Hypoglycemia in a Patient with Hypercortisolism and Adrenocortical Carcinoma: A Paradoxical Entity

Background

Adrenal cortical carcinoma (ACC) is a rare but aggressive cancer with an incidence of 0.72 cases per 1 million population per year. ¹ Median age of diagnosis is in fourth to fifth decade of life with female predilection.^2,3 More than 50% of the patient have symptoms related to excess hormone production.^4,5 The majority of ACCs secrete cortisol, manifesting as hyperglycemia and Cushing's syndrome; however, tumor-associated hypoglycemia (termed Anderson's syndrome) due to paraneoplastic secretion of insulin-like-growth factor (IGF)-2 is a paradoxical rare entity reported. ⁶ First described by Daughaday et al. in a patient with leiomyosarcoma with recurrent hypoglycemia, ACC now has been identified in various neuroendocrine tumors, adrenal, hepatocellular, gastrointestinal, and ovarian carcinoma.^7,8 Resection of the tumor is the ultimate management for correction of hypoglycemia and associated hormonal abnormality, but complete resection might not be feasible because of late presentation and progression of malignancy.

In this study, we discuss challenging case of metastatic adrenal carcinoma in young patient.

Case Presentation

Thirty-year-old male with no prior contact with health care presented with worsening left flank pain for 3 months. Tylenol and heating pads at home were not helping with the pain. Blood pressure was 160/90 mmHg, and heart rate was 80 bpm. Abdominal tenderness in left upper quadrant without any rebound tenderness, 3+ of pitting pedal edema was present. There was no moon face, buffalo hump, or abdominal striae. Initial laboratories showed leukocytosis, transaminitis, and hypokalemia (Table 1). Computed tomography (CT) scan of abdomen showed a 12 cm left suprarenal mass with multiple liver and lung metastasis (Fig. 1). Biopsy of a liver lesion showed adrenocortical carcinoma (Fig. 2), special stains were positive for calretinin, Melan A, and synaptophysin. Cytokeratin was negative (Table 2). His hospital course was complicated by refractory hypokalemia, hypertension, and symptomatic hypoglycemic episodes (blood glucose range 20–50 mg/dL). His serum cortisol level was high, failed to be suppressed by dexamethasone. Twenty-four hours urine catecholamines, metanephrines, and dehydroepiandrosterone sulfate (DHEAS) were normal, whereas aldosterone, testosterone, thyroid stimulating hormone, free thyroxine, insulin, proinsulin, and C-peptide levels were suppressed. IGF-2 binding protein came back to be high confirming paraneoplastic hypoglycemia (Table 1). After consultation with oncology and endocrinology, he was urgently started on metyrapone, mitotane, and chemotherapy (cisplatin, doxorubicin, and etoposide) to attempt rapid debulking of tumor. He was also started on hydrocortisone and octreotide to help with hypoglycemia. He was requiring scheduled oral and IV dextrose. He received cornstarch supplements, which helped to stabilize his blood sugar. Although he required multiple antihypertensives, including Aldactone for hypertension initially, later his blood pressure dropped and required addition of fludrocortisone. Surgical approach was considered as inappropriate because of significant metastatic burden and clinical instability. With chemotherapy he had absolute neutropenia and anemia, and required blood transfusion and granulocyte monocyte colony stimulating factor injection. His abdominal pain continued to worsen and his mitotane and metyrapone dose was increased to 1000 and 750 mg three times daily, respectively. Repeat CT scan of abdomen showed unchanged adrenal mass and metastasis. Second cycle of chemotherapy was given. He developed low-grade fever and blood culture grew Enterobacter cloacae. He developed pneumonia and went into hypoxic respiratory failure requiring intubation and mechanical ventilation. Urinary antigen for legionella was positive. He was on broad spectrum antibiotics with moxifloxacin. After multidisciplinary team discussion with the family regarding the prognosis, comfort care measures were applied. Patient died on 62nd day of initial presentation.

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FIG. 1.

CT scan of the abdomen showing left adrenal mass causing compression of spleen and displacement of kidney with extensive multiple metastasis in liver. CT, computed tomography.

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FIG. 2.

Biopsy of liver (A) hematoxylin and eosin stain showing metastatic adrenocortical carcinoma with normal liver tissue and tumor immunohistochemistry; (B) tumor cells positive for synaptophysin; (C) tumor cell positive for Melan A; (D) tumor cell positive for calretinin; (E) tumor cells are negative for cytokeratin (bottom). Cytokeratin positive bile ducts as internal control (top). Color images are available online.

Discussion

ACC are considered to have a significant genetic component with various tumor predisposition syndromes. Li–Fraumeni syndrome with mutation in Tp53 gene, Beckwith–Wiedemann syndrome with mutation in chromosome 11p15, Carney complex with mutation in gene PRKAR1A are known associations. In addition mutation in DNA mismatch repair gene and mutation of beta catenin pathway is also documented. ⁹ Biochemical and clinical evidence of excess adrenocortical hormone production is seen in half of the patients. ¹⁰ High cortisol levels can saturate 11B-hydroxysteroid dehydrogenase (HSD11B2) system, activating mineralocorticoid receptor causing hypertension and hypokalemia with hypercortisolism as seen in our patient. Paraneoplastic syndromes such as hyperreninemic hyperaldosteronism, erythropoietin-associated polycythemia, and leukocytosis are well recognized, whereas hypoglycemia is rare. Hypoglycemia in adrenocortical carcinoma is due to production of IGF-2. It has insulin-like activity activating insulin receptors and promoting glucose uptake. It further causes inhibition of glycogenolysis and gluconeogenesis causing low blood sugar^11,12

European Network for Study of Adrenal Tumor (ENSAT) is now widely adopted staging of ACC-stage 1 and 2 are confined to adrenal gland, stage 3 has locoregional extension, whereas stage 4 represents metastatic disease. ¹³ In total, 25%–30% of patients have metastatic disease at the time of presentation. ³ For every ACC patient, biochemical evaluation guided by clinical presentation is necessary. Dexamethasone suppression test, midnight salivary cortisol, and 24-hour urine cortisol can diagnose and estimate hypercortisolism. ¹⁴ Measurement of plasma renin, aldosterone, and DHEAS should be done to screen for mineralocorticoid activity and hyperandrogenism. DHEAS is considered as the most discriminative marker for ACC when compared with benign tumors. ¹⁵ Exclude pheochromocytoma by measuring metanephrine and normetanephrine in plasma or urine to prevent catecholamine surge during surgery. ¹⁶ IGF-2 measurement will help to diagnose tumor-associated hypoglycemia.

Gold standard treatment of ACC is surgical removal of mass for nonmetastatic disease, but it has remained suboptimal adjuvant therapy.^17,18 Mitotane with adrenolytic activity and specific destruction of inner zones of adrenal cortex is the only United States Food and Drug Administration (FDA) and European medicine executive agency approved drug for treating ACC. ¹⁹ Mitotane can be started as 1 g twice a day and increased by 0.5–1 g every week with target plasma concentration of 14–20 mg/L. Gastrointestinal, neurological, and endocrinological side effects have to be monitored and managed. ³ Cytotoxic chemotherapy with combination of mitotane plus etoposide, doxorubicin, and cisplatin is proven to have a good response rate. ²⁰ Hormonal abnormalities due to both ACC and treatment of ACC can be challenging. In metastatic ACC where surgical removal of mass is not an option, management of hypercortisolism can be difficult, but steroidogenesis inhibitor ketoconazole and metyrapone or direct glucocorticoid antagonist mifepristone can be used. ³ Tumor-associated hypoglycemia can be treated with glucose supplement and glucagon. Glucocorticoid therapy, which stimulates gluconeogenesis and partially suppresses IGF-2, has the most consistent benefit for managing hypoglycemia. Somatostatin analogues can be used in resistant cases. Management with enteral or parenteral nutrition should go side by side.^8,21

Over recent decades our knowledge regarding pathology of ACC has broadened, but it remains as a disease with poor prognosis. With various associated hormonal abnormality and limited available treatment options, management is complicated and challenging.