Summary

We describe a 56-year-old postmenopausal woman with hypertension, hypokalemia and severe alopecia who was found to have a 4.5-cm lipid-poor left adrenal mass on CT scan performed to evaluate her chronic right-sided abdominal pain. Hormonal studies revealed unequivocal evidence of primary aldosteronism and subclinical hypercortisolemia of adrenal origin. Although a laparoscopic left adrenalectomy rendered her normotensive, normokalemic and adrenal insufficient for 2.5 years, her alopecia did not improve and she later presented with facial hyperpigmentation acne, worsening hirsutism, clitoromegaly, and an estrogen receptor-positive breast cancer. Further testing demonstrated markedly elevated serum androstenedione and total and free testosterone and persistently undetectable DHEAS levels. As biochemical and radiologic studies ruled out primary adrenal malignancy and obvious ovarian neoplasms, a bilateral salpingo-oophorectomy was undertaken, which revealed bilateral ovarian hyperthecosis. This case highlights how the clinical manifestations associated with hyperaldosteronism and hypercortisolemia masqueraded the hyperandrogenic findings. It was only when her severe alopecia failed to improve after the resolution of hypercortisolism, hyperandrogenic manifestations worsened despite adrenal insufficiency and an estrogen receptor-positive breast cancer was found, did it becomes apparent that her symptoms were due to ovarian hyperthecosis.

Learning points:

• As cortisol cosecretion appears to be highly prevalent in patients with primary aldosteronism, the term ‘Connshing’ syndrome has been suggested.

• The associated subclinical hypercortisolemia could be the driver for the increased metabolic alterations seen in patients with Conn syndrome.

• The identification of these dual secretors before adrenal venous sampling could alert the clinician about possible equivocal test results.

• The identification of these dual secretors before unilateral adrenalectomy could avoid unexpected postoperative adrenal crises.

• Hyperfunctioning adrenal and ovarian lesions can coexist, and the clinical manifestations associated with hypercortisolemia can masquerade the hyperandrogenic findings.

Summary

We report the case of a 76-year-old male with a remote history of papillary thyroid cancer who developed severe paroxysmal headaches in the setting of episodic hypertension. Brain imaging revealed multiple lesions, initially of inconclusive etiology, but suspicious for metastatic foci. A search for the primary malignancy revealed an adrenal tumor, and biochemical testing confirmed the diagnosis of a norepinephrine-secreting pheochromocytoma. Serial imaging demonstrated multiple cerebral infarctions of varying ages, evidence of vessel narrowing and irregularities in the anterior and posterior circulations, and hypoperfusion in watershed areas. An exhaustive work-up for other etiologies of stroke including thromboembolic causes or vasculitis was unremarkable. There was resolution of symptoms, absence of new infarctions, and improvement in vessel caliber after adequate alpha-adrenergic receptor blockade for the management of pheochromocytoma. This clinicoradiologic constellation of findings suggested that the etiology of the multiple infarctions was reversible cerebral vasoconstriction syndrome (RCVS). Pheochromocytoma remains a poorly recognized cause of RCVS. Unexplained multifocal cerebral infarctions in the setting of severe hypertension should prompt the consideration of a vasoactive tumor as the driver of cerebrovascular dysfunction. A missed or delayed diagnosis has the potential for serious neurologic morbidity for an otherwise treatable condition.

Learning points:

• The constellation of multifocal watershed cerebral infarctions of uncertain etiology in a patient with malignant hypertension should trigger the consideration of undiagnosed catecholamine secreting tumors, such as pheochromocytomas and paragangliomas.

• Reversible cerebral vasoconstriction syndrome is a serious but reversible cerebrovascular manifestation of pheochromocytomas that may lead to strokes (ischemic and hemorrhagic), seizures, and cerebral edema.

• Alpha-adrenergic receptor blockade can reverse cerebral vasoconstriction and prevent further cerebral ischemia and infarctions.

• Early diagnosis of catecholamine secreting tumors has the potential for reducing neurologic morbidity and mortality in patients presenting with cerebrovascular complications.

Summary

A 29-year-old primigravida woman with a known history of primary aldosteronism due to a right aldosteronoma presented with uncontrolled hypertension at 5 weeks of estimated gestation of a spontaneous pregnancy. Her hypertension was inadequately controlled with pharmacotherapy which lead to the consideration of surgical management for her primary aldosteronism. She underwent curative right unilateral adrenalectomy at 19 weeks of estimated gestational age. The procedure was uncomplicated, and her blood pressure normalized post-operatively. She did, however, have a preterm delivery by cesarean section due to intrauterine growth retardation with good neonatal outcome. She is normotensive to date.

Learning points:

• Primary aldosteronism is the most common etiology of secondary hypertension with an estimated prevalence of 5–10% in the hypertensive population.

• It is important to recognize the subtypes of primary aldosteronism given that certain forms can be treated surgically.

• Hypertension in pregnancy is associated with significantly higher maternal and fetal complications.

• Data regarding the treatment of primary aldosteronism in pregnancy are limited.

• Adrenalectomy can be considered during the second trimester of pregnancy if medical therapy fails to adequately control hypertension from primary aldosteronism.

Summary

We report a rare case of concurrent medullary thyroid cancer (MTC) and papillary thyroid cancer (PTC) with intermixed disease in several of the lymph node (LN) metastases in a patient who was subsequently diagnosed with clear cell renal cell carcinoma (RCC). A 56 year old female presented with dysphagia and was found to have a left thyroid nodule and left superior cervical LN with suspicious sonographic features. Fine needle aspiration biopsy (FNAB) demonstrated PTC in the left thyroid nodule and MTC in the left cervical LN. Histopathology demonstrated multifocal PTC with 3/21 LNs positive for metastatic PTC. One LN in the left lateral neck dissection exhibited features of both MTC and PTC within the same node. In the right lobe, a 0.3 cm focus of MTC with extra-thyroidal extension was noted. Given persistent calcitonin elevation, a follow-up ultrasound displayed an abnormal left level 4 LN. FNAB showed features of both PTC and MTC on the cytopathology itself. The patient underwent repeat central and left radical neck dissection with 3/6 LNs positive for PTC in the central neck and 2/6 LNs positive for intermixed PTC and MTC in the left neck. There was no evidence of distant metastases on computed tomography and whole body scintigraphy, however a 1.9 x 2.5 cm enhancing mass within the right inter-polar kidney was discovered. This lesion was highly suspicious for RCC. Surgical pathology revealed a 2.5 cm clear cell RCC, Fuhrman grade 2/4, with negative surgical margins. She continues to be observed with stable imaging of her triple malignancies.

Learning points:

• Mixed medullary-papillary thyroid neoplasm is characterized by the presence of morphological and immunohistochemical features of both medullary and papillary thyroid cancers within the same lesion. Simultaneous occurrence of these carcinomas has been previously reported, but a mixed disease within the same lymph node is an infrequent phenomenon.

• Prognosis of mixed medullary-papillary thyroid carcinomas is determined by the medullary component. Therefore, when PTC and MTC occur concurrently, the priority should be given to the management of MTC, which involves total thyroidectomy and central lymph node dissection.

• Patients with thyroid cancer, predominantly PTC, have shown higher than expected rates of RCC. To our knowledge, this is the first report describing the combination of MTC, PTC, and RCC in a single patient.

Summary

Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of ACTH-independent Cushing syndrome (CS). This condition is characterized by glucocorticoid and/or mineralocorticoid excess, and is commonly regulated by aberrant G-protein coupled receptor expression may be subclinical, allowing the disease to progress for years undetected. Inhibin A is a glycoprotein hormone and tumor marker produced by certain endocrine glands including the adrenal cortex, which has not been previously investigated as a potential tumor marker for PBMAH. In the present report, serum inhibin A levels were evaluated in three patients with PBMAH before and after adrenalectomy. In all cases, serum inhibin A was elevated preoperatively and subsequently fell within the normal range after adrenalectomy. Additionally, adrenal tissues stained positive for inhibin A. We conclude that serum inhibin A levels may be a potential tumor marker for PBMAH.

Learning points:

• PBMAH is a rare cause of CS.

• PBMAH may have an insidious presentation, allowing the disease to progress for years prior to diagnosis.

• Inhibin A is a heterodimeric glycoprotein hormone expressed in the gonads and adrenal cortex.

• Inhibin A serum concentrations are elevated in some patients with PBMAH, suggesting the potential use of this hormone as a tumor marker.

• Further exploration of serum inhibin A concentration, as it relates to PBMAH disease progression, is warranted to determine if this hormone could serve as an early detection marker and/or predictor of successful surgical treatment.

Summary

A patient with atypical partial lipodystrophy who had a transient initial response to metreleptin experienced acute worsening of her metabolic state when neutralizing antibodies against metreleptin appeared. Because her metabolic status continued to deteriorate, a therapeutic trial with melanocortin-4 receptor agonist setmelanotide, that is believed to function downstream from leptin receptor in the leptin signaling system, was undertaken in an effort to improve her metabolic status for the first time in a patient with lipodystrophy. To achieve this, a compassionate use (investigational new drug application; IND) was initiated (NCT03262610). Glucose control, body fat by dual-energy X-ray absorptiometry and MRI, and liver fat by proton density fat fraction were monitored. Daily hunger scores were assessed by patient filled questionnaires. Although there was a slight decrease in hunger scales and visceral fat, stimulating melanocortin-4 receptor by setmelanotide did not result in any other metabolic benefit such as improvement of hypertriglyceridemia or diabetes control as desired. Targeting melanocortin-4 receptor to regulate energy metabolism in this setting was not sufficient to obtain a significant metabolic benefit. However, complex features of our case make it difficult to generalize these observations to all cases of lipodystrophy. It is still possible that melanocortin-4 receptor agonistic action may offer some therapeutic benefits in leptin-deficient patients.

Learning points:

• A patient with atypical lipodystrophy with an initial benefit with metreleptin therapy developed neutralizing antibodies to metreleptin (Nab-leptin), which led to substantial worsening in metabolic control. The neutralizing activity in her serum persisted for longer than 3 years.

• Whether the worsening in her metabolic state was truly caused by the development of Nab-leptin cannot be fully ascertained, but there was a temporal relationship. The experience noted in our patient at least raises the possibility for concern for substantial metabolic worsening upon emergence and persistence of Nab-leptin. Further studies of cases where Nab-leptin is detected and better assay systems to detect and characterize Nab-leptin are needed.

• The use of setmelanotide, a selective MC4R agonist targeting specific neurons downstream from the leptin receptor activation, was not effective in restoring metabolic control in this complex patient with presumed diminished leptin action due to Nab-leptin.

• Although stimulating the MC4R pathway was not sufficient to obtain a significant metabolic benefit in lowering triglycerides and helping with her insulin resistance as was noted with metreleptin earlier, there was a mild reduction in reported food intake and appetite.

• Complex features of our case make it difficult to generalize our observation to all leptin-deficient patients. It is possible that some leptin-deficient patients (especially those who need primarily control of food intake) may still theoretically benefit from MC4R agonistic action, and further studies in carefully selected patients may help to tease out the differential pathways of metabolic regulation by the complex network of leptin signaling system.

Summary

Pheochromocytoma (PHEO) in multiple endocrine neoplasia type 1 (MEN1) is extremely rare. The incidence is reported as less than 2%. We report a case of a 76-year-old male with familial MEN1 who was found to have unilateral PHEO. Although the patient was normotensive and asymptomatic, routine screening imaging with CT demonstrated bilateral adrenal masses. The left adrenal mass grew from 2.5 to 3.9 cm over 4 years with attenuation values of 9 Hounsfield units (HU) pre-contrast and 15 HU post-contrast washout. Laboratory evaluation demonstrated an adrenergic biochemical phenotype. Both ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) PET/CT and ¹²³I-metaiodobenzylguanidine (¹²³I-mIBG) scintigraphy demonstrated bilateral adrenal uptake. In contrast, ¹⁸F-fluorodihydroxyphenylalanine (¹⁸F-FDOPA) PET/CT demonstrated unilateral left adrenal uptake (28.7 standardized uptake value (SUV)) and physiologic right adrenal uptake. The patient underwent an uneventful left adrenalectomy with pathology consistent for PHEO. Post-operatively, he had biochemical normalization. A review of the literature suggests that adrenal tumors >2 cm may be at higher risk for pheochromocytoma in patients with MEN1. Despite a lack of symptoms related to catecholamine excess, enlarging adrenal nodules should be biochemically screened for PHEO. ¹⁸F-FDOPA PET/CT may be beneficial for localization in these patients.

Learning points:

• ¹⁸F-FDOPA PET/CT is a beneficial imaging modality for identifying pheochromocytoma in MEN1 patients.

• Adrenal adenomas should undergo routine biochemical workup for PHEO in MEN1 and can have serious peri-operative complications if not recognized, given that MEN1 patients undergo frequent surgical interventions.

• MEN1 is implicated in the tumorigenesis of PHEO in this patient.

Summary

Adrenocortical carcinoma (ACC) is an aggressive cancer that originates in the cortex of the adrenal gland and generally has a poor prognosis. ACC is rare but can be more commonly seen in those with cancer predisposition syndromes (e.g. Li-Fraumeni and Lynch Syndrome). The diagnosis of ACC is sometimes uncertain and it requires the use of precise molecular pathology; the differential diagnosis includes pheochromocytoma, adrenal adenoma, renal carcinoma, or hepatocellular carcinoma. We describe a case of a 57-year-old woman with Lynch Syndrome and metastatic ACC who was initially diagnosed as having pheochromocytoma. The tumor was first identified at 51 years of age by ultrasound followed by a CT scan. She underwent a left adrenalectomy, and the histopathology identified pheochromocytoma. Two years later, she had tumor recurrence with imaging studies showing multiple lung nodules. Following a wedge resection by video-assisted thoracoscopic surgery (VATS), histopathology was read as metastatic pheochromocytoma at one institution and metastatic ACC at another institution. She later presented to the National Institutes of Health (NIH) where the diagnosis of ACC was confirmed. Following her ACC diagnosis, she was treated with mitotane and pembrolizumab which were stopped due to side effects and progression of disease. She is currently receiving etoposide, doxorubicin, and cisplatin (EDP). This case highlights the importance of using a multi-disciplinary approach in patient care. Thorough evaluation of the tumor’s pathology and analysis of the patient’s genetic profile are necessary to obtain the correct diagnosis for the patient and can significantly influence the course of treatment.

Learning points:

• Making the diagnosis of ACC can be difficult as the differential diagnosis includes pheochromocytoma, adrenal adenoma, renal carcinoma, or hepatocellular carcinoma.

• Patients with Lynch Syndrome should undergo surveillance for ACC as there is evidence of an association between Lynch Syndrome and ACC.

• Conducting a complete tumor immunoprofile and obtaining a second opinion is very important in cases of suspected ACC in order to confirm the proper diagnosis.

• A multi-disciplinary approach including genetic testing and a thorough evaluation of the tumor’s pathology is imperative to ensuring that the patient receives an accurate diagnosis and the appropriate treatment.

Summary

Adrenococortical carcinoma (ACC) is a rare cancer, occurring at the rate of one case in two million person years. Cushing syndrome or a mixed picture of excess androgen and glucocorticoid production are the most common presentations of ACC. Other uncommon presentations include abdominal pain and adrenal incidentalomas. In the present report, a 71-year-old male presented with abdominal pain and was eventually diagnosed with ACC. He was found to have pulmonary thromboembolism following an investigation for hypoxemia, with the tumor thrombus extending upto the right atrium. This interesting case represents the unique presentation of a rare tumor, which if detected late or left untreated is associated with poor outcomes, highlighting the need for a low index of suspicion for ACC when similar presentations are encountered in clinical practice.

Learning points:

• ACC is a rare but aggressive tumor.

• ACC commonly presents with rapid onset of hypercortisolism, combined hyperandrogenism and hypercortisolism, or uncommonly with compressive symptoms.

• Clinicians should have a low index of suspicion for ACC in patients presenting with rapid onset of symptoms related to hypercortisolism and/or hyperandrogenism.

• Venous thromboembolism and extension of the tumor thrombus to the right side of the heart is a very rare but serious complication of ACC that clinicans should be wary of.

• The increased risk of venous thromboembolism in ACC could be explained by direct tumor invasion, tumor thrombi or hypercoagulability secondary to hypercortisolism.

• Early diagnosis and prompt treatment can improve the long-term survival of patients with ACC.

Summary

Mifepristone is a promising option for the management of hypercortisolism associated with hyperglycemia. However, its use may result in serious electrolyte imbalances, especially during dose escalation. In our patient with adrenocorticotropic hormone-independent macro-nodular adrenal hyperplasia, unilateral adrenalectomy resulted in biochemical and clinical improvement, but subclinical hypercortisolism persisted following adrenalectomy. She was started on mifepristone. Unfortunately, she missed her follow-up appointments following dosage escalation and required hospitalization at an intensive care level for severe refractory hypokalemia.

Learning points: