Ectopic Hormone Research Articles

THE MYOMATOUS ERYTHROCYTOSIS SYNDROME

Uterine leiomyomas are the most common benign pelvic tumours in females.Rarely they are associated with symptoms of ectopic hormone production. One of thesesyndromes is the myomatous erythrocytosis syndrome, which is a triad of polycythaemia,fibroid(s) and resolution of the polycythaemia after hysterectomy. The case presented is of apost-menopausal lady found to have a Hb of 21 during workup of a pelvic mass. A diagnosis ofsecondary polycythemia due to ectopic erythropoietin production by the fibroid was made. Afterfive sessions of phlebotomiesa target Hb of 15 was obtained for surgery. The haematologicalvalues restored to normal three days post-operatively. It has been postulated that all fibroidsproduce erythropoietin. Recognition and proper management of this condition is importantto differentiate between primary and secondary polycythaemia as primary polycythemiais a thromboembolic condition, to avoid un-necessary investigations and to prevent anycomplications secondary polycythaemia may have per-operatively.

Acromegaly With an Ectopic Clival Pituitary Adenoma

Ectopic pituitary adenomas usually occur within the sphenoid sinus or nasopharynx and seldom within the clivus. In this report, we describe the fourth case of ectopic growth hormone (GH)-secreting adenoma in the clivus. A 49-year-old female patient was admitted with acromegaly and blurred vision. Biochemical evaluation revealed a notable elevation in the GH level at >40 ng/mL (normal range, 0.0 to 5.0 ng/mL). A magnetic resonance imaging scan of the pituitary showed a mass below the sellar turcica. The patient underwent an endoscopic transnasal transsphenoidal approach to the sella, and the tumor in the clivus was completely removed. The tumor was separated from the intrasellar contents by intact bone of the sella. Histologic examinations of the resected tumor showed a chromophobe pituitary adenoma, and immunocytochemistry was positive for GH adenoma. Including our case, only 16 reported ectopic adenomas have occurred in the clivus. Relevant literature is briefly reviewed.

Myasthenia gravis as a presenting feature in a patient with SCLC: A case report

Small cell lung cancer (SCLC) is the most frequent cancer histology associated with paraneoplastic syndromes. These syndromes are typically caused by ectopic hormone production or immune-mediated tissue destruction caused by neural antigen expression from cancer cells. Lambert-Eaton myasthenic syndrome is well known to be a classical paraneoplastic syndrome of small cell lung carcinoma (SCLC).Only a few cases of myasthenia gravis (MG) and SCLC were previously reported. The causal association between lung cancer and non-thymomatous myasthenia gravis has not been clarified yet. To date, there has been no evidence supporting the speculation that association of myasthenia gravis with lung cancer might be one of the phenotypes of paraneoplastic syndrome. We present a case of a 47-year-old male ex-smoker with SCLC associated with myasthenia gravis evidenced by the clinical findings of ptosis, dysphagia, proximal weakness, and positive repetitive nerve stimulation (RNS) test.
 Bangladesh Journal of Neuroscience 2015; Vol. 31 (1): 50-55

Endocrine Paraneoplastic Syndromes: A Review

Paraneoplastic endocrine syndromes result from ectopic production of hormones by different tumors. Hypercalcemia of malignancy is the most common, mostly caused by ectopic parathyroid hormone related peptide (PTHrP) production which increases bone resorption. Other causes include the rare ectopic parathyroid hormone (PTH) production, ectopic production of 1, 25-(OH)2 vitamin D by the tumor and its adjacent macrophages and bone metastasis which by itself in addition to the local production of PTHrP at the level of the bone lead to bone resorption and thus hypercalcemia. Treatment includes extracellular fluid volume repletion, bisphosphonates or denosumab and calcitonin. Ectopic Cushing's syndrome caused by ectopic ACTH production results in hypokalemia, proximal muscle weakness, easy bruisability, hypertension, diabetes and psychiatric abnormalities including depression and mood disorders. Different diagnostic measures help to differentiate Cushing's disease from ectopic Cushing's syndrome. Treatment includes surgical resection of tumor and medical therapy to suppress excess cortisol production. Ectopic secretion of ADH has been associated with different tumor types. The best treatment options include removal of the underlying tumor, chemotherapy, or radiotherapy in addition to free water restriction, demeclocycline and vaptans. Ectopic growth hormone releasing hormone secretion has been identified with carcinoids, phechromocytoma and other tumors. Surgery is the mainstay of therapy with systemic therapy used in metastatic disease. Other rare ectopic hormone syndromes have also been identified including ectopic prolactin, ectopic erythropoietin, and thrombopoetin in addition to others.

A case of insulin and ACTH co-secretion by a neuroendocrine tumour

SummaryA 33-year-old male was diagnosed with a metastatic neuroendocrine carcinoma of uncertain primary. He defaulted from follow-up without therapy and some months later developed episodic severe hypoglycaemia, which was found to be associated with inappropriately elevated insulin and C-peptide levels. It was considered likely that the neuroendocrine tumour was the source of the insulin secretion. Diazoxide and somatostatin analogue were used to control hypoglycaemia. Much later in the course of the disease, he developed metabolic derangement, increased skin pigmentation and psychological disturbance, without frankly Cushingoid physical findings. Investigations revealed highly elevated cortisol levels (the levels having previously been normal) with markedly raised ACTH levels, consistent with the co-secretion of ACTH and insulin by the tumour. Treatment with metyrapone improved his psychological state and electrolyte imbalance. Unfortunately, despite several cycles of first-, second- and third-line chemotherapy from the start of the first hormonal presentation onwards, imaging revealed widespread progressive metastatic disease and the patient eventually passed away. This case highlights the importance of keeping in mind the biochemical heterogeneity of endocrine tumours during their treatment.Learning points The clinical presentation of insulin-secreting tumours includes symptoms of neuroglycopaenia and sympathetic overstimulation.Tumour-associated hypoglycaemia can be due to pancreatic insulinomas, and although ectopic hormone production occurs in a number of tumours, ectopic secretion of insulin is rare.A possible switch in the type of hormone produced can occur during the growth and progression of neuroendocrine tumours and, when treating neuroendocrine tumours, it is important to keep in mind their biochemical heterogeneity.

Thymic Neuroendocrine Carcinoma Producing Ectopic Adrenocorticotropic Hormone and Cushing's Syndrome

Neuroendocrine carcinoma of the thymus, previously termed thymic carcinoid, is a rare clinical entity. Rarer still are such cases presenting with endocrinopathies. We report a case of thymic neuroendocrine carcinoma presenting with ectopic adrenocorticotroic hormone production and resultant Cushing's syndrome.

A case report of an ectopic clival growth hormone adenoma associated with an empty sella and a review of the literature

A case report of an ectopic clival growth hormone adenoma associated with an empty sella and a review of the literature

Approach to Diagnosis and Treatment of Hypercalcemia in a Patient With Malignancy

Hypercalcemia is a common complication of malignancy and portends a worse prognosis. It causes a variety of symptoms in patients, which can range from confusion and polyuria to coma and death. There are 4 broad mechanistic categories to classify hypercalcemia of malignancy: local osteolysis secondary to metastatic cancer or multiple myeloma, excess parathyroid-related hormone, excess 1,25-dihydroxyvitamin D production, and ectopic parathyroid hormone production. Volume expansion with normal saline solution and treatment with intravenous bisphosphonates to decrease osteoclast-mediated bone destruction are effective initial therapies. Calcitonin, gallium nitrate, and corticosteroids can serve as adjunctive therapies. Denosumab is an attractive therapeutic option for refractory cases of hypercalcemia, although more data are required before this therapy can be recommended.

Growth hormone-releasing hormone-producing pancreatic neuroendocrine tumor in a multiple endocrine neoplasia type 1 family with an uncommon phenotype

The objective of this study was to describe a multiple endocrine neoplasia type 1 (MEN1) family characterized by primary hyperparathyroidism, in association with acromegaly because of ectopic growth hormone-releasing hormone (GHRH) secretion by a pancreatic neuroendocrine tumor in a young man and with a bronchial carcinoid in his mother. We investigate the clinical, radiological imaging, histopathologic findings, and therapy. An 18-year-old man successfully underwent subtotal parathyroidectomy for primary hyperparathyroidism. A subsequent genetic analysis showed a MEN1 gene mutation. Three years later, acromegaly because of ectopic GHRH secretion was diagnosed (pituitary MRI negative and elevated GHRH levels). A search for an ectopic tumor was unsuccessful and somatostatin analog therapy was started. Successively, scintigraphy with somatostatin analogs (68-Ga-DOTATOC-PET) showed three focal areas in the pancreatic tail. Distal pancreatectomy showed multiple pancreatic neuroendocrine tumors and hormonal status was normalized. Afterwards, the evaluation of the patient's mother, carrying the same mutation, indicated a primary hyperparathyroidism and a 4 cm lung mass. The patient underwent subtotal pneumonectomy and the histological analysis was consistent with the diagnosis of a typical bronchial carcinoid. In conclusion, an atypical phenotype may be recorded in MEN1 families, thus emphasizing the importance of the new imaging and surgical techniques in the diagnosis and treatment of such a rare disease.

A review of the use of somatostatin analogs in oncology.

Somatostatin is a neuropeptide produced by paracrine cells that are located throughout the gastrointestinal tract, lung, and pancreas, and is also found in various locations of the nervous system. It exerts neural control over many physiological functions including inhibition of gastrointestinal endocrine secretion through its receptors. Potent and biologically stable analogs of somatostatin have been developed. These somatostatin analogs show different efficacy on different receptors, and receptors are varyingly concentrated in specific tissues. Antitumor and antisecretory effects of somatostatin analogs in cancer have been shown in several in vivo and in vitro studies. However, these activities have not always yielded into clinically relevant patient outcome benefit. Somatostatin analogs are of clinical benefit in treating symptoms of ectopic hormone secretion (adrenocorticotropic hormone, growth hormone-releasing hormone) in lung cancer, without inducing a significant tumor response. They have also been shown to induce a statistically significant decrease in bone pain and increase in Karnofsky performance status in patients with metastatic prostate cancer. Somatostatin analogs alone or in combination with other agents have only limited antitumoral effect in breast cancer. In gastrointestinal cancers, studies have not shown an objective tumor response to somatostatin analogs except in endocrine tumors of the liver with symptomatic and biochemical improvement. In neuroendocrine tumors of the gastrointestinal system and pancreas, very high symptomatic and biochemical response rates have been achieved with somatostatin analogs. Antiproliferative activity has been clearly shown in metastatic midgut neuroendocrine tumors.

Ectopic Hypothalamic and Pituitary Hormone Secreting Syndromes

Recognition of the ectopic hormone secretion outside the primary hormone glands and tissues extends to early decades of the 20th century. Although several theories have been pro- posed for this entity, collection of secretory cells possessing the properties of amine precursor uptake and decarboxylation in some tissues and tumors have been the most justified proposal. As none of these theories completely provides a satisfactory explanation, roles played by more than 1 mechanism in the scenario are also probable. The ectopic production and secretion of corticotropin-releasing hormone, growth hormone-releasing hormone, gonadotropin-releasing hormone, adrenocortico- tropic hormone, prolactin, growth hormone, follicle-stimulating hormone, and luteinizing hormone have all been demonstrated in the tumors, as well as in the hyperplastic and chronic in- flammatory tissues outside the endocrine system. This review article focuses on the current available information on ectopic hypothalamic and pituitary hormone secreting syndromes, which may be beneficial for neurosurgeons.

Neuroendocrine Carcinoma of the Thyroid Causing Adrenocorticotrophic Hormone–Dependent Cushing's Syndrome

Cushing's syndrome (CS) due to ectopic adrenocorticotrophic hormone (ACTH) and/or ectopic corticotropic releasing hormone (CRH) secretion accounts for <10% of all CS. Neuroendocrine carcinomas rarely cause CS. These carcinomas have been found to secrete either ACTH or rarely CRH. Herein we report a case of neuroendocrine carcinoma originating from the thyroid as the source of ACTH-dependent CS. A 30-year-old woman with features of CS presented with severe respiratory distress. Six months before that, she was diagnosed with primary hypothyroidism and started on levothyroxine (LT4) therapy. Biochemical evaluation was done, and nonsuppressed serum cortisol levels following dexamethasone with high ACTH confirmed a diagnosis of ACTH-dependent CS. Magnetic resonance imaging of the brain showed a bulky pituitary gland. Adrenal imaging showed bilateral adrenal hyperplasia. A computerized tomography scan showed a large anterior mediastinal mass arising from the neck and extending behind the transverse aortic arch. She underwent emergency thoracotomy due to rapidly progressive superior mediastinal syndrome and left vocal cord palsy. At surgery, the mass was seen originating from the thyroid and the thymus was compressed posteriorly. Near total thyroidectomy and thymectomy with removal of pericardial seedlings were done. Histopathology revealed sheets, cords, and nests of round or oval tumor cells with hyperchromatic nuclei and scant cytoplasm with local invasion and lymphovascular embolization suggestive of a neuroendocrine carcinoma arising from thyroid, staining positive for cytokeratin, synaptophysin, and chromogranin-A, and negative for calcitonin and carcinoembryonic antigen. Here we report a case of a neuroendocrine tumor of the thyroid causing ACTH-dependent CS. The tumor was negative for calcitonin staining, indicating that this was not a medullary carcinoma of the thyroid. Neuroendocrine carcinomas originating from the thyroid gland are very rare. A thyroid tumor of neuroendocrine origin causing ACTH-dependent CS has not been reported previously.

A Case of Ectopic Growth Hormone Releasing Hormone (GHRH) from Pancreatic Neuroendocrine Tumor Resistant to Therapy

Introduction: Ectopic secretion of GHRH is a rare cause of acromegaly. However, its recognition is clinically important because different therapeutic approaches are required. Case Presentation: We present a challenging case of acromegaly secondary to ectopic GHRH secretion from pancreatic neuroendocrine tumor in a 52-year-old female. The patient is treated with different modalities which include pegvisomant in an attempt to control the stimulated GH-axis considering the limited data about its use in treatment of ectopic acromegaly. Conclusion: GHRH-secreting tumor is a rare cause of acromegaly. Surgical resection of the tumor is the therapy of choice whenever possible. However, further studies are warranted for unresectable tumor or resistant cases.

Recurrent Acute-Onset Cushing’s Syndrome 6 Years after Removal of a Thymic Neuroendocrine Carcinoma: From Ectopic ACTH to CRH

We describe a rare case of ectopic Cushing's syndrome that recurred 6 years after resection of a thymic neuroendocrine carcinoma. We discuss reasons for the differing clinical presentations, management, hormone profiles, as well as immunopathology. A 41-year-old male developed acute-onset Cushing's syndrome. Clinical presentation and laboratory results were compatible with ectopic adrenocorticotropin hormone (ACTH) production. Computerized tomography (CT) showed a 3.6 cm thymic tumor which was successfully resected. Plasma ACTH (P-ACTH) normalized the first postoperative day. Histopathology demonstrated a well-differentiated neuroendocrine carcinoma with diffuse positivity for ACTH and focal corticotropin-releasing hormone (CRH) reactivity in a few scattered cells. The patient was in remission for 6 years. He then again presented with acute-onset Cushing's syndrome. Fluorine-labeled dihydroxyphenylalanine ((18)F-DOPA) PET/CT showed local uptake in the mediastinum and he underwent repeat resection. However, P-ACTH remained increased (613 ng/l) and 24-h urinary cortisol was 36,720 nmol, suggesting incomplete tumor removal or metastatic spread. Metyrapone treatment was initiated but then withdrawn because the patient spontaneously recovered and cortisol metabolism gradually normalized within 3 weeks. Histopathology demonstrated a recurrent neuroendocrine carcinoma with the same features as the previous lesion but this time CRH was strongly positive in more numerous cells. Normalization of P-ACTH after primary surgery was compatible with ectopic ACTH production. However, the delayed fall in P-ACTH and serum cortisol is compatible with ectopic CRH production and stimulation of pituitary ACTH secretion, which gradually resolved. Although ectopic CRH production is very rare, the unusual dynamics illustrated here should raise the possibility of CRH production by a neuroendocrine tumor.

Cardiac, Hemorrhagic, and Coagulopathic Oncologic Emergencies

Cardiac, Hemorrhagic, and Coagulopathic Oncologic Emergencies

Ectopic Hormone‐Secreting Pheochromocytoma: A Francophone Observational Study

Ectopic hormone-secreting pheochromocytomas are rare; only case reports exist in the literature. This condition has been linked with increased malignancy, familial syndromes, and ACTH secretion. We wanted to test these hypotheses and shed light on the nature of ectopic hormone-secreting pheochromocytomas. This is a multicenter (francophone) observational study. Inclusion was based upon abnormal preoperative hormone tests in patients with pheochromocytoma that normalized after removal of the tumor. Where possible, immunohistochemistry was performed to confirm that ectopic secretion came from the tumor. Sixteen cases were found: nine female and seven male patients. Median age was 50.5 (range 31-89) years. Most presented with hypertension, diabetes, or cushingoid features. Ten patients had specific symptoms from the ectopic hormone secretion. Two had a familial syndrome. Of eight patients with excess cortisol secretion, three died as a result of the tumor resection: two had pheochromocytomas >15cm and their associated cortisol hypersecretion complicated their postoperative course. The other died from a torn subhepatic vein. The 13 survivors did not develop any evidence of malignancy during follow-up (median 50months). Symptoms from the ectopic secretion resolved after removal of the tumor. Immunohistochemistry was performed and was positive in eight tumors: five ACTH, three calcitonins, and one VIP. Most pheochromocytomas with ectopic secretion are neither malignant nor familial. Most ectopic hormone-secreting pheochromocytoma cause hypercortisolemia. Patients with a pheochromocytoma should be worked up for ectopic hormones, because removal of the pheochromocytoma resolves those symptoms. Associated cortisol secretion needs careful attention.

Ektope Hormonsekretion bei neuroendokrinen Tumoren

Ectopic hormone production is a rare complication in neuroendocrine tumors. Tumors producing corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) are most commonly observed, leading to the classical symptoms of Cushing’s syndrome. Additionally, a very low percentage of neuroendocrine tumors can produce growth hormone-releasing hormone (GHRH) leading to classical features of acromegaly. Moreover, ectopic antidiuretic hormone (ADH) secretion has been described in neuroendocrine tumors presenting as hyponatremia due to the syndrome of inappropriate ADH secretion. Other ectopic hormone secretions, such as paraneoplastic gonadotropin release are rarely observed. Ectopic hormone secretion is not usually associated with a detectable pituitary mass and diagnosis is based on the measurement of circulating peptides. This is frequently assisted by imaging techniques, such as somatostatin receptor scintigraphy. Therapeutically a curative approach is the primary goal but in advanced tumors palliative treatment aims to control symptoms with the help of specific antihormonal compounds, such as somatostatin analogues.

Gastric adenocarcinoma associated with lymphangitis carcinomatosa, adrenal metastasis with ectopic ACTH syndrome and malignant common bile duct stricture

Ectopic adrenocorticotrophic hormone (ACTH) syndrome (EAS) commonly occurs secondary to neuroendocrine tumours and small cell carcinoma of lung. EAS has also been reported in association with gastric carcinoids. But, the occurrence of EAS secondary to gastric adenocarcinoma has rarely been reported. A 45-year-old male patient from Bangladesh presented with abdominal pain, jaundice and hyperpigmentation. Extensive work-up revealed poorly differentiating mucin-secreting adenocarcinoma of stomach with lymphangitis carcinomatosa of lung, bilateral adrenal metastasis and malignant common bile duct (CBD) stricture. Laboratory reports were suggestive for ectopic ACTH production. Most of these features are very rare in adenocarcinoma of stomach, and all these rare events occurring in a single patient is probably the rarest.

Bilateral Simultaneous Laparoscopic Adrenalectomy in Cushing's Syndrome: Safe, Effective, and Curative

Surgical morbidity and mortality rates are high in patients with Cushing's syndrome. Nevertheless, simultaneous bilateral laparoscopic adrenalectomy (LA) is feasible in these patients with less morbidity and good long-term results. Consecutive 22 patients who underwent LA for Cushing's syndrome between 2003 and 2010 in our institute were retrospectively studied. Ninteen patients underwent bilateral simultaneous and three underwent unilateral LA. Seven patients had Cushing's syndrome after failed pituitary surgery and five each had ectopic adrenocorticotrophic hormone dependent syndrome and bilateral macronodular hyperplasia respectively. LA was bilaterally done by lateral transabdominal adrenalectomy in 15 patients and retroperitoneal endoscopic adrenalectomy in 4 on the right side. Mean operative time for simultaneous bilateral cases was 199.45±72.43 minutes with mean blood loss of 72.72±48.6 mL. Patients were fit for discharge by the fifth postoperative day from the surgical aspect. Surgical complication rate was 26% that included wound infections in two, port site hernia, pleural effusion, and atelectasis in one each. One patient died of sepsis (5% mortality). Satisfactory metabolic control was achieved in all observable patients in the long term although Addisonian crisis and Nelson syndrome were seen in 26% and 15% respectively. LA has all advantages of minimal access surgery in patients with Cushing's syndrome who are immunocompromised and at high risk of delayed wound healing and infections. Magnification decreases the risk of retained adrenal remnants. Despite advances in minimal access surgery, perioperative morbidity continues to be significant for the procedure.

Cushing’s Syndrome due to Ectopic ACTH from Bronchial Carcinoid: A Case Report and Review

Despite advances in analytic and imaging techniques, the syndrome of ectopic adrenocorticotrophic hormone (ACTH) secretion from a tumour resulting in Cushing's syndrome continues to pose difficult diagnostic and therapeutic challenges. Dynamic testing may be equivocal and radiology indeterminate. We report a patient presenting with Cushing's syndrome associated with ectopic ACTH secretion from a bronchial carcinoid whose management presented diagnostic and therapeutic challenges.