Discussion
A literature review reveals a limited number of case reports that
describe the conversion of a non-functional NET into a functional one.
Multiple case series estimate the rate of conversion to be between 3.4%
and 6.8%, but this date is mostly observational [11,12]. The
mechanism behind this conversion remains unclear, although some studies
have shown secondary conversion post-therapy with sunitinib or
traditional chemotherapy [13,14]. These studies suggest epigenetic
conversion of the primary NET, which may occur because of treatment, but
the mechanism is not well described. Among the few treatment options for
malignant insulinoma are Everolimus and Sunitinib. Everolimus inhibits
the MTOR pathway that is a part of insulin-related gluconeogenesis and
is effective as an adjunctive therapy in patients who are not a
candidate for surgical treatment [15]. Sunitinib is a tyrosine
kinase inhibitor that directly inhibits tumor growth, thereby reducing
insulin production, but it can sometimes cause paradoxical hypoglycemia
on its own [13,16].
Our patient was already diagnosed with metastatic pancreatic NET in the
outpatient setting prior to presentation. She had known metastases to
the liver and lungs when she was admitted for management of acute
pulmonary embolism. This tumor
had tested positive for NET tumor markers of synaptophysin and
chromogranin on initial evaluation. It is not common for functional
testing to occur for tumors unless the patient demonstrates any clinical
signs of a functional tumor, which is what this case report
describes. While hospitalized, the patient developed symptomatic
hypoglycemia with decreased blood glucose levels that improved with
glucose administration. These three clinical findings, also known as
Whipple’s triad [4], strongly raised the suspicion for conversion of
the primary pancreatic NET into an insulinoma. Subsequent measurements
of fasting insulin and c-peptide levels confirmed this diagnosis.
Interestingly, our patient did not receive any treatment prior to
conversion and had a much shorter time of conversion than is described
in the literature, 3 months vs. a median of 15 months in other reports
[11]. Due to her metastatic disease prior to conversion, treatment
options remained limited, and our patient’s prognosis was poor. She was
hospitalized numerous times for insulin-related complications and was
not a candidate for any aggressive therapy.
Our case describes one of the few instances of conversion from a
non-functional NET into an insulinoma without any prior treatment and
over a much shorter time frame. It also describes an aggressive clinical
course in these patients due to uncontrolled symptoms related to
hypoglycemia and a paucity of treatment options therein. Traditional
insulinoma treatments, including surgical resection, could have been
utilized, but metastatic disease made this impossible. Newer drugs such
as Everolimus and Sunitinib could have been an option for our patient
but were not an option as the patient declined these treatments. There
may have been some hesitation due to the novelty of these treatments and
a lack of strong evidence in their favor.