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.