ACTH-producing Adenoma Research Articles

Pituitary Apoplexy: Description of Medical and Surgical Treatment and Clinical, Visual, and Endocrinological Outcomes During the SARS-CoV-2 Pandemic and Over Three Years.

Pituitary apoplexy (PA) is a rare neuroendocrinological emergency. The SARS-CoV-2 pandemic recommendations led to a shift in the management of patients with pituitary diseases, especially in the decision-making between conservative and surgical treatment of patients with PA. This study aimed to describe the conservative and surgical treatment and the clinical, visual, and endocrinological outcomes in patients with PA at the Pituitary Center of Excellence (PTCEO) during the SARS-CoV-2 pandemic and within three years. This is a cohort study. Patients with PA between April 2020 and September 2023 were followed up. Treatment decisions, clinical manifestations, hormonal profile, and tumor size with MRI were described at the onset, at three months, six months, one year, two years, and three years after diagnosis. A total of 27 patients with PA diagnosis were included in the study. Of these, 12 patients were conservatively treated, six (50%) had prolactinomas, five (41.6%) had non-functioning adenomas, and one (8.3%) had pituicytoma. Fifteen patients were surgically intervened during the first hospitalization, nine (60%) had non-functioning adenomas, four (26.6%) had prolactinomas, one (6.6%) had ACTH-producing adenoma, and one (6.6%) had gonadotropinoma. Two patients from the conservatively treated group (one non-functioning adenoma and one pituicytoma) were intervened surgically at years 2 and 3, respectively. During the initial assessment, there were no statistically significant differences between patients in visual acuity (9 [75%] vs 15 [100%]), visual fieldaffection (8 [66.6%] vs 11 [73.3%]), and cranial nerve deficit (3 [25%] vs 6 [40%]). At six months follow-up, no statistically significant differences were found in the visual acuity improvement (8 [88%] vs 11 [100%]), visual field (8 [100%] vs 8 [72%]), and cranial nerve deficit between the two groups (3 [100%] vs 6 [100%]). Meanwhile, the average length of in-hospital stay was 1.5 vs 10 days (p = 0.019). The tumor size and largest diameter were smaller in the surgically treated group (6.2 vs. 0.5 cm3, p = 0.029 and 2.5 vs. 1.1 cm, p = 0.036, respectively). Visual acuity improved in nine (58.3%) patients at year 1:two (40%) conservative vs seven (100%) surgical (p = 0.039); six (85.7%) patients at year 2: two (66.6%) conservative vs. four (100%) surgical; and three (100%) patients on both groups at year 3. Fourteen patients needed hormonal substitution: 87.5% (eight [88.8%] conservative vs six [85.7%] surgical) at year 1, 85.7% (six patients in both groups) at year 2, and 80% (four conservativevs three [100%] surgical) at year 3. The thyrotropic axis was the most affected in both groups during the three years. During the first-year follow-up, six (85%) patients persisted with tumoral regression (2 [66.6%] conservative vs 4 [100%] surgical) and one (14.2%) patientfrom the medical group progressed. During the second and third years, 10 and three (100%) of the patients,respectively, showedthe regression of the tumoral volume in both groups. The clinical, visual, and neuroendocrinological outcomes were similar in both groups of patients with PA during the SARS-CoV-2 pandemic. In cases where the Pituitary Apoplexy Score (PAS)score does not surpass three points without neurological deterioration, conservative management can be consideredan adequate option for treatment.

Adrenocorticotropic hormone-producing pituitary adenoma with pituitary apoplexy treated by surgical decompression: a case report

BackgroundPituitary-dependent hypercortisolism (PDH) is one of the most common endocrine disorders in veterinary medicine. However, there are few reports on pituitary tumor apoplexy (PTA) in dogs and no reports on its surgical intervention in veterinary medicine. Accordingly, the appropriate treatment is unknown. Herein, a case of PDH and PTA in a dog treated surgically is described.Case presentationA mongrel female dog (spayed; age, 8 years and 8 months; weight, 6.1 kg) with persistently elevated alkaline phosphatase underwent adrenocorticotropic hormone (ACTH) stimulation testing (post-stimulation cortisol: 20.5 μg/dL), abdominal ultrasonography (adrenal gland thickness: left, 5.7 mm; right, 8.1 mm), and brain magnetic resonance imaging (MRI) (pituitary-to-brain ratio [PBR], 0.61) at the referral hospital, resulting in a diagnosis of PDH (day 0). On day 9, the dog visited XXXX for the preparation of pituitary surgery to treat PDH. However, on days 10–15, the dog developed a loss of energy and appetite, bloody diarrhea, vomiting, and a decreased level of consciousness. However, on day 16, the dog’s condition recovered. A preoperative MRI scan performed on day 52 (the day of surgery) showed apoplexy in the dorsal pituitary region (PBR, 0.68). Based on the PTA findings, the risks of surgery were described to the owner, and approval was obtained. At the time of trans-sphenoidal surgery, a partial pituitary resection was performed with preservation of the PTA area due to adhesions between the PTA area of the right side of the pituitary and surrounding tissues. The resected pituitary tissue was diagnosed as an ACTH-producing adenoma, with necrotic and hemorrhagic findings. As of day 290, endogenous ACTH and cortisol levels did not exceed the reference range.ConclusionsThe acute signs that occurred on days 10–15 were most likely caused by PTA. Therefore, when signs similar to those detected in acute hypoadrenocorticism are observed in dogs with PDH, it is necessary to include PTA as a differential diagnosis. Trans-sphenoidal surgery may be effective in PDH-affected dogs that develop PTA, but careful attention should be paid to tissue adhesions secondary to hemorrhage that may occur after PTA.

ODP355 The analysis of tumor infiltrative lymphocytes in corticotroph adenomas and its relation to hormonal status

Abstract Background Corticotrophs are a well-known tissue susceptible to cytotoxicity by lymphocytes, as seen in autoimmune hypophysitis, suggesting that immunological approach may be one of the therapeutic strategies for ACTH-producing adenomas. However, the efficacy of immune therapy for general ACTH-producing adenomas remains unclear. And cortisol levels expected to affect the tumor microenvironment (TME). Objectives To clarify whether ACTH-producing adenomas are sensitive to immunotherapy and if this approach can be a potential treatment for these challenging tumors. Methods TME was examined by immunostaining using pituitary adenomas specimens. This study consists of two phases: In phase 1, TME of ACTH-producing adenomas (n=29) was analyzed by comparing with GH-producing pituitary adenomas (GHomas) (n=10) and nonfunctioning pituitary adenomas (NPAs) derived from gonadotrophs origin (Gnomas) (n=10). In phase 2, corticotroph adenomas were divided into three groups that were considered to be at different cortisol exposure; naïve ACTH-producing adenomas (Naïve, n=29), treatment with metyrapone (Met, n=13), and silent corticotroph adenomas (SCAs) (n=12). These TME were analyzed and compared. To detect T-lymphocytes and M2 macrophages, antibodies to CD3, 4, or 8, and CD163 were used, respectively. The association between TME and patients’ background data including urinary free cortisol levels were analyzed. Results Phase 1: Tumor infiltrating lymphocytes (TILs) evaluated by CD3 + cells inACTH-producing adenomas were less than those in the GHomas (p<0. 01) and lower tendency compare to Gnomas (p=0. 05). Among them, CD8 + cells in ACTH-producing adenomas were less than both (p<0. 01, p<0. 01, respectively). CD163 + cells were widely distributed in ACTH-producing adenomas but less than Gnomas (p<0. 01). The number of CD163 + cells were not associated with tumor aggressiveness or invasiveness in ACTH-producing adenomas. Phase 2: First, SCAs, NPAs from corticotroph origin were compared to Gnomas, showing that less CD8 + cells were detected in SCAs (p<0. 01), suggesting low CD8 + cells were common feature of corticotroph adenomas regardless of cortisol level. Among 3 groups of different cortisol exposure, CD4 + cells were higher both in Met and SCAs than in Naïve (p<0. 01, p=0. 01, respectively), while CD8+ cells were not altered. In contrast, the number of CD163+ cells were lower in Met than Naïve (p<0. 01), suggesting the association between cortisol levels and the number of CD163 + cells. Conclusions We revealed for the first time that low TILs are common features among corticotroph adenomas regardless cortisol levels. Moreover, the CD4 + cells but not CD8 + cells were higher in tumors with low cortisol status, suggesting induction of CD8 + cells are required for the immune therapy to corticotroph adenomas. Regarding with CD163 + cells, no association with tumor behavior was shown rather related to cortisol exposure status. Presentation: No date and time listed

ODP624 A case of Cushing disease demonstrated rapid deterioration of clinical findings and marked hypercortisolemia

Abstract Introduction In cases of ACTH-dependent Cushing syndrome, the differentiation between Cushing disease and the ectopic ACTH syndrome (EAS) can sometimes be challenging. Herein we report on a case of Cushing disease who showed clinical features resembled EAS caused by malignant neoplasms and required a detour for the diagnosis. Clinical case A 49-year-old Japanese woman presented a rapid exacerbation of muscle weakness of her limbs, leg edema and moon face from two months ago. She did not have any past medical history, hypertension, diabetes mellitus, or osteoporosis. Her serum K was 2.6 mEq/L, ACTH level was 151 pg/mL, serum cortisol level was 36.6 μg/dL, and urinary free cortisol (UFC) level was 4250 μg/day. Serum cortisol after 1 mg dexamethasone suppression test (DST) showed 41.9 μg/dL and that after 8 mg DST was 14.1 μg/dL. A pituitary MRI demonstrated a poor enhancement area with a clear margin of 10 mm in diameter in her dorsal side of the pituitary gland. She was diagnosed with ACTH-dependent Cushing syndrome and metyrapone was initiated. Soon she developed severe cough with infiltrative shadows on her lungs two days later. Her respiratory condition deteriorated rapidly, and she was urgently transferred to our hospital and intubated one week later. She had complicated pneumocystis carinii, nocardia pneumonia, and severe respiratory failure based on immunodeficiency due to hypercortisolemia. She was treated with systemic management in the intensive care unit, infection treatment and dose adjustment of metyrapone. Her condition improved and she was extubated on the 8th day. Although she had the pituitary tumor, EAS caused by a malignant neoplasm was suspected because of a combination of rapid clinical deterioration, marked hypercortisolemia and hypokalemia. However gastrointestinal tract survey, 18F-PET/CT and somatostatin receptor scintigraphy did not show any significant lesions. Finally, selective inferior petrosal sinus sampling (IPSS) demonstrated over secretion of ACTH from the pituitary gland. ACTH decreased to an undetectable level and hydrocortisone was supplemented after transsphenoidal surgery. No recurrence was observed in 1 year of follow-up. Pathological findings showed a densely granulated type of ACTH-producing adenoma without Crooke's change. KI-67 index were 4.7%, which was higher than that in general ACTH producing pituitary adenomas. Conclusion We experienced Cushing disease with the rare clinical course. This case suggests that although a step-by-step approach is often adopted to make a differential diagnosis of patients with ACTH-dependent Cushing's syndrome, ultimately IPSS is required. Because her KI-67 index showed 3 or higher despite the gentle tumor behavior, careful follow-up is required. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

PMON102 Utility of the Desmopressin Stimulation Test to Detect Cyclic Cushing's Disease

Abstract Background Arginine-vasopressin stimulates pituitary ACTH secretion after binding to arginine-vasopressin receptor 1B on corticotropes. Desmopressin (DDAVP), which preferentially binds to arginine-vasopressin receptor 2, stimulates the release of ACTH in most patients with pituitary corticotrope adenomas (Cushing's disease, CD), but not in most patients with ectopic ACTH-producing tumors or healthy people. Cyclic CD is characterized by periods of normal or low cortisol and ACTH, interspersed with hypercortisolism. We postulated that the DDAVP stimulation test, with measurement of ACTH and cortisol after a 10 mcg injection of DDAVP, might confirm the presence of an ACTH-producing pituitary adenoma even during periods without hypercortisolemia. Clinical Case A 27-year-old woman was diagnosed with Cushing's disease one year after developing weight gain, striae, intermittent acne, balding, irregular menses, a dorsal fat pad and facial rounding. Pituitary MRI revealed a right-sided 7 mm microadenoma; inferior petrosal sinus sampling confirmed a pituitary source of ACTH. Transsphenoidal resection was performed 6 months later. Histology showed an ACTH-positive adenoma and cortisol levels fell to 33nmol/L (1.2 ug/dL). Ten months later, due to intermittent symptoms, testing confirmed elevated UFC, with midnight cortisol of 565 nmol/L (20.3 ug/dL). Pituitary MRI showed a new right-sided lesion, interpreted as a residual adenoma or postoperative changes. Repeat surgical resection was recommended. She presented to our institution for a second opinion. On evaluation three weeks after recurrent hypercortisolism was confirmed, ACTH was low-normal (11.9 pg/mL, RR 5.0-46.0) and serum cortisol was undetectable. This rapid decrease was thought to signify apoplexy of the remaining adenoma or cyclic Cushing's disease. An MRI excluded apoplexy. However, surgery seemed inappropriate given hypocortisolism. To evaluate for the possibility of cyclic Cushing's disease due to residual adenoma, we performed a DDAVP stimulation test. This showed significant increases in ACTH and cortisol levels from 0 min to a 30-minute peak (ACTH 31.6 to 73.1 pg/mL, 131% increase, nl <50%; cortisol 2.6 to 8.1 mcg/dL [72 - 225 nmol/L], 212% increase, nl <20%). This led to transsphenoidal resection of a right-sided lesion. Cortisol levels were undetectable on post-operative day 3 and pathology showed an ACTH-producing adenoma. One week postoperatively, a repeat DDAVP stimulation test showed an insignificant rise in ACTH, and undetectable cortisol throughout (ACTH 11.1 to 12.4 pg/mL, 12% increase; cortisol <1.0 mcg/dL, 0% increase), which was deemed to indicate successful resection of the residual adenoma. She continues to lose weight and her clinical features of cortisol excess are involuting. Conclusion This case demonstrates how the DDAVP stimulation test can be used to both confirm the presence of ACTH-producing pituitary adenomas and assess the response to surgical resection. It may be particularly useful in the setting of cyclic Cushing's disease when cortisol and ACTH levels are not persistently elevated. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Pituitary carcinoma - case series and review of the literature.

Although pituitary adenomas (PAs) account for 15% of intracranial tumors, pituitary carcinomas (PCs) are a rare entity. Most commonly, PCs evolve from aggressive PAs invading the surrounding structures and eventually leading to metastatic lesions. Due to the low incidence, the diagnosis and treatment remains challenging. We report a case series of five patients with pituitary carcinoma (PC) treated in our center. At first diagnosis 3 patients had an ACTH-producing adenoma, 1 a prolactinoma and 1 a double secreting adenoma (GH and prolactin). The mean time interval from initial diagnosis to diagnosis of PC was 10.7 years (range 5-20 years). All patients underwent multiple surgical resections and radiotherapy. Four patients were treated with temozolomide for metastatic disease. One patient with concomitant radiochemotherapy for local recurrence. Temozolomide led to a stable disease in 2 patients. One patient had a progressive disease after 9 cycles of temozolomide. In absence of standard treatment, immunotherapy was initiated, resulting in a stable disease.We report five cases of PCs. Three patients obtained a stable disease after tailored multidisciplinary treatment. Additionally, one patient was treated with immunotherapy, opening a new treatment option in PCs. Overall, PCs are rare intracranial neoplasms occurring several years after the initial diagnosis of aggressive PAs. Currently, the absence of predictive factors for an aggressive clinical course, provokes a challenging management.

Abstract #1183320: Cushing's Disease due to Recurrent Cystic Macroadenoma

Crooke's tumor is a rare histological type of ACTH-producing adenomas. The most frequent clinical presentation is as Cushing's syndrome in middle-aged women and on other occasions as silent corticotropic adenomas. We present the case of a patient with recurrent Cushing's disease due to cystic Crooke's tumor.

The Genomic Landscape of Corticotroph Tumors: From Silent Adenomas to ACTH-Secreting Carcinomas.

Corticotroph cells give rise to aggressive and rare pituitary neoplasms comprising ACTH-producing adenomas resulting in Cushing disease (CD), clinically silent ACTH adenomas (SCA), Crooke cell adenomas (CCA) and ACTH-producing carcinomas (CA). The molecular pathogenesis of these tumors is still poorly understood. To better understand the genomic landscape of all the lesions of the corticotroph lineage, we sequenced the whole exome of three SCA, one CCA, four ACTH-secreting PA causing CD, one corticotrophinoma occurring in a CD patient who developed Nelson syndrome after adrenalectomy and one patient with an ACTH-producing CA. The ACTH-producing CA was the lesion with the highest number of single nucleotide variants (SNV) in genes such as USP8, TP53, AURKA, EGFR, HSD3B1 and CDKN1A. The USP8 variant was found only in the ACTH-CA and in the corticotrophinoma occurring in a patient with Nelson syndrome. In CCA, SNV in TP53, EGFR, HSD3B1 and CDKN1A SNV were present. HSD3B1 and CDKN1A SNVs were present in all three SCA, whereas in two of these tumors SNV in TP53, AURKA and EGFR were found. None of the analyzed tumors showed SNV in USP48, BRAF, BRG1 or CABLES1. The amplification of 17q12 was found in all tumors, except for the ACTH-producing carcinoma. The four clinically functioning ACTH adenomas and the ACTH-CA shared the amplification of 10q11.22 and showed more copy-number variation (CNV) gains and single-nucleotide variations than the nonfunctioning tumors.

Diagnostic Threshold for Postoperative Secondary Adrenal Insufficiency After Transsphenoidal Resection of Pituitary Adenomas

Transsphenoidal surgery (TSS) is the first line treatment for pituitary adenomas. A well-known complication of TSS is secondary adrenal insufficiency with a reported risk of 4-9% after TSS. Currently, glucocorticoid replacement is recommended if postoperative AM cortisol is < 3 ug/dL. Postoperative adrenal insufficiency is ruled out if AM cortisol is > 15 ug/dL. However, further evaluation of the adrenal axis with ACTH stimulation test is recommended for intermediate cortisol levels 3-15 ug/dL. Other studies have proposed postoperative cortisol threshold of < 4-14 ug/dL for glucocorticoid replacement. Retrospective analysis of all patients undergoing TSS at a tertiary center from January 2013 through April 2016 was performed. ACTH producing adenomas (Cushing’s disease) were excluded. Of the 97 patients included, 17.5% (n=17) had secondary adrenal insufficiency requiring glucocorticoid replacement at 1 year post operatively. Mean age at presentation was 56 ± 16 years and 52% were female. Mean adenoma size was 25.3 ± 11.3 mm. Factors associated with adrenal insufficiency at 1 year post operatively were preoperative secondary adrenal insufficiency (AM cortisol 4.5 ± 1.9 vs 11.0 ± 1.0 µg/dL; p = 0.03), and preoperative adenoma contact with optic chiasm (15.7% vs 2.1%; p = 0.01). Day 1-7 postoperative cortisol was lower in the group with adrenal insufficiency at 1 year (5.6 µg/dL (IQR 1.9-11.5) vs 19.8 µg/dL (IQR 12.75-43.2); p=0.02). Age, gender, adenoma size, and cavernous sinus involvement were not associated with adrenal insufficiency at 1 year. A day 1-7 postoperative cortisol concentration of ≥8.0 µg/dL had a sensitivity of 75% and specificity of 92% in predicting adrenal insufficiency at 1 year. In patients with secondary adrenal insufficiency at 1 year (n=17), there was a higher frequency of concomitant loss of other pituitary hormone function at 1 year: secondary hypothyroidism 82% (n=14), secondary hypogonadism 70.6% (n=12) and diabetes insipidus 17.7% (n=3). A lower postoperative cortisol threshold of 8 µg/dL can be adopted for glucocorticoid replacement on discharge after TSS.

SAT-279 Crooke’s Cell Adenoma- an Aggressive Form of Cushing’s Disease

Introduction: Cushing’s disease is a condition of cortisol overproduction caused by an ACTH-producing tumor. Corticotroph cells surrounding an ACTH-producing tumor usually undergo Crooke’s hyaline change, where cytokeratin filaments accumulate in the cytoplasm in response to glucocorticoid excess. These changes are thought to be a mechanism of feedback inhibition and thus facilitate a suppression of ACTH. However, in a subtype of ACTH-secreting tumors known as Crooke’s cell adenomas (CCA), the ACTH-producing cells also undergo these hyaline changes. This would be expected to suppress hormone secretion but these cells are still able to release significant amounts of ACTH. Case presentation: A 32-year-old woman presented to the hospital after an episode of syncope. On head MRI, she was found to have a 2 cm sellar mass with optic chiasm compression. Labs showed low TSH, free FT4, T3, FSH, and LH. She was also pre-diabetic with an HgbA1c of 6.2%. Her baseline cortisol of 20.6 µg/dL did not suppress after 1 mg of dexamethasone. After receiving 4 mg of dexamethasone, her cortisol suppressed to 5.2 µg/dL. She was diagnosed with hypopituitarism except for cortisol and a likely ACTH-producing pituitary macroadenoma. She completed a transsphenoidal pituitary resection and pathology revealed Crooke’s hyaline changes with immunohistochemical stains positive for ACTH. The immunostain for the proliferation marker Ki67 showed a relatively low proliferation index. Her course was complicated by diabetes insipidus. She was ultimately discharged on 20 mg hydrocortisone each morning, 10 mg hydrocortisone each afternoon, desmopressin 0.05 µg daily, and levothyroxine 125 µg daily. Two weeks later, the patient was sent to the emergency room by her endocrinologist for hyperglycemia up to 288 mg/dL. She was also found to be newly diabetic with an HgbA1c of 6.5%. A fasting morning cortisol was collected during her admission and showed a cortisol level of <1.0 µg/dL, proving she was cured of Cushing’s disease. However, she will need close endocrinology follow up and MRI imaging of her pituitary for this aggressive type of pituitary adenoma. Discussion: We have come across an interesting case of a young woman who presented for syncope and was found to have a pituitary macroadenoma with pathology consistent with CCA. This type of ACTH-producing tumor is known for aggressive patterns including high rates of recurrence with rates of up to 60% reported in literature, persistent disease after surgery, malignant transformation, and metastases. Despite presentation and symptoms similar to those of other ACTH-producing adenomas, the dangerous pattern of Crooke’s cell adenomas necessitate long-term follow-up in affected patients.

OR25-06 Morning ACTH Levels as a Reliable Biomarker for Excluding Autonomous Cortisol Secretion in Incidetally Discovered Adrenal Adenomas. A Prospective Cohort

Adrenal incidentalomas are common with a prevalence of 3-10% and in up to 30% of cases may have probable autonomous cortisol secretion. Hypercortisolism is associated with substantial cardiometabolic morbimortality and can physiologically decrease ACTH levels. Objective: To determine the sensitivity, specificity, and positive and negative predictive values of ACTH levels in evaluating autonomous cortisol secretion in a prospective cohort of incidentally discovered adrenal adenomas. Methods: We prospectively evaluated 224 consecutive adult subjects with incidentally discovered adrenal masses on computed tomography. Finally, 168 participants with radiographic adenoma criteria underwent systematic hormonal assessment, including measurements of morning cortisol and ACTH on day 1, and a 1 mg dexamethasone suppression test (DST) on day 2. Hypercortisolism was excluded if the DST was < 1.8 mcg/dL. Autonomous cortisol secretion was defined as a DST > 5.0 mcg/dL and DST levels of 1.8-5.0 mcg/dL were considered to be possibly autonomous hypercortisolism. We evaluated the correlation of ACTH levels with clinical, radiographic, and endocrine variables. In order to identify the most sensitive threshold value for diagnosing autonomous cortisol secretion, we determined ROC curves and negative likelihood ratio (NLR). Concordance of repeated ACTH was assessed using Bland Altman analysis. Results: The characteristics of the cohort were mean age 56 (+/- 11.8) years, 76% female, adenoma size 19 (+/- 7) mm, and 13% bilateral adenomas. Mean ACTH was 15 (+/- 11) pg/ml (range 5-72) and the mean DST was 2.2 (+/- 3.0) ug/dL (range 0.4-25.9). Fifty-four (32%) participants had a DST ≥1.8mcg/dL and 13 (8%) a DST≥5.0 mcg/dL. We found no correlation between ACTH levels and age, gender or body mass index. ACTH was inversely associated with adrenal adenoma diameter (r=-3.3 p=0.002) and volume (r=-2.9 p=0.008). There was an inverse association between ACTH and DST values (r=-3.1 p=0.01). In the subgroup of patients with a second ACTH measurement we found high concordance, with mean difference of 0.16+/-3.6 pg/ml (p=0.83). ROC analysis showed that an ACTH ≥20 pg/ml had a sensitivity of 98% to exclude hypercortisolism, with a negative predictive value of 97% and a negative likelihood ratio of 0.06. The only case with DST≥1.8 and ACTH≥20 had Cushing′s phenotype with both an adrenal adenoma and a pituitary ACTH-producing adenoma. Systematic evaluation of morning cortisol and ACTH allowed the detection of 5 cases of false negative low DST values due to the use of non-oral corticosteroids. Conclusion: In this cohort, an ACTH ≥20pg/ml excluded autonomous cortisol secretion with excellent sensitivity and negative predictive value, providing strong reassurance that there is no clinically relevant hypercortisolism. Therefore, subjects with a normal DST and ACTH ≥20pg/ml should be candidates for relaxed surveillance.

Invasive Crooke cell adenoma in a patient with diffuse large B-cell lymphoma

Crooke cell adenoma (CCA) is an aggressive corticotroph subtype of pituitary adenoma often with cyclically elevated blood adrenocorticotropic hormone (ACTH), which preoperative diagnosis is challenging especially in the context of a functionally silent invasive tumor and a history of high-stage malignancy such as diffuse large B-cell lymphoma (DLBCL). Here, we report the first case of invasive CCA in a patient with DLBCL. A 71 year-old previously healthy man was recently diagnosed with DLBCL that was treated with CHOP-R chemotherapy. Within one week of completing his first cycle of chemotherapy, he had a frontal headache that progressed to right-sided proptosis. Cranial MRI showed a heterogeneously enhancing mass with invasion into the sellar and suprasellar compartment, compression of the optic chiasm, as well as extension into the clivus, bilateral cavernous sinuses, and the prepontine cistern. He underwent a partial resection for the pituitary tumor debulking. Pathological examination revealed CCA with invasion into the adjacent tissue. The patient had no history of Cushing disease or syndrome, but his blood ACTH was found to be elevated on the operation day. Our present case and literature review suggest that comorbidity of CCA or ACTH-producing adenoma and B-cell lymphoma deserves awareness in our clinical practice, as these two diseases and/or their therapies may interact substantially. CAA should be considered in the major differential diagnosis for an invasive sellar tumor, even without blood ACTH elevation and/or with a history of malignant lymphoma.

&lt;p&gt;Transsphenoidal Surgery in Canines: Safety, Efficacy and Patient Selection&lt;/p&gt;

Pituitary-dependent hyperadrenocorticism (PDH) is the cause of approximately 80-85% of naturally occurring cases of hyperadrenocorticism(HAC) in canines and is triggered by an adrenocorticotropic hormone (ACTH)-producing pituitary adenoma or hyperplasia of the corticotroph in the pituitary anterior lobe or intermediate lobe. Transsphenoidal surgery(TSS) is an effective treatment that can directly remove pituitary tumors that cause PDH in canines under a single course of general anesthesia. However, careful evaluations of the definitive diagnosis, adenoma size and growth rate, relationship with surrounding tissue, general condition, and neurosurgical procedural skill involved in each case are important to determine TSS suitability. The basic principle is to confirm that the present HAC case is PDH, that is, an ACTH-producing adenoma or the hyperplasia of the corticotroph originating from either the pituitary anterior or intermediate lobe. Evaluations based on endocrinology, particularly plasma ACTH concentration, and imaging diagnosis, particularly MRI is essential for definitive diagnosis. Enlarged pituitary tumors can shorten the post-TSS survival time, increase the recurrence rate of clinical symptoms, and increase the risk for developing permanent central diabetes insipidus. Therefore, complete removal of adenomas of up to Grade IIIA according to the MRI-based classification system is relatively easy to achieve with TSS, and long-term remission and survival can be expected.

Evaluation of different hydrocortisone treatment strategies in transsphenoidal pituitary surgery

BackgroundHydrocortisone treatment in transsphenoidal pituitary surgery has been debated. Although several publications advocate restrictive treatment, centers around the world administer stress doses of hydrocortisone in patients with presumed intact cortisol production. Our aim with this analysis was to compare postoperative hypocortisolism in patients who received three different protocols of hydrocortisone therapy during and after surgery.MethodThis was a retrospective observational study. Based on perioperative hydrocortisone dose given, patients were divided in three groups: high dose (HD), intermediate dose (ID), and low dose (LD). Postoperative evaluation of the pituitary function was performed using S-cortisol at day 4 and short Synacthen test (SST) at 6–8 weeks. Patients with ACTH-producing adenomas or preoperative hydrocortisone treatment were excluded.ResultThere was no difference between the groups regarding failure rate of SST. The rate of failed SST (all groups) was 51/186 (27%), 24/74 (32%) in the HD group and 26/74 (35%) and 11/38 (29%) in the ID and LD groups respectively. There was no significant difference between the ID and LD groups regarding S-cortisol at postoperative day 4 regarding serum cortisol level below 200 nmol/L. There was a significant but weak correlation, rs 0.330 (P < 0.01) between S-cortisol day 4 and SST at 4–6 weeks.ConclusionsPeri and postoperative hydrocortisone treatment did not affect SST response 6–8 weeks postoperatively, whereas the rate of patients with S-cortisol below 200 nmol/L at postoperative day 4 did. LD hydrocortisone therapy seems to favor a better endogenous production in the early postoperative phase.

MRI criteria of subtypes of adenomas and epithelial cysts of the pituitary gland.

This study aimed to assess the clinical applicability of MRI criteria for differentiation of pituitary adenomas and cystic pituitary lesions. One hundred ninety-eight consecutive patients with surgical resection of a pituitary adenoma/cystic pituitary lesion were retrospectively analyzed, blinded to clinical data and histopathological diagnosis. Different morphologic criteria were assessed: signal intensity in T2/T1w images, pattern of contrast enhancement, size, super-/infrasellar extension, and invasion of the cavernous sinus. For validation of the criteria, a second independent patient cohort (n = 102) was analyzed for diagnostic accuracy of the criteria. We identified differences between subtypes of pituitary adenomas regarding morphological MRI criteria. Especially, ACTH-producing adenomas and GH-producing adenomas showed partially specific imaging features. Application of our criteria on the second patient cohort (n = 102) did however not significantly improve diagnostic accuracy. Only differentiation between cystic pituitary lesions and adenomas was facilitated using these criteria, but did not reach statistical significance in this cohort (P = 0.352). MRI criteria might facilitate differentiation between pituitary adenomas and cystic pituitary lesions, but not between subtypes of pituitary adenomas. These subtypes show partially specific MR imaging features, however, due to a high variability knowledge of clinical symptoms and laboratory findings remain essential for the correct diagnosis.

Children with MEN1 gene mutations may present first (and at a young age) with Cushing disease.

Cushing disease (CD) is a rare entity caused by ACTH-secreting pituitary tumours, leading to prolonged hypercortisolism. Most cases are sporadic but can rarely occur in the context of familial predisposition, due to germline mutations in genes such as MEN1, leading to multiple endocrine neoplasia type 1, MEN1. We have reported previously that CD can be the first and only presenting manifestation of MEN1. In this report, we describe a cohort of paediatric patients who presented with CD as the first manifestation of MEN1. A retrospective analysis of paediatric patients admitted to the National Institutes of Health (NIH) Clinical Center for evaluation of hypercortisolism, between 1997 and 2017. MEN1 was diagnosed on a clinical, familial and/or genetic basis. Of a total of 238 children with CD, six patients were subsequently diagnosed with MEN1, three males and three females with a mean age at diagnosis of CD at 13.4±2.9years. Five of the six patients had familial MEN1 and one patient was a sporadic case. Additional manifestations of MEN1 included primary hyperparathyroidism in three patients and hyperprolactinemia in two patients. This report describes a paediatric patient population with MEN1 in whom CD was the initial manifestation, confirming a previous observation that paediatric patients with MEN1 may present first with an ACTH-producing adenoma. Therefore, germline MEN1 mutations should be sought in paediatric CD and tested for when there is a suggestive family history and/or other manifestations.

Cytohistological correlation in pituitary tumor and immunological assessment with the help of Ki-67.

Background:Tumors of the pituitary gland and sellar region represent approximately 10–15% of all brain tumors. Pituitary adenoma (PA), the most common pathology of the pituitary gland, can be effectively subclassified only with the help of immunohistochemistry (IHC). This is important and needed for individual patient management.Aims and Objectives:The objective of the study was to analyze the importance of intraoperative imprint smear cytology and correlating with final histopathological diagnosis. Furthermore, to classify the different types of PA with the help of IHC, prolactin (PRL), adrenocorticotropic hormone (ACTH), and growth hormone (GH) and to predict the benign, atypical, or malignant nature of the tumor with the help of prognostic marker Ki-67.Materials and Methods:A prospective study was done in 34 cases. The patients whose pituitary gland samples are referred from the endocrine and the neurosurgery department to the pathology department for histopathological examinations were selected. We have studied the clinical features, radiology and touch imprint cytology, histopathology, and IHC with the help of PRL, ACTH, GH, and Ki-67 of PA over 2 years.Results:In our study, we had 32 cases of PA of 34 cases over a span of 2 years. We have seen that there is a correlation between cytological and histological diagnosis of the subtypes of PA in 62% cases, and the Kappa statistics show a moderate extent of agreement (Kappa - 0.320, 95% confidence interval = 0.031–0.609). Ki-67 when compared to the radiological grading showed a high degree of comparability (Chi-square test: P < 0.001). All cases with invasion had a higher Ki-67. On using the Fisher's exact test, we found that the Ki-67 expression with GH-producing adenomas and ACTH-producing adenomas was comparable (P = 1.000) while in PRL-producing adenomas too this was not significant (P = 0.269).Conclusion:PA can be effectively classified with the help of IHC. Intraoperative cytology is important in diagnosing PA, but histopathology remains the gold standard in diagnosing and differentiating PA from other pathologies of the pituitary gland. The radiological grading together with immunological classification and the prognostic markers of Ki-67 is important in deciding the benign or atypical nature of the adenomas thus helping in better patient management.

A Rapid Biochemical and Radiological Response to the Concomitant Therapy with Temozolomide and Radiotherapy in an Aggressive ACTH Pituitary Adenoma

Background and Importance. In the last eight years temozolomide (TMZ) has been used as the last-line treatment modality for aggressive pituitary tumors to be applied after the failure of surgery, medical therapy, and radiotherapy. The objective was to achieve a rapid control of tumor growth and hormone normalization with concurrent chemoradiotherapy in a patient with very aggressive ACTH pituitary adenoma. Clinical Presentation. We describe a patient with an aggressive ACTH-producing adenoma treated with concurrent temozolomide and radiotherapy. The patient suffered from an aggressive ACTH adenoma resistant to surgical and medical treatment. After two months of concurrent temozolomide and radiotherapy, cortisol normalization and significant tumor shrinkage were observed. After 22 months of follow-up, there is still no evidence of tumor recurrence. Conclusion. Concurrent treatment with temozolomide and irradiation appears to be highly effective in the achievement of the tumor volume control as well as in the control of ACTH secretion in aggressive ACTH adenoma.

Ursolic acid suppresses growth and adrenocorticotrophic hormone secretion in AtT20 cells as a potential agent targeting adrenocorticotrophic hormone-producing pituitary adenoma

Adrenocorticotrophic hormone (ACTH)-producing pituitary adenoma leads to excess ACTH secretion, which is associated with significant mortality and impaired quality of life. Thus far, the first line therapy is the transphenoidal microsurgery. Considering the high recurrence rate and complications of surgery, novel agents, which directly target on pituitary ACTH-producing adenoma and suppress ACTH secretion are urgently required. In the present study, the effect of ursolic acid (UA) as a candidate agent targeting ACTH-producing AtT20 cells was investigated. It was demonstrated that UA inhibited the viability and induced apoptosis of AtT20 cells and decreased ACTH secretion. The process of apoptosis involved a decrease of the B cell lymphoma 2 (Bcl-2)/Bcl2-associated X protein ratio followed by a release of mitochondrial cytochrome c into the cytosol with subsequent activation of caspase-9, -3/7 and -8. The potential signaling pathway involved the activation of c-Jun N-terminal kinase (JNK) but not extracellular signal-regulated protein kinases1/2 and p38 mitogen-activated protein kinase. The JNK pathway participated in UA-induced mitochondrial apoptotic signaling transduction via increasing the phosphorylation and degradation of Bcl-2, which may be partly attenuated by the JNK inhibitor SP600125. In conclusion, the present study indicates that UA may be a promising candidate agent for the management of ACTH-producing pituitary adenoma.

Outcome of Surgical Treatment of 200 Children With Cushing's Disease

Factors influencing the outcome of surgical treatment of pediatric Cushing's disease (CD) have not been fully established. The aim of this study was to examine features influencing the outcome of surgery for pediatric CD. In this prospective observational study, the clinical, imaging, endocrinological, and operative outcomes were analyzed in consecutive patients treated at the National Institutes of Health (NIH) from 1982 through 2010. The study was conducted in a tertiary referral center. Two hundred CD patients (106 females, 94 males) were included. Mean age at symptom development was 10.6 ± 3.6 years (range, 4.0 to 19.0 y). Mean age at NIH operation was 13.7 ± 3.7 years. Twenty-seven patients (13%) had prior surgery at another institution. Magnetic resonance imaging identified adenomas in 97 patients (50%). When positive, magnetic resonance imaging accurately defined a discrete adenoma in 96 of the 97 patients (99%), which was more accurate than the use of ACTH ratios during inferior petrosal sinus sampling to determine adenoma lateralization (accurate in 72% of patients without prior surgery). A total of 195 of the 200 patients (98%) achieved remission after surgery (189 [97%] were hypocortisolemic; 6 [3%] were eucortisolemic postoperatively). Factors associated with initial remission (P < .05) included identification of an adenoma at surgery, immunohistochemical ACTH-producing adenoma, and noninvasive ACTH adenoma. Younger age, smaller adenoma, and absence of cavernous sinus wall or other dural invasion were associated with long-term remission (P < .05). A minimum morning serum cortisol of less than 1 μg/dl after surgery had a positive predictive value for lasting remission of 96%. With rare disorders, such as pediatric CD, enhanced outcomes are obtained by evaluation and treatment at centers with substantial experience. Resection of pituitary adenomas in pediatric CD in that setting can be safe, effective, and durable. Early postoperative endocrine testing predicts lasting remission. Because lasting remission is associated with younger age at surgery, smaller adenomas, and lack of dural invasion, early diagnosis should improve surgical outcome.