Case of Pancreatic Cancer with Formation

Koushiro Ohtsubo
1
, Hiroyuki Watanabe
1
, Gensaku Okada
1
, Tomoya Tsuchiyama
1
,
Hisatsugu Mouri
1
, Yasushi Yamaguchi
1
, Yoshiharu Motoo
1
, Takashi Okai
1
, Koji Amaya
2
,
Hirohisa Kitagawa
2
, Tetsuo Ohta
2
, Toshifumi Gabata
3
, Koichiro Matsuda
4
, Hideki Ohta
4
,
Norio Sawabu
1
Departments of 1Internal Medicine and Medical Oncology, Cancer Research Institute,
2Gastroenterological Surgery, and 3Radiology, Kanazawa University. Kanazawa, Japan.
4Department of Gastroenterology, Tonami General Hospital. Tonami, Japan
ABSTRACT
Context Mass-forming pancreatitis can be
divided into two distinct types: alcoholic and
autoimmune. There have been some cases of
an ambiguous diagnosis although care was
taken to differentiate between alcoholic mass-
forming pancreatitis, focal type autoimmune
pancreatitis and pancreatic cancer.
Case report We report a case of pancreatic
cancer mimicking alcoholic or autoimmune
pancreatitis with the formation of a mass in a
32-year-old man with a history of heavy
drinking.
Although
both
serum
immunoglobulin G and immunoglobulin G4
levels were normal, many serum auto-
antibodies, including the antinuclear antibody,
were detected. After he stopped drinking,
abdominal computed tomography showed a
pancreatic head mass 28 mm in diameter with
little and weak enhancement in the early and
delayed phases, respectively. Endoscopic
retrograde cholangiopancreatography showed
an obstruction of the main pancreatic duct in
the pancreatic head and marked stenosis of
the lower common bile duct. Although a
percutaneous ultrasound-guided pancreatic
biopsy demonstrated no evidence of
autoimmune pancreatitis, he was treated with
prednisolone to test the efficacy of steroid
therapy. However, the pancreatic mass
became enlarged after steroid therapy, and he
underwent surgery during which the mass was
found to be pancreatic cancer. Although the
patient was treated with gemcitabine, he died
5 months after surgery. We retrospectively
assessed DNA hypermethylation in the
patient’s pure pancreatic juice obtained on
admission. We observed hypermethylation of
the cancer-specific gene tissue factor pathway
inhibitor 2 (TFPI2).
Conclusion This finding suggests that if the
DNA hypermethylation of pure pancreatic
juice had been assayed before steroid therapy,
it would have supported the diagnosis of
pancreatic cancer, and steroid therapy could
have been avoided.
INTRODUCTION
Mass-forming pancreatitis can be divided into
two distinct types: alcoholic and autoimmune
[1]. Autoimmune pancreatitis is a new entity
characterized by diffuse enlargement of the
pancreas, diffusely irregular narrowing of the
main pancreatic duct, increased levels of
serum gammaglobulin, immunoglobulin G

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(IgG) or immunoglobulin G4 (IgG4), the
presence of antibodies, and severe lympho-
plasmacytic infiltration and fibrosis of the
pancreas [2, 3, 4, 5, 6, 7, 8]. Autoimmune
pancreatitis accompanied by the formation of
a mass has often been misdiagnosed as
pancreatic cancer [9, 10, 11, 12]. There have
been some cases of an ambiguous diagnosis
although care was taken to differentiate
between alcoholic mass-forming pancreatitis,
focal type autoimmune pancreatitis and
pancreatic cancer [13, 14]. We herein report
the case of a young man with pancreatic
cancer mimicking alcoholic or autoimmune
pancreatitis with the formation of a mass and
many auto-antibodies. In addition, we
described the usefulness of hypermethylation
analyses of pure pancreatic juice in the
diagnosis of pancreatic cancer.
CASE REPORT
In January 2002, a 32-year-old man consulted
a local hospital because of back and epigastric
pain. Although he was a heavy drinker (100
g/day ethanol for 12 years), he had no history
of pancreatitis. His serum level of pancreatic
enzymes was high, and abdominal computed
tomography (CT) showed pancreatic swelling,
suggesting acute alcoholic pancreatitis.
Although his symptoms disappeared when he
stopped drinking and was treated with
conservative therapy, his pancreatic head
remained swollen. He was referred to our
hospital for closer examination and treatment.
Biochemical tests showed elevation of his
pancreatic enzymes, including amylase (170
IU/L; reference range: 40-113 IU/L), lipase
(109 IU/L; reference range: 11-53 IU/L) and
elastase I (760 ng/dL; reference range: 100-
400 ng/dL). Autoimmune antibodies were
present, including antinuclear antibody
(ANA, x320; reference range: 0-20), anti-
DNA antibody (7 IU/mL; reference range: 0-6
IU/mL), anti-thyroglobulin antibody (TgAb,
5.5 IU/mL; reference range: 0-0.7 IU/mL),
anti-thyroid peroxidase antibody (TPOAb, 3.6
IU/mL; reference range: 0-0.2 IU/mL) and
anti-Ro/SS-A antibody (141.3 index;
reference range: 0-10 index) as well as
rheumatoid factor (26 IU/mL; reference
range: 0-20 IU/mL), although the patient did
not express the symptoms related to these
markers for the screening of autoimmune
pancreatitis. Both IgG and IgG4 were normal
as were the serum tumor markers carcino-
Figure 1. Abdominal computed tomography showing a
low density mass 28 mm in diameter in the pancreatic
head (a.), with little and weak enhancement in the early
(b.) and delayed phases (c.), respectively (arrows).

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embryonic antigen (CEA), carbohydrate
antigen 19-9 (CA 19-9) and DU-PAN 2.
Abdominal CT showed a low density mass 28
mm in diameter in the pancreatic head with
little and weak enhancement in the early and
delayed phases, respectively (Figure 1).
Abdominal ultrasound (US) revealed a low
echoic mass with mild main pancreatic duct
dilatation (Figure 2), and endoscopic
ultrasonography (EUS) showed a low echoic
mass with penetrating a duct sign 30 mm in
diameter (Figure 3). Endoscopic retrograde
cholangiopancreatography (ERCP) revealed
obstruction of the main pancreatic duct in the
pancreatic head and marked stenosis of the
lower common bile duct (Figure 4), and
magnetic resonance cholangiopancreatography
(MRCP) showed a mildly dilated main
pancreatic duct upstream from the stricture
(Figure 5a). Malignant cells were not
detected, and K-ras and p53 mutations were
not found in pure pancreatic juice collected by
endoscopic cannulation [15, 16, 17, 18]. A
percutaneous US-guided pancreatic biopsy
was performed to confirm the histological
Figure 4. Endoscopic retrograde cholangiopancreato-
graphy showing obstruction of the main pancreatic duct
in the pancreatic head (a. arrow) and marked stenosis
of the lower common bile duct (b. arrowhead).
Figure 3. Endoscopic ultrasonography showing a low
echoic mass (arrows) with penetrating duct sign (arrow
head) 30 mm in diameter in the pancreatic head.
Figure 2. Abdominal ultrasound showing a low echoic
mass (arrow) with dilatation of the mild main
pancreatic duct (arrow head) in the pancreatic head.

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40
findings. Although both mild fibrosis and
neutrophil infiltration were observed, we
observed no evidence of dense fibrous tissue,
lymphocyte or plasma cell infiltration, or
malignant cells.
Despite having stopped drinking, the
pancreatic head mass did not disappear. In
addition to tumor markers within normal
limits, negative cytology and mutations in
pure pancreatic juice, the concentrations of
many auto-antibodies including the ANA had
increased, suggesting autoimmune pancreatitis
rather than alcoholic mass-forming
pancreatitis or pancreatic cancer. He was
treated with 40 mg/day of prednisolone, but
the levels of the pancreatic enzymes and the
size of the pancreatic head mass did not
decrease. Six weeks later, the pancreatic head
mass became enlarged to 35 mm in diameter,
and the main pancreatic duct dilatation
deteriorated as seen by MRCP (Figure 5b).
His total bilirubin became markedly elevated
to 18.2 mg/dL (reference range: 0.3-1.2
mg/dL), and percutaneous transhepatic
cholangiodrainage was performed. Sub-
sequently, the pancreatic head mass was
resected by pancreaticoduodenectomy.
Pathological examination of the mass showed
that it was a moderately differentiated tubular
adenocarcinoma 40x30 mm in diameter. The
resection was not curative due to retro-
peritoneal invasion. The patient was treated
with gemcitabine 1,000 mg/m2/week for 3
weeks, followed by a 1-week rest.
Nevertheless, he died 5 months after surgery.
We retrospectively assessed DNA hyper-
methylation in this patient’s pure pancreatic
juice using the methylation-specific PCR
method [19]. The 5 markers selected were
preproenkephalin (ppENK), secreted frizzled-
related protein 1 (SFRP1, also known as
secreted apoptosis related protein 2, SARP2),
neuronal pentraxin II (NPTX2), claudin 5
(transmembrane protein deleted in
velocardiofacial syndrome, CLDN5) and
tissue factor pathway inhibitor 2 (TFPI2), for
all of which hypermethylation has been
documented in most pancreatic cancers, but
not in normal pancreatic tissue [20, 21, 22,
23, 24, 25, 26]. We observed hyper-
methylation of SFRP1, NPTX2 and TFPI2,
but not of ppENK, CLDN5, in this patient’s
pure pancreatic juice (Figure 6); these
findings were suggestive of pancreatic cancer.
DISCUSSION
Mass-forming pancreatitis can be divided into
two distinct types, each with its own distinct
Figure 5. Magnetic resonance cholangiopancreato-
graphy showing a mildly dilated main pancreatic duct
upstream from the stricture before steroid therapy (a.
arrow) and dilatation of the main pancreatic duct which
had worsened after steroid therapy (b. arrow).
Figure 6. Methylation-specific PCR analysis of TFPI2
in pure pancreatic juice from patients with pancreatic
cancer. The PCR products in the lanes U and M
indicate the presence of unmethylated (89 bp) and
methylated (95 bp) amplicons, respectively. Hyper-
methylation of TFPI2 was detected in cases 1 (this
case), 2, and 4.
DW: distilled water

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41
mechanism [1]. In alcoholic pancreatitis, mass
formation is thought to be due to a reparative
process for centroductal acute inflammation
with a background of chronic pancreatitis
whereas, in autoimmune pancreatitis, mass
formation is thought to be due to
lymphoplasmacytic infiltration with lymphoid
and fibrous proliferation in normal pancreatic
tissue [1]. The significant factors that
differentiate alcoholic mass-forming pancreatitis
from pancreatic cancer are age of onset,
alcoholism, history of pancreatitis, lower
serum levels of CA 19-9 and hypervascularity
[13]. Autoimmune pancreatitis is character-
ized by a diffuse enlargement of the pancreas,
diffusely irregular narrowing of the main
pancreatic duct, increased levels of serum
gammaglobulin, IgG or IgG4, the presence of
auto-antibodies, and severe lympho-
plasmacytic infiltration and fibrosis of the
pancreas [2, 3, 4, 5, 6, 7, 8]. Most patients
with autoimmune pancreatitis display diffuse
enlargement of the pancreas whereas others
show the formation of a mass. Some cases of
autoimmune pancreatitis with mass formation
have been misdiagnosed as being pancreatic
cancer [9, 10, 11, 12]. The significant factors
differentiating focal type autoimmune
pancreatitis from pancreatic cancer are lower
serum levels of CA 19-9, homogeneous
delayed enhancement on dynamic CT, and
ERCP showing a longer stenosed main
pancreatic duct and a thinner main pancreatic
duct upstream from the stricture [14]. In
addition, contrast-enhanced US and magnetic
resonance imaging have been shown to be
useful in the differential diagnosis of
pancreatic tumors [27, 28, 29].
This patient was a young man and a heavy
drinker, suggesting alcoholic mass-forming
pancreatitis while the increased levels of
many auto-antibodies, including ANA,
suggested
autoimmune
pancreatitis.
Moreover, his tumor markers were normal,
and his pure pancreatic juice was negative for
cytology and for K-ras and p53 mutations
[15, 16, 17, 18]. Taken together, these
findings suggested a diagnosis of alcoholic
mass-forming pancreatitis or autoimmune
pancreatitis.
Patients with autoimmune pancreatitis have
significantly higher levels of serum IgG4 than
do patients with pancreatic cancer [30], and
most autoimmune pancreatitis patients show
serum IgG4 elevation [30, 31, 32, 33], making
IgG4 a useful marker for distinguishing
autoimmune pancreatitis from other diseases
of the pancreas, such as pancreatic cancer. In
our patient, however, both serum IgG and
IgG4 levels were normal. Although CT with
enhancement in the delayed phase showed a
pancreatic head mass [13, 14], the degree of
enhancement was low. In addition, ERCP did
not show diffuse narrowing of the main
pancreatic duct but its obstruction while
obstruction of the main pancreatic duct has
been seen in patients with autoimmune
pancreatitis [9, 34]. Therefore, these findings
were suggestive of pancreatic cancer rather
than of alcoholic mass-forming pancreatitis or
autoimmune pancreatitis.
A US-guided percutaneous pancreatic biopsy
is useful in diagnosing a pancreatic mass,
whether malignant or not [35, 36].
Endoscopic ultrasound guided fine needle
aspiration (EUS-FNA) has been shown to be
useful in diagnosing pancreatic diseases,
including pancreatic cancer and autoimmune
pancreatitis [37, 38, 39]. Although we
performed a US-guided percutaneous
pancreatic biopsy, the specimen showed no
evidence of alcoholic mass-forming
pancreatitis, autoimmune pancreatitis or
pancreatic cancer, which may have been due
to sampling error.
Epigenetic alterations have been found to
induce the transcriptional silencing of tumor
suppressor genes, leading to carcinogenesis
[40, 41]. In pancreatic cancer tissue,
hypermethylation has been observed in
several tumor suppressor genes, including p16
[42, 43, 44], mutL homolog 1, colon cancer,
nonpolyposis type 2 (E. coli) (MLH1) [45],
and Ras association (RalGDS/AF-6) domain
family 1 (RASSF1) [46]. In addition,
hypermethylation of ppENKSFRP1NPTX2,
CLDN5 and TFPI2 has been documented in
most pancreatic cancer tissues, but not in
normal pancreatic tissues [20, 21, 22, 23, 24,
25, 26]. Using the methylation-specific PCR

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method, we therefore retrospectively assessed
DNA hypermethylation of these 5 markers in
pure pancreatic juice obtained on admission
[19]. The methylation-specific PCR method is
sufficiently sensitive to detect hyper-
methylation of DNA from a single cell out of
1,000 normal cells [19]. We found that the
SFRP1NPTX2 and TFPI2 genes were
hypermethylated in pure pancreatic juice of
our patient, results which suggested
pancreatic cancer. In particular, hyper-
methylation of TFPI2 in pure pancreatic juice
has been found to be cancer-specific and,
therefore, a useful marker in the diagnosis of
pancreatic cancer [23, 26]. On the other hand,
the CEA levels in pure pancreatic juice were
significantly higher in patients with pancreatic
cancer than in those with pancreatitis [47, 48,
49]. Furthermore, measurement of sialylated
stage-specific embryonic antigen-1 (SSEA-1)
and NCC-ST-439 in pure pancreatic juice
were useful for the diagnosis of pancreatic
cancer [50, 51]. However, the CEA, SSEA-1
and NCC-ST-439 levels in pure pancreatic
juice were not measured in this case. The
method of analyses of hypermethylation is
very different from that of tumor markers in
pure pancreatic juice. Therefore, analyses of
hypermethylation or tumor markers in
addition to quantitative K-ras or p53 mutation
in pure pancreatic juice would be promising
for the diagnosis of pancreatic cancer.
The algorithm of the diagnosis of pancreatic
cancer proposed by the Japan Pancreas
Society is as follows: clinical symptoms,
pancreatic enzymes, tumor markers, and US
in the first step; CT and magnetic resonance
imaging (or MRCP) in the second; EUS,
ERCP and positron emission tomography
(PET) in the third; if a diagnosis is not
determined, cytology or biopsy (by ERCP or
US/EUS guided) in the fourth. If pancreatic
cancer cannot be diagnosed by cytology or
biopsy, tumor markers, genetic and epigenetic
alterations in pure pancreatic juice are
recommended to differentiate pancreatic
diseases as mentioned above. In this patient, it
was difficult to differentiate between
pancreatic cancer and alcoholic mass-forming
pancreatitis or autoimmune pancreatitis.
Retrospectively, the significant findings were:
1) Although the patient’s serum IgG and IgG4
concentrations and his CT and ERCP results
were not inconsistent with alcoholic mass-
forming pancreatitis or autoimmune
pancreatitis, they were more suggestive of
pancreatic cancer. These findings indicate
that, if a histological diagnosis cannot be
determined by US-guided percutaneous
pancreatic biopsy or EUS-FNA, an open
biopsy should be performed [52]. 2) Although
autoimmune pancreatitis is readily responsive
to steroid therapy [8], we found that steroid
therapy had no effect on this patient. These
findings indicate that, if a response to steroid
therapy is not observed after 2 weeks, the
diagnosis should be re-considered. 3)
Hypermethylation analyses in pure pancreatic
juice supported the diagnosis. Therefore, if
this assay had been performed before the
initiation of steroid therapy, the latter could
have been avoided.
Although we observed many serum auto-
antibodies in this patient, he did not have the
symptoms related to these markers. The
reason these markers were elevated remains
unclear. These findings, however, led us to a
diagnosis of autoimmune pancreatitis and the
initiation of prednisolone treatment.
Treatment of mice with glucocorticoids has
been shown to almost completely inhibit the
immune response to tumor cells [53]. Steroid
therapy may therefore cause immunosup-
pression in the patients with malignancy,
leading to tumor enlargement. Therefore,
empirical steroid therapy should not be
administered as a tool for diagnosing
autoimmune pancreatitis.
In conclusion, we have reported the case of
pancreatic cancer in a young man, in whom it
was difficult to discriminate between
pancreatic cancer and alcoholic mass-forming
pancreatitis or autoimmune pancreatitis.
Received October 13th, 2007 - Accepted October
18th, 2007
Keywords
Autoimmune
Diseases;
Methylation; Pancreatic Juice; Pancreatic
Neoplasms; Pancreatitis, Alcoholic

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43
Conflict of interest The authors have no
potential conflicts of interest
Correspondence
Koushiro Ohtsubo
Department of Internal Medicine and Medical
Oncology
Cancer Research Institute
Kanazawa University
13-1 Takaramachi
Kanazawa 920-0934
Japan
Phone: +81-76.265.2783
Fax: +81-76.234.4524
E-mail: ohtsubo@kenroku.kanazawa-u.ac.jp
Document URL: http://www.joplink.net/prev/200801/03.html
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