Ectopic Production Research Articles

Ectopic ACTH Secretion in a Child With Metastatic Ewing's Sarcoma: A Case Report

Ectopic ACTH syndrome is rare in pediatric age. Sarcomas that cause Ectopic ACTH Syndrome (EAS) are even more uncommon. Currently, only three cases of EAS caused by Ewing' sarcoma have been reported. We detail a 10-year-old boy with Cushing's syndrome symptoms caused by ectopic ACTH production by a metastatic Ewing's sarcoma of the right ischio-pubic and ileo-pubic branches. The rapid appearance of cushingoid symptoms, with significant weight gain, acne, hirsutism, and hypercortisolism were implications of ectopic ACTH production as paraneoplastic Cushing's Syndrome. The very high levels of ACTH and non-suppression at the high dose dexamethasone test confirmed the clinical suspicion. We underline the possibility EAS was caused by an ACTH-secreting tumor, including soft tissue sarcomas.

Disseminated Strongyloides stercoralis Infection Associated with Endogenous Hypercortisolism - A Case Report.

Patients with Strongyloides stercoralis infections are usually asymptomatic but massive hyperinfection may occur in patients with diseases associated with abnormal cell-mediated immunity or receiving immunosuppressive therapy.The authors present the clinical case of a 49-year-old man with a history of diarrhoea and cramping abdominal pain, generalized oedema, petechial rash, melanoderma, cough and dyspnoea. He presented hypokalaemia and arterial hypertension and was admitted with the diagnostic hypothesis of Cushing’s syndrome or adrenocorticotropic hormone ectopic production. The patient developed respiratory failure associated with bilateral lung opacities and was admitted to the Intensive Care Unit. The abdominal computed tomography scan revealed liver and duodenal masses. The duodenal biopsy showed the presence of Strongyloides stercoralis and the liver biopsy showed the presence of small cell neuroendocrine carcinoma. The patient died 50 days after hospital admission. The high level of endogenous cortisol observed in this patient may have facilitated the progression to severe fatal infection.LEARNING POINTSStrongyloides stercoralis hyperinfection and disseminated disease can present as a multiorgan infection in immunocompromised patients with an appropriate clinical and epidemiological context.Strongyloides stercoralis hyperinfection and disseminated disease can present with no eosinophilia and negative parasitological stool tests in more than 70% of cases.

ARMC5 mutations are associated with high levels of proliferating cell nuclear antigen and the presence of the serotonin receptor 5HT4R in PMAH nodules.

Objective To analyze the morphological and functional characteristics of primary macronodular adrenal hyperplasia (PMAH) nodules carrying or not carrying ARMC5 mutations and the consequences of the presence of mutations in terms of the pattern of macronodule composition and functional state. Subjects and methods The analyses were performed by hematoxylin-eosin staining, immunohistochemistry, microdissection of spongiocyte tissue and RT-qPCR of histological sections from 16 patients diagnosed with PMAH with germline (5) or germline/somatic mutations (5) and without mutations (6) in the ARMC5 gene. Results Hyperplastic nodules were predominantly composed of spongiocytes in mutated and nonmutated sections. ARMC5 mRNA expression in spongiocytes was higher in ARMC5-mutated nodules than in ARMC5-nonmutated nodules, and homogenous ARMC5 protein distribution was observed. The presence of arginine-vasopressin receptor (AVP1AR) and ectopic ACTH production were observed in both cell populations regardless of ARMC5 mutations; the numbers of serotonin receptor (5HT4R)- and proliferating cell nuclear antigen (PCNA)-positive cells were higher in macronodules carrying ARMC5 mutations than in those without mutations. Conclusions Our results suggest that the presence of ARMC5 mutations does not interfere with the pattern of distribution of spongiocytes and compact cells or with the presence of AVP1AR, gastric-inhibitory polypeptide receptor (GIPR) and ectopic ACTH. Nevertheless, the higher numbers of PCNA-positive cells in mutated nodules than in nonmutated nodules suggest that mutated ARMC5 can be related to higher proliferation rates in these cells. In conclusion, our results provide more information about the crosstalk among abnormal GPCRs, ectopic ACTH in steroidogenesis and the ARMC5 gene, which may be relevant in understanding the pathogenesis and diagnosis of patients with PMAH.

Genetic Manipulation of Transcriptional Regulators Alters Nicotine Biosynthesis in Tobacco.

The toxic alkaloid nicotine is produced in the roots of Nicotiana species and primarily accumulates in leaves as a specialized metabolite. A series of metabolic and transport genes involved in the nicotine pathway are coordinately upregulated by a pair of jasmonate-responsive AP2/ERF-family transcription factors, NtERF189 and NtERF199, in the roots of Nicotiana tabacum (tobacco). In this study, we explored the potential of manipulating the expression of these transcriptional regulators to alter nicotine biosynthesis in tobacco. The transient overexpression of NtERF189 led to alkaloid production in the leaves of Nicotiana benthamiana and Nicotiana alata. This ectopic production was further enhanced by co-overexpressing a gene encoding a basic helix-loop-helix-family MYC2 transcription factor. Constitutive and leaf-specific overexpression of NtERF189 increased the accumulation of foliar alkaloids in transgenic tobacco plants but negatively affected plant growth. By contrast, in a knockout mutant of NtERF189 and NtERF199 obtained through CRISPR/Cas9-based genome editing, alkaloid levels were drastically reduced without causing major growth defects. Metabolite profiling revealed the impact of manipulating the nicotine pathway on a wide range of nitrogen- and carbon-containing metabolites. Our findings provide insights into the biotechnological applications of engineering metabolic pathways by targeting transcription factors.

Ciliary Rab28 and the BBSome negatively regulate extracellular vesicle shedding.

Cilia both receive and send information, the latter in the form of extracellular vesicles (EVs). EVs are nano-communication devices that influence cell, tissue, and organism behavior. Mechanisms driving ciliary EV biogenesis are almost entirely unknown. Here, we show that the ciliary G-protein Rab28, associated with human autosomal recessive cone-rod dystrophy, negatively regulates EV levels in the sensory organs of Caenorhabditis elegans in a cilia specific manner. Sequential targeting of lipidated Rab28 to periciliary and ciliary membranes is highly dependent on the BBSome and the prenyl-binding protein phosphodiesterase 6 subunit delta (PDE6D), respectively, and BBSome loss causes excessive and ectopic EV production. We also find that EV defective mutants display abnormalities in sensory compartment morphogenesis. Together, these findings reveal that Rab28 and the BBSome are key in vivo regulators of EV production at the periciliary membrane and suggest that EVs may mediate signaling between cilia and glia to shape sensory organ compartments. Our data also suggest that defects in the biogenesis of cilia-related EVs may contribute to human ciliopathies.

HSF2BP negatively regulates homologous recombination in DNA interstrand crosslink repair.

The tumor suppressor BRCA2 is essential for homologous recombination (HR), replication fork stability and DNA interstrand crosslink (ICL) repair in vertebrates. We show that ectopic production of HSF2BP, a BRCA2-interacting protein required for meiotic HR during mouse spermatogenesis, in non-germline human cells acutely sensitize them to ICL-inducing agents (mitomycin C and cisplatin) and PARP inhibitors, resulting in a phenotype characteristic of cells from Fanconi anemia (FA) patients. We biochemically recapitulate the suppression of ICL repair and establish that excess HSF2BP compromises HR by triggering the removal of BRCA2 from the ICL site and thereby preventing the loading of RAD51. This establishes ectopic expression of a wild-type meiotic protein in the absence of any other protein-coding mutations as a new mechanism that can lead to an FA-like cellular phenotype. Naturally occurring elevated production of HSF2BP in tumors may be a source of cancer-promoting genomic instability and also a targetable vulnerability.

Pou2f1 and Pou2f2 cooperate to control the timing of cone photoreceptor production in the developing mouse retina

Multipotent retinal progenitor cells (RPCs) generate various cell types in a precise chronological order, but how exactly cone photoreceptor production is restricted to early stages remains unclear. Here, we show that the POU-homeodomain factors Pou2f1/Pou2f2, the homologs of Drosophila temporal identity factors nub/pdm2, regulate the timely production of cones in mice. Forcing sustained expression of Pou2f1 or Pou2f2 in RPCs expands the period of cone production, whereas misexpression in late-stage RPCs triggers ectopic cone production at the expense of late-born fates. Mechanistically, we report that Pou2f1 induces Pou2f2 expression, which binds to a POU motif in the promoter of the rod-inducing factor Nrl to repress its expression. Conversely, conditional inactivation of Pou2f2 in RPCs increases Nrl expression and reduces cone production. Finally, we provide evidence that Pou2f1 is part of a cross-regulatory cascade with the other temporal identity factors Ikzf1 and Casz1. These results uncover Pou2f1/2 as regulators of the temporal window for cone genesis and, given their widespread expression in the nervous system, raise the possibility of a general role in temporal patterning.This article has an associated 'The people behind the papers' interview.

Pneumolysin Induces 12-Lipoxygenase-Dependent Neutrophil Migration during Streptococcus pneumoniae Infection.

Streptococcus pneumoniae is a major cause of pneumonia, wherein infection of respiratory mucosa drives a robust influx of neutrophils. We have previously shown that S. pneumoniae infection of the respiratory epithelium induces the production of the 12-lipoxygenase (12-LOX)-dependent lipid inflammatory mediator hepoxilin A3, which promotes recruitment of neutrophils into the airways, tissue damage, and lethal septicemia. Pneumolysin (PLY), a member of the cholesterol-dependent cytolysin (CDC) family, is a major S. pneumoniae virulence factor that generates ∼25-nm diameter pores in eukaryotic membranes and promotes acute inflammation, tissue damage, and bacteremia. We show that a PLY-deficient S. pneumoniae mutant was impaired in triggering human neutrophil transepithelial migration in vitro. Ectopic production of PLY endowed the nonpathogenic Bacillus subtilis with the ability to trigger neutrophil recruitment across human-cultured monolayers. Purified PLY, several other CDC family members, and the α-toxin of Clostridium septicum, which generates pores with cross-sectional areas nearly 300 times smaller than CDCs, reproduced this robust neutrophil transmigration. PLY non-pore-forming point mutants that are trapped at various stages of pore assembly did not recruit neutrophils. PLY triggered neutrophil recruitment in a 12-LOX-dependent manner in vitro. Instillation of wild-type PLY but not inactive derivatives into the lungs of mice induced robust 12-LOX-dependent neutrophil migration into the airways, although residual inflammation induced by PLY in 12-LOX-deficient mice indicates that 12-LOX-independent pathways also contribute to PLY-triggered pulmonary inflammation. These data indicate that PLY is an important factor in promoting hepoxilin A3-dependent neutrophil recruitment across pulmonary epithelium in a pore-dependent fashion.

Cushing´s syndrome: high aggressiveness of low-grade tumors

Cushing´s syndrome is caused by prolonged exposition supraphysiological to endogenous or exogenous cortisol. Ectopic production of adrenocorticotropic hormone by lung carcinoid tumors is relatively rare. Most documented cases have been reported individually. This rare neoplasm low grade that may secrete adrenocorticotropin (ACTH) leading to rapid development of hypercortisolism which is the main mode of discovery, can be a real aggressive form. This report shows a high aggressiveness of this endocrine neoplasia, wich was marked on the general, morphological, bone and psychiatric level. The trivialization of clinical signs had caused the delay in diagnosis with irreparable bone consequences.

PALMAR CREASE PIGMENTATION

A young lady presented with history of giddiness, blackouts, and darkness of her skin colour especially the face. On examination the colour of her skin was quite dark but not much darker than her spouse. She had buccal pigmentations and her palmar creases were obviously pigmented. Facility for short Synacthen test was not available. Her serum cortisol was on the lower normal side and ACTH was sky high; 1024 pg/ml (ref. range adults: 6-76 pg/ml). She was screened for ectopic ACTH production which could not reveal any pathology. Also plain abdominal x-ray didn’t show any adrenal calcification. She was labeled as Addison’s disease and improved drastically after replacement therapy (Cortisone + Fludrocortisone). Giddiness aloof, she was delighted with the fairness of her colour.

Hyponatremia in a Patient With Cancer

Hyponatremia in a Patient With Cancer

A mutant form of Dmc1 that bypasses the requirement for accessory protein Mei5-Sae3 reveals independent activities of Mei5-Sae3 and Rad51 in Dmc1 filament stability.

During meiosis, homologous recombination repairs programmed DNA double-stranded breaks. Meiotic recombination physically links the homologous chromosomes (“homologs”), creating the tension between them that is required for their segregation. The central recombinase in this process is Dmc1. Dmc1’s activity is regulated by its accessory factors including the heterodimeric protein Mei5-Sae3 and Rad51. We use a gain-of-function dmc1 mutant, dmc1-E157D, that bypasses Mei5-Sae3 to gain insight into the role of this accessory factor and its relationship to mitotic recombinase Rad51, which also functions as a Dmc1 accessory protein during meiosis. We find that Mei5-Sae3 has a role in filament formation and stability, but not in the bias of recombination partner choice that favors homolog over sister chromatids. Analysis of meiotic recombination intermediates suggests that Mei5-Sae3 and Rad51 function independently in promoting filament stability. In spite of its ability to load onto single-stranded DNA and carry out recombination in the absence of Mei5-Sae3, recombination promoted by the Dmc1 mutant is abnormal in that it forms foci in the absence of DNA breaks, displays unusually high levels of multi-chromatid and intersister joint molecule intermediates, as well as high levels of ectopic recombination products. We use super-resolution microscopy to show that the mutant protein forms longer foci than those formed by wild-type Dmc1. Our data support a model in which longer filaments are more prone to engage in aberrant recombination events, suggesting that filament lengths are normally limited by a regulatory mechanism that functions to prevent recombination-mediated genome rearrangements.

State of competition: conceptual shoehorning behind priority on calcitonin precursor biosynthesis

Until the 1950s, the first results in the studies of calcitonin-thyrocalcitonin were ignored in the accepted research scheme. However, it was José Fernández Nonídez from the Spanish School of Histology, died in Augusta (Georgia, USA) in 1947, whose expertise in the parafollicular cells of the mammalian thyroid had led him to an advanced understanding of this separate endocrine organ, which secretes calcitonin. The antecedent of the secretion was present in the cytoplasm of these cells, which Nonídez explained in a paper published in 1932. In 1973, a Spanish group from the Instituto Gregorio Marañón (Madrid) leading the research into the ectopic production of calcitonin identified the precursor responsible for its biosynthesis. Nonetheless, given the informal power in connection with the communication between the scientists, this significative contribution was absolutely discarded in terms of acknowledgment within their social circle. The services responsible for dissemination of scientific knowledge considered that priority should be given to another group of young scientists dedicated to pro-calcitonin evidence. The nature and extent of informal communication are highlighted in countries with different measures to guarantee the autonomy and independence of their state powers. Irrespectively of political circumstances, the paper is focused on the competition between two different approaches in science particularly important for progress in medicine: the perspective presented by experimental studies in basic sciences (in animals) and the models developed in clinical sciences. Stan rywalizacji: priorytetowe znaczenie biosyntezy prekursora kalcytoniny i zniekształcenia pojęciowe Abstrakt Do lat 50. XX w. nie uwzględniano w przyjętym schemacie badawczym pierwszych dowodów przemawiających za istnieniem kalcytoniny-tyrokalcytoniny. Jednakże, znajomość przez José Fernándeza Nonídeza (z hiszpańskiej szkoły histologii, który zmarł w Augusta (Georgia, USA) w 1947 r.) komórek pęcherzykowych tarczycy ssaków doprowadziła go do zaawansowanego rozumienia tarczycy jako odrębnego narządu endokrynnego, wydzielającego kalcytoninę. W artykule opublikowanym w 1932 r. Nonídez wyjaśnił, że prekursor wydzielania znajdował się w cytoplazmie komórek tarczycy. W 1973 r. hiszpańska grupa z Instituto Gregorio Marañón (Madryt), prowadząca badania nad ektopowym wydzielaniem kalcytoniny, zidentyfikowała prekursora odpowiedzialnego za biosyntezę kalcytoniny. Niemniej jednak, biorąc pod uwagę nieformalną władzę związaną z komunikacją między naukowcami, znaczący wkład Nonídeza został absolutnie odrzucony i nie zdobył uznania w tej grupie społecznej. Upowszechnianie usług wiedzy naukowej spowodowało, że przyznano priorytet odkrycia grupie młodych naukowców zajmujących się badaniami pro-kalcytoniny. Podkreślono charakter i zakres nieformalnej komunikacji w krajach, które wykorzystują różne środki dla zagwarantowania autonomii i niezależności uprawnień państwowych. Niezależnie od uwarunkowań politycznych artykuł koncentruje się na konkurencji między dwoma różnymi podejściami w nauce, szczególnie ważnymi dla postępu w medycynie: perspektywą przedstawioną w badaniach eksperymentalnych w naukach podstawowych (u zwierząt) i modelach opracowanych w naukach klinicznych.

The Clinicopathological Spectrum of Acromegaly.

Background: Acromegaly results from a persistent excess in growth hormone with clinical features that may be subtle or severe. The most common cause of acromegaly is a pituitary tumor that causes excessive production of growth hormone (GH), and rare cases are due to an excess of the GH-releasing hormone (GHRH) or the ectopic production of GH. Objective: Discuss the different diseases that present with manifestations of GH excess and clinical acromegaly, emphasizing the distinct clinical and radiological characteristics of the different pathological entities. Methods: We performed a narrative review of the published clinicopathological information about acromegaly. An English-language search for relevant studies was conducted on PubMed from inception to 1 August 2019. The reference lists of relevant studies were also reviewed. Results: Pituitary tumors that cause GH excess have several variants, including pure somatotroph tumors that can be densely or sparsely granulated, or plurihormonal tumors that include mammosomatotroph, mixed somatotroph-lactotroph tumors and mature plurihomonal Pit1-lineage tumors, acidophil stem cell tumors and poorly-differentiated Pit1-lineage tumors. Each tumor type has a distinct pathophysiology, resulting in variations in clinical manifestations, imaging and responses to therapies. Conclusion: Detailed clinicopathological information will be useful in the era of precision medicine, in which physicians tailor the correct treatment modality to each patient.

A rare case of duodenal carcinoid presenting as ectopic Cushing’s syndrome

ACTH-dependent Cushing syndrome (CS) due to an ectopic source is responsible for approximately 10-15% cases of Cushing’s syndrome. It is associated with various tumors such as small cell lung cancer and well-differentiated bronchial or gastrointestinal neuroendocrine tumors. Many a times ectopic ACTH production is difficult to manage, and identification of the source may take many years. Hormonal diagnostics include assessments in basic conditions as well as dynamic tests, such as the high-dose dexamethasone suppression test and corticotrophin releasing hormone (CRH) stimulation test. Treatment selection depends on the type of tumor and its extent. In the case of neuroendocrine tumors, the main treatments are surgery and administration of somatostatin analogues or bilateral adrenalectomy in refractory cases and if the source remains unidentified. Here, we report a case who presented with features of Cushing’s syndrome which eventually through workup led us to a diagnosis of duodenal carcinoid producing ectopic ACTH which is extremely rare and was successfully treated.

Ectopic prolactin production by lung cancer cells as an indicator of aggressive nature of tumors.

e20021 Background: Cancer cells use many unexpected molecular mechanisms to ensure their malignancy, and a comprehensive understanding of cancer cannot be achieved without a global consideration of all oncogenic events. Ectopic activation of tissue-specific hormones accompanies malignant transformation in many cancers. The aim of the study was to determine prolactin (PRL) levels in the blood, tumor and surrounding lung tissues in lung cancer patients of both sexes. Methods: Levels of PRL were measured in the blood and 10% homogenates of the tumor, perifocal tissues and intact lung tissues by radioimmune method using Immunotech kits (Czech Republic). The study included 33 men and 22 women with central and peripheral lung adenocarcinomas (T2-3N0-1M0), mean age 62±3.4 years, all women were menopausal. The comparison group included non-cancer patients (13 men and 12 women) operated on for chronic inflammatory lung diseases. Results: PRL levels in peripheral blood in 74% of men were increased by 3.7 times, and in 85% of women by 5.7 times. Peripheral cancer in men and women had no significant differences in prolactin levels; the hormone distribution was similar in the tumor, perifocal and intact tissues and was on average 1.5 times higher than in lung tissues in patients with inflammatory processes. Women with central cancer were characterized by higher tumor levels of PRL compared to men. In general, both in men and women, PRL levels in perifocal tissues and in intact lung tissue distant from the tumor focus were similar to tumor levels, which could indicate a general change in the organ metabolism, and not a local hormone synthesis by tumor tissues. Conclusions: The detected increase in the PRL content in lung tissues and in the blood may indicate the dysfunction of central regulatory mechanisms and a change in lung metabolism, being one of the links in the causal mechanisms of tumor development.

MON-333 Failure of Medical Therapy to Control Marked Hypercortisolemia by a Metastatic ACTH Producing Neuroendocrine Tumor

Objective: We present a young woman with rapidly progressive Cushing’s syndrome due to ectopic ACTH production from a pancreatic NET. We describe severe neurological and immunosuppressive sequalae of marked hypercortisolemia associated with chemotherapy and reconsider our therapeutic strategy. Case: A previously active and healthy 28 year old woman was admitted with weakness and leg swelling. Two months prior she noticed a petechial rash on her face, back and arms. One week prior she was found to have DM and elevated liver chemistries prompting an abdominal US showing abnormal liver architecture. An outpatient CT showed a 3.7 cm pancreatic mass with liver lesions. Pertinent findings: BP 118/74, rounded facies, acneiform rash and leg edema, WBC 9400/ul, Glucose 173mg/dl, A1C 8.1%, K 2.3meql/L, random cortisol 114ug/dl, ACTH 830pg/ml, Calcitonin 1135 pg/mL, Chromogranin A 1482 ng/mL and Glucagon 276 pg/mL. After a 2 mg DST, 8 AM cortisol was 123 mcg/dL. We planned to reduce her ectopic ACTH production and hypercortisolemia with ketoconazole and chemotherapy followed by bilateral adrenalectomy. FOLFOX protocol reduced ACTH to 76 pg/mL and Cortisol to 73 mcg/dL but she clinically deteriorated, delaying adrenal surgery. She began having muscle weakness, aphasia, and other polyneuropathies. Blood cultures were positive for K. pneuomoniae and she received antibiotics. Cultures were negative for fungemia. Brain MRI showed extensive subcortical changes suggestive of PRES. Cortisol levels increased to 635 mcg/dL! In addition to ketoconazole and spironolactone, mifepristone was started with improvements in her hypokalemia and glucose. Mental status did not improve and repeat MRI showed findings suggestive of multiple abscesses. She was no longer a candidate for further chemotherapy or surgery and died within 40 days of admission. Discussion: Autopsy showed NET with hepatic metastases and multiple organs with fungal hyphae indicating Aspergillus. Both hypercortisolemia and chemotherapy predisposes to opportunistic infections. This patient’s remarkably elevated cortisol levels raised the consideration of urgent adrenalectomy prior to chemotherapy to limit steroid related complications and the polypharmacy required to control this. Both cortisol and chemotherapy impair cell mediated immunity and down regulate pro-inflammatory cytokines providing the opportunity for fungal and other uncommon infections to develop. This patient’s outcome could not have been worse if we elected adrenalectomy as the first therapeutic option to preclude the marked immunosuppressant effects of persisting hypercortisolemia together with chemotherapy. Otherwise, in a patient so profoundly immunosuppressed by endogenous steroids, a multitude of fungi and other atypical infections which are difficult to detect, need be considered when sepsis develops in association with chemotherapy.

MON-332 Metastatic Pancreatic Neuroendocrine Tumor: A Very Rare Cause of Ectopic ACTH Production (ACTHoma)

Introduction Ectopic ACTH syndrome (EAS)is responsible for 10% of Cushing’s syndrome. Multiple tumors, most commonly small cell carcinoma of lung are associated with EAS. Pancreatic neuroendocrine tumors (pNETs) are usually associated with secretion of pancreatic polypeptide, gastrinomas, insulinomas, glucagonomas and vasoactive intestinal peptide (VIPomas). EAS or “ACTHomas” are rarely associated with pNETs. Case 76y/o man with ah/o hairy cell leukemia, bladder cancer (both in remission), and stage M1 unresectable pNET tumor with liver metastases presented with generalized weakness. Discovery of his pNET was incidentally noted during routine surveillance with CT monitoring following successful bladder cancer treatment six years ago. Treatment of his pNET initially began with Everolimus and then switched to Lanreotide injections. No evidence of Cushing’s Syndrome at the time of diagnosis. The lesions remained stable in size and patient was doing well. Physical exam was notable for lethargy, frailty, and absence of Cushingoid features. Labs showed serum glucose 231mg/dl, sodium 141mEq/L, potassium 2.4mEq/L, AM cortisol 116 ug/dL (range 6.7-22.6ug/dl) and ACTH was 209.6pg/mL (range 7.2-63.3pg/mL). Renin-aldosterone levels were normal. Cortisol level did not suppress with low dose or high dose dexamethasone. His hospital course was significant for persistent hypokalemia despite aggressive supplementation, difficult to control blood glucose, and worsening kidney function. EAS with pNET is very refractory to management and may be rapidly progressive. They occasionally demonstrate classic manifestations of Cushingoid features. However, they often lack the traditional phenotypic features of Cushing syndrome. Treatment options for EAS in the setting of an unresectable tumor include medical management versus bilateral adrenalectomy. Metyrapone, a cortisol synthesis inhibitor, can be an effective therapy. Ketoconazole, an antifungal that inhibits cortisol production can be an alternative, but may need weeks to achieve control. Etomodate can rapidly reduce cortisol levels, but requires intensive care monitoring. Somatostatin analogs may be effective by reducing ectopic ACTH production and stabilize tumor growth. Medical versus surgical management of Cushing’s syndrome was discussed with the patient and family, but they opted for hospice care. Conclusion We present a case of pNET associated with late onset EAS without obvious signs of Cushing’s syndrome. To our knowledge this late presentation of ACTH secretion in the setting of a stable pNET has not been previously reported in the literature. EAS due to pNET is rare and metabolic abnormalities can occur rapidly without other Cushingoid manifestations which can pose significant management challenges. High index of suspicion is required for early diagnosis. Due to the aggressive nature, the 5 years survival rate is 16%.

MON-409 Ectopic ACTH Syndrome with a Pituitary Mass

Background: The ectopic ACTH syndrome comprises 10% of Cushing’s syndrome cases. It is associated with an array of both highly malignant and more indolent tumors. Clinical features develop rapidly in ectopic ACTH syndrome. Distinguishing ectopic ACTH production from pituitary ACTH secretion is essential in determining appropriate management and may be challenging in the case of an occult neuroendocrine tumor. Clinical Case: A 46 year-old male presented to the ER after his PCP identified hypokalemia to 1.6 mmol/L (3.5- 5.0 mmol/L). He endorsed two weeks of proximal muscle weakness, lower extremity edema, a retro-orbital headache, and 10lb weight loss. Exam revealed mild facial fullness and pitting edema to the knees. No supraclavicular or dorsal cervical adiposity, violaceous abdominal striae or hyperpigmentation was observed. His blood pressure was elevated at 177/92 and an EKG revealed sinus bradycardia at a rate of 44 bpm. An 8AM cortisol was elevated at 67.4 mcg/dL (2.5-19.5 mcg/dL). ICU admission for blood pressure control and IV potassium supplementation was required. There was concern for Cushing’s disease given an inappropriately elevated ACTH level of 159.3 pg/mL (6-50 pg/mL). However, ectopic ACTH was highly suspected given the rapid development of symptoms and a smoking history of roughly 60 pack yrs. A CT of the chest, abdomen, and pelvis revealed no findings suspicious for malignancy. An MRI brain revealed a 19mm sellar and suprasellar mass atop the pituitary extending superiorly in the supra-diaphragmatic region adjacent to the pituitary stalk with a thickened, enhancing infundibulum. The patient required 60meq TID of oral KCl at discharge. Insulin dependent DMII rapidly developed in the weeks following discharge. An 8mg dexamethasone suppression test was performed with a baseline 8AM cortisol of 88 mcg/dL. Post dexamethasone, 8AM cortisol was 62 mcg/dL. Although these results were not consistent with the 50% reduction in cortisol levels expected by a pituitary adenoma in response to high dose dexamethasone administration, a trans-sphenoidal hypophysectomy was undertaken per patient preference. A pale discohesive tissue was identified intra-operatively which stained for ACTH, consistent with a corticotroph macroadenoma. An Indium-111 pentetreotide scan was negative for evidence of a somatostatin receptor expressing neoplasm. Two months after surgery, early-afternoon cortisol decreased to 7.5 mcg/dL. The patient’s insulin dependence gradually resolved as did his hypokalemia, edema, weakness, and weight loss. Conclusion: We describe an unusual case wherein clinical features of the ectopic ACTH syndrome developed over the course of two weeks in a lifelong smoker. Despite failing an 8mg dexamethasone test, a corticotroph macroadenoma was discovered. There was no identifiable source of ectopic ACTH on an octreotide scan despite a highly suggestible presentation.

SAT-494 A Very Rare Case: Hypercalcemia Caused by Ectopic PTH Secretion in Endometrial Cancer

Up to 40% of cancer patients develop hypercalcemia due to malignancy. Parathyroid hormone related peptide (PTHrP) secretion accounts for >80% of the cases. Here, we describe an unusual case of hypercalcemia due to PTH secretion by endometrial cancer. A 46-year old female presented with nausea, vomiting and right lower quadrant pain. She was noted to be tachycardic, with a pulse of 110 bpm; physical exam was significant only for mild abdominal distention. Laboratory analysis showed a serum calcium of 12.8 mg/dl (8.5-10.5), albumin of 3.8 g/dl (3.5-5), mild transaminitis and normal renal function. A contrasted CT of the abdomen and pelvis revealed a 26 cm right ovarian mass, hypodense lesions throughout the liver, moderate ascites and omental fat nodularity worrisome for ovarian malignancy and peritoneal carcinomatosis. Total abdominal hysterectomy with bilateral salpingo-oophorectomy with biopsy of small bowel mesentery and liver were performed. Pathology showed dedifferentiated endometroid adenocarcinoma with metastasis to the ovaries, liver and small bowel mesentery. Post-operatively, the calcium normalized but then gradually climbed to 12.6 mg/dl despite adequate intravenous hydration. Workup showed a PTH of 135 pg/ml (10-65), PTHrP was undetectable, 25 hydroxyvitamin D and 1,25 dihydroxyvitamin D were normal. Neck ultrasound was negative for an obvious parathyroid adenoma. However, immunohistochemical staining of the surgical pathology was strongly positive for PTH. Pamidronate 30 mg IV was administered. Serum calcium normalized , and the patient was discharged for outpatient neo-adjuvant chemotherapy. Unfortunately, she passed away from septic shock and multi-organ failure a few weeks after diagnosis. Hypercalcemia in malignancy may arise via three distinct mechanisms: (1) humoral hypercalcemia arising from tumor secretion of PTHrP or PTH; (2) osteolytic hypercalcemia from direct skeletal involvement, and (3) over secretion of 1,2 dihydroxyvitamin D. Very rarely, ectopic PTH production has been described in the literature as the cause of humoral hypercalcemia. By 2018, there were only 26 cases in the reported literature. Three were from gynecological cancer, with two related to ovarian cancer. Only one reported case was related to endometroid adenocarcinoma. To our knowledge, this is the second reported case. The presence of hypercalcemia in malignancy has been associated with increased mortality; the survival was two years in patients with mild hypercalcemia versus 1-2 months with more severe hypercalcemia. Though unusual, this case highlights the importance of considering ectopic PTH secretion rather than the default assumption of primary hyperparathyroidism in cancer patients with high calcium and PTH levels.