Paraneoplastic Cushing's Syndrome Research Articles

A clinical case demonstrating the challenges in diagnosing and managing Paraneoplastic Cushing's Syndrome

A clinical case demonstrating the challenges in diagnosing and managing Paraneoplastic Cushing's Syndrome

THU527 Metastatic Adenocarcinoma Of The Colon Concealing An ACTH Secreting Neuroendocrine Differentiated Cluster: A Lethal Zebra Within A Trojan Horse

Abstract Disclosure: M. Velasquez: None. S. Shekhar: None. R.M. Goyal: None. Background: Ectopic ACTH secreting tumors are responsible for almost 10% of all cases of Cushing Syndrome. Tumors associated with this entity are most commonly small cell lung, thymic, and pancreatic neuroendocrine tumors. Few cases of colon adenocarcinoma with paraneoplastic ACTH secretion have been reported. They are associated with poor outcomes. Clinical case: A 57-year-old previously healthy male presented with shortness of breath and hypertension. CTA of the chest revealed metastatic liver lesions. CT abdomen and pelvis confirmed metastatic liver lesions with an apple core colonic mass consistent with a primary malignancy. Liver biopsy showed well-differentiated neuroendocrine tumor; tumor cells were negative for CK20, chromogranin, and CD56 but positive for CK7 and synaptophysin. The Ki-67 index was 30%. He was not evaluated for paraneoplastic hormonal secretion and the colonic mass wasn’t biopsied at that time. Ga-DOTATATE scan was negative for somatostatin uptake. He was started on carboplatin-etoposide + dexamethasone (three doses of 4mg each). Two months later presented with large bowel obstruction. Colonoscopy was performed and histopathology demonstrated colonic adenocarcinoma with focal neuroendocrine differentiation with positive CDX2 and negative CK7 and CK20. Synaptophysin was diffusely positive with sparse chromogranin positivity. ACTH stain of the colonic biopsy was negative. Chemotherapy was switched to FOLFORINOX and dexamethasone (one dose of 12mg). After two weeks of being on this regimen, he developed refractory hypokalemia and metabolic alkalosis and was sent to the emergency department. Vitals signs were within normal limits except for mildly elevated blood pressure. Physical examination remarkable for redness of his truncal skin. He did have changes in his handwriting, 0/3 three-word recall, and reduced short term memory. Primary team performed a morning cortisol that was elevated, and endocrinology was consulted. Two repeated 8AM cortisol level and a serum ACTH were found to be elevated. An 8mg overnight dexamethasone suppression test revealed an increase in cortisol. MRI brain showed no evidence of intracranial abnormalities. Refractory hypokalemia due to ectopic ACTH-dependent Cushing syndrome was diagnosed warranting treatment with ketoconazole. Unfortunately, he developed septic shock which led to his demise. Conclusion: This case illustrates a paradoxical rise in serum cortisol levels after dexamethasone suppression test suggesting the presence of positive feedback effects of exogenous corticosteroids on tumor’s ACTH release/production. Recognition of this syndrome is critical to avoid unnecessary use of exogenous glucocorticoids since they could trigger paraneoplastic Cushing syndrome in these patients. Presentation: Thursday, June 15, 2023

Paraneoplastic Cushing syndrome caused by a pancreatic neuroendocrine tumor: a case report

Paraneoplastic Cushing syndrome caused by a pancreatic neuroendocrine tumor: a case report

A Rare Association of Thyroid Medullary Carcinoma with Paraneoplastic Cushing Syndrome: Effects of Multidisciplinary Approach

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Abstract #1325317: Malignant Ovarian Teratoma as Cause of Paraneoplastic Cushing Syndrome

Abstract #1325317: Malignant Ovarian Teratoma as Cause of Paraneoplastic Cushing Syndrome

PSAT387 An Unusual Case of Sporadic Metastatic Medullary Thyroid Cancer Without a Primary Tumor Presenting with Paraneoplastic Cushing's Syndrome

Abstract Introduction Medullary thyroid carcinoma (MTC) accounts for 5-10% of all thyroid cancers and up to 30% of MTCs are hereditary. Only 0.6% of MTCs are associated with a paraneoplastic ACTH-dependent Cushing's syndrome (CS) (PMID: 16029131). Even rarer are MTCs without a primary intra-thyroidal tumor. Here we describe a patient with metastatic MTC without a known primary intrathyroidal tumor presenting with paraneoplastic ACTH-dependent CS. Clinical Case A 47-year-old Ukrainian man was referred to our center for management of metastatic MTC. During evaluation of refractory diarrhea two years earlier, an elevated serum calcitonin (1758 pg/mL, normal: <11.5) led to the diagnosis. Thyroid ultrasound revealed a normal thyroid with bulky cervical lymphadenopathy. Cervical lymph node biopsy revealed metastatic MTC with positive calcitonin, synaptophysin, and chromogranin-A on immunohistochemistry (IHC) and RET protooncogene M918T pathogenic variant on molecular testing. Germline testing for RET pathogenic variants was negative. Prior to referral, the patient was on octreotide to control diarrhea and vandetanib for a few months, but they were discontinued due to financial stress. At our center, patient complained of 4-6 watery bowel movements daily. Physical examination revealed facial plethora, dorsocervical fat pad, central adiposity, wide purple striae, and pustular acne on the chest wall and proximal muscle weakness. Biochemical testing revealed elevated serum calcitonin (158,535 pg/mL, normal: <14.3), carcinoembryonic antigen (3,634 ng/mL, normal: 0.8–6.2), and chromogranin-A (5504 ng/mL, normal<93) levels. Morning serum cortisol (40.4 mcg/dL, normal: 3.7–19.4), and plasma ACTH (116.0 pg/mL, normal: 5.0-46.0) levels were elevated, along with markedly elevated 24-hour urine free cortisol levels (12,460.8 mcg/24-hour, normal: 35-45.0), consistent with ACTH-dependent Cushing's syndrome. Further IHC testing of the tumor biopsy sample revealed mild ACTH positivity. A pituitary MRI was normal. Stool osmolality studies showed a secretory diarrhea pattern. Computed tomography (CT) of neck and torso demonstrated bulky cervical, retroperitoneal, and inguinal lymphadenopathy, and extensive liver metastasis, all of which were strongly avid on an 18-fluorodeoxyglucose positron emission tomography CT scan, but poorly avid on a gallium-68 DOTATATE scan. Sodium fluoride bone scan revealed multiple osseous metastases in the spine, ribs, pelvis, and in the right femoral shaft. An adrenal CT scan revealed bilateral adrenal hyperplasia. The patient was unfortunately not eligible for any ongoing local clinical trials on RET-mutated cancer therapies. After extensive discussion with the patient, a palliative approach was pursued. The cervical lymphadenopathy and right femoral shaft metastasis were treated with external beam radiation. Diarrhea was controlled with loperamide. Cushing's syndrome was initially managed with metyrapone and ketoconazole, followed by bilateral adrenalectomy and hydrocortisone and fludrocortisone replacement. Conclusion Sporadic metastatic MTC can rarely present without an intrathyroidal primary tumor and may originate from ectopic C-cells. Paraneoplastic syndromes such as Cushing's syndrome can be observed in MTC due to ectopic-ACTH production. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Ectopic-Adrenocorticotropic Hormone secretion in adolescents and young adult patients with neuroendocrine neoplasm: a challenge for clinical and social management

Well and poorly differentiated neuroendocrine neoplasms (NENs) may be associated with an ectopic production of Adrenocorticotropic Hormone (ACTH) [1] that leads to a paraneoplastic Cushing Syndrome (CS). This heterogeneous clinical pattern is the result of a hypercortisolism [2] due to an uncontrolled and continuous hyperstimulation of the adrenal cortex, which escapes the negative feedback of the Hypothalamus-Hypophysis axis [3]. Among NENs, ectopic-ACTH secretion (EAS) has been historically associated with small-cell lung cancers (SCLCs), but the improvement of the knowledge and diagnostic techniques led to a broadening of the causes also to NENs with different morphologies and from other sites [4]. According to the previous published data, EAS by gastro-entero-pancreatic (GEP) NENs occurs in almost 13% of cases. Irrespective of the NENs site of origin and the biology (which means morphology and proliferation index), the CS may represent a life-threatening condition for the patients due the consequences of the mineralocorticoid effect of persistent high levels of cortisol. These patients may experience a plethora of different symptoms which includes diffuse oedema, overweight/obesity of the trunk and striae rubrae, but also severe hypokalemia and hypertension, that represent medical emergencies and tumor fatal consequences even without a progression disease [1]. EAS may initially occur with non-specific clinical manifestations, as psychiatric complaints, recurrent orthopedic issues, sexual and reproductive disfunctions [3] that are not easily related to a tumoral cause and lead the patient presents to many specialists before being referred to an endocrinology / oncology Center. For all these reasons, CS diagnosis is often delayed. In a very small pool of cases [5], EAS may occur in the peculiar category of the adolescents and young adults (AYA) patients, worldwide defined as the cancerpopulation between 15 and 39 years of age [6]. Generally, the cancer diagnosis in AYA population is delayed, on one hand due to the sense of invulnerability and the minimizing of the symptoms of AYA patients and, on the other, the trend of the providers to a low suspicion of cancer in AYA population. Therefore, the features of the AYA category together with the equivocal clinical patterns of CS may lead to a delay of the diagnosis and management of EAS by extra-pituitary NENs [3, 7]. Here we reported the case of a NEN AYA patient with CS by EAS and a review of the literature on this topic in this peculiar population.

Paraneoplastic Cushing's syndrome in metastatic poorly differentiated carcinoma of the kidney

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Paraneoplastic Cushing syndrome: Diagnostic and management challenge

Paraneoplastic Cushing syndrome: Diagnostic and management challenge

Paraneoplastic Cushing syndrome: Diagnostic and management challenge

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Paraneoplastic Cushing syndrome: Diagnostic and management challenge

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Lung Carcinoid Tumors and Paraneoplastic Cushing's Syndrome: Diagnostic and Therapeutic Difficulties - A Case Report

Introduction. - Paraneoplastic Cushing's syndrome is a rare cause of endogenous hypercorticism. It is caused by ectopic secretion of ACTH by a non-pituitary endocrine tumor. The aetiological biological and radiological data are often inconclusive, which creates a problem of differential diagnosis with Cushing's disease. In addition, these tumors are often small and their location is extremely variable. As a result, the difficulties of localization require the use of specific imaging techniques.Observation. - We report the observation of a 44-year-old man suffering from diabetes and high blood pressure, presenting a severe and rapidly progressive Cushing syndrome, in connection with a hypercorticism caused by an ectopic ACTH secretion. The thoracic computed tomography performed within the framework of a search for a neoplastic origin objectified a 15 mm nodule isolated at the level of the middle lobe, the scintigraphy with octreotide marked with indium-111 found a significant fixation at the level of the lung nodule. The patient had a middle lobe lobectomy. The outcome was favorable with regression of Cushing's syndrome. Pathological examination was in favor of a typical carcinoid tumor, and the immunohistochemical complement showed tumor cell positivity for ACTH, CD56, chromogranin, and synaptophysin.Conclusion. - This observation illustrates the dilemma between the need to locate an ectopic ACTH secretion and the control of aggressive and threatening Cushing's syndrome. Early use of the octreotide scintigraphy should be considered if a topographic diagnosis of the causative tumor cannot be done through conventional imaging techniques.

Paraneoplastic Cushing Syndrome and Membranous Glomerulonephritis Associated with Small Cell Lung Cancer

Paraneoplastic Cushing Syndrome and Membranous Glomerulonephritis Associated with Small Cell Lung Cancer

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.

68Ga-DOTATOC PET/CT in detecting neuroendocrine tumours responsible for initial or recurrent paraneoplastic Cushing's syndrome.

Paraneoplastic Cushing's syndrome (PCS) is frequently caused by neuroendocrine tumours (NETs). Approximately 20% of tumours are still occult years later. Gallium-68 somatostatin receptor-PET/CT is promising for the detection of the causal primary NET, but its role in case of recurrent PCS is rarely reported. We report our experience with DOTATOC PET/CT in localising the causal NET in cases of initial but also recurrent PCS, and its clinical impact. A retrospective review of all DOTATOC PET/CTs performed in consecutive patients referred for PCS to our centre, between January 2011 and June 2017, was done. Nineteen patients underwent 26 PET/CTs, 13 for detection of a primary NET, seven for persistent or recurrent PCS after resection, and six for surveillance after resection of NETs previously detected on a DOTATOC PET/CT in our centre. Among the 13 PET/CTs performed to search for primary NET, five were positive: four carcinoid lung tumours were confirmed after resection and one lung focus was not confirmed since surgery would have carried a high risk. Clinical impact was 23% (3/13). Among the seven PET/CTs performed for persistent or recurrent PCS, six were true-positive, with confirmation of metastatic lymph nodes after resection. Clinical impact was 57% (4/7). All PET/CTs performed for surveillance were true-negative. DOTATOC PET/CT seems to be a valuable tool for detection of the NET responsible for persistent or recurrent PCS after surgery. In this context, DOTATOC PET/CT was more effective than for the detection of the causal tumour in initial PCS.

Prognostic impact of paraneoplastic syndromes in patients with small cell lung cancer, real-world data.

e20082 Background: Small cell lung cancer (SCLC) remains an aggressive cancer, with a reported mOS of 15-20 mo when localized (L-SCLC) and 9-11 mo when extensive (E-SCLC). Paraneoplastic syndromes (PNS) are a debilitating condition either related to the embryogenic stem cell origin or to auto-immune antibodies produced against the tumor. These mechanisms may be even more relevant with the use of immunotherapy for first-line treatment of E-SCLC. Methods: We retrospectively reviewed our clinical database of patients diagnosed with SCLC between 2006 and 2017 at CHUM University Center. The primary outcome was to compare OS of patients with and without PNS in L-SCLC and E-SCLC. No patients received immunotherapy. Results: We identified 426 unselected SCLC patients, 39% L-SCLC and 61% E-SCLC. 84 patients (20%) were diagnosed with a PNS: 66 (15%) SIADH, 8 (2%) paraneoplastic Cushing syndromes, 2 (1%) humoral hypercalcemia and 8 (2%) paraneoplastic neurologic syndromes. 25% of patients with PNS vs 14% without PNS had a PS 3-4 and would not have been eligible to a clinical trial. 65% of patients with PNS received chemotherapy vs 63% without PNS. Neurologic PNS were all diagnosed in patients with L-SCLC. PNS affecting the central nervous system (4 limbic encephalitis and 1 cerebellar degeneration) were associated with a poorer prognosis than L-SCLC without PNS (mOS 3,5 mo vs 16,7 mo (p = 0,003)). The 2 patients with Lambert-Eaton myasthenic syndrome had a long survival (29 and 82 mo), but persistence of the neurologic symptoms. 86% of patients with paraneoplastic Cushing syndrome were diagnosed with an E-SCLC and had a worse prognosis than E-SCLC without PNS (mOS 1,1 mo vs 4,63 mo (p = 0,022)). SIADH had a significative poor impact on OS in patients with L-SCLC (mOS 10,1 mo vs 16,7 mo (p = 0,016)), but no impact in survival for patients with E-SCLC (mOS 3,63 mo vs 4,63 mo (p = 0,735)). Conclusions: PNS either in patients with L-SCLC or E-SCLC worsen the overall prognosis, except for Lambert-Eaton myasthenic syndrome. A more systematic detection of these syndromes is suggested before starting immunotherapy as first-line standard treatment for E-SCLC. Furthermore, this real-world unselected clinical cohort shows our E-SCLC patients have a worse prognosis than the clinical trial experience.

Illicit Upregulation of Serotonin Signaling Pathway in Adrenals of Patients With High Plasma or Intra-Adrenal ACTH Levels.

In the human adrenal, serotonin (5-HT), released by mast cells stimulates corticosteroid secretion through activation of type 4 serotonin receptors (5-HT4R). In primary pigmented nodular adrenocortical disease cells, activation of the cAMP/protein kinase A (PKA) pathway by PRKAR1A mutations triggers upregulation of the 5-HT synthesizing enzyme tryptophan hydroxylase (TPH) and the 5-HT4, 5-HT6, and 5-HT7 receptors. Because ACTH stimulates cortisol secretion through activation of PKA, adrenocortical tissues exposed to sustained stimulation by ACTH may harbor increased expression of TPH and 5-HT4/6/7 receptors. To investigate the effects of long-term ACTH stimulation on the serotonergic pathway in adrenals of patients with high plasma or intra-adrenal ACTH levels. Adrenal tissues were obtained from patients with Cushing disease, ectopic secretion of ACTH [paraneoplastic Cushing syndrome; (paraCS)], 21-hydroxylase deficiency (21-OHD), primary bilateral macronodular adrenal hyperplasia with intra-adrenal ACTH presence, or cortisol-producing adenomas. TPH and 5-HT4/6/7 receptor expression was investigated using RT-PCR and immunochemistry in comparison with normal adrenals. Primary cultured adrenocortical cells originating from a patient with paraCS were incubated with 5-HT and 5-HTR agonists/antagonists. TPH and/or 5-HT4/6/7 receptors were overexpressed in the different types of tissues. In paraCS cultured cells, the cortisol response to 5-HT was exaggerated compared with normal adrenal cells and the stimulatory action of 5-HT was reduced by 5-HT4R antagonist. Our results indicate that prolonged activation of the cAMP/PKA pathway by ACTH induces an aberrant serotonergic stimulatory loop in the adrenal cortex that likely participates in the pathogenesis of corticosteroid hypersecretion.

Paraneoplastic Cushing's syndrome related to recurrence of a malignant ovarian teratoma

Paraneoplastic Cushing's syndrome related to recurrence of a malignant ovarian teratoma

Case-series of paraneoplastic Cushing syndrome in small-cell lung cancer.

SummaryThe objective of this study is to report three cases of paraneoplastic or ectopic Cushing syndrome, which is a rare phenomenon of the adrenocorticotropic hormone (ACTH)-dependent Cushing syndrome. Three cases are reported in respect of clinical presentation, diagnosis and treatment in addition to relevant literature review. The results showed that ectopic ACTH secretion can be associated with different types of neoplasm most common of which are bronchial carcinoid tumors, which are slow-growing, well-differentiated neoplasms with a favorable prognosis and small-cell lung cancer, which are poorly differentiated tumors with a poor outcome. The latter is present in two out of three cases and in the remaining one, primary tumor could not be localized, representing a small fraction of patients with paraneoplastic Cushing. Diagnosis is established in the setting of high clinical suspicion by documenting an elevated cortisol level, ACTH and doing dexamethasone suppression test. Treatment options include management of the primary tumor by surgery and chemotherapy and treating Cushing syndrome. Prognosis is poor in SCLC. We concluded that in front of a high clinical suspicion, ectopic Cushing syndrome diagnosis should be considered, and identification of the primary tumor is essential.Learning points:Learning how to suspect ectopic Cushing syndrome and confirm it among all the causes of excess cortisol.Distinguish between occult and severe ectopic Cushing syndrome and etiology.Providing the adequate treatment of the primary tumor as well as for the cortisol excess.Prognosis depends on the differentiation and type of the primary malignancy.

Paraneoplastic Cushing's syndrome associated with neuroendocrine tumour of the pancreas: A case report and review of literature

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)