Current Management of Cystic Lesions of the Pancreas€¦ · Cystic lesions pancreas Introduction • Controversy: Who should undergo resection? 1995: “Given the current low morbidity

Current Management of Cystic Lesions of the Pancreas

Peter J. Allen, MD Associate Director, David Rubenstein Center for Pancreatic Cancer Research Murray F. Brennan Chair in Surgery Memorial Sloan Kettering Cancer Center New York, NY

Cystic lesions pancreas

Introduction • Controversy: Who should undergo resection?

1995: “Given the current low morbidity and mortality of pancreatic resection in specialized centers, it is our policy to resect all cystic tumors unless invasion of neighboring structures or the general condition of the patient precludes it.” Surg Clin N Amer. 1995;75:1001-1016. 2002: Society for Surgery of the Alimentary Tract: “The majority of patients with pancreatic cystic neoplasm referred to me are those with IPMN. These are all premalignant and should be resected.”

Allen PJ, et al. J Gastrointest Surg. 2003 Dec;7(8):970-977.


Introduction • Controversy: Who should undergo resection?

2005, American Surgical Association: Allen PJ, D’Angelica M, Gonen, M, Jarnagin W, Jaques D, Coit D, DeMatteo R, Fong Y, Blumgart L, and Brennan M. A selective approach to resection of cystic lesions of the pancreas

Allen PJ, et al. Ann Surg. 2006;244:572-582.


Introduction

• Radiographic finding with a broad histologic

differential:

Benign “Pre-Malignant” Malignant

Pseudocyst Serous cystadenoma Retention cyst Lymphangioma Acinar cell cystadenoma

IPMN Mucinous Cystic Neoplasm

Adenocarcinoma Neuroendocrine Solid pseudopapillary Lymphoma

Observe Resect


Overview • Clinical significance of cystic lesions of the pancreas • Accuracy of non-operative diagnosis

• Serous cystadenoma • Mucinous cystic neoplasm • Intraductal papillary mucinous neoplasms (IPMN)

• IPMN • Histopathologic sub-types • Current management recommendations • Defining high-risk lesions


Clinical significance: • de Jong et al.:

• 2803 consecutive MRI (abdomen), mean age 51 yrs 66 patients (2.4%) with cystic lesion pancreas 4/66 lesions (6%) larger than 2cm

de Jong K, et al. Clin Gastroenterol Hepatol. 2010;8:806-811.

U.S. Population: 317 million Mean age: 40 years Number of cystic lesions of the Pancreas!!: 317 x .018 = 5.7 million


Clinical significance: • Increasing identification and evaluation: MSKCC, 1995 – 2013: 2,245 patients in registry

evaluated (GI or surgery) for a cystic lesion of the pancreas (577.2).

Gaujoux S, et al. J Am Coll Surg. 2011;212(4):590-600.

>2,400 clinic visits (577.2) in GI and surgery in 2013


Clinical significance: • Increasing percentage of resections for cystic lesions

(MSKCC: 1995-2012, n=2,567):

0

50

100

150

200

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

Year

# re

sect

ed

Carcinoma (n=1474)

Non-carcinoma (n=1093)

Non-operative diagnosis

• Radiographic, endoscopic, and cytologic discrimination.

Test Accuracy

(mucinous vs. non-mucinous) CT imaging 45% -65% EUS morphology 51% Cytology 59% Cyst fluid CEA 70%-80%

Brugge WR, et al. Gastroenterology. 2005:126;1330-1336.



Non-operative diagnosis • Cyst fluid biomarkers

CEA>200ng/ml: positive predictive value of 80 - 94%

Brugge WR, et al. Gastroenterology. 2005:126;1330-1336. Allen P et al. Ann Surg. 2009:250;754-760.


Non-operative diagnosis: Serous cystadenoma Radiographic appearance: • Microcystic “honeycomb” • Central Calcification • “Solid component”

Endoscopic findings • Cyst fluid CEA – low

Natural history • Not metastatic


Non-operative diagnosis: Mucinous cystadenoma Radiographic appearance • Macrocystic • Unique to women (ovarian stroma) • No communication with duct

Endoscopic findings • Cyst fluid CEA elevated (>200ng/ml)

Natural history • “pre-malignant”


Non-operative diagnosis: IPMN • Radiographic appearance

• Branch duct • Main duct

• Endoscopic findings

• Bulging ampulla with mucin • Elevated fluid CEA

• Natural history

• Pre-malignant • Field defect: “Whole gland” process

IPMN

Introduction • Intraductal papillary mucinous neoplasms of the pancreas

first classified in 1996 by the World Health Organization.

• Interest has increased: • Increased use of cross-sectional imaging has resulted in

increased identification. • Only identifiable precursor lesion of pancreatic cancer! • Management controversy as frequency, site, and rate of

progression to invasive disease unknown.

Kloppel G, et al. Berlin, Germany: Springer;1996.

IPMN

Histopathologic sub-types

Gastric

• Gastric: thick finger-like papillae, eosinophilic cytoplasm, basal nuclei – similar to gastric foveolae. Tend to have LGD. • Intestinal: papillary projections, lined by columnar cells with cigar shaped nuclei - similar to colonic villous adenomas. Tend to have moderate or HGD. • Pancreatobiliary: arborizing papillae, enlarged hyperchromatic nuclei - similar to biliary papillomatosis. Tend to have HGD.

Intestinal

Pancreatobiliary

Oncocytic

Tubular Carcinoma

Colloid Carcinoma

IPMN

Histopathologic sub-types • IPMN progression pathways to carcinoma:

Adapted from: Takaori K. J Hepatobiliary Pancreat Surg. 2007;14(3):217.

Tubular Carcinoma

Colloid Carcinoma

IPMN

Management recommendations • Operative resection recommended when presumed risk of

high-grade dysplasia or invasive disease (high-risk lesion)

• Increased risk of high-risk disease when main duct is involved.

Johns Hopkins, 136 patients resected for IPMN HGD/Invasive disease Main Duct 60% Combined 40% Branch Duct 20%

D'Angelica M, et al. Ann Surg. 2004;239(3):400-408. Sohn TA, et al. Ann Surg. 2004;239(6):788-797.

IPMN

Management recommendations • Main duct IPMN: Operative resection recommended • Branch duct IPMN:

• Selective approach generally utilized • “Consensus” guidelines: Non-operative approach reasonable for

incidentally discovered BD IPMN <3 cm in diameter and without solid component.

• Size and solid component: two factors most frequently associated with high grade dysplasia or invasive disease

Tanaka M, et al. Pancreatology. 2012;12:183-197.

IPMN

Management recommendations • Branch duct IPMN, diameter and dysplasia:

Allen PJ. Surg Oncol Clin N Am. 2010;19(2):297-311.

IPMN

Management recommendations • Need for improved markers of high-risk disease

• Increased risk of high-grade dysplasia or carcinoma when

main duct is involved.

Johns Hopkins, 136 patients resected for IPMN HGD/Invasive disease Main Duct 60% Combined 40% Branch Duct 20%

D'Angelica M, et al. Ann Surg. 2004;239(3):400-408. Sohn TA, et al. Ann Surg. 2004;239(6):788-797.

IPMN – Current Directions

Improved identification of high-risk disease • Cyst fluid markers of dysplasia in IPMN: Mucins

Degree of Dysplasia Pancreatic Cyst Fluid Concentration (u/ml) MUC 2* MUC 4*

Carcinoma or High Grade Dysplasia 10 20.6 Low or Moderate Grade Dysplasia 4.4 4.5 * p<0.05

Maker AV, et al. Ann Surg Oncol. 2011;18(1):199-206.


Improved identification of high-risk disease • Markers of dysplasia in IPMN: Cytokines

IL 1b IL 8 IL 5

Maker AV, et al. Clin Cancer Res. 2011;17(6):1502-1508.


Improved identification of high-risk disease

• Multi-plex bead array (Luminex). Capture antibody on bead with unique spectral

properties.


Improved identification of high-risk disease Growth Factors: EGF/EGFR, HGF, IGFBP-1, NGF, ErbB2, SAA Immune Modulators: MPO, MIF, CD40L, MICA Chemokines/Cytokines: MIP1a, MIP1b, Eotaxin, MCP-1, IL-6, GCSF, Fractalkine, TNF-a, IP- 10, TNF-RI, IL-2, TGFa, SE-selectin, ULBP 1-3, IL-8 Angiogenesis: VEGF, MMP-9, MMP-2, MMP-7, sVCAM, TPA-1, Angiostatin, Resistin, FGFb Cellular/Tumor Antigens: CEA, CA19-9, CA-125, CK-19, CA15-3, CA72-4, AFP, S-100, mesothelin, sICAM Extracellular Matrix: MMP-2, MMP-9, Kallikrein 8, MMP-3, MMP-7, MMP-1, MMP-8, MMP-12, MMP13, tPAI-1, Kalikrein 10, IGFBP-1 Endocrine: FSH, LH, TSH, Prolactin, GH, ACTH, TTR, Leptin Cytosolic: HSP 27 Apoptosis: SCC, sFAS, sFASL


Improved identification of high-risk disease • Markers of dysplasia in IPMN (n=80):

Sadot E, et al. Ann Surg. 2014, in press.


Improved identification of high-risk disease • Tumor infiltrating neutrophils in IPMN:

• TIN Count: • Negative: ≤10 neutrophils/100 epithelial cells • Low: 11-15 neutrophils/100 epithelial cells • High: >15 neutrophils/100 epithelial cells

• TIN strongly associated with degree of dysplasia

Reid MD, et al. Mod Pathol. 2011;24(12):1612-1619.


Improved identification of high-risk disease • Tumor infiltrating neutrophils in IPMN (n=80):

IPMN Low-grade

(n=47)

IPMN High-grade

(n=21)

IPMN Carcinoma

(n=9) p-value

TIN Negative

45 (96%) 7 (33%) 0

<0.001 TIN Low 1 (2%) 7 (33%) 1 (11%)

TIN High 1 (2%) 7 (33%) 8 (89%)

Sadot E, et al. Ann Surg. 2014, in press.


Improved identification of high-risk disease • Cyst fluid markers of dysplasia: 80 patients with resected

IPMN.

Model 1: sFASL and IL-4 Model 2: MMP9 and CA72-4

Prob high risk = exp(L)/(1+exp(L) . L = -2.6 + 0.0000013 * MMP9 + 0.002 * CA72-4


Improved identification of high-risk disease • Clinical and radiographic markers of high-grade dysplasia or

invasive disease.

Correa-Gallego C, et al. Ann Surg Oncol. 2013;20(13):4348-4355.

Concordance index: 0.74

main-duct IPMN branch-duct IPMN

Outcomes for IPMN

Patients undergoing initial surveillance

January 2010

June 2010

56 yo, female, incidental, EUS cyst fluid CEA 400

Outcomes for IPMN

Patients undergoing initial surveillance: Clinic 8/15/2014

56 yo, female, incidental, EUS cyst fluid CEA 400

2009 2014

60 yo male, with new onset diabetes and slightly increased serum CA 19.9: 72.

2010 2014

Outcomes for IPMN

Summary • Cystic lesions of the pancreas occur in 2.5% of the

population (increasing prevalence with age) • Many of these lesions will represent pre-cancerous lesions:

IPMN and MCN • IPMN represents a whole gland process with several genetic

pathways to distinct forms of invasive cancer • Resection should be recommended when there is concern for

high-grade dysplasia Main duct IPMN Large branch duct lesions with mural nodules

Outcomes for IPMN

Conclusions • With respect to IPMN, our understanding of the disease

process is rudimentary. Treatment recommendations based on diagnostic tools

with very limited accuracy Molecular testing: GNAS vs KRAS? Inflammatory markers may provide a means for

detecting high risk lesions? • IPMN however, represents an opportunity to potentially

intervene prior to the development of an incurable disease, and is one where surgeons and pathologists lead in the research efforts.

Documents

Current Management of Cystic Lesions of the Pancreas€¦ · Cystic lesions pancreas Introduction • Controversy: Who should undergo resection? 1995: “Given the current low morbidity