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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_734_Библиотеки_им_академика_М_И_Перельмана.pdf
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G. Corvino et al.
was the only independent factor for remnant pancreatic recurrence [20]. Longterm surveillance for IOPN is needed [21]. Different histologic types and distinct
invasive components can coexist in the same IPMN; nonetheless, it is important to
keep in mind that, if a concomitant PDAC (i.e., a lesion separated from the IPMN
by an uninvolved segment of pancreatic parenchyma) is also present, this does not
imply that it originates from the IPMN [22]. The rate of the development of concomitant PDAC was found to be 0.8%, ranging from 0% to 7% [23]. The traditional idea of the adenoma-to-carcinoma sequence is not the only accepted model
of IPMNs progression [24]. Omori etal. [25] described three different pathways:
– The sequential type, where all driver mutations are shared by PDAC and co-
occurring IPMNs
– The branch-off type, where some driver mutations are shared by PDAC and co-
occurring IPMNs
– The de novo type, where PDAC has driver mutations not shared with co-
occurring IPMNs
This underlines that IPMNs are not per se precursors of adenocarcinoma and
that the pancreas of some patients with IPMNs may have an increased risk of developing PDAC (“eld cancerization” hypothesis) [22]. The branch-off PDAC subtype had a better prognosis than patients with de novo or the sequential PDAC
subtypes [25].
MCN
MCNs are considered either premalignant or already malignant entities. MCN is
found almost exclusively in women in the fourth/fth decade of life and more frequently in the body-tail location [26]. The characteristic location, the prevalence in
the female sex, and the ovarian-like stroma invariably present at pathology examination support the hypothesis of a derivation of MCN from the ovarian primordium.
MCNs are generally small, unifocal, round cysts and, by denition, without a connection to the pancreatic ductal system. From a clinical point of view, they can be
totally asymptomatic. Once they become signicantly large, undened epigastric
pain or sense of abdominal fullness is found to be due to compression of adjacent
anatomical structures. It is not always possible to distinguish MCNs from other
unilocular cystic lesions such as SCN or BD-IPMN, particularly once dealing with
a small cyst. The misdiagnosis rate in a recent, large surgical series was as high as
19.2%, and surgery could have been avoided in 8.3% of patients. In older studies
where almost all suspected MCNs were submitted to surgery, only 10–12% of
resected MCNs harbored either HGD or invasive cancer, questioning the appropriateness of liberal policies in terms of surgical indications [27]. In very recent years,
the follow-up of MCN of small size (<3cm) has been advocated by several centers [28].
15 Cystic Neoplasms
253
SCN
Serous cystadenomas are benign cystic tumors of the pancreas, usually discovered
incidentally in 50–70-year-old females (sex ratio 2:1) without preferential location
between pancreatic head or body/tail [26]. SCNs are usually sporadic, but they
could also develop in the setting of a Von Hippel–Lindau syndrome (VHL syndrome), occurring in 60–80% of VHL patients [29].
Despite some “malignant entities” have been described in previous reports,
SCNs are completely benign, as a recent clinicopathological review claried how
cases reported as “malignant” or “invasive” appear to no longer qualify for the
recent WHO denition of “malignancy” [30].
As for MCNs, there is a lack of communication with the pancreatic ductal system. Unlike the mucin-producing counterparts, they have no potential to evolve into
malignancy, so size becomes crucial in predicting the possible development of
symptoms. Because of their growth, patients may present with nonspecic symptoms like abdominal pain, abdominal mass, gastric outlet obstruction, and rarely
jaundice [7, 31, 32].
According to the morphology, ve SCN subtypes [33] are described:
• Microcystic: thin wall multiple cysts measuring <2cm separated by brous septa
oriented toward the center of the lesion. A calcied central scar may be present
(15% of cases). Sometimes if small and numerous cysts are present, they can
mimic a honeycomb or a sponge.
• Macrocystic: (<10%): coalescing cysts ≥2cm.
• Mixed (microcystic and macrocystic): a combination of the former patterns.
• Solid: absence of cystic spaces on histopathology, cells arranged in nests, sheets,
and trabeculae separated by thick brous bands.
• Unilocular: single cyst without septations [33].
The macrocystic and unilocular variants are associated with the highest risk of
misdiagnosis, particularly in young individuals and those located in the body tail. In
general, in the absence of typical radiological characteristics (central scar and highsignal- intensity microcysts on T2-weighted images on magnetic resonance imaging, MRI), the execution of EUS-FNA is recommended, especially once FNA is
performed to dene the presence of serum or mucin in the cyst. If a SCN is suspected or conrmed, surgery is indicated only if severe abdominal symptoms related
to the tumor (e.g., severe abdominal pain, obstructive jaundice, and gastric outlet
obstruction) are present. In asymptomatic patients, cyst size alone is not considered
an indication for resection, while during surveillance crossover to surgery may be
considered in patients presenting with fast growth, as frequently fast growing SCN
represents other misdiagnosed premalignant entities [31].
The European guidelines suggest surveillance discontinuation after 12months
from diagnosis but considering the risk of potential diagnostic mistakes, and the
absence of specic guidelines on SCN, surveillance should probably continue with
wider intervals (e.g., 24months) and stopped only in patients unt for surgery. If
254
radiologically or clinically suspicious features develop during surveillance, follow up intervals are shortened to 3–6months [33].
G. Corvino et al.
SPT
Solid pseudopapillary tumor (SPT) is dened by the WHO classication [3] as
“indolent tumors with low malignant potential,” but their etiology remains unknown.
They are rare entities, accounting for only 1–2% of all pancreatic tumors and
10–15% of cystic tumors of the pancreas [3]. They are more frequent in young
women with a median age of 25–35, without a preferential pancreatic location. Due
to its slow growth, SPT often remains asymptomatic. It generally has an expansive
rather than inltrative growth pattern, and when the nearby structures are involved,
the most common presenting symptoms are abdominal pain, vomiting, abdominal
discomfort, and a palpable mass. Other symptoms could be weight loss and only
rarely jaundice. Typically, SPT presents as a mass >5cm with both solid and cystic
components but, in some cases, it can have a wide range of morphologies, from
smaller completely solid tumors to larger mostly or completely cystic lesions [34,
35]. Approximately 10–15% of SPTs are metastatic at diagnosis, and the liver is the
most common site, followed by lymph nodes and peritoneum. Ductal obstruction is
rare and, when present, if associated with a solid mass, makes the differential diagnosis with adenocarcinoma challenging [36–38].
SPTs should always receive aggressive surgical treatment, as an excellent prognosis is achievable also in case of locally advanced, metastatic or recurrent disease,
reaching a 5-year disease-free and disease-specic survival of around 98%. Disease
recurrence after surgical resection is extremely uncommon, being reported between
3% and 9% and inltrative growth pattern, invasion of the capsule, and pancreatic
parenchyma invasion being the main predictors [34, 38, 39]. In selected cases, due
to the young age, a parenchyma-sparing surgery may be considered [38].
Differential Diagnosis ofPCNs
General Concepts
To date, the widespread use of diagnostic techniques such as computed tomography
(CT) and MRI has greatly increased the prevalence of PCNs. In a study conducted
in Germany, 49.1% of participants who underwent magnetic resonance cholangiopancreatography (MRCP) had the incidental nding of at least one PCN [1].
Nevertheless, the accuracy of radiological imaging in identifying specic PCN subtypes remains low [40]. Therefore, at diagnosis, it is not always possible to discriminate between different types of PCNs or between benign and malignant ones. Salvia
15 Cystic Neoplasms
etal. reported a rate of incorrect diagnosis in 22% of cases, with rare PCNs such as
cystic neuroendocrine tumor (NET) being the most misdiagnosed (46.7%). A high
rate of misdiagnosis was also observed for BD-IPMN (28%) and SCN (26.1%). The
higher diagnostic accuracy occurred in the case of SPT. Surprisingly, 5% of the
cysts were found to be PDAC and 9% of the resected cysts were histologically nonneoplastic. Although resected MD-IPMN had a correct preoperative diagnosis in
94% of cases, 42.2% of misdiagnosed lesions received a preoperative diagnosis of
MD- or MT-IPMN and were found to be non-neoplastic cysts on nal histological
examination [40]. BD-IPMNs have been associated with a high rate of misdiagnosis, with 20% of them having indeed a main pancreatic duct extension (MT-IPMN).
A high rate of misdiagnosis has also been found for MCN.Hence, having a comprehensive diagnostic evaluation is critical and diagnostic accuracy should be implemented through the use of endoscopic ultrasound (EUS) +/− ne needle aspiration
(FNA) with cystic uid analysis and contrast-enhanced endoscopic ultrasound
(CE-EUS), a real-time EUS evaluation after the peripheral intravenous administration of a US contrast agent, if possible [28]. Cytology might help only when malignant cells are identied. However, no denitive conclusions can be drawn if no
malignant cells are directly observed [40].
255
The Role ofCross-Sectional Imaging (CT, MRI, MRCP)
Among different cross-sectional imaging techniques, MRI/MRCP and CT represent the imaging techniques of choice. CT showed sensitivity and specicity of
about 70% and 90%, respectively, for detecting malignant PCNs but the accuracy
for a specic diagnosis is still low, ranging from 39% to 44% [41]. Sainani etal.
demonstrated an increased accuracy with higher resolution CT and a pancreas-specic protocol [42]. Waters and colleagues suggest that MRI/MRCP is superior in
diagnosing and classifying PCNs and the type and extent of IPMN in particular.
The real advantage of this technique is the differentiation from other lesions mimicking an IPMN, the evaluation of MPD involvement, and the identication of
small branch- duct- type lesions. MRI/MRCP has an accuracy of 40–50% for specic diagnosis but a sensitivity and specicity of around 90% in assessing MPD
communication. For this reason, it is considered the rst-level technique of choice
to study PCNs [41, 43].
The Role ofEUS
EUS represents a second-level technique allowing for high-resolution imaging of
the pancreas. EUS alone showed low accuracy in distinguishing mucinous from
non-mucinous cysts with better performance (accuracy between 40% and 96%)
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G. Corvino et al.
when histology is used [44, 45]. When it comes to diagnosing the specic subtype
of PCN, Giannone et al. reported a misdiagnosis rate of 18.5%. This rate is
reduced to 16% when EUS is performed. The accuracy in detecting the specic
type of cyst differs between IPMN (96%), SPT (80%), MCN (71%), and SCN
(58%). Among diagnostic accuracy, MPD dilatation, enhanced mural nodule, cyst
dimension, and cytologic sampling are associated with a higher rate of correct
diagnosis [46].
A considerable advantage of this method is the possibility to obtain an FNA for
cytology and cystic uid that can be used for amylase, lipase, carcinoembryonic
antigen (CEA), glucose levels, and molecular analysis.
Current diagnostic evaluation of pancreatic lesions can be improved including
CE-EUS [44] and contrast-enhanced harmonic EUS (CH-EUS), a real-time EUS
evaluation after the peripheral intravenous administration of a US contrast agent
performed under a dedicated contrast-harmonic mode, which represents the gold
standard in identifying MNs and ensures the best performance for predicting
malignancy. In detail, the CH-EUS performance for the characterization of MN
has a sensitivity of 97% and a specicity of 90%. Moreover, a negative CH-EUS
performed with dedicated contrast-harmonic could rule out malignant lesions with
a very low risk of error (2–2.5%) [47]. Cytology can be diagnostic, but FNA is not
always performed, and the sensitivity is limited by the scant cellularity.
Furthermore, the sample may not represent the entire lesion and no denitive conclusions can be drawn if no malignant cells are observed directly [48–50].
Recently, a systematic review evaluated the diagnostic performance and safety of
a novel imaging technique, needle-based confocal laser endomicroscopy (nCLE),
that allows for real- time microscopic imaging of the cyst wall, showing a diagnostic accuracy of 99% with a low rate of adverse events [51]. The evaluation of cyst
uid should include CEA, amylase, glucose, and potentially novel biomarkers.
Although traditional EUS sampling includes measurement of CEA, low pancreatic cyst uid glucose is associated with high sensitivity and specicity with signicantly improved diagnostic accuracy compared with CEA alone for the
diagnosis of mucinous versus non- mucinous pancreatic cystic lesions. The lower
level of glucose within the pancreatic cyst may reect more metabolic activity in
mucinous lesions, thus allowing for thresholds of <50mg/dL to be considered a
reasonable cut-off to identify mucinous lesions. Intracystic glucose measurements
offer several potential advantages due to availability and very low cost. CEA
(using the threshold of 192mg/dL) is a marker that distinguishes mucinous from
non-mucinous cysts, but is unable to distinguish IPMN from MCN and can’t identify malignant cysts. Very low CEA levels (<5ng/mL), instead, are more specic
for SCN, pseudocyst, or cystic NET; the main limitation is CEA variations existing among different assays. Amylase is historically used to exclude a pseudocyst
if <250U/L. [52, 53]
15 Cystic Neoplasms
257
Novel Biomarkers
With recent advancements in molecular technologies, investigators are now able to
detect variations in DNA, RNA, protein, and small molecules from limited amounts
of tissue. Such techniques have recently been introduced in cystic uid analysis [54].
DNA-Based Biomarkers
KRAS mutations are present in almost every PDAC (90%), being one of the earliest
mutations in pancreatic cancer tumorigenesis, and KRAS mutations combined with
multiple allelic losses were found to be associated with high specicity in detecting
advanced neoplasia within a mucinous PCN [55]. The combination of KRAS and
GNAS mutations was detected with good sensitivity and specicity in IPMNs.
While IPMNs are in general associated with KRAS, GNAS, and RNF43 mutations,
MCNs do not present with GNAS mutations [56]. VHL mutations are typically
associated with SCA and SPT which lack all of the above mentioned but show those
of CTNNB1 [57].
TP53, PIK3CA, PTEN, CDKN2A, and SMAD4 are typically present in advanced
neoplasia within a mucinous PCN [58–60].
Jones et al. showed that molecular studies using appropriate panels of genes
could change the diagnosis in 12% of cases [61]. In the same way, Singhi etal. have
identied a genetic panel which allowed the diagnosis of mucinous cysts with good
sensitivity and specicity [62].
MiRNA
Upregulation and downregulation of miRNA could be the other potential biomarkers for early detection of malignancy. Ryu etal. reported that miR-21 could potentially differentiate mucinous from non-mucinous with good sensitivity and
specicity. IPMNs could be associated with the upregulation of miR-155 and
miR-21 with the upregulation of both showing a correlation with the degree of dysplasia [63]. Matthei etal. reported a miRNA panel that could differentiate IPMN
with HGD from IPMN with LGD with a sensitivity and specicity of 89 and 100%,
respectively [64].
Protein-Based Biomarkers
The presence of MUC5AC is associated with mucinous cysts and elevated concentrations of MUC2 and MUC4 to mucinous PCNs with advanced neoplasia [65].
Furthermore, Marker et al. found elevated serum MUC5AC concentrations in
258
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G. Corvino et al.
patients with mucinous PCNs with advanced neoplasia [66]. Many others protein
such as plectin-1, SPINK1, and Das1 could be potential biomarkers [67–69].
Radiologic Features ofSpecic Subtypes ofPCNs
IPMNs
IPMNs radiologically appear as a cystic dilation involving the ductal system.
According to this, MD- or BD-IPMNs are dened. In MD-IPMNs, ductal dilation
could be present along the entire length of the duct or segmental (Fig. 15.1).
BD-IPMNs can present as unilocular or multilocular cystic lesions (cluster shapelike), that appear hyperintense on T2-weighted, separated by thin septa communicating with the MPD; MRCP has the highest accuracy to assess this communication
[70]. In MT-IPMNs, both branch and the main ducts are involved (Fig.15.2).
MCNs
MCNs are usually unilocular or oligo-locular (≤6 cysts), round, cystic lesions with
viscous mucinous content that makes the lesion variably hypodense at CT, depending on mucin concentration, and slightly hyperintense on T2-weighted images at
MRI.At CT, MCNs show irregular thick walls (>2mm) and sometimes internal
septa that enhance after contrast medium administration and, occasionally, peripheral calcications “eggshell” (10–25% of cases) [71, 72].
Fig. 15.1 (a) Contrast-enhanced CT of panductal MD-IPMN. (b) Gross Image of panductal MD-IPMN
15 Cystic Neoplasms
Fig. 15.2 MRCP showing
a MT-IPMN
Fig. 15.3 T2-weighted
MRI showing a typical
SCN with central scar of
the pancreatic head
259
SCNs
Radiological criteria of presumed SCN are central scar and/or high-signal-intensity
microcysts on T2-weighted images on MRI without communication with the MPD
(Fig.15.3). The majority of SCNs present as a microcystic variant; a well- demarcated
lesion, with plurilocular shapes characterized by the presence of numerous subcentimeter cysts separated by thin brous septa, which usually converge toward a
central brous scar; this latter may present calcications. These lesions can be multifocal in VHL patients. After the administration of medium contrast, it is possible
to appreciate the vascularization of the septa [33, 73]. In atypical SCN variants (e.g.,
oligocystic, macrocystic, solid, and unilocular), highly suspicious for other PCNs or
pancreatic solid neoplasms, EUS should be considered, and FNA of cyst uid analysis should be performed at the operator’s discretion. When FNA is performed, the
results are considered consistent with SCN if cuboidal cells on the specimen and
low CEA levels (<5ng/mL) in the cystic uid are present [29].
260
Fig. 15.4 Typical MRI
image of pancreatic
body-tail SPT
G. Corvino et al.
SPTs
SPTs present as large well-encapsulated masses with varying solid and cystic components, and sometimes completely solid or completely cystic masses can be
encountered (Fig. 15.4). They could be misdiagnosed as neuroendocrine tumors
(NET) but, differently from these, the enhancement of an SPT should be inferior to
that of the pancreatic parenchyma. Calcications and enhancing solid areas may be
present at the periphery of the mass [36, 74]. In case of entirely or partially cystic
lesions, MRI should be preferred and differential diagnosis with other PCNs should
be considered (Table15.2). Specic for the diagnosis could be the identication of
blood products that appear as hyperintense areas on T1-weighted images and homogeneously or inhomogeneously hypointense areas on T2-weighted images [75]. Of
note, the absence should not exclude the diagnosis [76].
At CE-EUS, SPT typically shows capsule rim enhancement, with non-enhancing
areas inside the lesions [76–78].
The Management ofPCNs
Regarding PCNs’ decision-making, three guidelines are currently available, namely
the International Guidelines of the International Association of Pancreatology
(IAP), European evidence-based guidelines (EEC) [79], and American
Gastroenterological Association guidelines (AGA).
Although they are not uniform regarding indications for surveillance, there is
consistent agreement regarding strong indications for surgery. Obstructive jaundice,
enhancing MN ≥5mm and a MPD size ≥10mm, the so-called high-risk stigmata
(HRS) in the IAP guidelines and “absolute indications” (AI) in EEC, are considered
indications for surgery [79, 80].
According to IAP guidelines, patients with “worrisome features” (WF) on imaging [cyst ≥3cm, enhancing MN <5mm, thickened enhanced cyst walls, MPD size
between 5 and 9mm, abrupt change in the MPD caliber with distal pancreatic atrophy, lymphadenopathy, an elevated serum level of carbohydrate antigen (CA)19-9,
and a rapid rate of cyst growth >5mm/2 years, pancreatitis] should, instead, be
15 Cystic Neoplasms
Table 15.2 Main features of PCNs
IPMN-MD IPMN-BD MCN SCN SPT
Age (years) 50–70 50–70 40–50 50–70 25–35
Gender Equal Equal 90–95%
Pancreatic
location
Radiological
ndings
Communication
w/main pancreatic
duct
Cystic uid
markers
Novel biomarkers KRAS+,
Reasons for
misdiagnosis
Malignant
potential
Equal Equal Body tail Equal Equal
Dilated
MPD
Yes Ye s No No No
Glucose
<50mg/dL,
CEA
>l92ng/mL,
Amylase
high
GNAS+,
RNF43+, VHL−
May mimic
MCN, SCN
60–92% 6–46% 10.9–12% Negligible 15%
Dilated side
branches
Glucose
<50mg/dL,
CEA
>l92ng/
mL,
Amylase
high
KRAS+,
GNAS+,
RNF43+, VHL−
May mimic
MCN, SCN
female
Small,
unilocular
cyst
Glucose
<50mg/dL,
CEA
>l92ng/mL,
Amylase
variable
KRAS+,
GNAS−,
RNF43+, VHL−
Plurilocular
lesions
mimic SCN
70% female 90% female
Multiple cysts
separated by
septa oriented
toward the
center of the
lesion
Glucose
>50mg/dL
CEA <5ng/mL,
Amylase low
KRAS−,
GNAS−,
RNF43−,
VHL+
Unilocular
lesions mimic
MCN; solid
lesions mimic
PanNET
Mass >5cm
with solid and
cystic areas
May mimic
PanNET or
MCN if
completely
cystic
261
evaluated by EUS, possibly with Doppler or contrast-enhancement. If EUS conrms a MN ≥5mm, MPD features suspicious for involvement or it obtains cytology
suspicious or positive for malignancy, surgery is indicated if clinically appropriate.
If these features are not conrmed at EUS, the patient can undergo surveillance with
a schedule adjusted to cyst size [80].
The “relative indications” (RI) considered by EEC have different cut-offs as
compared to IAP considering growth rate ≥5mm/year and cyst diameter ≥40mm.
In these guidelines, symptoms such as new-onset diabetes mellitus or acute pancreatitis are also taken into account [79].
The AGA guideline considers only symptomatic cysts. At least two high-risk
features, such as a size ≥3cm, dilated MPD or the presence of an associated solid
component should be examined with EUS-FNA. Patients with both a solid