Glucagonoma as a rare case of neuroendocrine tumor of the pancreas: a case report

Abstract

br/> Introduction: Glucagonoma is a rare neuroendocrine tumor with characteristic features such as the presence of the glucagon-producing tumor, diabetes, and necrolytic migratory erythema.
Case presentation: the 60-year-old patient was admitted to hospital with periodic pain in the right and middle upper abdominal appearing after eating. Laboratory tests presented a high glucose level and anemia. Tumor of the body and tail of the pancreas passing the organ pouch has been found during the surgery. Diagnosis of glucagonoma was confirmed in histopathological examination in immunohistochemical stainings: a positive reaction was observed with chromogranin, synaptophysin and CEA. The proliferative activity of Ki-67 was less than 1%. Staining for glucagon also was positive so confirmed the presence of neuroendocrine tumor - glucagonoma.
Conclusions: Glucagonoma sometimes may occur without characteristic features which may cause delayed diagnosis. Early diagnosis of glucagonoma is important because it increases the chances of successful recovery.

Full text

Prog Health Sci 2019, Vol 9, No 1 Glucagonoma – case report
169
Glucagonoma as a rare case of neuroendocrine tumor of the pancreas: a case
report
Zińczuk J.1 A-D*, Lewoniewska S.2 B,C,D, Zaręba K.4 B, C, Pryczynicz A.3C,E, Guzińska-
Ustymowicz K.3 F
1. Department of Clinical Laboratory Diagnostics, Medical University of Bialystok, Poland
2. Department of Medicinal Chemistry, Medical University of Białystok, Poland
3. Department of General Pathomorphology, Medical University of Białystok, Poland
4. 2nd Clinical Department of General and Gastroenterological Surgery, Medical University
of Białystok, Poland
__________________________________________________________________________________________
A- Conception and study design; B - Collection of data; C - Data analysis; D - Writing the paper;
E- Review article; F - Approval of the final version of the article; G - Other (please specify)
__________________________________________________________________________________________
ABSTRACT
__________________________________________________________________________________________
Introduction: Glucagonoma is a rare
neuroendocrine tumor with characteristic features
such as the presence of the glucagon-producing
tumor, diabetes, and necrolytic migratory erythema.
Case presentation: the 60-year-old patient was
admitted to hospital with periodic pain in the right
and middle upper abdominal appearing after eating.
Laboratory tests presented a high glucose level and
anemia. Tumor of the body and tail of the pancreas
passing the organ pouch has been found during the
surgery. Diagnosis of glucagonoma was confirmed
in histopathological examination in
immunohistochemical stainings: a positive reaction
was observed with chromogranin, synaptophysin
and CEA. The proliferative activity of Ki-67 was
less than 1%. Staining for glucagon also was positive
so confirmed the presence of neuroendocrine tumor
- glucagonoma.
Conclusions: Glucagonoma sometimes may occur
without characteristic features which may cause
delayed diagnosis. Early diagnosis of glucagonoma
is important because it increases the chances of
successful recovery.
Keywords: Glucagonoma, pancreas, neuro-
endocrine tumor, diabetes
_________________________________________________________________-_________________________
DOI:
*Corresponding author:
Justyna Zińczuk
Department of Clinical Laboratory Diagnostics, Medical University of Bialystok
Waszyngtona 15, 15-269 Białystok, Poland
Tel.: +48 85 831 8716; e-mail: justyna.zinczuk@umb.edu.pl
Received: 10.02.2019
Accepted: 25.04.2019
Progress in Health Sciences
Vol. 9(1) 2019 pp 169-173
© Medical University of Białystok, Poland

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INTRODUCTION
Glucagonoma is one of the rare pancreatic
neuroendocrine tumors, accounting for only 5% of
all cancers of this organ [1]. It is characterized by
excessive production of glucagon by the alpha cells
of the Langerhans islands and locates mainly in the
pancreatic tail due to the accumulation of islands in
this part of the organ. The incidence is 0.01-0.1 cases
per 100 000 people per year. Glucagonoma mainly
affects people 40-60 years old and occurs with
similar frequency for both men and woman. The
most characteristic symptom of glucagonoma is
dermal necrolytic migratory erythema (NME),
which is result of malnutrition and amino acid
deficiency caused by increase glucagon catabolism.
These lesions are present in approximately 55-90%
of all patients. Other symptoms include weight loss,
diabetes, glucose intolerance, inflammation of the
mucous membrane (tongue, lips), venous
thrombosis, diarrhea or neuropsychiatric disorders
(depression, psychosis) [2]. In laboratory tests -
anemia, hyperglycemia and an increase of glucagon
level has been reported in most cases [3]. One of the
elements of glucagonoma diagnosis is histopa-
thological examination including immunohisto-
chemical staining such as chromogranin or
synaptophysin specific for neuroendocrine tumors.
Additionally, in order to confirm diagnosis of
glucagonoma, staining for glucagon should be
performed. The authors describe the glucagonoma
case due to the rare occurrence of this hormone-
active pancreatic neuroendocrine tumor.
CASE PRESENTATION
A 60-year-old patient with a newly
diagnosed diabetes was admitted to 2nd Clinical
Department of General and Gastroenterological
Surgery at Medical University of Bialystok for
surgical treatment of a pancreatic tail tumor and
cholecystolithiasis. In the previous interview, there
were periodic pain in the right and middle
epigastrium, occurring mainly after eating. These
complaints were accompanied by significant weight
loss - about 7 kg in 3 months. In a family history, a
case of pancreatic cancer in a patient's brother has
been reported.
High blood glucose levels (160 mg/dL) in
many measurements were observed in laboratory
tests, whereas normocytic, normochromic anemia
(9.5 g/dL hemoglobin) was observed in the blood
morphology test. The level of chromogranin A,
which is a serum marker for neuroendocrine tumors,
was elevated to 625.7 ng/mL whereas normal range
equals <94 ng/mL. The serum glucagon level was
803 pg/mL (reference level 70-175 pg/mL). The
Erythrocyte Sedimentation Rate (ESR) was slightly
increased (31mm per hour). CEA markers (<0.50
U/ml) and CA 19-9 (2.18 U/ml) remained within the
reference values.
The abdominal CT (Computed
Tompgraphy) scan showed enlargement of the
pancreatic tail to 40 mm with unequal contours
without focal separation except for minor
calcification (Figure 1).
Figure 1. Contrast-enhanced computed tompgraphy scan of the abdomen reveals a tumor mass in the body and
the tail of the pancreas

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In the surrounding of the pancreatic tail has
been observed band-like thicknesses in the direction
of the spleen, peritoneum, fundus, prerenal and
adrenal fascia, segmental narrowing of the splenic
artery as well as obstruction and fibrosis of the
splenic vein with numerous collateral vessels. In
addition, gallstones were found.
The patient was qualified for surgical
treatment. During the procedure, tumor was found in
the tail and body of pancreas. The tumor infiltrated
peritoneum, left adrenal gland and left kidney.
Peripheral pancreatectomy with splenectomy and
cholecystectomy were performed. The postoperative
period was without complications. Glucose
abnormalities in the patient have normalized.
Diabetic counseling followed diet and glycemic
control. Patient in a general good condition was
discharged from hospital with a recommendation of
check visit.
Histopathological examination concerned a
fragment of the pancreas, cuted along a long axis. At
the cross section of the tail was solid yellow tumor
with poorly marked borders with small foci of
bloody sputum (Figure 2 A, B). The tumor had
dimensions 6.5x3x3.5cm. Pancreatic fibrosis was
reported in the tumor region. Moreover in the
neighborhood of the pancreas, numerous enlarged
pink-gray lymph nodes were presented.
Figure 2. A, B Glucagonoma in the body and tail of the pancreas. C. Microscopic examination revealed tumor
with the round cells containing fine-grained cytoplasm and the centrally located nucleus. Round or oval-shaped
nuclei contained fairly uniform, scattered, fine-grained chromatine. In single cells were present small cores (H&E,
original magnification ×40). D. Immunohistochemical staining shows strong homogeneous positive reaction for
chromogranin.
Postoperative histopathological
examination confirmed that the diagnosis was a
neuroendocrine tumor involving the tail of pancreas
(Figure 2C). In the immunohistochemistry
examination of the tumor, a strong homogeneous
positive reaction with antibodies against
chromogranin (Figure 2 D) and synaptophysin
(Figure 3 A) was observed. In addition, staining for
carcinoembryonic antigen was made and it was
positive (Figure 3 B). Ki-67 proliferation index was
less than 1% (Figure 3 C) . Glucagon staining was
also positive (Figure 3 D). These staining confirmed
the diagnosis of glucagonoma with degree of
differentiation G1 and pT2 N1 M0 stage IIB. Degree
of differentiation - G1 concern the tumors with low
proliferation index lower or equal 2%. The degree of

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pT2 indicates that the tumor is locally advanced.
This criterion also includes the tumor size to 40 mm.
Degree N1 attests to tumor metastases to regional
lymph nodes (In the two lymph nodes that were sent
to the study were tumor metastases), while M0
indicates absence of metastases to distant organs.
Stage IIB determines tumor as an average clinical
stage.
Figure 3. A. Immunohistochemical staining shows positive findings for synaptophysin. B. Immunohistochemical
staining shows positive findings for CEA. C. Ki-67 proliferation index less than 1%. D. Immunohistochemical
staining shows positive findings for glucagon
DISCUSSION
Glucagonoma is a rare neuroendocrine
tumor with a prevalence of 1 case per 20 million
people per year. The characteristic feature of
glucagonoma is the presence of three symptoms
typical for this disease unit. Triads of symptoms,
includes the presence of glucagon-producing tumor,
diabetes, and necrolytic migratory erythema [4].
This tumor was first described in 1942 by Becker [5],
who was characterized it by the presence of
cutaneous eczema. In 1966 McGavran et al [6] added
to the symptoms hyperglucagonemia and their
combination named as glucagonome syndrome
(GS). The term necrolytic migratory erythema was
developed in 1973 by Wilkinson [7] as a defining
characteristic of skin lesions developing in the
course of glucagonoma. Glucagonome syndrome is
divided into three different types: glucagonoma with
accompanying necrolytic migratory erythema,
glucagonoma with mild diabetes, and multi-
symptom glucagonoma.
The patient which has been described in this
paper had a glucagonoma syndrome with mild
diabetes. The patient had a large tumor located in the
tail of the pancreas with metastases to the two lymph
nodes. Literature describes cases of glucagonoma
with tumor localization in the head of the pancreas,
but in most cases the tumor locates in the tail of this
organ because of the high density of alpha islands in
the region. Endocrine symptoms are more common
in advanced stages of the disease and can be related
to the size of the tumor. The tumor-altered organ
produces large amounts of glucagon which, under
physiological conditions, stimulates processes that
increase blood glucose levels by demonstrating an
insulin-antagonistic effect. In case of overproduction
of this hormone activates additional metabolic
pathways - intensification of gluconeogenesis,

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glycogenolysis and lipolysis, which in consequence
leads to disorders of glycemia, insulin resistance and
development of diabetes.
Glucose level in our patient was 160 mg/dL,
which is due to the fact that the patient developed
mild diabetes mellitus. Except for diabetes, a
significant weight loss was reported in the patient, as
well as anemia and gall bladder stones. Weight loss,
which is an inseparable part of developing
glucagonoma is results of increased metabolism by
the growing tumor, which in turn results in the
extinction of the body. Diarrhea is often seen in
patients who may further increase weight loss [7].
The patient did not have necrolytic migratory
erythema - NME, which is one of the most
characteristic symptoms of glucagonoma and have
occurred in approximately 70% of patients with this
diagnosis. In available literature has been reported
only one clinical case of glucagon without skin
lesions [8]. In the patient family history was
diagnosed pancreatic cancer in the patient's brother.
In most cases available in literature in the patient's
family histories were no found any neuroendocrine
tumors or other pancreatic tumors [9]. In addition,
patients with suspected neuroendocrine tumors
perform laboratory tests such as blood morphology,
ESR or tumor diagnostic markers CA 19-9, whose
elevation may indicate pancreatic cancer but its
normal level does not exclude the onset of the
disease.
Confirmation of neuroendocrine tumor
diagnosis requires histopathological examination
and immunohistochemical diagnosis based on
positive staining on chromogranin or synaptophysin.
Chromogranin is used to diagnose neuroendocrine
tumors because it is a protein secreted by
neuroendocrine cells. Synaptophysine is a protein
present in all healthy and neoplastic neuroendocrine
cells [10]. For the differentiation of the neuro-
endocrine tumor subtype, a glucagon assay was
performed in our patient. Positive expression result
showed that the tumor originated from pancreatic
alpha cells. In addition, we were performed staining
for carcinoembryonic antigen and Ki-67 protein. The
Ki-67 protein is used to evaluate proliferative
activity and shows of the potential for tumor
malignancy [10].
CONCLUSIONS
Glucagonoma sometimes may occur
without characteristic features such as necrolytic
migratory erythema which may cause delayed
diagnosis. The diagnosis of tumor focus on image-
based diagnosis and laboratory tests, but
histopathologic diagnosis is necessary to confirm the
specific type of tumor. Time to diagnosis is an
important prognostic factor because of its metastatic
potential to surrounding lymph nodes and the liver.
Early diagnosis of the underlying symptoms of
glucagonoma allows for rapid diagnosis and
increases the chances of successful cure.
Conflicts of interest
The authors declare that they have no conflicts of
interest.
Financial disclosure/funding
No funding was received.
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