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\begin{document}

\title{Metastatic Insulinoma: A Case of Conversion from a Non-Functional
Neuroendocrine Tumor}



\author[1]{Venkata Srihari Buddhavarapu}%
\author[2]{Gagandeep Dhillon}%
\author[3]{Harpreet Singh Grewal}%
\author[1]{Brian Soles}%
\author[4]{Luke Halbur}%
\author[5]{Salim Surani}%
\author[6]{Rahul Kashyap}%
\affil[1]{Banner Baywood Heart Hospital}%
\affil[2]{BWMC}%
\affil[3]{Florida State University College of Medicine}%
\affil[4]{Ironwood Cancer and Research Centers}%
\affil[5]{Texas A\&M University System}%
\affil[6]{WellSpan Health}%


\vspace{-1em}



  
  \date{May 20, 2024}


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\textbf{Introduction}

Pancreatic neuroendocrine tumors are a subset of Neuroendocrine tumors
(NET) that mainly originate from the neuroendocrine system. They account
for less than 10\% of total NETs and have a general incidence of 0.5 per
100,000 persons per year {[}1{]}. Only 10 to 30\% of these tumors are
hormone-secreting, with the majority being insulinomas. The tumors are
often found incidentally in the pancreas or GI system on imaging.
Pathological specimens are generally positive for Chromogranin A and
Synaptophysin but can additionally be positive for other serum markers
such as Insulin, Gastrin, and VIP, depending on the subtype of NET
{[}2{]}. General management includes surgery for localized disease and
surgery/chemotherapy in combination for extensive disease. Prognosis is
poor for those with liver metastases, with an overall mortality rate
greater than \textgreater{} 80\%. Functional tumors are generally
localized and rarely present as metastatic disease {[}3{]}.

Among functional NETs, Insulinomas are the most common. Incidence is
around 1 to 3 cases per million and is usually present in the pancreas
over 99\% of the time {[}4{]}. Diagnosis is established with symptomatic
hypoglycemia in the setting of elevated insulin and c-peptide levels
after a 72-hour fasting test. Blood glucose levels usually improve with
Glucagon or Dextrose administration. These lesions are amenable to
treatments such as alcohol ablation, radiofrequency ablation,
embolization, or surgical resection. Surgical resection is the preferred
option for isolated lesions as it is often curative {[}5{]}. Symptomatic
management of hypoglycemia involves dextrose administration and
Diazoxide. Diazoxide inhibits the release of insulin from insulinoma
cells and is often the only effective measure prior to surgery {[}6{]}.
Somatostatin analogs such as octreotide are also used in combination
with diazoxide in more severe cases but can lead to episodes of
hypoglycemia {[}7{]}. Cases involving surgical management have a good
prognosis {[}6,7{]}.

Malignant insulinomas only account for about 5\% of all insulinomas at
presentation {[}8,9{]}. In patients with distant metastases, surgical
resection with lymph node dissection improves prognosis. However, the
overall difference is minimal, and the data is limited in these cases
{[}10{]}. Overall, these patients do quite poorly due to limited
treatment options. There are very few case reports that discuss the
conversion of non-functional metastatic NET into a malignant insulinoma.
This case report presents such a conversion in an elderly female
patient.

\textbf{Case Presentation}

Our case involves a 73-year-old woman with a prior medical history of
Diabetes Mellitus type 2 and a recent diagnosis of non-hormone-secreting
high-grade pancreatic neuroendocrine tumor with metastases to the liver,
who presented for admission for bilateral pulmonary embolism. Pancreatic
neuroendocrine tumor had been diagnosed from liver biopsy specimens
showing positivity for Synaptophysin and Chromogranin. The pathology
images are shown in Figure 1A and 1B.

\textless{}Insert Figures 1A and 1B\textgreater{}

The patient's only complaints were generalized weakness, and she denied
any respiratory complaints upon presentation. The patient was previously
diabetic as well and was on a home regimen of Tresiba insulin 20 units
daily and Metformin 1000mg twice daily. She had taken both medications
the day before the presentation, and neither was restarted on admission
as the patient's blood glucose was near normal. Physical examination
findings were unremarkable, including a normal oxygen saturation on room
air. Laboratory findings revealed significant hypoglycemia with a blood
glucose of 48. The patient was started on IV Dextrose 5\% with normal
saline at 125ml/hr and IV heparin infusion at 18 units/kg/hr and was
subsequently admitted for further management. Of note, the patient's
pancreatic tumor prior to presentation was 2.7cm in size and was a Grade
3 tumor with a Ki-67 proliferative index of 40\%. Figures 2 and 3
demonstrate the initial pancreatic mass with liver metastases on
imaging. She was stage IV at this point in time based on the scoring of
T2, N1, M1a using the WHO guidelines.

\textless{}Insert Figures 2 and 3\textgreater{}

The patient continued to have persistent hypoglycemia over the next few
days and was subsequently started on dextrose 10\% with free water at 80
ml/hr. The patient's appetite was also poor, contributing to her
hypoglycemia episodes. On hospital day 4, the patient had a syncopal
episode due to a blood glucose level of 30. This improved with the
administration of two dextrose 50 ampoules. Endocrinology workup was
initiated, and the patient was started on a 72-hour fasting test. Plasma
glucose was 130mg/dL at the start of the test (normal is
\textgreater{}70mg/dL). The patient made it to only 2 hours of fasting
before becoming symptomatic. Blood glucose reached 53 mg/dL at that
time, and the decision was made to discontinue the test. Blood work done
at that time revealed elevated c-peptide levels of 7.0 ng/ml (normal
range is 1.1 to 4.4 ng/ml) and an insulin level of 136 \selectlanguage{greek}µ\selectlanguage{english}U/ml (normal
range is 2 to 25 \selectlanguage{greek}µ\selectlanguage{english}U/ml). The patient was confirmed to have had a
conversion of her high-grade neuroendocrine tumor from
non-hormone-secreting to an insulinoma. On hospital day 5, the patient
was started on an octreotide injection of 100 mg thrice daily by the
consulting endocrinologist. She was also started on Dexamethasone 2mg
twice daily. Despite these interventions, the patient continued to have
frequent episodes of hypoglycemia. Her oral caloric intake had improved
during this time and did not significantly contribute to hypoglycemia.
At this point, the first line treatment for insulin-related
hypoglycemia, Diazoxide, was considered by the treatment team. On
hospital day 7, the patient was started on diazoxide 50mg every 8 hours.
Her blood sugar continued to fluctuate after this treatment, and she
remained on a Dextrose 10\% infusion. Her Dexamethasone was switched to
oral prednisone 40 mg daily. On this regimen, the patient's blood
glucose levels did improve. She was weaned from Dextrose 10\% infusion
with further episodes of significant hypoglycemia. She was discharged
home on hospital day 10 with a regimen of prednisone 40 mg daily and
diazoxide 75 mg at night. The patient was also started on FOLFOX
chemotherapy prior to discharge. The entire timeline of our case is
shown in Figure 4.

\textless{}Insert Figure 4\textgreater{}

The patient did establish outpatient follow-up with oncology and
endocrinology. The patient was hospitalized multiple times for recurrent
hypoglycemia. After these episodes, she was also maintained on
Octreotide as an outpatient. Alternative treatment options such as
Everolimus and Sunitinib were discussed with the patient and family,
including their risks and benefits. The patient and family declined
these interventions. On repeat staging imaging, the patient was noted to
have a spinal lesion at T12. This was biopsied and positive for
synaptophysin and chromogranin, confirming the further spread of the
neuroendocrine tumor. Ki-67 proliferative index was greater than 50\%,
indicating a grade 3 tumor as well.

The patient continued to do poorly overall. She declined palliative
chemotherapy and was eventually placed in hospice care. The patient was
discharged home and passed away a few weeks later.

\textbf{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\emph{.} 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.

\textbf{Conclusion}

Our case report involves the conversion of a metastatic non-functional
NET into a functional malignant insulinoma. The key clinical points from
this case report are as follows: 1) When a non-functional neuroendocrine
tumor converts into a functional one, the prognosis worsens
significantly. 2) Alternative treatments beyond conventional
chemotherapy are required for patients with aggressive insulinomas. 3)
More research is required to evaluate treatments such as Everolimus and
Sunitinib for their use in cases of malignant insulinomas.

\textbf{References}

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2. Ma ZY, Gong YF, Zhuang HK, et al.: Pancreatic neuroendocrine tumors:
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3. Konukiewitz B, Jesinghaus M, Kasajima A, Kloppel G: Neuroendocrine
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8. Crippa S, Zerbi A, Boninsegna L, et al.: Surgical management of
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pancreatic resections. Arch Surg. 2012, 147:261-266.
10.1001/archsurg.2011.1843

9. Service FJ, McMahon MM, O'Brien PC, Ballard DJ: Functioning
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10.1016/s0025-6196(12)62083-7

10. Sada A, Glasgow AE, Vella A, Thompson GB, McKenzie TJ, Habermann EB:
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11. Wynick D, Williams SJ, Bloom SR: Symptomatic secondary hormone
syndromes in patients with established malignant pancreatic endocrine
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12. de Mestier L, Hentic O, Cros J, et al.: Metachronous hormonal
syndromes in patients with pancreatic neuroendocrine tumors: a
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13. Clover T, Abdelkader A, Guru Murthy GS: Transformation of a
non-secretory neuroendocrine tumor to insulinoma after treatment with
Sunitinib: A case report and review of the literature. J Oncol Pharm
Pract. 2019, 25:1516-1519. 10.1177/1078155218791309

14. Crona J, Norlen O, Antonodimitrakis P, Welin S, Stalberg P, Eriksson
B: Multiple and Secondary Hormone Secretion in Patients With Metastatic
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101:445-452. 10.1210/jc.2015-2436

15. Baratelli C, Brizzi MP, Tampellini M, et al.: Intermittent
everolimus administration for malignant insulinoma. Endocrinol Diabetes
Metab Case Rep. 2014, 2014:140047. 10.1530/EDM-14-0047

16. Raymond E, Dahan L, Raoul JL, et al.: Sunitinib malate for the
treatment of pancreatic neuroendocrine tumors. N Engl J Med. 2011,
364:501-513. 10.1056/NEJMoa1003825\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

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Figure 1A and 1B: Liver tissue specimen showing positive staining for
Chromogranin and Synaptophysin\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

Figure 2: Axial post contrast CT image demonstrates the heterogeneously
enhancing mass in the pancreatic head and proximal body (red arrows),
compatible with the known primary neuroendocrine tumor. Incidentally,
hepatic metastases are also partially seen (blue arrow).\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image4/image4}

\end{center}
\end{figure}

Figure 3: Coronal T2 weighted image of the abdomen demonstrates a cystic
lesion in the pancreatic head, corresponding to the patient's known
pancreatic neuroendocrine tumor. Also seen are faintly T2WI hyperintense
right hepatic lobe lesions, in keeping with the widely metastatic
disease\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image5/image5}

\end{center}
\end{figure}

Figure 4: A timeline of our case presentation

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