Cancers of the ductal epithelium in the pancreas are

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1 July 2007 EDITORIALS El-Serag HB, Kvapil P, Hacken-Bitar J, Kramer JR. Abdominal obesity and the risk of Barrett s esophagus. Am J Gastroenterol 2005;100: Edelstein ZR, Farrow DC, Bronner MP, Rosen SN, Vaughan TL. Central adiposity and risk of Barrett s esophagus. Gastroenterology 2007;133:(In press). 7. Nilsson M, Johnsen R, Ye W, Hveem K, Lagergren J. Obesity and estrogen as risk factors for symptomatic gastroesophageal reflux. JAMA 2003;290: Jacobson BC, Somers SC, Fuchs CS, Kelly CP, Camargo CA Jr. Body-mass index and symptoms of gastroesophageal reflux in women. N Engl J Med 2006;354: Akgun H, Lechago J, Younes M. Estrogen receptor-beta is expressed in Barrett s metaplasia and associated adenocarcinoma of the esophagus. Anticancer Res 2002;22: Address requests for reprints to: Jesper Lagergren, MD, ESOGAR, P9:03, Karolinska University Hospital, SE Stockholm, Sweden. jesper.lagergren@ki.se; fax: (46) by the AGA Institute /07/$32.00 doi: /j.gastro Location, Location, Location: Precursors and Prognoses for Pancreatic Cancer See Branch duct intraductal papillary mucinous neoplasms: observations in 145 patients who underwent resection Rodriquez JR, Salvia R, Crippa S, Warshaw AL, Bassi C, Falconi M, Thayer SP, Lauwers GY, Capelli P, Mino Kenudson M, Razo O, McGrath D, Pederzoli P, and Fernández-del Castillo C, on page 72. Cancers of the ductal epithelium in the pancreas are unusually lethal. Infiltrating pancreatic ductal adenocarcinoma (PDA), the entity typically implied by the more generic pancreatic cancer, portends a dismal prognosis and, uniquely among all the epithelial malignancies, is rarely curable even when resected at the earliest stages of invasion. Intriguingly, however, not all cancers with ductal differentiation are equivalent. The location within the ductal tree and the specific type of precursor lesion cystic or not together with the modifying influences of both the complement and the chronology of acquired mutations, all contribute to determining disease behavior and prognosis in ways we are only beginning to understand. Precursors to Invasive Disease Pancreatic intraepithelial neoplasias (PanINs) are the most common precursors to PDA. PanINs are microscopic, asymptomatic lesions of the terminal ductules first described at the turn of the last century (reviewed in Hruban and Ali 1 ), and they appear to progress to invasive disease most readily in the head and uncinate process of the organ (Figure 1). The elaboration of histologic 2 4 and genetic models 5 for disease progression has provided insight into mechanisms of pathogenesis and helped to shape and stimulate research in the field. Increasing degrees of cellular and architectural atypia chronicle the course of preinvasive disease from PanIN-1 to PanIN-2 to PanIN-3, or carcinoma in situ. A corresponding program of genetic progression involves prominent mutations in a circumscribed cast of players including the KRAS2 protooncogene and the CDKN2A/INK4A, TP53, and SMAD4/ DPC4 tumor suppressor genes (TSGs). Less commonly, early neoplastic lesions in the pancreatic ducts are cystic (Figure 1). These cystic neoplasms are macroscopic and often symptomatic and, therefore, frequently detected early (reviewed in Adsay 6 ). Two broad categories of cystic neoplastic precursors have been described: mucinous cystic neoplasms (MCN) and intraductal papillary mucinous neoplasms (IPMN). Because these lesions have been recognized only more recently and occur less frequently, our understanding of the natural history and molecular pathogenesis of the cystic neoplasms has lagged behind that of PanINs. In 1978, Compagno and Oertel 7 formally distinguished serous cystadenomas, which are typically benign, from MCNs which have the potential to invade. IPMNs were first described as a distinct form of precursor lesion to invasive ductal adenocarcinomas by Ohhashi and Takekoshi 8 in 1982, although in retrospect they were observed 50 years before that (reviewed in Hruban 9 ). For the subsequent 15 years, discussion and debate, first centered in Japan and then expanding internationally, led to a panoply of categories, criteria and, ultimately, confusion regarding these cystic entities. 10 In 1996 and 1997, the Armed Forces Institute of Pathology (AFIP) and World Health Organization (WHO), respectively, codified the nomenclature and definitions for the cystic neoplasms. 11,12 Distinct clinical, histopathologic and genetic criteria now distinguish these classes of cystic lesions from each other and from PanINs (Table 1). MCNs possess a mucin-containing epithelial lining and are typically found in the periphery of the body and

2 346 EDITORIALS GASTROENTEROLOGY Vol. 133, No. 1 tail of the pancreas. They tend to occur earlier in life, in the 5th decade, and intriguingly manifest a strong gender bias, occurring vastly more commonly in women (ratio of 10 20:1). They are further defined by their characteristic ovarian stroma, a reference to their densely packed stromal cells with wavy nuclei and expression of progesterone and estrogen receptors. The precise relationship of MCNs to the ductal tree is controversial: because they typically lack direct contiguity with the rest of the ductal system (but see Yamaguchi and Tanaka 13 ), they have been proposed to represent de novo structures. However, it is equally plausible that they arise from the terminal ductules and as they expand they become detached from their terminal branch creating the appearance of an independent structure. IPMNs arise in the main (M-IPMN) or branch (Br- IPMN) pancreatic ducts and usually in the head of the gland. These mucin-producing neoplasms are characterized by extensive intraductal growth and cystic dilation of the large pancreatic ducts. The papillary projections that frequently develop IPMNs can cause acute pancreatitis when they obstruct the lumen. IPMNs occur in the 7th and 8th decades of life, are slightly more common in men than women (ratio of 1.5:1) and progress either to colloid carcinomas, characterized by extracellular pools of mucin, or to tubular (ductal) carcinomas. Prognoses Conventional PDAs, that is, those arising from PanINs, have an overall 5-year survival of 5% and a median survival of 4 6 months in the setting of advanced disease. 14 Few patients survive beyond 1 year. Despite extraordinary advances in surgical technique and postoperative care, 5-year survival after a pancreaticoduodenectomy a Whipple procedure is a sobering 15% 20%, and survival beyond 10 years is essentially nil. Performing an extended lymph node dissection in addition does not help. 15,16 Microscopic metastasis appears to be an extremely early manifestation of the infiltrating cancers that develop from PanINs. Invasive carcinomas that arise from either of the cystic precursors, however, have a dramatically better prognosis. Although the invasive tubular carcinomas that can arise from either IPMNs or MCNs strongly resemble the histologic features of their PanIN-PDA counterparts, long-term survival after resection of either an IPMN or an MCN in association with an invasive carcinoma ranges from 40% 60% 9 (Table 1). These differences also underscore the importance of establishing whether or not an infiltrating carcinoma has arisen in association with and presumably therefore from a cystic neoplasm. With the ever-improving sensitivity and expanding use of a variety of imaging modalities, cystic neoplasms are being discovered more frequently, often as incidental findings. 17 Therein lies both an opportunity and a dilemma: that they can be detected early creates an opportunity for definitive intervention at the preinvasive stage; that they appear to progress to invasive disease less frequently or rapidly than PanINs, however, makes intervention unnecessary in many cases. So, when to cut? Branches in Ductal and Decision Trees As with PanINs before, rigorous histopathologic criteria for MCNs and IPMNs are spurring inquiries into the clinical manifestations and molecular mechanisms of these cystic neoplasms. There has been an increasing awareness, for example, that even within the category of IPMNs, not all lesions are equivalent Location within the ductal tree appears to correlate with biological behavior: IPMNs that arise in the major branches of the main pancreatic duct seem to be less aggressive than their counterparts arising with the main duct itself. A consensus drafted after an international conference in Sendai, Japan, suggested guidelines for the management of IPMNs and MCNs and summarized the current state of knowledge on branch versus main duct IPMNs. 25 Because of the measurable propensity for main duct IPMNs to become invasive, resection in all circumstances was recommended. The opinion for IPMNs in the branch ducts was different: For asymptomatic lesions 3 cm in diameter and without detectable mural nodules or dilatation of the main duct, the possibility of expectant management was suggested while acknowledging the need for more data. In the current issue of GASTROENTEROLOGY, Rodriguez et al 26 report the largest study to date of Br-IPMNs, lending further credence to the idea that Br- IPMNs represent less lethal forms of these cystic neoplasms than their main duct counterparts, and substantiating the use of distinct criteria for management. The authors identified a combined total of 363 histologically confirmed IPMNs resected at their respective institutions (Massachusetts General Hospital, Boston, and University of Verona, Italy) between 1990 and Of these, 145 were identified as pure Br-IPMNs primarily by the absence of the characteristic stroma that accompanies MCNs and which otherwise renders these 2 entities more difficult to distinguish. Consistent with experience elsewhere, the number of resections performed by the authors for IPMNs increased dramatically over the past decade, from a baseline of 1 2 per year 15 years ago to the mid 20s over the past few years. At the same time, the ratio of procedures for asymptomatic and incidental IPMNs to symptomatic lesions has decreased substantially. The majority of the neoplasms were located at the head or uncinate process. Resected specimens were classified as benign if found to represent adenomas (46%) or borderline neoplasms (32%; Br-IPMNs with low- and moderate-grade dysplasia, respectively, in the current terminology) and malignant if they contained carcinoma in situ (high-grade dysplasia; 11%) or invasive disease (11%). Segregating preinvasive from invasive IPMNs would perhaps be more useful, however, as the single most important prognosticator for

3 July 2007 EDITORIALS 347 Figure 1. Distinct precursors to invasive ductal adenocarcinomas of the pancreas. Preinvasive lesions in the ductal epithelium differ in size, location, histologic appearance and clinical behavior. IPMN, intraductal papillary mucinous neoplasm (M-, main duct; Br-, branch duct); MCN, mucinous cystic neoplasm; PanIN, pancreatic intraepithelial neoplasia. Artwork by David W. Ehlert. patients with an IPMN is the presence or absence of an invasive component. The clinical characteristics of patients with Br-IPMNs were similar to those described for IPMNs as a group. Most patients were symptomatic with a median duration of symptoms of approximately 5 months, although abdominal pain was more common in the benign than malignant groups (46% vs 26%; P.025) in contradistinction to a prior series. 27 Apart from a couple more cases of jaundice in the malignant group (4 vs 2; but P.022), there were no additional distinguishing features to alert for malignancy. Interestingly, median serum CA 19-9 was identical in the 2 groups, although the upper boundary for patients with carcinoma in situ or invasive carcinoma was considerably higher. These findings confirm the lack of sensitivity of these markers for pancreatic neoplasms in general. In a previous study of M-IPMNs, these same authors identified jaundice and the recent onset or worsening of preexisting diabetes mellitus as clinical features distinguishing IPMNs with high-grade dysplasia or invasion from those with low- or moderate-grade dysplasia. 28 On the other hand, abdominal pain was more frequent and duration of symptoms longer in patients with earlier stage disease, although again by no means can invasive carcinoma be excluded by such criteria. The relationships between jaundice and abdominal pain, respectively, to stage of disease were similar in Br-IPMNs. Reviewing their considerable experience with both main 28 and branch duct IPMNs (current study), the authors confirm the growing consensus that IPMNs that develop in the branch duct are less likely to display moderate- or highgrade dysplasia (46% vs 12%) and less likely to be frankly invasive (42% vs 11%). Once they become invasive, the 5-year actuarial survival after resection for M-IPMNs ( 60%) and Br-IPMNs ( 63%) are similar. The measurable 10-year survivals of 40% for resected IPMNs with invasive carcinoma are in complete contrast to that for PDA ( 2%). 15,29 And again consistent with previous studies, as well as the current consensus recommendations for the management of Br-IPMNs, 25 size 3 cm, nodules or a thick ( 3 mm) cyst wall were more predictive of invasive carcinoma arguing for resection. Indeed, none of the early stage IPMNs were 3 cm or had a thickened wall, and only 4% had nodules. Finally, several groups have identified a low but significant rate of recurrence or metachronous neoplasms in patients undergoing partial resections for both invasive and noninvasive IPMNs, suggesting the possibility of a multifocal process or a field defect of the ductal epithelium (see Chari et al 30 ). Nevertheless, the challenging and often dire consequences of brittle diabetes, together with the relatively low penchant for invasion and metastasis, make limited resection to achieve negative margins Table 1. Basic Features of Routes to Invasive Ductal Adenocarcinoma of the Pancreas Survival after resection of invasive disease Precursor Size Primary location in pancreas Location along ductal tree 5-year 10-year PanIN microscopic H periphery (terminal 15-20% 2% ductules) MCN macroscopic B/T periphery 40-60% insf. data IPMN Main duct macroscopic H central Branch duct macroscopic H/B central 60% 40% H, head; B, body; T, tail.

4 348 EDITORIALS GASTROENTEROLOGY Vol. 133, No. 1 followed by close surveillance preferable to total pancreatectomy for the management of IPMNs. The cellular and clinical behavior of IPMNs also raise an intriguing question regarding the potential role for resection of isolated or limited metastatic lesions when they do develop. Resection of a limited number of liver metastases from colorectal cancer, for example, has been shown to dramatically prolong survival and sometimes achieve cure (reviewed in Yoon and Tanabe 31 ). Genes Although each of the histologically defined routes to invasive disease described here share overlapping spectra of mutations in critical oncogenes and TSGs, important differences confirm their designation as distinct entities. For example, mutations in DPC4/SMAD4 are almost universal in MCNs with invasive carcinoma and are found in more than half of conventional PDAs, but are essentially never encountered in IPMNs. 9 Moreover, IPMNs demonstrate mutations in PIK3CA (11%) 32 and LKB1/STK11 (30%), 33 events that have not been described for PanIN-PDA or MCN-invasive carcinoma. Differences in their underlying cancer genomes are also reflected in distinct profiles of mucin expression. 34 Thus, PanINs are both anatomically and genetically distinct from IPMNs. They appear to more closely resemble MCNs genetically and, because both IPMNs and MCNs arise in the periphery of the parenchyma, they may both also originate in the terminal ductules (notwithstanding the controversy regarding the origin of MCNs). M-IPMNs and Br-IPMNs may also be different molecularly as M-IPMNs tend to show more intestinal differentiation, characterized by expression of MUC2, MUC5AC, and CDX2; Br-IPMNs reveal a more gastric-foveolar pattern of differentiation, expressing MUC2 but not MUC5AC or CDX2. 35 Our understanding of mechanisms of disease pathogenesis has been furthered through the systematic introduction of the relevant mutations, alone and in various combinations, into the mouse genome (reviewed in Hrubin et al 36 and Rustgi 37 ). These studies have established the essential role of activating mutations in Kras2 in initiating PanINs and confirmed PanINs as bona fide precursors to PDA. 38 Point mutations in Trp53 39 or deletion of the combined Ink4a/Arf 40 loci have each been shown to cooperate with oncogenic Kras2 mutation to hasten disease progression. Interestingly, each of these combinations appears to represent unique genetic paths to invasive disease and each, despite giving rise to PanINs which then progress, nevertheless demonstrate distinct histologic and clinical behaviors. More recently, similar strategies were used to demonstrate that early mutation of Dpc4/Smad4 in the context of oncogenic Kras2 induces cystic neoplasms, which could progress to invasive disease in association with additional mutations in the other principal TSGs implicated in PDA, such as Trp53 and Cdkn2a/Ink4a. 41,42 The cystic lesions were further defined as MCNs by their clinical presentation, gross findings, and histopathology, particularly the demonstration of ovarian stroma. 42 The distinctive cellular behaviors of primary cells isolated from the models of MCNinvasive carcinoma and PanIN-PDA were telling: Cells from the former model were less likely to migrate or to undergo epithelial-to-mesenchymal transition in vitro, helping to explain their lower propensity for invasion and metastasis as is seen in the human correlate. 42 The Road Ahead The targeting strategies used in the animal models described introduce the respective mutations in cells throughout the length of the pancreas. Nevertheless, in both models of advanced PDA, for example, aggressive infiltrating adenocarcinomas develop primarily at the head of the pancreas, precisely as is seen in human PDA. In the model of MCNs, on the other hand, multilocular cystic neoplasms are seen predominantly in the body and tail, again as is seen in human MCNs. Together with the collective clinical experience, these observations suggest the potential existence of unique factors in the periampullary microenvironment compared with more distal portions of the pancreas, and perhaps within the central versus peripheral regions of the parenchyma, which may differ in their ability to cooperate with specific genetic events. Alternatively or additionally, there may be intrinsic differences in the epithelial cells, or their tissue progenitors, along the length of the ductal tree. It is perhaps instructive in this regard to recall the distinct developmental histories of the head/uncinate process and the body and tail of the organ. Both the ventral and a portion of the dorsal pancreatic buds contribute to the head and uncinate process during embryogenesis, whereas the body and tail of the mature organ derive solely from the dorsal bud. 43 Thus, with their origins in distinct regions of the foregut endoderm and exposed to potentially unique influences during development, the cells that inhabit the adult pancreas may retain distinctive properties that reflect their genesis. Understanding how discrete regions of the pancreatic ductal epithelium respond to or resist specific genetic perturbations during the course of malignant transformation will provide essential clues in the struggle to gain the upper hand over these formidable cancers. SUNIL R. HINGORANI Fred Hutchinson Cancer Research Center Clinical Research and Public Health Sciences Divisions Seattle, Washington References 1. Hruban RH, Ali SZ. Pathology of the exocrine pancreas. In: Von Hoff DD, Evans DB, Hruban RH, eds. Pancreatic Cancer. Sudbury, MA: Jones and Bartlett, 2005:15 27.

5 July 2007 EDITORIALS Cubilla AL, Fitzgerald PJ. Morphological lesions associated with human primary invasive nonendocrine pancreas cancer. Cancer Res 1976;36: Klimstra DS, Longnecker DS. K-ras mutations in pancreatic ductal proliferative lesions. Am J Pathol 1994;145: Hruban RH, Adsay NV, Albores-Saavedra J, Compton C, Garrett ES, Goodman SN, Kern SE, Klimstra DS, Kloppel G, Longnecker DS, Luttges J, Offerhaus GJ. Pancreatic intraepithelial neoplasia: a new nomenclature and classification system for pancreatic duct lesions. Am J Surg Pathol 2001;25: Hruban RH, Wilentz RE, Kern SE. Genetic progression in the pancreatic ducts. Am J Pathol 2000;156: Adsay NV. Pathological classification of cystic neoplasms of the pancreas. In: Von Hoff DD, Evans DB, Hruban RH, eds. Pancreatic Cancer. Sudbury, MA: Jones and Bartlett, 2005: Compagno J, Oertel JE. Mucinous cystic neoplasms of the pancreas with overt and latent malignancy (cystadenocarcinoma and cystadenoma). A clinicopathologic study of 41 cases. Am J Clin Pathol 1978;69: Ohhashi KMY, Takekoshi T. Four cases of mucin producing cancer of the pancreas on specific findings of the Ampulla of Vater (Abstr). Prog Diagn Endosc 1982;20: Hruban RH, Pitman MB, Klimstra DS. Tumors of the pancreas. Atlas of tumor pathology. 4th series, Fascicle 6. Washington, DC: Armed Forces Institute of Pathology, Yamaguchi K, Tanaka M. Intraductal papillary-mucinous tumor of the pancreas: a historical review of the nomenclature and recent controversy. Pancreas 2001;23: Kloppel G, Solcia E, Longnecker DS, Capella C, Sobin LH. Histological typing of tumors of the exocrine pancreas. New York: Springer, Solcia E, Capella C, Kloppel G. Tumors of the pancreas. Atlas of tumor pathology. 3rd series ed. Washington, DC: Armed Forces Institute of Pathology, Yamaguchi K, Tanaka M. Radiologic imagings of cystic neoplasms of the pancreas. Pancreatology 2001;1: Warshaw AL, Fernandez-del Castillo C. Pancreatic carcinoma. N Engl J Med 1992;326: Yeo CJ, Cameron JL, Lillemoe KD, Sohn TA, Campbell KA, Sauter PK, Coleman J, Abrams RA, Hruban RH. Pancreaticoduodenectomy with or without distal gastrectomy and extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma, part 2: randomized controlled trial evaluating survival, morbidity, and mortality. Ann Surg 2002;236: ; discussion Farnell MB, Pearson RK, Sarr MG, DiMagno EP, Burgart LJ, Dahl TR, Foster N, Sargent DJ. A prospective randomized trial comparing standard pancreatoduodenectomy with pancreatoduodenectomy with extended lymphadenectomy in resectable pancreatic head adenocarcinoma. Surgery 2005;138: ; discussion Fernandez-del Castillo C, Targarona J, Thayer SP, Rattner DW, Brugge WR, Warshaw AL. Incidental pancreatic cysts: clinicopathologic characteristics and comparison with symptomatic patients. Arch Surg 2003;138: ; discussion Traverso LW, Peralta EA, Ryan JA Jr, Kozarek RA. Intraductal neoplasms of the pancreas. Am J Surg 1998;175: Kobari M, Egawa S, Shibuya K, Shimamura H, Sunamura M, Takeda K, Matsuno S, Furukawa T. Intraductal papillary mucinous tumors of the pancreas comprise 2 clinical subtypes: differences in clinical characteristics and surgical management. Arch Surg 1999;134: Terris B, Ponsot P, Paye F, Hammel P, Sauvanet A, Molas G, Bernades P, Belghiti J, Ruszniewski P, Flejou JF. Intraductal papillary mucinous tumors of the pancreas confined to secondary ducts show less aggressive pathologic features as compared with those involving the main pancreatic duct. Am J Surg Pathol 2000;24: Sohn TA, Yeo CJ, Cameron JL, Iacobuzio-Donahue CA, Hruban RH, Lillemoe KD. Intraductal papillary mucinous neoplasms of the pancreas: an increasingly recognized clinicopathologic entity. Ann Surg 2001;234: ; discussion Doi R, Fujimoto K, Wada M, Imamura M. Surgical management of intraductal papillary mucinous tumor of the pancreas. 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6 350 EDITORIALS GASTROENTEROLOGY Vol. 133, No. 1 Perez-Gallego L, Redston M, Tuveson DA. Pathology of genetically engineered mouse models of pancreatic exocrine cancer: consensus report and recommendations. Cancer Res 2006;66: Rustgi AK. The molecular pathogenesis of pancreatic cancer: clarifying a complex circuitry. Genes Dev 2006;20: Hingorani SR, Petricoin EF, Maitra A, Rajapakse V, King C, Jacobetz MA, Ross S, Conrads TP, Veenstra TD, Hitt BA, Kawaguchi Y, Johann D, Liotta LA, Crawford HC, Putt ME, Jacks T, Wright CV, Hruban RH, Lowy AM, Tuveson DA. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 2003;4: Hingorani SR, Wang L, Multani AS, Combs C, Deramaudt TB, Hruban RH, Rustgi AK, Chang S, Tuveson DA. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 2005;7: Aguirre AJ, Bardeesy N, Sinha M, Lopez L, Tuveson DA, Horner J, Redston MS, DePinho RA. Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. Genes Dev 2003;17: Bardeesy N, Cheng KH, Berger JH, Chu GC, Pahler J, Olson P, Hezel AF, Horner J, Lauwers GY, Hanahan D, DePinho RA. Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer. Genes Dev 2006;20: Izeradjene K, Combs C, Best M, Gopinathan A, Wagner A, Grady WM, Deng CX, Hruban RH, Adsay NV, Tuveson DA, Hingorani SR. Kras(G12D) and Smad4/Dpc4 haploinsufficiency cooperate to induce mucinous cystic neoplasms and invasive adenocarcinoma of the pancreas. Cancer Cell 2007;11: Slack JM. Developmental biology of the pancreas. Development 1995;121: Address requests for reprints to: Sunil R. Hingorani, MD, PhD, Fred Hutchinson Cancer Research Center, Clinical Research and Public Health Sciences Divisions, 1100 Fairview Avenue N, M5-C800, Seattle, Washington srh@fhcrc.org. Supported in part by NCI P30 CA15704, NCI K08 CA114028, AACR- PanCAN Career Development Award and the Canary Foundation. I thank Ralph Hruban for comments on the manuscript and both he and Volkan Adsay for helpful discussions by the AGA Institute /07/$32.00 doi: /j.gastro The Tissue Biology of Ductular Reactions in Human Chronic Liver Disease See Progressive fibrosis in nonalcoholic steatohepatitis: association with altered regeneration and a ductular reaction by Richardson MM, Jonsson JR, Powell EE, Brunt EM, Neuschwander-Tetri BA, Bhathal PS, Dixon JB, Weltman MD, Tilg H, Moschen AR, Purdie DM, Demetris AJ, and Clouston AD, on page 80. Whether there were liver stem cells in animal or human livers was a topic of great debate for decades until their existence was confirmed and their most prominent source identified as the canal of Hering, the meeting point of the hepatocyte canalicular system and the smallest, most proximal branches of the biliary tree. 1 The debate often centered on whether the rodent variant of hepatic stem/progenitor cells (HSPC), so-called oval cells, were in fact a stem/progenitor population or merely proliferating cholangiocytes. Once data appeared demonstrating that oval cells function as HSPC and arise directly from the biliary tree, it became clear that the functioning of these cells in rodents and humans was somewhat different from other organ systems in which stem cells appeared to have only a repopulating or regenerative function. In the liver they were, indeed, both biliary epithelial cells, part of the conduction system for bile out of the liver, and HSPC, an interestingly complex physiology. In more recent years, it has been recognized that these HSPC are embedded in a network of cellular interactions at the tissue level with at least one specific anatomic location, the so-called stem cell niche. 2,3 This systems concept of cellular interactions is reflected in the terminology shift proposed by a consensus panel convened under the auspices of the Hans Popper Hepatopathology society, referring to the ductular reactions as reactive lesions comprising intermediate hepatobiliary cells (functioning at least as HSPC, if not playing other roles) as well as other cell types including, although not limited to, inflammatory, stromal, and endothelial cells. 4 From a variety of sources (summarized in Theise 3 ) we can draw a preliminary diagram of these cell:cell and cell:matrix relationships that comprise the niche (Figure 1). Some of these relationships immediately suggest hypotheses worth investigating. For example, we have previously questioned whether, when acute injury is severe enough to extend all the way from acinus zone 3 into zone 1 (where the Canals of Hering are located), destruction of an hepatocyte linked to an HSPC of the Canals of Hering could disinhibit this HSPC, unlocking its proliferative potential (or, stated conversely, does the hepatocyte keep its proliferation in check)? Is bile not only acted upon by the cholan-