Mass Spectrometry-Based Proteomic Discovery of Prognostic Biomarkers in Adrenal Cortical Carcinoma

Adrenal cortical carcinoma (ACC) is an extremely rare disease with a variable prognosis. Current prognostic markers have limitations in identifying patients with a poor prognosis. Herein, we aimed to investigate the prognostic protein biomarkers of ACC using mass-spectrometry-based proteomics. We performed the liquid chromatography–tandem mass spectrometry (LC–MS/MS) using formalin-fixed paraffin-embedded (FFPE) tissues of 45 adrenal tumors. Then, we selected 117 differentially expressed proteins (DEPs) among tumors with different stages using the machine learning algorithm. Next, we conducted a survival analysis to assess whether the levels of DEPs were related to survival. Among 117 DEPs, HNRNPA1, C8A, CHMP6, LTBP4, SPR, NCEH1, MRPS23, POLDIP2, and WBSCR16 were significantly correlated with the survival of ACC. In age- and stage-adjusted Cox proportional hazard regression models, only HNRNPA1, LTBP4, MRPS23, POLDIP2, and WBSCR16 expression remained significant. These five proteins were also validated in TCGA data as the prognostic biomarkers. In this study, we found that HNRNPA1, LTBP4, MRPS23, POLDIP2, and WBSCR16 were protein biomarkers for predicting the prognosis of ACC.

Large Invasive Adrenal Cortical Carcinoma in a Patient With Neurofibromatosis Type I

Background: Adrenal cortical carcinoma is a rare neoplasm. Adrenal cortical carcinoma has previously been reported in less than 10 cases of patients with Neurofibromatosis Type I. Clinical Case: A 44-year-old Hispanic man with Neurofibromatosis Type I (NF1) presented with progressive hypoxia, tachypnea and abdominal pain. Intubation was required with 100% FiO2. CT angiogram of the chest and abdomen showed a 9.5 cm left adrenal mass with tumor thrombus in the left adrenal vein, distal left renal vein, IVC extending into the right atrium, suggestive of an adrenocortical carcinoma. Café-au-spots, neurofibromas and Lisch nodules were seen on physical exam but no signs suggestive of a functional adrenal cortical carcinoma. Transthoracic echocardiogram demonstrated a large well circumscribed echo-dense mass filling the right atrial cavity. Hemodynamically he was unstable with labile blood pressures due to right atrium thrombus burden. He was supported pending pheochromocytoma investigation. Biochemical work up revealed an elevated 24-hour free cortisol concentration of 95.9 ug/d (<=60ug/d) with a normal 24-hour urine metanephrine and normetanephrine [140ug/d (55-320ug/d) and 448 ug/d (114-865ug/d]. Plasma free metanephrine level was normal 0.43 (0.00-0.49nmol/L) and the normetanephrine levels was increased at 2.7 (0.00-0.89nmol/L) consistent with stress response. Serum aldosterone level and renin activity with potassium and DHEA-S levels were normal. Once pheochromocytoma was ruled out, he successfully underwent a left nephrectomy, left adrenalectomy, IVC thrombectomy, right atrium thrombectomy under a multidisciplinary team of surgeons. Surgery was well tolerated and he was discharged home 11 days later. Pathology confirmed adrenal cortical carcinoma, stage 4, with involvement of endocardium and left renal vein with mitotic count greater than 20/50 high-power fields, consistent with a high-grade tumor. Summary: Patients with NF1 have a higher predilection to develop tumors including pheochromocytoma, paraganglioma, gastrointestinal stromal tumor, and pancreatic neuroendocrine tumor. NF1 association with adrenal tumors is well known, most commonly pheochromocytomas which occur in 0.1–5.7% of patients with NF1. However, based on a literature search there have been less than 10 case reports which postulate an association between NF1 and ACC. Genetic analysis of these reported cases suggest a loss of heterozygosity at the NF1 locus as a possible explanation of development of ACC in patients with NF1. Conclusion: Adrenal cortical carcinoma is rare but should be considered in a patient with NF1 and adrenal mass when plasma/urine metanephrines are not suggestive of pheochromocytoma.

An Opportunity Missed: Managing an Aggressive Adrenal Cortical Carcinoma

Introduction: Adrenal cortical carcinoma (ACC) is a rare endocrine tumor with an incidence of up to 2 persons per million population. Complete surgical resection is the first-line therapy for localized tumors, while debulking surgery, radiation therapy, and/or chemotherapy may also be options for palliation in advanced ACC. Biochemical and radiographic evaluation of a newly discovered adrenal mass maximizes the opportunity for the patient to undergo a complete, margin-negative resection of the primary tumor, which is the most powerful determinate of long-term survival. Here we present the case of an extremely aggressive high grade adrenal cortical carcinoma that increased from 4 cm to 17 cm within 4 months, metastasizing to the lung, liver and left kidney prior to resection. Case summary: A 42-year-old woman presented to the Emergency Department (ED) with abdominal pain and was found to have hypokalemia and an incidental left adrenal mass measuring 4.9 x 4.6 cm. She was discharged home with instructions to follow up with her primary care physician for further workup. Unfortunately, she was lost to follow-up for 3 months. Her initial biochemical evaluation at follow-up did not show evidence of adrenal insufficiency or elevated metanephrines. A repeat outpatient CT chest abdomen pelvis revealed increased tumor size to 12.3 x 10.8 x 12.5 cm, with unclear renal vs adrenal origin, and multiple liver and lung metastases. She subsequently underwent left radical nephrectomy, adrenalectomy, splenectomy as well as a partial diaphragmatic resection 4 months after her initial ED presentation. The surgical specimen measured 17 x 11.5 x 8 cm. Endocrinology was consulted post-operatively to evaluate for relative adrenal insufficiency given hypotension & altered mental status. Further evaluation revealed new-onset hirsutism, male-pattern hair loss, proximal muscle weakness, and significant weight loss over the prior 3 months. Post-operative laboratory evaluation was significant for sustained hypokalemia of 2.4 mmol/L, 24 hour urine cortisol of 1326 mcg/24 hr (normal 3.5–45), as well as elevated DHEA-S of 994 mcg/dL (normal 27–240), and testosterone of 294 ng/dL (normal 10–75). Surgical pathology demonstrated a high-grade adrenal cortical carcinoma. Oncology was consulted and the patient was started on spironolactone for the hypokalemia, but declined any further therapy for her ACC and subsequently died 2 weeks later. Conclusion: This case illustrates how ACC can behave aggressively and further emphasizes the need for timely and complete biochemical evaluation of adrenal incidentalomas. This is particularly true with the presence of suspicious radiologic features such as size more than 4 cm and heterogeneous appearance. All patients with an adrenal incidentaloma should undergo biochemical and imaging evaluation, guided by thorough history-taking and physical exam, to ensure optimal outcomes.