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G. Corvino et al.
component and a dilated MPD and/or concerning features on EUS-FNA have a
clear indication for surgery [81].
MN is the only independent predictor of IC and HGD for all types of IPMNs
(except for the prediction of HGD in BD-IPMNs) with a sensitivity and a specicity
of 62.2% and 75.1%, respectively. For BD-IPMN, the presence of MNs has the
highest prognostic factor power for malignancy, followed by MPD dilatation and
thick septum/wall. The risk of malignancy is directly proportional to the size of the
mural nodule but further studies are needed to provide a dimensional cut-off [44]. If
the arterial phase of MRI doesn’t clarify the presence of a MN, it is indicated to
perform CH-EUS that ensures the best performance in detecting MN and possibly
differentiate them from mucin clots. According to EEC guidelines, the hyperenhancement of a mural nodule, solid mass, or septations on CE-EUS represents features at high risk for malignant transformation of the cyst, and EUS-FNA of the
lesion should be considered [82, 83].
Some authors reported high rates of malignancy associated with a MPD dilation
between 5 and 9mm [84, 85]. However, malignancy development was shown to be
very rare in presence of MPD dilatation alone, as it was associated with a signicantly increased incidence of cancer only when associated with other features [86].
Therefore, a dilated MPD in the absence of other clinical and radiological predictors
of malignancy may not be used as the sole reason to select patients with presumed
IPMNs for surgery. Moreover, these ndings reinforce the concept that once a
dilated MPD has been detected, further assessment by EUS is necessary, as MPD
can appear dilated for other conditions (e.g., chronic pancreatitis) difcult to assess
with cross-sectional imaging alone [46, 86, 87].
Regarding the size of the cystic lesion, the cut-offs proposed by the guidelines
(cyst size ≥3cm for IAP and ≥4cm for EEC) are chosen arbitrarily as a surgical
indication. Pergolini etal. showed that small BD-IPMNs (<1.5 cm) without WFs
have a signicantly lower risk of malignant degeneration compared to larger cysts
[88]. In clinical practice, a greater role should be assigned to the rate of growth
rather than the cyst size at a single observation; a growth rate ≥2.5mm/year is the
main predictor of malignancy development in presumed BD-IPMN without WF or
HRS [89].
Serum CA19-9 is an independent predictor of malignancy in IPMNs, and a
CA19-9 value higher than 37U/L is associated with an increased risk of invasive
carcinoma [90, 91].
Further observational studies are needed to better clarify the natural history of
PCNs. In an analysis conducted in the US, only 23% of operated IPMNs contained
invasive or HGD at nal pathology [92]. Therefore, in a multicentric study [93], the
role of dynamic variables associated with malignant disease was explored in estimating the presence of HGD and IC at the nal pathological examination. In patients
with BD-IPMNs, the development of additional WFs and HRS during surveillance
was independently associated with the diagnosis of HGD at the nal pathological
examination but considering the different WFs, no single WF was found to be signicantly associated with the presence of HGD at the nal pathological examination. Among HRS, only jaundice was associated with the diagnosis of IC.
15 Cystic Neoplasms
263
In a recent surgical series from Heidelberg, the timeliness of resection based on
nal histology was classied as too early (adenoma and LGD), timely (intermediategrade dysplasia and in situ carcinoma), and too late (IC). According to the authors,
30.4% of the patients were operated too early and 34.5% too late. The resection was
considered timely in 35.1% of cases, but radiological criteria for malignant conditions in this group were detected only in one-third of patients [94]. The low rate of
detectable features specic for HGD and the uncertainty about IPMN’s biological
behavior make it controversial to consider “too early” and “too late” the resections
carried out for LGD or IC. In this regard, IPMNs have been compared to the
Schrödinger’s cat paradox [95]; unless the observer (surgeon) opens the box
(patient’s belly), the cat (IPMNs) is both alive (low-grade) and dead (high-grade) at
the same time [96].
The specic type of surgery is based according to the cyst’s location, and major
pancreatic resections with standard lymphadenectomy are the goal standard: pancreatoduodenectomy (PD), distal pancreatectomy (DP), or total pancreatectomy
(TP) should be performed, either with an open or minimally invasive approach [97].
TP is indicated in cases of diffuse MPD involvement, multifocal disease in patients
with a family history positive for PDAC and persistent HGD at the resection margin.
When facing a multifocal IPMN, each lesion should be evaluated for surgical resection as a single entity.
It is very important to highlight the role of the frozen section to drive the extent
of the resection when performing a partial pancreatectomy [80, 98, 99]; whereas in
case of HGD or IC, further resection up to TP is needed, in case of LGD it should
be avoided [80]. The frozen section is important also to identify the presence of a
denuded epithelium, associated with a poor diagnostic value of the examination; in
this case, the need for further resection should be evaluated carefully [100]. To drive
the extension of the resection, the direct visualization of the ductal system with
pancreatoscopy can be also considered [101, 102].
When considering surgery, it should be always taken into account that pancreatic
surgery is still burdened by high rates of major morbidity (dened as Clavien-Dindo
≥3) and mortality [103]. DP with or without splenectomy is burdened by a major
morbidity rate ranging from 14 to 38% and mortality from 0 to 2% [103–105]. To
personalize the possible surgical indication toward less aggressive management in
the absence of features suggestive of malignancy for presumed IPMNs, the risk of
major morbidity and postoperative pancreatic insufciency can be preoperatively
established according to the type of surgical intervention. Among PD/TP, age and
body mass index (BMI) dened three different classes for predicting postoperative
major morbidity (Clavien–Dindo C3), being greater (ranging from 20 to 36%) for
older and overweight patients. Two risk classes of major morbidity, with respective
probabilities of 5% and 25%, were identied by the preoperative presence of diabetes for DP patients. In this study, long-term outcomes for PD and DP patients were
analyzed; new-onset diabetes and worsening of pre-existing diabetes were experienced, respectively, by 25.6 and 66.7% of patients and age, CACI score, history of
diabetes, and DP were associated with an increased risk [28].
264
The role of chemotherapy in IPMNs is not clear. In the postoperative setting,
despite the lack of randomized controlled studies, retrospective series suggest that
adjuvant chemotherapy improves survival, but only in invasive IPMNs with nodal
disease or tubular differentiation [106].
Regarding MCNs, upfront surgery should be considered for lesions with MNs,
enhancing walls or cyst size ≥50mm. In a large surgical series, HGD or IC was
never found in lesions smaller than 5cm [28]. In the absence of these features, the
incidence of overt malignancy is negligible and surveillance can be the rst option.
Cytology might help only when malignant cells are identied. However, no denitive conclusions can be drawn if no malignant cells are observed directly. Radical
resection of noninvasive neoplasms (limited to the ovarian stroma) ensures cure,
and the recurrence is rare with 5-year disease-specic survival for MCNs around
100% and 58% for patients with noninvasive and invasive tumors, respectively
[107]. The radiologic post-resection surveillance depends on nal pathology: benign
MCNs, after radical resection, do not require a follow-up as the risk for recurrence
is absent, while in cases of MCN associated with IC, patients should receive a follow- up similar to patients with PDAC [108].
G. Corvino et al.
Surveillance Options forPCNs
The ultimate goal in the surveillance of PCNs is to identify neoplasms which will
eventually evolve into malignancy. The decision to initiate a surveillance protocol
should consider not only the cyst’s characteristics but also the clinical history, the
patient’s age and comorbidities, familiarity, and above all the patient’s will. To date,
numerous studies have shown that surveillance can be safe, particularly when facing
BD-IPM without WF or HRS [109–111].
Guidelines
According to the IAP guidelines [80], if there are no WFs or HRS on initial observation, it is advisable to re-evaluate with MRI/MRCP or possibly CT after 3–6months
to rule out abrupt changes in cyst features. As mentioned earlier, a surveillance
protocol can be initiated if such features are not conrmed. Thereafter, the surveillance protocol may be performed at longer intervals, depending on the size of the
cyst. A shorter interval (3–6months) should be applied for patients with a family
history of hereditary PDAC.On the other hand, the EEC guidelines [79] propose the
same management of patients with sporadic IPMN.
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265
The AGA guidelines [81] evaluate only symptomatic PCNs. They advise that
patients with pancreatic cysts <3cm without a solid component and dilated pancreatic duct should undergo MRI for surveillance in 1year and then every 2years for
a total of 5years if there is no change in size or characteristics. The same protocol
is applied for patients undergoing EUS-FNA and lacking the features mentioned.
According to EEC guidelines [79], a surveillance protocol should be considered
if there are no relative indications [MPD dilatation between 5 and 9.9mm, cystic
growth rate >5mm/year, increased level of serum CA 19-9 (>37U/mL), symptoms,
enhancing mural nodules (<5 mm), and/or a cyst diameter ≥40 mm) or absolute
indications [jaundice, the presence of an enhancing mural nodule (≥5mm) or a solid
component, positive cytology, or a MPD measuring ≥10mm] are present. A 6-month
follow-up in the rst year and yearly thereafter is considered adequate when no risk
factors are present. For patients with relative indications for surgery or the “elderly”
affected by severe comorbidity, a 6-month follow-up is recommended.
Surveillance Discontinuation
An urgent issue for healthcare systems is the possibility of surveillance discontinuation in selected patients. The extensive use of MRI and CT of thousands of individuals through repeated scans is becoming relevant for healthcare systems.
Furthermore, the psychological burden associated with a surveillance program is of
no less importance. Indeed, patients under surveillance for presumed IPMN at low
risk of malignancy may present with a “sword of Damocles” effect, presenting subclinical symptoms of somatization, depression, anxiety, sleep disorders, and feeling
less healthy than patients undergoing surgery [112].
Both IAP and EEC guidelines [79, 80] advise surveillance indenitely until the
patient remains t for surgery while the AGA guidelines [81] are the only ones to
propose a stop of surveillance if the characteristics of the cyst have not changed
after 5years. Marchegiani etal. have identied in “trivial cysts” the potential targets
for follow-up discontinuation; trivial BD-IPMNs are those without WF or HRS at
baseline and not developing WF or HRS for at least 5years from baseline. After
5years of follow-up, the overall cumulative risk of developing WF/HRS and IC was
4.4% and 1.1%, respectively (similar to that of the general population older than
65years and postoperative mortality due to pancreatic surgery in high-volume centers). In conclusion, a trivial BD-IPMN in patients aged >65years might not increase
the risk of developing PC compared to the age-matched general population [89].
Pergolini etal., on the contrary, suggest that surveillance should not be interrupted
in all BD-IPMNs, even in those under surveillance for over 5years with a stable
lesion, and intensication of follow-up might be required after the rst 5years [88].
As a matter of fact, the debate is still ongoing.
266
G. Corvino et al.
Follow-Up Strategy
The follow-up strategy includes dedicated pancreatic protocol CT and pancreatic
MRI/MRCP.Pancreatic MRI/MRCP is more sensitive than CT for identifying communication between the cysts and the pancreatic duct system, and the presence of a
mural nodule or internal septations [70]. The use of CT should be considered to
detect calcication and to exclude malignancy or concomitant PDAC, vascular or
peritoneal involvement, metastatic disease, and suspected postoperative recurrence
of PDAC [79]. EUS should be reserved for patients with WF.CH-EUS is not used
in all centers but is helpful to better evaluate the vascularization of a mural nodule,
solid mass, or septations [47]. Fluid markers such as CEA or Ca 19.9 may help with
the diagnosis of invasive cancer.
Follow-Up andOutcome ofResected IPMN
A new IPMN or a concomitant PDAC may appear even 10years after resection,
therefore IAP and AGA guidelines advocate life-long surveillance protocol with
different intervals depending on the nal histology. In particular, if the nal histology of an IC is found, then the follow-up does not differ from that of a PDAC.In the
case of MD-IPMN or HGD, the reassessment is on a six-month basis in the rst
2years and then annually. IPMN with LGD dysplasia should be followed up in the
same manner of non-resected IPMN.
An analysis of 130 patients who underwent resection of noninvasive IPMNs
revealed that the 1-, 5-, and 10-year risks of developing a new IPMN are 4%, 25%,
and 62%, respectively [113]. The risk of developing an invasive IPMN at 1-, 5-, and
10years is 0%, 7%, and 38%, respectively [114].
The Verona Policy
From the author’s point of view, several subsequent evaluations of the dynamic
changes in time of a pancreatic cystic lesion play a more relevant role in the decisionmaking rather than taking a single “picture.” As a matter of fact, a growth rate
≥2.5 mm/year is the main predictor of malignancy development in presumed
BD-IPMN without WF or HRS.This reinforces the patient-tailored approach based
on radiological features, presence of symptoms, and tness for surgery in order to
avoid upfront surgery in patients that potentially could never develop any HRS or
WF. The authors recommend surveillance with an MRI/MRCP associating serological tumor markers testing (CEA and CA 19-9) after a short interval (3–6months)
in the rst year. In the absence of any suspicious characteristics, surveillance should
be continued initially every 12months and thereafter up to 18months. If relevant
15 Cystic Neoplasms
267
modications appear, we recommend CH-EUS to advise the decision between surgical resection and surveillance continuation. If relative contraindications are present at the rst observation, CH-EUS with FNB or FNA is recommended as the
rst step.
In case of presumed MCN, <5cm in size and without MNs, enhancing walls and
Ca19-9in range, non-operative management is recommended, particularly in young
patients.
Conclusions
The prevalence of cystic lesions is sharply increasing, due to the more extensive use
of CT and MRI.It is essential for the clinician to differentiate between malignant
lesions and the ones that may evolve into malignant forms, from those that are not.
There are three different guidelines to refer to, namely IAP, AGA, and EEC, in the
management of these complex pathologies. These guidelines are mainly based on
surgical series and experts’ consensus but represent a great tool for the initial diagnostic framework, indications for surgery, and surveillance protocols. A combined
approach with MRI, EUS +/− FNA with possible analysis of the cystic uid and
CE-EUS has allowed for improving the diagnostic accuracy even if the misdiagnosis rate is still high. A future perspective is represented by the execution of molecular analyses. As discussed above, several subsequent evaluations of the dynamic
changes in time of a pancreatic cystic lesion play a more relevant role in the
decision- making of the management rather than taking a single “picture.” The overall major postoperative morbidity and mortality of patients undergoing pancreatic
resection for PCNs remain relatively high, similar to that for other indications. For
this reason, a tailored approach based on the patient’s will, age, frailty, and life
expectancy is mandatory. Once the patient is considered unt for surgery for any
reason, no further surveillance is required.
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