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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