Journal Reading Presented by Dr. 陳志榮

An Illustrated Consensus on the Classification of Pancreatic Intraepithelial Neoplasia and Intraductal Papillary Mucinous Neoplasm Original article Hruban RH, Takaori K, Klimstra DS, Adsay NV, Albores-Saavedra J, Biankin AV, Biankin SA, Compton C, Fukushima N, Furukawa T, Goggins M, Kato Y, Kloppel G, Longnecker DS, Luttges J, Maitra A, Offerhaus GJ, Shimizu M, Yonezawa S. Am J Surg Pathol Aug;28(8): Am J Surg Pathol Aug;28(8):

Introduction Identification and treatment of pre-invasive lesions in the ducts of the pancreas is important. Identification and treatment of pre-invasive lesions in the ducts of the pancreas is important. Noninvasive precursors: Noninvasive precursors: (1) Pancreatic intraepithelial neoplasm (PanINs) (2) Intraductal papillary mucinous neoplasm (IPMN) (3) Mucinous cystic neoplasm the first two lack the internationally accepted nomenclature and diagnostic criteria. the first two lack the internationally accepted nomenclature and diagnostic criteria.

Introduction Pancreatic intraepithelial neoplasia (PanIN): first proposed in Pancreatic intraepithelial neoplasia (PanIN): first proposed in Developed at a National Cancer Institute in Developed at a National Cancer Institute in Progression model for pancreatic neoplasia: Progression model for pancreatic neoplasia: a series of molecular analyses a series of molecular analyses

Intraduction

Introduction

Introduction Papillomatosis of pancreatic duct: case report in 1936 Papillomatosis of pancreatic duct: case report in 1936 A series of intraductal neoplasm of pancreas: byOhhashi et al in A series of intraductal neoplasm of pancreas: byOhhashi et al in Intraductal papillary mucinous neoplasm (IPMN): introduced by Sessa et al in Intraductal papillary mucinous neoplasm (IPMN): introduced by Sessa et al in A progression model for IPMNs: a growing body of molecular and clinical evidence. A progression model for IPMNs: a growing body of molecular and clinical evidence.

Introduction

Introduction

Introduction 2002, Nagoyo, Japan: PanIN and IPMN should be revised and clarified 2002, Nagoyo, Japan: PanIN and IPMN should be revised and clarified 2003, The Johns Hopkins Hospital: 2003, The Johns Hopkins Hospital: (1) Characteristics of PanIN and IPMN (2) Ambiguities in the previous classification systems (3) Revised definition

General Feature of PanIN and IPMN PanIN/L-1A and PanIN-1B: common incidental finding PanIN/L-1A and PanIN-1B: common incidental finding Higher-grade PanIN: more often associated with an invasive cancer. Higher-grade PanIN: more often associated with an invasive cancer. (1) PanIN-1 lesions: 40% of adult pancreas without cancer (PanIN-3 lesions are seen in <5% of such pancreas) (2) PanIN-3: 30%~50% of pancreas with invasive ductal carcinoma. ductal carcinoma.

General Feature of PanIN and IPMN Higher grade of PanIN: can be a precursors of invasive carcinoma Higher grade of PanIN: can be a precursors of invasive carcinoma (1) Same genetic alterations in invasive ductal carcinoma and PanINs: KRAS2, TP53/p53, CDKN2A/p16, and MADH4/SMAD4/DPC4 genes (2) Continum of intraductal neoplastic progression: greater numbers of genetic alteration in higher- grade PanIN lesions.

General Feature of PanIN and IPMN IPMN: IPMN: (1) Typical radiographically identifiable ductal dilatation: (a) Main duct type: main pancreatic ducts (a) Main duct type: main pancreatic ducts (b) Branch duct type: secondary ducts (b) Branch duct type: secondary ducts (c) Mixed type: both (c) Mixed type: both (2) Associated with an invasive adenocarcinoma: particular main duct type. (a) Colloid (mucinous noncystic) carcinoma: (a) Colloid (mucinous noncystic) carcinoma: approximately one half approximately one half (b) Conventional tubular adenocarcinoma: (b) Conventional tubular adenocarcinoma: the most of remainder the most of remainder

General Feature of PanIN and IPMN IPMN: can be a precursors of invasive carcinoma IPMN: can be a precursors of invasive carcinoma (1) Same genetic alterations in conventional ductal adenocarcinoma: KRAS2, TP53/p53, and CDKN2A/p16 genes. ductal adenocarcinoma: KRAS2, TP53/p53, and CDKN2A/p16 genes.

General Feature of PanIN and IPMN (2) Frequencies and stage of neoplastic progression : differ from PanIN. from PanIN. (a) CDKN2A/p16 gene, may be inactivated through (a) CDKN2A/p16 gene, may be inactivated through aberrant DNA methylation. aberrant DNA methylation. (b) IPMNs with carcinoma in situ: microsatellite (b) IPMNs with carcinoma in situ: microsatellite instability (-), high telomerase activity (+), and COX-2 instability (-), high telomerase activity (+), and COX-2 expression (+). expression (+). (c) IPMNs: one third with inactived Peutz-Jeghers gene (c) IPMNs: one third with inactived Peutz-Jeghers gene STK11/LKB1 ( some patients with Peutz-Jeghers STK11/LKB1 ( some patients with Peutz-Jeghers syndrome develop IPMNs ). syndrome develop IPMNs ). (d) IPMNs: rare abnormalities in the MADH4/SMAD4/DPC4 gene, in contrast to ductal adenocarcinomas and PanIN-3 lesions.(~30%) (d) IPMNs: rare abnormalities in the MADH4/SMAD4/DPC4 gene, in contrast to ductal adenocarcinomas and PanIN-3 lesions.(~30%)

General Feature of PanIN and IPMN Surgical resection: treatment of choice for most IPMNs Surgical resection: treatment of choice for most IPMNs IPMNs resected before the development of invasive carcinoma are highly curable. IPMNs resected before the development of invasive carcinoma are highly curable. The prognosis is worse once invasive carcinoma develops: colloid type of invasive carcinoma has better prognosis than tubular type of invasive carcinoma. The prognosis is worse once invasive carcinoma develops: colloid type of invasive carcinoma has better prognosis than tubular type of invasive carcinoma.

General Feature of PanIN and IPMN Immunohistochemistry: MUC proteins Immunohistochemistry: MUC proteins (1) MUC2 : expressed in many IPMNs. (1) MUC2 : expressed in many IPMNs.

General Feature of PanIN and IPMN PanINs and IPMNs share many fundamental features: PanINs and IPMNs share many fundamental features: (1) Intraductal growth (2) Columnar, mucin- producing cells (3) Flat or papillae (4) A range of cytologic and architectural atypia (5) Precursors to invasive adenocarcinoma (6) Sequentially accumulate similar genetic alterations with increasing cytoarchitectural atypia. alterations with increasing cytoarchitectural atypia.

General Feature of PanIN and IPMN Sometimes, intraductal neoplasm may be almost impossible to classify by morphology alone. Sometimes, intraductal neoplasm may be almost impossible to classify by morphology alone. (1) PanIN: typical arise in the smaller ducts, may involve the large ducts may involve the large ducts (2) IPMNs: usually involve the larger ducts, may involve small ducts may involve small ducts

General Feature of PanIN and IPMN Despite this overlap, there are abundant data suggesting that PanINs and IPMNs represent two separate classes of intraductal neoplasia of pancreas. Despite this overlap, there are abundant data suggesting that PanINs and IPMNs represent two separate classes of intraductal neoplasia of pancreas.

General Feature of PanIN and IPMN

Ambiguities in the Previous Classification Systems The size of involved duct: The size of involved duct: (1) Size: the only factor used to distinguish between PanINs and IPMNs in the previous classification system (2) Some IPMNs involve the branch ducts and can be <1 cm, and still other IPMNs extend into the smallest caliber pancreatic ducts (3) Some PanINs can involve the main pancreatic duct and ducts involved with PanINs can be large due to secondary dilatation from an obstructing mass or stricture New definitions were needed that encompass these possibilities. New definitions were needed that encompass these possibilities.

Ambiguities in the Previous Classification Systems Measurement of involved duct: no specific guidelines: Measurement of involved duct: no specific guidelines: (1) The anatomic terms are particularly hard to apply to histological sections. (2) Extent of ductal dilatation often is difficult to establish based on the diameter of the duct: impossible to determine the original caliber of an involved duct

Ambiguities in the Previous Classification Systems Reproducible criteria: the previous classification system failed to provide to distinguish between retention cysts and IPMNs. Reproducible criteria: the previous classification system failed to provide to distinguish between retention cysts and IPMNs. “Cancerization of the duct”: a histologic finding to be distinguished from PanIN, “Cancerization of the duct”: a histologic finding to be distinguished from PanIN,

Ambiguities in the Previous Classification Systems Reactive change: Reactive change: (1) Previous classification system : against diagnosing PanIN in the setting of inflammation (2) Now recognized that PanIN lesions can, and often do, occur in the setting of chronic pancreatitis.

Ambiguities in the Previous Classification Systems Complex lesins: multiple lesions are present in a single pancreas. Complex lesins: multiple lesions are present in a single pancreas. Limits of radiologic detection: the use of radiologic detectability in the definitions of PanINs and IPMNs should be abandoned Limits of radiologic detection: the use of radiologic detectability in the definitions of PanINs and IPMNs should be abandoned

Ambiguities in the Previous Classification Systems It was recognized that the current grading systems for PanINs (PanIN-1, PanIN-2, and PanIN-3) and IPMNs (IPMN adenoma, IPMN borderline, IPMN carcinoma in situ) lack interobserver reproducibility. It was recognized that the current grading systems for PanINs (PanIN-1, PanIN-2, and PanIN-3) and IPMNs (IPMN adenoma, IPMN borderline, IPMN carcinoma in situ) lack interobserver reproducibility. A better consensus on the features defining each grade is needed. A better consensus on the features defining each grade is needed.

Ambiguities in the Previous Classification Systems It was acknowledged that different histologic types of papillae may occur in IPMNs and that criteria and designations for each different type need to be better defined. It was acknowledged that different histologic types of papillae may occur in IPMNs and that criteria and designations for each different type need to be better defined.

Revised Definitions

Guidelines for Evaluation of PanINs Size: Size: (1) <5mm: cross sectioned diameter: from basement membrane to basement membrane. (2) >5mm: carefully examination of multiple sections of the pancreatic ducts Neoplasms: Neoplasms: (1) Not mean to suggest the lesion need clinical treatment. (2) Clonal proliferation with alterations in cancer- related genes.

Guidelines for Evaluation of PanINs PanINs-1 and -2 : PanINs-1 and -2 : (1) Typically incidental findings (2) Unproved clinical significance. PanIN-3: PanIN-3: (1) Thought to have clinical significance: (a) Potential to progress to invasive carcinoma (a) Potential to progress to invasive carcinoma (b) Information regarding progression is limited (b) Information regarding progression is limited Difference with IPMN: when PanIN involving the main pancreatic duct Difference with IPMN: when PanIN involving the main pancreatic duct (1) Papillae in PanINs: usually are not as tall and complex as those in IPMNs. (2) Abundant luminal mucin production is a feature of IPMNs. (3) MUC2 expression is a specific but relatively insensitive marker of an IPMN and is generally not present in PanINs.

Guidelines for Evaluation of PanINs If multiple distinct PanINs in a single pancreas: If multiple distinct PanINs in a single pancreas: (1) Graded separately (2) Many prefer to list the range and/or the highest grade of PanIN present. the highest grade of PanIN present.

Guidelines for Evaluation of PanINs Reactive epithelial changes from PanINs: Reactive epithelial changes from PanINs: (1) A heterogeneous cell population (2) Prominent nucleoli (3) Intraepithelial inflammatory cells, particularly neutrophils should all suggest a reactive process. should all suggest a reactive process. In general, it is agreed that one should be conservative in categorizing a lesion as a PanIN in the setting of inflammation. In general, it is agreed that one should be conservative in categorizing a lesion as a PanIN in the setting of inflammation.

Guidelines for Evaluation of PanINs “Cancerization of the ducts,” and can occur either as direct continuity of invasive carcinoma. “Cancerization of the ducts,” and can occur either as direct continuity of invasive carcinoma. (1) These processes should be distinguished from PanIN-3. (2) Suggest secondary ductal involvement: (a) An abrupt transition from markedly atypical to (a) An abrupt transition from markedly atypical to normal-appearing epithelium normal-appearing epithelium (b) Continuity of the involved duct with invasive (b) Continuity of the involved duct with invasive carcinoma carcinoma

Guidelines for Evaluation of IPMNs Entirely submitted for histologic examination: Entirely submitted for histologic examination: The associated invasive cancer is the most important determinant of prognosis for patients with an IPMN. The associated invasive cancer is the most important determinant of prognosis for patients with an IPMN.

Guidelines for Evaluation of IPMNs Differential diagnosis of IPMNs: Differential diagnosis of IPMNs: (1) PanINs: If both PanINs and an IPMN are present in a single pancreas, efforts should be made to separate these lesions using the above-mentioned criteria. (2) Mucinous cystic neoplasm: (a) The presence of ovarian-type stroma (a) The presence of ovarian-type stroma (b) The absence of ductal involvement (b) The absence of ductal involvement (3) Retention cysts: (a) Flat, or at most very low papillary, epithelium. (a) Flat, or at most very low papillary, epithelium. (b) Epithelial atypia is minimal in retention cysts (b) Epithelial atypia is minimal in retention cysts (c) Usually unilocular. (c) Usually unilocular.

Guidelines for Evaluation of IPMNs Involvement what kind of ducts? Involvement what kind of ducts? (1) Main duct type ? branch duct type? Or mixed type? Branch duct-type IPMNs are usually confined to the head/tail of the pancreas, they tend to occur at a younger age, and they less often are associated with an invasive cancer than main duct type IPMNs Branch duct-type IPMNs are usually confined to the head/tail of the pancreas, they tend to occur at a younger age, and they less often are associated with an invasive cancer than main duct type IPMNs (2) Efforts should be made, radiographically or at the time of gross examination of resected specimens, to determine if an IPMN involves the main pancreatic duct or a branch duct.

Issues Requiring Further Study Neoplasm ? Lesion? Hyperplasia? Neoplasm ? Lesion? Hyperplasia? (1) These entities with the modifying term “lesion” (“PanIN/L-1A”) to acknowledge that the neoplastic nature of many cases of PanIN-1A has not been unambiguously established. (2) Similarly, the Japanese classification system for IPMNs includes “Intraductal papillary mucinous tumor - hyperplasia”for histologically low-grade structures without atypia. (3) Additional study is needed to identify reproducible criteria to distinguish hyperplastic lesions from low-grade neoplasms.

Issues Requiring Further Study Reproducible criteria? Reproducible criteria? (1) Morphometric evidence that a two-tier system (low- grade/high-grade) may be more reproducible. (2) It was the consensus of the group that further genetic and morphologic studies should be conducted to refine the histologic grading of PanINs and IPMNs.

Issues Requiring Further Study Histologic classification of IPMN: Histologic classification of IPMN: (1) Morphologically, IPMNs may have a variety of different cytoarchitectural features even in different regions of a single neoplasm. (2) Some separate IPMNs into clear-, dark-, and compact-cell types based on the density of the cytoplasm and the shape of the epithelial cells, and the expression patterns of MUC1, MUC2, and MUC5AC (3) It also has been proposed that IPMNs should be subdivided into gastrointestinal, pancreaticobiliary, and oncocytic subtypes. It was the consensus of the group that further clinical, genetic, and morphologic studies are needed to refine the histologic classification of IPMNs.

Issues Requiring Further Study Finally, some of the group speculated on the interesting possibility that some IPMNs may begin as PanINs that then progress along a different pathway of neoplasia than conventional pancreatic ductal adenocarcinoma. Finally, some of the group speculated on the interesting possibility that some IPMNs may begin as PanINs that then progress along a different pathway of neoplasia than conventional pancreatic ductal adenocarcinoma.

Conclusion IPMNs and PanINs are important precursors to invasive adenocarcinoma of the pancreas. It is our hope that the proposed revised definitions and diagnostic guidelines presented will help advance the study of these lesions such that genesis of pancreatic cancer will be elucidated and that pancreatic cancer, one of the most dreadful diseases of humankind, can one day be treated at the preinvasive stage. IPMNs and PanINs are important precursors to invasive adenocarcinoma of the pancreas. It is our hope that the proposed revised definitions and diagnostic guidelines presented will help advance the study of these lesions such that genesis of pancreatic cancer will be elucidated and that pancreatic cancer, one of the most dreadful diseases of humankind, can one day be treated at the preinvasive stage.