Ectopic corticotropin(ACTH) secretion has been described in case series,most comonly arising from the pancreatic neuroendocrine tumors(NETs) and pulmonary carcinoids ,with very small number of thymic NETs, small cell lung cancer, pheocromocytomas and medullary thyroid cancer. NETs are tumours that mostly involve the gastrointestinal system. Common primary sites in the gastrointestinal system include the pancreas, small intestine, rectum and appendix. Neuroendocrine tumor with the potential to produce various hormones and peptides that cause paraneoplastic syndromes, such as Ectopic Cushing syndrome (ECS). , Diagnose of ECS in neuroendocrine tumor is difficult and has no a good prognosis because of its atypical features and the aggressive nature of the syndrome.
We report the case of a 34-year-old man with ectopic Cushing’s syndrome due to excessive adrenocorticotropic hormone secretion by a neuroendocrine tumor and its liver metastases.
Keywords: Ectopic Cushing’s syndrome,Gastrointestinal system, Neuroendocrine tumour
In 15% of cases, Cushing syndrome is caused by nonpituitary tumors secreting ACTH—the ectopic ACTH syndrome.1Depending on local referral practice, approximately 20% of cases of ectopic ACTH syndrome are induced by indolent tumors, such as benign bronchial carcinoids, that produce ACTH.1,2ECS occurs usually in elderly but some cases reported a sporadic form in young patients. It is rare, appearing in 50% of cases in lung cancer (8–20% in small-cell lung carncer(SCLC),30–46% in carcinoid tumors from which 80% are intrabronchial and rarely in adenocarcinoma), in addition to thymic neoplasms in 15%, pancreatic neuroendocrine tumors, pheochromocytomas , medullary thyroid cancers, unidentified tumors in 12–19% of cases. Less commonly, it is associated with breast, paragangliomas, kidney, esophagus and prostate cancer 3, 5, 7. In contrast to ACTH secretion from pituitary adenomas, ectopic ACTH production is not responsive to normal glucocorticoid feedback6 because of the defective glucocorticoid receptor(GR) or GR-signaling mechanism.7 However, this sensitivity to glucocorticoid feedback is far from clearcut, which is one reason why the differential diagnosis of ACTH-dependent Cushing syndrome can be challenging.
A 34-year-old man presented with unexplained progressive weight loss,depressed mood, facial plethora, back pain and diabetes mellitus from 1 year ago.Physical examination revealed a blood pressure of 130/80 mm Hg, pulse of 88 bpm, moon face, purple striae of abdomen, central obesity, supraclavicular fat pad, proximal muscle weakness of lower extremity and tenderness at L2-L3.
Laboratory testing showed hypokalemia, metabolic alkalosis and increased 24 h urinary free cortisol (4419 mic g per day, normal range:4.3-176). After a 1mg overnight dexamethasone suppression test, serum cortisol was 36mic g/dl(normal, < 1.8). After a low dose dexamethasone suppression test, serum cortisol was still at 14 mic g/dl (normal, < 1.8) and Urinary free cortisol was 140 mic g per day.Plasma ACTH was elevated at 69 pg/ml(normal range: 7.2-63).After a high dose dexamethasone suppression test, urine free cortisol was 4222 mic g per day that suggesting ectopic ACTH-secretion (EAS).
IN order to explain of chronic back pain, the patient underwent a MRI of Lumbar spine that demonstrated compression fracture associated with change of signal intensity represented as decrease signal on T1 and T2W images in the body of L4 vertebrae and compression fracture in anterior aspect of L3,L2 and T12 vertebrae associated with mild change of signal intensity. Whole body bone scan by Tc-99m MDP demonstrated abnormal increase uptake with different intensity in T12 to L5 particularly in L1 and focal uptakes in anterioaspect of right 4th , 5th ribs and left second rib(Fig 1). Patient underwent lumbar biopsy ,and pathology don’t showed any malignancy.Bone mineral densitometry of lumbar was cosistent of osteopenia.
In order to localize the source of ACTH secretion, the patient had an computed tomography(CT) of chest, abdomen and pelvic. Spiral chest CT scan with contrast showed no pulmonary lesion.Spiral abdominal and pelvic(triphasic) CT scan with contrast demonstrated multiple hypodense mass (with maximum size of 64*50mm) in both liver lobe with contrast enhancement and remained hypodense in delayed phase mostly suggestive of metastatic lesion. Pancrease showed normal size and density with sever ductal dilation in body and tail.Pancreatic head and neck was normal and no definite mass are seen in pancrease. Spleen and retropritoneum was normal. Colonoscopy and upper endoscopy neither revealed any pathological findings.MRCP demonstrated pancreatic duct at head and neck had normal size, but at body and tail was not clearly visualized.Multy cystic appearance at projection of body and tail of pancrease in favor of IMPN or chronic pancreatitis was seen.
The patient underwent a percutaneous liver biopsy.Pathological examination of the tissue was consistent of neuroendocrine tumor. Immunohistochemical (IHC) findings were compatible with our diagnose,anti -synaptophysin antibody staining was positive and anti-chromogranin antibody staining was negative(Fig 2).Ki67 reported lower than %1.
A whole body scan by Tc-99m octrotide showed multiple intense and round shape abnormal uptakes in liver parenchyma and there are also two extrahepatic activities beneath the left lobe activity can be due to pancreatic lesions(Fig 3).
During admission, the patient was continued on replacement for hypokalemia and muscle weakness reduced. The patient treated with aclasta, calcium,ketoconazole 800mg/day , Sandostatine LAR and Everolimus .At 2 month follow-up, the patient had regained strength and muscle mass, and did not need further potassium replacement, and felt fine.In addition,after treatment, 24h urinary cortisol level was normal and hydrocortisone 25mg /day was administered.
Ectopic Cushing’s syndrome induced by high levels of ACTH, produced by different types of tumours. These tumours consist of NETs, medullary thyroid cancers,small cell lung carcinomas,islet cell tumors, thymus tumours ,pheochromocytomas and carcinomas of the pancreas.8-11The symptoms intensity depends on the tumour aggressiveness and the serum cortisol levels. The clinical manifestations are different kinds, from incidental diagnosis in asymptomatic patients to cushing syndrome with proximal muscle weakness, striae, skin pigmentation, hypertension, abdominal pain and high susceptibility to infection.12-14
NETs are distributed throughout the body and originate from neuroendocrine cells. They produce various hormones and substances including ACTH. These secretions cause different symptoms and signs. NETs mostly involve the gastrointestinal system and lungs. Gastrointestinal NETs usually involve the pancreas,appendix,small bowel and rectum.8,17,18
NETs have also been observed in other sites such as the prostate,lymph nodes, ovaries and cervix.8,15,17 The clinical presentation of these tumours depends on their location, and the types of substances and hormones they produce. NETs that secret ACTH can cause ectopic Cushing’s syndrome. An CTand octreotide scan are helpful in localising the lesions with ectopic ACTH secretion.In these patients, serum ACTH level is elevated and not suppressed after high dose of dexamethasone. There would be no need for further diagnostic workup in the majority of cases.8
In a number of cases Other diagnostic modalities such as radioguided surgery have been proven helpful.8,11 In radioguided surgery, radiolabelled pentetreotide is injected pre-operatively and positive sites are detected using a gamma counter intra-operatively. NETs have specific immunohistochemistry features. chromogranin A , cytokeratins ,Synaptophysin, , and neuron-specific enolase are usually positive.8,17,18
For the treatment of hypercortisolism medical and surgical methods can be used. Medications such as ketoconazole , aminoglutethimide and metyrapone are effective in symptomatic management , but in patients who do not control with medical management, a bilateral adrenalectomy are preferred.9 It should be noted that despite the presence of liver metastases, resection of NETs is recommended because it can reduce and control symptoms, provides palliation and can improve survival.19
ACTH secreting tumors can be difficult to diagnose, in such cases the first aim is to lower blood cortisol medically or through bilateral adrenalectomy to avoid Cushing’s complications such as severe infections and such patients should then be followed up through imaging studies (CT, MRI, scintigraphy or PET) to detect the tumor and resect it which is the definitive treatment of these patients.
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