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Cystic Neoplasms of the Pancreas

Article  in  New England Journal of Medicine · October 2004

DOI: 10.1056/NEJMra031623 · Source: PubMed

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 The new england journal of medicine

review article

current concepts

Cystic Neoplasms of the Pancreas

William R. Brugge, M.D., Gregory Y. Lauwers, M.D., Dushyant Sahani, M.D.,
Carlos Fernandez-del Castillo, M.D., and Andrew L. Warshaw, M.D.

From the Gastrointestinal Unit (W.R.B.) and

the Departments of Pathology (G.Y.L.), Ra-
diology (D.S.), and Surgery (C.F.C., A.L.W.),
Massachusetts General Hospital, Boston.
Address reprint requests to Dr. Brugge at
the Gastrointestinal Unit, Blake 452c,
p hysicians from a wide range of disciplines are being confront-
ed with questions regarding the management of cystic lesions of the pancreas.
Owing to recent improvements in pancreatic imaging, an increasing number of
cystic lesions have been identified in asymptomatic patients as well as in patients pre-
senting with jaundice, pancreatitis, or abdominal pain. Here we review recent develop-
Massachusetts General Hospital, 55 Fruit
St., Boston, MA 02114, or at wbrugge@ ments in the understanding and management of cystic lesions of the pancreas.
partners.org.

N Engl J Med 2004;351:1218-26. pathology

Copyright © 2004 Massachusetts Medical Society.
Because inflammatory pseudocysts constitute a majority of cystic lesions of the pancre-
as, the clinical challenge is the differential diagnosis and management of cystic neo-
plasms, which represent less than 10 percent of pancreatic neoplasms. In the 1990s, at
our institution, the proportion of pancreatic resections that were performed for cystic
neoplasms doubled, from 16 percent to 30 percent.1
With increasing experience with these lesions has come a refinement of our under-
standing of the pathology of pancreatic cystic neoplasms (Fig. 1) and of their natural
history. These tumors encompass a spectrum of benign, malignant, and borderline
neoplasms that either are primarily cystic or result from the cystic degeneration of solid
tumors (Table 1). Among these neoplasms, serous cystadenomas (32 to 39 percent),
mucinous cystic neoplasms (10 to 45 percent), and intraductal papillary mucinous neo-
plasms (21 to 33 percent) represent the majority of the cases encountered in prac-
tice.2,3 Solid pseudopapillary neoplasms represent less than 10 percent; however, these
neoplasms, which occur predominantly in young women, are important, because they
are characterized by a low-grade potential for the development of cancer and, when
limited to the pancreas, have a high rate of cure.4
Serous cystadenomas, which are lined by a simple, glycogen-rich cuboidal epitheli-
um, have an extremely low potential for malignant disease.5 Usually small and micro-
cystic, they may grow to be quite large. Solid and oligocystic variants of serous adeno-
mas have also been reported.6 Interestingly, chromosomal alterations (deletion and
mutation) of the gene for von Hippel–Lindau disease located on chromosome 3p25
have been found in the DNA extracted from a majority of serous cystadenomas.7,8
The histopathological features of mucinous cystic neoplasms and intraductal pap-
illary mucinous neoplasms are almost identical except for a dense mesenchymal ovar-
ian-like stroma, which is a requisite feature of mucinous cystic neoplasms.9 Character-
istically, mucinous cystic neoplasms lack a communication with the pancreatic ductal
system, whereas a communication is a key feature of intraductal papillary mucinous
neoplasms.9 The World Health Organization classification describes three stages of
these neoplasms — benign (adenomatous), low-grade malignant (borderline), and
malignant (carcinoma in situ and invasive cancer).10,11 In a series of 61 patients with
mucinous cystic neoplasms, 44 percent of the neoplasms were classified as adenoma-

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 current concepts

changes from benign status to carcinoma in situ

A are routinely curable by means of complete surgi-
cal resection.13,16 Intraductal papillary mucinous
neoplasms with evidence of changes to an adeno-
matous or borderline stage also have an excellent
prognosis, although the presence of carcinoma in
situ may worsen this prognosis.17 In the resection
of intraductal papillary mucinous neoplasms, it is
important to achieve a negative surgical margin at
the duct, even in the absence of an invasive adeno-
carcinoma, in order to prevent a recurrence of the
tumor.18,19 Some studies have suggested that the
branch-duct variant of intraductal papillary mucin-
B ous neoplasms, when such tumors can be clearly
distinguished, constitutes a distinctive group with
a somewhat lower potential for malignant disease
that may not require the aggressive surgical man-
agement that other papillary mucinous neoplasms
require.20

Figure 1. Histologic Features of Intraductal Papillary
Mucinous Neoplasms.
The neoplasms are characterized by a distended main
pancreatic duct displaying profuse papillary fronds
(Panel A) and borderline dysplasia (Panel B).
tous, 8 percent as borderline, and 15 percent as car-
cinoma in situ.12 Invasive adenocarcinomas ac-
counted for the remaining 33 percent of these
tumors.12 Other series have shown that approxi-
mately 8 percent of mucinous cystic neoplasms con-
tain invasive carcinoma; this discrepancy among
the series is likely to be due to differences in the
pathological sampling.13 Carcinoma in situ is found
in 5 to 27 percent of intraductal papillary mucin-
ous neoplasms and invasive carcinoma in 15 to 40
percent.14 The common occurrence of genetic al-
terations with ductal adenocarcinomas has also
been noted, with point mutations of the K-RAS gene
reported in parallel with the degree of cytologic
atypia.15
An understanding of the natural history of these
neoplasms, especially with regard to the risk of Cystic lesions in the pancreas are increasingly be-
malignant degeneration, is important for manage- ing discovered because of the wide use of trans-
ment. Mucinous cystic neoplasms with evidence of abdominal ultrasonography, computed tomogra-
clinical presentation
Many patients with a pancreatic cystic lesion present
with no relevant signs or symptoms.21,22 Often the
lesion is serendipitously detected by abdominal ul-
trasonography or cross-sectional imaging studies
performed for the evaluation of another condition.
When the lesion is symptomatic, the patient may
present with recurrent pancreatitis, chronic abdom-
inal pain, or jaundice. These symptoms often indi-
cate a lesion obstructing a pancreatic biliary duct or
a communication between a cystic lesion and the
pancreatic ductal system. Patients with an advanced
cystic neoplasm present with symptoms similar to
those of pancreatic ductal carcinoma, including
pain, weight loss, and jaundice.22
True cystic lesions of the pancreas may be con-
fused with pseudocysts owing to similarities in
the clinical presentations and in the characteristics
visualized in imaging studies.23 Pseudocysts may
arise after an episode of acute pancreatitis or insid-
iously in the setting of chronic pancreatitis, and
they are frequently, but not invariably, associated
with pain. Large pseudocysts can compress the
stomach, duodenum, or bile duct, resulting in ear-
ly satiety, vomiting, or jaundice.
diagnosis

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 The new england journal of medicine

Table 1. Epidemiologic and Biologic Characteristics of Pancreatic Cystic Neoplasms.

Sex Peak Decade % of Cystic Malignant Potential

Type Predilection of Life Neoplasms and Natural History

Serous cystadenoma Female 7th 32–39 Resection curative; serous cystadeno-

carcinoma extremely rare
Mucinous cystic neoplasm Female 5th 10–45 Resection curative, regardless of
degree of epithelial dysplasia; poor
prognosis when invasive adenocar-
cinoma present
Intraductal papillary mucinous Equal 6th–7th 21–33 Excellent prognosis for lesions show-
neoplasm distribution ing only adenomatous and border-
line cytologic atypia; poor progno-
sis when invasive carcinoma
present
Solid pseudopapillary neoplasm Female 4th <10 Indolent neoplasm with rare nodal and
extranodal metastases; excellent
prognosis when completely resected
Cystic endocrine neoplasm Equal 5th–6th <10 Similar to solid neuroendocrine
distribution neoplasm
Ductal adenocarcinoma with Slight male 6th–7th <1 Dismal prognosis, similar to solid
cystic degeneration predominance adenocarcinoma
Acinar-cell cystadenocarcinoma Male 6th–7th <1 Similar to solid type; aggressive neo-
plasm with slightly better progno-
sis than ductal adenocarcinoma

phy (CT), and magnetic resonance imaging (MRI)
for the detection of a variety of conditions (Table
2).24 CT is an excellent test for cystic lesions in the
pancreas, not only for the initial detection of a le-
sion but also for the characterization of such le-
sions by visualization of the calcification of the cyst
wall, septa, mural nodules, and findings sugges-
tive of pancreatitis (Fig. 2).25,26 MRI has the added
advantage of providing better characterization of
the morphologic features of a cyst and possibly of
showing a communication between the cyst and
the pancreatic duct.27 Transabdominal ultrasonog-
raphy may aid in the differentiation of solid and
cystic lesions, but a complete evaluation of the pan-
creas is often difficult owing to the presence of
overlying bowel gas.
The presence of a central scar visualized with
the use of CT or MRI is a highly diagnostic feature
that is found in about 20 percent of serous cystad-
enomas. Serous cystadenomas are typically com-
posed of honeycomb-like microcysts, but on CT
they may appear solid or show a single dominant
macrocavity — features that can result in the con-
fusion of these tumors with mucinous cystadeno-
mas.28,29 Mucinous cystic neoplasms, in contrast,
are typically unilocular or multilocular, with a small
number of discrete compartments.26,30 The un-
common finding of peripheral eggshell calcifica-
tion on CT is specific to a mucinous cystic neoplasm
and highly predictive of cancer.12,25
Intraductal papillary mucinous neoplasms may
involve the main pancreatic duct exclusively, a side
branch of the main duct, or both. Magnetic reso-
nance cholangiopancreatography can adequately
indicate the extent of dilatation of the pancreatic
duct, the size of mural nodules, and the presence of
a communication between the duct and the cystic
lesion.27,31,32 Newer developments in CT — for ex-
ample, high-resolution multislice helical imaging
— in combination with postprocessing techniques
such as curved reformations can provide details in
imaging studies of intraductal papillary mucin-
ous neoplasms, including the presence of a ductal
communication, similar to the findings on mag-
netic resonance cholangiopancreatography.33 The
presence of mural nodules and a segmental or dif-
fuse dilatation of the main pancreatic duct greater
than 15 mm in diameter has been reported as in-
dicative of the development of malignant disease.31
The role of positron-emission tomography with
18F-fluorodeoxyglucose in the evaluation of cystic
neoplasms has not been established.34 Although
these features are visible on imaging, there is a sub-
stantial overlap in the morphologic features of

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 current concepts

cystic neoplasms. The ability of CT and MRI to di-

or epithelial cells
Unilocular with thick

(polymorphonu-
clear leukocytes
Thin, dark, opaque,
wall; septations

dence of mucin
es) without evi-
agnose a specific cystic lesion accurately and to

Inflammatory cells

or macrophag-
nonmucinous
dence of pan-
unusual; evi-

creatitis may
Pseudocyst
determine whether malignant disease is present

be present
remains uncertain.25,35
The diagnosis of a pancreatic pseudocyst de-
pends on the clinical history and the associated
findings within the pancreas, such as gland atro-

microscopy
and macro-

on electron
phy, duct dilatation, calcification of the parenchy-

Cystadeno-
Acinar-Cell

Cylindrical or
carcinoma

cells with
zymogen
granules
cuboidal
cystic le-
Mixed features of sol- Variable appear- Mass with local- Microcystic

present
Thin, clear
ma, and calculi in the pancreatic duct. On CT, the

sions
appearance of a pseudocyst is that of a low-attenu-
ation, unilocular cyst with accompanying signs of

fluid collection
acute or chronic pancreatitis.36 The density of the

Adenocarcinoma

ized adjacent

ity of adeno-
Similar to mucinous Cellular aspirate with Small cells with Various cellular-

tous cellular
Degeneration

carcinoma-
with Cystic
fluid in a complex pseudocyst may be higher than

elements
Thin, bloody
Ductal
that in an uncomplicated pseudocyst, owing to the
presence of hemorrhage or gas that develops as a
result of bacterial infection. In categorizing uniloc-
ular cystic lesions, noninvasive imaging methods

and-pepper
phic nuclei
Nonmucinous

monomor-

chromatin
Neoplasm
Endocrine
have limitations when there are no obvious clinical

with salt-
toplasm;
scant cy-
Cystic
and morphologic hallmarks of pancreatitis and no

ance
communication with the pancreatic duct.25
When cross-sectional imaging does not provide

balls, macrophag-
a definitive diagnosis, additional information may

with round nuclei,

id mass with fluid

may contain PAS-

positive globules;
tures; bland cells
and hemorrhage

myxoid stromal
Pseudopapillary

papillary struc-
be sought by means of aspiration of the contents of
Neoplasm

Necrotic debris
a cyst.37 Cytologic examination of cyst fluid and the
Solid

es visible
analysis of a variety of biochemical and tumor
markers may aid in establishing a diagnosis. How-
ever, cytologic analysis of cyst fluid has identified
cells that indicate the presence of malignant dis-
macrocystic and

cystic neoplasm
Papillary Mucinous

Thin, clear, nonmuci- Viscous, clear, with Viscous, clear, with

microcystic le-
Microcystic or honey- Macrocystic; malig- Mixed features of

ease or a benign mucinous cystic lesion in perhaps

sions; dilated
duct may be
Intraductal

Neoplasm

only half the aspirates obtained.38 Only inflamma-

present

tory cells should be present in fluid aspirated from mucin

pseudocysts.39
A variety of tumor markers present in the fluid
in a cyst have been proposed for use in the differen-
may have thick-
Cystic Neoplasm

columnar mu-
cellularity and
with variable

with variable
tiation among the major types of cystic lesions
nant lesions

Mucin-rich fluid
ened wall or

cinous cells
Mucinous

septations

(Table 3).40 Although cancer antigen (CA) 19-9 is

Table 2. Diagnostic Features of Pancreatic Cystic Lesions.*

mucin

atypia
associated with pancreatic adenocarcinoma, its
concentration in cyst fluid has not been established
as a useful indicator for discriminating between
mucinous and nonmucinous cystic lesions.41 Stud-
clear cytoplasm;
boidal cells with
combed lesion;

Monomorphic cu-

(PAS-positive)
20 percent are
Cystadenoma

glycogen-rich

ies conducted in the past decade have suggested

nous, bloody
macrocystic

* PAS denotes periodic acid–Schiff stain.

Serous

cytoplasm

that carcinoembryonic antigen and CA 72-4 are

useful for identifying mucinous lesions.42 The pres-
ence of a mucin-like antigen that reflects the pres-
ence of a mucinous epithelium has also been used
to diagnose mucinous lesions and cancers.43 The
phy and computed
Morphologic features
on ultrasonogra-

Appearance of fluid

findings in a recent series called into question the

Diagnostic Feature

Cytologic feature
tomographic

use of carcinoembryonic antigen as a marker for

scanning

mucinous lesions, and other studies have reported

the superiority of extracellular mucin in the cyst
fluid to carcinoembryonic antigen as a means to
identification.44,45 Although amylase is not a tu-

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 The new england journal of medicine

cystic lesions of the pancreas and to guide fine-nee-

A dle aspiration.48 The high-resolution imaging pos-
sible with endoscopic ultrasonography permits the
identification of the morphologic features of vari-
ous cystadenomas and has been used to aid in the
differential diagnosis of these lesions49 (Fig. 3).
However, the detailed features that can be visual-
ized with this technique do not appear to be suffi-
ciently accurate to allow a differentiation between
benign and malignant cystadenomas unless there
is evidence of a solid mass or an invasive tumor
outside the pancreas.50 The finding of obstruction
of the pancreatic duct is suggestive of malignant
disease arising from a cystic neoplasm.51 Endo-
B scopic ultrasonography is currently the technique
of choice for guiding the aspiration of pancreatic
cystic lesions because of its safety record and its ca-
pacity to obtain cyst fluid; the aspirate can be exam-
ined for tumor markers and for cytologic features.
Intraductal neoplasms can be visualized with
endoscopic retrograde cholangiopancreatography
and with endoscopic ultrasonography (Fig. 3B). On
endoscopy, the appearance of a mucin extrusion
from a widely patent ampulla is pathognomonic of
an intraductal papillary mucinous neoplasm. The
use of injections of contrast material in the main
pancreatic duct will enhance the characteristic find-
ings of mucinous filling defects, ductal dilatation,
and cystic dilatation of side branches. The charac-
Figure 2. Computed Tomographic (CT) Scans of a Serous teristic papillary projections arising from the wall
Cystadenoma and a Mucinous Cystadenoma. of the main pancreatic duct can also be visualized
A serous cystadenoma appears as a well-defined mass directly on endoscopic pancreatoscopy.52 Endo-
in the distal body of the pancreas with fine surface lobu-
scopic ultrasonography may assist in the detection
lations and a honeycomb pattern (arrow) due to the pres-
ence of numerous microcysts (Panel A). A central scar is of malignant disease arising from intraductal pap-
not seen. An axial CT image of a mucinous cystadenoma illary mucinous neoplasms by showing wall inva-
shows a well-defined cyst in the body of the pancreas with sion and may be used to guide fine-needle aspira-
internal septations and few macrocysts (Panel B, arrow). tion to suspicious lesions.52,53 The staging of
intraductal papillary mucinous neoplasms on the
basis of endoscopic ultrasonographic examina-
mor marker, its presence in cyst fluid is often used tion alone may be compromised by inflammatory
as an indicator of a communication between a cyst- changes in the surrounding parenchyma that may
ic lesion and the ductal system. Amylase-rich fluid simulate malignant disease.54
is uniformly found in pancreatic pseudocysts and
in cysts that are associated with intraductal papil- management
lary mucinous neoplasms, whereas low concen-
trations of amylase are found in the fluid of both The management of cystic neoplasms of the pan-
serous cystadenomas and the great majority of creas has not been standardized and is evolving.
mucinous cystadenomas.40,46 Serum levels of CA Surgical resection is indicated for most such le-
19-9 are slightly elevated in some patients who sions in patients who are symptomatic and for
have malignant cystic lesions.47 whom the surgical risk is low; the proper evalua-
In the past several years, endoscopy and endo- tion and subsequent management of disease in pa-
scopic ultrasonography have been used to diagnose tients without symptoms have not been fully de-

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 current concepts

Table 3. Tumor Markers in Cyst Fluid in the Differential Diagnosis of Cystic Lesions of the Pancreas.*
Intraductal Ductal
Mucinous Papillary Solid Cystic Adenocarcinoma Acinar-Cell
Tumor Serous Cystic Mucinous Pseudopapillary Endocrine with Cystic Cystadeno-
Marker Cystadenoma Neoplasm Neoplasm Neoplasm Neoplasm Degeneration carcinoma Pseudocyst
relative concentrations in cyst fluid
CEA Low High High Low Unknown Unknown Unknown Low but variable
CA 72-4 Low High High Unknown Unknown Unknown Unknown Low but variable
CA 19-9 Variable Variable Variable Unknown Unknown Unknown Unknown High
CA 125 Low Variable Low Unknown Unknown Unknown Unknown Low
CA 15-3 Low High Low Unknown Unknown Unknown Unknown Low
Amylase Low Low High Low Low Unknown High High

* CEA denotes carcinoembryonic antigen, and CA cancer antigen.

fined. Accurate delineation of the type of tumor

and of the prognosis are particularly important, A
because over a third of cystic lesions are discovered
incidentally.2 On the one hand, a blanket policy of
resection for all would certainly lead to the removal
of some potentially malignant mucin-producing
cystic neoplasms before the patients become symp-
tomatic and have a lower rate of cure. On the other
hand, such an approach would also lead to surgery
for some serous cystadenomas and other benign
lesions that might never cause problems.
In addition to the presence or absence of symp-
toms, other factors to be considered in the manage-
ment of cystic neoplasms of the pancreas include B
the patient’s age, the degree of surgical risk for
the patient, and the location and size of the lesion
(Fig. 4). High-resolution CT or MRI should be per-
formed as part of planning in all cases. Endoscop-
ic ultrasonography, as compared with CT and MRI,
provides further detail of the morphologic features
of the lesion as well as an opportunity to obtain
specimens of the fluid and the cyst wall, all of which
provide additional information about the nature
of the lesion, particularly for the differentiation
among mucinous lesions, nonmucinous lesions,
and pseudocysts. However, endoscopic ultrasonog-
raphy is not indicated when surgery is planned, re-
gardless of the outcome of the study (i.e., for a pa-
tient at low risk from surgery who is symptomatic).
In intermediate cases, endoscopic ultrasonography Figure 3. Endoscopic Images of a Mucinous Cystic
and fine-needle aspiration are useful to guide man- Neoplasm and a Benign Intraductal Papillary Mucinous
Neoplasm.
agement toward observation when the lesions show
Panel A shows an endoscopic ultrasonogram of a malig-
minimal potential for malignant disease or toward nant mucinous cystic lesion with an adjacent mass (arrow).
resection when there is a substantial risk of it. Panel B shows an endoscopic retrograde cholangiopan-
The current rate of death among patients under- creatographic image of a benign, main-duct intraductal
going pancreatic resection in specialized centers is papillary mucinous neoplasm.
less than 2 percent.55 The improvement in the mor-

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 The new england journal of medicine

Intraductal papillary mucinous neoplasms are

more frequently located in the head of the pancreas
CT or MRI scan
and therefore require a pancreatoduodenectomy.
However, because they tend to grow longitudinally
along ducts, rather than radially into the parenchy-
Risk–benefit analysis of surgical ma, the resection margins of intraductal papillary
resection of a cystic lesion
mucinous neoplasms must be examined intraoper-
atively with a frozen section to confirm clearance of
the tumor. As many as 19 percent of patients who
Low surgical risk and Moderate surgical High surgical risk have an intraductal papillary mucinous neoplasm
substantial benefits risk and unknown or and minimal benefits
moderate benefits require a total pancreatectomy because of the ex-
Example: A young Example: An elderly
woman with ab- Example: A middle- man with cardio-
tensive involvement of the ductal system. Since pan-
dominal pain and aged woman with pulmonary disease createctomy cannot be performed safely in all hos-
a large mucinous a cystic lesion 3 cm and a presumed
cystadenoma in in diameter in the benign intraductal
pitals, the relative risk of the procedure must be
the pancreatic tail body of the pancreas papillary mucinous considered when the physician is recommending
neoplasm in the whether and where surgical treatment should take
head of the pancreas
place.
The prognosis for patients who have undergone
Reassessment with resection of a mucinous cystic neoplasm without
the use of endoscopic evidence of transmural invasion is excellent (nearly
ultrasonography, fine- Monitor with CT,
Surgical resection needle aspiration, and endoscopic ultra- 100 percent).9,57 Even for intraductal papillary mu-
analysis of cyst fluid sonography, or both
(cytologic examination,
cinous neoplasms containing carcinoma (which
carcinoembryonic make up almost 60 percent of resected tumors),
antigen, and amylase) the five-year rate of survival is over 50 percent.18
Some aspects of the management of cystic neo-
Figure 4. Algorithm for the Management of Cystic Lesions of the Pancreas. plasms remain unsettled.57 Our recommendations
for the management of this disease are limited by
the difficulty of distinguishing accurately between
benign and malignant or potentially malignant mu-
bidity and mortality associated with surgery has ex- cinous lesions before resection and by the incom-
panded the acceptability of surgery for the preemp- plete understanding of the natural history of these
tive treatment of benign and premalignant cystic neoplasms. Were it possible to predict the likeli-
lesions. Because most mucinous cystic neoplasms hood and the rate of progression to invasive can-
are located in the tail of the pancreas, a distal pan- cer in a given patient, potentially we could offer
createctomy is sufficient for such premalignant le- continued observation or no resection for some.
sions. Unless invasive carcinoma is suspected or Likewise, very little information is available on the
discovered at surgery, often the spleen can be pre- growth rate of serous cystadenomas and on the
served. Serous cystadenomas, which have a more likelihood of these lesions’ producing symptoms.21
uniform distribution throughout the pancreas, as The development of new treatments for cystic tu-
compared with mucinous cystic neoplasms, are re- mors of the pancreas, such as ethanol ablation and
sected with the appropriate pancreatic segment — radiofrequency ablation, or even the use of cyclo-
distal, proximal (Whipple’s resection), or middle oxygenase inhibitors to arrest the progression of
pancreatectomy; the last is a relatively new tech- adenomas to cancer, await further understanding
nique for use with lesions in the neck or proximal of the biology of cystic neoplasms.
body of the pancreas.56

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