Periadrenal Adipose Tissue Research Articles

8204 Rare Asymptomatic Presentation Of A Large Pheochromocytoma

Abstract Disclosure: A. Lorin: None. C.K. Persaud: None. M.H. Kemm: None. Background: Pheochromocytoma is a rare neuroendocrine tumor arising from chromaffin cells of the adrenal medulla. It is associated with excessive release of catecholamines causing symptoms of hypertension, palpitations, diaphoresis, and headaches. These symptoms are particularly prominent with larger pheochromocytomas. We present the case of a large 13 cm pheochromocytoma (PCC) without the typical associated symptoms. Clinical Case: A 45-year-old male with medical history of osteoarthritis and gastroesophageal reflux presented to his primary care doctor with 2 months of intermittent right upper quadrant abdominal pain associated with nausea. Work up with CT abdomen/pelvis found a 9.3 cm heterogeneous right adrenal mass with mass effect on the right liver lobe, superior pole of the right kidney, duodenum, and pancreatic head. Hormonal testing was notable for plasma metanephrine 257.8 pg/mL (0-88), plasma normetanephrine 12063.7 pg/mL (0.0-218.9), 24 hr urine metanephrine 159 mcg/24 hr (58-276), 24 hr urine normetanephrine 22575 mcg/24 hr (156-729), and chromogranin A 5387 mg/mL (0-101.8). Given lab evaluation, diagnosis was made of pheochromocytoma, and patient was initiated on alpha blockade with doxazosin. Patient’s blood pressure and heart rate were at goal prior to doxazosin initiation and patient needed to be decreased from 1 mg daily to 0.5 mg daily due to side effects of low blood pressure and orthostatic hypotension. Patient had an uncomplicated open right adrenalectomy with pathology showing a 13 cm pheochromocytoma with invasion through the capsule into the periadrenal adipose tissue. Genetic testing revealed no known mutation variants associated with PCC. Labs drawn two weeks postoperatively showed resolution of elevated plasma metanephrine, normetanephrine, and chromogranin A. Conclusion: While the patient had an elevated plasma metanephrine, the normetanephrine was predominantly elevated. Such a hormone profile is more common in extra-adrenal PCCs, consistent with cluster 1 associated genes. This noradrenergic phenotype is likely a reason the patient did not have typical symptoms, despite the size of his pheochromocytoma. A proposed pathophysiologic mechanism for this is the dissociation of renal medulla from the cortex given the large size of the tumor. This would lead to lower local availability of corticosteroid to potentiate the conversion of norepinephrine to epinephrine, thus decreasing likelihood of classical PCC symptoms. Despite lack of expected symptoms and an imaging initially concerning for adrenocortical carcinoma, we should recognize the potential for a large adrenal tumor to represent PCC and evaluate accordingly. Presentation: 6/1/2024

12386 Unilateral Spontaneous Adrenal Hemorrhage In Pregnancy

Abstract Disclosure: A. Gondhi: None. M. Campana: None. M. Riofrio: None. J. Fazendin: None. D. Vodopivec: None. Unilateral Spontaneous Adrenal Hemorrhage In Pregnancy Introduction: Spontaneous adrenal hemorrhage (SAH) in pregnancy is a rare and under recognized entity with an incidence of 0.14% - 1.1%, mostly unilateral. We present a case of unilateral SAH managed with adrenalectomy during pregnancy. Case presentation: A 24-year-old 14-weeks pregnant woman was referred for right flank pain and nausea due to right adrenal lesion. Medical history significant for 4 first trimester miscarriages and family history of Breast cancer and Uterine cancer in mother, Pancreatic cancer in multiple family members on paternal side. She was hemodynamically stable. Abdominal-US showed right adrenal lesion. Non-contrast MRI abdomen showed a large collection in the right adrenal gland measuring 9.6cm x 9cm. Ability to assess for underlying lesion challenging given the amount of blood products and lack of IV contrast. Laboratory analysis showed an appropriately suppressed cortisol with 1 mg overnight dexamethasone suppression test (cortisol 1.3 mcg/dl, N<1.8 mcg/d Dexamethasone level 332 ng/dl, N<180-550 ng/dl), normal DHEA-S (135 mcg/dl, N=18-391mcg/dl), non-suppressed ACTH (18 pg/ml, N 7.2-63 pg/ml), normal aldosterone (8.1 ng/dl, N=3-39.2 ng/dl) with a non-suppressed renin (17.8 pg/ml, N=4.2-52.2 pg/ml), normal fractionated plasma metanephrines (Free metanephrines <0.2 nMol/L, N<0.0.5nMol/L Free normetaphrines <0.2 nMol/L, N<0.9nMol/L), negative Antiphopholipid antibody testing (Beta 2 Glycoprotein I IgM <2 U/ml, N<20U/ml, Beta 2 Glycoprotein I IgG 2.2 U/ml, N<20U/ml). The patient underwent a laparoscopic converted to open right adrenalectomy. Pathology showed a 9.6cm adrenal gland with organizing hematoma, vascular congestion, and hemorrhage. It also showed periadrenal adipose tissue with atypia, MDM2 gene amplification by FISH negative – ruling out liposarcoma. Post-operatively, her symptoms resolved without complications to the pregnancy. Differentials for adrenal hemorrhage in this pregnant patient include: 1) underlying adrenal tumor (most commonly pheochromocytoma), 2) coagulopathy (e.g. antiphospholipid syndrome), and 3) pregnancy-related adrenal hemorrhage (rare, mostly unilateral due to increased vascular flow to the adrenal gland and the hypercoagulability). After evaluating the adrenal functionality, APLAS and assessing the malignant potential with imaging studies; conservative management is appropriate in stable patients. Our patient underwent surgery due to recurrent intractable pain, and uncertainty regarding malignant potential of the adrenal mass given history of multiple cancers in the family. Conclusion: Our case highlights that when indicated, adrenalectomy in the II trimester is a safe and effective option in pregnancy. Individualized treatment should be chosen for each patient following shared decision-making. Presentation: 6/1/2024

Extra-adrenal adrenocortical cancer associated with multiple endocrine neoplasia type 1.

Adrenocortical carcinoma (ACC) is a rare malignant tumour arising from the adrenal cortex, with an estimated annual incidence of one to two patients per million. Ectopic ACCs are extremely rare. The majority of ACCs are sporadic; however, ACC has been linked with genetic disease processes, including multiple endocrine neoplasia type-1 (MEN-1). We present the case of a 66-year-old lady referred with newly diagnosed diabetes on a background of primary hyperparathyroidism. Examination revealed Cushingoid features, and hormonal evaluation confirmed ACTH-independent Cushing's syndrome. Morning cortisol after a 1 mg overnight dexamethasone suppression test was 548 nmol/L with an undetectable ACTH <3.0 pg/mL. Dehydroepiandrosterone sulphate was 5.3 μmol/L and androstenedione 3.49 nmol/L, both of which were normal. Testosterone was suppressed at <0.4 nmol/L. Imaging revealed a 6 × 6 × 4.5 cm right-sided presumed adrenal lesion, a pancreatic lesion (2.5 × 1.6 cm), and bilateral pulmonary nodules (0.9 × 0.8 cm, 0.7 × 0.6 cm, 0.3 cm). Right adrenalectomy was performed, and histology was consistent with an extra-adrenal ACC (Weiss score 5/9) within the peri-adrenal adipose tissue. The resected adrenal gland was normal. Lung biopsy confirmed metastatic ACC tissue, and endoscopic ultrasound-guided biopsy of the pancreatic lesion revealed a pancreatic neuroendocrine tumour, which was confirmed biochemically to be an insulinoma. Genetic assessment confirmed MEN-1. This case highlights the importance of screening for MEN-1 in at-risk patients and the need for close clinical follow-up. To our knowledge, this is the first case report of extra-adrenal ACC in MEN-1 syndrome. Adrenal lesions in MEN-1 syndrome have significant malignant potential. Newly diagnosed lesions should be followed closely with short-interval imaging, and a lower threshold for surgical removal is suggested. Primary hyperparathyroidism is often the earliest laboratory or clinical manifestation of MEN-1 syndrome. A detailed medical and family history is vital in order to appropriately identify patients at risk of MEN-1. To our knowledge, this is the first case report of extra-adrenal adrenocortical carcinoma in MEN-1 syndrome.

FRI246 A Rare Case Of An Adrenal Gland Hemangioma In A 68-year-old Female

Abstract Disclosure: R. Daas: None. S. Logan: None. R. Voss: None. V. Tarasova: None. T. Glushko: None. J. Hernandez Prera: None. S. Agosto Salgado: None. J. Hallanger-Johnson: None. C. Veloski: None. Background: Adrenal gland hemangiomas are extremely rare, with less than one hundred cases reported in the literature. Although benign and usually asymptomatic, they can be confused with adenomas, pheochromocytomas, or malignant adrenal tumors and preoperative diagnosis is challenging. Clinical Case: A 68-year-old female with a history of breast cancer completes an abdominal/ pelvic MRI due to abdominal and back pain that reveals a 1.4 cm right adrenal mass with T2 bright enhancement prompting concern for pheochromocytoma, lipid poor adenoma, or metastasis. An adrenal protocol contrast CT abdomen redemonstrated a 1.3 cm brightly enhancing right adrenal nodule with precontrast Hounsfield units (HU) of 35, postcontrast HU of 236, and delayed HU of 81. Absolute washout was 77.1%, consistent with an adenoma, however, the enhancement profile was also concerning for pheochromocytoma. Labs showed ACTH 15.2 pg/mL (7.2 - 63.3 pg/mL), cortisol 14.7 ug/dL (3.7 - 19.4 ug/dL), dexamethasone suppression test with cortisol 1.3 ug/dL (3 – 41 ug/dL), aldosterone 12 ng/dL (4.0 - 31.0 ng/dL), renin 0.1 ng/mL/hr (0.5 - 4.0 ng/mL/hr), potassium 4.0 mmol/L (3.4 - 4.5 mmol/L), DHEA-S 122 ug/dL (9 - 246 ud/dL), total testosterone 41.38 ng/dL (3.00 – 41.00 ng/dL), free testosterone 3.7 pg/mL (0.6 - 3.8 pg/mL), plasma normetanephrines 0.82 nmol/L (0 - 0.89 nmol/L), and plasma metanephrines 0.14 nmol/L (0 - 0.49 nmol/L), 24-hour urine: norepinephrine 47 ug/d (14 – 120 ug/d), epinephrine &amp;lt;4 ug/d (1 – 14 ug/d), dopamine 236 ug/d (71 – 485 ug/d), metanephrines 86 ug/d (36 – 229 ug/d), and normetanephrines 258 ug/d (95 – 650 ug/d). The patient was asymptomatic, without high blood pressure, tachycardia, or hypokalemia. Despite the unremarkable lab workup, surgical excision of the nodule was recommended due to concern for silent pheochromocytoma or metastasis given the imaging findings and history of breast cancer. She was pretreated with doxazosin and had a right adrenalectomy. Pathology revealed a 1 cm hemangioma involving the periadrenal adipose tissue with ERG positive, CD31 positive, and D2-40 negative immunohistochemical staining. She was monitored post-operatively for transient hypotension and tachycardia and was discharged in stable condition. Conclusion: The differential diagnosis for adrenal gland incidentalomas is quite broad, however, patient history, along with laboratory and imaging studies, can help guide management. Adrenal gland hemangiomas are rare, non-functional, and have a propensity to bleed, but are benign and have a good prognosis. Presentation: Friday, June 16, 2023

Unique Gene Expression Signature in Periadrenal Adipose Tissue Identifies a High Blood Pressure Group in Patients With Cushing Syndrome.

Cushing syndrome (CS) is a rare disease caused by excess cortisol levels with high cardiovascular morbidity and mortality. Hypertension in CS promotes hypercortisolism-associated cardiovascular events. Adipose tissue is a highly plastic tissue with most cell types strongly affected by the excess cortisol exposure. We hypothesized that the molecular and cellular changes of periadrenal adipose tissue in response to cortisol excess impact systemic blood pressure levels in patients with CS. We investigated gene expression signatures in periadrenal adipose tissue from patients with adrenal CS collected during adrenal surgery. During active CS we observed a downregulation of gene programs associated with inflammation in periadrenal adipose tissue. In addition, we observed a clustering of the patients based on tissue gene expression profiles into 2 groups that differed in blood pressure levels (CS low blood pressure and CS high blood pressure). The 2 clusters showed significant differences in gene expression pattens of the renin-angiotensin-aldosterone-system. Renin was the strongest regulated gene compared with control patients and its expression correlated with increased blood pressure observed in our patients with CS. In the CS high blood pressure group, systemic renin plasma levels were suppressed indicative of an abnormal blood pressure associated with periadrenal adipose tissue renin-angiotensin-aldosterone-system activation. Here, we show for the first time a relevant association of the local renin-angiotensin-aldosterone-system and systemic blood pressure levels in patients with CS. Patients from the CS high blood pressure group still had increased blood pressure levels after 6 months in remission, highlighting the importance of local tissue effects on long-term systemic effects observed in CS.

Anastomosing haemangioma of the adrenal gland: Aclinicopathological series of seven cases.

Anastomosing haemangioma is a rare benign vascular neoplasm that may histologically mimic angiosarcoma. We report the largest single institution series of anastomosing haemangioma in the adrenal gland with emphasis on clinical and radiological features. Our laboratory information system was searched for a 25-year period (1999-2023), yielding seven cases confirmed as anastomosing haemangioma of the adrenal gland after pathologicalre-review. Clinical, radiological and pathological information was obtained from medical charts and submitting pathologists. Of a total of seven patients, four (57.1%) were men and three women, ranging in age from 37 to 75 years (mean = 61). Six of seven patients underwent adrenalectomies and one had radical nephrectomy. Tumours ranged from 0.7 to 6.4 cm (mean = 2.1 cm) and five of seven (71%) were grossly well-circumscribed. Five of seven lesions were found incidentally at imaging for other indications. All tumours were unifocal except one, which presented with multifocal disease with a concurrent adjacent retroperitoneal anastomosing haemangioma. Three of five tumours imaged with contrast enhancement were almost completely hyperenhancing with a small central non-enhancing portion, features overlapping with pheochromocytoma. One of seven tumours involved the peri-adrenal adipose tissue with a focally infiltrative pattern. There were no recurrences or metastases in six patients with available follow-up data (median = 95 months). Benign anastomosing haemangiomas of the adrenal gland tend to occur in older patients, may mimic pheochromocytoma on imaging and must be distinguished from angiosarcoma pathologically. Better awareness of this entity by pathologists, radiologists and surgeons is crucial to appropriate work-up, diagnosis and management.

Development of an osteosarcoma model with MYCN amplification and TP53 mutation in hiPS cell-derived neural crest cells.

Mesenchymal stem cell- or osteoblast-derived osteosarcoma is the most common malignant bone tumor. Its highly metastatic malignant phenotypes, which are often associated with a poor prognosis, have been correlated with the modulation of TP53- and cell-cycle-related pathways. MYC, which regulates the transcription of cell-cycle modulating genes, is used as a representative prognostic marker for osteosarcoma. Another member of the MYC oncoprotein family, MYCN, is highly expressed in a subset of osteosarcoma, however its roles in osteosarcoma have not been fully elucidated. Here, we attempted to create an in vitro tumorigenesis model using hiPSC-derived neural crest cells, which are precursors of mesenchymal stem cells, by overexpressing MYCN on a heterozygous TP53 hotspot mutation (c.733G>A; p.G245S) background. MYCN-expressing TP53 mutated transformed clones were isolated by soft agar colony formation, and administered subcutaneously into the periadrenal adipose tissue of immunodeficient mice, resulting in the development of chondroblastic osteosarcoma. MYCN suppression decreased the proliferation of MYCN-induced osteosarcoma cells, suggesting MYCN as a potential target for a subset of osteosarcoma treatment. Further, comprehensive analysis of gene expression and exome sequencing of MYCN-induced clones indicated osteosarcoma-specific molecular features, such as the activation of TGF-β signaling and DNA copy number amplification of GLI1. The model of MYCN-expressing chondroblastic osteosarcoma was developed from hiPSC-derived neural crest cells, providing a useful tool for the development of new tumor models using hiPSC-derived progenitor cells with gene modifications and in vitro transformation.

PSAT025 Functional Adrenocortical Oncocytic Neoplasm: A Rare Cause of ACTH Independent Cushing's Syndrome

Abstract Background Adrenal oncocytomas (AOCs) or adrenocortical oncocytic neoplasms (ACONs) are extremely rare tumors of adrenal glands characterized by the presence of oncocytes, which are epithelial cells with eosinophilic cytoplasm. Only about 140 cases have been reported in literature so far. AOCs are more common in females (2.5: 1), more prevalent on the left adrenal gland (3.5: 1), and tumor size ranges from 3 to 17 cm. About two thirds of AOCs are reported to be nonfunctioning, and only less than 6% of functioning are cortisol secreting. The malignant potential of these tumors has been described quite variably in current literature. Based on the most recent systematic literature review, about 35% were found to be benign, 24% malignant, and 41% borderline, based on the Lin Weiss Bisceglia system. The mainstay of treatment is surgical resection. Here we describe a case where biochemical workup and pathology revealed a functional AOC with uncertain malignant potential. Clinical Case A 68 year old female with hypertension was found to have an incidental left 3 cm adrenal nodule on CT abdomen and pelvis during a workup for hematuria. The nodule was biopsied and initially found to be benign. Afterwards, she was referred to endocrinology where biochemical testing was consistent with ACTH-independent Cushing's syndrome. She had three elevated late night salivary cortisol - 0.10 mcg/dL, 0.14 mcg/dL, and 0.19 mcg/dL (≤0. 09 mcg/dL), three abnormal 1 mg dexamethasone suppression tests - 16.4 mcg/dL, 15.1 mcg/dL, and 17.1 mcg/dL (&amp;lt;1.8 mcg/dL), two normal 24 hour urinary cortisol - 22.5 and 31.5 mcg/24h (4-50 mcg/24h), and ACTH &amp;lt;5 pg/mL (6-50 pg/mL). She was then referred to surgery and was treated by laparoscopic adrenalectomy. Surgical pathology showed a 3.5 cm adrenal cortical tumor with oncocytes infiltrating into the periadrenal adipose tissue, with positive staining for synaptophysin and negative for P53. On Ki67 staining, some hot spots were greater than 5%. Therefore, the tumor was characterized as AOC with undetermined malignant potential or a low grade, oncocytic adrenocortical carcinoma. She was evaluated by oncology and radiation oncology, and it was decided to monitor the patient without systemic therapy or adjuvant radiation therapy. A surveillance approach was favored given that the risks of adjacent bowel and kidney toxicity outweighed the benefits of radiation. Conclusion We hereby report a case of AOC with undetermined malignant potential. This case highlights many challenges in the diagnosis, management and long-term surveillance of patients with AOCs, and need for further research. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Analysis of the miRNA expression from the adipose tissue surrounding the adrenal neoplasia.

BackgroundPrimary aldosteronism (PA) is characterized by several metabolic changes such as insulin resistance, metabolic syndrome, and adipose tissue (AT) inflammation. Mi(cro)RNAs (miRNAs) are a class of non-coding small RNA molecules known to be critical regulators in several cellular processes associated with AT dysfunction. The aim of this study was to evaluate the expression of some miRNAs in visceral and subcutaneous AT in patients undergoing adrenalectomy for aldosterone-secreting adrenal adenoma (APA) compared to the samples of AT obtained in patients undergoing adrenalectomy for non-functioning adrenal mass (NFA).MethodsThe quantitative expression of selected miRNA using real-time PCR was analyzed in surrounding adrenal neoplasia, peri-renal, and subcutaneous AT samples of 16 patients with adrenalectomy (11 patients with APA and 5 patients with NFA).ResultsReal-time PCR cycles for miRNA-132, miRNA-143, and miRNA-221 in fat surrounding adrenal neoplasia and in peri-adrenal AT were significantly higher in APA than in patients with NFA. Unlike patients with NFA, miRNA-132, miRNA-143, miRNA-221, and miRNA-26b were less expressed in surrounding adrenal neoplasia AT compared to subcutaneous AT in patients with APA.ConclusionThis study, conducted on tissue expression of miRNAs, highlights the possible pathophysiological role of some miRNAs in determining the metabolic alterations in patients with PA.

Effect of two hypercaloric diets on the hormonal and metabolic profile of the adrenal gland.

Who disrupts who? It is not clear what the interaction is between a high calorie diet (HCD) and adrenal axis activation in obesity. The goal was to assess the effect of two hypercaloric diets commercialized in Algeria on the hormonal and metabolic profile of the adrenal gland in rabbits. Two classes of local male adult rabbits (n=16) and a finishing diet (FD) as a control for 15weeks. It has been shown that HCD-received animals have developed visceral obesity, dyslipidemia and insulin resistance IR by dramatically increasing body weight, visceral fat tissue and adrenal weight, combined with elevated plasma levels of ACTH, cortisol, leptin and insulin. The HCD diet increased the levels of cortisol in the visceral adipose tissue (VAT), in peri-adrenal adipose tissue (PAAT), and decreased cortisol levels in the liver. HCD also causes the process of inflammatory fibrosis associated with the migration and spread of chromaffin cells in the adrenal gland. This study gives new insights into how diet-induced obesity studied on local rabbits affects the biology of the adrenal gland. The correlation of these changes with paracrine connections between the chromaffin cell and glomerulosa indicates potential therapeutic methods for obese-related steroid hormone dysfunction.

PCSK9 Inhibitors for the Management of Mitotane-Induced Hypercholesterolemia in Adrenocortical Carcinoma

Background: After surgical resection in adrenocortical carcinoma (ACC), mitotane is often used as adjuvant therapy. However, mitotane can cause adverse effects, such as inducing hypercholesterolemia by stimulating HMG-CoA reductase. In addition, mitotane is a strong CYP3A4 inducer which presents a challenge with statins, such as lovastatin, simvastatin, and atorvastatin. We present a case using a PCSK9 inhibitor in mitotane-induced hypercholesterolemia which was refractory to the maximum dose of rosuvastatin. Clinical Case: A laparoscopic left adrenalectomy was performed on a 45-year old female with Stage 3 (T3, NX, M0) ACC (4.5 x 3.4 x 3.2 cm). Her ACC was determined to be high grade with a mitotic rate 20/50 HPF and Ki-67 of 18.7% with lymphovascular invasion and tumor invasion of periadrenal adipose tissue. Following surgical resection, she started adjuvant therapy mitotane and oral hydrocortisone replacement, as well as 6 weeks of radiation therapy. Prior to starting mitotane, her LDL-C was 133 mg/dL (normal range <130 mg/dL) and treated with simvastatin 40 mg daily. A drug interaction was identified between simvastatin and mitotane, with mitotane reducing effects of simvastatin via CYP3A4 induction, so rosuvastatin 10 mg daily was started instead. A trial of combination rosuvastatin and ezetimibe was used; however, patient discontinued ezetimibe due to reported side effects. As the dose of mitotane increased to achieve a blood concentration of 14–20 mcg/mL, LDL-C simultaneously increased along with a corresponding dose increase of rosuvastatin. While being on mitotane 2 g daily and rosuvastatin 40 mg daily, her lipids peaked with LDL-C 219 mg/dL. The decision was made to start evolocumab administered as 140 mg subcutaneously every 2 weeks in addition to rosuvastatin 40 mg daily. After 4 months of therapy with combination evolocumab and rosuvastatin, her LDL-C decreased to 111 mg/dL, a 49% reduction, while achieving a mitotane concentration of 13 mcg/mL using 4 g daily. Conclusion: Utilizing a PCSK9 inhibitor, such as evolocumab, allows the dose of mitotane to be increased to achieve a therapeutic level while maintaining adequate control of cholesterol. With options for management of mitotane-induced hypercholesterolemia being limited, off-label use of a PCSK9 inhibitor can be justified clinically as moderate LDL-C reduction has also been shown in a prior published case report (1). Evolocumab is a well-tolerated subcutaneous injection, and should be considered for patients with resistant hypercholesterolemia while on mitotane.

Never Forget the Family History: MEN2A Syndrome Presenting as Metastatic Medullary Thyroid Cancer and Bilateral Pheochromocytoma

Abstract Introduction: MEN 2A is an autosomal dominant hereditary syndrome considered part of the medullary thyroid carcinoma (MTC) syndromes. This is characterized by MTC, pheochromocytoma, and parathyroid hyperplasia or adenomas causing primary hyperparathyroidism (PHPT). Clinical Case: A 34 year old female was referred to our clinic for multi-nodular goiter diagnosed during routine gynecologic evaluation. A thyroid ultrasound revealed a heterogeneous right thyroid lobe with a hypoechoic 2.5 cm nodule, associated macro calcifications and increased vascularity; and a left nodule measuring 2.3 cm with the same characteristics. Bilateral thyroid nodule biopsies were performed, resulting in MTC confirmed by positive calcitonin staining. Pre-operative studies revealed serum calcitonin and carcinoembryonic antigen (CEA), both of which are considered serologic markers of MTC activity, at 4,340 pg/ml (n &amp;lt;= 5) and 276.2 ng/mL (n &amp;lt;= 2.5 in non-smokers) respectively. The patient reported father with history of unspecified thyroid cancer, and paternal uncle with history of pheochromocytoma with a p.Cys634Trp mutation in RET proto-oncogene. Due to her family history, pre-operative screening for primary hyperparathyroidism (PHPT) resulted in a calcium 10 mg/dL (n 8.6-10.2), PTH 34 pg/mL (n 14-64). Additionally, screening for pheocromocytoma revealed an elevated 24 hour urine metanephrines of 2,276 (n &amp;lt;= 49-290) ug/24h, plasma metanephrines, including fractionated metanephrine (MN) at 163 (n &amp;lt;= 57) pg/ml, fractionated nor-metanephrine (NMN) at 182 (n &amp;lt;= 148) pg/ml, and total, Free (MN+NMN) metanephrines at 345 (n &amp;lt;= 205) pg/ml. CT abdomen revealed bilateral adrenal nodules, right measuring 1.4 x 3.3 cm and left 2.4 x 3.3 cm. The patient underwent posterior retroperitoneoscopic adrenalectomy with cortex sparing prior to thyroidectomy. Adrenal pathology resulted in bilateral pheochromocytoma with peri-adrenal adipose tissue microscopic involvement, and positive synaptophysin and S-100 stain. Subsequently, she underwent total thyroidectomy with extensive cervical lymph node resection, with pathology resulting in MTC with lymph node metastasis, involving 5/18 cervical lymph nodes. Post-operative labs revealed serum calcitonin &amp;lt;= 2 pg/ml, CEA 26.8 ng/mL, MN &amp;lt; 25 pg/ml, NMN 102 pg/ml, and MN+NMN of 102 pg/ml, which suggested initial surgical success. Post-operative genetic test evaluation revealed abnormal RET oncogene testing compatible with MEN 2A, variant 1: c.1902C&amp;gt;G (p.Cys634Trp). Conclusion: This case illustrates that patients presenting with MTC and reporting family history of thyroid cancer should be screened for familial MTC syndrome. Patients with RET mutation should be screened for pheochromocytoma prior to surgery for MTC to prevent life-threatening hypertensive crisis.

Retrospective Evaluation of The Cases with Malignant Pheochromocytoma: A Single Center Experience

IIntroduction&#x0D; &#x0D; The aim of this study was to evaluate the clinicodemographic factors and features of tumors in patients with malignant pheochromocytoma.&#x0D; &#x0D; Methods:&#x0D; &#x0D; We retrospectively evaluated the data of 5 cases admitted to our department between 2013 and 2020 and diagnosed with malignant pheochromocytoma.&#x0D; &#x0D; Results:&#x0D; &#x0D; The patients included three females with mean age of 45 years at presentation. Three cases were diagnosed with pheochromocytoma after hypertensive attack and two cases were diagnosed after detection of adrenal mass. The average diameter of the adrenal mass of the cases was 58 mm. Extesion to periadrenal adipose tissue was detected in two patients, vascular invasion in one patient, and capsule invasion in 1 patient in the surgery-resected specimen. Intraabdominal lymph node metastasis was found in 1 patient and metastatic focus was seen in the liver in 1 patient at the time of the diagnosis. During follow-up, perirenal region metastasis was detected in 1 patient. Bone metastasis was seen in 3 patients, lymph node metastasis in 2 patients and lung metastasis in 1 patient. Transperitoneal surrenalectomy was performed in all cases. Lutetium-177, radiotherapy and surgery were the preferred adjuvant therapies. Three patients died because of progression of the disease or acute complications and the other 2 patients are still under follow-up in our clinic.&#x0D; &#x0D; Conclusion:&#x0D; &#x0D; Malignant pheochromocytoma is rare and definitive criteria for malignancy is not established. Prognosis is poor and there is no curative treatment. Resection of malignant pheochromocytoma with intent to cure, which may improve symptoms and possibly survival is important.

Role of PDK4 in insulin signaling pathway in periadrenal adipose tissue of pheochromocytoma patients.

Studies have shown that pheochromocytoma (PHEO) is associated with glucose intolerance and decreased insulin sensitivity. In adipocytes, pyruvate dehydrogenase kinase 4 (PDK4) is involved in glucose uptake. However, very little is known about the role of PDK4 in the insulin signaling pathway in the adipose tissue of PHEO patients. We analyzed the expression of adipokines, oxidative stress-related genes, PDK4, phosphorylated AMPK (pAMPK) and phosphorylated IRS1 (pIRS1) in the periadrenal adipose tissue (peri-A) of patients with PHEO and non-functioning adrenal adenoma (NFA). We also investigated the effects of epinephrine on PDK4, pAMPK and pIRS1 in human stromal vascular fraction (SVF) cells, mouse 3T3-L1 preadipocytes and brown preadipocytes. PHEO patients had higher mRNA levels of PGC1α, C/EBPα, C/EBPβ, COXII and AP2 and lower mRNA levels of PPARγ in their peri-A than NFA patients. Decreased pAMPK and increased PDK4 and pIRS1 were observed in the peri-A of PHEO patients. PHEO patients also had significantly higher NOX4 protein expression and lower Nrf2 and HO-1 protein expression in their peri-A than NFA patients. In vitro, epinephrine treatment upregulated PDK4 expression, inhibited AMPK phosphorylation and enhanced IRS1 phosphorylation. The knockdown of PDK4 by siRNA upregulated pAMPK and downregulated pIRS1. In conclusion, PDK4 may play an essential role in hypercatecholamine-induced insulin resistance in the periadrenal adipose tissues of PHEO patients.

Adrenal Vascular Changes in COVID-19 Autopsies.

To the Editor.—For the past 2 months, New York City has been the epicenter of the ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 virus). The disease (coronavirus disease 2019 [COVID-19]) most acutely and severely affects the lungs, requiring mechanical ventilation in a subset of cases. Other organs, including the heart, kidneys, liver, and gastrointestinal tract, can also be involved. The pathophysiology and the extent of multiorgan involvement is poorly understood. We report pathological findings in the adrenal glands of the first 5 postmortem examinations of patients with COVID-19 diagnosed on clinical grounds with confirmatory real-time polymerase chain reaction testing of nasopharyngeal swab. Two patients were brought to the emergency room in cardiac arrest and could not be resuscitated. Three were briefly hospitalized, 2 for 24 hours and 1 for 72 hours. There were 4 males and 1 female, ranging from 59 to 90 years of age and with the following co-morbidities: hypertension (5 of 5), diabetes (3 of 5), ischemic cardiomyopathy (3 of 5), chronic lung disease (2 of 5, 1 with chronic obstructive pulmonary disease and 1 with interstitial lung disease), prostate carcinoma (2 of 5), and recent spinal surgery (1 of 5). Blood cultures were negative in the 3 patients tested. On microscopic examination, acute fibrinoid necrosis of small vessels, mainly arterioles in adrenal parenchyma, adrenal capsule, and in the immediately adjacent periadrenal adipose tissue, was identified. Subendothelial vacuolization and apoptotic debris were present (Figure, A–C). No significant inflammation, adrenal parenchymal infarcts, or thrombi were appreciated. The vascular pathology was disproportionately conspicuous in adrenal and not as easily identified in other organs examined.Fibrinoid necrosis describes vessel wall necrosis with fibrin and serum protein accumulation conveying an eosinophilic amorphous appearance on histology. With Masson's trichrome stain, the amorphous fibrinoid material is red, unlike collagen that stains blue (Figure, D). Arteriolar hyalinosis is another term used to describe the accumulation of pink amorphous material in vessel walls. This is thought to relate to hypertension, but is not typically associated with vessel necrosis and endothelial apoptosis. Hyalinosis may explain some of the histopathology; however, many of the vessels we observed were either necrotic or associated with apoptosis. It is unclear if the adrenal vasculopathy is because of hypoxia, abnormal vascular reaction and blood flow patterns, direct viral cytopathic effect, an immune-mediated injury, or a combination of events. Acute fibrinoid necrosis is classically described in malignant hypertension (first by Volhard and Fahr1 in 1914), mainly in kidneys, and in immune-mediated vasculitides. While SARS-CoV-2 infection seems to more severely affect patients with a history of hypertension,2 most critically ill patients with COVID-19 need vasopressors for persistent hypotension.3 Two of 3 hospitalized patients described had recorded high blood pressure values and 1 was hypotensive on arrival. Localized fibrinoid necrosis is also mentioned in a report of pathological findings in SARS virus infection.4 SARS-CoV-2 virus gains entry to the cell via the angiotensin-converting enzyme 2 receptor,5 which is most abundant in lung alveolar cells, but also present in endothelia and other tissues, providing a possible mechanism for vascular injury.6Adrenal hormones are involved in modulating inflammatory responses7 and adrenal gland dysfunction has been described in patients with community-acquired pneumonia.8In general, adrenal function is not routinely assessed in an intensive care unit setting. The most common indication for corticosteroid administration in an intensive care unit is refractory hemodynamic shock. According to several critical care societies, acute respiratory distress syndrome management can include corticosteroids, as they may decrease the time on a ventilator and reduce mortality.9 Corticosteroids are also administered if there is suspicion of adrenal insufficiency or if they are indicated because of an underlying condition. Currently, the World Health Organization and major critical care and infectious diseases associations advise against routine corticosteroid use in COVID-19 patients, mainly out of concern for slowing viral clearance. However, early reports from China and Europe suggested that corticosteroids are useful in severe COVID-19 and some experts posit that severe cytokine release syndrome seen in some patients warrants the use of corticosteroids or other targeted immunosuppressants.9–12It is interesting to consider that adrenal insufficiency secondary to the vasculopathy described here may contribute to the cytokine storm observed in patients with severe COVID-19. Clinical studies to further assess adrenal function in COVID-19 may help in understanding the pathogenesis of disease in severely affected patients and hopefully lead to therapeutic protocols that may rescue an increased number of patients.

SAT-259 Acromegaly by Pituitary Adenoma Associated with ACTH-Independent Cushing Syndrome by Adrenal Carcinoma: Case Report

Introduction: The coexistence of acromegaly and Cushing’s syndrome is quite rare. Case reports with this association have been described in the literature, including both ACTH-dependent and ACTH-independent Cushing’s syndrome. In these cases, when considering ACTH-independent hypercortisolism, the main etiology reported is adrenal adenoma. We will describe the case of an acromegalic patient with ACTH-independent cushing syndrome due to adrenal cortical carcinoma. Clinical Case: A 62-year-old male patient with acromegaly diagnosed by headache investigation. He had a previous medical history of T2DM for 20 years, grade III obesity (BMI 40.3), hypertension, obstructive sleep apnea and depression. Initial investigation showed IGF-1 levels of 818 ng/mL (81–225), GH: 3.39 ng/mL (<0.97), prolactin diluted: 2.578 ng/mL (2.1–17, 7), LH: <0.07 mIU/mL (1.5–9.3), FSH: 0.6 mIU/mL (1.4–18.1), total Testosterone: 51 ng/dL (241- 827) Cortisol at 8 AM: 15 µg/dL, TSH: 1.54 µg/dL (0.55–4.78), free T4: 1.0 ng/dL (0.89–1.76) and brain MRI with a large expansive sella turcica process, invading the right cavernous sinus, with growth to the sphenoid sinus and suprasellar compressing the optic chiasm, suggestive of pituitary macroadenoma. He underwent transsphenoidal resection with histology confirming a prolactin and GH co-secretory pituitary adenoma with Ki-67: 5%. He started treatment with octreotide LAR (30 mg/month) and cabergoline (3.5 mg/week) and underwent 25 radiotherapy sessions. Three years after the diagnosis of acromegaly, the patient underwent CT scan of the abdomen, which identified a 3.8 cm left adrenal nodular lesion that evolved in the 12-month control exam to nodular image with lobulated contours (5.0 x 3.4 cm) and non-contrast phase density > 25 HU. At that time, he had two 24-hour cortisoluria samples: 640.9 and 637 µg/24hs (54–403) and ACTH <5.0 pg/mL (<46).The patient underwent videolaparoscopic adrenalectomy confirming the pathology of the lesion compatible with adrenal cortical carcinoma with invasion of the capsule and peri-adrenal adipose tissue and Ki-67: 20%. Even after primary resection of the adrenal lesion, the patient evolves with local and metastatic progression of the disease, dying a few months later, due to infectious complications of a new surgical approach. Conclusions: To the best of our knowledge, this is the first case of ACTH-independent Cushing’s syndrome caused by adrenocortical carcinoma in an acromegalic patient.

SUN-378 Adrenocortical Carcinoma Diagnosed During Evaluation of an Incidentally Discovered Adrenal Mass

Background. Adrenocortical carcinoma (ACC) is a rare neoplasm with an estimated incidence of 0.5-2.0 per million per year. Most patients present with symptoms or signs of hormone excess or complaints related to tumor mass effect. We present a case of ACC discovered incidentally on computed tomography (CT) imaging of the abdomen. Case. A 59-year-old female presented to the emergency department (ED) after falling in her shower. She felt light headed before the fall, but she denied loss of consciousness or confusion after the event. The patient was noted to be hypertensive (185/105 mm Hg) and hypokalemic (2.6 mM, 3.6-5.1). A contrast enhanced abdominal CT scan revealed a 9.1 cm heterogeneous left adrenal mass. Plasma metanephrine and normetanephrine levels were unremarkable. Morning cortisol failed to suppress during a 1 mg overnight dexamethasone suppression test (10.1 μg/dL, < 1.8), and plasma midnight cortisol was unequivocally elevated at 24.3 μg/dL (< 7.5). ACTH (5 pg/mL, 6-58) and DHEA (0.159 ng/mL, 0.630-4.700) levels at 8 AM were both low. Postsurgical histopathology was notable for high grade mitoses (> 20/50 high powered fields), capsular invasion into peri-adrenal adipose tissue, and lymphovascular invasion, though surgical margins were uninvolved by tumor. No evidence of locoregional or distant metastases was observed on tumor staging, leading to a diagnosis of stage III ACC (T3N0M0). The patient elected treatment with local external beam radiation but declined mitotane. Secondary adrenal insufficiency is managed with hydrocortisone. Discussion. This patient’s case illustrates the female predominance (1.5-2.5:1) and typical time of diagnosis (fifth-to-sixth decade) reported in adult cases of ACC. It is unusual because only 20-30% of cases are diagnosed incidentally during imaging for an unrelated medical problem, and ACC accounts for only about 2-5% of incidentally diagnosed adrenal masses. The size (> 4 cm) and heterogeneity of the patient’s tumor were radiographic features indicating ACC, and the finding of adrenal hypercortisolemia is consistent with the high prevalence (45-70%) of metabolically active tumors that predominantly secrete cortisol. Hypertension and hypokalemia likely reflect saturation of renal 11-β-hydroxysteroid dehydrogenase with excess cortisol, though the patient lacked the features of rapidly progressive Cushing’s syndrome described in many cases of cortisol secreting ACC. Most cases of ACC are stage II or higher at initial diagnosis, and five-year survival for advanced stage ACC is only 10-25%. Disease stage and completeness of resection are the most important factors that influence prognosis, though high mitotic rate and hypercortisolemia in this patient’s case are negative prognostic factors. Adjuvant mitotane appears to improve recurrence-free survival, and radiation reduces the rate of local tumor recurrence.

Not all glucocorticoid-induced obesity is the same: differences in adiposity among various diagnostic groups of Cushing syndrome.

The cAMP signaling pathway is implicated in bilateral adrenocortical hyperplasias (BAHs), which are often associated with ACTH-independent Cushing syndrome (CS). Although CS is invariably associated with obesity and is frequently associated with PKA signaling defects, we recently reported that its different forms appear to also present with variable weight gain and adiposity. The present study was aimed at characterizing further the phenotypic and molecular differences in periadrenal adipose tissue (PAT) among patients with subtypes of CS, by anthropometric/biochemical analyses and quantification of PKA expression and activity in BAHs in comparison to a non-CS group with aldosterone producing adenomas (APAs). Glucocorticoid levels, serum parameters, and BMI were analyzed among a larger patient cohort including those with different forms of CS, APAs, and Cushing disease. Abdominal CT scans were available for a small subset of patients examined for fat distribution. PAT collected during adrenalectomy was assayed for PKA activity, cAMP, and PKA expression. BMI and BMI z-score were lower in adults with PPNAD with PRKAR1A mutations and in pediatric patients with PPNAD with and without PRKAR1A mutations, respectively. Patients with PPNAD had higher cAMP levels in PAT and different fat distribution. Thus, PKA activity in PAT differed between CS diagnostic groups. Increased cAMP and PKA activity may have contributed to phenotypic differences among subtypes of CS. In agreement with the known roles of cAMP signaling in the regulation of adiposity, patients with PPNAD were less obese than other patients with CS.

Differences in Adiposity in Cushing Syndrome Caused byPRKAR1AMutations: Clues for the Role of Cyclic AMP Signaling in Obesity and Diagnostic Implications

The cAMP signaling pathway is implicated in bilateral adrenocortical hyperplasias. Bilateral adrenocortical hyperplasia is often associated with ACTH-independent Cushing syndrome (CS) and may be caused by mutations in genes such as PRKAR1A, which is responsible for primary pigmented nodular adrenocortical disease (PPNAD). PRKAR1A regulates cAMP-dependent protein kinase (PKA), an essential enzyme in the regulation of adiposity. Although CS is invariably associated with obesity, its different forms, including those associated with PKA defects, have not been compared. The purpose of this study was to characterize the phenotypic and molecular differences in periadrenal adipose tissue (PAT) between patients with CS with and without PRKAR1A mutations. Samples from adrenalectomies of 51 patients were studied: patients with CS with (n = 13) and without (n = 32) PRKAR1A mutations and a comparison group with aldosterone-producing adenomas (APAs) (n = 6). In addition, clinical data from a larger group of patients with Cushing disease (n = 89) and hyperaldosteronism (n = 26) were used for comparison. Body mass index (BMI), abdominal computed tomography scans, and cortisol data were collected preoperatively. PAT was assayed for PKA activity, cAMP levels, and PKA subunit expression. BMI was lower in adult patients with CS with PRKAR1A mutations. cAMP and active PKA levels in PAT were elevated in patients with CS with PRKAR1A mutations. Increased PKA signaling in PAT was associated with lower BMI in CS. Differences in fat distribution may contribute to phenotypic differences between patients with CS with and without PRKAR1A mutations. The observed differences are in agreement with the known roles of cAMP signaling in regulating adiposity, but this is the first time that germline defects of PKA are linked to variable obesity phenotypes in humans.

A logistic regression model for predicting malignant pheochromocytomas

It is well known that no single histological feature is diagnostic for malignant pheochromocytomas (PCCs). So we developed a logistic model based on a series of clinical and pathological features to predict malignance in PCCs, and evaluated its diagnostic performance. In all 130 cases with malignant or benign PCCs, 15 predictive variables were observed and entered in the logistic regression analysis in a backward stepwise way. The diagnostic performance of this logistic model was evaluated by calculating the area under the receiver operating characteristic (ROC) curve. In logistic analysis, of the 15 variables entered in the logistic regression analysis, 9 were retained in the model. High cellularity had the highest odds ratio (OR), followed by spindle cell (>10% of tumor volume), atypical mitotic figure, periadrenal adipose tissue invasion, mitotic figures [>3/10 high-power field (HPF)], cellular monotony, capsular invasion, vascular invasion, and central or confluent tumor necrosis. High cellularity, spindle cell (>10% of tumor volume) and atypical mitotic figure were selected to built a logistic model. This model had the area under the ROC curve of 0.927 (95% confidence interval 0.883-0.971). The application of the model can benefit the clinical management decision for patients with PCCs. We still emphasize, however, that a clinical prospective evaluation is needed to confirm its actual value.