1. The document presents Italian consensus guidelines for the diagnostic workup and follow up of cystic pancreatic neoplasms (CPNs). 2. It provides 52 statements with evidence levels and recommendations on topics including clinical evaluation, imaging, endoscopic ultrasound, cyst fluid markers, and pathology. 3. The guidelines are intended to standardize the evaluation and management of CPNs according to morphology and symptoms, while taking into account resources in the Italian healthcare system.

1. ITALIAN CONSENSUS GUIDELINES FOR
DIAGNOSTIC WORK-UP AND FOLLOW-UP OF
CYSTIC PANCREATIC NEOPLASMS
Elisabetta Buscarini Raffaele Pezzilli

2. WHO classification of cystic pancreatic tumors, 2010
 CPNs: mostly detected incidentally
 High prevalence: 2.6% -19.6%
 Increase of CPNs prevalence with age: 8% below 70 yrs up to 35% >90 yrs

3. serous
mucinous
IPMN
pseudopapillary
Type Sex Meanageatdiagnosis
serous 50
mucinous 50
IPMN >60
pseudopap 30

4. AIGO and AISP have fostered consensus guidelines :
– limited to the diagnostic work-up and follow-up of all CPNs according to
WHO classification
– based on a sound consensus methodology to allow evaluation of
published data and of their quality, and to synthesize them with expert
opinion
– clinically oriented
– taking into account also the characteristics of Italian Health Care
System, with its inherent availability of different diagnostic techniques
– applicable only for patients “fit for treatment” at the time of diagnosis or
along the follow up
Consensus guidelines CPNs

5. COHORDINATORS
Elisabetta Buscarini
Raffaele Pezzilli
Renato Cannizzaro
Massimo Falconi
CLINICAL
Renato Cannizzaro
Luca Frulloni
Stefano Crippa
Riccardo Casadei
Alessandro Zerbi
EUS
Claudio De Angelis
Paolo Arcidiacono
Paolo Bocus
Pietro Fusaroli
Luca Barresi
IMAGING
Giovanni Morana
Silvia Venturini
Mirko D’Onofrio
Lucia Calculli
Claudio Pasquali
LABORATORY
Massimo Gion
Daniela Basso
Maurizio Ventrucci
Rodolfo Rocca
Gabriele Capurso
PATHOLOGY
Giuseppe Zamboni
Vincenzo Villanacci
Vincenzo Canzonieri
Gianpaolo Balzano
Donatella Pacchioni
Consensus guidelines CPNs
Teams

6. Luca Albarello
Lorenzo Camellini
Rita Conigliaro
Giuseppe Del Favero
Giovanna Del Vecchio Blanco
Pierluigi Di Sebastiano
Carlo Fabbri
Niccola Funel
Andrea Galli
Armando Gabbrielli
Rossella Graziani
Andrea Laghi
Giampiero Macarri
Fabrizio Magnolfi
Guido Manfredi
Marco Marzioni
ConsensusParticipants
Fabio Monica
Nicola Muscatiello
Massimiliano Mutignani
Antonio Pisani
Enrico Scarano
Marco Spada
Alessandro Zambelli
Representative of SIED
Guido Costamagna
Representative of SIGE
Paolo Cantù
Representative of SIGENP
Tiziana Guadagnini
Representative of SIUMB
Carla Serra
Representative of the GP
Marco Visconti
Representative of citizen and patient rights
Paolo Federici

7. Levels of evidence
Oxford Centre for Evidence-Based Medicine Medicine

8. Grades of recommendation
The strength of eachrecommendationdepends on the
category of the evidencesupportingit
Oxford Centre for Evidence-Based Medicine

9. Consensus Guidelines CPNs
Fifty-two questions
1. Clinical framework, 12 statements
2. Laboratory, circulating, 5 statements
3. Radiology, 5 statements
4. EUS, 13 statements
5. Laboratory, intracystic, 11 statements
6. Pathology, 6 statements

10. CLINICAL EVALUATION

11. Statement
All patients with pancreatic cystic neoplasms require a diagnostic work-up
EL 2a, RG B
After exclusion of patients neither suitable for any treatment
nor wishing a diagnostic definition, which patient with
pancreatic cystic lesion needs further diagnostic work up?

12. Statement
Signs/symptoms include: abdominal pain, acute pancreatitis, nausea and
vomiting, weight loss also due to exocrine pancreatic insufficiency with
steatorrhea, anorexia, recent onset or worsening diabetes, obstructive
jaundice, and palpable mass
EL 4, RG D
After setting definition on the basis of the presence/absence of
sign/symptoms, depict accordingly clinical scenarios.
In symptomatic patients which are signs/symptoms due to a
pancreatic cystic lesion?

13. Symptomatic Lesions

14. Statement
In the setting of symptomatic patients, high resolution imaging
techniques including MRI with MRCP and/or MDCT scan with
pancreas protocol represent the first diagnostic step
EL 1a, RG A
In the setting of symptomatic patients which diagnostic
technique/s is/are necessary before treatment?

15. Asymptomatic Lesions

16. Statement
A family history for pancreatic cancer and/or other malignancies and a
personal and familial history consistent with Von Hippel-Lindau disease
have to be searched
Serum CA19-9 and glucose level have to be evaluated as well
EL 2a, RG B
Which data regarding personal or familial history, and which
laboratory findings have to be searched for in asymptomatic
patients?

17. Statement
An enhancing solid component within the cyst represents an indication for
treatment
For IPMNs the presence of a main duct > 10 mm is another indication for
treatment
EL 2a, RG B
In asymptomatic patients are there morphological findings
of the cystic pancreatic neoplasms which can address
straightforward to treatment?

18. In asymptomatic patients which technique/s is/are
necessary to address the patient with pancreatic cystic
lesion either to treatment or to follow-up?
Statements
In this setting pan exploring high resolution imaging techniques
including MRI with MRCP and/or MDCT scan with pancreas protocol
represent the first diagnostic step
EL 4, RG C
When “worrisome” morphological features are identified or in patients
with uncertain radiologic diagnosis (i.e. small branch-duct IPMN versus
small SCN) EUS with FNA for cytology is recommended
EL 4, RG C

19. Regarding the follow-up of patients where observation has
been chosen, and bearing in mind that follow-up aims to:
1) demonstrate the size variations over the time (either as
cystic lesion increase or decrease in size or disappears);
2) diagnostic confirmation (test of time),
we need to answer to the following questions:Which is the test
of choice for follow-up?
Statement
The test of choice for follow-up is MRI with MRCP.
At any follow-up evaluation a careful clinical examination to look for
symptoms and laboratory tests including, CA 19.9 and glucose levels
has to be performed, especially in mucinous lesions
EL 2a, RG B

20. Which is the timing?
Statement
Follow-up timing should be carried out at least yearly and be related
with morphological characteristics of the cystic lesion, family history of
pancreatic cancer, diabetes mellitus and serum CA 19-9 levels
EL 3, RG B

21. Suggested follow-up timing according
to the type of cystic lesion

22. TEST 1
F, 32 yo, incidentaldiscovery
F, 38 yo,
incidentaldiscoveryduringpregnancy

23. Do cystic lesions of the pancreas exclude the patient from
organ transplantation?
Statement
No
EL 4, RG C

24. Which diagnostic work-up is required in organ transplant candidates
with evidence of a cystic lesion of the pancreas without
morphological characteristics of malignancy?
Statement
MRI/ MRCP and EUS with FNA are recommended. Laboratory tests including CA 19.9
and glucose level and a careful clinical evaluation for cyst-related symptoms should be
carried out.
EL 4, RG C

25. In the organ transplanted patient does the presence of an
asymptomatic cystic lesion of the pancreas without morphological
aspects of malignancy require alternative follow-up strategies in
diagnostic tests and timing?
Statement
No
EL 4, RG C

26. LABORATORY &CIRCULATING
MARKERS

27. Which is the post-test probability that an abnormal serum
CA19.9 level recognizes a malignant behavior of a
pancreatic cystic neoplasm?
Statement
CA19.9 is not a marker of CPNs malignancy. However serum CA19.9
determination provides additional information within the diagnostic
work up since a positive result is associated with the presence of an
invasive carcinoma with a SP ranging from 79 to 100% and a PPV of
74%. Conversely a negative result does not exclude the presence of a
malignancy (SS 37-80%)
EL 4, RG C

28. CROSS SECTIONAL IMAGING
&
NUCLEAR MEDICINE

29. Which is the best imaging modality among US/CEUS, MDCT,
MRI - MRCP, secretin MRCP, FDG-PET for differentiating
between benign and malignant cystic pancreatic lesions?
Statement
Conventional US of the pancreas is not able to definitively diagnose
CPNs
EL 5; RG C
The different dynamic imaging modalities (CEUS, MDCT, MR) have
similar high accuracy.
EL 1b; RG A
Available data do not support the use of S-MRCP in the differential
diagnosis of benign versus malignant CPNs
EL 5; RG D
The accuracy of FDG-PET-CT is high
EL 1b; RG B

30. Which is the best imaging modality among US/CEUS, MDCT,
MRI - MRCP, secretin MRCP, FDG-PET for differentiating
between mucinous and non-mucinous cystic pancreatic
lesions?
Statement
MDCT and MR are the best imaging modalities for differentiating
mucinous and non-mucinous CPNs, both with high accuracy
EL 1b; RG A
There are no corresponding detailed data on CEUS and 18FDG-PET
Data supporting the use of S-MRCP are not available
EL 5; RG D

31. Which is the role of different imaging techniques in patients
with CPNs (diagnostic algorithm)?
Statement
MR and MDCT are first level techniques in the differentiating benign from
malignant CPNs. CEUS has similar performances than MR and MDCT, when
CPNs is visible at US
MR with MRCP is the best imaging modality to evaluate the communication of
CPNs with the main pancreatic duct
EL 1b; RG A
Based on the above statements, MR with MRCP is the imaging method of
choice for the study of CPNs
18FDG-PET must be considered as a second level, if clinical suspicion for
malignancy is high and other imaging modalities are inconclusive or if other
imaging modalities are suspicious for malignancy but with a low level of
confidence.
EL 5; RG D

32. Which is the role of different imaging techniques
(US/CEUS, MDCT, MRI - MRCP, secretin MRCP, 18FDG-PET-
CT) for the follow up of patients with asymptomatic CPNs?
Statement
The role of single method is depending on both the size and the number of
CPNs
Single cyst:
Small (< 1 cm)
• visible at US: US preferred until size change occurs.
• not visible at US: MR/MRCP
Large (≥ 1 cm)
• visible at US: US preferred until size change occurs. If size change
occurs,
• not visible at US: MR with MRCP or MDCT (the latter with the above
limitations).
In case of strict follow-up (e.g. 3 months), MDCT should be used only in older
patients without renal insufficiency or in patients with absolute
contraindications to MR
Multiple cysts:
•MR with MRCP

33. ENDOSONOGRAPHY & ERCP

34. Statement
EUS can identify morphological features which increase the suspicion for
malignancy in CPNs. However EUS morphologic features alone cannot
exclude the presence of malignancy in CPNs
EL 2b, RG B
What is the role of EUS in differentiating between benign
and malignant CPNs?

35. Statement
Although EUS morphology alone cannot provide a definite differential
diagnosis between mucinous and non-mucinous CPNs, some EUS
features offer useful information on the type of lesion
EL 4, RG C
What is the role of EUS in differentiating between mucinous
and non-mucinous pancreatic cystic lesions?

36. Statement
Contrast enhanced EUS may be helpful in differential diagnosis of
CPNs and in ruling out neoplastic degeneration. Analysis of intracystic
nodules at contrast enhanced EUS may help in differentiating neoplastic
vegetations from mucus and debris
EL 4, RG C
Does the use of contrast during EUS increase the
diagnostic accuracy of EUS for CPNs?

37. Statement
EUS-FNA is indicated when a previous diagnostic modality has depicted
CPNs with worrisome features other than an enhancing solid component
or when the other diagnostic modalities fail to give either a definite
diagnosis or in cases of advanced malignant cystic lesions when
chemotherapy is considered
EL 2a, RG B
When is EUS-FNA recommended for differentiating between
benign and malignant CPNs?

38. Statement
EUS-FNA is indicated when the other diagnostic modalities fail to give
a definite differential diagnosis
EL 2a, RG B
When is EUS-FNA recommended for differential
diagnosis between mucinous and non–mucinous CPNs?

39. TEST 2
F, 74 yo, recurrentepigastricpain&recentdiabetesonset

40. M, 64 yo, incidentaldiscovery
TEST 3

41. Statement
Diagnostic ERCP for the evaluation of CPNs is indicated only if
endoscopic views of the papillary area, pancreatoscopy, or intraductal
ultrasound are still required at the end of the diagnostic work-up for a
definite diagnosis in patients with suspected IPMN
EL 4, RG C
Which is the diagnostic role of ERCP in patients with CPNs?

42. Statement
EUS-FNA of CPNs entails a rate of intra-cyst hemorrhagearound 4%.
Usually bleeding is self-limiting. No death has been reported after EUS-
FNA performed in the standard modality with standard needles. Different
risks of complications have been reported with different technical
modalities of FNA or using different devices.
EL 4, RG C
Which is the expected complication rate due to EUS-
FNA?

43. Statement
There are not sufficient data to show that antibiotic prophylaxis reduces
the rate of infectious complications.
EL5, RG D
Does antibiotic prophylaxis reduce the infectious
complication rate of EUS-FNA of CPNs?

44. LABORATORY- MARKERS IN CYST FLUID

45. Is the determination of intracystic CEA useful in the
differential diagnosis between benign and malignant cystic
pancreatic lesions?
Statement
Intracystic CEA is not accurate in recognizing malignant from non-
malignant lesions
EL 2a, RG B

46. Is the determination of intracystic CEA useful in the
differential diagnosis between mucinous and non-mucinous
cystic pancreatic lesions?
Statement
Increased CEA levels in cyst fluid are helpfulindistinguishing
mucinous from not mucinous CPNs
EL 2a, RG B

47. Is the determination of intracystic amylase useful in the
differential diagnosis of cystic pancreatic lesions?
Statement
The determination of amylase in cyst fluid is helpful to determine the
differential diagnosis among CPNs. High amylase levels are usually
associated with a communication between pancreatic duct and
cystic lesion, as for the majority of IPMNs
EL 2c, RG B

48. How much does a combination of intracystic tests increase
their performances?
Statement
The determination of both CEA and amylase is recommended to help
in distinguishing mucinous from non-mucinous cyst lesions
EL 2c, RG B

49. Are there specific recommendations for the assessment of
positive/negative cutoff point of CEA, Amylase and CA19.9
in cyst fluid ?
Statement
No evidence exist on cutoff to be used in the clinical practice. In
addition, cutoff values are partially related to the used assay method
EL 5, RG D

50. PATHOLOGY

51. Can cytological examination differentiate between benign
and malignant cystic pancreatic lesions?
Statement
The cytological examination is useful in the differential diagnosis
between benign and malignant cystic pancreatic lesions
EL 2a, RG B

52. How could be differentiated a mucinous from a non-
mucinous cystic lesion by cytological examination?
Statement
The presence of extracellular, thick mucus, and the recognition of
an atypical epithelial cell component with intracytoplasmic
mucin, represent the diagnostic hallmark of mucinous cystic lesions
EL 2c, RG B

53. Which is the diagnostic value of high-grade cellular atypia?
Statement
The presence of cells with high grade atypia is the best cytological
marker of a malignant cystic neoplasms
EL 2b, RG B

54. TEST 4

55. TEST 5
F, 75 yo, incidentaldiscovery

56. TEST 5
CEA > 150,000 ng/ml
Amylase 84 U/ml
No malignantcells

57. Future developments
The consensus process has highlighted some areas particularly in
need of study:
1. Available data on natural history of CPNs are still very limited
2. Studies of CPNs with transcutaneous imaging are barely
comparable to EUS studies as the latter generally deal with smaller
CPNs or more difficult to interpret: studies comparing the yield and
impact of these techniques in similar CPNs are thus desirable
3. The laboratory examination of CPN fluid still requires a
standardization
4. AIGO and AISP will validate present guidelines with a prospective
data collection in order to evaluate the improvement of both patient
management and efficiency in resource utilization