Micronodular Hyperplasia Research Articles

12573 Management Challenges In A Young Male With Bilateral Macronodular Adrenal Hyperplasia

Abstract Disclosure: C. Nguyen: None. V. Ghernautan: None. L.Y. Melendez-Ramirez: None. M.C. Chiang: None. D. Lovre: None. Bilateral adrenal hyperplasia (BAH) may present in isolation or as part of a syndrome. It is classified according to nodule size as Macronodular: primary bilateral macronodular adrenal hyperplasia (PBMAH), or Micronodular: primary pigmented micronodular adrenal hyperplasia (PPNAD) and isolated micronodular adrenal hyperplasia (iMAD). High variability in cortisol secretion and disease progression is seen in both forms subclinical and overt Cushing’s Syndrome (CS). In PBMAH, bilateral adrenalectomy is advised for remission of CS, but benefits must be weighed against risks of lifelong adrenal insufficiency. A 45-year-old male with hypertension, depression, prediabetes, obesity presented to clinic for second opinion regarding incidentally discovered adrenal nodules five years prior with negative initial hormonal workup. Over the previous year he had gained 20 lbs. and developed proximal muscle weakness and sleep apnea. Physical exam showed uncontrolled hypertension and increased abdominal and supraclavicular fat. Hormonal testing revealed hypercortisolism. Adrenal CT confirmed bilateral adrenal nodules up to 4.9 cm with absolute washout ≥60% consistent with benign etiology. CS secondary to PBMAH was diagnosed. Prior to surgical evaluation. Ketoconazole 200 mg twice daily was started and titrated to 400 mg twice daily over the next three months. ACTH became detectable and symptoms of hypercortisolism improved. Right adrenalectomy was performed. Surgical pathology showed golden yellow-orange nodules with minimal grey adrenal parenchyma without necrosis or hemorrhage. The gland was 9.5 x 5.8 x 2.6 cm and weighed 85 g. Microscopic examination showed macronodular hyperplasia. Following surgery, he experienced a 17-pounds weight loss, improvement in blood pressure and quality of life. Three months later, hypercortisolism recurred. He elected to be monitored clinically and contemplating option of left adrenalectomy.Our case highlights the challenges in the care of patients with PBMAH. Bilateral adrenalectomy (BA) is the classical treatment. Its disadvantages include life-long hormone replacement with risk for adrenal crisis, increased morbidity, and mortality. Surgical alternatives, such as unilateral adrenalectomy (UA) and UA with subtotal contralateral adrenal resection, have shown promising results with up to 90% remission rates. The role of adjuvant novel medical therapy is unknown. Studies to compare cost, quality of life, cardiovascular risk, comorbidities, and life span between BA and UA are lacking. New biomarkers are needed to allow closer monitoring of disease progression. Additional research is necessary on medical management of hypercortisolism recurrence after UA and its long-term safety. Finally, given the presence of germline defects associated with adrenal hyperplasia, genetic testing should be offered to all patients with BAH. Presentation: 6/1/2024

8034 Putting the Pieces Together: Carney Complex, A Hyper-Rare Congenital Neoplastic Syndrome

Abstract Disclosure: G. Fontanazza: None. A.R. Conforti: None. K. Bird: None. M. Caplan: None. Intro: Carney complex (CNC) is an autosomal dominant disorder characterized by multisystem neoplasia that primarily affects the thyroid, pituitary, and adrenal glands. Its prevalence is not well established, as only 750 cases have been reported worldwide. This condition arises when an inactivating PRKAR1A gene mutation results in dysregulated cell proliferation and tumorigenesis. Complications include the potential for malignant transformation and systemic manifestations, necessitating comprehensive management and ongoing surveillance of disease progression. Case: The patient is a 58-year-old woman who initially presented as a teenager with complaints of hirsutism, truncal obesity, and violaceous abdominal striae. Initial workup revealed a low-dose dexamethasone suppression test that resulted in a non-suppressed cortisol levels. She also had undetectable adrenocorticotropic hormone (ACTH) levels. Imaging revealed no pituitary masses and demonstrated slight bilateral adrenal enlargement without adenomas. Despite these results, she was empirically treated for presumed pituitary-dependent Cushing's disease and received external beam radiation. Despite treatment, she continued to have episodes of hypercortisolism that were apparent clinically and biochemically. Over time, she developed a cardiac myxoma with six cerebrovascular accidents and multiple benign tumors. As an adult, she underwent extensive endocrine evaluation, which revealed urine cortisol excretion that paradoxically rose in response to dexamethasone. ACTH levels were always undetectable, even when she was significantly hypercortisolemic. Genetic testing revealed a homozygous mutation in the melanocortin-2 receptor (MC2R). Accordingly, she elected to have a bilateral adrenalectomy and was started on hydrocortisone and fludrocortisone. Discussion: The patient exhibited ACTH-independent micronodular adrenal hyperplasia and its most frequent variant, primary pigmented nodular adrenocortical disease. Bilateral pigmented nodular hyperplasia is a finding which can occur in association with CNC and cause episodic hypercortisolism. These patients have been shown to respond to dexamethasone with a paradoxical increase in glucocorticoid excretion. While management requires ongoing surveillance, this patient had not been diagnosed until later in life and did not have regular screening. When speculating on the late detection, her story reflects the parable of the blind men and the elephant: endocrinology managed Cushing's disease, cardiology managed atrial myxoma, and oncology managed osteochondromyxomas. Limited perspective with specialized management and an inability to see the whole picture led to prolonged diagnosis with unfortunate sequelae. This report encourages physicians to develop perspective awareness and to consider the entire picture when treating patients. Presentation: 6/2/2024

8130 A Case of Cushing’s Disease Presenting with Posterior Reversible Encephalopathy Syndrome

Abstract Disclosure: A.H. Chincholi: None. M.D. Goldberg: None. Introduction: Posterior reversible encephalopathy syndrome (PRES) is characterized by headaches, altered mental status, vision changes, and seizures, along with characteristic imaging findings of bilateral white matteredema in the posterior cerebral hemispheres. The syndrome often occurs in the context of severe hypertension, and has previously been reported in 6 patients with Cushing’s syndrome (CS) - 4 with ectopic sources of ACTH, 1 with micronodular adrenal hyperplasia and 1 pediatric case with Cushing’s disease. Clinical Case: An 18-year-old-man was admitted to our hospital after experiencing a second seizure at home. His presentation was significant for lethargy, hypertension, facial plethora, acne, proximal muscle weakness,central obesity, extensive purple striae, hyperglycemia, and hypokalemia. Two months prior, a diagnosis of ACTH-dependent CS had been made at an outside facility when he presented with a hypertensive emergency and new-onset diabetes. One month prior, he had been hospitalized with pneumonia complicated by acute kidney injury requiring temporary hemodialysis, and his first seizure. Brain MRI had shown extensive T2/FLAIR hyperintensities in the temporal lobes and cerebellum,consistent with PRES. On this admission, morning serum cortisol was 56.1 mcg/dL, and then 57.9 mcg/dL following 10 mg dexamethasone at night; ACTH was 120 pg/mL, and 24-hour UFC was 2,204 mcg. Ketoconazole and spironolactone were added, with no appreciable improvement in his cortisol levels but normalization of blood pressure. He required up to 150 units of insulin per day to manage his hyperglycemia. PituitaryMRI revealed a 0.6 cm adenoma, along with the T2/FLAIR hyperintensities. Chest CT showed no masses. A 10 mcg IV desmopressin stimulation test resulted in a 248% increase in ACTH and 32% increase in cortisol, and a second MRI with a 3T scanner measured the pituitary adenoma to be 1.0 cm. It was concluded that he had Cushing’s disease, and he underwent transsphenoidal resection of the pituitary adenoma. The surgery was curative, as reflected by postoperative central adrenal insufficiency. The patient was discharged on postoperative day 3 with oral hydrocortisone. Two weeks later, he was euglycemic off insulin and his blood pressure had normalized off spironolactone. Three months later, his muscle weakness and his headaches had completely resolved. Brain MRI showed complete resection of the pituitary adenoma and resolution of the white matter changes. Conclusion: To our knowledge, this is the first report of PRES associated with CS due to an ACTH-secreting pituitary adenoma in an adult. We suspect that this patient’s marked secondary hypertension triggered the reversible encephalopathy. Providers should be aware of this potential complication of hypercortisolism. This case also highlights the utility of desmopressin stimulation test in defining the cause of ACTH-dependent CS. Presentation: 6/3/2024

Comprehensive clinicopathologic features in autoimmune atrophic gastritis: Insights from a European cohort of 57 patients

ContextAutoimmune atrophic gastritis (AAG) is a frequently underdiagnosed disease due to its broad-spectrum clinical presentation. The diagnosis is based on histological confirmation of corpus-restricted metaplastic chronic atrophic gastritis. ObjectiveTo thoroughly describe the histological features of a European cohort of AAG patients. DesignClinical and pathological data of 57 out of 676 patients diagnosed with AAG were reviewed. ResultsThirty-nine patients were female and eighteen were male. The mean age was 62 years. Antibodies were identified in 32/42 patients (76 %). Vitamin B12 levels were low (< 200 pg/mL) in 37/54 patients (69 %). Serum gastrin levels was elevated (> 115 pg/mL) in all cases tested. Associated autoimmune/inflammatory conditions were identified in 20/57 patients (35 %). Histologically, deep chronic inflammation was present in 46/57 (81 %) patients. Complete destruction of oxyntic glands was observed in 45/57 (79 %) patients. Pyloric metaplasia was present in 54/57 (95 %) patients, intestinal metaplasia in 51/57 (89 %) patients, and pancreatic metaplasia in 20/57 (35 %) patients. Among ECL cell proliferation, linear hyperplasia was present in all 57/57 patients, micronodular hyperplasia in 55/57 patients, and adenomatoid hyperplasia in 10/57 patients. ECL cell dysplasia was identified in 5/57 patients, and neuroendocrine microtumor in 4/57 patients. ConclusionsThe diagnosing of AAG remains challenging due to the greater variability in symptoms than previously recognized. It is important to consider chronic AAG, especially with other concurrent autoimmune conditions. The importance of accurate diagnosis and surveillance is based on the potential development of type 1 gastric neuroendocrine tumor and increased risk of gastric adenocarcinoma.

Gastric Carcinoma in Autoimmune Gastritis: A Histopathologic and Molecular Study

Patients with autoimmune gastritis (AIG) have a 13-fold risk of developing type-1 neuroendocrine tumors, whereas the risk for gastric adenocarcinoma is still uncertain. Here we describe the clinicopathologic and molecular features of a series of gastric carcinomas (GC) arising in the context of AIG. A total of 26 AIG-associated GC specimens were collected from 4 Italian Institutions. Immunohistochemistry for MUC1, MUC2, MUC5AC, MUC6, CDX2, HER2, PD-L1, CLDN18, mismatch repair (MMR) proteins, and p53 and EBV-encoded RNA (EBER) in situ hybridization were performed. Histologic and immunohistochemical features were jointly reviewed by 5 expert gastrointestinal pathologists. Next-generation sequencing analysis (TrueSight Oncology 500, Illumina) of 523 cancer-related genes was performed on 19 cases. Most tumors were diagnosed as pT1 (52%) and they were located in the corpus/fundus (58%) and associated with operative link for gastritis assessment stage II gastritis (80.8%), absence of parietal cells, complete intestinal metaplasia, and enterochromaffin-like-cell micronodular hyperplasia. Only 4 (15.4%) GCs were diagnosed during follow-up for AIG. The following histotypes were identified: 20 (77%) adenocarcinomas; 3 (11%) mixed neuroendocrine–non-neuroendocrine neoplasms, and 2 (8%) high-grade solid adenocarcinomas with focal neuroendocrine component, 1 (4%) adenocarcinoma with an amphicrine component. Overall, 7 cases (27%) showed MMR deficiency, 3 (12%) were positive (score 3+) for HER2, 6 (23%) were CLDN18 positive, and 11 (42%) had PD-L1 combined positive score ≥ 10. EBER was negative in all cases. Molecular analysis revealed 5/19 (26%) microsatellite instability (MSI) cases and 7 (37%) tumor mutational burden (TMB) high. The most frequently altered genes were TP53 (8/19, 42%), RNF43 (7/19, 37%), ERBB2 (7/19, 37% [2 amplified and 5 mutated cases]), ARID1A (6/19, 32%), and PIK3CA (4/19, 21%). In summary, AIG-associated GCs are often diagnosed at low stage in patients with longstanding misrecognized severe AIG; they often display a neuroendocrine component or differentiation, have relatively higher rates of MMR deficiency, and TMB high.

P-47 Rare case of acromegaly due to plurihormonal pituitary adenoma and ACTH-independent Cushing syndrome

Abstract Introduction The concurrence of acromegaly and Cushing syndrome is infrequent. Pituitary adenomas are responsible for acromegaly and for Cushing syndrome in about 95% and 80% of cases respectively. Except adrenal adenoma, the other causes of Cushing syndrome remain rare. We here describe a case of a Tunisian patient with acromegaly due to plurihormonal pituitary adenoma and ACTH-independent Cushing syndrome with bilateral macronodules. Clinical Case A 35-year-old male patient was diagnosed with acromegaly by acrofacial dysmorphia. He had a family history of type 2 diabetes mellitus and hypertension but no endocrine diseases. He has diabetes mellitus for 15 years, hypertension and obstructive sleep apnea. Physical examination showed multiple blue nevi in the trunk. IGF-1 was elevated (1680ng/mL) and GH levels were not suppressed after an oral glucose load (nadir 78ng/mL). He had hypogonadotropic hypogonadism with normal prolactin (9,66ng/mL). Basal cortisol, FT4 and TSH levels were in the normal ranges. Pituitary MRI showed pituitary macroadenoma of 25×20.7 mm, invading both cavernous sinuses and compression of optic chiasma. He underwent transsphenoidal resection with histology confirming a prolactin, GH and LH co-secretory pituitary adenoma. He received postoperatively somatostatin analogue and cabergoline, in addition to external radiotherapy. Ultrasonography found infracentimetric EU-TIRADS 2 left nodule and multiple colloid cysts of the thyroid, testicles microlithiasis and no cardiac myxomas. Nine years after the diagnosis of acromegaly, bilateral adrenal adenomas (left:14 mm, right: 9 mm) were incidentally discovered by CT-scan done for abdominal pain. Low dose dexamethasone suppression test was carried out showing no suppression of cortisol and the low ACTH level confirmed ACTH-independent Cushing syndrome. Conclusion In our patient, at least two endocrine syndromes deserve to be mentioned. The first syndrome is Multiple Endocrine Neoplasia Type 1 but calcium and PTH levels were normal and there was no sign for neuroendocrine tumors. The second one is Carney's complex since our patient has acromegaly and multiple blue nevi which are two major criteria confirming the diagnosis. Cushing syndrome in Carney's complex is related to primary pigmented nodular adrenal disease characterized by micronodular hyperplasia. However, bilateral macronodules could be found in up to 30% of cases.

CT-based radiomics nomogram for differentiation of adrenal hyperplasia from lipid-poor adenoma: an exploratory study

BackgroundTo establish and verify a radiomics nomogram for differentiating isolated micronodular adrenal hyperplasia (iMAD) from lipid-poor adenoma (LPA) based on computed tomography (CT)-extracted radiomic features.MethodsA total of 148 patients with iMAD or LPA were divided into three cohorts: a training cohort (n = 72; 37 iMAD and 35 LPA), a validation cohort (n = 36; 22 iMAD and 14 LPA), and an external validation cohort (n = 40; 20 iMAD and 20 LPA). Radiomics features were extracted from contrast-enhanced and non-contrast CT images. The least absolute shrinkage and selection operator (LASSO) method was applied to develop a triphasic radiomics model and unenhanced radiomics model using reproducible radiomics features. A clinical model was constructed using certain laboratory variables and CT findings. Radiomics nomogram was established by selected radiomics signature and clinical factors. Nomogram performance was assessed by calibration curve, the areas under receiver operating characteristic curves (AUC), and decision curve analysis (DCA).ResultsEleven and eight extracted features were finally selected to construct an unenhanced radiomics model and a triphasic radiomics model, respectively. There was no significant difference in AUC between the two models in the external validation cohort (0.838 vs. 0.843, p = 0.949). The radiomics nomogram inclusive of the unenhanced model, maximum diameter, and aldosterone showed the AUC of 0.951, 0.938, and 0.893 for the training, validation, and external validation cohorts, respectively. The nomogram showed good calibration, and the DCA demonstrated the superiority of the nomogram compared with the clinical factors model alone in terms of clinical usefulness.ConclusionsA radiomics nomogram based on unenhanced CT images and clinical variables showed favorable performance for distinguishing iMAD from LPA. In addition, an efficient unenhanced model can help avoid extra contrast-enhanced scanning and radiation risk.

Mifepristone-Induced Hypothyroidism.

Medications are known to affect the thyroid physiology and are a known cause of hypothyroidism. There is an ever-growing list of medications that affect the thyroid by 1 or more mechanisms. Mifepristone is presently used for the treatment of mild autonomous cortisol secretion (MACS). Hypothyroidism is not a known side effect of this medication. We present a 71-year-old woman with newly diagnosed impaired fasting glucose, dyslipidemia, and osteopenia presenting with a 3-year history of unintentional 15-pound weight gain (despite exercise and a good diet) and increased anxiety. Her physical examination was pertinent for mild lower extremity edema, easy bruising, and skin thinning. Workup revealed adrenocorticotropic hormone (ACTH)-independent MACS from bilateral micronodular hyperplasia of the adrenals. Since she was not a surgical candidate, medical management with mifepristone was chosen. While on mifepristone, she complained of excessive fatigue, a workup done revealed new-onset hypothyroidism. Given her symptoms and bloodwork, she was started on levothyroxine. After stopping mifepristone, she was biochemically and clinically euthyroid and was eventually off levothyroxine. The mechanism by which mifepristone induces hypothyroidism is unknown. Except for a multicenter case series suggesting that mifepristone increases thyroid hormone requirements in patients with central hypothyroidism, to the best of our knowledge, the literature on euthyroid patients developing hypothyroidism secondary to mifepristone is scarce. In conclusion, while the hypothyroidism seems reversible our case highlights the importance of getting baseline thyroid function tests (TFTs) and repeating them while on the medication. Treatment of hypothyroidism is based on symptoms and bloodwork.

Current approach of primary bilateral adrenal hyperplasia.

To discuss the most recent findings on the pathophysiology, the genetic and molecular causes of primary bilateral adrenal hyperplasia (PBAH). The diagnostic approach of patients with PBAH will also be presented in detail with an emphasis on the emerging diagnostic tools and finally, the treatment of PBAH will be discussed with an emphasis on the newest surgical and medical treatment approaches. PBAH is a highly heterogeneous condition mostly detected incidentally on abdominal imaging. Based on the size of the nodules, PBAH is subdivided into primary bilateral macronodular adrenal hyperplasia (PBMAH) and micronodular adrenal hyperplasia. A substantial proportion of patients with PBMAH harbor a germline mutation of the armadillo repeat containing 5 tumor suppression gene and therefore genetic testing is strongly recommended. Measurements of plasma or urinary multisteroid profiles show promising results in that PBMAH has a distinctive plasma steroid fingerprint that can help in diagnosis and subtyping of PBMAH. Finally, although surgery is the mainstay of treatment of patients with PBAH, medical therapy is increasingly emerging as an alternative option. PBAH is a poorly studied and therefore a challenging disease to diagnose and treat. Hopefully with these newest diagnostic and therapeutic tools, a more comprehensive approach will be adopted.

Clinical and genetic heterogeneity of micronodular adrenal hyperplasia

Micronodular adrenal hyperplasia is a rare cause of ACTH-independent Cushing syndrome. It can be divided into two entities: primary pigmented nodular adrenocortical disease (PPNAD) and non-pigmented micronodular adrenocortical disease, among which familial and sporadic forms are distinguished. The most common is the genetically determined familial form PPNAD, as one of the components of Carney complex. The vast majority of patients have identifiable pathogenic variants in the PRKAR1A gene. In addition to the PRKAR1A gene mutations, inactivating mutations in the genes encoding phosphodiesterases (PDE11A4 and PDE8B), as well as PRKACA gene amplification, have been described in individuals with isolated forms. Despite the relative antiquity of the description of micronodular adrenal hyperplasia and the Carney comlex, a detailed study of pathophysiological mechanisms, genetic and clinical aspects of this pathology, nowadays, clinicians continue to face «atypical» cases. Thus, the nature of this disease is not well understood and requires further research. This review presents the accumulated data on micronodular adrenal hyperplasia, genetics aspects, and also describes 2 unique clinical cases of isolated PPNAD with unilateral adrenalectomy results.

Bilateral Adrenal Hyperplasia: Pathogenesis and Treatment.

Bilateral adrenal hyperplasia is a rare cause of Cushing’s syndrome. Micronodular adrenal hyperplasia, including the primary pigmented micronodular adrenal dysplasia (PPNAD) and the isolated micronodular adrenal hyperplasia (iMAD), can be distinguished from the primary bilateral macronodular adrenal hyperplasia (PBMAH) according to the size of the nodules. They both lead to overt or subclinical CS. In the latter case, PPNAD is usually diagnosed after a systematic screening in patients presenting with Carney complex, while for PBMAH, the diagnosis is often incidental on imaging. Identification of causal genes and genetic counseling also help in the diagnoses. This review discusses the last decades’ findings on genetic and molecular causes of bilateral adrenal hyperplasia, including the several mechanisms altering the PKA pathway, the recent discovery of ARMC5, and the role of the adrenal paracrine regulation. Finally, the treatment of bilateral adrenal hyperplasia will be discussed, focusing on current data on unilateral adrenalectomy.

Colocalization of Wnt/β-Catenin and ACTH Signaling Pathways and Paracrine Regulation in Aldosterone-producing Adenoma.

Aldosterone-producing adenomas (APAs) are a common cause of primary aldosteronism (PA). Despite the discovery of somatic mutations in APA and the characterization of multiple factors regulating adrenal differentiation and function, the sequence of events leading to APA formation remains to be determined. We investigated the role of Wnt/β-catenin and adrenocorticotropin signaling, as well as elements of paracrine regulation of aldosterone biosynthesis in adrenals with APA and their relationship to intratumoral heterogeneity and mutational status. We analyzed the expression of aldosterone-synthase (CYP11B2), CYP17A1, β-catenin, melanocortin type 2 receptor (MC2R), phosphorlyated cAMP response element-binding protein (pCREB), tryptase, S100, CD34 by multiplex immunofluorescence, and immunohistochemistry-guided reverse transcription-quantitative polymerase chain reaction. Eleven adrenals with APA and 1 with micronodular hyperplasia from patients with PA were analyzed. Main outcome measures included localization of CYP11B2, CYP17A1, β-catenin, MC2R, pCREB, tryptase, S100, CD34 in APA and aldosterone-producing cell clusters (APCCs). Immunofluorescence revealed abundant mast cells and a dense vascular network in APA, independent of mutational status. Within APA, mast cells were localized in areas expressing CYP11B2 and were rarely colocalized with nerve fibers, suggesting that their degranulation is not controlled by innervation. In these same areas, ß-catenin was activated, suggesting a zona glomerulosa cell identity. In heterogeneous APA with KCNJ5 mutations, MC2R and vascular endothelial growth factor A expression was higher in areas expressing CYP11B2. A similar pattern was observed in APCC, with high expression of CYP11B2, activated β-catenin, and numerous mast cells. Our results suggest that aldosterone-producing structures in adrenals with APA share common molecular characteristics and cellular environment, despite different mutation status, suggesting common developmental mechanisms.

Interaction Between Wnt/β-catenin and ACTH Signaling Pathways and Paracrine Regulation in Aldosterone Producing Adenoma

Primary aldosteronism (PA) is the most frequent form of secondary arterial hypertension and is caused in the majority of cases by an aldosterone producing adenoma (APA) or bilateral adrenal hyperplasia. Different somatic mutations have been identified in APA and in other aldosterone producing structures, which can be distinct within the same adrenal, suggesting multiple mechanisms underlying APA development. Also, APA show important cellular and molecular heterogeneity which may be due to interaction of different signaling pathways involved in adrenal cortex cell differentiation and function. The aim of this study was to investigate the role of Wnt/β-catenin and ACTH signaling as well as elements of paracrine regulation of aldosterone biosynthesis and vascularization in the development of APA and aldosterone producing cell clusters (APCC) and their relationship with intratumoral heterogeneity and mutational status. We performed immunohistochemistry and multiplex immunofluorescence (CYP11B2, CYP17A1, β-catenin, MC2R, pCREB, Tryptase, S100, CD34) multispectral image analysis on 11 adrenals with APA and one with micronodular hyperplasia from patients with PA. CYP11B2 (aldosterone synthase) IHC guided RT-qPCR was performed on RNA extracted from formalin-fixed paraffin-embedded tissues in 7 adrenals. Multiplex immunofluorescence revealed high abundance of tryptase positive mast cells and a dense vascular component in APA, which were independent of the mutational status. Within APA, mast cells were mainly localized in zones expressing CYP11B2, but not in areas expressing CYP17A1, and were rarely colocalized with nerve fibers, suggesting that their activity is not controlled by innervation. In cells expressing aldosterone synthase, β-catenin was activated, i.e. shows nuclear and/or cytoplasmic staining, features suggestive of a zona glomerulosa cell identity; MC2R was found at the cell membrane. Expression of MC2R mRNA was observed at different levels in APA, similar to expression of MRAP and VEGFA; MRAP2 was not detected. Within heterogeneous APA carrying KCNJ5 mutations, both MC2R and VEGFA expression was higher in areas expressing CYP11B2. Remarkably, this pattern was maintained in APCC, where cells show high CYP11B2 expression, together with activated β-catenin, independently of the mutation status. In addition, a high number of mast cells was detected around APCC, with a reorganization of the capillaries around the CYP11B2 positive cells. Our results suggest that aldosterone producing structures in adrenals with APA share common molecular characteristics and cellular environment, despite different mutation status. Mast cells appear to be closely associated with cells expressing aldosterone synthase, both in APA and APCC, and their role in regulating aldosterone biosynthesis in the context of somatic mutations in PA remains to be established.

A Parathyroid-Gut Axis: Hypercalcemia and the Pathogenesis of Gastrinoma in Multiple Endocrine Neoplasia 1.

Patients with multiple endocrine neoplasia 1 (MEN1) syndrome have a germline mutation in the MEN1 gene. Loss of the wild-type allele can initiate endocrine tumorigenesis. Microscopic and macroscopic pituitary, parathyroid, and pancreatic tumors (referred to as the 3 P's) show loss of the wild-type MEN1 allele up to 100%. In contrast, the duodenal gastrinoma pathogenesis in MEN1 syndrome follows a hyperplasia-to-neoplasia sequence. Gastrinomas have loss of heterozygosity of the MEN1 locus in <50%, and invariably coincide with linear, diffuse, or micronodular gastrin-cell hyperplasia. The factor initiating the gastrin-cell hyperplasia-to-neoplasia sequence is unknown. In this perspective, we argue that hypercalcemia may promote the gastrin-cell hyperplasia-to-neoplasia sequence through the calcium sensing receptor. Hypercalcemia is present in almost all patients with MEN1 syndrome due to parathyroid adenomas. We propose a parathyroid-gut axis, which could well explain why patients with MEN1 syndrome are regularly cured of duodenal gastrinoma after parathyroid surgery, and might cause MEN1 syndrome phenocopies in MEN1-mutation negative individuals with parathyroid adenomas. This perspective on the pathogenesis of the gastrin-cell hyperplasia and neoplasia sequence sheds new light on tumorigenic mechanisms in neuroendocrine tumors and might open up novel areas of gastrinoma research. It may also shift focus in the treatment of MEN1 syndrome-related gastrinoma to biochemical prevention.

Gastric enterochromaffin-like cell changes in multiple endocrine neoplasia type 1.

Gastric enterochromaffin-like cell (ECL) tumours can occur in patients with multiple endocrine neoplasia type 1 (MEN1), especially in those affected by Zollinger Ellison syndrome (ZES). Since the prevalence of ECL lesions is not well defined yet, the present study evaluated the presence and extent of ECL lesions in MEN1 patients with and without ZES. Multiple endocrine neoplasia type 1 patients being part of a regular screening program (2014-2018) underwent gastroduodenoscopies with biopsies of the stomach and determination of serum gastrin and chromogranin A levels. Haematoxylin- and immunostaining with chromogranin A, gastrin and VMAT I and II (vesicular monoamine transporter I and II) of the biopsies were performed. Thirty-eight MEN1 patients, of whom 16 (42%) were diagnosed and treated earlier for ZES, were analysed. In ten of 16 (62.5%) ZES patients, a locally scattered, mixed image of diffuse, linear and micronodular mild hyperplasia was present. In addition, two of these patients (13%) showed small (max 1.5mm in size) intramucosal ECL tumours. Neither ECL changes, nor tumours were found in MEN1 patients without ZES (n=22). In MEN1/ZES patients, the median serum gastrin level was significantly elevated compared to MEN1 patients without ZES (206pg/ml vs. 30.5pg/ml, p<.001). A subgroup analysis of the serum gastrin and chromogranin A levels of MEN1/ZES patients with or without ECL hyperplasia did not show significant differences (gastrin level: p=.302, chromogranin A: p=.464). Enterochromaffin-like cell hyperplasia and gastric carcinoids occur only in MEN1 patients with ZES, but less frequently than reported.

First Somatic PRKAR1A Defect Associated With Mosaicism for Another PRKAR1A Mutation in a Patient With Cushing Syndrome.

Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of ACTH-independent Cushing syndrome (CS) associated mostly with Carney complex (CNC), a rare autosomal dominant multiple neoplasia syndrome. More than two-thirds of familial cases and approximately one-third of sporadic cases of CNC harbor germline inactivating PRKAR1A defects. Increasingly sensitive technologies for the detection of genetic defects such as next-generation sequencing (NGS) have further highlighted the importance of mosaicism in human disease. A 33-year-old woman was diagnosed with ACTH-independent CS with abdominal computed tomography showing bilateral micronodular adrenal hyperplasia with a left adrenal adenoma. She underwent left adrenalectomy with pathology demonstrating PPNAD with a 1.5-cm pigmented adenoma. DNA analysis by Sanger sequencing revealed 2 different PRKAR1A variants in the adenoma that were absent from DNA extracted from blood and saliva: c.682C > T and c.974-2A > G. "Deep" NGS revealed that 0.31% of DNA copies extracted from blood and saliva did in fact carry the c.682C > T variant, suggesting low-level mosaicism for this defect. We present a case of PPNAD due to low-level mosaicism for a PRKAR1A defect which led to the formation of an adenoma due to a second, adrenal-specific, somatic PRKAR1A mutation. The identification of mosaicism for PRKAR1A, depending on the number and distribution of cells affected has implications for genetic counseling and tumor surveillance. This is the first recorded case of a patient with PRKAR1A mosaicism, PPNAD, and an adenoma forming due to complete inactivation of PRKAR1A in adrenal tissue from a second, somatic-only, PRKAR1A coding sequence mutation.

Routine histopathologic examination of the resected specimen after laparoscopic sleeve gastrectomy – what can be expected?

Background Laparoscopic Sleeve Gastrectomy (LSG) is nowadays an established bariatric procedure. Although preoperative gastroscopy is recommended to rule out severe pathologies, there is little evidence about the role of routine histopathologic examination of resected specimens. We sought to identify the prevalence of histopathological relevant findings in patients undergoing LSG and to evaluate their impact in clinical practice. Methods A retrospective analysis on a prospectively collected dataset on patients undergoing LSG between August 2009 and May 2018 in two bariatric centers was performed. Demographic and clinical data and histopathological results were analyzed. Results Sixhundred-thrirteen patients were identified, mean age was 43.1 years (14–75), average body mass index was 44.8 kg/m2 (34.4–73.9). Histopathology revealed abnormal findings in 47.97% of the patients, most common pathology was chronic non-active or minimally to moderate active gastritis (n = 202;32.95%). Among others, Helicobacter-associated gastritis (n = 33;5.38%), intestinal metaplasia (n = 13;2.12%), micronodular enterochromaffine-like cell hyperplasia (n = 2; 0.33%) and gastrointestinal stromal tumors (n = 6; 0.98%) were present. No malignancies were found. Histopathological results required a change in the postoperative management in 48 patients (7.83%). The costs of histopathological assessment ranged between 0.77% and 2.55% of per-case payment. Conclusion A wide range of histopathological findings occur in specimens after LSG, requiring a relevant number of patients additional therapies or surveillance. Therefore, routine histopathological examination after LSG is recommendable.

Clinicopathological features of autoimmune gastritis

Objective: To study the clinicopathological characteristics and pathologic diagnosis of autoimmune gastritis. Methods: Fourteen biopsies of autoimmune gastritis were collected from January 2018 to March 2019 at Guangdong Provincial People's Hospital. Their clinical data, histological features and immunohistochemical (IHC) results were analyzed, with review of relevant literature. Results: All 14 patients' ages ranged from 41 to 79 years (mean 55 years). There were 12 females and 2 males. All patients had non-specific symptoms, but they all had positive serum anti-parietal cell antibody and/or anti-intrinsic factor antibody. Seven patients had variable degree of anemia. Two patients had concomitant H. pylori infection. Two patients presented with multiple protruding polyps in corpus/fundus, 0.2 to 0.9 cm in diameter, or multiple large lobulated and broad based polyps (0.8 to 3.5 cm in diameters). The former cases were diagnosed as type 1 neuroendocrine tumors, the latter were multiple hyperplastic polyps. Microscopically, autoimmune gastritis showed typical morphology, characterized by diffuse corpus-restricted atrophic gastritis with variable proportions of intestinal metaplasia, or pseudopyloric metaplasia, pancreatic, acinar metaplasia, foveolar hyperplasia and hyperplasia of the endocrine-like cells (ECL cells). Hyperplasia of ECL cells often needed IHC staining to confirm. CgA/Syn IHC stain highlighted linear and micronodular ECL cell hyperplasia. In the absence of concurrent or past H. pylori infection, the antrum was usually normal. Gastrin IHC stain showed hyperplasia of gastrin-producing cells (G cells) in the antrum. Two cases were in the early phase, six were in florid phase, and six were end phase. Conclusions: Most patients of autoimmune gastritis have non-specific symptoms or are asymptomatic and show various endoscopic findings. There are three histologic phases of autoimmune gastritis. Recognition of this entity would be beneficial for pathologists to avoid misdiagnosis. Pathologists can make preferred diagnosis of autoimmune gastritis depending on the histologic clues and prompt appropriate and timely management for the patients.

SUN-162 Isolated Primary Pigmented Micronodular Adrenal Disease. Unilateral or Bilateral Adrenalectomy? Two Cases Report

Background: Isolated primary pigmented nodular adrenal disease (i-PPNAD) is a particular case of micronodular bilateral hyperplasia (MiBAH) leading to Cushing syndrome (CS). We present two patients with i-PPNAD who undergone unilateral adrenalectomy with different disease outcomes. Case 1: A 56 yo man presented with typical signs and symptoms of CS, including central weight gain, proximal muscle weakness, hypertension and marked osteoporosis. A biochemical investigation showed an assessment of late-night salivary cortisol - 23 nmol/l (n <9), 24h urinary free cortisol (UFC)- 1206 nmol/24h (n-60–413). The 1 mg DST showed post-DST cortisol 617 nmol/l (n<50). ACTH concentration was suppressed at 1.1 pg/ml (n-7–66). Adrenal CT-scan was normal. PPNAD was assumed and the screening for Carney complex components was negative. After left adrenalectomy, histological examination confirmed the diagnosis of PPNAD. However, biochemical remission wasn’t achieved: postoperative UFC-860 nmol/24h. Thus, the right adrenalectomy was conducted. Case 2: A 40 yo female presented with long term drug-corrected (beta-blockers, ACE inhibitor) arterial hypertension, menstrual dysfunction and clinical features of CS (central obesity, proximal muscle weakness, hirsutism), without osteoporosis. Baseline hormonal evaluation documented slightly increased level of salivary cortisol- 9,8 nmol/l (n <9), post 1 mg DST cortisol - 470 nmol/l (n<50) and ACTH-concentration below detection <1 pg/ml (n-7–66). However, UFC was normal – 215 nmol/l (n-60–413). Abdominal CT-scan revealed micronodular hyperplasia of the left adrenal and was suggestive of possible right adrenal gland hyperplasia. We performed left adrenalectomy. In the early postoperative period, adrenal insufficiency was diagnosed and thus it required hydrocortisone replacement. Discussion: We obtained two opposite results: in case 1, an expected remission after unilateral adrenalectomy was not achieved, while patient No.2 developed adrenal insufficiency, which was a more favourable prognostic sign and attested to the successful outcome of surgical treatment. A possible explanation of the ineffectiveness of surgical intervention in patient No.1 was primary more severe hypercortisolism. It is also necessary to take into account that according to the CT data of the patient No.1, both adrenal glands were within normal ranges and did not differ from one another, while in the patient No.2, the lesion was more prominent on the right side. Conclusion: Diagnostic of i-PPNAD and choice of intervention can be precarious, consequently more studies are needed to define to which patients unilateral adrenalectomy could be an efficient treatment modality. It is possible to perform unilateral adrenalectomy with subsequent assessment of cortisol levels, in case of lack of remission the contralateral adrenalectomy is required.

SUN-LB96 Basal Contralateral Aldosterone Suppression Is Rare in Lateralized Primary Aldosteronism and Can Be Useful in Predicting Surgical Outcome

Background: Adrenal venous sampling (AVS) is performed to distinguish between unilateral or bilateral source of aldosterone in primary aldosteronism (PA). Unilateral aldosteronomas should lead to suppression of renin and contralateral (CL) aldosterone secretion, assessed by the CL suppression ratio. We recently found that CL aldosterone suppression was relatively rare using the ratio of basal aldosterone concentration of the opposite adrenal vein/periphery (AOPP/AP) in contrast to the traditional cortisol-corrected aldosterone ratio ((A/C)OPP(A/C)P). Pathology studies showed frequent zona glomerulosa (ZG) hyperplasia adjacent to a dominant aldosteronoma, which could also indicate probable ZG hyperplasia in the CL adrenal. The ratio of basal CL suppression could be a usefull parameter to predict cure following unilateral adrenalectomy (UA), but controversy remains in the literature.Objectives:1. To evaluate the prevalence of basal CL suppression using the AOPP/AP ratio as compared to the (A/C)OPP/(A/C)P ratio at previously established cut-offs.2. To determine the best cut-off to predict clinical and biochemical surgical cure in two Canadian referral centers.3. To compare the accuracy of the AOPP/AP ratio to the basal lateralization ratio (LR) and the post-ACTH LR in predicting the surgical outcome. Methods: 330 patients with PA and successful bilateral simultaneous basal and post-ACTH stimulated AVS (selectivity index >2 basally and >5 post-ACTH) were included; 124 patients found to be lateralized underwent UA. The follow-up data were evaluated for clinical and biochemical cure at 3 and 12 months using the PASO criteria. Results: Using AOPP/AP and (A/C)OPP/(A/C)P at the cut-off of 1, the prevalence of CL suppression is 6% and 45%, respectively. The median CL suppression ratio is 2.3 (1.3-5.1) in lateralized cases of PA using AOPP/AP. Using ROC curves, the AOPP/AP ratio is associated with clinical cure at 3 and 12 months and biochemical cure at 12 months. (A/C)OPP/(A/C)P is associated with biochemical cure only. The cut-offs for AOPP/AP offering the best sensitivity and specificity for clinical and biochemical cures at 12 months are 2.15 (Se 63% and Sp 71%) and 6.15 (Se 84% and Sp 77%), respectively. Basal LR and post-ACTH LR are associated with clinical cure but only the post-ACTH LR is associated with biochemical cure. Conclusions: Basal CL suppression defined by the AOPP/AP ratio is rare and incomplete compared to the traditional (A/C)OPP/(A/C)P ratio in lateralized cases of PA. This may reflect the frequent micronodular hyperplasia adjacent to dominant aldosteronomas and possibly in the CL adrenal. Basal CL aldosterone suppression may predict clinical postoperative outcome, but with modest accuracy.