Adenocarcinoma of the Pancreas - Precursors

Prof. Luigi Tornillo

PathoBasic

21.06.2016

• Introduction

• Precursors of pancreas carcinoma

• Reporting

• Molecular pathology

Pancreatic Cancer Action Network 2012

Ductal Adenocarcinoma of the Pancreas

• Mortality ≈ Incidence

• M/F ≈ 1

• Average age 60-80 ys

Globocan 2012

„Whether the dismal

prognosis of patients

with pancreatic

cancer...is a result of

late diagnosis or early

dissemination of

disease...is not

known“

Yachida et al. , Nature 2010

Tumors of the pancreas (WHO, 2010) Epithelial tumours

Benign Aciuar cell cystadenoma

Serous cystadenoma

Premalignant lesions Pancreatic Intraepithelial Neoplasia, grade 3 (PanIN –3)

Intraductal papillary mucinous neoplasm with low- or intermediate-grade dysplasia

Intraductal papillary mucinous neoplasm with high-grade dysplasia

Intraductal tubulopapillary neoplasm

Mucinous cystic neoplasm with low- or intermediate-grade dysplasia

Mucinous cystic neoplasm with high-grade dysplasia

Malignant Ductal adenocarc inoma

o Adenosquamous carcinoma

o Colloid carc inoma

o Hepatoid Carcinoma

o Medullary Carcinoma

o Signet ring cell carc inoma

o Undifferentiated car cinoma

o Undifferentiated car cinoma with osteoclast-like giant cells

Acinar cell carcinoma

Acinar cell cystadenocarcinoma

Intraductal papillary mucinous neoplasm with an associated invasive carc inoma

Mixed acinar-ductal carc inoma

Mixed acinar-neuroendocrine carcinoma

Mixed ductal neuroendocrine carc inoma

Mucinous cystic neoplasm with an associated invasive carcinoma

Pancreatoblastoma

Serous cystadenocarcinoma

Solid-pseudopapillary neoplasm

Neuroendocrine tumors

Mature teratoma

Non-epithelial tumors

Secondary Tumors

„By the late 1990s, over 70 different terminologies were used to describe non-invasive ductal lesions...“

Koorstra et al. , Langebeck Arch Sur, 2008

Preneoplastic lesions

• Pancreatic Intraepithelial Neoplasia (PanIN)

• Intraduct. Papill. Muc. Neoplasm (IPMN)

• Mucinous Cystic Neoplasm (MCN)

– Low-grade

– High-grade

Basturk et al., AJSP 2015

PanIN

„...small (usually <0.5 cm) intraductal mucin-producing, usually papillary, neoplasms that usually grow in the smaller pancreatic ducts, characterized by varying degrees if cytolgic dysplasia and atypia“

Hruban & Klimstra, Sem Diag Pathol, 2014

PanIN, Low-grade (PanIN 1)

PanIN, low-grade (PanIN 2)

PanIN, high-grade (PanIN 3)

„PanIN 1 is considered hyperplastic and benign. PanIN2 is low-grade dysplasia, and PanIN-3 is high-grade dysplasia or carcinoma in situ“

Chari et al., Pancreas 2015

PanIN

• Low-grade

– Frequently in non-neoplastic

– Rarely near ADC

– Chronic Pancreatitis: KRAS und p16 chanhges

• High-grade

– Rarely in non-neoplastic

– Frequently near ADC (DD: ductular spread)

Sipos et al., Pancreatology, 2009 Yachida, Nature 2010

IPMN

„.. a grossly visible (1 cm), predominantly papillary or rarely flat, noninvasive mucinproducing epithelial neoplasm arising in the main pancreatic duct or branch ducts“

Basturk et al., AJSP, 2015

IPMN

• 2 macroscopic categories – Main duct (MD), Branch duct (BD)

• 4 microscopic categories – Gastric, Intestinal, Pancreatobiliary, Oncocytic

• 2 grades – Low-grade

– High-grade

IPMN, HG

Basturk et al., AJSP, 2015 IPMN histologic subtypes

PanIn vs. IPMN

• PanIN – <0.5 cm

– Generally gastric type

– WT-GNAS

• IPMN – >1 cm

– Gastric, biliary, oncocytic, intestinal

– GNASmut

– „Incipient IPMN“ (0.5-1 cm)

Cave: intraductal spread of invasive carcinoma

Adsay et al., Ann Surg 2016

PanIN vs IPMN: meaning

• PanIn

– Report HG only

– RR: not important in the presence of ADC

– Frozen section

• IPMN

– Always report

– RR: always report (higher recurrence)

– Frozen section

„...if a patient has an invasive ductal adenocarcinoma of the pancreas, do not overtreat PanINs at a margin“

Hruban & Klimstra, Sem Diag Pathol, 2015

Mucinous cystic neoplasm

• Cyst forming, mucin-secreting (average 6,5 cm)

• Ovarian-type stroma

• Tail of the pancreas

• NO communication with ducts (imaging!)

• W>>M, 50ys

• Associated with ADC – Better prognosis

LG-MCN

HG-MCN

Cave: focality. Generous sampling! Fukushima et al., Sem Diag Pathol, 2014

PanIN: Reporting

• Low-grade PanIN (reporting not needed)

– If reported, comment on its clinical inconsequences

• High-Grade PanIN

• WHO 2010 in parentheses

• F.e. „Pancreatic Intraepithelial neoplasia, high-grade (PanIN3)“

– Not critical on RR in the presence of ADC

IPMN (and CMN): reporting

• IPMN/MCN, low-grade, high-grade (highest focus)

• IPM/MCN with associated invasive carcinoma (colloid type, tubular type)

– If in doubt „indeterminate for invasion“

– NOT „invasive“, „malignant“, „cystadenocarcinoma“

• Histologic type

– (15% mixed)

• Duct type not needed

Frozen section

• HG and ADC often multifocal

– Discrepancy

• LG-lesions mainly without meaning

• „No high-grade dysplasia or invasive carcinoma at margin. Low-grade epithelium present“

– No further resection

Adsay et al., Ann Surg 2016

„...the key to understanding pancreatic cancers lies in an appreciation of a core set of pathways and processes.“

Jones et al, Science 2008

Jones et al., Science 2008

IPMN

• GNAS (intestinal type, colloid carcinoma, CDX2+) – G-Protein (cAMP)

• RNF43 – Ubiquitin ligase - Proteasome

• KRAS

• Oncocytic type rarely mutations, indolent course

• DPC4 (SMAD4) (high-grade – invasive)

IPMN: genetics

Klöppel et al., Sem Diag Pathol, 2014

DAC + MCN

• Tumor suppressor genes

– p53 50-80% late event

– DPC4/SMAD4 55% (del+mut) – local Extension !!!

– p16INK4 95% (del+mut+epigenetic)

– BRCA2 7% (del+mut)

• Oncogenes

– RAS 90% (mut) early

– RNF 43

Pancreas carcinoma: Genetics

Cowan, Cancer J 2014

Springer et al., Gastroenterology 2015

• 130 cyst fluids

– 96 IPMN, 12 CMN, 12 SCA, 10 SPN

• Mutations of 6 oncogenes and 5 TSGs, LOH, aneuploidy

• Identification of benign 88%

Literatur

• Adsay V et al., Ann Surg, 2016;263:162-77

• Basturk O et al., Am J Surg Pathol, 2015;39:1730-41

• Hruban RH and Klimstra, DS, Sem Diag Pathol, 2014; 31:443-

51

• Klöppel et al., Sem Diag Pathol, 2014; 31:452-66

• Fukushima et al., Sem Diag Pathol, 2014; 31:467-64

• Matthaei H et al., J Gastroenterol, 2015;50:520-32

• Springer et al., Gastroenterology 2015;149:501-10

• Yachida et al., Nature 2010;467:114-7

• Sipos B et al., Pancreatology, 2008;9:45-54

• Jones S, et al., Science, 2008; 321(5897):1801-6