ResearchPad - endocrine-neoplasia-case-reports-ii https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[MON-917 Carney Complex Due to a Contiguous Gene Deletion Syndrome (17q24.2-17q24.3)]]> https://www.researchpad.co/article/elastic_article_8777 Background

While genomic rearrangements of chromosome 17 are not uncommon, deletions of chromosome band 17q24.2-q24.3 are rare, and associated features include cardiac abnormalities, characteristic facial appearance, short stature, obesity, syndactyly, intellectual disability, seizures, delayed dentition, and features of Carney Complex. It has been suggested that the involvement of KCNJ2, PRKCA, CACNG gene cluster (CACNG1, CACNG4, CACNG5), and PRKAR1A genes contribute to this phenotype. A case of a child with a 3.7 Mb deletion at chromosome band 17q24.2-q24.3, as well as a 2.1 Mb gain at chromosome 17q22, is described.

Clinical Case

A now 6 year old female was born at 34 weeks gestational age with prenatal course complicated by oligohydramnios and intrauterine growth restriction. Birth weight was at the 9th percentile, and birth length was at the 92nd percentile. She was noted to have a patent ductus arteriosus (PDA), poor suck and swallow, and dysmorphic features. Chromosome microarray revealed a 3.7 Mb deletion at Chromosome 17q24.2-q24.3, involving KCNJ2, PRKCA, CACNG gene cluster (CACNG1, CACNG4, CACNG5), and PRKAR1A, as well as a 2.1 Mb gain at Chromosome 17q22, involving C17orf112 and KIP2B.

At 6 years old, she continues to be small for weight (-4.5 SDs), BMI (-4.22 SDs), and height (-2.5 SDs), though with appropriate pre-pubertal linear growth velocity. She is minimally verbal and continues to receive physical, occupational and speech therapies. Examination showed dysmorphic facial features, including triangular face with pointed chin, prominent forehead with low-set ears, retro-micrognathia, almond-shaped eyes with up-slanting palpebral fissures, bulbous nose, thin lips, and irregularly-shaped teeth. She had bilateral 5th digit clinodactyly, tapering of the distal aspects of bilateral first digits of the hands, and syndactyly of bilateral 2nd/3rd digits of the feet. She had scant freckling over the nasal bridge and cheeks, as well as freckles of the left arm, left groin, and back. She had no clinical stigmata of hypercortisolism. Echocardiogram continues to show a PDA with no cardiac myxomas. Thyroid ultrasound was normal. However, she does have mild hypercalcemia, most recently 2.61 mmol/L (2.15-2.55), and mildly elevated alkaline phosphatase of 341 U/L (96-297).

Conclusion

This case highlights a child with many of the previously reported findings associated with 17q24.2-q24.3 deletions. However, she also was noted to have a 2.1 Mb gain at chromosome 17q22 involving C17orf112 and KIP2B genes, which have not yet been associated with a clinical phenotype. It is therefore unclear if her phenotype is partially explained by the chromosomal gain. Clinicians should suspect a contiguous gene deletion syndrome in a patient with Carney Complex and atypical features. Patients with this condition have also been described as “Carney Complex-plus”, a term that we do not recommend be used.

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<![CDATA[MON-903 Sporadic Phaeochromocytoma, Pancreatic Neuroendocrine Tumour and a Sacral Hibernoma: A Case Report]]> https://www.researchpad.co/article/elastic_article_8758 Most phaeochromocytomas and pancreatic neuroendocrine tumours are sporadic in nature however the presence of multiple neuroendocrine tumours raises the suspicion of a hereditary endocrinopathy. Hibernomas, benign tumours that morphologically resemble brown fat, do not possess a clear aetiology and a link with other neuroendocrine tumours remains unclear. We report an unusual case of a concurrent sporadic phaeochromocytoma, pancreatic neuroendocrine tumour and a sacral hibernoma. A 61 year old female presented with a 3 month history of abdominal pain which led to the discovery of a lesion in her right adrenal gland and a soft tissue mass at the pancreatic tail on a CT Abdomen. The adrenal lesion was biochemically suggestive of a phaeochromocytoma (plasma normetanephrine 4930 pmol/L, plasma 3-methoxytyramine 580 pmol/L, urinary noradrenaline 5564 pmol/day, urinary dopamine 4720 nmol/day). A 68Ga-DOTATATE-PET-CT scan revealed DOTATATE avid lesions in the right adrenal gland, tail of pancreas and right sacral ala. Following preoperative medical therapy, the patient underwent a right adrenalectomy and a resection of the distal pancreatic lesion.Histopathology confirmed a phaeochromocytoma with no conscipicouous mitotic activity, and the pancreatic tail lesion was consistent with a well-differentiated neuroendocrine tumour (NET) (Ki-67 score <3%). Following normalisation of the serum catecholamines, a biopsy of the sacral lesion was undertaken, which returned positive for a hibernoma. Genetic testing revealed no identifiable genetic mutations.This case reports the synchronous presence of a phaeochromocytoma, pancreatic NET and sacral hibernoma with no identifiable genetic mutation. To date, the association between hibernomas and neuroendocrine tumours has not been fully established, but a few case reports suggest a possible association between MEN1 and hibernomas.

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<![CDATA[MON-911 Debilitating Neuropsychiatry Symptoms in Pancreatic Insulinoma Co-Secreting Serotonin and IGF-1]]> https://www.researchpad.co/article/elastic_article_8712 Background:

Insulinoma is the most common type of functioning pancreatic neuroendocrine tumor (NET). Polyhormonal secretions from the NET, giving rise to distinct clinical symptoms such as carcinoid symptoms are rare. Clinical Case: We report a 68-year-old woman who presented with four months history of recurrent diaphoresis, palpitations, tremors and chest tightness. These were associated with episodic paroxysms of flushing and diarrhoea. The physical examination was unremarkable. She was a well-nourished woman with BMI of 28 kg/m2. Initial laboratory tests ruled out any renal, liver abnormalities with normal cortisol and thyroid function test. Further evaluation confirms insulin mediated hypoglycaemia with low random blood sugar 2.5 mmol/l (4.4-7.8) and failure to suppress C-peptide, 1092 pmol/L (298-2350) and insulin levels, 12.7 mU/L (3-25). Urine 5-HIAA was markedly elevated 2430.37 µmol/day (3.66-42.89) with borderline elevation of serum chromogranin A level 122 ng/mL (27-94). IGF-1 was also raised at 416 ug/L (91-282). Two months later she presented with new onset of delirium, incoherence, agitation and restlessness independent of her hypoglycaemic events. These symptoms deteriorated and fluctuates throughout the day with period of normalcy in between. This has led to requirement of a full time caregiver for her. Cranial CT excluded any brain pathology. We are faced with a diagnostic challenge to localize the primary lesion as radiological imaging so far were normal. GALLIUM-68 PET CT showed physiological uptake in the uncinate process of the pancreas (SUVmax 14.4). Endoscopic ultrasound of the pancreas was normal. An intra-arterial calcium stimulation test with hepatic venous sampling (ASVS) confirms a lesion at the head of pancreas with two times increment of insulin from baseline at the gastroduodenal artery distribution. Despite elimination of hypoglycaemic events with Diazoxide 100mg twice daily, her neuropsychiatric symptoms persisted. We postulate that this might be from excessive peripheral production of serotonin by the pancreatic carcinoid tumour or a niacin deficiency state because of metabolic diversion of its precursor, tryptophan. Conclusion:

This case highlights the occurrence of debilitating neuropsychiatry manifestations in a likely neuroendocrine tumour arising from the head of pancreas secreting insulin, serotonin and IGF-1.

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<![CDATA[MON-912 Undiagnosed Chronic Eczema as a Presentation of Glucagonoma in MEN 1 Syndrome]]> https://www.researchpad.co/article/elastic_article_8641 Background: Glucagonomas are pancreatic tumors arising from the islets cell of Langerhans that over secrete glucagon. Necrolytic migratory erythema (NME) is an important feature for the recognition of glucagonomas. Glucagonomas occurring in MEN1 is infrequent and seen in less than 3% of all glucagonomas.

Clinical Case: A 51-year-old male presented to the clinic multiple visits for rash affecting the legs and genital area of two months. His medical history include type 2 DM and HT. The rash was attributed to subacute eczema and treated with topical steroids but showed no improvement. The skin eruption initially appeared on lower extremities progressed to trunk, and face. The skin lesions were associated with weight loss and stomatitis. On physical examination, skin showed ill-defined erythematous plaque exhibiting annular pattern, scale, and erosion on all extremities and perioral area. When the skin lesions healed, the new cutaneous eruptions occurred. Laboratory testing revealed plasma glucose of 185 mg/dL. The skin biopsy reported vacuolated keratinocytes in the epidermis with eosinophil cytoplasm, compatible with NME leading to further workup for pancreatic tumor. CT abdomen revealed tumor mass 9.6x6 cm at the pancreatic tail and multiple nodules in the liver. Somatostatin receptor scintigraphy showed an area of increased radiotracer uptake at the tail of the pancreas and multiple liver nodules corresponding to the previous CT scan. Serum glucagon was 923 pg/mL, confirming the diagnosis for glucagonoma. The patient was treated with distal pancreatectomy, and enucleation of liver metastases. Histopathological reported grade 2 well-differentiated NET. During the admission, the patient was found to have a parathyroid level of 79.3 pg/mL and increased uptake in the left and right lower regions of the thyroid gland from parathyroid MIBI scan, indicating hyperfunctioning parathyroid glands. All pituitary hormones were within normal ranges and no pituitary tumor was detected by the MRI brain. BMD showed osteoporosis at the lumbar spine and left femoral neck. The patient was referred to general surgery for subtotal parathyroidectomy. Pathological of resected parathyroid glands reported parathyroid hyperplasia. Postoperative PTH level and calcium were returned to normal range. Genetic testing focused on MEN1 gene, and the mutation was identified. After four months follow up plasma glucagon decreased to 425 pg/dL, patient had complete resolution of the cutaneous lesions.

Conclusion: Glucagonomas are a rare pancreatic tumors and often difficult to recognize. Chronic eczema may misdiagnose for NME and delay diagnosis. NME can be challenging for physicians to recognize NME which is an important key to diagnose glucagonoma. Even though MEN1 association with glucagonoma is infrequent, awareness of such is important to allow appropriate testing for MEN1 in patients with glucagonoma.

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<![CDATA[MON-918 Familial Paraganglioma: Familiar Case Report]]> https://www.researchpad.co/article/elastic_article_8583 Introduction: Pheochromocytomas and Paragangliomas (PGL) are rare tumors originating from chromaffin cells. They may be sporadic or associated with familial inherited genetic syndromes around 50-80%. There are several PGL syndromes, the most common being PGL 1 (SDHD mutations), PGL 2 (SDHAF), PGL 3 (SDHC), PGL 4 (SDHB), PGL 5 (SDHA), PGL 6 (SLC25A11) and PGL 7 (DLST). SDHB mutations generate a higher probability of malignant PGL, as well as risk of renal, GIST and pituitary neoplasms. We report the case of a patient with a positive family history for the autosomal dominant SDHB mutation.Clinical cases: FZR, male, 19 years old, history of headache, sweating, palpitations, and sudden onset tremors associated with hypertensive peaks. Physical examination: Blood Pressure 140x90mmHg lying down, 110x70 standing up. Performed examinations, of which altered, showed: Plasma metanephrines: 82 pg/mL (RV <65), Plasma normetanephrines: 1.488pg/mL (VR <196), Urinary Catecholamines: 1.784mcg/24h (RV: 80-500), Abdomen Resonance showed an expansive, solid, heterogeneous abdomen mass in posterior contact with the left psoas muscle, medial with the aorta, and lateral with jejunum loops, measuring 7x3.5 cm. MIBG scintigraphy: abnormal uptake in left kidney. Family history: uncle diagnosed with cervical paraganglioma with cervical lymph node metastasis, gastric GIST and PCR genetic sequencing identifying mutation in SDHB (Q.137 G > T in exon 2). Asymptomatic second cousin with positive genetic analysis for the same mutation and another deceased first cousin diagnosed with pheochromocytoma with bone metastasis. He underwent tumor resection that identified retroperitoneal paraganglioma with 10% KI67, Protein S-100, Chromogranin-A and Synaptophysin positive. Carried out PCR genetic analysis that identified the same Q.137 G > T mutation in exon 2 of the SDHB gene in heterozygosis.Twenty-six relatives were called for mutation research, of which 5 positive for the SDHB mutation, until now, including the patient’s mother and twin brother, both already investigating related diseases.We await new family members and, subsequently, the result of the mutation analysis to continue the clinical and laboratory follow-up of this family.Conclusion: Although rare, this condition should be remembered as a differential diagnosis of diseases with such clinical symptoms and, once characterized, investigate possible associations with genetic syndromes.

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<![CDATA[MON-924 Susceptibility Genetic Testing and Functional Imaging Modalities in the Management of Bladder Paragangliomas]]> https://www.researchpad.co/article/elastic_article_8552 Introduction: Bladder Paragangliomas (PGLs) are rare neuroendocrine tumors derived from sympathetic paraganglionic tissue within the bladder wall, accounting for <1% of all Pheochromocytomas and Paragangliomas (PPGLs). >40% of PPGLs are associated with inherited syndromes through mutations affecting citric acid cycle enzymes (commonly SDH). Susceptibility gene identification has important implications for long-term care and facilitates targeted cascade genetic screening. Functional imaging using MIBG, Gallium DOTATATE and FDG-PET have become important tools in both diagnosis and treatment (Peptide Receptor Radionuclide Therapy).

Clinical Cases: We report the demographics, clinical characteristics and novel features of 7 patients with bladder PGLs. The series includes 2 females and 5 males, median age 38 years (range 14-68). 5 presented with hematuria and 2 were detected incidentally (1 found on radiological imaging and the other during cystoscopy surveillance). Other symptoms reported were headaches, sweating and palpitations which were relieved by urination. Only 1/7 had a known family history of PGLs. 5/7 patients had elevated plasma normetadrenaline levels and 2 had non-elevated catecholamine metabolites (these 2 patients were asymptomatic).

6/7 patients had genetic testing performed and pathogenic variants were identified in 4 (Fumarate hydratase (FH), SDHA, SDHB*2 genes) and no pathogenic variant identified in 2 patients in our genetic panel of 10 PPGL genes. All primary tumors demonstrated MIBG avidity and in 2 patients assessed there was PGL FDG-PET avidity. Metastatic disease was present in 2 patients (2 SDHB mutations; with 1 MIBG avid bone and 1 FDG-PET avid nodal metastasis). SDHB immunostaining on resected histology was available for 3 cases - absent SDHB immunostaining in the patient with SDHA mutation and strongly positivity in 2 patients (1 with no genetic mutation and in 1 with FH mutation).

Conclusions: The majority (>65%) of patients with bladder PGL have a germ line mutation in a susceptibility gene involving the citric acid cycle. An extended gene panel should be performed in all patients diagnosed with bladder PGLs including SDHA and FH gene mutations. SDH immunostaining of tumour can indicate SDHx gene defects but can be normal in FH mutations. SDHB is associated with increased risk of malignant/metastatic behavior. All 3 modalities of functional imaging (Ga DOTATATE, FDG PET, & MIBG) have a role in the assessment and treatment decision making in the management of bladder PGLs.

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<![CDATA[MON-904 Behind the Mask: The Stories of Insulinoma- a Case Series]]> https://www.researchpad.co/article/elastic_article_6991 Introduction: Insulinoma is a rare, slow growing pancreatic neuroendocrine tumor, leading to hyperinsulinemic hypoglycemia. It runs a very insidious course often masquerading as neurologic, psychological or cardiac disease. We present a series of four cases with varying clinical presentations, diagnoses and latency to diagnosis.

Case Report: This is a retrospective analysis of four cases of Insulinoma diagnosed between Sep 2016 and Mar 2019. All the patients were males and aged 36, 22, 63 and 15 years respectively. Baseline characteristics, duration to diagnosis of Insulinoma, diagnosis and treatment given before definitive diagnosis and post-surgery outcomes were analyzed. All the four patients had relatively long latency to diagnosis despite frequent, spontaneous hypoglycemic episodes, longest being ten years. The patients had a neurological and/or psychiatric diagnosis prior to definitive diagnosis. The symptoms improved with consumption of food. One of the four patients was on antipsychotics for episodic abnormal behavior before the diagnosis of Insulinoma. Two of them were on anti-epileptic medications for seizures. All the insulinomas were localized with CECT without requirement for additional localization techniques. All our patients responded well to surgical resection of the tumor. All insulinomas were benign grade 1 tumors. Acanthosis nigricans regressed in all the patients post-surgery. In addition, all the patients had significant weight loss post-surgery. Two of the four patients developed diabetes mellitus and were on insulin therapy.

Conclusion: A strong index of suspicion of Insulinoma is warranted while dealing with patients presenting with seizure disorders, behavioral abnormalities and neurological symptoms because the spectrum of symptoms is wide and non-specific. Seeking diagnosis is of utmost importance because of implications on treatment and prognosis.

Reference:

Valente LG, Antwi K, Nicolas GP, Wild D, Christ E. Clinical presentation of 54 patients with endogenous hyperinsulinaemic hypoglycaemia: a neurological chameleon (observational study). Swiss Med Wkly. 2018 Nov 18;148:w14682.

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<![CDATA[MON-925 A Wolf in Sheep’s Clothing: Intermittent Hypercalcemia from an Intrathyroidal Parathyroid Carcinoma]]> https://www.researchpad.co/article/elastic_article_6818 Parathyroid carcinomas have an estimated prevalence of <0.1% of all cancers and is found in <1% of patients with primary hyperparathyroidism (PHPT). While they frequently present with PTH- mediated hypercalcemia, they are often distinguished by severe hypercalcemia and markedly elevated PTH levels compared to their benign counterparts. Parathyroid cancers most often arise from existing parathyroid glands, making them identifiable with standard imaging modalities such as parathyroid sestamibi scan, thyroid ultrasound, and 4-D CT scan. There are reports of non-functioning parathyroid carcinomas, including those that are intrathyroidal. Most of the reported cases are found de novo. We present a case of an intrathyroidal parathyroid carcinoma with intermittent hypercalcemia. A 72-year-old man with a history of Graves’ disease and RAI ablation in the 1970’s was found to have hypercalcemia up to 14.1 mg/dL (8.5 - 10.1) with a PTH level of 223 pg/mL (14 - 64). He denied any constipation, bone pain, fractures, renal stones, or changes in mental status. Thyroid ultrasound demonstrated a 3.9 cm R lobe complex nodule reported as TI-RADS 4, and a hypoechoic 1.0 cm nodule in the L lobe. No definitive parathyroid adenoma was reported. A parathyroid sestamibi scan showed persistent uptake in area of the L 1.0 cm nodule favoring a PTH adenoma while the R nodule had initial radiotracer uptake with delayed washout but no technetium uptake. Laboratory evaluation demonstrated a 24-hour urinary calcium of 338 mg/24hr, low 25-OH vitamin D, and normal vitamin D 1,25 levels. Osteoporosis was diagnosed by BMD with T-score of -3.2 at the femoral neck. Repeat serum corrected calcium level was 9.7 mg/dL and PTH was 93 pg/mL. FNA cytology of the R thyroid mass was reported as benign thyroid tissue. Due to size of the R thyroid nodule, the patient underwent a R hemithyroidectomy with L parathyroidectomy. Intraoperative PTH levels decreased from 154 to 120 pg/mL after removal of L parathyroid adenoma; PTH level decreased further to 12.9 pg/mL after R hemithyroidectomy. Surgical pathology revealed 4.5 cm R parathyroid carcinoma without thyroid tissue with positive margins, and a hypercellular L parathyroid gland. PHPT resolved. After review of all aspects of the case and discussion with patient, the decision was made to monitor his calcium and PTH levels and repeat BMD 1 year from resection. This is an uncommon presentation of a rare endocrine malignancy. To our knowledge, there are few case reports of non-functional parathyroid carcinomas that were initially reported as thyroid cancer or benign thyroid tissue after biopsy. This report underscores the importance in keeping this rare diagnosis in the evaluation of PTH-mediated hypercalcemia.

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<![CDATA[MON-908 Carcinoid Causing Catastrophic Calcemia]]> https://www.researchpad.co/article/elastic_article_6809 Intro: Carcinoid tumors are rare, slow growing, indolent neuroendocrine tumors typically originating from enterochromaffin in the gastrointestinal tract and bronchopulmonary tree1. While often found to be secreting serotonin, many different secretory products have been described2. We present the case of a patient with refractory hypercalcemia due to a carcinoid tumor producing parathyroid hormone related peptide (PTHrP). Case: A 65-year-old male was found to have hypercalcemia of 14.7 mg/dL after presenting for nausea and vomiting. He was treated with Zolendronic acid and intravenous (IV) fluids as initial work-up revealed an appropriately suppressed parathyroid hormone level, no monoclonal spike, and a PTHrP that was dramatically elevated. He refused further work-up initially but was admitted two months later for persistent severe hypercalcemia. Computed tomography imaging showed innumerable liver lesions. Histologic analysis of the largest liver lesion was consistent with carcinoid tumor. For the next two years, he was managed outpatient with Pamidronate, Denosumab, and Sandostatin, along with two liver embolizations. Control of serum calcium levels became more difficult and he had multiple hospitalizations for symptomatic hypercalcemia until chemotherapy, Sunitinib, was initiated. Calcium levels normalized for one year after starting Sunitinib prior to onset of suspected medication-induced pancreatitis. He was switched to Everolimus but did not respond to that and was readmitted mere weeks later for symptomatic hypercalcemia and a combination of Folinic acid, Fluorouracil, and Oxaliplatin (Folfox) was started. He continued to get frequent bisphosphonates and IV fluids along with Folfox but several months later he stopped responding to all medical options. His calcium level climbed to 19.9mg/dL and he underwent a technically complicated surgical procedure in which significant tumor burden was removed from his liver. Since surgery, the patient has remained normocalcemic without additional medical therapy. Discussion: Carcinoid tumors are uncommon with reported incidence of 40 per one million people2. PTHrP is most commonly produced by squamous cell lung cancer, renal cell cancer, gynecologic cancers, and lymphoma3. Carcinoid tumors producing PTHrP with resultant hypercalcemia is rare with a few cases reported in literature4. Our patient had a complex treatment course including IV fluids, anti-resorptive agents, somatostatin analogs, liver embolization, chemotherapeutic agents, and eventual surgical debulking. Surgical intervention is not commonly required for carcinoid tumors5. This patient had a rare tumor, producing an uncommon hormone, and required extensive treatment. This case shows the importance of a multidisciplinary approach in patients with hypercalcemia secondary to carcinoid tumors but refractory to traditional therapy.

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<![CDATA[MON-902 Etomidate - an Under Utilized but Safe and Efficacious Drug to Treat Acute Severe Cushing’s Syndrome- Case Reports of Ectopic ACTH Syndrome from Neuroendocrine Malignancies]]> https://www.researchpad.co/article/elastic_article_6686 Background: Intravenous etomidate infusion, in non-hypnotic doses, rapidly lowers cortisol levels by blocking 11-beta hydroxylation of deoxycortisol to inhibit cortisol production. It is an underutilized drug due to concerns of excess sedation and ICU monitoring.

Clinical Case 1: A 44 year-old female with HTN, diabetes, and recently diagnosed pancreatic neuroendocrine tumor with liver metastases presented with altered mentation. Labs showed severe hypokalemia, metabolic alkalosis, serum AM cortisol >60.2 ug/dL (n 6.7-22.6 ug/dL), ACTH of 698.1 pg/mL (n 7.2-63.3 pg/mL), 24-hour urine free cortisol (UFC) of 5791 ug/24hr (n 5-64 ug/24hr), midnight salivary cortisol of 8.04 ug/dL (n <0.01-0.09), and abnormal low dose (LDDST) and high dose (HDDST) dexamethasone suppression tests each with cortisol >60.2 ug/dL. She developed worsening psychosis, likely secondary to hypercortisolism. After ICU transfer, etomidate infusion was initiated at 2.5 mg/hr and titrated upward, leading to rapid drop in cortisol levels and concomitant improvement in mentation. No respiratory or airway difficulties developed. Ketoconazole and metyrapone were started and etomidate was weaned off. Steroids were added once cortisol levels fell below 10 ug/dL as part of “block and replace.” The patient eventually underwent bilateral adrenalectomy with improvement in hemodynamic and blood glucose parameters. She was discharged on physiologic replacement doses of hydrocortisone and fludrocortisone, with no reported issues two months later.

Clinical Case 2: A 51 year-old man with one month of hematochezia presented with hypertension, severe hypokalemia, metabolic alkalosis, and QTc prolongation. Colonoscopy was unremarkable; however, labs revealed a cortisol of 43.1 ug/dL, ACTH of 83.6 pg/mL, and 24-hour UFC of 7,494 ug/L, with an abnormally elevated LDDST. Imaging showed a pancreatic mass and multiple hypodense liver lesions. The overall presentation was suggestive of ectopic ACTH syndrome due to metastatic neuroendocrine carcinoma, which was confirmed on biopsy. Chemotherapy, ketoconazole, and metyrapone inadequately lowered cortisol. Etomidate drip was initiated at 3 mg/hr in the ICU, with rapid reduction in cortisol levels to <20 ug/dL without respiratory compromise. Attempts to wean off etomidate were unsuccessful and the patient underwent bilateral adrenalectomy. The surgery was compromised due to extensive liver and pancreatic enlargement, and follow up imaging revealed incomplete resection. 8am cortisol level (off etomidate) was >60.0 ug/dL. Metyrapone and ketoconazole were resumed and hydrocortisone was later initiated for “block and replace”. The patient remains in critical condition.

Conclusion: Etomidate-in non- hypnotic doses is useful for the rapid lowering of cortisol levels.

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<![CDATA[MON-909 Diabetic Ketoacidosis Following Treatment of Endogenous Hyperinsulinism]]> https://www.researchpad.co/article/elastic_article_6661 Background: There has been only one case of Diabetic Ketoacidosis (DKA) reported following treatment of endogenous hyperinsulinism in a 16 month old.[1] This has not yet been described in adults.

Clinical Case: An 85 Y/O M with a PMH of metastatic gastric adenocarcinoma complicated by gastric outlet obstruction requiring TPN was admitted for symptomatic hypoglycemia. On the day of admission, his wife noted that he appeared confused and checked his capillary blood glucose, which was 35, prompting her to call EMS who gave him IV dextrose 50% (D50).

In the ED, he was placed on continuous dextrose 10% (D10) due to persistent hypoglycemia. To investigate the cause of hypoglycemia, D10 was stopped and a fast test was initiated. The patient developed symptomatic hypoglycemia 9 hours after stopping the D10. Laboratory results showed: plasma glucose 43 mg/dL, c-peptide 3.1 nmol/L, pro-insulin 18.7 pmol/L, insulin 10.7 uU/mL, beta-hydroxybutyrate (BHOB) 0.08 mmol/L. Insulin antibody and screen for oral hypoglycemic drugs were negative. Glucagon administration raised his blood glucose from 43 mg/dL to 50 mg/dL, 84 mg/dL, and 106 mg/dL after 10, 20, and 30 minutes, respectively. A diagnosis of endogeneous hyperinsulinism was made and the patient was started on Diazoxide 50 mg TID which was increased to 150 mg TID 2 days later. On day 3, Prednisone 20 mg daily was started due to inability to come off the D10 drip completely. On day 4 he was taken off D10. Due to plasma glucose >150 mg/dL, prednisone dose was reduced to 10 mg and then 5 mg on day 5 and 6, respectively. On day 8, he was found to be in DKA with a plasma glucose of 250 mg/dL, metabolic acidosis with an anion gap of 20, HCO3 of 15 mg/dL, undetectable insulin levels and BHOB of 5.49 mmol/L. Prednisone and Diazoxide were discontinued and he was started on an intravenous insulin infusion. Within 24 hours he became persistently hypoglycemic requiring D50 and prednisone was restarted. DKA developed once again and the patient was subsequently made comfort measures only. Further investigation of his endogenous hyperinsulinism was not pursued. The patient was transferred to inpatient hospice, where he passed away several days later.

Conclusion: This is the first reported case of an adult patient with documented endogenous hyperinsulinism developing DKA following treatment with diazoxide and prednisone. Reference: (1) Mangla et al. J Ped End Met. 2018; 31(8): 943-945.

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<![CDATA[MON-919 Primary Neuroendocrine Tumor of the Central Nervous Sistem, a Case Report and Literature Review]]> https://www.researchpad.co/article/elastic_article_6459 Introduction

Neuroendocrine Neoplasms are rare, with an incidence of 5 to 100,000 inhabitants, constituting 1% of all malignancies, presenting high survival rates in general, even in metastatic diseases. However, in those poorly differentiated, as in the following case, survival is around 4% in 5 years. We will describe a case of primary neuroendocrine tumor in the brain, of which is uncommon in the literature.

Clinical case

A 26 years women was referred to the ER of Santa Casa de São Paulo, in January 2019, to be evaluated by neurosurgery, due to progressive left hemiparesis and headache for 3 months, which got worse in 4 days. On CT scan, there was a 6 x 6 cm solid-cystic, expansive, lesion in the right frontal lobe, with perilesional edema and contralateral midline 1.3cm deviation and subfalcine herniation.

Thus, the tumor was resected soon, with anatomopathological analysis showing poorly differentiated tumor of cells with scarce cytoplasm, hyperchromatic nuclei and high mitotic activity.

Immunohistochemical analysis finds 50% Ki67, with focal p53, TTF1, CD99, CD 56 and synaptophysin positivity. The main hypotheses, then, consisted of Neuroendocrine Carcinoma.

Four months after surgery, the patient reported worsening deficit, headache, pain, weight loss, being referred to the Emergency Room, once more. In RM an expansive lesion was found 6.6 x 4.4 cm, in the right frontoparietal surgical cavity, edema, compression and 0,4 cm midline deviation.

The patient was once again submitted to emergency neurosurgery, with microsurgical resection. The pathology was identical to the previous one.

We proceed with hormonal evaluation, regarding to Medular Thyroid carcinoma, Gastrinoma, Insulinoma, Pheochromocytoma, Carcinoid tumor and others.

Imaging exams were also performed to investigate other primary sites: no changes in CT scan of the chest and abdomen and PET CT FDG. However, this one showed recurrence of the intracranial lesion, with three sites of involvement, all hypermetabolic: one of 4.1 x 2.9 cm (SUV 4.9) and another of 3.9 x 3.3 cm (SUV 8, 4) in the right frontoparietal region and medial nodule to the right thalamus of 1.2 cm (SUV 6.1).

Patient currently maintain left hemiparesis, frequent pain, taking carbamazepine due to epileptic seizures, and considerable weight loss. She has an important limitation of daily activities and basic self-care, with 50% Karnofsky scale. Due to relapse, palliative radiotherapy was initiated in the region of the tumors.

Conclusion

The patient had a poor outcome in relation to cancer, with little possibility of treatment due to poor tumor differentiation and poor performance status.

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<![CDATA[MON-905 A Case of Cushing’s Disease with Glucocorticoid Positive-Feedback]]> https://www.researchpad.co/article/elastic_article_6232 Background: Although paradoxical response of cortisol (F) during high dose dexamethasone (Dex) suppression test (DST) is observed in a part of ectopic ACTH syndrome, few reports have been shown in Cushing’s disease (CD). It suggests a presence of glucocorticoid (GC)-driven positive-feedback loop. However, the underlying mechanism remains elusive. Here we present a case of CD showing clear clinical and pathophysiological evidences of GC positive-feedback using ex vivo 3-dimensional (D) culture method.

Case: A 62-year-old woman manifested typical Cushing’s symptoms, including moon face, central obesity, hypertension, hypokalemia, and vertebral fractures. Endocrinological data were consistent with a diagnosis of CD; morning plasma ACTH 299 pg/mL, serum F 28 μg/dL, midnight serum F 43 μg/dL, and 24hr urinary free cortisol 988 μg/day. CRH test showed a slight increase in plasma ACTH levels (1.4 fold), and pituitary MRI revealed a 14 mm macroadenoma invading into the left cavernous sinus. Interestingly, both 1 mg and 8 mg DST showed a paradoxical increase in serum cortisol levels (27.7→64.7μg/dL and 17.17→35.68μg/dL, respectively). These data indicated a presence of positive-feedback response to GC in the tumor. Indeed, after the initiation of metyrapone (1,000 mg/day) administration for the treatment of hypercortisolemia, plasma ACTH levels were decreased to 147.5 pg/mL accompanied with the decrease in serum F levels to 4.12 μg/dL. Moreover, pituitary tumor obviously shrank during the metyrapone treatment. Thereafter, we undertook transsphenoidal surgery and plasma ACTH and serum F levels decreased to 35.8 pg/mL and 7.6μg/dL, respectively.

ex vivo studies: To prove the presence of the positive feedback response and explore the underlying mechanisms, we performed a primary culture experiment using the tumor and applied 3D culture method. The resected tumor tissue was enzymatically digested, dispersed and embedded into the Matrigel. Then cells were treated with Dex (0.1-10 nM), and ACTH concentrations were measured after 72 hrs. Interestingly, ACTH levels significantly increased by 10 nM Dex treatment at 72 h (129 %, p <0.01), indicating a paradoxical response to Dex in the tumor ex vivo.

Conclusions: To our knowledge, this is the first case of CD who showed clinically obvious GC positive-feedback that was proved by ex vivo 3D primary culture cell models. Notably, tumor shrinkage was observed during the metyrapone treatment, suggesting that GC positive-feedback mechanisms also involve tumor proliferation. Further investigation is required for elucidating the underlying mechanisms.

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<![CDATA[MON-906 MULTIPLE ENDOCRINE NEOPLASIA TYPE 2A: Familiar Case Report]]> https://www.researchpad.co/article/elastic_article_6165 Introduction: Multiple endocrine neoplasia type 2A (MEN 2A) is a autosomal dominant transmission inherited syndrome which oncogenesis is based on germline mutations with RET proto-oncogene function gain. Patients have medullary thyroid carcinoma (CMT) and some develop unilateral or bilateral pheochromocytoma and/or primary hyperparathyroidism, its frequency depends on the inherited RET mutation. We present a case of a mother and daughter with marfanoid habitus and MEN 2A syndrome confirmed by genetic analysis that identified mutation in the RET gene, codon 634.Clinical cases: 35-year-old woman with weight loss, sweating, nausea, hypertensive peaks, syncope episodes and marfanoid habitus, with plasma metanephrines 9.1nmol/L (RV<0.5), bilateral adrenal tumors on MRI (4.7x4.5x3.3 cm left adrenal and 7.4x7.3x6.3 cm) and MIBG scintigraphy high uptake bilateral, with diagnosis of bilateral pheochromocytoma. She also had calcitonin 49.40pg/mL (RV<6.4), calcium 11.9mg/dL (RV 8.6-10.2), PTH 372.7pg/mL (RV15-65) and cervical ultrasound (USG) with solid and hypoechogenic thyroid nodule, diagnosed with CMT and primary hyperparathyroidism with 6 possible parathyroid glands by SPECT CT scintigraphy. Genetic panel by NGS identify germline mutation in RET códon 634 - minsense mutation: c.1900T>C. The patient denied prior family history. In the familiar screening, her 18-year-old daughter has a marfanoid habitus, serum calcitonin 48.8pg /mL (RV<9.8), CEA 3.8ng/mL(RV<3.0), cervical USG shows a thyroid nodule of 0.7x0.5x0.5cm, solid, hypoechoic, with microcalcifications and a central compartiment lymph node, whose puncture calcitonin > 2000pg/mL and 118pg/mL, respectively. She features plasma metanephrines 0.5mmol/L (RV<0.5), normal plasma normetanephrines, MIBG scintigraphy and adrenal MRI without alterations and absence of primary hyperparathyroidism. She has the same mutation as her mother.Conclusion: Although rare, it is essential to know the clinical and laboratory changes in MEN 2A in order to enable early diagnosis and treatment. Also, investigate every first-degree relative is important so complications and mortality of this syndrome can be reduced.

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<![CDATA[MON-923 MENIN Gene Mutation: Unity Amidst Diversity]]> https://www.researchpad.co/article/elastic_article_6054 Introduction

The MEN 1 syndrome is an enigmatic disorder, manifesting a wide spectrum of disorders, in members of a family, harbouring the same gene mutation. We present one such family, with a MENIN gene mutation with marked diversity in the clinical presentation

Clinical cases

1992: RB (Age: 13) presented with accelerated puberty, galactorrhoea and a lactotroph adenoma. Treated with Bromocriptine, followed by hypophysectomy and radiotherapy. He was on hormone replacement for hypopituitarism.

1996: He gained 21 kg of weight and had recurrent episodes of convulsions with unconsciousness.He had hypoglycaemia (13mg/dl; N >70), with hyperinsulinemia (58uIU/ml; N<25). MRI abdomen showed a mass (3.4 x 3.0 cm) over the tail of the pancreas for which a distal pancreatectomy was done (HPE: Neuroendocrine tumour).

2013: He had pain in the lower limbs with hypercalcemia (11.4mg%; N: 8.5-10.5) and hyperparathyroidism (329 pg/ml; N: 10-61) (MIBG Scan: parathyroid adenomas treated by bilateral inferior parathyroidectomy).

2016: He had hypoglycaemia with hyperinsulinemia with multifocal pancreatic NETs. These were enucleated at surgery.

2017: He developed Zollinger Ellison syndrome with raised basal gastrin levels (Gastrin: >200ng/ml; N<180) and multiple duodenal ulcers (Treatment: Pantoprazole). He simultaneously had recurrent hyperparathyroidism and underwent a total parathyroidectomy with allograft. The allograft initially showed evidence of hyperparathyroidism followed by hypoparathyroidism.

His father VB (Age: 56) was seen by us in 1996 for skin lesions and a malignant thymic carcinoid, to which he succumbed to, shortly after the surgery. His aunt, SB (Age: 18), has a lactotroph adenoma with severe insulin resistance characterised by obesity, acanthosis nigricans and hyperandrogenism.

2009: His paternal uncle PB (Age: 54) had a pituitary macroadenoma. He underwent a hypophysectomy and was lost to follow up.

2018: PB had massive haemoptysis. A bronchoscopy showed nodules in the right lung which on biopsy revealed a NET. The whole body scan showed a hilar and mediastinal mass along with metastatic disease to the adrenals, liver, spine, skull and rectum. The histopathology examination revealed a malignant carcinoid

Clinical lesson

Whole exome sequencing of the two of the affected members showed mutations of the MENIN gene at exon 2 c.G2492T:p.G831V; g. chr10. This common mutation in the family was associated with a wide spectrum of diverse clinical manifestations which include the classic disease, malignant carcinoids of the lung and acromegaloid variant of Type A insulin resistance with hyperandrogenism. These observations suggest the unity amidst diversity in the enigmatic syndrome that encompasses MEN1.

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<![CDATA[MON-921 Autonomous Cortisol Secretion Coexisting with Pancreatic Neuroendocrine Tumor: A Rare Presentation]]> https://www.researchpad.co/article/elastic_article_6017 Introduction: neuroendocrine tumors (NET) are a very rare and heterogeneous group of malignancies that can be associated with adrenocortical tumors in approximately 20% of the cases, mostly bilateral and non-functioning. Autonomous cortisol secretion occurs in less than 10% of adrenal incidentalomas and the coexistence of pancreatic neuroendocrine neoplasms and autonomous cortisol secretion is not well-described.

Clinical case: a 54-year-old man with previous history of systemic hypertension and type 2 diabetes mellitus, presented with left hypochondrium pain in the last 18 months, associated with abdominal distension, constipation and nausea. Physical examination without abnormalities. Abdominal tomography demonstrated dilatated pancreatic duct and a solid heterogeneous nodule in left adrenal, measuring about 2.7 cm. Ecoendoscopy revealed a heterogeneous, hypoechoic and oval nodular lesion, located at the transition of pancreatic head and uncinate process, measuring 1.5x1.1cm. Biopsy was performed, showing a pattern of neuroendocrine neoplasia, with chromogranin and synaptophysin +, Ki67 1%. Gallium-68 dotatate PET revealed two pancreatic nodular formations, one in proximal neck/body (1.5 cm) and the other in pancreatic tail (1 cm), presenting SUV of 20.4 and 21, respectively. Adrenal nodule presented minimal increase in radiopharmaceutical concentration. To exclude the hypothesis of metastasis, PET FDG was performed, showing physiological uptake in adrenal nodule. Pituitary MRI had no abnormalities.

Chromogranin A and gastrin values were normal. Pheochromocytoma and primary hyperaldosteronism were excluded. Hypercortisolism investigation presented the following results: 23h salivary cortisol 167ng/dl (NR < 100), 24-hour free urinary cortisol 42.1 mcg/24h (NR 4.2-60), post-1mg and 2mg dexamethasone serum cortisol of 10.8 mcg/dl and 3.8 respectively (serum dexamethasone levels of 193 and 780 ng/dl; NR > 130), ACTH 13 and 11 pg/ml.

By these results, coexistence of non-functioning pancreatic neuroendocrine tumor and autonomous cortisol secretion was confirmed. A total pancreatectomy with partial gastrectomy and bileodigestive anastomosis was performed. Pathological anatomical evidence demonstrated a well-differentiated neuroendocrine tumor (NET G1) and immunohistochemistry analyses showed positive chromogranine A, synaptophysine, Ki67 1% and negative ACTH. Clinical follow-up of the adrenal adenoma was preferred.

Conclusion: although most adrenocortical tumors associated with NET are nonfunctional, hypercortisolism should be considered. Adrenal metastasis and ectopic ACTH secretion are differential diagnosis. Clinical follow-up is an option when patient is asymptomatic and comorbidities are well-controlled.

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<![CDATA[MON-922 Multiple Endocrine Neoplasia Type 1- A Clarion Call for Clarity]]> https://www.researchpad.co/article/elastic_article_5960 A 35-year-old gentleman presented with epigastric pain and bilious emesis. He also endorsed urinary frequency, non-bloody diarrhea and diffuse bone pain. On physical examination he had epigastric tenderness and multiple hyperpigmented skin lesions.

An abdominal computed tomography (CT) scan revealed multiple diverticula with peri-colonic fat stranding in the descending and sigmoid colon, concerning for diverticulitis. He was started on a course of metronidazole and ciprofloxacin. A 3.1 cm mass was incidentally noted in the uncinate process of the pancreas. Bilateral adrenal nodules were also appreciated.

An endoscopic ultrasound (EUS) guided trans-gastric fine needle aspiration biopsy was performed, revealing a well differentiated pancreatic neuroendocrine tumor (pNET - pT3N1Mx, intermediate risk). Chromogranin A was elevated to 108 ng/ml (reference range <93 ng/ml). Serum and urine metanephrine, V-peptide, gastrin, glucagon and parathyroid hormone related peptide were all normal; indicating a nonfunctioning neuroendocrine tumor. He underwent a pancreaticoduodenectomy. Octreotide scan was unrevealing for residual uptake. Adrenal biopsy revealed adrenal adenomas.

Three years later, he presented with severe abdominal pain and a new pancreatic mass was noted on CT. Chromogranin A was elevated to 227 ng/mL. EUS revealed a 0.35 cm mass in the bed of the pancreatic head, encasing the superior mesenteric artery. Pathology was positive for recurrence of the neuroendocrine tumor.

He was hypercalcemic to 11.4 mg/dL and parathyroid hormone was elevated to 319 pg/mL. CT neck revealed a 0.1 cm nodule concerning for parathyroid adenoma. He underwent a subtotal parathyroidectomy.

Genetic testing confirmed Multiple Endocrine Neoplasia Type 1 (MEN1) with a heterozygous mutation of the menin1 gene.

MEN1 is a rare genetic syndrome with affected individuals at increased risk of developing pancreatic, pituitary, parathyroid gland and cutaneous tumors. With a kaleidoscope of presentations, clinicians must maintain a high index of suspicion for MEN1, particularly for cases with nonfunctioning pNETs which present insidiously and are the foremost cause of mortality in MEN1 patients.1

Further clarity is needed on MEN1 associated pNET prognostic risk stratification, surveillance and targeted immunochemotherapy.2 Timely and algorithmic screening for MEN 1 syndrome in patients with pancreatic incidentalomas is essential to improving patient outcomes.

1.

Kamilaris CDC, Stratakis CA. Multiple Endocrine Neoplasia Type 1 (MEN1): An Update and the Significance of Early Genetic and Clinical Diagnosis. Front Endocrinol. 2019;10:339. doi:10.3389/fendo.2019.00339

2.

Yates CJ, Newey PJ, Thakker RV. Challenges and controversies in management of pancreatic neuroendocrine tumours in patients with MEN1. Lancet Diabetes Endocrinol. 2015;3(11):895-905. doi:10.1016/S2213-8587(15)00043-1

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<![CDATA[MON-916 Pure Large Cell Neuroendocrine Carcinoma (LCNEC) of the Gall Bladder in a Patient with Down Syndrome - a Rare Case of an Aggressive Tumor of the Gall Bladder]]> https://www.researchpad.co/article/elastic_article_5905 Background: Pure large cell neuroendocrine carcinoma of the gall bladder (LCNEC-GB) is an extremely rare entity, with only 12 such cases reported in literature to date. None has been reported in a patient with genetic disorders. We describe the case of a patient with pure LCNEC-GB in the presence of Down syndrome and prior biliary atresia.

Case:

A 49-year-old female with Down Syndrome and history of neonatal surgery for congenital duodenal atresia presented with fever, vague abdominal discomfort and 6 month history of 15 pound weight loss. CT abdomen revealed a 5 X 4.2 cm exophytic, heterogeneously enhancing mass in the gall bladder fossa extending into segment 4B-5 of liver with mild intrahepatic biliary dilation, along with a 9 cm cystic lesion in continuity with the duodenum which was confirmed to a dilated duodenal anastomosis (from prior biliary surgery) on endoscopy. There was high suspicion for malignancy (gall bladder carcinoma versus intrahepatic cholangiocarcinoma) and subsequent metastatic workup including tumor markers, staging CT chest, MRI of the abdomen and diagnostic laparoscopy was negative.

The patient underwent robotic converted to open en bloc resection of the gallbladder mass with segment 4B-5 liver resection and adherent loops of small bowel as well as resection of the dilated duodenal anastomosis followed by reconstruction with a gastrojejunostomy and Roux-en-Y/small bowel entero-enterostomy and closure of duodenotomy.

Pathology demonstrated poorly differentiated “pure” large cell neuroendocrine carcinoma (G3), 6 cm in greatest dimension, with invasion of liver, duodenum and stomach, negative liver and gastric/small bowel margins. Lymphovascular invasion (LVI) was present with no perineural invasion (PNI), and 3/15 lymph nodes involved. Staging was determined to be pT4pN1.

Patient was considered for adjuvant chemotherapy based on few case reports (platinum/etoposide) but unfortunately developed systemic complaints of fevers, fatigue, pain in bones and joints 2 months post operatively. Workup revealed metastatic disease which was confirmed on biopsy. Several small satellite liver lesions were also identified which was consistent with metastatic hepatic disease. Patient and family elected to proceed with hospice. Patient died within 4 months of surgery.

Conclusion:

Pure LCNEC-GB is an extremely rare and aggressive tumor with a poor prognosis as seen in our patient. This is the first reported case of pure LCNEC-GB in a patient with a genetic syndrome, although it is unknown if it had any causal relationship with the tumor. Prior biliary atresia/post -surgical inflammation may have also contributed to its pathogenesis by plausible development of metaplasia and expression of neuroendocrine cells which are normally absent in the gall bladder. Our case might help shed some light into pathogenesis and genetic basis if any of this rare entity.

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<![CDATA[MON-915 Acute Abdominal Pain and the Pheochromocytoma]]> https://www.researchpad.co/article/Na21267ed-6e29-4889-85a8-d3826b86be43 <![CDATA[MON-914 Ectopic ACTH Syndrome Caused by Adenocarcinoma of Lung - a Rare Association with Rare Complication]]> https://www.researchpad.co/article/N50b26254-2798-437c-b2fb-1464ba744790 20 pg/ml-ACTH dependent Cushing’s) Biopsy of neck node revealed poorly differentiated adenocarcinoma. PET scan showed left lung upper & lower lobe masses. A diagnosis of ectopic ACTH syndrome was made, the source of which was adenocarcinoma of lung, which has been very rarely reported to be associated with it. Oral ketoconazole was started followed by Chemotherapy with paclitaxel & carboplatin. Within the next 7 days patient developed pleural effusion, neutropenia & worsened rapidly. BAL revealed Nocardia species, known to be associated with hypercortisolism. He was treated with appropriate antibiotics & supportive treatment but succumbed to septic shock. CONCLUSION If a patient presents with rapidly evolving symptoms of Cushing’s syndrome, ectopic ACTH syndrome should be considered. The presence of wasting and weight loss, hypokalemic alkalosis, pedal edema & marked hyperpigmentation should also alert towards the diagnosis. Histopathological confirmation of malignancy is important, as in our case with ectopic ACTH where the source was an adenocarcinoma of the lung, of which only 5 cases have been reported till now (Ectopic ACTH more commonly associated with SCLC). Finally, in cases of severe hypercortisolemia, there should be a high index of suspicion for opportunistic infections including invasive fungal infections, Nocardiosis etc, so that specific antibiotic therapy can be initiated. Typical features like fever, leukocytosis can be absent. Treatment of underlying hypercortisolism with surgical/medical management prior to initiation of chemotherapy has been shown to reduce the frequency of infections. ]]>