RARE-15ACTH-SECRETING PITUITARY CARCINOMA METASTATIC TO THE LIVER IN A PATIENT WITH A HISTORY OF ATYPICAL PITUITARY ADENOMA AND CUSHING'S SYNDROME

Abstract A 49-year old woman with a 5-year history of Cushing's syndrome was evaluated. Biochemical measurements revealed high cortisol and adrenocorticotropic hormone (ACTH) levels consistent with the ACTH-dependent type of Cushing's syndrome. However, the source of ACTH seemed to be autonomous as she demonstrated abnormal feedback control, with lack of response to metyrapone and high doses of dexamethasone. A search for an ectopic ACTH-secreting nonpituitary neoplasm was unsuccessful. Transsphenoidal pituitary exploration revealed a normal pituitary gland, but an ectopic pituitary adenoma was found incidentally in the mucosa of the sphenoid sinus. This adenoma stained strongly positive for ACTH on immunocytochemical studies. Resection of this lesion led to remission of the Cushing's syndrome. This variant of ACTH-dependent Cushing's syndrome can mimic the ectopic ACTH-dependent type and should be looked for in patients who fail to respond to pituitary operation.

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Case report: ACTH-secreting pituitary carcinoma metastatic to the liver in a patient with a history of atypical pituitary adenoma and Cushing’s disease

Diagnostic Pathology ◽

10.1186/s13000-017-0624-5 ◽

2017 ◽

Vol 12 (1) ◽

Cited By ~ 2

Author(s):

Amy S. Joehlin-Price ◽

Douglas A. Hardesty ◽

Christina A. Arnold ◽

Lawrence S. Kirschner ◽

Daniel M. Prevedello ◽

...

Keyword(s):

Case Report ◽

Pituitary Adenoma ◽

Cushing’S Disease ◽

Pituitary Carcinoma ◽

Cushing's Disease ◽

History Of ◽

Atypical Pituitary Adenoma ◽

Acth Secreting

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Arterial thrombosis as primary presentation of endogenous Cushing’s syndrome

BMJ Case Reports ◽

10.1136/bcr-2018-227491 ◽

2019 ◽

Vol 12 (2) ◽

pp. bcr-2018-227491

Author(s):

Vijay Alexander ◽

Maria Koshy ◽

Riddhi Dasgupta ◽

Ronald Albert Carey

Keyword(s):

Cushing’S Syndrome ◽

Arterial Thrombosis ◽

Clinical Manifestations ◽

Dynamic Mri ◽

Cushing's Syndrome ◽

Positron Emission ◽

History Of ◽

Laboratory Investigations ◽

Primary Presentation

Cushing’s syndrome is known to present with a characteristic set of clinical manifestations and complications, well described in literature. However, hypercoagulability remains an under recognised entity in Cushing’s syndrome. A 31-year-old woman from Southern India presented with history of fever, left upper quadrant pain and progressive breathing difficulty for 3 weeks. Clinical examination revealed discriminatory features of Cushing’s syndrome. Laboratory investigations showed biochemical features of endogenous ACTH-dependent Cushing’s syndrome. Imaging of the abdomen revealed splenic collection, left-sided empyema and extensive arterial thrombosis. Gadolinium enhanced dynamic MRI of the pituitary gland revealed no evidence of an adenoma while a Ga-68 DOTATATE positron emission tomography CT scan ruled out an ectopic Cushing’s. A diagnosis of endogenous Cushing’s syndrome causing a prothrombotic state with extensive arterial thrombosis was made. She was initiated on oral anticoagulation and oral ketoconazole for medical adrenal suppression. She subsequently underwent bilateral adrenalectomy and was well at follow-up.

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A Natural History of Adrenocorticotropin-Independent Bilateral Adrenal Macronodular Hyperplasia (AIMAH) from Preclinical to Clinically Overt Cushing's Syndrome.

Endocrine Journal ◽

10.1507/endocrj.48.677 ◽

2001 ◽

Vol 48 (6) ◽

pp. 677-683 ◽

Cited By ~ 20

Author(s):

AKIKO OHASHI ◽

YUYA YAMADA ◽

KATSUHIKO SAKAGUCHI ◽

TORU INOUE ◽

MASAHARU KUBO ◽

...

Keyword(s):

Natural History ◽

Cushing’S Syndrome ◽

Cushing's Syndrome ◽

History Of

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An Immunoperoxidase Study of a Human Pituitary Adenoma Associated with Cushing's Syndrome

Pathology - Research and Practice ◽

10.1016/s0344-0338(84)80026-6 ◽

1984 ◽

Vol 178 (4) ◽

pp. 349-354 ◽

Cited By ~ 2

Author(s):

B. Wowra ◽

J. Peiffer

Keyword(s):

Pituitary Adenoma ◽

Cushing’S Syndrome ◽

Cushing's Syndrome ◽

Human Pituitary ◽

Human Pituitary Adenoma

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Cushing's Syndrome with a Large Pituitary Adenoma Producing both Corticotropin-releasing Hormone (CRH) and Adrenocorticotropin (ACTH).

Internal Medicine ◽

10.2169/internalmedicine.41.549 ◽

2002 ◽

Vol 41 (7) ◽

pp. 549-554 ◽

Cited By ~ 2

Author(s):

Yuya YAMADA ◽

Akiko OHASHI ◽

Toru INOUE ◽

Katsuhiko SAKAGUCHI ◽

Takahiro TSUJIMURA ◽

...

Keyword(s):

Pituitary Adenoma ◽

Cushing’S Syndrome ◽

Cushing's Syndrome ◽

Corticotropin Releasing Hormone ◽

Releasing Hormone

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Levoketoconazole, the 2S,4R Enantiomer of Ketoconazole, a New Steroidogenesis Inhibitor for Cushing’s Syndrome Treatment

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa989 ◽

2021 ◽

Author(s):

Sara G Creemers ◽

Richard A Feelders ◽

Frank H de Jong ◽

Gaston J H Franssen ◽

Yolanda B de Rijke ◽

...

Keyword(s):

Pituitary Adenoma ◽

Cushing’S Syndrome ◽

Cell Number ◽

Cushing's Syndrome ◽

Variable Degree ◽

Acth Secretion ◽

Adrenal Steroid ◽

Liquid Chromatography Tandem Mass ◽

Ic50 Values

Abstract Introduction Racemic ketoconazole (RK) is a steroidogenesis inhibitor used for treatment of Cushing’s syndrome. Levoketoconazole (COR-003), the pure 2S,4R enantiomer, is potentially more potent and safe compared to RK. We compared in vitro effects of levoketoconazole and RK on adrenocortical and pituitary adenoma cells. Materials and methods HAC15 cells and 15 primary human neoplastic adrenocortical cultures (+/- ACTH), and murine (AtT20) and human corticotroph adenoma cultures were incubated with levoketoconazole or RK (0.01-10µM). Cortisol and ACTH were measured using a chemiluminescence immunoassay system, and steroid profiles by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results In HAC15, levoketoconazole inhibited cortisol at lower concentrations (IC50: 0.300µM) compared to RK (0.611µM; P<0.0001). IC50 values of levoketoconazole for basal cortisol production in primary adrenocortical cultures varied over a 24-fold range (0.00578µM to 0.140µM), with in two patients a higher sensitivity of levoketoconazole versus RK (2.1- and 3.7-fold). LC-MS/MS analysis in selected cases revealed more potent inhibition of cortisol and other steroid profile components by levoketoconazole versus RK. In AtT20, levoketoconazole inhibited cell growth and ACTH secretion (10µM: -54% and -38%, respectively), and levoketoconazole inhibited cell number in one of two primary human corticotroph pituitary adenoma cultures (-44%, P<0.001). Conclusion Levoketoconazole potently inhibits cortisol production in adrenocortical cells, with a variable degree of suppression between specimens. Levoketoconazole inhibits adrenal steroid production more potently compared to RK and might also inhibit ACTH secretion and growth of pituitary adenoma cells. Together with previously reported potential advantages, this indicates that levoketoconazole is a promising novel pharmacotherapy for Cushing’s syndrome.

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Prolonged remission after long-term treatment with steroidogenesis inhibitors in Cushing's syndrome caused by ectopic ACTH secretion

Acta Endocrinologica ◽

10.1530/eje-11-0949 ◽

2012 ◽

Vol 166 (3) ◽

pp. 531-536 ◽

Cited By ~ 13

Author(s):

S T Sharma ◽

L K Nieman

Keyword(s):

Cushing’S Syndrome ◽

Cushing's Syndrome ◽

Term Treatment ◽

Sustained Remission ◽

Ectopic Acth ◽

Ectopic Acth Secretion ◽

Free Cortisol ◽

Long Term Treatment ◽

History Of

Spontaneous remission is rare in ectopic ACTH syndrome (EAS). We describe four patients with presumed EAS in whom long-term treatment with steroidogenesis inhibitors was followed by prolonged remission of hypercortisolemia. Biochemical testing was consistent with EAS, but imaging failed to identify a tumor. Patients were treated with ketoconazole alone or with mitotane and/or metyrapone to control hypercortisolemia. Dexamethasone was added when a block and replace strategy was used. Treatment with steroidogenesis inhibitors for 3–10 years in these patients was followed by a prolonged period of remission (15–60 months). During remission, the first patient had an elevated ACTH, low cortisol and 24-h urinary free cortisol (UFC), and adrenal atrophy on computerized tomography scan during remission, suggesting a direct toxic effect on the adrenal glands. Cases 2 and 3 had normal to low ACTH levels and low-normal UFC, consistent with an effect at the level of the ectopic tumor. They did not have a history of cyclicity and case 3 has been in remission for ∼5 years, making cyclic Cushing's syndrome less likely. Case 4, with a history of cyclic hypercortisolism, had normal to slightly elevated ACTH levels and low-normal UFC during remission. The most likely etiology of remission is cyclic production of ACTH by the ectopic tumor. Spontaneous and sustained remission of hypercortisolemia is possible in EAS after long-term treatment with steroidogenesis inhibitors; a drug holiday may be warranted during chronic therapy to evaluate this. The pathophysiology remains unclear but may involve several different mechanisms.

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ACTH-Producing Thymic Carcinoid: A Rare Cause of Cushing’s Syndrome

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.2025 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A990-A990

Author(s):

Lisette Patricia Rodriguez ◽

Wende Michele Kozlow

Keyword(s):

Cushing’S Syndrome ◽

Mediastinal Mass ◽

Cushing's Syndrome ◽

Anterior Mediastinal Mass ◽

Thymic Carcinoid ◽

Acth Secretion ◽

Ectopic Acth ◽

Ectopic Acth Secretion ◽

History Of

Abstract Background: Thymic carcinoids are rare neoplasms that account for less than 5% of all thymic tumors. Approximately 25% of these tumors will result in Cushing’s syndrome due to ectopic ACTH secretion. These tumors can also be associated with MEN1 syndrome. This is a case report of a patient with history of macroprolactinoma now presenting with Cushing’s syndrome due to ectopic ACTH production from a thymic carcinoid tumor. Clinical Case: This is a 57 year old male with history of pituitary macroprolactinoma diagnosed in 2011, now status post transsphenoidal resection and external beam radiation therapy, with persistent hyperprolactinemia on cabergoline, who presented to our clinic for a routine follow up visit. Patient had already developed secondary hypogonadism and secondary hypothyroidism as a consequence of treatment for the macroprolactinoma. He complained of worsening fatigue and weight gain ongoing for several months. Laboratory studies revealed an hemoglobin A1c of 8.3% (nl < 5.7%), TSH 0.24 MIU/L (0.4-4.5 MIU/L), free T4 1.2 ng/dL (0.8-1.8 ng/dL), 8 AM cortisol 31.4 mcg/dL (4-22 mcg/dL), ACTH 185 pg/mL (6-50 pg/dL), prolactin 29.6 ng/mL (2-18 ng/mL), IGF-1 88 ng/mL (50-317 ng/mL). Follow up labs confirmed cushings syndrome: cortisol AM-DST 36.4 mcg/dL (< 2 mcg/dL), free urinary cortisol 291.9 mcg/24h (2-50 mcg/24h). Pituitary MRI showed empty sella turcica. Cortisol after an 8 mg DST 32.5 mcg/dL (< 5 mcg/dL). CT chest, abdomen and pelvis revealed an heterogeneously enhancing solid anterior mediastinal mass measuring 4.9 x 3.1 x 4.3 cm. Whole body OctreoScan showed a markedly hyperintense large mass adjacent to the right heart border measuring 47 x 32 mm. He was referred to cardiothoracic surgery and underwent a right video-assisted thoracic surgery with resection of the anterior mediastinal mass. Pathology revealed a thymic well-differentiated neuroendocrine tumor with strong cytoplasmic staining for ACTH. It was also positive for OSCAR, Cam5.2, synaptophysin, CD56, and S100. Ki67 stain was positive in fewer than 1% of tumor cells. Final diagnosis was carcinoid tumor. Conclusion: Cushing’s syndrome secondary to ectopic ACTH secretion from a thymic carcinoid is rare. The presence of two MEN1-associated tumors in this patient, macroprolactinoma and thymic carcinoid, is highly suggestive of a clinical diagnosis of MEN 1.

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Pleurihormonal Pituitary Adenomas Presenting as Acromegaly

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.1227 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A602-A602

Author(s):

Megan Schwehr ◽

Mayumi Endo

Keyword(s):

Pituitary Adenoma ◽

Cushing’S Syndrome ◽

Cushing’S Disease ◽

Pituitary Adenomas ◽

Brain Mri ◽

Fatty Infiltration ◽

Cushing's Syndrome ◽

Cushing's Disease ◽

Peripheral Muscle ◽

Suppression Test

Abstract Background: Pleurihormonal pituitary adenomas represent 10-15% of all functioning pituitary adenomas1. One of the rarest combinations is ACTH-GH co-secretion with concomitant acromegaly and Cushing’s disease. Clinical Case: 30-year-old female with type 2 diabetes (A1c 11.4%) developed rapidly progressive peripheral neuropathy. Labs revealed a transaminitis. Hepatic ultrasound revealed fatty infiltration of the liver consistent with steatosis. Patient endorsed life-long “chicken legs”, buffalo hump, and easy bruising. She continued to have worsening paresthesias and stated her teeth were “more translucent”. At an endocrinology visit peripheral muscle wasting, atraumatic bruising at the ankles and toes,and striae on the abdomen, shoulders, breasts, and armpits were noted. She had also noted teeth separation and thinning over time and worsening diffuse joint aches. Lab results showed elevated cortisol value of 8.4 mcg/dl after 1 mg dexamethasone suppression test. 24-hour urine cortisol was elevated (87 ug/24 hrs, nl < 45 ug/24 hrs), confirming the diagnosis of Cushing’s syndrome. ACTH was inappropriately normal (56 pg/mL, nl 7.2 – 63 pg/mL), suggesting ACTH dependency. IGF-1 was elevated twice (328 ng/dL and 391 ng/dL, nl <303 ng/dL), and a GH suppression test was abnormal (GH 1.14 ng/mL at 90 minutes) confirming the diagnosis of acromegaly. Brain MRI revealed a cystic pituitary microadenoma (0.5 x 0.5 x 0.6 cm), and the patient underwent surgical resection via transnasal transsphenoidal pituitary surgery with total tumor removal. Immunostaining was positive for only synaptophysin and ACTH. Postoperative diagnosis of Cushing’s disease was made, with formal diagnosis of acromegaly pending improvement in follow-up IGF-1 levels. Literature reviews have revealed very few cases of pleurihormonal pituitary adenomas presenting with concomitant Cushing’s Syndrome and acromegaly. Roca et. al examined 17 studies which described 20 patients with this condition; only 4 presented with symptoms of both acromegaly and Cushing’s disease. In many cases previously reported, the clinical presentation of Cushing’s syndrome was subtle, often with subclinical Cushing’s syndrome, while patients had florid symptoms of acromegaly.1. Conclusion: This Cushing’s predominant case of a GH-ACTH co-secreting tumor is an incredibly rare presentation for this pleurihormonal pituitary adenoma, which is already a rare diagnosis. References: 1.Roca E, Mattogno PP, Porcelli T, Poliani L, Belotti F, Schreiber A, Maffezzoni F, Fontanella MM, Doglietto F. Plurihormonal ACTH-GH Pituitary Adenoma: Case Report and Systematic Literature Review. World Neurosurg. 2018 Jun;114:e158-e164. PMID: 29501516.

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