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Ectopic Acth Syndrome From Metastatic Pancreatic Neuroendocrine Tumor
Richa Handa, MD, and Akhil Rahman, MD (Consultant. 2017;57(8):472-475.)
Ectopic adrenocorticotropic hormone (ACTH) syndrome is a rare disease with a reported incidence of 0.1 cases per million per year. Various cancers can cause ectopic ACTH syndrome. Hypercortisolism (Cushing syndrome) and metabolic changes such as hypokalemia (which is found in almost 70% of cases) and metabolic alkalosis are common in patients with ectopic ACTH syndrome.
Pancreatic neuroendocrine tumors are rare neoplasms with an incidence of 1 case per 100,000 per year. Chromogranin A (CgA) and synaptophysin test results are positive in patients with these tumors. Pancreatic neuroendocrine tumors are also associated with various genetic syndromes such as multiple endocrine neoplasia type 1, von Hippel-Lindau disease, neurofibromatosis, and tuberous sclerosis. Functioning pancreatic neuroendocrine tumors cause clinical syndromes due to hypersecretion of various hormones.
Patients with an ACTH-secreting pancreatic neuroendocrine tumor usually present with liver metastasis, because ACTH released by a pancreatic tumor enters enterohepatic circulation, is rapidly metabolized by the liver, and does not produce any symptoms, whereas ACTH produced by bronchial, ovarian, and other neuroendocrine tumors enters the systemic circulation and results in clinical manifestations earlier, leading to earlier diagnosis. In one case series, 10 patients with hypercortisolism secondary to ectopic ACTH secretion by a pancreatic neuroendocrine tumor were studied; all of them showed liver metastases at presentation. A review of the known 42 cases of pancreatic neuroendocrine tumors associated with hypercortisolism found 88% of patients to have metastases, 60% of whom died in 2 years or less.
We present a case in which a patient presenting with diarrhea eventually received a diagnosis of metastatic neuroendocrine tumor involving the liver, with the primary tumor located in the pancreas.
CASE PRESENTATION
A 51-year-old man with a history of hypertension, insulin-dependent diabetes mellitus, and morbid obesity after gastric bypass surgery presented to the emergency department with a 4-week history of diarrhea, generalized weakness, weight gain, and lower extremity swelling. He had also noticed high blood glucose levels despite having used the prescribed insulin dosage.
The patient had an elevated blood pressure at 182/65 mm Hg, obesity, abdominal distension, and bilateral lower extremity pitting edema. There were no other focal signs.
Results of initial laboratory studies showed severe hypokalemia with a potassium level of less than 1.5 mEq/L (reference range, 3.5-5.0 mEq/L), metabolic alkalosis with a carbon dioxide level of 40 mEq/L (reference range, 22-31 mEq/L), and hypochloremia with a chloride level of 92 mEq/L (reference range, 98-108 mEq/L). The patient’s renal function was within normal range. The albumin level was low at 2.3 g/dL (reference range, 3.5-5.0 g/dL).
The patient’s liver function test results were also abnormal, with an alkaline phosphate level of 249 U/L (reference range, 26-126 U/L), an aspartate aminotransferase level of 74 U/L (reference range, 0-46 U/L), and an alanine aminotransferase level of 69 U/L (reference range, 6-40 U/L). Cortisol levels were also elevated at 101.4 µg/dL (reference range, 5-25 µg/dL) and remained high even after a high-dose dexamethasone suppression test. ACTH levels were elevated at 164 pg/mL (reference range, < 46 pg/mL). Stool test results showed no ova or parasites but were positive for a fat level of more than 100 drops/hpf, and the results of a celiac disease panel were negative.
Computed tomography (CT) scans of the chest and abdomen/pelvis showed innumerable low-attenuation lesions scattered throughout the liver, with the largest measuring up to 5.5 cm in diameter (Figures 1A-1C); the lesions were likely related to metastasis. A questionable lesion was also noticed at the head of the pancreas (Figure 2), and the scan showed bowel-wall thickening involving the proximal descending colon (Figure 3).
The patient underwent colonoscopy, the findings of which were within normal limits. Esophagogastroduodenoscopy with biopsy was also done, the results of which showed ulceration at the gastroenteric anastomosis, but the biopsy results showed no evidence of malignancy. Because of the presence of multiple low-attenuation lesions, the patient also underwent CT-guided liver biopsies, the histology results of which were positive for poorly differentiated large-cell neuroendocrine carcinoma (Figure 4). Liver biopsies were also positive for the neuroendocrine markers CgA, synaptophysin, neuron-specific enolase, and CD56. Cancer antigen 19-9 levels were very high at 2027.9 U/mL (reference range, ≤ 35 U/mL). Carcinoembryonic antigen levels were elevated at 17.7 ng/mL (reference range, 0-5.0 ng/mL).
During the course of hospitalization, the patient remained hypertensive and hypokalemic even after regular potassium replacement. Eventually, the patient was started on chemotherapy because of the extensive liver metastases. Despite the aggressive treatment, the patient died after 3 weeks of hospitalization.
DISCUSSION
The presentation of ectopic ACTH production secondary to a pancreatic neuroendocrine tumor can be very vague and can vary from diarrhea (as in our patient’s case) to life-threatening manifestations such as hypertensive crisis and diabetic ketoacidosis. Pancreatic neuroendocrine tumors usually present with advanced and metastatic disease, which is found in almost 75% of cases. These tumors also have a high recurrence rate, despite resection of the primary lesion, and their secretion of multiple hormones leads to differing clinical manifestations.
Finding the source of ectopic ACTH production sometimes can be difficult because of the small size of the tumor. Approximately 12% to 19% of tumors are not identified despite extensive workup. In our patient’s case, we were able to see multiple small lesions on the liver during imaging, which helped us diagnose the condition. Primary sites usually include the lungs, but cases have been reported in which the primary site has been the pancreas (8%), thymus (11%), mid gut, hind gut, prostate, ovary, uterus, cervix, and thyroid. Approximately two-thirds of the tumors are located in the neck, thorax, and adrenal glands, and only one-third are found in intra-abdominal organs.
The combination of octreotide scan, CT, magnetic resonance imaging, and positron emission tomography scans have been used to localize the tumor. Bilateral inferior petrosal sinus sampling usually shows absent central to peripheral gradient and is considered to be the gold standard for differential diagnosis. In our patient’s case, biochemical tests, imaging, immune cytochemical studies, and cytological studies helped us to diagnose ectopic ACTH syndrome.
Treatment usually involves medical and surgical therapy, given that these tumors have a very high recurrence rate of 30% to 50%. Dopamine agonists, ketoconazole, mitotane, metyrapone, etomidate, and aminoglutethimide have been used to control steroidogenesis. More specific treatment with somatostatin analogues such as octreotide, lanreotide, and pasireotide has also been used. Interferon-alfa, which inhibits angiogenesis, stimulates T cells, and induces cell-cycle arrest, also has been used. Various chemotherapeutic agents such as everolimus (an inhibitor of the mammalian target of rapamycin) and sunitinib and bevacizumab (angiogenesis inhibitors) have also been used. Combination therapy with streptozocin-doxorubicin or streptozocin-fluorouracil has been used with limited success.
Ultimately, palliative care including arterial embolization and radiofrequency ablation of unresectable tumors is the goal of treatment in some patients. Debulking can also be performed to reduce tumor load. Our patient had received a diagnosis of a poorly differentiated large-cell neuroendocrine tumor and had positive test results for CgA and synaptophysin. The patient did not undergo surgical resection because of extensive metastases involving the liver, but he did undergo chemotherapy before his death after 3 weeks of hospitalization.
CONCLUSION
Pancreatic neuroendocrine tumors have variable but sometimes life-threatening manifestations. A high index of suspicion and early diagnosis are important to decrease overall mortality. The diagnosis of neuroendocrine tumors is usually delayed by 7 years from the first symptoms. Prognosis depends mainly on the histology of primary tumor. The 5-year survival rate of patients with pancreatic neuroendocrine tumor is 65%, and the 10-year survival rate is 45%, depending on the stage and grade of the tumor, whereas the survival rate of patients with pancreatic neuroendocrine carcinoma ranges from 1 month to 1 year.
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