Discussion:
Pancreatic neuroendocrine tumors (P-NETs) are rare with ectopic (ACTH) secretion syndrome an even rarer clinical manifestation with only a few cases reported in the literature. The most common ectopic ACTH‐producing tumors are thoracic (bronchial and thymic) and gastroenteropancreatic (NET), followed by medullary thyroid carcinoma, small cell lung cancer, and pheochromocytoma1. These tumors are clinically distinct from the more common, well differentiated, low or intermediate grade neuroendocrine tumors. There are limited cases of HGNEC diagnosed and reported in the literature, thus there is not standardized staging, classification or treatment regimens at this time. Travis et al. first reported this in 1991 after examining a case series of pulmonary cancers in 35 patients and acknowledged this as a distinct subtype of pulmonary cancer. This classification was sustained until 2015 when it was sub classified as a neuroendocrine carcinoma by the WHO International Classification of Tumours.
The incidence of P-NETs is difficult to categorize due to the fact that most international cancer registries do not collect information on tumor grade, but available data suggests that high grade neoplasms are rare. Registries from Netherlands, United States and Norway suggests an annual incidence between 0.2-0.5 per 100,000 inhabitants1 2, 3. Within the last few decades the incidence is noted to be increasing, but this may coincide with the changes in the nomenclature and classification, resulting in more awareness. Unlike its lung cohort, the risk factors for P-NETs are not well elucidated and more data is being compiled. The largest case series reported a medium overall survival (OS) of 13.2 months and a 3 year OS of 8.7% for all patients1,2. Histopathologically, HGNEC has an architecture consistent with neuroendocrine differentiation. The cells are arranged in an organoid, trabecular or palisading pattern, with prominent necrosis. Evidence of neuroendocrine differentiation is demonstrated by immunoreactivity for chromogranin and synaptophysin3. The mitotic rate tends to be considerably larger than what is seen in atypical carcinoid cells with WHO criteria stating cut off above >10/2 mm23. Our patient had a mitoses rate greater than 40 mitosis per 2 mm E^E.
These tumors have an aggressive natural history constituted by early, rapid widespread metastasis. HGNECs are very difficult malignancies to diagnose due to the subtle presentation1. Ectopic adrenocorticotropic hormone (ACTH) secretion syndrome is a rare clinical manifestation, but is responsible for 15% of all cases of Cushing syndrome4,5. This has been previously well documented in the subset of small cell carcinoma of the lung, but not the pancreatic subset. However, pancreatic islet tumors constitute 1 of the 4 histological subsets (small cell, pheochromocytoma, and carcinoid tumors) of ectopic ACTH-producing tumors and therefore, this possibility can be extrapolated to the neuroendocrine tumor2. Most patients present with a number of cushingoid features to include facial plethora, ecchymoses, muscle weakness, hypertension and laboratory derangements such as severe hypokalemia and glucose intolerance. Our patient presented with clinical features of hirsutism, virilization, hypokalemia and metabolic alkalosis.
The treatment for metastatic P-NETs is difficult to determine due to the general lack of data from prospective trials. Some patients present with potentially resectable metastatic disease and hence may benefit from a combination of chemotherapy and surgical resection. For patients who do not meet this criteria, such as our patient, recommendations are to treat in similar fashion to its cohort, small cell carcinoma. Chemotherapy regimens use in this setting are platinum-based (cisplatin or carboplatin) with etoposide2,3. This regimen has been well established in several retrospective studies as a first line treatment. Recently there have been experimentation with several classes of drugs to include rapamycin (mTOR) inhibitors such as Everolimus, Temozolomide and Capecitabine2. Various treatments are being explored with aim for DNA synthesis interruption by alkylation, pyrimidine analogs or platinum exposure. Recently there has been exploration into molecularly therapies with sunitinib and PD-1 inhibitor Pembrolizumab. Preliminary data suggests that HGNEC are less responsive but if there are high levels of mutations or microsatellite instability, then immunotherapies such as Pembrolizumab should be considered early in the course of the disease6. In our patient, she had multiple complications due to mineralocorticoid excess including severe electrolyte/metabolic derangements, as well as elevated cardiac markers, which increased risk of complications due to cisplatin therapy. Therefore, it was elected to proceed with carboplatin in the palliative setting.
Hormonal hypersecretion plays a large role in tumor morbidity and mortality depending on the type of hormone. Cushing syndrome is a result of excess cortisol release, which can be caused by a number of etiologies to include ectopic ACTH production, as seen in our patient. This can result in a number of systemic issues to include hypertension, myopathy, and osteoporosis, poor wound healing and psychiatric disturbance4. The serum ACTH and cortisol were both very elevated in our patient. In order to control the excessive amount of tumor driven hormone release there are three classes of drugs available for use to include steroidogenesis inhibitors, neuromodulators of ACTH release and glucocorticoid receptor-blocking agents5. Current guidelines suggest steroidogenesis inhibitor mitotane as first line in combination with chemotherapy7. Due to limitations in the Tricare network, many steroidogenesis inhibitors are not readily available including mitotane, metyrapone, and mifepristone. Ketoconazole, used in our patient, works through inhibition of 17-20 desmolase, blockade of 17-hydroxylase, and inhibition of 21- and/or 11-hydroxylase8. Time to peak concentration is around 2 hours9, therefore even though it might take several weeks to achieve full inhibition, Ketoconazole should have a readily available effect.
This case highlights several important clinical implications. Firstly, HGNEC is a rare neoplasm that is often difficult to differentiate. Treatment, while available, is limited and associated with poor outcomes. Secondly, treatment should consist of a multidisciplinary discussion in order to facilitate an effective plan of action for patients with this disease process. Thirdly, although mitotane is the first line adrenolytic therapy, not every facility may have this readily available10. Lastly, the past decade has seen a shift of focus from empiric therapeutic trials to pathological and molecular profiling–based studies that may help define and select patient subtypes that could benefit from subtype-specific treatment.
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