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AACE Clin Case Rep. 2020 Jan-Feb; 6(1):
e46–e49. Published online 2020 Jan 3.
doi: 10.4158/ACCR-2019-0211
PMCID: PMC7279770PMID: 32524009
MANIFESTATIONS OF GLUCAGONOMA SYNDROME
Mauricio Alvarez, MD,corresponding
author1 Andres Almanzar, MD,1 Fabian
Sanabria, MD,1 Gustavo Meneses, MD,1
Louis Velasquez, MD,1 and Luis Zarate,
MD2
Author information Article notes
Copyright and License information
Disclaimer
This article has been cited by other
articles in PMC.
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Abstract
Objective:
Glucagonoma is a rare neuroendocrine
tumor of the pancreas. We present the
case of a young female patient who
presented with the major clinical
manifestations of glucagonoma syndrome.

Methods:
The major clinical manifestations of
glucagonoma syndrome are described in a
44-year-old, female patient. Beyond
glucagonoma, the patient also displayed
deep venous thrombosis, depression,
diabetes, and necrolytic migratory
erythema. We discuss the difficulty of
treatment of patients with glucagonoma
due to the low prevalence of the
disorder, scarcity of medical evidence,
lateness of diagnosis with liver
metastases in most cases, and poor
response to chemotherapy with high rates
of relapse after surgery. In this case,
pancreatectomy and hepatic lobectomy
followed by somatostatin analogue therapy
was the chosen treatment strategy.

Results:
The clinical findings were pancreatic and
hepatic masses, proximal deep venous
thrombosis, depression, diabetes, and
necrolytic migratory erythema. The
patient also had elevated levels of
glucagon. Pancreatectomy and right
hepatic lobectomy were performed and
confirmed the glucagonoma.

Conclusion:
Our case adds new knowledge about
glucagonoma which is important due to the
low incidence of the disease and the
particular characteristics of the
syndrome.

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INTRODUCTION
Glucagonoma is an extremely rare
pancreatic neuroendocrine tumor (PNET),
originating in the alpha cells of the
pancreatic islets that produce glucagon
(1–4). The incidence is approximately 1
case in 20 million people per year
(1,2,5). Since it is a slow-growing tumor
and the symptoms are nonspecific, the
diagnosis is usually late, at an advanced
stage of the disease (2,6). The treatment
of choice is surgery due to the poor
response to chemotherapy (6,7).

Morbidity from PNETs is mostly due to

necrolytic migratory erythema (NME) and
malnutrition, which can be partially
improved by somatostatin analogs, amino
acid infusion, and antibiotics (6,7). The
low prevalence of glucagonoma syndrome
(GS) and its particular clinical
characteristics, in addition to the
relative lack of experience in management
given the low number of cases reported,
make the presentation of this case
important. We present the case of a
female patient who presented the major
characteristics of GS.

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CASE REPORT
A 44-year-old, female patient was
admitted to the emergency department due
to a 2-day history of edema and pain in
the right lower limb. Doppler venous
ultrasound showed extensive thrombosis of
the iliac and right femoral veins. She
had lability of mood, easily provoked
crying, and a constitutional syndrome
with loss of 20 kg in the last year.
Physical examination revealed
erythematous migratory skin lesions that
left hyperpigmented lesions on the face
and extremities and angular cheilitis
(Fig. 1 and and2).2). There was no
relevant family history of cancer or
diabetes. She had not received any
previous treatment. The patient consented
to the publication of the clinical case
and the images.

An external file that holds a picture,

illustration, etc.
Object name is i2376-0605-6-1-e46-f01.jpg
Fig. 1.
Migratory necrolytic erythema on the face
showing hyperpigmented and erythematous
lesions.

An external file that holds a picture,

illustration, etc.
Object name is i2376-0605-6-1-e46-f02.jpg
Fig. 2.
Cheilitis and glossitis.

The possibility of a paraneoplastic

syndrome was considered. Blood chemistry
studies showed normocytic anemia and
fasting hyperglycemia (176 mg/dL) as the
only abnormal findings. Autoimmunity
studies with antinuclear antibodies and
neutrophil cytoplasmic antibodies were
also normal. Abdominal tomography and
octreotide scan were performed resulting
in detection of a large pancreatic mass
(Fig. 3) and 2 metastases in the right
lobe of the liver.
An external file that holds a picture,
illustration, etc.
Object name is i2376-0605-6-1-e46-f03.jpg
Fig. 3.
Axial computed tomography of the abdomen
showing masses in the pancreatic tail and
right hepatic lobe.

Due to the presence of a large pancreatic

tumor with liver metastasis that was
associated with migratory dermatitis,
depression, hyperglycemia, and deep vein
thrombosis, the probability of a
glucagon-producing PNET was considered.
Indeed, the patient's glucagon level was
elevated at 2,144 pg/dL (normal range is
50 to 100 pg/dL), consistent with a
glucagonoma. A tomography-guided liver
biopsy was performed to confirm the
diagnosis.

Pancreatectomy with hepatic lobectomy

confirmed the presence of a large mass in
the tail of the pancreas. Histopathology
confirmed the PNET (Fig. 4) with a Ki-67
proliferation index of 7%. This is
equivalent to a grade 2 neoplasm
according to the 2010 World Health
Organization grading system for PNETs.
Immunohistochemistry for glucagon
staining was positive. After the surgery
there was temporary improvement of skin
lesions for 6 months and improvement of
nutritional status. The patient's
glucagon level decreased to 563 pg/dL
after surgery, her mood improved, and
depression symptoms resolved.

An external file that holds a picture,

illustration, etc.
Object name is i2376-0605-6-1-e46-f04.jpg
Fig. 4.
Histology (×40) showing nodular and
trabecular structures formed by cells
with broad, granular eosinophilic
cytoplasm and homogeneous nuclei. Slight
pleomorphism and some visible nucleoli
are also observed, but no important
mitotic activity is observed.
The patient continued treatment with
somatostatin analogs due to the
subsequent appearance of metastasis in
the left hepatic lobe after surgery,
consistent with the persistence of high
glucagon levels after surgery. Gallium-68
dotatate positron emission tomography
with computed tomography was performed
suggesting high expression of
somatostatin receptors. Tolerance to
somatostatin analogs was adequate except
for the occurrence of mild diarrhea and
abdominal pain. After 1 year of follow
up, most of the symptoms improved and
there was no progression of the disease
by control images.

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DISCUSSION
GS is a paraneoplastic phenomenon
characterized by NME, diabetes mellitus
or glucose intolerance, neuropsychiatric
changes, and thrombotic events associated
with elevated glucagon levels (1–4). Our
case presented with each of the 4
components of the syndrome as she had
recurrent venous thrombosis in the lower
limbs, depression, diabetes mellitus, and
severe skin lesions compatible with NME.

Glucagonoma is an extremely rare PNET,

originating in the alpha cells of the
pancreatic islets that produce glucagon.
The incidence is approximately 1 case in
20 million people per year (1–3,5). Only
about 2% of PNETs are glucagon producers
and the majority are located in the tail
of the pancreas (2). Glucagonoma tumors
are sporadic in most cases, however,
about 3% are associated with inherited
disorders such as multiple endocrine
neoplasia type 1 and less frequently with
von Hippel-Lindau syndrome (2). Our case
meets the characteristics of a
glucagonoma and was a large mass in the
pancreatic tail, however it is a sporadic
case because no evidence of multiple
endocrine neoplasia was found.
The average age of diagnosis of
glucagonoma is during the fifth and sixth
decades of life. Since it is a
slow-growing tumor and the symptoms are
nonspecific, the diagnosis is usually
late with a mean of 39 months from the
onset of symptoms and often occurs at an
advanced stage (2,6). At the time of
diagnosis, more than 50% of cases have
already metastasized (6). Our case had an
evolution of 2 years from the onset of
symptoms to diagnosis, and she had liver
metastases.

NME is the most characteristic clinical

manifestation of the disease and is
present in up to 70% of cases (4,6,8,9).
Often, as in this case, NME is the first
manifestation of the disease. In our
patient, skin manifestations were the
most florid during the course of the
disease and were the ones that led to the
suspicion of glucagonoma.

The treatment of choice for glucagonoma

is surgery given the poor response to
chemotherapy. In cases of early
diagnosis, surgical resection could be
curative (6–8). The morbidity of GS is
mostly due to NME, which, as it did in
our case, frequently produces extensive
lesions that affect the quality of life
of the patient. Necrolytic erythema can
improve up to 50% with somatostatin
analogs, amino acid infusion, and
antibiotics (6,7). There are other
treatment options such as
chemoembolization and radiotherapy (8).
In 2 case series with >20 patients in
each, the response to chemotherapy was up
to 50% (10,11).

The first-line therapy for

well-differentiated PNETs is use of
somatostatin analogs. A trial called
CLARINET (12) compared lanreotide and
placebo in patients with
well-differentiated PNETs with Ki-67
indices <10% and showed that estimated
rates of progression-free survival at 24
months were 65.1% (confidence interval of
95% with a range of 54.0% to 74.1%
survival) in the lanreotide group and
33.0% (confidence interval of 95% with a
range of 23.0% to 43.3% survival) in the
placebo group. The most frequent adverse
effects were diarrhea, abdominal pain,
and cholelithiasis. Another trial called
PROMID (13) compared octreotide and
placebo in patients with midgut,
well-differentiated neuroendocrine
tumors. Median time to tumor progression
in the octreotide group and placebo group
was 14.3 and 6.0 months, respectively
(hazard ratio of 0.34 with a confidence
interval of 95% and a range of 0.20 to
0.59; P = 0.000072).

The majority of well-differentiated

(grades 1 or 2, according to the 2010
World Health Organization grading system
for PNETs) gastroenteropancreatic
neuroendocrine tumors express high levels
of somatostatin receptors. As such,
treatment with a targeted radiotherapy
with lutetium-177 (Lu-177), a beta-wave
and gamma-wave emitting radionuclide, has
emerged as a second-line therapy for
advanced and progressive midgut
neuroendocrine tumors. In the phase III
trial called NETTER 1 (14), which
evaluated the efficacy and safety of
Lu-177 dotatate, 229 patients were
randomized to Lu-177 plus octreotide or
octreotide alone. Progression-free
survival at month 20 was 65.0%
(confidence interval of 95% with a range
of 50.0% to 76.8% survival) in the Lu-177
dotatate group and 10.8% in the control
group (confidence interval of 95% with a
range of 3.5% to 23.0% survival).

The effectiveness and safety of therapy

with Lu-177 dotatate was recently
evaluated in patients with
well-differentiated, functional PNETs of
grade 1 or 2 (15). This study included 8
patients with glucagonoma. Partial or
complete responses were found in 59% of
patients and disease control in 78% of
patients with improvement of symptoms in
71% of patients and decrease in hormone
levels in 80% of patients.

Another second-line option is everolimus,

which works by inhibition of the
mammalian target of rapamycin pathway and
does not depend on the expression of
somatostatin receptors. One trial called
RADIANT 3 (16), with 410 patients with
grade 1 or 2 gastroenteropancreatic
neuroendocrine tumors with radiologic
progression within the previous 12
months, tested everolimus. In this study,
everolimus significantly prolonged
progression-free survival. In our case,
surgery and treatment with somatostatin
analogs were initially performed, with
improvement of the symptoms of MNE,
nutritional status, glycemic control, and
depression. While additional therapeutic
options have been proposed for PNETs,
surgery with total resection of the tumor
remains the only curative option for
patients with glucagonoma. In our case,
the resection of the majority of the
tumor burden produced temporary remission
of most of the symptoms that affected the
patient's quality of life.

Go to:
CONCLUSION
It is important to emphasize that
treatment of PNETs should be carried out
by a multidisciplinary team with
experience and with the necessary
resources to provide adequate care.

Go to:
Abbreviations
GS glucagonoma syndrome
Lu-177 lutetium-177
NME necrolytic migratory erythema
PNET pancreatic neuroendocrine tumor
Go to:
Footnotes
DISCLOSURE

The authors have no multiplicity of

interest to disclose.
Go to:
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Articles from AACE Clinical Case Reports
are provided here courtesy of American
Association of Clinical Endocrinology
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