Adrenal Bed Research Articles

Synchronous bilateral adrenalectomy for ACTH-independent Cushing's syndrome in children: multidisciplinary management.

ACTH-independent Cushing's syndrome (CS) in children is very rare but potentially fatal. In bilateral nodular hyperplasia, synchronous bilateral adrenalectomy (SBA) represents the definitive treatment to correct hypercortisolism. We aim to report the multidisciplinary management of this rare condition. Presentation, management, and outcomes of all children with ACTH-independent CS who underwent SBA in a tertiary reference centre between 1992-2022 were retrospectively analysed. Ten children were included: six with McCune Albright syndrome, four with primary pigmented nodular adrenocortical disease (three with Carney complex). Presentation varied according to age at diagnosis. In infants (n=7), failure to thrive with anorexia (n=7), cushingoid facies (n=7), arterial hypertension (n=6), hypotonia (n=5), hyperglycaemia (n=4), liver dysfunction (n=4), and hypercalcemia with nephrocalcinosis (n=4) were the main reasons for urgent hospitalization. Prepubertal children (n=3) presented with linear growth arrest associated with obesity, cushingoid facies, and hirsutism. SBA was indicated in severe neonatal hypercortisolism, or in those that were non-responsive to medical treatment. SBA was performed by robot-assisted laparoscopy (n=6), laparoscopy (n=2) or laparotomy (n=2). One post-operative complication occurred (seroma in the adrenal bed). During follow-up (median: 4.8 years) no deaths or acute adrenal crisis occurred. Paediatric CS must be referred to a paediatric centre with medical and surgical expertise. Shared-decision making regarding SBA must be prompt to allow rapid cure of CS, even if it implies lifelong steroid replacement. This avoids long-term complications of hypercortisolism, particularly cognitive decline. Robot-assisted SBA is feasible and safe, even in infants when performed by an experienced robotic team.

In Vivo Formation of Adrenal Organoids in a Novel Porcine Model of Adrenocortical Cell Transplantation.

Recognizing the limitations of current therapies for Addison's disease, novel treatments that replicate dynamic physiologic corticosteroid secretion, under control of ACTH, are required. The aim of these experiments was to evaluate the feasibility of adrenocortical cell transplantation (ACT) in a large animal model, adapting methods successfully used for intracutaneous pancreatic islet cell transplantation, using a fully biodegradable temporizing matrix. Autologous porcine ACT was undertaken by bilateral adrenalectomy, cell isolation, culture, and intracutaneous injection into a skin site preprepared using a biodegradable temporizing matrix (BTM) foam. Hydrocortisone support was provided during adrenocortical cell engraftment and weaned as tolerated. Blood adrenocortical hormone concentrations were monitored, and the transplant site was examined at endpoint. Outcome measures included cellular histochemistry, systemic hormone production, and hydrocortisone independence. Transplanted adrenocortical cells showed a capability to survive and proliferate within the intracutaneous site and an ability to self-organize into discrete tissue organoids with features of the normal adrenal histologic architecture. Interpretation of systemic hormone levels was confounded by the identification of accessory adrenals and regenerative cortical tissue within the adrenal bed postmortem. Corticosteroids were unable to be completely ceased. ACT in a large animal model has not previously been attempted, yet it is an important step toward clinical translation. These results demonstrate rhe potential for ACT based on the development of adrenal organoids at the BTM site. However, the inability to achieve clinically relevant systemic hormone production suggests insufficient function, likely attributable to insufficient cells through delivered dose and subsequent proliferation.

SAT555 Utility of 18F-DOPA PET/CT in the Diagnosis of Medullary Thyroid Cancer in a Patient with Multiple Endocrine Neoplasia Type 2B

Abstract Disclosure: D.G. Varghese: None. S. Akshintala: None. A. Jha: None. S. Gubbi: None. A. Reno: None. J. Klubo-Gwiezdzinska: None. K. Pacak: None. J. Glod: None. J. Del Rivero: None. Background: MEN2B is a cancer predisposition syndrome caused by an activating mutation in the RET proto-oncogene. It is characterized by medullary thyroid cancer (MTC), pheochromocytoma (PHEO), and extra endocrine features. U/S, CT, MRI and 18F-fluorodeoxyglucose (18F-FDG), 18F-fluorodihyroxyphenylalanine (18F-FDOPA), 68Ga-DOTA-(0)-Tyr(3)-octreotate (68Ga-DOTATATE) PET/CT scans have been used for the diagnosis and follow up of MTC. However, there is increasing evidence of 18F-FDOPA PET as more specific imaging modality in the diagnosis of MTC since L-type amino acid transporters have shown to be present in MTC cells.Clinical Case: 26-year-old female presented with HTN at the age of 17. The patient developed episodes of nausea/vomiting, intermittent headaches with systolic BP in the 190’s. Further work-up revealed bilateral adrenal nodules with elevated plasma metanephrines. The patient underwent left adrenalectomy and a year later, right adrenal nodule resection confirming PHEO. On follow up, calcitonin was elevated, and the patient underwent a total thyroidectomy with bilateral central lymph node dissection. At age 19 she was diagnosed with MEN2B (RET mutation, p.Met918Thr). With rising calcitonin, she was referred to our institution for further evaluation. Her serum calcitonin was 31986(<7.6 pg/ml), CEA 631 (0.8-3.4 ng/ml), fractionated plasma normetanephrine 565 (18-112 pg/ml), and metanephrine 304 (12-61 pg/mL). MRI of the abdomen showed enlarging adrenal masses. 18F-FDG PET/CT scan showed a focus of uptake (SUVmax of 8.5) in posterior right thyroid bed, uptake in the liver (SUVmax of 7.5) and uptake in the right adrenal gland and left adrenal bed; 68Ga-DOTATATE PET/CT scan showed a faint uptake in the right thyroid lobe (SUVmax of 2.7) and an 18F-FDOPA PET/CT scan showed intense uptake in both lobe of the thyroid, multiple lesions in the liver and suspicious focus in the right adrenal bed. The patient underwent bilateral adrenalectomy for recurrent PHEO and her plasma metanephrines normalized. Conclusion: This case adds to the mounting evidence in the usage of 18F-FDOPA PET/CT scan as a useful imaging modality for MTC especially in the setting of MEN2B syndrome. A head-to-head comparison in 18 patients, both per patient and per lesion sensitivity by 18F-FDOPA PET/CT (72%, 85%) was found to be statistically superior compared to 68Ga-DOTATATE PET/CT (33%, 20%), and 18F-FDG PET/CT (17%, 28%). A meta-analysis conducted in MTC consisting of 306 patients from 14 studies, 18F-FDOPA compared to 18F-FDG and 68Ga-DOTATATE showed the highest surface under the cumulative ranking curve (SUCRA) value in both patient and lesion-based analyses irrespective of serum calcitonin/CEA values or calcitonin doubling time. The potential for use of 18F-FDOPA as a diagnostic agent and the potential to provide insight into possible therapeutic targets are unknown and should be further studied. Presentation Date: Saturday, June 17, 2023

Laparoscopic adrenalectomy for adrenal metastases of solid tumors.

In patients with history of cancer adrenal metastases can be found in up to 70% of adrenal tumors detected during follow-up. Currently, laparoscopic adrenalectomy (LA) is considered the gold standard approach for benign adrenal tumors but is still controversial in malignant disease. Depending on the patient's oncological status, adrenalectomy might be a possible treatment option. Our objective was to analyze the results of LA for adrenal metastasis from solid tumors in two referral centers. Retrospective analysis of 17 patients with non-primary adrenal malignancy treated with LA between 2007 and 2019 was performed. Demographic and primary tumor data, type of metastasis, morbidity, disease recurrence and evolution were evaluated. Patients were compared according to type of metastases: synchronous (< 6months) vs metachronous (≥ 6months). 17 patients were included. Median metastatic adrenal tumor size was 4cm (IQR, 3-5.4). We had one conversion to open surgery. Recurrence was found in 6 patients with one recurring in the adrenal bed. The median OS was 24 (IQR, 10.5-60.5) months and 5-year OS was 61.4% (95%CI: 36.7%-81.4%). Patients with metachronous metastases had better overall survival vs. patients with synchronous metastases (87% vs. 14%, p = 0.0037). LA for adrenal metastases is a procedure associated with low morbidity and acceptable oncologic outcomes. Based on our results, seems reasonable to offer this procedure to carefully selected patients, mainly those with metachronous presentation. Indication of LA must be done on a case by case evaluation in the context of a multidisciplinary tumor board.

ODP597 Clinical case of uncomplicated pregnancy in a patient with adrenocortical carcinoma during treatment with mitotane

Abstract Background Mitotane/o,p'DDD is adrenolytic and antitumor therapeutic agent used in the first line drug therapy of advanced adrenocortical carcinoma (ACC) as well as an adjuvant therapy after surgical resection of the primary tumor at moderate/high risk of recurrence. Mitotane is a metabolite of endocrine disruptor DDT and classified among teratogenic compounds. Preterm births and early pregnancy loss have been reported in female patients exposed to mitotane during pregnancy. Clinical Case At age 33, the patient underwent left adrenalectomy for "adrenocortical adenoma". Three years later, she was admitted to our Centre because of rapid development of Cushing's syndrome. Hormonal assessment revealed markedly increased urinary free cortisol level and abnormal overnight dexamethasone suppression test; ACTH was undetectable. Computed tomography revealed lungs and liver secondary masses, as well as tumor mass in the left adrenal bed. According to the above parameters, advanced ACC was suspected. During microscopy and immunohistochemistry of paraffin-embedded tissue blocks, tumor tissue after left adrenalectomy was identified as ACC. The patient started chemotherapy according to EDP-M (etoposide, doxorubicin, and cisplatin) protocol. Prior to chemotherapy initiation, mitotane and oral contraceptive pills were given. She also received glucocorticoid and mineralocorticoid replacement therapy. After three courses of chemotherapy, chest, abdomen and pelvis computed tomography disclosed complete regression of all the tumor masses. The patient continued mitotane, glucocorticoid and mineralocorticoid replacement drugs during the following year. Serial 18F-fluorodeoxyglucose-positron emission tomography scans were negative. One and a half years after cessation of chemotherapy, the patient chose to stop oral contraceptives. Several months later, the patient learned that she was pregnant (12 weeks of gestation) while on mitotane and adrenal replacement therapy. At this point, the patient and her partner were informed of the possible teratogenic effect of mitotane and strongly advised to terminate the pregnancy, but they decided to continue the pregnancy. Mitotane treatment was stopped immediately. The serum concentration of the drug was 16.8 mg/mL, within the therapeutic range (14–20 mg/mL). Glucocorticoid supplementation with hydrocortisone was continued. The course of the pregnancy was uncomplicated. A male infant was delivered breech by cesarean section at a gestation of 39 weeks. Birth weight was 3050 g, length 46 cm, and head circumference 36 cm. Apgar scores were 8, 9 and 9 at 1, 5 and 10 min, respectively. Newborn examination revealed no anomalies and no hyperpigmentation. Blood pressure, heart rate, and temperature were normal. Conclusion To our knowledge, we present the first case of uncomplicated pregnancy in a patient with adrenocortical carcinoma and therapeutic serum concentration of mitotane. Our report suggests that mitotane can not affect normal development of the fetus. Nevertheless, until more data are available, pregnancy should be avoided in women being treated with mitotane for ACC. Presentation: No date and time listed

Pheochromocytoma recurrence in hereditary disease: does a cortical-sparing technique increase recurrence rate?

BackgroundPosterior retroperitoneoscopic adrenalectomy is an appealing approach for patients with hereditary pheochromocytoma and lends well to cortex preservation. We sought to examine pheochromocytoma recurrence in patients with hereditary pheochromocytoma in the era of posterior retroperitoneoscopic adrenalectomy and evaluate the predictors of recurrence. MethodsPatients with hereditary pheochromocytoma who underwent adrenalectomy for pheochromocytoma between 1995 and 2020 with biochemical cure and follow-up >1 year were identified. Recurrence was defined as plasma metanephrines above the upper limit of normal with radiographic evidence of disease in the ipsilateral adrenal bed. ResultsSeventy-eight hereditary pheochromocytoma patients (median age = 32.4 years; 60.3% women) underwent 114 adrenalectomies for pheochromocytoma. Of these patients, 40 had multiple endocrine neoplasia type 2A (51.3%), 10 had multiple endocrine neoplasia type B (12.8%), 17 had von Hippel-Lindau disease (21.8%), and 11 had neurofibromatosis type 1 (14.1%). Thirty-eight adrenalectomies (33.3%) were performed before the introduction of posterior retroperitoneoscopic adrenalectomy and 76 (66.7%) after. Cortical-sparing technique was performed in 62 (54.4%) adrenalectomies, with no difference in its use before and after posterior retroperitoneoscopic adrenalectomy introduction (P > .05). During a median follow-up of 80.7 months (interquartile range 43.4–151.2), 12 ipsilateral recurrences (10.5%) were identified. There was no difference in recurrence before and after the introduction of posterior retroperitoneoscopic adrenalectomy or by surgical technique or approach of the entire cohort (P > .05). Recurrence was more common in those with RET M918T mutation (23.5% vs 8.2%; P = .05). Patients with RET M918T mutations had a shorter recurrence-free survival (P = .013). On multivariate analysis, only RET M918T mutation was independently associated with an increased recurrence risk (hazard ratio = 4.30; 95% confidence interval, 1.26–14.66; P = .019). ConclusionThe introduction of posterior retroperitoneoscopic adrenalectomy did not influence the recurrence rate after adrenalectomy for hereditary pheochromocytoma patients. Patients with a RET M918T germline mutation are at increased risk for pheochromocytoma recurrence and may benefit from initial total adrenalectomy.

Is there a role for surgery after chemotherapy in recurrent/metastatic adrenal cortical cancer (ACC)?

5092 Background: ACC is a rare endocrine malignancy. Patients with metastatic disease at diagnosis are often treated palliatively with systemic therapy. It is unclear if neoadjuvant cytoreduction with chemotherapy can render metastatic or previously resected but locally recurrent patients become surgical candidates and impact overall survival (OS). Methods: A retrospective single institution review (2002-2019) of metastatic ACC patients was performed. Descriptive statistics were used and OS was estimated by Kaplan-Meier method. Results: Out of 84 patients with metastatic ACC [30 (20.7%) upfront and 54 (37.2%) after definitive therapy], 51 received systemic therapy with mitotane and etoposide-doxorubicin-cisplatin (EDP) as standard 1st line regimen and varied subsequent lines of therapy. Two patients were excluded as they were lost to follow-up. Among the included 49 patients, 29 were females (59.2%) and 26 patients (53.1%) had functional tumors at baseline. Out of 33 patients who had information available on tumor grade, 26 (78.8%) were high grade. Nine pts (18.4%) underwent surgery after receiving systemic therapy (eight after EDP in first line and one after pembrolizumab in third line). These patients were younger (median age 39 years compared to 52.5 years for those receiving only chemotherapy), had locally recurrent disease (all nine patients) with four having evidence of progressive liver metastasis. Median number of EDP cycles delivered before surgery was 4 (range 3-7). The patient who underwent surgery after pembrolizumab received nine cycles of preoperative pembrolizumab. Five pts (55.5%) had partial response, three (33.3%) had disease progression and one (11.1%) had stable disease prior to surgery. Patients underwent surgery after a mean interval of 3.1 months (m) (1.1-5.1) after systemic therapy. Six patients had no evidence of disease (NED) (five with disease limited to adrenal bed) after surgery. Eight out of nine patients recurred after surgery with a median time of 6.1 m (4.4-7.8). The median OS for the entire cohort was 26 m (95% CI 22.3-35.2). This was not significantly better for patients undergoing surgery [median OS 31.2 m (95% CI 21.4-63.3) vs 24.7 m (95% CI 17.7-35.2) p = 0.48]. Patients rendered NED after surgery had numerically better OS than those with residual disease or those receiving only chemotherapy [median OS 39.6 m (24.8.-NR), vs 23.5 m (21.4-NR) vs 24.7 m (17.7-35.2), p = 0.271]. Higher Ki-67 predicted for inferior OS in the entire cohort with no effect of age, gender, tumor grade or functional status. Conclusions: Attempting to downstage patients with metastatic or locally recurrence with systemic therapy does not seem to prolong OS in patients with ACC. Selected patients with limited disease burden, who can be rendered disease free by surgery, may be suitable for this approach.

Combination of Mitotane and Locoregional Treatments in Low-volume Metastatic Adrenocortical Carcinoma.

European and French guidelines for ENSAT stage IV low tumor burden or indolent adrenocortical carcinoma (ACC) recommend a combination of mitotane and locoregional treatments (LRT) as first-line treatment. Nevertheless, the benefit of LRT in combination with mitotane has never been evaluated in this selected group of patients. This work aimed to evaluate the therapeutic strategy of LRT combined with mitotane in patients with low tumor burden stage IVA ACC. A retrospective chart review was performed from 2003 to 2018 of patients with stage IV ACC with 2 or fewer tumoral organs who received mitotane in our center. The primary end point was the delay between mitotane initiation and first systemic chemotherapy. Secondary end points were progression-free survival (PFS) and overall survival (OS) from mitotane initiation. Adjusted analyses were performed on the main prognostic factors. Out of 79 included patients, 48 (61%) patients were female and the median age at stage IVA diagnosis was 49.8 years (interquartile range [IQR], 38.8-60.0 years). Metastatic sites were mainly lungs (76%) and liver (48%). Fifty-eight (73%) patients received LRT including adrenal bed radiotherapy (14 patients, 18%), surgery (37 patients, 47%), and/or interventional radiology (35 patients, 44%). Median time between mitotane initiation and first chemotherapy administration was 9 months (IQR, 4-18 months). Median PFS1 (first tumor-progression) was 6.0 months (95% CI, 4.5-8.6). Median OS was 46 months (95% CI, 41-68). PFS1, PFS2, and OS were statistically longer in the mitotane plus LRT group compared to the mitotane-only group (hazard ratio [HR] = 0.39; 95% CI, 0.22-0.68; HR = 0.35; 95% CI, 0.20-0.63; and HR = 0.27; 95% CI, 0.14-0.50, respectively). Ten (13%) patients achieved complete response (CR), all from the mitotane plus LRT group. Our results endorse European and French guidelines for stage IV ACC with 2 or fewer tumor organs and favor the combination of mitotane and LRT as first-line treatment. For the first time, a significant number of CRs were observed. Prospective studies are expected to confirm these findings.

High Prevalence of Adrenal Remnant Tissue in Patients Undergoing Bilateral Adrenalectomy for Cushing's Disease.

Bilateral adrenalectomy (BLA) is a treatment option for patients with Cushing's Disease (CD) if transsphenoidal pituitary surgery fails or is not a therapeutic option. For most patients, BLA eliminates endogenous glucocorticoid and mineralocorticoid production, but for a small number of patients, endogenous secretion of adrenal hormones from adrenal tissue continues or recurs, leading to signs and symptoms of hypercortisolism. If adrenal tissue is confined to the adrenal bed, it is considered adrenal remnant tissue, while if it is outside the adrenal bed, it is considered adrenal rest tissue. We retrospectively evaluated morning serum cortisol, nighttime serum cortisol, nighttime salivary cortisol, and 24-h urine free cortisol on at least three occasions in 10 patients suspected of having endogenous cortisol production. Imaging of adrenal remnant tissue was also reviewed. Ten of 51 patients who underwent BLA during this time period had adrenal remnant/rest tissue marked by detectable endogenous glucocorticoid production; 9 of the 10 patients had signs and symptoms of hypercortisolism. Localization and treatment proved difficult. We conclude that the incidence of adrenal remnant/rest tissue in those undergoing BLA following unsuccessful pituitary surgery was 12% although there may have been a selection bias affecting this prevalence. The first indication of remnant tissue occurrence is a reduction in glucocorticoid replacement with symptoms of hypercortisolism. If this occurs, endogenous cortisol production should be tested for by cortisol measurements using a highly specific cortisol assay while the patient is taking dexamethasone or no glucocorticoid replacement. Endocrinologists need to monitor the development of both adrenal remnant tissue and Nelson's syndrome following BLA.

Hematoma escrotal como signo infrecuente de hemorragia suprarrenal en recién nacidos

Antecedentes: El hematoma escrotal es una manifestación rara de hemorragia suprarrenal neonatal (0.2% de los recién nacidos). Se asocia comúnmente a la hipoxia perinatal, pero puede suceder de manera espontánea en pacientes sin patología aparente. La aparición de este signo se explica por la llegada al escroto de la sangre del lecho suprarrenal a través del canal inguinal. Resumen del caso: Varón de 24 horas de vida, nacido a término, con un peso adecuado para la edad gestacional, presenta hematoma y aumento de tamaño del hemiescroto derecho. La ecografía doppler descarta torsión testicular, identificando una estructura compatible con hematocele. La ecografía abdominal mostró signos sugestivos de hemorragia suprarrenal derecha. Se decide manejo conservador y seguimiento con pruebas de imagen, evolucionando favorablemente hacia la remisión. Conclusiones: Destacamos la importancia de incluir la hemorragia de la glándula suprarrenal en el diagnóstico diferencial de escroto agudo, ya que su detección mediante ultrasonidos puede evitar la cirugía innecesaria en el recién nacido

SAT-223 Metastatic Pheochromocytoma in MEN2A: Clinical Features, Laboratory Data and Radiological Findings of a Rare Association - Case Report

Background: Multiple endocrine neoplasia type 2A (MEN2A) is an autosomal dominant syndrome caused by inactivating mutations in the RET proto-oncogene. It is characterized by medullary thyroid carcinoma (MTC), pheochromocytoma (PHEO) and hyperparathyroidism (HPTH). MTC is one of the initial manifestations in 90% of patients. PHEO affects approximately 50% of patients, is almost always benign (98% of cases), usually bilateral and confined to the adrenal glands. HPTH occurs in 20-30% of patients. The clinical presentation, evolution and prognosis of metastatic PHEO associated with RET mutations are not yet well known. Clinical Case: A previously healthy man was initially diagnosed with hypertension at 24 years of age. Two years later, after recurrent paroxysms of headache, tremors and tachycardia, the patient was suspected of having bilateral PHEO based on laboratory and radiological findings. Bilateral adrenalectomy was performed and the anatomopathological analysis confirmed the suspected diagnosis.Soon afterward, although the patient was asymptomatic, with urinary metanephrines in the normal range, two possibly metastatic lesions were identified – one in the liver (9 x 8 mm) and one in the left adrenal bed. Some of the patient’s family members were also found to have PHEO and/or MTC, leading to the diagnosis of MEN2A. A RET germline mutation in codon 634 (p.Cys634Phe) of exon 11 was then found in the patient’s family pedigree. At the time, the patient (index case) had no evidence of MTC or HPTH.Diagnostic 131I-MIBG scintigraphy showed increased uptake in the patient’s liver. The subsequent percutaneous liver biopsy confirmed the presence of metastatic PHEO. Interestingly, no significant 18F-FDG uptake was found on the 18F-FDG-PET/CT scan in the metastatic PHEO sites. For more than 10 years of follow-up with no specific treatment, the metastatic lesions demonstrated slow growth rates; metanephrine levels, although increased (total = 1422 mcg/24h, NR <1000; normetanephrine = 676 mcg/24h, NR <320; and metanephrine = 574 mcg/24h, NR <390), were relatively stable; blood pressure and adrenergic symptoms were under control with a few antihypertensive medications.At 36 years of age, the calcitonin level was slightly increased (8.6 pg/mL, NR <8.4) and a minuscule thyroid nodule (3 x 3 x 2 mm) was identified on the ultrasound scan. Prophylactic thyroidectomy was performed, with a diagnosis of a 2.5-mm MTC. More recently, an increase in the metanephrine levels was found and treatment with iobenguane 131I may be an option. Conclusion: Patients with metastatic PHEO caused by mutations in the RET proto-oncogene (MEN2A) may have a long survival time. In such patients, an 18F-FDG-PET/CT scan may exhibit low sensitivity for the diagnosis of metastasis and the onset of PHEO may precede that of MTC by many years.

SUN-911 Immunotherapy Use in Adrenocortical Carcinoma with Encouraging Results- a Case Report

Adrenocortical carcinoma (ACC) is a rare cancer with a very poor prognosis with median survival of around 17 months. We present a patient with metastatic ACC in whom the response to PD1 inhibitor pembrolizumab has been promising.Case report: A Caucasian female patient presented at the age of 19 y with weight gain, hypertension, moon facies, supraclavicular fullness and increased hair growth on her upper back. Serum potassium concentration was 2.6 mmol/l, cortisol was 46 mcg/dL (nl = 3-12mcg/dL), and plasma ACTH concentration was < 5 pg/ml (nl = 6-58pg/ml). CT abdomen revealed a 5.4 cm right adrenal mass. For ACTH-independent Cushing’s Syndrome, she underwent right adrenalectomy within 1 week of presentation. Pathology revealed a 6.5 cm ACC with negative margins, with sinusoidal invasion, but no vascular or capsular invasion. Mitosis rate was 15-20/HPF with atypical mitotic figures. Immunohistochemistry showed no loss of expression of mismatch repair gene products associated with microsatellite instability. She was unable to tolerate mitotane. Genetic analysis was negative for TP53 mutation, and she underwent radiation to the adrenal bed within 6 months following adrenalectomy. She remained without biochemical or structural evidence of disease recurrence until 2.5 years following adrenalectomy, when AM cortisol was 6 mcg/dL (nl < 1.8) after 1 mg and after 2 mg of dexamethasone the previous evening. CT scan of the pelvis, abdomen, and chest revealed 5 solid masses scattered within the lungs. The largest of these being 2.3 cm and 2 cm, and the other 3 being approximately 1 cm. Fine needle aspiration biopsy of the lung lesion revealed ACC metastases. Immunotherapy with pembrolizumab 200 mg every 3 weeks was initiated and continued for 2 years, with a side effect being grade 1 diarrhea. At 1 year after initiating pembrolizumab, she developed primary adrenal insufficiency that is being treated with 0.1 mg/d of fludrocortisone and low dose glucocorticoid replacement (hydrocortisone: 10mg in the morning and 5 mg in the evening), to avoid immune suppression. Pulmonary nodules decreased in size to 6 mm over the 2 years of pembrolizumab therapy and remained stable in size 1 year following completion of pembrolizumab therapy at which time the early morning serum cortisol concentration remained undetectable with a plasma ACTH concentration of 1177 pg/ml (nl = 6-50 pg/ml). In summary, this patient with ACC with normal mismatch repair gene expression demonstrated both structural and biochemical responses to 2 years of pembrolizumab therapy. The major side effect has been primary adrenal insufficiency. The biochemical and structural responses have been durable for 1 year after completion of pembrolizumab therapy.Conclusion: This patient with microsatellite stable ACC has had a 36-month response to pembrolizumab.

SUN-160 Development of Adrenocortical Carcinoma in an Adrenal Nodule After Nine Years of Size Stability on Imaging: A Case for Critical Review of Efficacy of Radiographic Size Criteria

BACKGROUND: Current consensus guidelines for adrenal incidentalomas smaller than 4 cm recommend re-evaluation up to 2 years. Although there is no consensus for imaging surveillance beyond 2 years, in general, stability in size over time is considered a sign of benign nature. Clinical Case: A 50-year-old African-American woman presented to Endocrinology for resistant hypertension since age 30 and an enlarging right adrenal nodule. She was obese, weighing 138.8 kg with a BMI of 55.97 kg/m2, without clinical Cushingoid features. At her first visit she was taking the following antihypertensives: amlodipine, losartan, hydrochlorothiazide, and clonidine patch. She took no other prescription medications. Her baseline metabolic blood profile was normal. Further testing revealed a profile consistent with possible primary hyperaldosteronism and subclinical Cushing’s syndrome: plasma aldosterone 17 ng/dl, plasma renin activity 0.232 ng/ml/hour, ACTH 10 pg/ml, AM cortisol 8.3 mcg/dl, DHEAS 30 mcg/dl, and 1mg dexamethasone suppression test resulted in cortisol of 7.6 mcg/dl (normal < 1.8 mcg /dl) with a simultaneous dexamethasone level of 357 ng/dl (140 – 295 ng/dl). However, 24-hour urinary free cortisol and urinary metanephrines were within reference ranges. Further confirmatory tests were not performed due to her imaging findings, as described below.The earliest abdominal imaging was a CT abdomen with contrast in 2005 which measured a 2.1 cm right adrenal mass. For various reasons she had repeat CT contrast imaging in 2006, 2007, 2012, and 2014 demonstrating no changes in the dimensions of her adrenal nodule, noting all the studies were performed with contrast only and without Hounsfield unit (HU) measurements. In 2017, a CT abdomen with adrenal protocol demonstrated a right adrenal mass measuring 4 cm x 3.5 cm (increased from 2.1 X 1.2 cm in 2014), characterized by 43 HU pre-contrast, 71 HU post-contrast, and an absolute washout of 29%. Due to high suspicion for malignancy, a PET-CT was performed with FDG, which revealed high uptake in the right adrenal mass.She was referred for a right adrenalectomy and pathology showed adrenocortical carcinoma with some infiltration into adipose tissue. There was a high mitotic index (42 per 50 high powered fields) and Ki67 of 35%, classified as Stage III pT3NxM0. She was referred to oncology and treated with external radiation to the adrenal bed along with initiation of mitotane. Conclusion: This case infers that long-term size stability of an adrenal nodule does not confer full confidence of a benign process. Compared with previous reports in the literature describing long latencies for ACC, this is one of the longest records of size stability over 9 years followed by a size increase 3 years later.

Comparison of Pheochromocytoma-Specific Morbidity and Mortality Among Adults With Bilateral Pheochromocytomas Undergoing Total Adrenalectomy vs Cortical-Sparing Adrenalectomy

Large studies investigating long-term outcomes of patients with bilateral pheochromocytomas treated with either total or cortical-sparing adrenalectomies are needed to inform clinical management. To determine the association of total vs cortical-sparing adrenalectomy with pheochromocytoma-specific mortality, the burden of primary adrenal insufficiency after bilateral adrenalectomy, and the risk of pheochromocytoma recurrence. This cohort study used data from a multicenter consortium-based registry for 625 patients treated for bilateral pheochromocytomas between 1950 and 2018. Data were analyzed from September 1, 2018, to June 1, 2019. Total or cortical-sparing adrenalectomy. Primary adrenal insufficiency, recurrent pheochromocytoma, and mortality. Of 625 patients (300 [48%] female) with a median (interquartile range [IQR]) age of 30 (22-40) years at diagnosis, 401 (64%) were diagnosed with synchronous bilateral pheochromocytomas and 224 (36%) were diagnosed with metachronous pheochromocytomas (median [IQR] interval to second adrenalectomy, 6 [1-13] years). In 505 of 526 tested patients (96%), germline mutations were detected in the genes RET (282 patients [54%]), VHL (184 patients [35%]), and other genes (39 patients [7%]). Of 849 adrenalectomies performed in 625 patients, 324 (52%) were planned as cortical sparing and were successful in 248 of 324 patients (76.5%). Primary adrenal insufficiency occurred in all patients treated with total adrenalectomy but only in 23.5% of patients treated with attempted cortical-sparing adrenalectomy. A third of patients with adrenal insufficiency developed complications, such as adrenal crisis or iatrogenic Cushing syndrome. Of 377 patients who became steroid dependent, 67 (18%) developed at least 1 adrenal crisis and 50 (13%) developed iatrogenic Cushing syndrome during median (IQR) follow-up of 8 (3-25) years. Two patients developed recurrent pheochromocytoma in the adrenal bed despite total adrenalectomy. In contrast, 33 patients (13%) treated with successful cortical-sparing adrenalectomy developed another pheochromocytoma within the remnant adrenal after a median (IQR) of 8 (4-13) years, all of which were successfully treated with another surgery. Cortical-sparing surgery was not associated with survival. Overall survival was associated with comorbidities unrelated to pheochromocytoma: of 63 patients who died, only 3 (5%) died of metastatic pheochromocytoma. Patients undergoing cortical-sparing adrenalectomy did not demonstrate decreased survival, despite development of recurrent pheochromocytoma in 13%. Cortical-sparing adrenalectomy should be considered in all patients with hereditary pheochromocytoma.

Tumor growth rate in metastatic adrenocortical carcinoma using two-dimensional computer tomography scan.

e16125 Background: Adrenocortical carcinoma (ACC) is a rare tumor with an incidence of 1.5–2 per million people per year. It has a poor prognosis with an overall 5-year mortality of 75-80%. The treatment of choice for a localized primary or recurrent tumor is radical surgical resection. However, patients with recurrent or metastatic disease are infrequently cured by surgery alone and chemotherapy has limited benefits. Little is known about the growth rate of metastatic lesions or how disease burden varies among patients, which poses a considerable obstacle in patient care as 17–53% of patients present with distant metastases at the time of diagnosis. Most ACC metastases are found in the liver, lung, bone, and retroperitoneum. Methods: This study retrospectively analyzed the growth rate of metastatic ACC lesions in the lung, liver, lymph nodes, and adrenal bed using serial two-dimensional segmentation of computer tomography images from 10 patients seen at the National Institutes of Health. All patients were females (mean age of 61 years; range, 49–70 years) who had an ACC diagnosis for a mean of 7 years (range, 3–14 years). Only lesions that exhibited FGD-PET avidity were included with up to five lesions per organ recorded. Results: Of the 10 patients, 7 showed metastatic disease at primary diagnosis, although all patients developed recurrent and/or distant metastatic lesions throughout the course of their disease (3 patients had lung lesions, 6 had liver lesions, 8 had adrenal bed recurrence, and 5 had lymph node involvement). Compared over a 6-month period without treatment alteration (change in chemotherapy, surgical intervention, or ablation) lung lesions increased by 11.6%, liver lesions decreased by 17.9%, retroperitoneal lesions increased by 69.25%, and lymph node lesions increased by 9.2%. Conclusions: Treatment of metastatic lesions, particularly in the liver, can increase long-term survival. Understanding growth rates of metastatic tumors may lead to improved treatment of patients with ACC.

SAT-317 The Importance of Accurate Genetic Diagnosis Highlighted in a Case of Recurrent Bilateral Pheochromocytomas

Background It is estimated that one-third of patients with pheochromocytomas and paragangliomas (PPGL) have germline mutations. This patient with bilateral pheochromocytomas was initially diagnosed with MEN2A syndrome, underwent prophylactic total thyroidectomy, only to be diagnosed with a different germline mutation subsequently. Clinical case This patient first presented at 12 years of age, with hypertensive emergency and a right 8cm adrenal tumour with spontaneous haemorrhage. He underwent emergency right adrenalectomy, with histology confirming a pheochromocytoma. Post-operatively, urinary metanephrines were normal and symptoms resolved. 7 years later, he re-presented with headache, postural hypotension, cutaneous lichen amyloidosis and elevated urinary normetanephrine (NMT). CT abdomen showed 2 left adrenal masses with no residual right adrenal lesion. Open left adrenalectomy was performed and 3 pheochromocytoma nodules of 8 to 10mm in size were found. Urinary NMT was normal post-surgery. He was commenced on hydrocortisone and fludrocortisone replacement. In view of his young age and bilateral pheochromocytomas, genetic testing was done. RET proto-oncogene testing showed a silent mutation in Exon 13 Codon 769 CTT->CTG coding for Leucine, suggestive of MEN2A syndrome. His calcium and parathyroid hormone were normal. Although asymptomatic, he underwent prophylactic total thyroidectomy. However, histology revealed no endocrine cell hyperplasia. At age of 33 years, his symptoms recurred. Plasma free NMT was raised, 3.29nmol/L (reference <0.71nmol/L), while plasma metanephrine and 3-methoxytyramine were normal. Ga68-DOTAPEPTIDE PET/CT showed one tracer-avid lesion in each adrenal bed, suspicious of recurrent bilateral disease. He underwent open bilateral adrenalectomy and histology confirmed bilateral recurrent pheochromocytomas. Post-operatively, his plasma NMT has normalised. His atypical presentation for MEN2A syndrome prompted a repeat hereditary PPGL genetic testing. A pathogenic variant in the SDHD gene, namely c.3G>C (Initiator codon) was identified, while his previous MEN2A mutation of indeterminate significance was deemed not pathogenic. His father subsequently tested positive for SDHD mutation and is undergoing further investigations. Conclusion Major advances in the understanding of hereditary PPGL have been made over the last decade. Identification of the correct germline mutation is important to predict risks of malignancy, recurrence and guide early treatment. This case highlights the importance of comprehensive, targeted genetic testing with trained geneticist over traditional single gene tests and the need to interpret results with caution. Reference Pheochromocytoma and Paraganglioma: An Endocrine Society Clinical Practice Guideline. Jacques W.M. Lenders et al. J Clin Endocrinol Metab.2014; 99 (6): 1915-1942.

Improvement in Recurrence-free Survival with Adjuvant Radiation in Adrenocortical Carcinoma

Adrenocortical carcinoma (ACC) is a rare malignancy with high rates of local recurrence and poor prognosis. Given high propensity to metastasize, the role of post-operative radiation therapy (RT) in localized ACC has been controversial. We sought to evaluate the benefit of adjuvant RT to local control in our updated institutional ACC database. From 424 patients in our ACC database, we retrospectively identified patients who underwent adjuvant RT at our institution from 1999 to 2017. Patients that were treated with surgery followed by adjuvant RT were matched to patients who only underwent resection on the basis of stage, surgical margin status, tumor grade, and adjuvant mitotane use. Local recurrence was defined as adrenal bed or abdominal failure. Overall and recurrence-free survival probabilities were estimated using the Kaplan-Meier method. Distributions were compared between cases and controls using the log-rank test statistic. Cox proportional hazards regression models were used to estimate the hazard ratio for time-to-event endpoints comparing controls to cases after adjustment for age at event and gender. Of 424 patients, 78 patients with ACC were selected, half who underwent adjuvant radiation. Patients were matched 1:1 without significant differences with respect to stage, margin status, grade, or mitotane use, although there were more females than males in the matched group (52.8% females with RT, 82% without RT). Median radiation dose was 55 Gy (range 45-60 Gy). Local recurrence was less common with adjuvant RT (13 vs 26 local failures in those treated with and without RT, respectively, (p = 0.038, hazard ratio [HR] 2.20; 95% confidence interval [CI] 1.04-4.63)). Five-year recurrence-free survival for patients with RT was 46.7% and 16.9% for patients without (p = 0.016; HR 2.32, 95% CI 1.14-4.57). There was numerically better overall survival in patients that received RT (72.1% versus 55.1%), although this was not statistically significant (p = 0.424, HR 1.46, 95% CI 0.58-3.68). Adjuvant RT following gross resection of ACC significantly improves recurrence free-survival in this retrospective case-matched cohort analysis. Even though, this represents the largest series to date on adjuvant RT for ACC, prospective confirmation of this data is needed.

Uncommon primary hydatid cyst occupying the adrenal gland space, treated with laparoscopic surgical approach in an old patient.

Hydatid disease (HD) is caused by Echinococcus Granulosus (EG), which is a larva endemic in many undeveloped areas. The most common target is the liver (59%–75%). The retroperitoneal space is considered as a rare localization. We report an uncommon case of HD located in the adrenal gland space.Presentation of case. This is a 78-year-old Moroccan woman, with right flank pain for eight months previously. She denied contact with dogs or sheep. Her physical examination was normal. There was no pathological alteration of laboratory exams. CT scan measuring 5 cm without clear signs for a sure diagnosis found a round lesion in the right adrenal gland. An abdominal MRI showed a round mass of 34 x 27 mm with fluid component without a clear plane of dissection from kidney and liver. A laparoscopic procedure was performed to obtain a histological diagnosis. We reached a conclusive diagnosis of Hydatid cyst of right adrenal gland space.Hydatid cysts often develop in the liver. The location in the adrenal bed is rare without clinical signs related to alteration of the gland’s secretion. Hydatid cyst identification in the adrenal gland space is based on ultrasonography, CT or MRI scans. The differential diagnosis includes various benign and malignant lesions. Laparoscopic procedure is the best approach available to obtain a histological diagnosis and a curative treatment.The best treatment for HD is the pericystectomy. Laparoscopic surgery can guarantee a radical resection of these lesions when it performed by an expert surgeon.

Neurofibromatosis Type 1 With Ampullary Somatostatinoma, Small Bowel GISTs, and Extraadrenal Composite Pheochromocytoma-Ganglioneuroma

Background: Neurofibromatosis type 1 (NF1) is an autosomal dominant hereditary tumor syndrome. Increased risk of GI tumors including neurofibromas, GISTs, and periampullary carcinoids is reported. Periampullary somatostatinomas as well as true neurogenic tumors including extra-adrenal pheochromocytomas (paragangliomas) and ganglioneuromas have also been reported. This case study reviews a patient with NF1 and multiple intra-abdominal neoplasms. Case: A 32 year old male presented with six months of jaundice, dark urine, and weight loss. CT showed dilated intrahepatic ducts, and elevated bilirubin and ALP. ERCP with biopsy of the ampulla was positive for invasive malignancy with neuroendocrine differentiation. Pancreaticoduodenectomy showed lowgrade somatostatinoma of the ampulla and an incidental duodenal GIST. CT scan at year two found an enlarging upper abdominal mass concerning for nodal metastasis. Ex-lap removal found a paraganglioma in association with ganglioneuroma. Given the pathology, the diagnosis of NF1 was confirmed with mutation analysis showing a truncating mutation in the NF1 gene. His exam showed multiple café au lait spots on the trunk and upper extremities, multiple neurofibromas, and axillary freckling. Years later he had a progressive right adrenal nodule and elevated plasma/urine metanephrines. Resection of a paracaval functional paraganglioma and partial right adrenalectomy with postoperative XRT to the right adrenal bed was performed. One year later, CT and OctreoScan showed a tumor corresponding with nodularity in the jejunal limb and pancreaticobiliary anastomosis. Surgery confirmed proximal and distal jejunal GISTs. Systemic octreotide treatment is under consideration. Discussion: Alterations in the NF1 gene (tumor suppressor) encodes for the protein neurofibromin. Unlike sporadic GISTs, NF1 associated GISTs do not usually harbor c-KIT or PDGFRA mutations. Pheochromocytomas reportedly affect 0.1-6% of NF1 patients. 3/14 reported cases of composite pheochromocytoma-ganglioneuroma were associated with NF1. The combination of pheochromocytoma and GIST has been described in 14 NF1 case. Periampullary tumors in NF1 patients are most commonly carcinoid, but most do not develop somatostatinoma syndrome. To our knowledge this if the first case of a patient with NF1 diagnosed with ampullary somatostatinoma, small bowel GISTs, and extra-adrenal composite pheochromocytoma-ganglioneuroma occurring together.Figure 1

Pure aldosterone-secreting adrenocortical carcinoma in a patient with refractory primary hyperaldosteronism.

SummaryWe describe a young male patient with longstanding hypertension, who was diagnosed with primary hyperaldosteronism and treated by an attempted retroperitoneoscopic total unilateral adrenalectomy for a left-sided presumed aldosterone-secreting adenoma. Imaging had shown an unremarkable focal adrenal lesion with normal contralateral adrenal morphology, and histology of the resected specimen showed no adverse features. Post-operatively, his blood pressure and serum aldosterone levels fell to the normal range, but 9 months later, his hypertension recurred, primary aldosteronism was again confirmed and he was referred to our centre. Repeat imaging demonstrated an irregular left-sided adrenal lesion with normal contralateral gland appearances. Adrenal venous sampling was performed, which supported unilateral (left-sided) aldosterone hypersecretion. Redo surgery via a laparoscopically assisted transperitoneal approach was performed and multiple nodules were noted extending into the retroperitoneum. It was thought unlikely that complete resection had been achieved. His blood pressure returned to normal post-operatively, although hypokalaemia persisted. Histological examination, from this second operation, showed features of an adrenocortical carcinoma (ACC; including increased mitoses and invasion of fat) that was assessed as malignant using the scoring systems of Weiss and Aubert. Biochemical hyperaldosteronism persisted post-operatively, and detailed urine steroid profiling showed no evidence of adrenal steroid precursors or other mineralocorticoid production. He received flank radiotherapy to the left adrenal bed and continues to receive adjunctive mitotane therapy for a diagnosis of a pure aldosterone-secreting ACC. Learning points Pure aldosterone-secreting ACCs are exceptionally uncommon, but should be considered in the differential diagnosis of patients presenting with primary aldosteronism.Aldosterone-producing ACCs may not necessarily show typical radiological features consistent with malignancy.Patients who undergo surgical treatment for primary aldosteronism should have follow-up measurements of blood pressure to monitor for disease recurrence, even if post-operative normotension is thought to indicate a surgical ‘cure’.Owing to the rarity of such conditions, a greater understanding of their natural history is likely to come from wider cooperation with, and contribution to, large multi-centre outcomes databases.