation therapy (RT) a median of 2.0 years (0.1-22.5) after initial TSS. Patients who received RT were younger (median age 46 v 58, p < 0.0001), had larger tumors (28 mm v 22 mm, p < 0.0001), were more likely to have visual symptoms (65% v 34%, p = 0.0002), and were more likely to have hypopituitarism (93% v 62%, p < 0.0001). Patients with hypopituitarism reported worse energy and fatigue and cognitive function (p < 0.03). Patients who received RT reported significantly worse general health, physical health, physical fatigue and cognitive functioning (p < 0.05). The largest QoL differences were in patients who experienced a financial stressor, independent of treatment type. CONCLUSION: Hypopituitarism, radiation therapy after TSS, and financial stressors are associated with more impaired QoL in patients with NFPMA. Awareness of these factors can better guide use and timing of radiation therapy in addition to identifying patients who can benefit from multidisciplinary surveillance.

Pituitary surgery in Cushing's disease: first line treatment and role of reoperation.

Cushing's disease is the most common cause of endogenous hypercortisolemia, and transsphenoidal surgery remains the first line therapy for removal of the ACTH-secreting adenoma. While post-operative remission rates are high in experienced hands, there remains a 2% risk of recurrence per year. Patients with the highest chance for cure are those with small, non-invasive tumors that are visible on pre-operative MRI and identified during surgery and are performed by high-volume pituitary neurosurgeons. Surgery for persistent or recurrent disease is frequently indicated and is most successful in the hands of experienced surgeons and in cases where tumor is visible on MRI.

High Histone Deacetylase 2/3 Expression in Non-Functioning Pituitary Tumors.

Epigenetic modification of chromatin is involved in non-malignant pituitary neoplasia by causing abnormal expression of tumor suppressors and oncogenes. These changes are potentially reversible, suggesting the possibility of targeting tumor cells by restoring the expression of epigenetically silenced tumor suppressors. The role of the histone deacetylase (HDAC) family in pituitary tumorigenesis is not known. We report that HDAC2 and 3, Class I HDAC members, are highly expressed in clinically non-functioning pituitary adenomas (NFPAs) compared to normal pituitary (NP) samples as determined by RT-PCR and immunohistochemical staining (IHC). Treatment of a human NFPA derived folliculostellate cell line, PDFS, with the HDAC3 inhibitor RGFP966 for 96 hours resulted in inhibition of cell proliferation by 70%. Furthermore, the combination of RGFP966 with a methyltransferase/DNMT inhibitor, 5'-aza-2'-deoxycytidine, led to the restoration of the expression of several tumor suppressor genes, including STAT1, P16, PTEN, and the large non-coding RNA tumor suppressor MEG3, in PDFS cells. Our data support the hypothesis that both histone modification and DNA methylation are involved in the pathogenesis of human NFPAs and suggest that targeting HDACs and DNA methylation can be incorporated into future therapies.

Sprouting Angiogenesis in Human Pituitary Adenomas.

Introduction: Angiogenesis in pituitary tumors is not fully understood, and a better understanding could help inform new pharmacologic therapies, particularly for aggressive pituitary tumors. Materials and Methods: 219 human pituitary tumors and 12 normal pituitary glands were studied. Angiogenic genes were quantified by an angiogenesis qPCR array and a TaqMan probe-based absolute qPCR. Angiogenesis inhibition in pituitary tumors was evaluated in vitro with the endothelial tube formation assay and in vivo in RbΔ19 mice. Results: 71 angiogenic genes, 40 of which are known to be involved in sprouting angiogenesis, were differentially expressed in pituitary tumors. Expression of endothelial markers CD31, CD34, and ENG was significantly higher in pituitary tumors, by 5.6, 22.3, and 8.2-fold, respectively, compared to in normal pituitary tissue. There was no significant difference in levels of the lymphatic endothelial marker LYVE1 in pituitary tumors compared with normal pituitary gland tissue. Pituitary tumors also expressed significantly higher levels of angiogenesis growth factors, including VEGFA (4.2-fold), VEGFB (2.2), VEGFC (19.3), PGF (13.4), ANGPT2 (9.2), PDGFA (2.7), PDGFB (10.5) and TGFB1 (3.8) compared to normal pituitary tissue. Expression of VEGFC and PGF was highly correlated with the expression of endothelial markers in tumor samples, including CD31, CD34, and ENG (endoglin, a co-receptor for TGFß). Furthermore, VEGFR inhibitors inhibited angiogenesis induced by human pituitary tumors and prolonged survival of RbΔ19 mice. Conclusion: Human pituitary tumors are characterized by more active angiogenesis than normal pituitary gland tissue in a manner consistent with sprouting angiogenesis. Angiogenesis in pituitary tumors is regulated mainly by PGF and VEGFC, not VEGFA and VEGFB. Angiogenesis inhibitors, such as the VEGFR2 inhibitor cabozantinib, may merit further investigation as therapies for aggressive human pituitary tumors.

Recurrent Acromegaly in a Patient With a CHEK2 Mutation.

Background/Objective: CHEK2 is a cell-cycle checkpoint kinase and is part of the ATM-CHEK2-p53 cascade, which is protective against carcinogenesis. We describe a germline CHEK2 mutation in a patient with acromegaly and other tumors. Case Report: We present a woman with a germline CHEK2∗ 110delC mutation previously diagnosed with fibroadenoma of the breast and papillary thyroid carcinoma. She presented with acromegaly at age 48 (insulin-like growth factor 1, 556 mcg/L [reference range, 90-360] and lack of growth hormone suppression on glucose tolerance testing) and underwent transsphenoidal resection of a somatotroph microadenoma. Four years after surgery, she developed recurrent growth hormone excess. She was treated with cabergoline, which was discontinued due to intolerance, and transitioned to lanreotide depot, which was switched to pegvisomant because of prediabetes. Her insulin-like growth factor 1 levels remained normal on pegvisomant. Follow-up magnetic resonance imaging examinations showed no evidence of tumor progression. Shortly after the diagnosis of acromegaly, the patient was diagnosed with endometrial carcinoma, bilateral ovarian cystadenomas, and uterine leiomyomas. She was additionally found to have a nonfunctioning adrenal nodule and hyperplastic and adenomatous colon polyps. There are multiple family members with malignancies, including colon, thyroid, and lung cancer. Discussion: This is a novel report of a patient with a pathogenic germline CHEK2 mutation and multiple malignant and benign tumors, including recurrent acromegaly. Conclusion: Our data raise the possibility that CHEK2 mutations may be involved in the development of acromegaly. Additional studies are needed to elucidate the potential role of CHEK2 mutations in the pathogenesis of somatotroph adenomas.

Quality of life after long-term biochemical control of acromegaly.

PURPOSE: To assess long-term quality of life (QoL) in patients with sustained biochemical control of acromegaly, comparing those receiving vs not receiving pharmacotherapy (primary analysis); to assess change in QoL over time (secondary analysis). METHODS: Cross-sectional study, with a secondary longitudinal component, of 58 patients with biochemically controlled acromegaly. All had participated in studies assessing QoL years previously, after having undergone surgery ± radiotherapy. One cohort received medical therapy [MED (n = 33)]; the other did not [NO-MED (n = 25)]. QoL was assessed by the 36-Item-Short-Form Health Survey (SF-36), Acromegaly Quality of Life Questionnaire (AcroQoL), Gastrointestinal Quality of Life Index (GIQLI), Symptom Questionnaire, and QoL-Assessment of Growth Hormone Deficiency in Adults (QoL-AGHDA). RESULTS: Mean (± SD) duration of biochemical control was 15.0 ± 6.4 years for MED and 20.4 ± 8.2 years for NO-MED (p = 0.007). 58% of subjects scored < 25% of normal on ≥ 1 SF-36 domain and 32% scored < 25% of normal on ≥ 4 of 8 domains. Comparing MED vs NO-MED and controlling for duration of biochemical control, there were no significant differences in QoL by SF-36, AcroQOL, GIQLI, Symptom Questionnaire, or QoL-AGHDA. Growth hormone deficiency (GHD) but not radiotherapy predicted poorer QoL. In MED, QoL improved over time in three AcroQoL domains and two GIQLI domains. In NO-MED, QoL worsened in two SF-36 domains and two Symptom Questionnaire domains; QoL-AGHDA scores also worsened in subjects with GHD. CONCLUSION: A history of acromegaly and development of GHD, but not pharmacologic or radiotherapy, are detrimental to QoL, which remains poor over the long-term despite biochemical control.

The Prolactin per Unit Tumor Volume Ratio Accurately Distinguishes Prolactinomas From Secondary Hyperprolactinemia due to Stalk Effect.

OBJECTIVE: The prolactin levels alone are insufficient to distinguish between some cases of prolactinomas and stalk effect. We aimed to formally characterize the relationship between serum prolactin and prolactinoma volume, determine a cutoff for prolactin/mm3 that accurately distinguishes prolactinomas from stalk effect, and validate this cutoff in a cohort selected to include ambiguous prolactin values ranging from 50 to 150 ng/mL. METHODS: We used the Research Patient Data Registry and transsphenoidal surgery database in our institution to retrospectively identify adult patients with clinically nonfunctioning (NF) tumors (primary analysis, n = 279; validation cohort, n = 10) and prolactinomas (primary analysis, n = 94; validation cohort, n = 18). Solid tumor volumes were measured by Visage 7 software, and cystic foci within tumors were excluded. RESULTS: Prolactin levels were significantly correlated with prolactinoma volume (r2 = 0.801) but were not a relevant predictor of NF tumor size (r2 = 0.015). The prolactin/mm3 values did not overlap between NF tumors (median, 0.016; interquartile range, 0.009-0.028) and prolactinomas (median, 0.551; interquartile range, 0.265-0.845) (P < .0001). A cutoff of 0.065 ng/mL)/mm3 correctly discriminated between prolactinomas and NF tumors in all 401 patients in the primary analysis and validation cohort. CONCLUSION: The prolactin/volume ratio correctly distinguished all prolactinomas from stalk effect in this study, including a validation cohort specifically chosen for potential ambiguity. To our knowledge, this study is the first formal volumetric analysis of prolactin secretion in pituitary adenomas, and our results suggest that the measurement of prolactin/mm3 is a valuable tool to better characterize challenging cases of primary tumoral secretion versus secondary hyperprolactinemia due to stalk effect.

Consensus on diagnosis and management of Cushing's disease: a guideline update.

Cushing's disease requires accurate diagnosis, careful treatment selection, and long-term management to optimise patient outcomes. The Pituitary Society convened a consensus workshop comprising more than 50 academic researchers and clinical experts to discuss the application of recent evidence to clinical practice. In advance of the virtual meeting, data from 2015 to present about screening and diagnosis; surgery, medical, and radiation therapy; and disease-related and treatment-related complications of Cushing's disease summarised in recorded lectures were reviewed by all participants. During the meeting, concise summaries of the recorded lectures were presented, followed by small group breakout discussions. Consensus opinions from each group were collated into a draft document, which was reviewed and approved by all participants. Recommendations regarding use of laboratory tests, imaging, and treatment options are presented, along with algorithms for diagnosis of Cushing's syndrome and management of Cushing's disease. Topics considered most important to address in future research are also identified.

Effects of growth hormone receptor antagonism and somatostatin analog administration on quality of life in acromegaly.

OBJECTIVE: Acromegaly is associated with impaired quality of life (QoL). We investigated the effects of biochemical control of acromegaly by growth hormone receptor antagonism vs somatostatin analog therapy on QoL. DESIGN: Cross-sectional. PATIENTS: 116 subjects: n = 55 receiving a somatostatin analog (SSA group); n = 29 receiving pegvisomant (PEG group); n = 32 active acromegaly on no medical therapy (ACTIVE group). MEASUREMENTS: Acromegaly QoL Questionnaire (AcroQoL), Rand 36-Item Short Form Survey (SF-36) and Gastrointestinal QoL Index (GIQLI); fasting glucose, insulin and IGF-1 levels (LC/MS, Quest Diagnostics). RESULTS: There were no group differences in mean age, BMI or sex [(whole cohort mean ± SD) age 52 ± 14 years, BMI 30 ± 6 kg/m2 , and male sex 38%]. Mean IGF-1 Z-scores were higher in ACTIVE (3.9 ± 1.0) vs SSA and PEG, which did not differ from one another (0.5 ± 0.7 and 0.5 ± 0.7, P < .0001 vs ACTIVE). Eighty-three per cent of PEG previously received somatostatin analogs, which had been discontinued due to lack of efficacy (52%) or side effects (41%). There were no differences in the four QoL primary end-points (AcroQoL Global Score, SF-36 Physical Component Summary Score, SF-36 Mental Health Summary Score and GIQLI Global Score) between SSA and PEG. Higher HbA1c, BMI and IGF-1 Z-scores were associated with poorer QoL in several domains. CONCLUSION: Our data support a comparable QoL in patients receiving pegvisomant vs somatostatin analogs, despite the fact that the vast majority receiving pegvisomant did not respond to or were not able to tolerate somatostatin analogs.

Multidisciplinary management of acromegaly: A consensus.

The 13th Acromegaly Consensus Conference was held in November 2019 in Fort Lauderdale, Florida, and comprised acromegaly experts including endocrinologists and neurosurgeons who considered optimal approaches for multidisciplinary acromegaly management. Focused discussions reviewed techniques, results, and side effects of surgery, radiotherapy, and medical therapy, and how advances in technology and novel techniques have changed the way these modalities are used alone or in combination. Effects of treatment on patient outcomes were considered, along with strategies for optimizing and personalizing therapeutic approaches. Expert consensus recommendations emphasize how best to implement available treatment options as part of a multidisciplinary approach at Pituitary Tumor Centers of Excellence.

Clinical MEN-1 Among a Large Cohort of Patients With Acromegaly.

CONTEXT: Clinical multiple endocrine neoplasia type 1 (MEN-1) is diagnosed by the presence of at least 2 MEN-1-associated tumors. Many patients with acromegaly and clinical MEN-1 yield negative testing for MEN1 mutations. While cases of acromegaly and primary hyperparathyroidism (PHP) with negative genetic testing have been reported, its prevalence among patients with acromegaly is undetermined, and the clinical presentation has not been well characterized. OBJECTIVES: The main goals of this study are: (1) To determine the prevalence of clinical MEN-1 with PHP in patients with acromegaly and characterize their clinical features; and (2) to evaluate the genetic basis for the coexistence of acromegaly and PHP. DESIGN: Retrospective record review and genetic analysis. SETTING: Clinical Research Centers. PARTICIPANTS: 414 patients with acromegaly. INTERVENTIONS: Clinical evaluation and DNA sequencing for MEN1, CDKN1A, CDKN1B, CDKN2B, CDKN2C, and AIP genes. MAIN OUTCOME MEASUREMENTS: Clinical and genetic analysis. RESULTS: Among patients with acromegaly, clinical MEN-1, as defined by the presence of at least one other MEN-1-associated tumor, was present in 6.6%. PHP occurred in 6.1%; more than half had parathyroid hyperplasia. DNA sequencing was unrevealing for genetic mutations, except for 1 case of a CDC73 mutation. Acromegaly was diagnosed at an older age with a higher prevalence of malignancies (specifically breast and thyroid) in patients with coexisting PHP than those with isolated acromegaly. CONCLUSIONS: A distinct phenotype is described in patients with clinical MEN-1 and negative genetic testing for mutations previously associated with this syndrome. Further studies are needed to identify other genes that may explain the association between PHP and acromegaly.

Stereotactic Radiation as Salvage Therapy for Recurrent Rathke Cleft Cysts.

BACKGROUND: Rathke cleft cysts (RCCs) are sellar-based cystic lesions that are often found incidentally but occasionally become symptomatic with significant visual and/or endocrine deficits. The standard of treatment is surgery, but rare cases of multiply recurrent RCCs can be refractory to surgical drainage, leading to significant morbidity. OBJECTIVE: To demonstrate the safety and feasibility of fractionated stereotactic radiotherapy (SRT) as salvage therapy in multiply recurrent RCCs refractory to surgical drainage. METHODS: An IRB-approved retrospective review at a single institution was conducted to identify and describe patients with multiply recurrent RCCs refractory to surgical drainage who underwent SRT. RESULTS: From 1994 to 2015, 6 patients (5 female) who underwent SRT for recurrent RCCs were identified. A total of 4 presented with visual deficits, and 2 presented with endocrine dysfunction and severe headaches prior to their initial drainage. All patients had initial postoperative improvement but then developed multiple, symptomatic recurrences. Median number of surgical drainage procedures prior to radiotherapy was 3. A total of 3 patients underwent LINAC-based SRT, and 3 had proton-based SRT. Treatment doses were 45 Gy over 25 fractions (n = 5) and 50.4 Gy over 28 fractions (n = 1). Median follow-up after radiation therapy was 69 mo (range 24-154 mo). In the follow-up period, stabilization of the RCC was achieved, although 2 patients required additional drainage procedures. Only 1 patient developed new hypothyroidism and hypoadrenalism after SRT. CONCLUSION: In rare cases of multiply recurrent RCCs refractory to repeat surgical drainage, stereotactic fractionated radiation therapy is a safe and effective salvage therapy.

MRI texture analysis in acromegaly and its role in predicting response to somatostatin receptor ligands.

PURPOSE: Given the paucity of reliable predictors of tumor recurrence, progression, or response to somatostatin receptor ligand (SRL) therapy in acromegaly, we attempted to determine whether preoperative MR image texture was predictive of these clinical outcomes. We also determined whether image texture could differentiate somatotroph adenomas from non-functioning pituitary adenomas (NFPAs). METHODS: We performed a retrospective study of patients with acromegaly due to a macroadenoma who underwent transsphenoidal surgery at our institution between 2007 and 2015. Clinical data were extracted from electronic medical records. MRI texture analysis was performed on preoperative non-enhanced T1-weighted images using ImageJ (NIH). Logistic and Cox models were used to determine if image texture parameters predicted outcomes. RESULTS: Eighty-nine patients had texture parameters measured, which were compared to that of NFPAs, while 64 of these patients had follow-up and were included in the remainder of analyses. Minimum pixel intensity, skewness, and kurtosis were significantly different in somatotroph adenomas versus NFPAs (area under the receiver operating characteristic curve, 0.7771, for kurtosis). Furthermore, those with a maximum pixel intensity above the median had an increased odds of IGF-I normalization on SRL therapy (OR 5.96, 95% CI 1.33-26.66), which persisted after adjusting for several potential predictors of response. Image texture did not predict tumor recurrence or progression. CONCLUSION: Our data suggest that MRI texture analysis can distinguish NFPAs from somatotroph macroadenomas with good diagnostic accuracy and can predict normalization of IGF-I with SRL therapy.

Biochemical Control in Acromegaly With Multimodality Therapies: Outcomes From a Pituitary Center and Changes Over Time.

PURPOSE: To determine the prevalence of insulin-like growth factor-1 (IGF-1) normalization with long-term multimodality therapy in a pituitary center and to assess changes over time. METHODS: Patients with acromegaly (N = 409), with ≥1 year of data after surgery and at least 2 subsequent clinic visits were included in long-term analysis (N = 266). Biochemical data, clinical characteristics, and therapeutic interventions were reviewed retrospectively. RESULTS: At diagnosis, mean [standard deviation] age was 43.4 [14.3] years, body mass index was 28.5 (24.9-32.1) kg/m2 (median, interquartile range), serum IGF-1 index (IGF-1 level/upper limit of normal) was 2.3 [1.7-3.1], and 80.5% had macroadenomas. Patients with transsphenoidal surgery after 2006 were older [46.6 ± 14.3 vs 40.0 ± 13.4 years; P < 0.001]. Age and tumor size correlated inversely. Overall (N = 266), 93.2% achieved a normal IGF-1 level during 9.9 [5.0-15.0] years with multimodality therapy. The interval to first normal IGF-1 level following failed surgical remission was shorter after 2006: 14.0 (95% confidence interval, 10.0-20.0) versus 27.5 (22.0-36.0) months (P = 0.002). Radiation therapy and second surgery were rarer after 2006: 28 (22%) versus 62 (47.0%); P < 0.001 and 12 (9.4%) versus 28 (21.2%); P = 0.010, respectively. Age at diagnosis increased over time periods, possibly reflecting increased detection of acromegaly in older patients with milder disease. Male gender, older age, smaller tumor and lower IGF-1 index at diagnosis predicted long-term sustained IGF-1 control after surgery without adjuvant therapies. CONCLUSION: The vast majority of patients with acromegaly can be biochemically controlled with multimodality therapy in the current era. Radiotherapy and repeat pituitary surgery became less frequently utilized over time. Long-term postoperative IGF-1 control without use of adjuvant therapies has improved.

Intraoperative MRI for Pituitary Adenomas.

Since the 1990s, MRI scanners have been incorporated into the operating room environment. Studies of the use of intraoperative MRI (iMRI) for pituitary adenomas have shown that images are highly sensitive and specific for residual tumor detection, especially at higher Tesla magnet strengths. Given this accuracy, iMRI also increases the rates of achieving gross total resection (GTR). Owing to the slow-growing nature of pituitary adenomas, comparison of long-term control rates with and without use of iMRI remains to be studied, but the increased rates of GTR with this technology are promising for improved long-term outcomes.

The Utility of Intraoperative Cytological Smear and Frozen Section in the Surgical Management of Patients with Cushing's Disease due to Pituitary Microadenomas.

Cushing's disease (CD) is most commonly caused by a microadenoma, which at surgical exploration may not provide adequate tissue for pathologic diagnosis using standard techniques. We wished to determine the accuracy of intraoperative pathologic examination and whether the addition of intraoperative cytology increased the diagnostic yield. We reviewed the pathology reports from 403 operations on 341 patients with CD microadenomas from a single institution. The concordance rates of intraoperative diagnoses (cytology and frozen) with the final (paraffin section) pathological diagnosis were calculated. The overall pathologic confirmation of an adenoma (by either cytology, frozen, or paraffin section) was compared with the result from a historical cohort (using only standard frozen section analysis but not intraoperative cytology) and the pooled result from a meta-analysis of previously published data. The concordance rate between frozen section diagnosis and paraffin section histology was 390/403 (96.8%). The concordance rate between cytological smear and paraffin section histology was 213/246 (86.6%). In 54 cases (13.4%) with ultimate remission, pathologic confirmation was obtained only on intraoperative pathology (frozen section or cytology). Overall, pathologic confirmation was obtained in 326 operations (80.9%) by at least one pathological modality. The overall pathological confirmation of an adenoma was greater after the introduction of intraoperative cytology when compared with the historical control (67.1%, p = 0.015), and compared with the pooled rate of published data from the meta-analysis (72.1%, p < 0.001). Our findings suggest that addition of intraoperative cytological analyses during surgery for CD is an additional useful diagnostic tool for both neurosurgeons and pathologists.

TWO SYNCHRONOUS PITUITARY ADENOMAS CAUSING CUSHING DISEASE AND ACROMEGALY.

OBJECTIVE: To report the first case of 2 synchronous pituitary adenomas, 1 corticotroph and 1 somatotroph, with distinct molecular lineages confirmed by differential hormone and S-100 protein expression. METHODS: A case report followed by a literature review are presented. RESULTS: A 68-year-old woman presented for evaluation of resistant hypertension. Biochemical testing demonstrated adrenocorticotropic hormone (ACTH)-dependent hypercortisolemia and growth hormone (GH) excess. Pituitary magnetic resonance imaging (MRI) revealed a 2 cm left sellar lesion consistent with a pituitary macroadenoma. The patient therefore underwent transsphenoidal surgery for a presumed cosecreting ACTH and GH macroadenoma. Tumor immunohistochemical staining (IHC) was positive for ACTH, but negative for GH. Postoperative biochemical testing confirmed remission from Cushing disease, but the insulin-like growth factor 1 (IGF-1) level remained elevated. Postoperative MRI demonstrated a small right sellar lesion that, in retrospect, had been present on the preoperative MRI. Resection of the right lesion confirmed a GH-secreting adenoma with negative ACTH staining. After the second surgery, the IGF-1 level normalized and blood pressure improved. Further pathologic examination of both surgical specimens demonstrated differential expression of S-100 protein, a folliculostellate cell marker. Reverse transcription polymerase chain reaction of messenger ribonucleic acid from the left sellar lesion was positive for ACTH and negative for GH, confirming the IHC results. Germline mutations in genes known to be associated with pituitary adenoma syndromes (MEN1, CDC73, CDKN1A, CDKN1B, CDKN2B, CDKN2C, and AIP) were not detected. CONCLUSION: Although the pathogenesis of synchronous pituitary adenomas has not been fully elucidated, this case report suggests that they can have distinct molecular lineages.

MRI texture analysis as a predictor of tumor recurrence or progression in patients with clinically non-functioning pituitary adenomas.

BACKGROUND: There are limited predictors of prognosis in patients with clinically non-functioning pituitary adenomas (NFPAs). We hypothesized that MRI texture analysis may predict tumor recurrence or progression in patients with NFPAs undergoing transsphenoidal pituitary surgery (TSS). OBJECTIVE: To characterize texture parameters on preoperative MRI examinations in patients with NFPAs in relation to prognosis. METHODS: Retrospective study of patients with NFPAs who underwent TSS at our institution between 2009 and 2010. Clinical, radiological and histopathological data were extracted from electronic medical records. MRI texture analysis was performed on coronal T1-weighted non-enhanced MR images using ImageJ (NIH). MRI texture parameters were used to predict tumor recurrence or progression. Both logistic regression and Cox proportional hazard analyses were conducted to adjust for potential confounders. RESULTS: Data on 78 patients were analyzed. On both crude and multivariable-adjusted analyses, mean, median, mode, minimum and maximum pixel intensity were associated with the risk of pituitary tumor recurrence or progression after TSS. Patients whose tumor mean pixel intensity was above the median for the population had a hazard ratio of 0.44 (95% CI: 0.21-0.94, P = 0.034) for recurrence or progression in comparison with tumors below the median. CONCLUSIONS: Our data suggest that MRI texture analysis can predict the risk of tumor recurrence or progression in patients with NFPAs.

Characterization of cyclic Cushing's disease using late night salivary cortisol testing.

OBJECTIVE: To characterize a cohort of patients with cyclic Cushing's disease (CD) in comparison with noncyclic CD using late night salivary cortisol (LNSC) and examine the diagnostic sensitivity of LNSC in comparison with that of 24-hour urine-free cortisol (UFC) in this population. DESIGN: Retrospective study of patients with CD seen in our institution between 2008 and 2017. PATIENTS: A total of 205 patients, including 17 (8%) with cyclic CD (based on a minimum of 3 peaks and 2 troughs in cortisol levels). In a secondary analysis, 38 patients (19%) with cyclic CD were identified (based on a criterion of at least 2 peaks and 1 trough). MEASUREMENTS: Data on presentation, laboratory tests and outcomes were extracted. The diagnostic sensitivity of LNSC vs UFC in establishing cyclic CD was calculated. Kaplan-Meier analyses of recurrence after transsphenoidal pituitary surgery (TSS) were performed. RESULTS: The interval between presentation and TSS was significantly longer in patients with cyclic CD (P < .0001) in comparison with those with noncyclic CD. The sensitivity of LNSC in establishing cyclic CD was 88% and was higher than that of UFC (12%, P = .007). There were no differences in remission and recurrence rates between patients with cyclic CD and those with noncyclic CD. CONCLUSIONS: Patients with cyclic CD account only for a minority of those with CD, but may require a lengthier diagnostic evaluation. The use of LNSC on multiple occasions provides a more sensitive method of detecting cyclic CD than UFC. Outcomes of TSS in cyclic CD are comparable to those with noncyclic disease.