Cystic tumours of the pancreas and PanIN

Jean-François FléjouService d’Anatomie Pathologique

Hôpital Saint-Antoine, AP-HP, UPMC - Paris 6, France

Cystic tumours of the pancreasClassically rare : - 5% of pancreatic tumours (?)- 5 to 10% of pancreatic cystic lesions (pseudocysts = 90%)

BUT : . More and more often fortuitously discovered (1% of abdominal CT scans)

. May be malignant or premalignant

--> Specific diagnostic and therapeutic issues

Epithelial cystic tumoursBenign

Intraducal papillary mucinous adenomaMucinous cystadenomaSerous cystadenoma (micro or macro-cystic)Benign cystic neuroendocrine tumourAcinar cell cystadenomaDermoid cystCystic hamartoma

BorderlineBorderline IPMTBorderline mucinous cystic tumourSolid pseudopapillary tumour

MalignantIPM carcinomaMucinous cystadenocarcinomaSerous cystadenocarcinomaCystic pancreatoblastomaCystic metastasisMalignant cystic neuroendocrine tumour

Classification of pancreatic cystic tumoursfrom Kosmahl et al 2004

Non tumorous epithelial cystsCongenital cystLymphoepithelial cystNon neoplastic mucinous cystObstructive cystEndométrial cyst

Non epithelial cystic tumoursBenign (lymphangiomas…)Malignant (sarcomas…)

Non tumorous non epithelial cystsPseudocystsParasitic cysts

Relative frequency of cystic neoplasms of the pancreas

Warshaw et al AFC 1997 Kosmahl et al

130 cases 527 cases 418 cases*

Mucinous cystic tumors 49% 44% 8%

Serous cystadenomas 31% 32% 10%

IPMT 11,5% 11% 18%

Solid pseudopapillary T 3% 4% 21%

Cystic endocrine tumor 1,5% 2% 4%

*includes pseudocysts

Cystic endocrine tumour

Clinical features

MEDIAN AGE FEMALE (%) SYMPTOMS HEAD (%)

Serous

cystadenoma

65 yrs 80 pain +

mass +/-

fortuitous +++

40

MCN 60 yrs 90 pain +++

mass ++

fortuitous +

20

IPMN 55 ans 40 acute

pancreatitis

+++

fortuite ++

60

Solid PP tumour 25 yrs 98 mass +

fortuitous +

Serous cystadenoma

• Often fortuitously discovered• Pancreatic head in women > 60 yrs• Typical microcystic appearence on imaging

• Benign : no surgery

Serous cystadenoma

• Typical epithelium

Serous cystic tumours

Atypical forms

• unilocular

• « malignant » : serous cystadenocarcinoma, no experience…

• Numerous synonyms (Frantz tumour …)

• Young female patients• Most often benign• Large, well limited• Suggestive histology,

characteristic IHC (β-catenin)• Histogenesis still debated

• 10% malignant cases, no markers: must be removed

Solid pseudopapillary tumour

Precancerous lesions of the pancreas

• Cancer of the pancreas = ductal adenocarcinoma• Poor prognosis, poorly recognised fisk factors, no

mass screening• Only 3 recognised precancerous lesions:

• Mucinous cystic neoplasms (MCN)• Intraductal papillary mucinous neoplasms (IPMN)• Pancreatic intraepithelial neoplasia (PanIN)

MCNs

• Female, body and tail• Independant from the ductal system• Uni or multicystic (cysts >2cm)• Various histogenetic hypotheses

• Premalignant : must be removed

MCNs2 components

• Epithelial with varied atypias: frombenign to malignant with invasion

• Mesenchymal « pseudo-ovarian »underlying stroma

IPMN - definition– Abnormal proliferation of the epithelium from a pancreatic

duct, secreting mucus, leading to duct dilation

– Adenoma, borderline, in situ carcinoma, invasive adenocarcinoma (WHO)

Hruban, 2004

• Papillomatosis• Villous adenoma• Papillary adenoma• Adenomatosis• Mucin hypersecreting tumor• Intraductal papillary tumor

• Mucinous ductal ectasia• Ductectatic mucinous

cystadenoma

Identical ductal cellIdentical risk of malignancy

WHO (1996): INTRADUCTAL PAPILLARY MUCINOUS TUMOR (IPMT)

Wirsung / secondary ducts

IPMN Pancreato-biliary Intestinal Oncocytic Gastric

MUC1

MUC2

MUC5AC

malignant SD +++

IPMNs : main questionsTo diagnose ?

EUS + punction: moderate sensitivity and specificity Benign or malignant ?

risk factors: main duct, major dilatation, mural noduleTopography and extension ?

frozen section +++Prognosis after resection ?

benign: excellent!malignant: better as ductal adenocarcinoma

Surveillance, no surgery ??small size, secondary ducts, asymptomatic

IPMN / PanIN

Hruban, 2004

Comparison PanIN - IPMN

PanIN IPMNClinical Dg No Yes

Visible on macroscopy. No YesMucin visible on macro No Yes

True papillae No YesMUC2 + No Yes

Loss SMAD4 30% PanIN3 RareAssoc. Mucinous AK No Yes

Hruban et al, Am J Surg Pathol 2004

• « Lesions » of small pancreatic ducts have been described for a long time: – Sommers Gastroenterology 1954 « pancreatic duct hyperplasia

and cancer »• Confusing terminology

– lesion, metaplasia, hyperplasia, dysplasia, neoplasia…• Significance still unclear

– Preneoplastic, paraneoplastic, nothing to see with cancer…• Pancreatic intraepithelial neoplasia « PanIN »

– Hruban et al, Am J Surg Pathol 2001 and 2004

Nal 1

32

Ductal extension, to distinguish from PanIN

IPMN

Molecular sequence // morphological sequence

PanIN – Diagnostic reproducibility (Hruban et al, Am J Surg Pathol 2001)

35 cases, before and after consensus between 8 experts• Before : 70 designations, 4 classifications• After :

– Consensus 5 pathologists 27/35 cases, 6 pathologists 17/35, 7 pathologists 10/35

– Kappa : 0.43 (PanIN-1), 0.14 (PanIN-2), 0.42 (PanIN-3)

Frequency of PanINPanIN PanIN-3

Normal pancreas

16% 0%

Pancreatitis 60% 4%

Cancer 82% 40%

Andea et al, Mod Pathol 2003

Very high frequency in asymptomatic patients with a strong family history of pancreatic cancer

Brune et al, Am J Surg Pathol 2006

J Hepatobiliary Pancreat Surg 2007

Mucinous cystic neoplasms: distinct pathway

Ponction

PSEUDOCYST SEROUS

CYSTADENO-

MA

MUCINOUS

CYSTADENO-

MA

MUCINOUS

CYSTADENO-

CARCINOMA

Amylase high low variable variable

Ca 19-9 variable low high high

CEA variable low high high

Ca 72-4 low low high high

Ca 15-3 low low low high

Mucins M1 variable low high high

Conclusions

• Cystic tumours of the pancreas are a specific subgroup ofpancreatic tumours

• They represent rare examples of pancreatic precancerouslesions (MCN & IPMN)

• IPMNs (macroscopic lesion) may be difficult todistinguish from PanIN (microscopic lesion)

• PanIN probably represents an important preneoplasticlesion of ductal adenocarcinoma of the pancreas

• It is important to diagnose and treat these lesions,especially in patients at high risk of pancreatic cancer

Diagnosis ?

Lymphoepithelial cyst