Classification of Pancreatic Neoplasms

SEROUS CYSTIC NEOPLASMS ACINAR CELL NEOPLASMS Microcystic serous cystadenoma Acinar cell cystadenoma Diagnosis of Cystic and Intraductal Macrocystic serous cystadenoma Acinar cell carcinoma Solid serous adenoma Acinar cell cystadenocarcinoma Serous cystadenocarcinoma PANCREATOBLASTOMA Tumors of the Pancreas MUCINOUS CYSTIC NEOPLASMS Mucinous cystic neoplasm with low grade dysplasia SOLID-PSEUDOPAPILLARY NEOPLASM Mucinous cystic neoplasm with moderate dysplasia Mucinous cystic neoplasm with high grade dysplasia NEUROENDOCRINE NEOPLASMS Mucinous cystic neoplasm with invasive carcinoma Neuroendocrine microadenoma Well differentiated pancreatic neuroendocrine tumor INTRADUCTAL NEOPLASMS Functioning Intraductal papillary-mucinous neoplasms Insulinoma Intraductal tubulopapillary neoplasms Glucagonoma David S. Klimstra, M.D. Somatostatinoma INVASIVE DUCTAL ADENOCARCINOMA Gastrinoma Tubular adenocarcinoma VIPoma Department of Pathology Adenosquamous carcinoma PPoma Colloid (mucinous noncystic) adenocarcinoma Non-functioning Hepatoid carcinoma Poorly differentiated neuroendocrine carcinoma Memorial Sloan-Kettering Cancer Center Signet ring cell carcinoma Small cell carcinoma Undifferentiated carcinoma Large cell neuroendocrine carcinoma Anaplastic carcinoma Sarcomatoid carcinoma NEOPLASMS WITH MIXED DIFFERENTIATION Carcinosarcoma Mixed acinar-neuroendocrine carcinoma Undifferentiated carcinoma with osteoclast-like giant cells Mixed acinar-ductal carcinoma Mixed ductal-neuroendocrine carcinoma Mixed acinar-neuroendocrine-ductal carcinoma

Classification of Pancreatic Neoplasms: Ductal Neoplasms Cystic Pancreatic Neoplasms SEROUS CYSTIC NEOPLASMS ACINAR CELL NEOPLASMS Microcystic serous cystadenoma Acinar cell cystadenoma Macrocystic serous cystadenoma Acinar cell carcinoma Solid serous adenoma Acinar cell cystadenocarcinoma Serous cystadenocarcinoma PANCREATOBLASTOMA MUCINOUS CYSTIC NEOPLASMS z Fundamentally cystic neoplasms Mucinous cystic neoplasm with low grade dysplasia SOLID-PSEUDOPAPILLARY NEOPLASM Mucinous cystic neoplasm with moderate dysplasia Mucinous cystic neoplasm with high grade dysplasia NEUROENDOCRINE NEOPLASMS • Serous cystic neoplasms Mucinous cystic neoplasm with invasive carcinoma Neuroendocrine microadenoma Well differentiated pancreatic neuroendocrine tumor • Mucinous cystic neoplasms INTRADUCTAL NEOPLASMS Functioning Intraductal papillary-mucinous neoplasms Insulinoma Intraductal tubulopapillary neoplasms Glucagonoma z Secondarily cystic neoplasms Somatostatinoma INVASIVE DUCTAL ADENOCARCINOMA Gastrinoma Tubular adenocarcinoma VIPoma • Solid pseudopapillary neoplasm Adenosquamous carcinoma PPoma Colloid (mucinous noncystic) adenocarcinoma Non-functioning • Most other primarily solid neoplasms Hepatoid carcinoma Poorly differentiated neuroendocrine carcinoma Signet ring cell carcinoma Small cell carcinoma Undifferentiated carcinoma Large cell neuroendocrine carcinoma z Intraductal neoplasms Anaplastic carcinoma Sarcomatoid carcinoma NEOPLASMS WITH MIXED DIFFERENTIATION Carcinosarcoma Mixed acinar-neuroendocrine carcinoma • Intraductal papillary mucinous neoplasm Undifferentiated carcinoma with osteoclast-like giant cells Mixed acinar-ductal carcinoma Mixed ductal-neuroendocrine carcinoma • Intraductal oncocytic papillary neoplasm Mixed acinar-neuroendocrine-ductal carcinoma Cystic Pancreatic Neoplasms Cystic Pancreatic Neoplasms

Intraductal papillary mucinous neoplasms 40% ¾ Intraductal papillary mucinous neoplasms 40% Serous cystic neoplasms 30% Serous cystic neoplasms 30% Solid pseudopapillary neoplasm 12% Solid pseudopapillary neoplasm 12% Mucinous cystic neoplasms 10% ¾ Mucinous cystic neoplasms 10% Cystic ductal adenocarcinoma 4% Cystic ductal adenocarcinoma 4% Cystic pancreatic endocrine neoplasm 2% Cystic pancreatic endocrine neoplasm 2% Others 2% Others 2%

¾Model of neoplastic progression

Ductal Adenocarcinoma of the Pancreas Ductal Adenocarcinoma: Survival after Resection Genetic Features

1.0 Ü Negative Lymph Nodes (n = 263)  Positive Lymph Nodes (n = 411) z K-ras mutations (95%) .8 z p16 abnormalities (90%)

.6 z p53 mutations (60%)

.4 z DPC4 / Smad4 mutations (55%) Proportion Surviving z .2 Her2/neu overexpression (95%) z BRCA2 mutations (5%) 0.0 z STK11/LKB1 mutations (5%) 0 20 40 60 80 100 120 140 160 180 200 z hMLH-1, hMSH-2 mutations (5%) MONTHS ¾ Promotor methylation of numerous genes zMSKCC 10/15/1983 - 4/14/2002 n = 674 p = 0.0003 Ductal Adenocarcinoma: Genetic Features

¾ K-ras mutations (95%) ¾ p16 abnormalities (90%) ¾ p53 mutations (60%) ¾ DPC4 / Smad4 mutations (55%) z Her2/neu overexpression (95%) z BRCA2 mutations (5%) z STK11/LKB1 mutations (5%) z hMLH-1, hMSH-2 mutations (5%)

Precursors to Invasive Ductal Adenocarcinoma

• Pancreatic Intraepithelial Neoplasia (PanIN) • Intraductal Papillary Mucinous Neoplasms • Mucinous Cystic Neoplasms PanIN Pancreatic Intraepithelial Neoplasia: Pancreatic Intraepithelial Neoplasia Background

• Metaplastic and proliferative lesions long recognized • Some common, age-related, often incidental • Others more associated with invasive ductal PanIN 1A PanIN 1B adenocarcinomas • Spectrum of intraepithelial lesions • Morphologic progression: metaplasia->hyperplasia->dysplasia • Accumulation of genetic abnormalities • “PanIN” terminology proposed, 1994 ¾ Target for earlier detection of pancreatic carcinoma PanIN 2 PanIN 3

PanINs in Autopsy Studies Molecular Alterations in PanINs

Kozuka* Mukada** 1979 1982 Invasive n 1174 206 n PanIN 1A PanIN 1B PanIN 2 PanIN 3 Carcinoma Invasive carcinoma 24 (2.0%) 1 (0.5%) Invasive carcinoma K-ras 35% 45% 65% 85% 90% Simple hyperplasia 213 (18.1%) 90 (43.7%) Hyperplasia p53 0% 0% <5% 20% 55% Papillary hyperplasia 78 (6.6%) 58 (28.2%) Mild dysplasia HER-2/neu 82% 86% 92% 100% 69% Atypical hyperplasia 13 (1.1%) 10 (4.9%) Moderate-severe dysplasia p16 24% 19% 55% 71% 95% 6 (2.9%) Carcinoma in situ DPC-4 0% 0% 0% 31% 55%

*Cancer 1979; 43:1418-1428 **Tohoku J Exp Med 1982; 137:115-124 From: Wilentz et al., Cancer Res 60: 2002, 2000. Pancreatic Intraepithelial Progression of Intraductal Neoplasia (PanIN) Neoplasia to Invasive Carcinoma

• THREE cases reported • All had documented CIS (PanIN 3) in resection specimens with involvement of margins • Associated with invasive carcinoma: new carcinoma after 9 yrs • Associated with pancreatitis and pseudocyst: carcinoma after 10 yrs • Associated with pancreatitis: carcinoma found 17 months later • Evidence of progression • Difficulty of temporal follow-up of intraductal lesions

Brat et al., Am J Surg Pathol 1998; 22: 163-9.

PanINs: Translation to the Issues Regarding PanINs Surgical Pathology Report z PanI Neoplasm z Molecular phenotype emerging z Reflects clonal nature and expression of cancer associated genes z Does not mean “requires clinical treatment” z Natural history largely unknown z PanINs 1 and 2 z Identification at clinical level difficult z Common incidental findings z Generally not reported z PanIN 3 ¾ Need measurable markers of late stage preinvasive z Strongly suspected to be significant neoplasia (PanIN 3) z However, “the clinical significance and therefore appropriate management have not been established” (yet) ¾ Need clinically detectable model for preinvasive neoplasia Intraductal Papillary-Mucinous Neoplasms

z Uncommon tumors of pancreatic ducts with papilla formation and mucin hypersecretion z Clinically detectable z Often lack invasive carcinoma (65-75%) z Histologic similarities with PanINs z (?) Same molecular pathway as PanINs and conventional ductal adenocarcinoma Intraductal Papillary-Mucinous Neoplasms: Intraductal Ultrasound

Hara et al. Gastroenterology 2002; 122: 34 Intraductal papillary mucinous neoplasm with invasive colloid carcinoma Intraductal papillary mucinous neoplasm with invasive tubular adenocarcinoma Development of Carcinoma in IPMNs

Intestinal type papillae Pancreatobiliary type papillae

Colloid carcinoma Tubular carcinoma

IPMN: Survival Intraductal Papillary Mucinous Neoplasms: Classification

1.0 1.0 WHO 2000 AFIP Fascicle n = 32 n = 32 .8 .8 Intraductal papillary mucinous IPMN with low grade dysplasia n = 13 adenoma .6 .6 n = 30 Intraductal papillary mucinous IPMN with moderate dysplasia .4 .4 neoplasm, borderline n = 17 Cumulative Survival Cumulative Survival .2 .2 Intraductal papillary mucinous IPMN with high grade dysplasia p = 0.01 p = 0.008 carcinoma in situ 0 0 0 24 48 72 96 120 144 168 192 0 24 48 72 96 120 144 168 192 Time (months) Time (months) Papillary mucinous carcinoma IPMN with an associated invasive carcinoma (specify non-invasive () non-invasive () type) invasive (- - - -) invasive colloid carcinoma (- - - -) invasive tubular carcinoma ( - ) Intraductal Papillary Mucinous Neoplasms: Intraductal Papillary-Mucinous Classification WHO 2010 AFIP Fascicle Neoplasms: Main vs. Secondary Ducts

IPMN with low grade dysplasia IPMN with low grade dysplasia • 70% involve main duct, 30% confined to

IPMN with intermediate grade IPMN with moderate dysplasia secondary (branch) ducts dysplasia • Secondary duct type confined to head/neck • Secondary duct type in younger patients IPMN with high grade dysplasia IPMN with high grade dysplasia • Secondary duct type less aggressive • Main duct type: 20% CIS, 37% invasive carcinoma IPMN with an associated IPMN with an associated • Secondary type: 15% CIS, 0% invasive carcinoma invasive carcinoma invasive carcinoma

Terris et al., Am J Surg Pathol 2000; 24: 1372-7.

Papilla Types in IPMNs Intraductal Oncocytic Papillary Neoplasm Gastric Intestinal Pancreatobiliary Oncocytic Intraductal Tubulopapillary Neoplasm C.B.D. of the Pancreas

z Also reported as “Intraductal Tubular Carcinoma”

z Approximately 35 cases reported

z Mean age = 54 yrs (range = 25-72); F > M P.D. z Symptoms: chronic pancreatitis Amp.

z Location: head > tail; 30% diffuse involvement

z Favorable outcome

Tajiri et al. Pancreas 2004; 29: 116-122 Yamaguchi et al. Am J Surg Pathol 2009; 33: 1164-1172 Klimstra et al. Am J Surg Pathol 2011; (in press) Intraductal Neoplasms: Mucin Expression in Immunohistochemistry Pancreatic Ductal Neoplasia

Keratins Glycoproteins Cam5.2 100 CEA (m) 85 zMucinous change common in neoplasia AE1:AE3 95 CA19-9 90 CK7 70 B72.3 50 CK19 85  CK20 30

Lineage Markers zIncrease in normal mucins Chromogranin (35) z CA19-9 Synaptophysin (35) Trypsin 0 zExpression of tumor-associated glycoproteins Chymotrypsin 0 z CEA, B72.3, CA125, CA72-4, CA15-3 ¾Mucins are secreted MUCs in Pancreatic Neoplasia MUC Proteins MUC1 MUC2

z Mammary type mucin z Numerous (>20) species identified z Intestinal (goblet) type mucin z Maintenance of lumen formation z Protective function z Variety of functions z Inhibitory role in cell-cell, cell- stroma interaction z Gel formation z Membrane bound vs. secreted z Inhibits cytotoxic immunity against z Tumor suppressor activity z MUCs 1-7 studied in the pancreas tumor cells z Considered as a marker of “indolent z Activation of tumorigenesis phenotype” in pancreas ca. z MUC1, MUC5B, MUC6 mRNA present in normal pathways pancreas; protein expression less consistent z Considered as a marker of z MUC2, MUC3A, MUC4, MUC5AC, MUC7 absent “aggressive phenotype”

z Aberrant expression in intraductal and invasive pancreatic neoplasia

z MUC1, MUC4, MUC5AC, MUC6 in infiltrating ductal adenocarcinoma

Tubular (conventional ductal) ca. Colloid (mucinous non-cystic) ca. Morphologic Subtypes of IPMNs: Pancreatobiliary Type

MUC1

MUC2

MUC1 MUC2

MUC1: 90% of cases MUC1: 0% of cases MUC5AC MUC2: 1% of cases MUC2: 100% of cases Morphologic Subtypes of IPMNs: Morphologic Subtypes of IPMNs: Intestinal (Villous) Type Gastric Foveolar Type

MUC1 MUC1

MUC2 MUC2

MUC5AC MUC5AC

MUC Expression in Pancreatic Neoplasia CDX2 in Pre-invasive Neoplasia

Tubular Colloid IPMN IPMN IPMN PanIN z IPMN

Ca Ca Int. PB Gastric z Gastric: 0/17 (0%)

z Intestinal: 12/13 (95%)

z Pancreatobiliary: 0/9 (0%)

MUC1 +++ - - +++ - +++ z Oncocytic: 0/2 (0%)

z PanIN

z All: 2/23 (9%)

MUC2 - +++ +++ - - - p = 0.000001 Pancreatic carcinogenesis

CDX2 in Invasive carcinomas IPMC- non invasive . z Colloid Carcinoma: 10/11 (90%) ..Colloid z The only negative colloid ca. arose in . ca. association with a PB type IPMN IPMAdenoma z Tubular Carcinoma: 12/74 (16%) Tubular z Usually focal inv. .

p = 0.0001

PanIN I-II PanIN III (CIS) Tubular inv.

Genetic Features of IPMN - Intestinal Invasive Colloid Carcinoma Intraductal Papillary Mucinous Neoplasms

K-ras p53 DPC4 p16 STK11/LKB1 PIK3CA

Ductal >95% 50-70% 40-60% 95% Adenocarcinoma 5% 1% early late late mid

Intraductal Papillary 80% 25-65% 5% 50%** Mucinous Neoplasms 25% 10% early late late mid Normal Expression of DPC4/Smad4

**promoter methylation IPMN: Exome Sequencing Multilocular IPMN

z KRAS (codon 12) and GNAS (codon 201) mutations in 80% and 60%, respectively

z GNAS HQFRGHVIRU*VĮRQHRIWKHJXDQLQHQXFOHRWLGH-binding proteins (G-proteins); role in cellular signal transduction z GNAS mutants maintain a permanent association with GTP and induce continuous 1 constitutive adenylate cyclase activation with cyclic AMP formation 2 z RNF43 mutated in 75%

z The protein encoded by RNF43 has been shown to have intrinsic E3 ubiquitin ligase activity

z Mutations in APC in 25% 3

Wu et al., Sci Transl Med 2011;3:92ra66 Wu et al., PNAS 2011;108:21188

IPMNs vs. PanINs: Multilocular IPMNs Similarities

z Each locule monoclonal z Both are inherently intraductal

z Both are composed predominantly of columnar, mucin- z Some different locules from the same case harbor producing cells

different mutations z Both may be either flat or papillary

z Both exhibit a range of cytoarchitectural atypia z Two adjacent locules more likely to contain the z Both are recognized precursors to invasive adenocarcinoma

same KRAS or GNAS mutation than two z Both sequentially accumulate similar genetic alterations with topographically separate locules increasing cytoarchitectural atypia z PanINs may involve large ducts and IPMNs may involve small ducts Wu, et al, Sci Transl Med 2011;3:92ra66 Pancreatic Intraepithelial Intraductal Papillary Mucinous IPMNs vs. PanINs: Neoplasia (PanIN) Neoplasm (IPMN) Differences

z Clinical presentation

z Size of involved ducts

z Abundance of papillae

z Special papilla subtypes

z CK20, MUC2, CDX2 = intestinal type IPMN

z Molecular phenotypes overlap

6 mm, incidental lesion IPMN vs PanIN Mega-PanIN vs Micro-IPMN Guidelines Guidelines z “PanINs usually involve Ɣ Review radiologic findings for features of IPMN ducts < 5 mm in Ɣ Review gross findings for papillae and/or cysts diameter” Ɣ Get step sections to verify the size of the ducts and investigate for (1) tall papillae, (2) abundant luminal mucin, z “IPMNs usually produce and (3) MUC2 immunoexpression, any of which, if present, a lesion greater than 1 cm point towards an IPMN in diameter” IPMN with coexisting PanINs IPMN vs Retention cyst vs IPMN with extension to z Retention cysts occur secondary to small ducts pancreatic ductal obstruction z Minimal or no atypia

z Unilocular It can be difficult (if not z Low cuboidal or flat epithelium impossible) to distinguish z “PanIN can occur” (?) between IPMNs and PanINs affecting the same pancreas

Mucinous cystic neoplasm Mucinous Cystic Neoplasms

• Mean age = 45 yrs • Female >>>> male (20-40:1) • Tail /Body >>>> Head • Mean size = 8.5 cm (up to 36 cm) Mucinous cystic neoplasm Mucinous cystic neoplasm

Mucinous cystic neoplasm Mucinous cystic neoplasm Mucinous cystic neoplasm Mucinous cystic neoplasm

Mucinous cystic neoplasm Mucinous cystic neoplasm

A103

Estrogen receptors Inhibin Mucinous cystic neoplasm Mucinous cystic neoplasm

Mucinous cystic neoplasm with invasive carcinoma Mucinous Cystic Neoplasms: Classification

W.H.O. AFIP Fascicle

Mucinous cystadenoma MCN with low grade dysplasia

Mucinous cystic neoplasm, MCN with moderate borderline dysplasia

Mucinous cystadenocarcinoma MCN with high grade in situ dysplasia

Invasive mucinous MCN with associated cystadenocarcinoma invasive carcinoma Mucinous Cystic Neoplasms: Mucinous Cystic Neoplasms: Classification (WHO 2010) Behavior

z 41 patients: Alive and Well 20 MCN with low grade dysplasia Alive with tumor 1 Dead of tumor 12 Operative deaths 1 Unrelated deaths 7 MCN with intermediate grade dysplasia z Mean survival of those dying of tumor = 30 months

MCN with high grade dysplasia z Of those alive and well, Definitive carcinoma 5 Atypical epithelium 8 MCN with associated invasive carcinoma Apparently benign 4 z Of those dying of tumor, (“mucinous cystadenocarcinoma”) Definitive carcinoma 9 ¾ Atypical epithelium 2 ¾ Apparently benign 1

Data from: Compagno J, Oertel JE, Am J Clin Pathol 69:573,1978.

Malignant Potential in Mucinous Cystic Neoplasms: Mucinous Cystic Neoplasms Clinical Behavior

• 56 Cases: • 22 adenomas (F/U median 42.5 mos, range 4-114 mos) • 12 borderline tumors (F/U median 69.5 mos, range 9-180 mos) z Overall indolent; less than 10% mortality • 22 carcinomas (F/U median 23 mos, range 2-134 mos) • 6 non-invasive (F/U median 76 mos) z Sampling issue paramount • 3 intratumoral • 5 within the tumor wall z Recognize clear-cut malignancy when present • 8 extrapancreatic tissues z Exercise caution when absent ¾ All alive and well except those with invasion of tumor wall or extrapancreatic tissues (8/13 DOD, mean survival 11 mos)

Zamboni et al, Am J Surg Pathol 1999; 23: 410 Genetic Features of Mucinous Cystic Neoplasms: Mucinous Cystic Neoplasms Differential Diagnosis

• Radiographic / Gross K-ras p53 DPC4 p16 GNAS RNF43 • Intraductal papillary mucinous neoplasm (IPMN) • Macrocystic serous cystadenoma • Solid pseudopapillary neoplasm Ductal >95% 50-70% 40-60% 95% ¾ Pseudocyst 0% 0% Adenocarcinoma early late late mid • Microscopic • IPMN • Ductal adenocarcinoma with mucinous glands Mucinous Cystic 70-85% 35-50% 50% 15%** ¾ Pseudocyst 0% 50% Neoplasms Early Late Late mid

**promoter methylation

Mucinous Cystic Neoplasm vs. Pseudocyst Serous Neoplasms

z Microcystic serous cystadenoma • Microcystic adenoma • Glycogen-rich adenoma z Macrocystic serous cystadenoma • Oligolocular ill-demarcated adenoma z Solid serous adenoma z Serous cystadenocarcinoma Serous Cystic Neoplasms Microcystic serous cystadenoma

y Mean age = 65 yrs y Female > male (7:3) y Associated with von Hippel Lindau syndrome y Head = Body / Tail y Mean size = 6 cm (up to 30 cm)

Microcystic serous cystadenoma Macrocystic serous cystadenoma Macrocystic serous cystadenoma Solid serous adenoma

PAS

dPAS Serous cystadenocarcinoma Serous Cystic Neoplasms: Differential Diagnosis

y Radiographic / Gross y Microcystic y Large: ???? y Small: any macrocystic lesion y Macrocystic y Branch duct IPMN y Mucinous cystic neoplasm y Retention cyst y Microscopic y Microcystic y Lymphangioma y Renal cell carcinoma y Macrocystic y Lymphangioma

Pancreatic Neoplasms with Pancreatic Neoplasms with Degenerative Cystic Change Degenerative Cystic Change

z Ductal adenocarcinoma z Pancreatic endocrine neoplasm

z Acinar cell carcinoma Solid Pseudopapillary Neoplasm z Many synonyms z “Solid and cystic tumor”, “solid and papillary epithelial neoplasm”, “papillary-cystic carcinoma”, “Hamoudi tumor”, “Frantz’s tumor”, ad nauseum z 2-5% of pancreatic neoplasms z Tumor of young females z F:M = 9:1; Mean age = 28 yrs z Symptoms usually related to presence of mass z Detected during pregnancy, after trauma, incidentally dPAS Vimentin

D-1-antitrypsin E-catenin Solid Pseudopapillary Neoplasm: Staining Results Stain % Positive ¾ Trypsin 0 ¾ Chymotrypsin 0 ¾ Lipase 0 ¾ Chromogranin 0 ¾ Synaptophysin 30 ¾ Neuron Specific Enolase 80 ¾ CD56 95 ¾ Mucicarmine 0 ¾ CEA 5 ¾ Keratin 32 ¾ Vimentin 100 ¾ Į-1-antitrypsin 84 ¾ CD10 75 ¾ CD117 50 ¾ E-catenin (nuclear) 90 ¾ Progesterone receptors 75

Solid Pseudopapillary Neoplasm: Solid Pseudopapillary Neoplasm: “Hyaline Globules” Genetic Features

z APC / E-catenin pathway (90%) z E-catenin mutations z Overexpression of cyclin D1 D-1-antitrypsin z No abnormalities in “ductal adenocarcinoma genes” z K-ras z p53 z DPC4

D-1-antitrypsin Solid Pseudopapillary Neoplasm: Diagnostic Issues in Prognosis Pancreatic Cysts z Very low grade malignant neoplasm z Complete resection usually curative ¾Preoperative Diagnosis z Metastases z Radiology z 10-15% of patients z Cytology z Liver and peritoneum (NOT lymph nodes) z Cyst fluid biochemical analysis z Long-term survival possible z Cyst fluid proteomic analysis z Cyst fluid molecular analysis z High grade malignant transformation z Cyst fluid miRNA detection z Two cases reported z Diffuse sheets of cells, pleomorphism, mitoses z Rapid dissemination and death

Preoperative Diagnosis of Preoperative Diagnosis of Pancreatic Cysts IPMNs: Radiographic Criteria

zDistinguish Mucinous from Non-mucinous Lesions zMain duct involved z Pseudocyst z Serous cystic neoplasm z> 3 cm. z Cystic neuroendocrine neoplasm zSolid mural nodule ¾Distinguish Low Grade Dysplasia from High zGrowth during F/U Grade Dysplasia and Invasive Carcinoma z Resection vs. follow-up z Optimum test: positive = high grade; negative = low grade

z Acceptable test: negative = low grade Allen et al. J Gastrointest Surg 2003; 7: 970 Intraductal papillary mucinous neoplasm, FNA cytology Cyst Fluid Analysis for Diagnosis of Cystic Lesions

z Measure viscosity, amylase, glycoproteins (CEA, CA72-4, CA125, CA19-9, CA15-3) z High amylase, low viscosity, low glycoproteins in pseudocyst z Low amylase, low viscosity, low glycoproteins in serous cystadenoma z High viscosity, high glycoproteins in mucinous neoplasms

Cyst Fluid Analysis MUC Measurement for Diagnosis of Cystic Lesions for Diagnosis of Cystic Lesions z CEA levels more sensitive than all other glycoproteins (even in combination) z Fluid CEA of 192 ng/ml separates mucinous vs. z MUC1, MUC2, MUC4, and MUC5AC nonmucinous cysts (79% accuracy) analyzed by ELISA z Cytology accuracy = 59% z z EUS appearance accuracy = 51% Low risk (low grade / moderate dysplasia) z Less sensitive to distinguish low grade vs. high z High risk (high grade dysplasia / carcinoma) grade dysplasia (>2500 ng/ml = worrisome) z Proteomic profiling: CEA, CA72.4 = mucinous

Brugge et al. Gastroenterology 2004; 126: 1330 Pitman et al. Pancreatology 2008; 8: 277 Maker et al. Ann Surg Oncol 2011;18:199 Allen et al. Ann Surg 2009; 250: 754 Histologic Subtype Correlates MUCs are Elevated in High Risk IPMNs with MUC Expression

* *

Degree of Dysplasia Pancreatic Cyst Fluid Concentration (u/mL) MUC 2* MUC 4* Carcinoma or High Grade Dysplasia 10 20.6 Low Grade or Moderate Dysplasia 4.4 4.5 * p<0.05

Molecular Diagnosis Molecular Diagnosis of Pancreatic Cystic Lesions of Pancreatic Cystic Lesions

z Utilizes aspirated cyst fluid

z DNA quantification, K-ras mutation, mutational amplitude, LOH analysis

z More frequent K-ras mutation, LOH with greater degree of dysplasia

z Some low grade (+), some high grade (-)

Khalid et al. Clin Gastroenterol Hepatol 2005; 3: 967 Schoedel et al. Diagn Cytopathol 2006; 34: 605 Wu et al., Sci Transl Med 2011;3:92ra66 Khalid et al. Gastrointest Endosc 2009; 69: 1095 Wu et al., PNAS 2011;108:21188 Cystic and Intraductal Neoplasms z Mucinous changes are characteristic of precursor lesions z PanINs, IPMNs, and MCNs are precursors to Ca z Neoplastic progression (increasing dysplasia) occurs in these neoplasms z Separate pathways of carcinogenesis occur in the pancreas z Understanding of the alterations in mucins and genetic markers with tumor progression may guide diagnosis and therapy