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Pathology of Genetically Engineered Mouse Models of Pancreatic Exocrine Cancer: Consensus Report and Recommendations

Ralph H. Hruban^1,2, N. Volkan Adsay⁵, Jorge Albores-Saavedra⁶, Miriam R. Anver⁷, Andrew V. Biankin³, Gregory P. Boivin⁸, Emma E. Furth⁹, Toru Furukawa¹², Alison Klein^1,2, David S. Klimstra¹³, Gnter Klppel¹⁴, Gregory Y. Lauwers¹⁵, Daniel S. Longnecker¹⁷, Jutta Lttges¹⁸, Anirban Maitra^1,2,4, G. Johan A. Offerhaus¹⁹, Lucía Pérez-Gallego²⁰, Mark Redston¹⁶ and David A. Tuveson^10,11

Departments of ¹ Pathology, ² Oncology, and ³ Surgery and ⁴ the Institute for Genetic Medicine, The Sol Goldman Center for Pancreatic Cancer Research, The Johns Hopkins Medical Institutions, Baltimore, Maryland; ⁵ Department of Pathology, Wayne State University, Harper Hospital, Detroit, Michigan; ⁶ Department of Pathology, Louisiana State University, Shreveport, Louisiana; ⁷ Pathology/Histochemistry Laboratory, SAIC Frederick, Inc., Frederick, Maryland; ⁸ Department of Pathology, The University of Cincinnati, Cincinnati, Ohio; Departments of ⁹ Pathology, ¹⁰ Medicine, and ¹¹ Cancer Biology, Abramson Family Cancer Research Institute, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania; ¹² International Research and Educational Institute for Integrated Medical Sciences, Tokyo Women's Medical University, Tokyo, Japan; ¹³ Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York; ¹⁴ Department of Pathology, University of Kiel, Kiel, Germany; ¹⁵ Department of Pathology, Massachusetts General Hospital; ¹⁶ Department of Pathology, Brigham and Woman's Hospital, Boston, Massachusetts; ¹⁷ Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hamsphire; ¹⁸ Department of Pathology, Teaching Hospital University Homburg, Saarbrücken, Germany; ¹⁹ Department of Pathology, The Academic Medical Center, Amsterdam, the Netherlands; and ²⁰ Comparative Pathology, Spanish National Cancer Centre, Madrid, Spain

Requests for reprints: Ralph H. Hruban, The Sol Goldman Pancreatic Cancer Center, The Johns Hopkins Hospital, 401 North Broadway, Weinberg 2242, Baltimore, MD 21231. Phone: 410-955-9132; Fax: 410-955-0115; E-mail: rhruban{at}jhmi.edu.

	Abstract

Top Abstract Introduction and Objectives Development of the Normal... Genetically Engineered Mouse... General Approach to the... Description and Nomenclature of... General Comments about Existing... Conclusions References

 
Several diverse genetically engineered mouse models of pancreatic exocrine neoplasia have been developed. These mouse models have a spectrum of pathologic changes; however, until now, there has been no uniform nomenclature to characterize these changes. An international workshop, sponsored by The National Cancer Institute and the University of Pennsylvania, was held from December 1 to 3, 2004 with the goal of establishing an internationally accepted uniform nomenclature for the pathology of genetically engineered mouse models of pancreatic exocrine neoplasia. The pancreatic pathology in 12 existing mouse models of pancreatic neoplasia was reviewed at this workshop, and a standardized nomenclature with definitions and associated images was developed. It is our intention that this nomenclature will standardize the reporting of genetically engineered mouse models of pancreatic exocrine neoplasia, that it will facilitate comparisons between genetically engineered mouse models and human pancreatic disease, and that it will be broad enough to accommodate newly emerging mouse models of pancreatic neoplasia. (Cancer Res 2006; 66(1): 95-106)

	Introduction and Objectives

Top Abstract Introduction and Objectives Development of the Normal... Genetically Engineered Mouse... General Approach to the... Description and Nomenclature of... General Comments about Existing... Conclusions References

 
The study of human pancreatic cancer is hampered by the advanced stage at which most patients present, the low neoplastic cellularity of most human pancreatic cancers, the inaccessibility of the organ to biopsy, and the extraordinarily high mortality rate of the disease (1). Genetically engineered mouse models, which recapitulate human pancreatic neoplasia, have the potential to advance our understanding of the pathobiology of noninvasive and invasive pancreatic neoplasia and to facilitate the development of novel tests for the early detection of pancreatic neoplasia and new therapies for invasive cancer (2).

A number of remarkable models of pancreatic disease have recently been developed in genetically engineered mice (2–9). These models use a variety of approaches to target the expression of mutant or endogenous genes in specific cellular compartments. It should therefore not be surprising that a broad spectrum of pathologic changes develop in these models. Some of these changes histologically mimic human disease, whereas others are not encompassed in the existing nomenclatures for human pancreatic neoplasia.

An international workshop, sponsored by The National Cancer Institute and the University of Pennsylvania, was held in Philadelphia, PA from December 1 to 3, 2004 with the goals of (a) describing the histopathology of pancreatic exocrine neoplasia in existing genetically engineered mouse models and (b) developing a standard nomenclature for these lesions. It is anticipated that this nomenclature will standardize the reporting of the pancreatic pathologic changes in genetically engineered mouse models and that it will facilitate comparisons among mouse models as well as between mouse models and human disease. Although it is obviously impossible to anticipate all of the morphologic patterns that may be seen in newly emerging mouse models, the proposed classification is intended to be flexible enough to accommodate variations in the existing morphologies, and by incorporating some of the more common patterns observed thus far only in humans, to enable continued use of the classification as new mouse models are developed. In addition, workshop participants thought it was important to specifically address the interpretation of mouse pancreatic intraepithelial neoplasia (mPanIN), and that a collection of annotated images should be created to facilitate the promulgation of this nomenclature. The new nomenclature and selected images are presented here, and additional images are provided on the Web.²¹

Although the nomenclature was developed to parallel the existing nomenclature for human pancreatic exocrine neoplasia (1, 10), the group felt it was important to emphasize that genetically engineered mice differ significantly from humans, and that mouse lesions histologically similar to human lesions may be genetically or biologically quite different. Thus, great care should be taken in applying findings in mice to the human condition without further investigation.

	Development of the Normal Pancreas

Top Abstract Introduction and Objectives Development of the Normal... Genetically Engineered Mouse... General Approach to the... Description and Nomenclature of... General Comments about Existing... Conclusions References

 
Before discussing the details of the pathologic changes in genetically engineered mouse models of pancreatic neoplasia, a brief review of the normal development of the mouse pancreas will provide a frame of reference for the genetic manipulations and subsequent changes in the models.

Development of the exocrine pancreas. Pancreatic development in the mouse is orchestrated by a cascade of transcription factors that are sequentially expressed in specific cell types as the organ develops (Fig. 1). Although molecular events involved later in pancreatic differentiation are similar in both the ventral and dorsal pancreatic anlagen, early specification of these two regions of endoderm towards a pancreatic fate differs (11). Development of the pancreas begins with inhibition of hedgehog signaling in a discrete region of dorsal endoderm by factors secreted by the notochord (12, 13). This absence of hedgehog signaling determines the pancreatic lineage of epithelium that becomes the dorsal pancreatic bud visible at E9.5 (13, 14). In contrast, the default developmental program for ventral endoderm in this region is towards a pancreatic fate. The expression of fibroblast growth factor by cardiogenic mesoderm induces hedgehog expression and thereby specifies a hepatic fate in the foregut endoderm adjacent to the nascent ventral bud, thus limiting the anterior extent of the ventral pancreatic bud (15).

View larger version (31K): [in this window] [in a new window]   Figure 1. Gene expression during pancreatic development. Reprinted with permission of Jones and Bartlett Publishers from Pancreatic Cancer by Von Hoff et al., 2005.

The pancreatic epithelium proliferates and branches, and the dorsal and ventral buds ultimately fuse, resulting in an epithelial tubular complex containing all the precursor cells of the mature organ at E12.5 (11). These multipotential Pdx1-positive pancreatic precursor cells differentiate along islet, acinar, and ductal lineage pathways (Fig. 1) from E13.5 to E17.5 to give rise to the definitive cell types of the mature pancreas (11).

p48 is the pancreas-specific subunit of the heteromeric bHLH protein complex called PTF1 (19). Although, initially, p48 was thought to be an exocrine-specific transcription factor, more recent evidence suggests it has a role earlier in pancreatic development and is required for the commitment of all three pancreatic cell lineages (20). Expression of p48 is restricted to the pancreatic anlagen of the Pdx1 expression domain, and the overlapping activities of Pdx1, p48, and pbx1, a member of the three amino acid loop extension class of homeodomain transcription factors, may delineate the endodermal domains committed to pancreatic development (11). The mechanism of final lineage commitment of Pdx1/p48–positive cells is not fully understood. Cells committed to the exocrine lineage lose Pdx1 expression but maintain p48 expression. Recent evidence suggests that terminally differentiated acinar cells are more closely related to islet cells than ductal cells, and that commitment to a ductal lineage occurs earlier than the divergence of acinar and islet cell lineages through a mechanism that is yet to be identified (11).

Although cells committed to the acinar lineage lose Pdx1 expression but maintain p48 expression, islet cell precursors maintain Pdx1 expression, lose p48 expression, and express the bHLH factor neurogenin 3 (21). Further lineage specification of islet cell precursors is regulated by neuroD (also known as ß cell E-box transactivator-2), Pax6, Pax4 and Nkx2.2, Nkx6.1, and Glut2 (21). A small proportion of endocrine cells in the pancreas appears early in pancreatic development. This population of cells is thought to be analogous to the enteroendocrine cells located in the gastrointestinal tract. These cells are mostly glucagon immunoreactive, are not dependent on Pdx1 or p48 for development, and may contribute to the glucagon-positive mantle of mature islets (11). Finally, Notch signaling in developing pancreas inhibits p48 function and loss of Notch signaling permits acinar cell differentiation and subsequent production of pancreatic zymogens (22, 23). In addition, Notch acts to maintain a pool of undifferentiated cells in the mature organ, and Notch activity, as measured by Hes1 expression, is present in a small number of exocrine cells in the mature pancreas (23).

The histology of the normal mouse pancreas does not differ significantly from the histology of the normal human pancreas. An interesting feature of the normal mouse pancreas is the variability from mouse to mouse and region to region of the density of islets of Langerhans.

This framework for the normal development of the pancreas provides insight into approaches employed to generate the genetically engineered mouse models examined by this working group. These approaches have also been guided by the growing body of information on the oncogenes and tumor suppressor genes targeted in human pancreatic adenocarcinomas (24) and by our current understanding of gene expression in normal mature acinar and ductal cells.

	Genetically Engineered Mouse Models

Top Abstract Introduction and Objectives Development of the Normal... Genetically Engineered Mouse... General Approach to the... Description and Nomenclature of... General Comments about Existing... Conclusions References

 
Twelve genetically engineered mouse models were submitted to the workshop participants (Table 1).

(a) An elastase (Ela)-Kras^G12D transgenic mouse model was submitted by Grippo et al. (6). The model uses the rat elastase promoter to drive the expression of mutant Kras (a glycine to aspartate mutation). Elastase is a protein primarily expressed in cells committed to acinar differentiation.

(b) Sandgren and Schmid submitted a distinct transgenic model in which the expression of transforming growth factor- (TGF-) is driven by the rat elastase promoter (5). Some of these mice were also crossed with p53^+/– mice (25).

(c) In the model submitted by Konieczny, the expression of mutant Kras (Kras^G12D) is driven by the endogenous Mist1 promoter (26). Mist1 is a transcription factor expressed in early development of the foregut endoderm (ed 10.5) and restricted to acinar cells in the adult pancreas (Fig. 1). In this model, the Kras^G12D cDNA is "knocked-in" to the coding region of Mist1 by gene targeting in embryonic stem cells.

(d) A conditional Kras^G12V model was submitted by Guerra et al. (27). This is a mutant Kras^{G12V-ires-BGeo} "knock-in" model in which the endogenous Kras oncogene is transcriptionally silenced by a LoxP-flanked stop element, and expression is induced upon doxicycline administration (in a tet-o-cre; Elastase-rtTA background). The mice are constitutionally heterozygous for wild-type Kras.

(e) In the model submitted by Bardeesy, conditional Kras^G12D mice (7) are crossed with conditional Ink4a/Arf null mice (9). In the conditional Kras^G12D mice, endogenous expression of mutant Kras is activated by a Pdx1-Cre transgene (7). The Ink4a/Arf null mice have a conditional deletion of exons 2 and 3 of the Ink4a/Arf locus that concomitantly eliminates both p16^INK4A and p19^ARF in the same cells that activate Kras^G12D expression.

(f) and (g) Hingorani submitted two models. The first model was the conditional Kras^G12D mice described above (7). In the second model, the conditional Kras^G12D mice were crossed with mice harboring a G-to-A substitution at nucleotide 515 of the endogenous p53 (p53+/515A) corresponding to the p53R175H hotspot mutation in human cancers (28). Thus, in these models, both Kras^G12D and Trp53^R172H are expressed at physiologic levels in the context of their wild-type counterparts (29).

(h) Lewis submitted a model that somatically delivers mouse polyoma virus middle T antigen (PyMT)-bearing avian retroviruses (RCAS) to mice that express TVA, the receptor for avian leucosis sarcoma virus subgroup A (ALSV-A) under control of the elastase promoter (4).

(i) The K19-KRAS model submitted by Rustgi was created using a cytokeratin 19 promoter to drive the expression of mutant Kras (a glycine-to-valine mutation; ref. 3).

(j) Means submitted a model in which the Pdx1 promoter is used to drive the expression of heparin-binding epidermal growth factor–like growth factor (HB-EGF; ref. 30).

(k) Thayer submitted a model in which the expression of full-length rat sonic hedgehog (Shh) is driven by the Pdx1 promoter (8).

(l) Bar-Sagi submitted a model of chronic pancreatitis in which the elastase promoter is used to drive the expression of a mutant trypsinogen gene (PRSS1^R122H). This mutation removes an autocleavage site in the trypsin protein, leading to increased trypsin activity.

	General Approach to the Evaluation of Changes in the Pancreas

Top Abstract Introduction and Objectives Development of the Normal... Genetically Engineered Mouse... General Approach to the... Description and Nomenclature of... General Comments about Existing... Conclusions References

 
Because the spectrum of pathologies seen in genetically engineered mouse models is so broad, and to help accommodate emerging models, the working group first developed a general approach to the evaluation of genetically engineered mouse models of pancreatic neoplasia (Table 2). All changes in the genetically engineered mouse models should be evaluated relative to gender, age, and strain-matched controls, optimally using littermates.

After the gross examination is completed and tissues are harvested for any special studies, the remainder of the pancreas should be entirely submitted for microscopic examination. Because the relationship of the pancreas and the pancreatic ducts to the duodenum is often of interest, the duodenum can be included in the sections. Ten percent neutral buffered formalin is a versatile fixative for routine histology, but other fixatives may be used depending on the studies planned.

Microscopic evaluation of the compartments affected. The first step in the microscopic evaluation of the pancreas is to determine which cellular compartments (acinar, ductal, endocrine, and interstitial compartments) are affected. Each compartment should be evaluated systematically, and the involvement of more than one compartment should be documented. Although it is recognized that it is not always possible to determine with certainty which compartments are affected by a process, the procedure of systematically assessing each compartment can provide a useful framework for beginning the challenging task of evaluating the complex changes possible in a genetically engineered mouse model.

The changes within each compartment can then be separated into architectural and cytologic changes. Architectural changes alter the relationships among cells or the organization of a compartment. Architectural changes therefore include (a) formation of new abnormal elements including masses (solid masses, papillae, cysts, etc.), (b) an aberrantly located compartment within the pancreas (e.g., ducts within an islet of Langerhans), (c) transformation within preexisting units (cystic change within ducts, etc.), and (d) infiltration by cells not normally found in the gland (inflammatory infiltrates, secondary tumors, etc.). Each of the architectural changes should be described and categorized as focal, multifocal, or diffuse.

Cytologic changes are alterations at the cellular and subcellular levels and include hypertrophy, atrophy, hyperplasia, metaplasia, proliferation, atypia, and cell death (apoptosis or necrosis). The cellular compartments in which each cytologic change occurs should be documented. Definitions of selected terms are provided in Table 3.

	Description and Nomenclature of Lesions of the Exocrine Pancreas

Top Abstract Introduction and Objectives Development of the Normal... Genetically Engineered Mouse... General Approach to the... Description and Nomenclature of... General Comments about Existing... Conclusions References

Cystic papillary neoplasms. Cystic papillary neoplasms are large (>1 mm) cystic structures composed of usually papillary, noninvasive epithelial proliferations with varying degrees of cellular atypia (Fig. 2A). Lesions <1 mm may represent mPanIN (see below). The predominant direction of differentiation is along ductal cell lines. Those that are not predominantly ductal should not be classified as cystic papillary neoplasms but should instead be classified based upon the predominant line of differentiation (or under Mixed Neoplasms if there are significant components of more than one cell line; see below). An attempt should be made to determine whether the lesion is intraductal and, if so, if it is arising in the main pancreatic ducts or in a smaller peripheral duct. Cystic papillary neoplasms arising in the larger ducts may resemble human intraductal papillary mucinous neoplasms (32). These lesions may be associated with inflammatory/fibrotic changes in the surrounding pancreas.

View larger version (146K): [in this window] [in a new window]   Figure 2. A, cystic papillary neoplasm. The cystic structures are composed of papillary, noninvasive epithelial proliferations with varying degrees of cellular atypia. B-D, mPanIN. These glandular epithelial proliferations are confined to the pancreatic ducts, the ducts measure <1 mm, and they occur in an appropriate setting. A, H&E-stained section from the Ela-KRASG12D model; B and D, from the Pdx1-cre; LSL-KrasG12D model; C, from the Ela-tTA; tet-o-cre; LSL-KrasG12V-ires-BGeo model.

mPanIN. Much of the discussion at the workshop centered on the definition of potential morphologic precursors to invasive ductal adenocarcinoma. In humans, clinical, morphologic, and molecular studies have all suggested that microscopic epithelial proliferations within the smaller (<5 mm in humans) pancreatic ducts progress to invasive ductal adenocarcinoma (34–36). In humans, these lesions are classified as PanIN, and in humans, PanINs can be graded based on the degree of cytologic and architectural atypia present as PanIN-1, PanIN-2, and PanIN-3 (Table 6; ref. 34).

mPanIN was defined as a lesion that meets the following criteria: (a) It is a ductal epithelial proliferation confined to the native pancreatic ducts. (b) The involved ducts measure <1 mm. (c) It occurs in an appropriate setting. That is, mPanIN should be distinguished from acinar-ductal metaplasia. In restricting the classification of mPanINs to lesions that occur in the appropriate setting, we are not suggesting that small intraductal glandular proliferations that occur in the setting of acinar-ductal metaplasia are not biologically similar to mPanINs; rather, we are attempting to maintain close parallels with human disease. Developing insights may ultimately lead to change of definitions, but our current understanding of human intraductal epithelial proliferations is that the setting in which they occur determines their biology and setting is therefore reflected in the definition of mPanINs. (d) The lesion does not show significant acinar differentiation. (e) Evidence suggests that the lesion is neoplastic (morphology, clonality, presence of additional genetic changes, progression, transplantation). Representative examples are illustrated in Fig. 2B-D. The degree of cytologic and architectural atypia in these lesions can be graded, and grading should parallel that in human PanIN (mPanIN-1, mPanIN-2, and mPanIN-3; see Table 6). mPanIN can occur in a pancreas with or without an associated invasive carcinoma, and evidence exists that mPanINs may progress to invasive carcinoma, because they appear before the invasive component in some models (7).

Invasive ductal adenocarcinoma. Invasive ductal adenocarcinomas constitute the vast majority of malignant neoplasms of the pancreas in humans. They are defined as malignant epithelial neoplasms with ductal differentiation that have penetrated through the ductal basement membrane (Fig. 3A). Ductal differentiation is primarily defined at the light microscopic level by the formation of glands and can be supported by special stains for mucin or immunolabeling for markers of ductal differentiation (e.g., cytokeratin 19). Invasive ductal adenocarcinomas are subdivided into five groups (see Table 5) as defined below. One of the characteristic features of invasive carcinomas of the pancreas in humans is that they are associated with an intense desmoplastic reaction. Desmoplasia is the cellular fibroinflammatory response, which may accompany an invasive ductal adenocarcinoma. The term desmoplasia should not be used in the absence of an invasive carcinoma.

View larger version (130K): [in this window] [in a new window]   Figure 3. A, invasive ductal adenocarcinoma. This malignant epithelial neoplasm shows prominent ductal differentiation and has penetrated through the basement membrane. B, sarcomatoid carcinoma. A spindle cell morphology predominates in this undifferentiated carcinoma. C, undifferentiated carcinomas with a metaplastic component. Note the cartilage formation. D and E, acinar cell carcinoma. Note the formation of acini (D) and the expression of chymotrypsin (E). F, ductular-insular complex. G and H, acinar-ductal metaplasia. Note the formation of tubular structures with both ductal and acinar differentiation that replace acinar parenchyma. The ductular and acinar units in (H) are separated by mature fibrous tissue, which is characteristic in this model and exemplifies involvement of the interstitial compartment. H&E-stained sections from the Pdx1-cre; LSL-KrasG12D; LSL-p53R172H model (A), from the Pdx1-cre; LSL-KrasG12D; Ink4a/Arf fl/fl model (B), from the TVA-RCAS-PyMT model (C), from the Ela-TGF; p53 -/- model (D), the Pdx1-HB-EGF model (F), the Ela-KRASG12D (G) model, and the Ela-TGF model (H). Immunolabeling for chymotrypsin in the Ela-TGF; p53–/– model (E).

The subtypes of invasive adenocarcinoma include:

a. Tubular adenocarcinoma is an invasive malignant epithelial neoplasm with ductal differentiation and without a predominant component of any of the other carcinoma types (Fig. 3A; refs. 1, 10). Evidence of ductal differentiation can include morphology supported by special stains for mucin or immunolabeling (e.g., for cytokeratin 19).

b. Adenosquamous carcinoma is a malignant epithelial neoplasm of the pancreas with significant components of both ductal and squamous differentiation (1, 10).

c. Colloid (mucinous noncystic) carcinoma is an infiltrating adenocarcinoma in which 80% of the neoplasm is characterized by mucin-producing neoplastic epithelial cells suspended in large pools of extracellular mucin (39). Thus far only described in humans, colloid carcinomas are usually associated with intraductal papillary mucinous neoplasms (40).

d. Medullary carcinoma is a malignant epithelial neoplasm characterized by poor differentiation, a syncytial growth pattern, pushing borders, and necrosis. To date, it has only been reported in humans (41).

e. The undifferentiated carcinoma is an invasive, malignant epithelial neoplasm that shows no glandular, acinar, endocrine, or squamous differentiation (1, 10). Undifferentiated carcinoma can have a variety of microscopic appearances. Anaplastic giant cell carcinomas are composed of relatively noncohesive pleomorphic mononuclear cells admixed with bizarre, frequently multinucleated giant cells containing abundant eosinophilic cytoplasm (1). When the spindle cell morphology is predominant, the neoplasm may resemble a sarcoma, and this form of undifferentiated carcinoma can be designated sarcomatoid carcinoma (Fig. 3B; ref. 1). Sometimes, there is sufficient mesenchymal differentiation to result in heterologous stromal elements, such as bone, cartilage, or striated muscle (Fig. 3C; refs. 1, 10). Such carcinomas should be designated as adenocarcinomas with a metaplastic component, and the metaplastic component should be named.

B. Acinar Lesions
Acinar cell lesions include both neoplasms and hyperplastic lesions. Acinar cell lesions are microscopically distinct epithelial lesions with evidence of pancreatic acinar differentiation. This differentiation can be identified at the light microscopic level but is best shown by immunohistochemical labeling for pancreatic exocrine enzymes (lipase, amylase, trypsin, or chymotrypsin), or by the ultrastructural demonstration of zymogen granules within the neoplastic cells. Historically, well-differentiated noninvasive lesions have been classified according to size. Focal hyperplasia is used to designate lesions <1 mm; acinar cell nodule designates lesions 1 to 5 mm; and acinar cell adenoma lesions >5 mm. If dysplasia (atypia) is present in these lesions, it should be documented. The predominant acinar neoplasm seen in the mouse models is the acinar cell carcinoma (Fig. 3D and E). Acinar cell carcinoma is a solid or cystic invasive epithelial neoplasm with acinar differentiation (morphology supported by immunolabeling for exocrine enzymes [e.g., chymotrypsin and amylase] or electron microscopy; ref. 42).

C. Epithelial Neoplasms with Mixed or Uncertain Directions of Differentiation
Neoplasms with multiple lines of differentiation ("mixed neoplasms"). It is recognized that pancreatic neoplasms, particularly those neoplasms that arise in genetically engineered mouse models, can show more than one direction of differentiation. Each component comprising >20% of the neoplasm should be designated. Examples include mixed acinar-endocrine, ductal-acinar, ductal-endocrine, and ductal-endocrine-acinar carcinomas. If a minor (<20%) component of a secondary line of differentiation is detected, the neoplasm should be classified based upon the predominant line of differentiation. Pancreatoblastoma, a human neoplasm containing squamoid nests and commonly exhibiting acinar, endocrine, and ductal differentiation, is also regarded as a type of neoplasm with multiple lines of differentiation.

Cystic papillary neoplasms should not be confused with solid-pseudopapillary neoplasms (1, 43). Solid-pseudopapillary neoplasms have not been reported in genetically engineered mouse models. In humans, solid-pseudopapillary neoplasms are epithelial neoplasms composed of noncohesive cells that surround delicate blood vessels and form solid masses with frequent cystic degeneration (1, 43).

D. Other Lesions
Ductulo-insular lesion. Ductulo-insular lesion is the aberrant presence of proliferating ductules within an islet of Langerhans (Fig. 3F). These should not be considered mPanINs as they are not arising in the appropriate setting.

Acinar-ductal metaplasia. Acinar-ductal metaplasia is a common finding in genetically engineered mouse models, particularly those models that use acinar promoters, such as elastase. Acinar-ductal metaplasia is characterized by the abnormal formation of tubular structures (i.e., tubular complexes) with both ductal and acinar differentiation that replace acinar parenchyma (Fig. 3G and H). The sharp transition between normal caliber ducts and acini is lost. The process is usually diffuse, it can be proliferative, it can be mucinous, and it can have scattered endocrine cells. Those with mucinous lining, if examined out of context, are very similar to human PanIN-1A. Importantly, the lesions are located within the acinar compartment of the pancreas rather than in the native ducts. A similar acinar-ductal metaplasia can be seen in human pancreata, particularly in the setting of chronic pancreatitis. Although some lesions of acinar-ductal metaplasia may progress to neoplastic lesions and models, which generate these lesions, may provide useful insight into human disease, the group felt that it is important to clearly distinguish acinar-ductal metaplasia from intraductal lesions that meet the criteria for mouse PanIN (see above). This distinction will help establish the importance (or lack thereof) of the setting in which intraductal lesions develop.

Ductal-intestinal metaplasia. Ductal-intestinal metaplasia is the replacement of the normal exocrine pancreas with cells showing mature intestinal differentiation (Fig. 4A). Intestinal differentiation is defined by light microscopic examination and can be supported by stains for mucin and immunohistochemical labeling for markers of intestinal differentiation, such as cdx2.

View larger version (164K): [in this window] [in a new window]   Figure 4. A, ductal-intestinal metaplasia. The normal exocrine pancreas is replaced with cells showing mature intestinal differentiation. B, chronic pancreatitis with acinar dropout, fibrosis, and chronic inflammation. C and D, human PanIN grades PanIN-2 (C) and PanIN-3 (D). E, human infiltrating tubular (ductal) adenocarcinoma. Note the haphazard arrangement of glands and the desmoplasia. F, human acinar cell carcinoma. Note the granular cytoplasm and single prominent nucleoli. H&E-stained sections of the Pdx1-Shh model (A), the Ela-PRSS1 model (B), and surgically resected human pancreata (C-F).

Chronic pancreatitis. Chronic pancreatitis is the irreversible loss of acinar tissue associated with replacement fibrosis (Fig. 4B). An inflammatory cell infiltrate is usually present and is often mixed, composed of lymphocytes, plasma cells, and macrophages. In some instances, an acute inflammatory cell infiltrate may be present, reflecting ongoing acute pancreatitis.

For purposes of comparison, representative examples of human infiltrating ductal adenocarcinoma, pancreatic intraepithelial neoplasia, and acinar carcinoma are illustrated in Fig. 4C-F.

	General Comments about Existing Models

Top Abstract Introduction and Objectives Development of the Normal... Genetically Engineered Mouse... General Approach to the... Description and Nomenclature of... General Comments about Existing... Conclusions References

 
In the last phase of the workshop, the group reviewed each of the 12 submitted existing genetically engineered mouse models of pancreatic exocrine neoplasia (Tables 1 and 7; refs. 3–9, 26, 29, 30). This provided an opportunity to validate the new nomenclature, as well as a framework in which to categorize the existing genetically engineered mouse models. Investigators from each of these genetically engineered mouse models were invited to submit representative formalin-fixed, paraffin-embedded tissue blocks to the workshop. H&E-stained sections were prepared from each block, as well as a mucicarmine stain and a panel of immunohistochemically labeled slides. These included immunohistochemical labeling for synaptophysin (DakoCytomation, Copenhagen, Denmark; 1:100), cytokeratin 19 (DakoCytomation, 1:50), and chymotrypsin (Biodesign International, Saco, ME; 1:100). The mucin-stained slides and the panel of immunohistochemically labeled slides were sent to workshop participants before the workshop, and a complete set of slides and multiheaded microscopes were available for additional slide reviews at the workshop. The group felt that although there was significant variation among the models, the three acinar models could be broadly grouped together, as could the three endogenous Kras models.

Because the intraductal lesions in the small ducts in these models developed in the setting of extensive acinar-ductal metaplasia, the group felt that these models did not develop mPanIN as strictly defined above despite the presence of mucin staining that could be shown in metaplastic ductal structures that could resemble mPanIN in isolation.

Endogenous Kras models. Four models were broadly grouped together as endogenous Kras models. These included the Kras^{G12V-ires-BGeo} model submitted by Guerra et al. (27) and the Kras^G12D model developed by Hingorani (7). The Kras^G12D model was subsequently used to develop the Kras^G12D + Ink4a/Arf model submitted by Bardeesy (9) and the Kras^G12D + p53^R172H model submitted by Hingorani et al. (29). Acinar-ductal metaplasia was much less extensive in these models than it was in the three acinar promoter models. The four endogenous Kras models developed mPanIN lesions, including mPanIN-1, mPanIN-2, and mPanIN-3 (Fig. 2B-D; ref. 34). All developed invasive ductal adenocarcinomas, some with metastases. The carcinomas that developed in these models were well differentiated, poorly differentiated, and undifferentiated (Fig. 3A and B).

Lewis TVA-RCAS model. The TVA-RCAS model submitted by Lewis was relatively unique (4). The PyMT model developed cystic papillary neoplasms with ductal differentiation and carcinomas with mixed acinar-endocrine differentiation when deficient for Ink4a/Arf and undifferentiated carcinomas in mice null for p53 and heterozygous for Ink4a/Arf in the pancreas (Fig. 3C).

Rustgi K19-KRAS. The K19-KRAS model submitted by Rustgi showed minimal morphologic changes, although cells isolated from the pancreata of these animals showed an interesting in vitro phenotype (3).

Pdx1-HB-EGF. The pdx1-HB-EGF model submitted by Means developed ductulo-insular lesions (Fig. 3F; ref. 30). No mPanIN lesions were identified in the slides submitted for review, and the animals did not develop invasive carcinoma.

Pdx1-Shh. The Pdx1-Shh model submitted by Thayer showed extensive ductal-intestinal metaplasia with atypia (Fig. 4A; ref. 8). No mPanIN lesions were identified, and the animals did not develop invasive carcinoma.

ELA-PRSS1. The ELA-PRSS1^R122H model submitted by Bar-Sagi showed chronic pancreatitis with a lymphocytic infiltrate and acinar-ductal metaplasia (Fig. 4B). No mPanIN lesions were identified, and the animals did not develop invasive carcinoma.

Thus, the pathologic changes identified in all of the models submitted to the meeting could be classified using the new nomenclature and classification system. The group of pathologists reviewing the pathology felt that the two-step process in which the general features of the model were evaluated and then the specific changes classified was very useful.

	Conclusions

Top Abstract Introduction and Objectives Development of the Normal... Genetically Engineered Mouse... General Approach to the... Description and Nomenclature of... General Comments about Existing... Conclusions References

 
Early transgenic models of exocrine pancreatic cancer relied on the elastase promoter and primarily yielded acinar cell carcinomas (44). In the last decade, there has been a wonderful growth in the number of genetically engineered mouse models of pancreatic neoplasia (2–9, 27, 29). A variety of promoters can now be exploited to target specific cell types in the pancreas at different stages of development. The changes produced in these genetically engineered mouse models are complex, making it difficult to compare the findings in the models. Here, we present a proposed nomenclature for the pathology of genetically engineered mouse models of pancreatic neoplasia that we hope will gain international acceptance.

A two-phase approach to the evaluation of genetically engineered mouse models of pancreatic neoplasia is presented. Models should first be evaluated using a general approach to describe the pathologic changes in a broad sense: the compartments that are affected and the general nature of the process within each compartment. After this general description, a more specific approach can be taken to establish a specific pathologic diagnosis.

The review of a large number of mouse models also provided an opportunity to identify several general differences between the pathology identified in the genetically engineered mouse models and the pathology seen in humans. First, human pancreatic ductal adenocarcinoma tends to be moderate or poorly differentiated, whereas many of the models produced anaplastic carcinomas. Second, most neoplasms in humans show a single direction of differentiation, whereas multilineage differentiation, including acinar differentiation, was often seen in the genetically engineered mouse models. Third, pancreatic intraepithelial neoplasia in humans often, although not always, occurs in the relatively intact pancreatic parenchyma. By contrast, many of the duct lesions in genetically engineered mouse models arose in the background of diffuse acinar-ductal metaplasia. Fourth, most human pancreatic carcinomas are solitary, whereas multifocality seems to be common in the genetically engineered mouse models. Finally, intense desmoplasia is a characteristic feature of invasive ductal adenocarcinoma in humans. By contrast, little to no desmoplasia was seen in most carcinomas in the genetically engineered mouse models.

The group felt it was important to emphasize two points. First, the classification of genetically engineered mouse models of pancreatic neoplasia is not a static process. It is fully anticipated that new models will be created and that some of these new models will develop lesions that are not easily classifiable using the proposed framework. Furthermore, the classification system needs to be further tested and validated. As such, the classification system presented should be viewed as a "working formulation" and not as a final unchangeable product. Second, the group felt that each of the models submitted for review has its own unique merits in advancing our understanding of pancreatic neoplasia. The classification system proposed is not meant to be used to value one model over another. Rather, the purpose of the classification is to provide an internationally acceptable framework to facilitate comparisons between genetically engineered mouse models and human pathology.

	Acknowledgments

 
Grant support: National Cancer Institute Mouse Models Consortium, National Cancer Institute/NIH contract NO1-CO-12400, NIH Specialized Programs of Research Excellence in Gastrointestinal Cancer grant CA62924, and Sol Goldman Pancreatic Cancer Research Center.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

	Footnotes

 
²¹ http://www.abcc.ncifcrf.gov/LASP/lasp_index.php.

²² Unpublished.

Received 6/27/05. Revised 10/18/05. Accepted 11/11/05.

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Top Abstract Introduction and Objectives Development of the Normal... Genetically Engineered Mouse... General Approach to the... Description and Nomenclature of... General Comments about Existing... Conclusions References

 

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