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51
ETIOLOGY
Few entities within the practice of pancreatic surgery have garnered more
interest and discussion in the last decade than pancreatic cystic lesions.
Cystic lesions of the pancreas can be divided broadly into inammatory
and neoplastic categories. Inammatory cysts of the pancreas, primarily
comprised of pseudocysts, will be discussed elsewhere in this handbook.
e objective of this chapter is to characterize pancreatic cystic lesions that
arise of neoplastic etiology.
Cystic lesions of the pancreas, though once believed to be rare, may
be present in up to 25% of patients based on autopsy studies and up to 15%
of patients based on cross-sectional imaging studies. Although there are
numerous ways to subdivide pancreatic cystic lesions, the most clinically
relevant way to further categorize cystic pancreatic lesions is based on their
malignant potential. ree broad categories commonly used to describe
pancreatic cysts lesions are benign, premalignant, or malignant.
Benign
Although benign from an oncologic standpoint, benign cysts may grow to
cause local compressive symptoms or other complications of mass eect.
ey are also important to recognize because they may mimic premalig-
nant or malignant lesions of the pancreas.
Serous cystic neoplasms (SCNs), also known historically as serous cystad-
enomas (SCA), are the most common benign cystic neoplasm of the pancreas.
ese lesions are lined by glycogen-rich cuboidal epithelium. ese lesions
are most common in women (70%) and usually occur sporadically. In some
patients, they can be multifocal, but this multifocality is most common in
association with the autosomal dominant von Hippel-Lindau syndrome. SCN
may be macrocystic (Fig. 5.1) or microcystic with multiple small septations.
Microcystic SCN often have a characteristic honeycomb appearance allowing
them to be more readily recognized on cross-sectional and endoscopic ultra-
sound (EUS) imaging. Importantly, however, tightly packed multifocal branch
duct intraductal papillary mucinous neoplasm (IPMN) can mimic microcys-
tic SCN, making it sometimes indistinguishable. Although less common, the
macrocystic variety of SCN can notoriously mimic mucinous cystic lesions
(both mucinous cystic neoplasms [MCN] and IPMN). Lymphoepithelial cysts
are much rarer than their benign counterparts and more commonly occur in
men. ese lesions are lined with keratinized squamous epithelium and have
a characteristic exophytic appearance on cross-sectional imaging (Fig. 5.2).
ey have been known to erode into surrounding structures, which often ren-
ders these cysts symptomatic, and they may sometimes appear malignant in
nature. Finally, simple pancreatic cysts are unilocular and invariably benign.
ese cysts may have some association with polycystic disease of other
organs (kidney, liver), but do not demonstrate a gender or age predilection.
Pancreatic Cysts Including
Intraductal Pancreatic
Mucinous Neoplasm (IPMN)
Joshua A. Waters and C. Max Schmidt
5
Section I / Pancreas52
Premalignant and Malignant
e clinical importance of identication of premalignant/malignant pan-
creatic cysts cannot be overstated. eir identication represents an
opportunity to intervene prior to the development of invasive pancreatic
malignancy. at said, the majority of premalignant pancreatic cysts will
FIGURE 5.1 CT scan demonstrating a macrocystic serous cystic neoplasm (SCN) within
the body of the pancreas.
FIGURE 5.2 Arterial-phase CT scan demonstrating the characteristic exophytic appearance
of a pancreatic lymphoepithelial cyst.
Chapter 5 / Pancreatic Cysts Including Intraductal Pancreatic Mucinous Neoplasm (IPMN) 53
not transform into pancreatic cancer in a given patient’s lifetime, so
surveillance is often recommended. Pancreatic cysts in the premalignant/
malignant category include mucinous cysts (MCN and IPMN), cystic neuro-
endocrine tumors, and solid pseudopapillary neoplasm (SPN).
Mucinous cystic neoplasms (MCNs) occur primarily in female patients
in the fth to sixth decade of life. ese are mucin-lled lesions without
any connection to the pancreatic ductal system. ey are unifocal and
macrocytic with histology demonstrating ovarian-type stroma. ey may
demonstrate calcications. When MCN transform, they become mucinous
cystadenocarcinoma, which may represent up to 10% to 20% of MCN. Early
in their course, mucinous cystadenocarcinoma may represent a more indo-
lent form of cancer when compared to pancreatic adenocarcinoma. ese
lesions may stain positive for human chronic gonadotropic or estrogen
receptors. Intraductal papillary mucinous neoplasm (IPMN) represents a
spectrum of lesions with several common features including pancreatic
ductal connection, mucin-producing epithelium, and papillary histology
(Fig. 5.3). ese cystic lesions may be unifocal, multifocal, or multicentric
and occur most commonly in older patients (sixth to seventh decade).
Anatomically, IPMN may involve the main or branch pancreatic ducts or
both. Invasive IPMN is the malignant endpoint in the IPMN oncologic spec-
trum. Malignant lesions may represent around 25% of all resected IPMN
specimens and fall into two distinct histologic subtypes. e tubular sub-
type imitates the appearance and behavior of pancreatic ductal adeno-
carcinoma, whereas the colloid subtype is characterized by large pools of
extracellular mucin and follows a relatively more indolent course. Cystic
pancreatic neuroendocrine tumors (pNETs) are rare variants of typical
pNET and may occur anywhere on the spectrum from benign to malignant
behavior. ese lesions occur more commonly in women and are typically
sporadic, though they may exist as part of a multiple endocrine neoplasia
syndrome. Solid and cystic pseudopapillary neoplasms (SPNs) are rare het-
erogenous solid and cystic lesions that occur almost exclusively in younger
FIGURE 5.3 Hematoxylin and eosin stain histologic operative specimen demonstrating the
prominent mucin-laden papillary epithelial architecture consistent with IPMN.
Section I / Pancreas54
women. ese lesions represent a spectrum from premalignant to
m
alignant (about 10%), but generally have an indolent course.
DIAGNOSIS
e explosion in interest surrounding cystic lesions of the pancreas is due
in part to their increased recognition through improved resolution and
broader use of contemporary cross-sectional imaging. In addition, there is
an increased awareness of the importance of pancreatic cyst identication
and characterization to promote early detection, prevention, and potential
cure of pancreatic cancer. A comprehensive approach to evaluation and
characterization of these lesions is critical to determine: rst, the type of
cystic lesion and, second, the relative oncologic risk of the lesion. Diagnosis
relies on clinical, serologic, radiologic, cytopathologic, and cyst uid (bio-
chemical and DNA) evaluation.
Clinical
Obtaining a detailed clinical history and physical examination plays an
important role in the diagnosis and dierentiation of pancreatic cystic
lesions. As highlighted above, the epidemiologic patterns of these cysts with
regard to age and sex may aid in the development of the initial dierential
diagnosis (e.g., MCN occurring primarily in females). Symptoms attribut-
able to any of these lesions may be subtle. In observational studies, the most
commonly reported symptoms include epigastric pain or fullness, early
satiety, and sometimes nausea. Evaluation for symptoms related to pancre-
atic exocrine and endocrine dysfunction is also important. Compression or
occlusion of the pancreatic ductal system secondary to a cystic lesion may
result in a spectrum of exocrine pancreatic dysfunction and ultimately fail-
ure. Symptoms of exocrine insuciency may initially present as bloating
and atulence, but ultimately may progress to steatorrhea, malabsorption,
and weight loss. Pancreatic duct obstruction may also precipitate pancre-
atitis. Derangements in insulin production may lead to new-onset or wors-
ening diabetes mellitus in some patients. As with most pancreatobiliary
malignancies, the presence of jaundice and cachexia is an ominous sign,
which may indicate advanced malignancy. Physical examination will typi-
cally be somewhat low yield in these lesions. ese patients rarely present
with reproducible epigastric tenderness on exam, but a palpable abdominal
mass may be present in the setting of larger lesions.
Serologic
e use of laboratory studies in the diagnosis and workup for cystic lesions
of the pancreas may be of some adjunctive value. Assay for the develop-
ment of new or worsening diabetes (serum hemoglobin A
1c
, fasting serum
glucose) as well as pancreatic enzymes (serum amylase and lipase) to assess
for pancreatitis in the setting of epigastric pain and nausea should be per-
formed. Additionally, serum tumor markers for pancreaticobiliary malig-
nancy, particularly cancer antigen (CA) 19-9, should be checked, as this has
been shown to correlate with presence of invasive disease in the setting of
IPMN. Elevation of serum alkaline phosphatase has been correlated with
malignancy in pancreatic head cysts well prior to elevation of bilirubin. As
of yet, there are no other viable serologic biomarkers for diagnosis or deter-
mination of malignant potential of pancreatic cystic lesions.
Radiologic
Cross-sectional imaging is the workhorse for the initial diagnosis and
c
haracterization of pancreatic cysts. Although debate exists as to their
Chapter 5 / Pancreatic Cysts Including Intraductal Pancreatic Mucinous Neoplasm (IPMN) 55
relative value, computed tomography (CT) and magnetic resonance
imaging/magnetic resonance cholangiopancreatography (MRI/MRCP) are
the two primary noninvasive imaging modalities utilized for characteriza-
tion these lesions.
Regardless of the modality utilized, certain radiologic characteristics
of pancreatic cystic lesions may suggest a particular etiology. Two elements,
with rare exception, that are predictive of IPMN are ductal connection and
multifocality. ese two features are extremely rare in other cystic lesions.
A central stellate scar is a classic nding for SCN, and mural calcications
may often be present in (but are not pathognomonic of) MCN (Fig. 5.4).
Finally, in the setting of malignant degeneration, cystic lesions of the pan-
creas on cross-sectional imaging may demonstrate features of invasion into
extrapancreatic organs, vascular structures, or the biliary tree. Peritoneal
and hematogenous metastases may also be detected in this setting.
Dual-phase intravenous contrast-enhanced computed tomography
(CT) scan is the mainstay for initial diagnosis and characterization of pan-
creatic cysts. Many pancreatic cysts (up to 30%) will actually be identied as
incidentally detected lesions on CT scan performed for other indications.
Current high-resolution CT scan technology allows for very accurate char-
acterization of these lesions. Most cystic lesions will appear hypodense with
respect to the surrounding pancreatic parenchyma on CT. It is critical to
obtain thin (1mm) cuts through the pancreas as smaller lesions are easily
overlooked with less detailed imaging.
Magnetic resonance cholangiopancreatography (MRCP) is another non-
invasive imaging modality that has gained wide acceptance as important
adjunct in characterizing pancreatic cysts. e ability to obtain a detailed
pancreatic ductogram (Fig. 5.5) may provide the clinician with information
regarding ductal connection (MRI is two to three times more sensitive than
CT scan alone) and may be more accurate in delineating subtle main pan-
creatic duct (MPD) involvement. Some authors suggest that MRCP is supe-
rior in dening IPMN type and extent and routinely employ this technique
in preoperative planning and surveillance strategies.
FIGURE 5.4 MCN of the pancreas with the associated mural calcication seen on CT.
Section I / Pancreas56
Positron emission tomography (PET) scan has been examined as an
adjunctive imaging study to determine the presence of
18
udeoxyglucose
(FDG) avid foci within IPMN particularly as a marker for invasive malig-
nancy. Currently, PET scanning is used to help with clinical decision making
in cases where there is a high index of suspicion for malignancy concomi-
tant with a moderate to high risk of surgical intervention. e sensitivity of
PET scan for high-grade dysplastic lesions and small foci of invasive cancer
is limited, resulting in a signicant false-negative rate.
Although noninvasive imaging techniques are the frontline in the
diagnosis of pancreatic cystic lesions, endoscopic ultrasound (EUS) has
become very important in the detailed evaluation for many pancreatic
cysts. Although EUS is highly operator dependent, this technique allows for
detailed characterization of cyst size, number, relationship with vascular
and ductal structures, and presence of an associated mass or mural nod-
ule. e presence of mural nodule or associated mass (Fig. 5.6) in the set-
ting of IPMN in particular has been reproducibly demonstrated as a strong
predictor of underlying malignancy, and EUS is the most accurate method
of identifying and characterizing these features. Additionally, this modal-
ity provides the surgeon or gastroenterologist with the ability to perform
ne needle or core biopsy with assay of cyst wall or uid. Limitations of
EUS include diculty in fully assessing the pancreatic uncinate process, the
invasive nature of the test, and the aforementioned operator dependence.
In addition, this modality is not generally available outside of the larger
centers.
Endoscopic retrograde cholangiopancreatography (ERCP) was at one
time commonly used in the diagnosis of IPMN. It has very little role in the
workup of other cystic pancreatic lesions, as it can only evaluate cysts that
are contiguous with the MPD. Interestingly, ERCP was noted to have a
false-negative rate in the evaluation of IPMN, particularly in branch-type
FIGURE 5.5 MRCP illustrating the grapelike morphology of a branch-type IPMN with an
obvious ductal connection.
Chapter 5 / Pancreatic Cysts Including Intraductal Pancreatic Mucinous Neoplasm (IPMN) 57
lesions, where mucin plugging may preclude a full and accurate ductogram.
Additionally, there is limited ability to sample non–main duct–involved
IPMN. For these reasons, ERCP has been largely supplanted by EUS and
cross-sectional imaging techniques, especially MRI/MRCP.
Cytopathologic
Cytopathology, typically derived from ne needle aspiration (FNA)
obtained via EUS guidance, has very high specicity (95% to 100%) but
limited sensitivity (50% to 60%) for underlying malignancy in the setting of
mucinous cystic lesions (MCN and IPMN). us, a cytopathologic nding of
high-grade atypia is almost always indicative of an underlying malignant
lesion. Cytopathology is highly accurate (nearly 100%) in the characteriza-
tion of cystic pNET and nearly as accurate for identifying SPN. Limitations
of EUS–FNA cytopathology include diculty in accessing the pancreatic
uncinate and the need for transgastric passage of the biopsy needle, which
may result in false-positive assays for mucin.
Cyst Fluid Analysis
One of the best ways to dierentiate pancreatic cysts is via cyst uid anal-
ysis. e most useful biochemical marker is carcinoembryonic antigen
(CEA). A high CEA level at a threshold of greater than 192 ng/mL is 80%
accurate in dierentiating mucinous (IPMN, MCN) from nonmucinous
(SCN) lesions. e higher the CE A, the more certain the lesion is to be muci-
nous. is is important, as nonmucinous lesions less commonly represent
malignant risk. Absolute CEA level is not an accurate indicator of malig-
nancy. Cyst epithelial DNA shed into the cyst uid allows for genetic char-
acterization of these lesions. A commercial test (PathFinder TG) assesses
the quantity and quality of DNA within the specimen as well as the presence
FIGURE 5.6 EUS illustrating mural nodularity within a branch-type IPMN. This feature
alone is highly suggestive of malignancy.
Section I / Pancreas58
and copy number of Kirsten rat sarcoma viral oncogene homolog (Kras)
mutations, guanine nucleotide protein GSα (GNAS) mutations, and mic-
rosatellite instability to predict loss of heterozygosity at specic loci (e.g.,
17q). is test is strongly correlated with malignancy in mucinous cystic
lesions, particularly in recent multi-institutional molecular registry studies.
Future pancreatic cyst characterization in cases undiagnosed by cytopa-
thology will likely be largely dictated by cyst uid analysis. Table 5.1 indi-
cates a number of DNA and biochemical markers, respectively, at various
stages of commercial development in the characterization of pancreatic
cysts. Importantly, CA19-9 and amylase have not been found to be accurate
indicators of malignancy or ductal connectivity.
MANAGEMENT
Nearly all decisions regarding the management of pancreatic cysts hinge on
either the presence of symptoms or the risk of existing or future progression
to malignancy. is highlights the critical role of clinical history, preopera-
tive imaging, and cytopathologic analysis in the evaluation and manage-
ment of these lesions. Although algorithms for preoperative evaluation and
operative decision making exist, the approach to each patient should be
individualized based on symptoms, anticipated malignant potential, extent
of disease, and patient tness.
Operative Indications and Technical Tips
e indications for resection of cystic pancreatic lesions are typically
approached based on two primary considerations, symptoms and oncologic
risk. When dealing with lesions on the low end of the malignant risk spec-
trum (e.g., SCN), the decision to embark on pancreatic resection is driven
by the goal to alleviate present and future symptoms. For example, some
authorities have suggested that SCN should be considered for resection when
they reach a diameter of 4cm or greater, as these lesions may have a greater
propensity for future growth and worsening symptoms. is preemptive
approach is not endorsed by all pancreatic surgeons, however ; so patients
should be carefully considered for operative versus expectant management.
A much more clear set of indications are apparent in those patients
with evidence of invasive malignancy. ese patients should be approached
with resection criteria similar to those utilized in pancreatic ductal ade-
nocarcinoma. Importantly, invasive pancreatic cystic lesions have dem-
onstrated a lower rate of vascular and lymphatic invasion than “garden
variety” pancreatic cancer, so are in general more amenable to resection.
e most controversial (and most studied) set of indications regarding
resection for cystic pancreatic lesions are for IPMN. Numerous retrospec-
tive series have demonstrated MPD involvement as an independent pre-
dictor of malignancy in IPMN (up to 60% at the time of resection). For this
DNA Markers in Cyst Fluid and/or Cyst Epithelium According
to Pancreatic Cyst Type
TABLE
5.1
Type KRAS GNAS RNF43 CTNNB1 VHL
IPMN + + +
MCN + +
SPN +
SCN +
KRAS, Kirsten rat sarcoma oncogene; GNAS, guanine nucleotide–binding protein alpha-stimulating,
complex locus; RNF43, ring nger protein 43; CTNNB1, beta-catenin gene; VHL, von Hippel-Lindau.
Chapter 5 / Pancreatic Cysts Including Intraductal Pancreatic Mucinous Neoplasm (IPMN) 59
reason, all t patients with main duct involvement should be considered
for pancreatic resection. Typically, the degree of oncologic risk in main
duct IPMN is dened based on the maximal segmental cystic dilation of
the MPD. An MPD ≥5 mm is worrisome, and if ≥10mm, it is considered
a high-risk stigmata of malignancy according to the international consen-
sus guidelines (2012). e decision to resect cystic lesions not involving the
main duct is more complex. In surgical series, branch duct IPMN malig-
nant risk has been reported to occur in 5% to 20% of (mostly symptomatic)
patients. e incidence of malignancy in MCN is similar to that in IPMN.
e presence of high-risk stigmata (i.e., mural nodularity), concerning cyto-
pathology or multiple mutations on molecular proling, should strengthen
the case for resection. e relationship between cyst size and malignancy
has been a debated topic in the literature, with most current series dem-
onstrating no correlation, though some demonstrate positive relationship.
Current international consensus guidelines no longer dictate a size cuto
recommendation for operative resection.
Preoperative Considerations
When considering pancreatic resection in the management of cystic neo-
plasms of the pancreas, the primary goal is to perform segmental pancre-
atic resection to encompass all evident disease. In dealing with the unifocal
cystic lesions of the pancreas, this approach is usually straightforward. For
lesions of the pancreatic head and uncinate process, pancreaticoduode-
nectomy is the most common approach, whereas for lesions of the body/
tail, distal (left-sided) pancreatectomy is typically appropriate. In distal
pancreatectomy, splenic preservation is preferred unless there is a signi-
cant chance invasive disease is present or the lesion is intimately associated
with the splenic hilum or vessels. Patients with larger (>
2.5
cm) cystic pNET
may also benet from splenectomy for optimal lymph node retrieval. Some
authors have advocated enucleation in select cases and demonstrated
reduced operative morbidity and potential mortality. Enucleation should
only be considered if the preoperative likelihood of invasive malignancy is
expected to be low and the lesion is not in close proximity to or involving
the MPD. Tail lesions as they approach the spleen may be less optimal for
enucleation. is is in part due to minimal parenchyma spared with enucle-
ation and an elevated chance for MPD injury due to the small size of the
MPD and the diculty of intraoperative ultrasound to accurately discrimi-
nate relationship of the cyst to the MPD. Multifocal cystic lesions, that is,
IPMN, may require substantially more complex preoperative planning. It is
not uncommon to have radiologic evidence of branch duct IPMN in mul-
tiple anatomic distributions, which would not be encompassed by a single
segmental pancreatic resection. e use of total pancreatectomy carries an
unbalanced and generally unacceptable risk of morbidity and mortality in
the setting of often premalignant and indolent disease. us, the approach
(except in unusual cases) is to perform segmental resection to include the
most oncologically concerning lesion(s) (i.e., mural nodularity, high-grade
atypia, main duct involvement), with subsequent surveillance of the resid-
ual gland/cysts.
Intraoperative Considerations
Several important technical points should be considered when conduct-
ing pancreatic resection for cystic lesions of the pancreas. Although cross-
sectional imaging may provide an excellent roadmap to guide the extent
of pancreatic resection, these lesions may be dicult to identify intraop-
eratively. erefore, liberal use of intraoperative ultrasound to identify the
cyst or cysts should be considered, particularly when planning
en
ucleation,
Section I / Pancreas60
as this may aid in dening the anatomic relationship with the MPD.
Additionally, when undertaking resection for IPMN, particularly main duct
involved, frozen section should be obtained to ensure that no high-grade
dysplasia or invasive IPMN is present at the resection margin. Additional
margins should be taken when feasible in the setting of high-grade dyspla-
sia or frank invasion. If the main duct margin is positive for low- to mod-
erate-grade dysplasia but the gross lesion appears to be removed, further
resection is dictated based upon preoperative discussions of future symp-
tom management, malignant risk, patient preoperative pancreatic func-
tional reserve, and patient tness.
Postoperative Management and Complications
e postoperative management of a patient undergoing segmental pan-
creatic resection for any cystic lesion of the pancreas is largely similar to
a patient undergoing pancreatectomy for other indications. Patients with
pancreatic cystic lesions typically have softer pancreatic parenchyma
(unless they have a history of signicant pancreatitis). e MPD diameter
is also typically small, as there is rarely an obstructing mass. Given these
factors, the rate of pancreatic stula has been reported to be elevated when
compared to stula rates after resection for other indications. Additionally,
although enucleation may represent a less morbid approach to certain cys-
tic lesions, some authors have suggested an elevated risk of pancreatic s-
tula development compared to segmental resection. Early recognition and
percutaneous drainage (if necessary) of pancreatic stulas not controlled
by operatively placed drains (if present) is imperative to reduce major com-
plication such as systemic inammatory response or sepsis, vascular pseu-
doaneurysm, breakdown of enteric or biliary reconstruction, and wound
infection/dehiscence.
OUTCOMES AND FOLLOW-UP
Cystic neoplasms of the pancreas represent a unique opportunity for the
clinician to intervene prior to the development of pancreatic malignancy.
When resected in the premalignant or in situ setting, the disease-specic
survival for IPMN or MCN may approach 95% to 100% at 5 years. Even in the
setting of invasive IPMN, the overall survival and stage-matched survival is
favorable when compared to patients undergoing resection for typical duc-
tal adenocarcinoma.
Patients undergoing resection for cystic lesions should undergo rou-
tine postoperative follow-up with clinical exam and cross-sectional imag-
ing as appropriate. For invasive cystic lesions, this will likely entail every
a 6-month exam and imaging surveillance unless dictated dierently by
medical oncology treatment or trial protocol. For nonmalignant pNET and
SPN, this may entail interval exam and surveillance imaging for a period of
at least 5 years. For SCN or noninvasive MCN, as long as margins were clear,
surveillance imaging is not required. On the other hand, IPMN requires a
more involved postoperative surveillance strategy. As mentioned previ-
ously, because of its multicentric/multifocal nature, operative management
of IPMN often requires segmental resection of the most concerning lesion,
thereby leaving low-risk disease in the remnant gland. e risk prole of the
residual disease has been demonstrated to be related to the histologic grade
of the resected disease. ose patients with low- to moderate-grade IPMN
on initial resection have an exceedingly small risk of progression to malig-
nancy in the remnant gland, whereas patients with high-grade disease in
the resected specimen (even with negative margins) are at higher risk of
cancer progression in the remnant gland and should be considered for a