Ectopic Cushing’s Syndrome and Severe Hypocalcemia Due to Medullary Thyroid Cancer Responsive to Selpercatinib

Abstract Introduction: Cushing’s syndrome (CS) due to ectopic ACTH production from medullary thyroid carcinoma (MTC) is characterized by rapid progression of disease, leading to hyperglycemia and hypokalemia. However, hypercortisolemia leading to hypocalcemia is rarely seen. Initiation of selpercatinib greatly improved hypocalcemia and ectopic CS in this case. Clinical Case: A 41-year-old man with a history of MTC (variant RET p.M918T) post thyroidectomy in 2018 developed progressive weight gain, lower extremity edema, weakness, new onset diabetes, severe refractory hypocalcemia and hypokalemia requiring multiple hospitalizations. On initial presentation to our institution, he was lethargic, had multiple ecchymoses, peripheral edema and proximal myopathy. Laboratory evaluation revealed Ca 5.4 mg/dL (NR 8.9 - 10.3), albumin 3 g/dL (NR 3.5 - 5.1), iPTH 1.4 pmol/L (NR 1.6 - 6.9), 25-OH vitamin D 23 pg/mL (NR 25–80) while taking elemental calcium 1500 mg every 6h, calcitriol 0.25 mcg/d and vitamin D3 1000 IU/d. Serum cortisol measured at 9:30 pm was 136 ug/dL (NR 2.5–11.9), ACTH 1,145 pg/mL (NR 7.2–63.3) and 24-h UFC 27,629 ug/d consistent with CS due to ectopic ACTH production. Calcitonin and CEA were 18,687 pg/mL (NR 0–7.5) and 3,766 ng/mL (NR 0–4.7). CT abdomen revealed numerous bilateral liver lesions and bilateral adrenal hyperplasia. In addition to high doses of oral calcium and calcitriol, he required calcium drip up to 1.5mg/kg/hr for about 1 week. He simultaneously began cabozantinib, ketoconazole and metyrapone. Hospital course was complicated by infections and recurrent scrotal bleeding, so he was switched to selpercatinib. Two days after starting selpercatinib, ketoconazole was discontinued, and metyrapone has been gradually reduced. Most recent calcitonin was 149 pg/mL, CEA 97.8 ng/mL and 24-h UFC 10 ug/d on metyrapone 250 mg twice daily. Similarly, refractory hypocalcemia greatly improved, last serum Ca was 8.3 mg/dL on elemental calcium 480 mg/d. He has made significant clinical gains and has returned home from rehab. Clinical Lesson: Hypocalcemia is rarely described as a complication in patients with CS. Our patient had underlying hypoparathyroidism and vitamin D deficiency; however, hypocalcemia was initially refractory to high doses of calcium and calcitriol and only improved with treatment of CS. We suspect hypercortisolemia impaired 25 to 1,25 D activation, thereby reducing calcium absorption, and likely inducing hypercalciuria. These deleterious effects of severe hypercortisolemia combined with underlying hypoparathyroidism led to severe and refractory hypocalcemia requiring repeated admissions, and only improved once his ectopic CS due to MTC was recognized and controlled. The RET kinase inhibitor, selpercatinib, induced a rapid decline in calcitonin, CEA and ACTH levels, and with metyrapone, enabled control of hypercortisolemia and its complications.

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Presentation of a Medullary Endocrine Neoplasia 2A Kindred with Cushing's Syndrome

The American Surgeon ◽

10.1177/000313480807400714 ◽

2008 ◽

Vol 74 (7) ◽

pp. 659-661

Author(s):

Victor Zaydfudim ◽

Daniel G. Stover ◽

Susan W. Caro ◽

John E. Phay

Keyword(s):

Genetic Testing ◽

Thyroid Carcinoma ◽

Medullary Thyroid Carcinoma ◽

Cushing’S Syndrome ◽

Cushing's Syndrome ◽

Ectopic Acth ◽

Medullary Thyroid ◽

Endocrine Neoplasia ◽

Ectopic Acth Production ◽

Men 2A

Although medullary thyroid cancer (MTC) can produce adrenocorticotropic hormone (ACTH) in up to 40 per cent of cases as determined by immunohistochemistry, clinical hypercortisolism is rarely seen. We report a medullary endocrine neoplasia 2A (MEN 2A) kindred whose proband case presented with Cushing's syndrome (CS). This 51-year-old woman presented with debilitating weakness, exertional dyspnea, 50 pound weight gain, moon facies, worsening hypertension, striae, and hirsutism. A comprehensive evaluation diagnosed ectopic ACTH production from unresectable metastatic MTC to the liver. Genetic testing revealed a germline RET proto-oncogene mutation at codon 609. Further genetic testing identified six family members with the same mutation. The patient underwent palliative bilateral laparoscopic adrenalectomies with significant improvement in major comorbidities. Overall CS resulting from ectopic ACTH overproduction by MTC is rare, occurring in 0.6 per cent of all patients with medullary thyroid carcinoma. About 50 cases have been previously reported in the literature, but only three in families with MEN 2A. We describe the first case of a MEN 2A kindred presenting with CS from ectopic ACTH production by metastatic medullary thyroid carcinoma. We advocate consideration of early bilateral laparoscopic adrenalectomies in patients with symptomatic hypercortisolism from unresectable metastatic medullary thyroid carcinoma.

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Cushing's syndrome due to ectopic ACTH production by a nasal paraganglioma

Endocrinology Diabetes and Metabolism Case Reports ◽

10.1530/edm-13-0038 ◽

2013 ◽

Vol 2013 ◽

Cited By ~ 3

Author(s):

F Serra ◽

S Duarte ◽

S Abreu ◽

C Marques ◽

J Cassis ◽

...

Keyword(s):

Cushing’S Syndrome ◽

Microscopic Analysis ◽

Cushing's Syndrome ◽

Ectopic Acth Syndrome ◽

List Type ◽

Rare Tumour ◽

Ectopic Acth ◽

Ectopic Acth Production ◽

The Right

Summary Ectopic secretion of ACTH is an infrequent cause of Cushing's syndrome. We report a case of ectopic ACTH syndrome caused by a nasal paraganglioma, a 68-year-old female with clinical features of Cushing's syndrome, serious hypokalaemia and a right paranasal sinus' lesion. Cranial magnetic resonance image showed a 46-mm mass on the right paranasal sinuses. Endocrinological investigation confirmed the diagnosis of ectopic ACTH production. Resection of the tumour normalised ACTH and cortisol secretion. The tumour was found to be a paraganglioma through microscopic analysis. On follow-up 3 months later, the patient showed nearly complete clinical recovery. Ectopic ACTH syndrome due to nasal paraganglioma is extremely uncommon, as only two other cases have been discussed in the literature. Learning points Ectopic Cushing's syndrome accounts for 10% of Cushing's syndrome etiologies. Most paraganglioma of the head and neck are not hormonally active. Nasal paraganglioma, especially ACTH producing, is a very rare tumour.

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

International Journal of Advances in Medicine ◽

10.18203/2349-3933.ijam20192270 ◽

2019 ◽

Vol 6 (3) ◽

pp. 959

Author(s):

Siddharth Pugalendhi ◽

Tarun Kumar Dutta ◽

Dhivya . ◽

Kiran Yadav

Keyword(s):

Neuroendocrine Tumors ◽

Cushing’S Syndrome ◽

Cushing Syndrome ◽

Somatostatin Analogues ◽

Cushing's Syndrome ◽

High Dose ◽

Ectopic Acth ◽

High Dose Dexamethasone ◽

Ectopic Acth Production ◽

Duodenal Carcinoid

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.

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Cushing’s syndrome due to ectopic ACTH production by (neuroendocrine) prostate carcinoma

Pituitary ◽

10.1007/s11102-008-0100-z ◽

2008 ◽

Vol 12 (3) ◽

pp. 280-283 ◽

Cited By ~ 15

Author(s):

R. A. Alwani ◽

S. J. C. M. M. Neggers ◽

M. van der Klift ◽

M. G. A. Baggen ◽

G. J. L. H. van Leenders ◽

...

Keyword(s):

Cushing’S Syndrome ◽

Prostate Carcinoma ◽

Cushing's Syndrome ◽

Ectopic Acth ◽

Ectopic Acth Production

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Cushing’s syndrome with intermittent ectopic ACTH production

Journal of Endocrinological Investigation ◽

10.1007/bf03349570 ◽

1990 ◽

Vol 13 (4) ◽

pp. 317-326 ◽

Cited By ~ 10

Author(s):

A. van Coevorden ◽

E. Laurent ◽

F. Rickaert ◽

O. van Reeth ◽

E. Van Cauter ◽

...

Keyword(s):

Cushing’S Syndrome ◽

Cushing's Syndrome ◽

Ectopic Acth ◽

Ectopic Acth Production

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Relationship of Ectopic ACTH Production to Tumor Differentiation: A Morphologic and Immunohistochemical Study of Prostatic Carcinoma with Cushing’s Syndrome

The Journal of Urology ◽

10.1016/s0022-5347(17)53938-5 ◽

1982 ◽

Vol 127 (3) ◽

pp. 612-612

Author(s):

M.F. Vuitch ◽

G. Mendelsohn

Keyword(s):

Cushing’S Syndrome ◽

Prostatic Carcinoma ◽

Immunohistochemical Study ◽

Cushing's Syndrome ◽

Tumor Differentiation ◽

Ectopic Acth ◽

Ectopic Acth Production ◽

Relationship Of

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An unusual primary biphasic neuroendocrine carcinoma of lung associated with ectopic ACTH production and Cushing's syndrome

Diagnostic Histopathology ◽

10.1016/j.mpdhp.2014.01.001 ◽

2014 ◽

Vol 20 (2) ◽

pp. 91-94

Author(s):

A. Hamid Kazerouni ◽

J. Neil Walker ◽

Ashley B. Grossman ◽

Runjan Chetty

Keyword(s):

Neuroendocrine Carcinoma ◽

Cushing’S Syndrome ◽

Cushing's Syndrome ◽

Ectopic Acth ◽

Ectopic Acth Production

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ACTH-Dependent Cushing’s Syndrome in an Elderly Woman with Pituitary, Adrenal, and Intrathoracic Lesions

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.215 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A107-A107

Author(s):

Emily A Japp ◽

Alice C Levine

Keyword(s):

Cushing’S Syndrome ◽

Cushing's Syndrome ◽

Middle Lobe ◽

Receptor Expression ◽

Laboratory Evaluation ◽

Ectopic Acth ◽

Case Record ◽

Pet Ct ◽

Free Cortisol ◽

Right Middle Lobe

Abstract A 77-year-old female with rheumatoid arthritis on etanercept, depression on venlafaxine, and treated hypothyroidism presented with easy bruising and muscle weakness. She denied any steroid use. She had normal BP and BMI, but appeared mildly Cushingoid with round facies, and increased dorsocervical and supraclavicular fat. Laboratory evaluation showed: ACTH 70.8 pg/mL (< 63.3), cortisol 24.3 ug/dL, 24 h urine free cortisol 223 ug (< 50), salivary cortisol 0.428 ug/dL, DHEA-S 165.7 ug/dL (< 142.8), LH 0.1 mIU/mL, FSH 2.7 mIU/mL, and hgbA1C 6.1 % (< 5.6 %). All other hormonal testing was normal. MRI of the pituitary showed a 4 x 2 x 3 mm hypoenhancing defect of the anterior pituitary. CT of the chest and abdomen showed a 1.1 cm left adrenal nodule, and a 1 cm non-specific right middle lobe lung nodule. Inferior petrosal sinus sampling (IPSS) with CRH did not show a central ACTH step-up. PET/CT with DOTATATE showed mildly increased tracer uptake in the right middle lobe measuring 1 cm with SUV max 3.7, and a 0.6 cm left apical subpleural nodule with SUV max 1.9. The patient underwent a right middle lobectomy and pathology was positive for typical carcinoid. Post-operatively, she needed hydrocortisone replacement for 9 months. ACTH was 19.7 pg/dL, cortisol 9.5 ug/dL, DHEA-S 31.3 ug/dL, LH 61.8 mIU/mL, and FSH 112.4 mIU/mL. Her Cushingoid features and myopathy resolved. This case highlights several challenges in the diagnosis and source localization in patients with ACTH-dependent Cushing’s Syndrome (CS). In this slim, elderly female, the typical features of CS were subtle. In addition, dynamic biochemical testing with high dose dexamethasone does not reliably distinguish eutopic from ectopic ACTH-dependent CS, as the sensitivity and specificity range from 60–80%. Thus, the diagnosis largely depends on sophisticated imaging and IPSS. The patient had pituitary, adrenal, and lung lesions. The pituitary lesion initially pointed towards a central ACTH source, but IPSS was negative. The prevalence of pituitary incidentalomas is high, at 10.6% based on autopsy data, with an increasing proportion being recognized in the elderly. Adrenal incidentalomas are also often noted in older individuals, but that was clearly not the cause of CS in this patient with a non-suppressed DHEA-S and elevated ACTH. PET/CT with DOTATATE has emerged as a sensitive test for the detection of often small tumors producing ectopic ACTH and was positive in the lung lesion. In spite of newer localization techniques, the source of ectopic ACTH often remains unidentified (12.5% in a large retrospective case-record study). False negatives on PET/CT with DOTATATE imaging may be due to cortisol’s suppressive effect on the somatostatin receptor expression in neuroendocrine tumors. Thus, in cases of ACTH-dependent CS with negative IPSS, ectopic ACTH must remain as a likely source, and be re-explored after medical treatment of the hypercortisolism.

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Ectopic Cushing’s From Metastatic Prostate Cancer

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.1539 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A757-A757

Author(s):

Zachary Bloomer ◽

Jennifer Teague ◽

Nicole Vietor

Keyword(s):

Prostate Cancer ◽

Cushing’S Syndrome ◽

Metastatic Prostate Cancer ◽

Systemic Chemotherapy ◽

Bronchial Carcinoma ◽

Cushing's Syndrome ◽

Ectopic Acth ◽

Ectopic Acth Production ◽

Urine Cortisol ◽

Castrate Resistant

Abstract Objective: Ectopic ACTH production from malignancy is a rare etiology of Cushing’s syndrome. The most common tumors associated with this syndrome include small cell lung cancer, pancreatic neuroendocrine tumors, pheochromoctoma, thymic carcinoma, and bronchial carcinoma. Metastatic prostate cancer does not commonly produce ACTH. Here, we present a rare case of Cushing’s syndrome due to metastatic prostate cancer. Case Report: Patient is a 64 year old man with a 2 year history of castrate-resistant prostate cancer who was admitted for the 2nd time in 1 month for profound weakness and new onset hypokalemia. Initial analysis revealed hypertension with systolic blood pressure in the 150s, potassium in the mid 2s, an ACTH level of >1000pg/mL, and a 24-hr urine cortisol of almost 10,000mcg/24hrs. This was confirmed on repeat analysis. Metyrapone was initiated for treatment of hypercortisolemia and systemic chemotherapy with Cisplatin/Irinotecan was started to treat metastatic prostate cancer. ACTH and 24-hr urine cortisol levels returned to normal within a few weeks of therapy. The patient was able to discontinue Metyrapone following systemic chemotherapy treatment. Subsequent labs following discontinuation of metyrapone confirmed ongoing resolution of hypercortisolemia. Conclusion: This case represents an extremely rare cause of Cushing’s syndrome. Metastatic prostate cancer can rarely produce ACTH and cause clinical Cushing’s syndrome. Ectopic Cushing’s syndrome is often due to very aggressive tumors and is associated with a poor prognosis. Rapid recognition and treatment of this condition can be lifesaving.

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