August 29, 2008
Presentation of a Medullary Endocrine Neoplasia 2A Kindred With Cushing’s Syndrome
By Zaydfudim, Victor Stover, Daniel G; Caro, Susan W; Phay, John E
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. Medullary thyroid carcinoma (MTC) is a rare thyroid malignancy comprising three to five per cent of all thyroid cancers, with fewer than 1000 cases occurring in the United States annually. About 25 per cent of all MTC is associated with multiple endocrine neoplasia/familial medullary thyroid carcinoma hereditary cancer syndromes. Multiple endocrine neoplasia 2A (MEN 2A) is genetically identified by a mutation in the RET proto-oncogene, usually at one of five cysteine residue locations in the extracellular domain of the transmembrane tyrosine kinase.1 These mutations allow activation of tyrosine kinase without prior dimerization. Although genetic testing detects RET mutations with 98 per cent sensitivity and MEN 2A is transmitted as an autosomal dominant trait, only 60 to 70 per cent of the cases present clinically.2 The penetrance of MTC in MEN 2A is nearly 100 per cent, 40 to 50 per cent for pheochromocytomas, and 20 to 30 per cent for parathyroid adenomas with associated hyperparathyroidism.3, 4Medullary thyroid cancer can produce ACTH in up to 40 per cent of cases by immunohistochemistry, however Cushing's syndrome (CS) as a result of medullary thyroid carcinoma is rare. It has been described to occur as a result of ectopic overproduction of adrenocorticotropic hormone (ACTH) or corticotropin releasing hormone in 0.6 per cent of patients with medullary thyroid carcinoma.5 Four previous studies reported hypercortisolism from ectopic ACTH production by MTC in patients with MEN 2 syndrome, however we present the first MEN 2A kindred whose proband case presented with CS. This investigation was reviewed and approved by Vanderbilt University Medical Center Institutional Review Board.
A 51-year-old woman presented with a 1-year history of a 50- pound weight gain, fatigue, abdominal striae, new onset diabetes, hypertension, amenorrhea, lower extremity edema, and depression. Her initial evaluation revealed elevated urine Cortisol at 528 [mu]g/ 24 hours (normal 4-50 [mu]g/24hrs) and elevated ACTH at 172 pg/mL (normal 7-51 pg/mL). Dexamethasone suppression test showed a failure to suppress with a post-dexamethasone urine Cortisol of 658 [mu]g/ 24 hours. Magnetic resonance imaging of the head revealed a normal pituitary gland. Triple-contrast computed tomography imaging of abdomen and pelvis revealed bilateral adrenal gland hyperplasia as well as diffuse hepatic tumor involvement (Fig. 1). A core needle biopsy of her liver tumor demonstrated a neuroendocrine malignancy. With the presumptive diagnosis of metastatic neuroendocrine tumor, the patient was initiated on an intense chemotherapeutic regiment consisting of octreotide, ketoconazole, 5-flourouracil, and streptozosin. After a poor clinical response she was referred to our medical center for further evaluation and treatment.
Further investigation revealed a plasma metanephrine of
The patient's hypercortisolism could not be controlled medically. Her metastatic, ACTH-producing MTC could not be resected. After a multidisciplinary discussion, we felt the patient's best option was bilateral adrenalectomies aimed to remove end-organ production of Cortisol and palliate her symptoms. Bilateral laparoscopic adrenalectomies were performed confirming extensive hepatic involvement with metastatic MTC. Pathologic examination of her adrenals revealed bilateral mildly enlarged glands with diffuse hyperplasia. The patient had an uneventful postoperative recovery and was discharged home on postoperative day 3.
FIG. 1. Triple-phase CT scan demonstrating widespread involvement of the liver by metastatic thyroid cancer (solid black arrowhead) and thickened adrenal glands bilaterally (white arrows).
Since the time of the patient's initial diagnosis, her family has undergone extensive genetic screening and cancer risk counseling. Further testing of her kindred has identified six other family members with the RET proto-oncogene missense mutation at codon 609 (Fig. 2). Five of these family members have undergone total thyroidectomy and central neck compartment lymph node dissection. Three of these patients had medullary thyroid carcinoma localized to the thyroid gland at the time of resection, and two had parathyroid adenomas. The sixth patient is a 2-year-old male and will have a thyroidectomy when he is 5-years-old. The patient described in this report has been enrolled in a Phase II tyrosine kinase inhibitor trial and at the time of preparation of this manuscript had a 10 per cent decline in the size of her hepatic metastases.
Cushing's syndrome due to ectopic ACTH production was first described by Grant Liddle in 1962, but remains a significant diagnostic challenge.6 Smallridge et al.7 summarized a number of previously published series implicating neoplastic ACTH secretion. In their review the following tumors were culprits for ectopic ACTH syndrome: lung cancer (19-50%), carcinoids (5-39%), pancreatic tumors (6-16%), pheochromocytoma (2-25%), and MTC (2-6%).7 Aniszewski et al.8 published a large single center review of CS resulting from ectopic ACTH production and found only 9/106 (8%) patients with medullary thyroid carcinoma. Interestingly in this series all patients with MTC had metastatic disease for 4 to 24 years before onset of CS. Although there is a relative paucity of data, MTC seems to be the only ectopic ACTHproducing tumor in which this phenomenon occurs; all other tumors producing ACTH are known to have CS as a presenting symptom before development of systemic metastases. Another retrospective series from the French tumor registry found 10 patients with ectopic ACTH production among 1637 patients (0.6%) with diagnosed MTC.5 Among these patients 3/10 had MEN 2A, but in two of these patients pheochromocytomas may have been secreting ectopic ACTH.
FIG. 2. Pedigree of MEN 2A kindred. Black arrowhead indicates proband case, who presented with Cushing's syndrome. (HPT, hyperparathyroidism; square: male; circle: female; strikethrough: deceased.)
TABLE 1. Patients with Cushing's Syndrome Secondary to Ectopic ACTH Production in the Setting of MEN 2. Surgical Treatment Column Includes Organs Removed During Treatment.
As such, CS syndrome resulting from ectopic ACTH overproduction by medullary thyroid carcinoma as a part of MEN 2A syndrome is exceedingly rare. Table 1 summarizes four previously published reports of ectopic ACTH production as a result of MEN 2. One of these patients had MEN 2B and had overproduction of corticotropin releasing hormone. Two other patients with MEN 2A had both MTC and pheochromocytoma, the latter being the more likely source for ectopic ACTH. We describe the first family cohort of MEN 2A, whose proband case presented with Cushing's syndrome secondary to ectopic ACTH production by metastatic medullary thyroid cancer. In our patient, diagnosis of metastatic MTC led to genetic screening and identification of Cys609Tyr at codon 609 of RET proto-oncogene, diagnostic for MEN 2A. Once the patient was identified as the proband case, further family screening revealed six other family members with the same mutation. Five out of six family members have already undergone thyroidectomy with central lymph node compartment dissection; the other patient is awaiting his fifth birth year. As a result of the relatively late presentation of Cushing's syndrome in medullary thyroid carcinoma-in this case after unresectable hepatic metastasis-we favor palliative bilateral adrenalectomies aiming for resolution of cortisol-induced side effects. Because ACTH-producing MTC often presents with widely metastatic disease, we contend that palliative bilateral adrenalectomies allow for symptom reduction in patients that may survive for years even with widely metastatic disease. Moreover, a return to physiologic equilibrium would allow the patient to enroll in emerging clinical trials of new molecularly engineered therapies with increased promise of improved patient outcomes.
Supported in part by T32 HS 013833 educational grant (V.Z.) from the Agency for Healthcare Research and Quality, United States Department of Health and Human Services.
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VICTOR ZAYDFUDIM, M.D.,* DANIEL G. STOVER, M.D.,* SUSAN W. CARO, M.S.N., A.P.N.G.,[dagger] JOHN E. PHAY, M.D.*
From the * Department of Surgery, Division of Surgical Oncology and the [dagger] Family Cancer Risk Service, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
The first two authors contributed equally to this manuscript.
Presented at the Annual Scientific Meeting and Postgraduate Course Program, Southeastern Surgical Congress, Birmingham, AL, February 9-12, 2008.
Address correspondence and reprint requests to John Phay, M.D., Department of Surgery, Vanderbilt University Medical Center, 597 Preston Research Building, Nashville, TN 37232-6860. E-mail: [email protected]
Copyright Southeastern Surgical Congress Jul 2008
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