A semicentennial of pancreatic pathology: the genetic revolution is here, but don’t throw the baby out with the bath water!

Journal Pre-proof A Semicentennial of Pancreatic Pathology: The Genetic Revolution Is Here, But Don’t Throw the Baby Out With The Bath Water!

Ralph H. Hruban, David S. Klimstra, Guiseppe Zamboni, Günter Klöppel PII:

S0046-8177(19)30164-9

DOI:

https://doi.org/10.1016/j.humpath.2019.08.024

Reference:

YHUPA 4918

To appear in:

Human Pathology

Received date:

26 August 2019

Accepted date:

28 August 2019

Please cite this article as: R.H. Hruban, D.S. Klimstra, G. Zamboni, et al., A Semicentennial of Pancreatic Pathology: The Genetic Revolution Is Here, But Don’t Throw the Baby Out With The Bath Water!, Human Pathology(2019), https://doi.org/ 10.1016/j.humpath.2019.08.024

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© 2019 Published by Elsevier.

Journal Pre-proof A Semicentennial of Pancreatic Pathology: The Genetic Revolution Is Here, But Don’t Throw the Baby Out With The Bath Water! *

Ralph H. Hruban, M.D.1, David S. Klimstra, M.D. 2, Guiseppe Zamboni, M.D. 3, and Günter Klöppel, M.D. 4

The Sol Goldman Pancreatic Cancer Research Center, Departments of Pathology and Oncology, the Johns Hopkins University School of Medicine, Baltimore, MD, USA; 2The Department of Pathology, Memorial Sloan Kettering Cancer Center, NY, USA; 3Sacro Cuore Don Calabria Hospital, Italy; and 4Technical University of Munich, Munich, Germany

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1

Address Correspondence to:

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Ralph H. Hruban, M.D.

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The Sol Goldman Pancreatic Cancer Research Center Department of Pathology

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The Johns Hopkins University School of Medicine

600 North Wolfe Street Baltimore, MD 21287

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Carnegie Room 415

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Email: [email protected]

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Phone: (410) 955-9790 Fax: (410) 955-0394

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Based, in part, on the Maude Abbott Lecture given by Ralph Hruban at the 2014 Annual Meeting of the United States and Canadian Academy of Pathology.

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Journal Pre-proof Abstract

The last fifty years have witnessed an explosion in our understanding of the pathology of pancreatic diseases. Entities known to exist 50 years ago have been defined more precisely and are now better classified. New entities, previously not recognized, have been discovered and can now be treated. Importantly, new tools have been developed that have unraveled the

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fundamental biological drivers of a number of pancreatic diseases. Many of these same tools have also been applied clinically, supplementing the tried and true hematoxylin and eosin

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stained slide with a plethora of new, highly sensitive and specific tests that improve diagnostic

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accuracy and delineate best treatments. As exciting as these many advances are, our

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knowledge of pancreatic pathology remains incomplete, and there is much to be learned.

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Key words: Pancreas, pancreatic, pathology, history

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Journal Pre-proof Introduction

Before we dive into the dramatic changes that have occurred over the last 50 years in pancreatic pathology, we thought it would be illustrative to reflect on the >2,000 year history of modern (western) medicine, as in doing so it becomes clear that the one constant in medicine is change. Simply put, the history of pancreatic pathology, like all medical history, has been

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marked by transformative waves of innovation that fundamentally change our concept of entire

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fields.(1)

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Modern western medicine began when Hippocrates (460-370 BCE) and his followers on the island of Kos separated that which is natural from that which is supernatural. Shortly

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thereafter, Herophilus (335- 255 BCE), who was educated by Praxagoras of Kos, is credited with

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the first description of the pancreas.(1-3) The revolution created by the separation of medicine from superstition was quickly overtaken by another revolution, led by Galen of Pergamon (129

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ACE-c.200/c.216 ACE). Galen brought science to medicine. He based his writings on dissection

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and experimentation on animals, proving, for example, that voice is generated in the larynx.

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Unfortunately, Galen believed that the pancreas was just padding to protect the abdominal vasculature, that “Nature created ‘so-called pancreas’ and spread it beneath all vessels.”(1, 4)

Galen’s teachings prevailed for more than a thousand years, until the Dutch anatomist Andreas Vesalius (1514-1564) brought on the next disruptive wave of innovation. In his classic book, De Humani Corporis Fabrica Vesalius showed that several keystones of Galenic anatomy were incorrect. As Vesalius famously wrote, Galen “was fooled by his monkeys.”(1, 5) Although Vesalius revolutionized the understanding of the anatomy of a number of key structures, the pancreas was once again left behind as he chose to illustrate the abdominal organs with the pancreas dissected away in order highlight the splenic and superior mesenteric veins.

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Journal Pre-proof Importantly, Vesalius promulgated the idea that dogmas should be challenged, and that students should dissect and study for themselves. Johann Georg Wirsüng (1589-1643) did just that, and in Padua in 1642 discovered that the pancreas has a duct.(1, 6) With this discovery, the study of the pancreas forever changed; if it has a duct, the pancreas must be producing something!

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Giovanni Battista Morgagni (1682-1771), whose classic book De Sedibus et Causis Morborum per Anatomen Indigatis established the field of morbid anatomy, brought on the next

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disruptive revolution in medicine by showing that disease has its origins in the organs. As he

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beautifully put it, “symptoms are the cry of the suffering organs.”(1, 7) Indeed, in what may

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have been one of the earliest clinical descriptions of pancreatic cancer, he described the pain

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experienced by a patient with pancreatic tumor as being just as great as if he were being torn to pieces by dogs.(1, 8) The next transformation in medicine was initiated by Rudolf Virchow (1821-

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1902) with his book Die Cellularpathologie in which he brilliantly showed that disease occurs at the level of the cell.(9) Today, more than 100 years later, the microscope remains the

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foundation of pancreatic pathology.

Diagnosis after death became common practice; diagnosis during life was another matter. Physicians in the French schools promulgated careful observation and physical examination, and soon diseases could be diagnosed clinically. Ludwig Courvoisier (1843-1918) found that a palpable gallbladder is a sign of pancreatic cancer, and Armand Trousseau (18011867) reported that spontaneous venous thromboses are associated with pancreatic cancer.(1) In a remarkable twist of fate, Trousseau diagnosed his own fatal gastric cancer when he developed venous thromboses. By contrast, the diagnosis of diabetes mellitus was way ahead

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Journal Pre-proof of the game. Diabetes mellitus (honey sweet) was recognized over three thousand years ago, and in 1776 Dobson showed that excess glucose caused the sweetness of the urine.(10)

The final challenge remained treatment, and this long road, on which we are just beginning our journey, started with Allen Oldfather Whipple (1881-1963). Successful pancreatic resections were first performed by Walther Kausch (1867-1928), but it was Whipple, a surgeon

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at Columbia University, who, in the 1930s and 1940s, promulgated the surgical resection of pancreatic masses, in a procedure that now bears his name, the “Whipple operation.” (1, 11)

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With safe surgery, pancreatic resections grew exponentially at expert centers, providing

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pathologists with the materials they would need to create the revolution that has marked the

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last 50 years of pancreatic pathology.(11, 12)

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Pancreatic Pathology in 1970

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With little surgical volume to guide the classification of diseases of the pancreas, the classification of neoplasms of the pancreas was rudimentary in 1970 (Figure 1).(1) A clinically

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meaningful classification was hindered by the lack of significant clinical information; computed

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tomography (CAT scanning) was not invented until 1972. Much of the focus was on pseudocysts, and knowledge of other entities was, in retrospect, crude. For example, cystic neoplasms of the pancreas were broadly lumped together under the designations “cystadenoma” and “cystadenocarcinoma.”(13-16) The classification of solid neoplasms similarly suffered. It wasn’t until the late 1970s and early 1980s that classifications based on phenotype began to pave the way for studies that correlated phenotype with clinical outcome.(17, 18) Furthermore, although syndromic neuroendocrine neoplasms (“functional islet cell tumors”) were recognized and wellcharacterized because of their associated distinctive symptomatology, nonsyndromic neuroendocrine neoplasms were rare and were poorly described.(19-21) It was not recognized that all neuroendocrine neoplasms are malignant, and much effort was expended attempting to distinguish “benign” from “malignant” islet cell tumors. At the “molecular” level, none of the genes

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Journal Pre-proof that drive pancreatic neoplasia were known. Similarly, little was known about the underlying

etiologies of the two most important non-neoplastic diseases of the pancreas, diabetes mellitus and pancreatitis. Diabetes was simply classified into a juvenile and adult form, and key findings

such as insulitis and amyloidosis had been ascribed to these two forms; pancreatitis was wellrecognized, but the focus was almost entirely on alcoholic and gallstone pancreatitis and their

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treatment.(22)

In the following sections, we trace the unimaginable progress that has been made over

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the past 50 years in several areas of pancreas pathology (Figure 1).(23)

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Genetics of Pancreatic Ductal Adenocarcinoma

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Perhaps the greatest advances in the past fifty years have come from the discovery of the genetic drivers of pancreatic diseases, and the subsequent application of genetic tools to

(Table 1).

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dissect out disease causing pathways and to define entities based on these genetic drivers

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The first gene found to be targeted in pancreatic cancer, by which we mean invasive

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ductal adenocarcinoma, was KRAS.(24) Oncogenes were first described by Varmus, Bishop and Vogt in 1976 when they demonstrated that viral src oncogene is a normal chicken gene transduced by viruses, thereby converting a normal gene into a potent oncogene.(25) In 1987, Murray Korc, using a primitive polymerase chain reaction (PCR) machine built by Paul Meltzer analyzed RNA from human pancreatic cancers and they observed a faint abnormal band suggestive of KRAS gene mutations (personal communication). They did not publish this finding as it wasn’t definitive, and in 1988 Almoguera, Shibata and Perucho were the first to publish definitive KRAS gene mutations in human pancreatic cancer.(24)

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Journal Pre-proof The first tumor suppressor gene found to be genetically inactivated in pancreatic cancer was TP53. The TP53 gene was discovered in 1979, but it was initially misclassified as an oncogene.(26) It wasn’t until 1989 that TP53 was correctly classified as a tumor suppressor gene, and in 1991 C. Barton, J. Neoptolemos, and G. Klöppel first reported TP53 gene mutations in human pancreatic cancer.(27) Thus, in the early days of the cancer genetic revolution, discoveries in pancreatic cancer

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followed discoveries in other cancer types by many years if not by decades. This changed

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dramatically in the 1990s. Slowly but surely, discoveries in pancreatic cancer started to precede

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those made in other cancer types. This pivot occurred because of a confluence of events. First, a handful of surgeons, John Cameron at Johns Hopkins, Andrew Warshaw at the

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Massachusetts General Hospital, Murray Brennan at Memorial Sloan Kettering, and, in Europe,

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Franz Kümmerle, Michael Trede, Hans Beger and Marcus Büchler dedicated their careers to improving pancreas surgery.(28, 29) For example, at Johns Hopkins John Cameron personally

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performed more than 2,400 pancreatoduodenectomies.(28) As these surgeons developed more

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and more experience, their teams were able to reduce dramatically the mortality rates of

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pancreatic surgery.(30, 31) Patients flocked to specialized centers of excellence, and suddenly scientists had access to large numbers of surgically resected pancreatic cancers to study. At Johns Hopkins, the dramatic increase in pancreas surgery fed into a genetics laboratory run by a young, extremely creative scientist, Scott Kern. The molecular revolution was beginning and Kern, who had trained in Bert Vogelstein’s lab, was looking for a cancer to study. Kern brought tireless dedication, extraordinary creativity, a willingness to go out on a limb, and an insistence that his lab focus on big, important questions to pancreatic cancer research.(32, 33) He was also a trained gastrointestinal pathologist and he quickly recognized that the low neoplastic cellularity of pancreatic cancer would hinder the discovery of cancer

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Journal Pre-proof causing genes. Kern therefore xenografted human pancreatic cancers into nude mice, creating highly cellular lesions that formed the basis for gene discovery.(34) The impact of a creative scientist having access to large numbers of biosamples can be seen in the rapid pace of gene discovery that followed. The p16/CDKN2A gene was discovered by Kamb and colleagues in 1994, and later that same year, Kern and colleagues reported that p16/CDKN2A was also targeted in pancreatic cancer.(35, 36) That next year, in 1995, Kern, using

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the technique of “representational difference analysis” developed by M. Wigler at the Cold

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Spring Harbor Laboratories, discovered a homozygous deletion in a pancreatic cancer that

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proved to be the BRCA2 gene.(37) Immediately after BRCA2 was discovered, in 1996, Kern carefully mapped overlapping homozygous deletions on chromosome 18q in a series of

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pancreatic cancers and discovered the SMAD4 gene.(38) Pancreatic cancer scientists were no

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longer followers; they were now leading the field of cancer research. Searching the entire genome, one gene at a time, for pancreatic cancer genes was

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laborious and time consuming. In an audacious effort, Vogelstein and colleagues, in 2008, used

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Sanger sequencing to sequence the entire exome of a series of pathologically and clinically well-

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annotated pancreatic cancers.(39) The core signaling pathways targeted in pancreatic cancer were defined across the entire exome (Figure 2). Four years later, the International Cancer Genome Consortium (ICGC), led by Andrew Biankin and Sean Grimonds, reported the sequencing the genomes of a series of pancreatic cancers, and in 2017 The Cancer Genome Atlas program (TCGA), led by Ben Raphael and Ralph Hruban, reported an in depth integrated characterization of the genetic alterations and gene expression changes in pancreatic cancer.(40, 41) In 2016, Nicholas Roberts and colleagues reported the sequencing of the germline genomes of 638 individuals with familial pancreatic cancer.(42) In the flash of slightly less than a decade, pancreatic cancer became one of the best-understood cancers at the genetic

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Journal Pre-proof level. Large-scale team science was required for these efforts to succeed, and the pancreatic cancer field, with its collaborative spirit, was uniquely suited to succeed (Figure 3).

Applying genetics to patient care

Pathologist have taken advantage of the genetic advances described above and have

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used genetics as a tool to improve the classification and treatment of pancreatic neoplasms.

Genetics has helped classify pancreatic neoplasms. For example, it was unclear which

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cells in undifferentiated carcinomas with osteoclast-like giant cells were neoplastic; the

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prominent giant cells, or the scattered atypical mononuclear cells. Westra and colleagues used

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KRAS and TP53 mutations to show that it is the atypical mononuclear cells that are neoplastic

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and share genetic features with conventional ductal adenocarcinoma, and that the osteoclastlike giant cells are reactive, supporting the classification of these neoplasms as true

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carcinomas.(43) In another example, Agaimy and colleagues used SMARCB1 (INI1) loss to define a previously unrecognized rhabdoid subtype of undifferentiated carcinoma of the pancreas.(44)

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Genetics has not replaced morphology, instead, pancreatic pathologists have used it as a tool to

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advance morphology-based tumor classification.(45)

Genetics has also improved our clinical ability to make diagnoses. The SMAD4 gene is inactivated in 55% of pancreatic cancers, and immunolabeling for the Smad4 protein reflects SMAD4 gene status.(46) One can therefore use Smad4 immunolabeling to determine, for example, whether an atypical gland in a small pancreatic biopsy is likely malignant.

Genetics has also been used to guide therapy. Medullary carcinomas of the pancreas often have microsatellite instability, and cancers with microsatellite instability are exquisitely sensitive to immunotherapy.(47) Similarly, pancreatic cancers arising in individuals with a 9

Journal Pre-proof deleterious variant in a germline Fanconi anemia pathway gene (BRCA1, BRCA2, or PALB2) are sensitive to poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors.(48) We foresee a future in which pathologists, integrating tumor histology with genetics, will be the ones determining the best treatment for our patients.

A personalized treatment approach made possible by the revolution in cancer genetics

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has been tested in the IMPACT and COMPASS trials, and one-quarter to a half of pancreatic cancers harbor mutations that are potentially therapeutically targetable.(49, 50) The challenge

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is to identify these therapeutic targets and treat the patients in the face of a rapidly progressing

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Pancreatic Intraepithelial Neoplasia

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disease.(49, 50)

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The lesions that we today call pancreatic intraepithelial neoplasia (PanIN) were described more than 100 years ago by S.P.L. Hulst in 1905 when he described

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“Zwischenformen;” lesions in between normal ducts and invasive cancer, in the pancreas.(51)

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Sommers et al., and Cubilla and Fitzgerald drew attention to an association of PanIN with

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pancreatic cancer, and Klöppel et al. reported on the relationship of human PanIN to experimental pancreatic carcinogenesis in Syrian hamsters.(52-54) Klimstra and Longnecker then introduced the term PanIN in an editorial 1994, and genetic analyses, spearheaded by Wilentz and Hruban, helped establish PanINs as bona fide precancers (Figure 4).(55-62) The recognition that PanINs are precancers has formed a scientific basis for early detection and chemo/immune prevention research.

Cystic neoplasms

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Journal Pre-proof The first real break in our understanding of cystic neoplasms of the pancreas came in 1978 when J.E. Oertel and J. Compagno, and independently D.J. Hodgkinson and colleagues, separated serous from mucin-producing cystic neoplasms of the pancreas (63, 64). These groups recognized that serous cystic neoplasms composed of glycogen-rich cuboidal cells were benign, while the mucin-producing cystic neoplasms had significant malignant potential (Figure 5). This was a critical advance as it identified a distinct cystic neoplasm that was almost

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uniformly benign, and therefore did not require aggressive management.

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Soon thereafter, in 1982, K. Ohhashi and colleagues in Japan described four mucin-

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producing tumors of the pancreas that had led to duct dilatation and that are today known as intraductal papillary mucinous neoplasms (IPMNs) (Figure 5), a term introduced in 1994 by Sessa

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and colleagues.(65, 66) As IPMNs had several features in common with mucinous cystic

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neoplasms (MCNs), the clear separation of MCNs from IPMNs by Zamboni and colleagues in 1999 allowed follow-up studies showing that non-invasive mucinous cystic neoplasms, defined

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by the presence of ovarian stroma, are cured when surgically resected. (67, 68) By contrast,

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there is a significant risk of synchronous and even metachronous disease with IPMNs.(69)

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Again, careful pathologic studies helped define clinically significant groups of patients. The report by K. Ohhashi and colleagues began what would prove to be a long series of noteworthy contributions by investigators in Japan characterizing IPMNs.(70) Grossly and clinically, it was recognized that IPMNs involving the main pancreatic duct are more likely to harbor high-grade dysplasia or an associated invasive carcinoma than are IPMNs that arise in branches off the main duct.(71, 72) This finding helped prioritize which patients needed surgery, and which had a low risk of developing invasive cancer and could therefore be clinically observed – an important contribution given the high frequency with which IPMNs are now being detected on cross-sectional imaging (73).

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Journal Pre-proof At the microscopic level, it quickly became clear that the neoplastic cells of IPMNs can have a variety of directions of differentiation. Biliary, intestinal, and gastric directions of differentiation were identified, as were intraductal neoplasms with tubulopapillary architecture and intraductal neoplasms with oncocytic differentiation.(66, 74-76) This histologic classification of intraductal neoplasms was useful for pathologists as it helped define the observed patterns of progression. For example, it was shown that invasive colloid carcinomas of the pancreas almost

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always arise in association with IPMNs with intestinal differentiation.(77) The grading of

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dysplasia was also improved over time.(70) The term “adenoma” was replaced by low-grade

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dysplasia, and “in situ carcinoma” was replaced with high-grade dysplasia, reflecting the continuous spectrum of neoplastic evolution that occurs in IPMNs and reducing the confusion

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generated by the use of the term “malignant IPMN.”(78)

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As experience correlating preoperative clinical findings with pathological examination of resected lesions grew, consensus criteria were developed to guide the clinical management of

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patients with IPMNs. The “Sendai criteria” were developed by M. Tanaka and colleagues in

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Sendai Japan in 2004 and published in 2006, and these criteria were subsequently revised as the

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“Fukuoka criteria” in 2012.(79, 80) These criteria have proven valuable in the preoperative management of the growing number of patients being diagnosed with a pancreatic cyst, and the development of these criteria highlights the impact pathologists and clinicians can have when they work closely together. The Fukuoka criteria, however, are not perfect. They have high sensitivity in identifying high-risk cysts, but poor specificity.(81) Pancreas pathologists have risen to the challenge of improving the management of pancreas cysts by correlating cyst histopathology with the results of genetic sequencing. Indeed, the most recent advances in the management of cystic neoplasms of the pancreas have come from genetics. The exomes of a series of surgically

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Journal Pre-proof resected and pathologically well-characterized cystic neoplasms of the pancreas have been sequenced, and the results directly correlated with cyst pathology.(82, 83) Remarkably, the genetic alterations identified closely match the histologic cyst type, some genetic alterations correlate with grade of dysplasia, and the genetic changes in the neoplastic cells can be detected in cyst fluid.(82-84) The close correlation of genetic alterations with cyst pathology allows for the development of new clinical tests based on cyst fluid sequencing to aid in the

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preoperative diagnosis and management of cysts in the pancreas.(82, 85)

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These same genetic tools have been used to improve the classification of cystic lesions

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in the pancreas. Genetic analyses have shown that many intraductal lesions intermediate in size between PanINs and IPMNs are, in fact, small (“incipient”) IPMNs; that IPMNs can be truly

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multifocal; and that some IPMNs progress to invasive cancer.(45, 86, 87) More recently, O.

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Basturk and colleagues showed that intraductal tubulopapillary neoplasms (ITPNs) lack the common alterations of IPMNs and represent a distinct neoplastic entity.(88) Similarly, A. Singhi

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has shown that, unlike other intraductal neoplasms, gene fusions cause intraductal papillary

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oncocytic neoplasms (IOPNs), further helping to establish IOPNs as a unique tumor type

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(personal communication).

Acinar neoplasms and solid pseudopapillary neoplasm Our understanding of non-ductal pancreatic neoplasms, such as the family of pancreatic neoplasms with acinar differentiation (acinar cell carcinoma, mixed acinar carcinomas with neuroendocrine and/or ductal differentiation, and pancreatoblastoma) along with solid pseudopapillary neoplasm, has also increased dramatically in the past 50 years. The distinction of acinar cell carcinoma from other types of pancreatic cancer was initially based upon the occasional occurrence of a dramatic syndrome of subcutaneous fat

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Journal Pre-proof necrosis and polyarthralgia, first reported by Berner in 1908.(89) Additional case reports subsequently characterized the histologic features of acinar cell carcinoma, which was defined by evidence that the neoplastic cells produce exocrine enzymes such as trypsin, chymotrypsin, and lipase, the last responsible for the classic paraneoplastic syndrome now designated the lipase hypersecretion syndrome, or pancreatic panniculitis.(90) Demonstration of enzyme production by the neoplastic cells, now regarded as the sine qua non of the diagnosis, was first

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based on electronic microscopy, and in 1987 Morohoshi et al. first used immunohistochemical

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labeling for trypsinogen, chymotrypsinogen, and lipase to define acinar differentiation in

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pancreatic neoplasms.(91, 92) The first modern clinicopathologic studies of acinar cell carcinoma were published in the early 1990s by Klimstra et al. and Hoorens and colleagues.(93,

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94) With the morphologic features more fully delineated, the genetic alterations that drive

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acinar cell carcinoma and related mixed acinar neuroendocrine, mixed acinar ductal, and mixed acinar neuroendocrine ductal carcinomas could then be characterized.(95-100) The mutations

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commonly found in ductal adenocarcinomas, KRAS in particular, were rarely detected; instead,

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alterations in the wnt pathway (APC primarily), mismatch repair genes, and DNA repair genes

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such as BRCA1/2 were found. In 2014, Chmielecki et al. first demonstrated BRAF and RAF1 fusions in acinar cell carcinomas; these alterations and other potentially targetable genetic changes have now been shown in 35-65% of these carcinomas.(101) Pancreatoblastoma was first reported by Becker in 1957 and the term pancreatoblastoma was proposed by Horie at al. in 1977.(102, 103) Immunohistochemical studies demonstrating consistent acinar differentiation, along with common less abundant elements showing neuroendocrine and ductal differentiation, paralleled the work in acinar cell carcinomas, as did molecular studies that similarly showed alterations in the wnt pathway mostly involving CTNNB1 rather than APC.(104) The other alterations found in acinar cell

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Journal Pre-proof carcinomas are lacking in pancreatoblastoma, however, as are mutations in the genes altered in ductal adenocarcinomas. Solid pseudopapillary neoplasm was first illustrated by Frantz in the Armed Forces Institute of Pathology Fascicle on Tumors of the Pancreas in 1959(Figures 1 and 5).(105) Over the past decades, numerous studies using electron microscopy, immunohistochemistry, and molecular analyses have failed to fully define the direction of differentiation for this enigmatic

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neoplasm, and no normal cellular counterpart exists. Abraham et al.’s finding of nearly universal

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mutations in CTNNB1 led to a helpful immunohistochemical marker, -catenin, which shows

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diffuse abnormal nuclear labeling.(106) Many other markers are typically expressed but lack specificity, and the immunohistochemical evaluation is largely based on excluding acinar and

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specific neuroendocrine differentiation. Despite the lack of clarity about its differentiation, solid

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pseudopapillary neoplasm has highly reproducible clinical features.(107) It largely affects young women and has an outstanding prognosis, with long-term survival even in the 10-15% of

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patients with metastatic disease.

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Pancreatic neuroendocrine tumors The past fifty years have also witnessed dramatic developments in our understanding of the genetic drivers of pancreatic neuroendocrine tumors (PanNETs), as well as significant improvements in the classification of these neoplasms. Fifty years ago, the “grading” of PanNETs was an unusual combination of staging and histologic grading. Today, thanks in many ways to the work of the European NeuroEndocrine Tumor Society (ENETS), a reproducible grading system based on histomorphology and proliferation rate has been developed that accurately predicts patient prognosis.(108, 109) Most recently, the introduction of a four tier grading system, one that separates well-

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Journal Pre-proof differentiated PanNETs grades 1-3 from poorly-differentiated neuroendocrine carcinomas (NECs) has allowed the development of distinct treatment protocols for patients with very high risk lesions.(110) Just as the sequencing of pancreatic cancer provided deep insights into the fundamental biology of pancreatic cancer, so too has the sequencing of the exomes of a series of wellcharacterized PanNETs profoundly advanced our understanding of PanNETs.(111, 112) In sharp

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contrast to the genetic profile of ductal adenocarcinomas, the genes targeted in PanNETs

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include MEN1, DAXX, ATRX and several mTOR pathway genes including TSC2.(111, 112) The

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alterations in DAXX and ATRX in PanNETs were discovered to be tightly linked to alternative lengthening of telomeres (ALT), a unique mechanism of telomere maintenance.(111, 112) Thus,

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the study of tumors of the pancreas led to the discovery of the genetic basis of a novel

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mechanism of telomere maintenance. Pancreas cancer research is again leading the field! This new understanding of the genetics of PanNETs has been used to support the

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separation of poorly-differentiated NECs from grade 3 well-differentiated PanNETs, as MEN1,

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DAXX, ATRX and mTOR pathway genes are not typically targeted in NECs. Instead, NECs typically

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harbor TP53 and RB1 gene alterations.(113) Immunohistochemical markers for most of these genomic alterations allow simple application in routine diagnosis.(114) This separation of PanNETs from NECs is another example of how the integration of genetics has added to, and not replaced, morphologic diagnoses in the pancreas. Similarly, particular tumor morphologies have been discovered to characterize two recently described inherited tumor syndromes, familial insulinomatosis and glucagon cell hyperplasia and neoplasia (GCHN). (115-117) These syndromes were found to be linked to germ line mutations in the genes MAFA1 and GR, respectively. Pathologists have shown that the insulin producing PanNETs in insulinomatosis all have a trabecular histology and develop from

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Journal Pre-proof islets without any preceding insulin cell hyperplasia, and that the glucagon-producing PanNETs in GCHN emerge from islets with conspicuous glucagon cell hyperplasia. (118, 119)

Non-neoplastic Beta Cell Disorders

Our understanding of diabetes mellitus has also advanced dramatically. Diabetes is no longer considered a single disease, but instead is now recognized to be a group of disorders

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whose major types are juvenile onset diabetes, now called type 1, and adult onset or type 2

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diabetes. The insulin producing beta cells of the pancreatic islets have an essential role in both

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forms of diabetes, although their histological changes are often not eye-catching. It is therefore not surprising that the changes in the beta cells have only been defined in the last 50 years.

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Meticulous histopathological studies in type 1 diabetics revealed that the cause of the

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insulin deficiency in these patients is an autoimmune process with beta cell destruction by Tlymphocytes, a finding called insulitis.(120-122) Type 2 diabetes remains to be a complex and

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enigmatic disease in which the beta cells are involved, but are only one player in a combination

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of pathogenetic factors that include obesity, insulin resistance and strong genetic susceptibility.

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In sharp contrast to type 1 diabetes, the beta cells in type 2 diabetes are always present in the pancreas, although their number may be reduced, particularly if they are affected by deposition of islet amyloid polypeptide in the islets. The conclusion from these observations is that the beta cells in type 2 diabetes develop an increasing (inborn?) inability to deliver enough insulin, mainly because of excessive demand due to long-lasting insulin resistance related to obesity. The last fifty years have witnessed dramatic improvements in our understanding of other diseases that disturb the regulation of glucose. For example, the morphology of congenital hyperinsulinism in infancy (CHI), was described in its various forms in the 70s, 80s and 90s under the term nesidioblastosis, and the first underlying genetic changes causing CHI were discovered 17

Journal Pre-proof at the end of the 90s.(123-127) These genetic studies revealed a number of abnormalities in genes whose proteins are all involved in the process of insulin secretion.(128) Diffuse disease is most frequently associated with recessively inherited loss-of-function mutations of ABCC8 (SUR1) or KCNJ11 (Kir6.2), both of which code for proteins regulating the K(ATP)-channel in the beta cell membrane that controls insulin secretion by beta cell depolarization, increased Ca2+ entry, and elevated intracellular Ca2+. In focal disease there is a paternally inherited KCNJ11 or

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ABCC8 mutation and the loss of the corresponding maternal allele in β cells of a group of

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islets.(129) Recently a morphological variant has been genetically defined, which is a kind of

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mixture (“mosaicism”) of diffuse with focal disease, in which hyperactive islets are located in one or in a few adjacent lobules, whereas hypoactive islets are present in the whole

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pancreas.(130, 131)

Pancreatitis

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Our understanding of pancreatitis has similarly undergone significant change over the

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past five decades, again, thanks to significant contributions from pathologists.(132) Acute and

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chronic pancreatitis were long-regarded as two separate diseases. However in the 80s and 90s it was recognized, in studies analyzing the pancreatic changes in resection specimens of patients with a long history of recurrent pancreatitis, that chronic pancreatitis, particularly when caused by alcohol abuse, evolves from recurrent episodes of acute pancreatitis, a pathogenetic concept that was termed the necrosis-fibrosis sequence.(133-135) In other studies it was noted that the pathology of chronic pancreatitis, which was formerly considered to be uniform and “nonspecific,” varies according to the different causative factors of the disease, such as alcohol abuse, inherited gene mutations, autoimmune syndromes, metabolic disturbances, environmental conditions and anatomical abnormalities.(136) The rather vague descriptive

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Journal Pre-proof term chronic sclerosing pancreatitis has therefore been replaced by etiologically more specific terms, such as alcoholic chronic pancreatitis, hereditary pancreatitis, autoimmune pancreatitis , paraduodenal pancreatitis and obstructive chronic pancreatitis. Among these forms of pancreatitis two have received particular attention in recent years: autoimmune pancreatitis and hereditary pancreatitis.

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The association of pancreatitis with autoimmune diseases, including Sjögrens syndrome and sclerosing cholangitis, has been recognized for more than a half century.(137-144) Patients

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with autoimmune pancreatitis sometimes undergo surgery because the disease can clinically

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mimic a neoplasm, giving pathologists an opportunity to define the histopathology of this

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disease and describe its lymphoplasmacytic and fibrosing features. The fact that patients with

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this type of pancreatitis respond rapidly to steroid therapy fostered the hypothesis that the disease has an autoimmune pathogenesis.(145, 146) In 2001 Hamano and colleagues reported

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the association with elevated serum IgG4 levels.(147) This discovery aided diagnosis as pathologists can now use immunolabeling for IgG4 to make diagnoses on limited biopsies.(148,

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149) Subsequently, two forms of autoimmune pancreatitis were recognized: type I is

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characterized by increased numbers of IgG4 expressing cells, periductal lymphoplasmacytic infiltrates, storiform fibrosis, obliterative venulitis and is commonly associated with a generalized disorder called IgG4 related disease, and type II, which is often associated with inflammatory bowel disease, by the presence of granulocytic epithelial lesions (GELs) in the pancreas.(148, 150-157) Deltlefsen and colleagues described the deposition of complement at the basement membrane of pancreatic ducts, and recently, M. Shiokawa and colleagues suggested that the autoantigen responsible for autoimmune pancreatitis is a cleaved form of laminin 511, and antibodies to laminin 511 are already being used to aid in clinical diagnoses.(158-160) As exciting and clinically useful as these advances are, we by no means truly 19

Journal Pre-proof understand autoimmune pancreatitis. If antibodies to cleaved laminin 511 cause the disease, why are IgG4 levels increased?

Another major revolution in pancreatitis has been the discovery of germline variants that predispose to the disease. Whitcomb and colleagues first reported that germline variants in PRSS1 cause pancreatitis in 1996, and in the ensuing decades SPINK1, CFTR, CTRC and other

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genes have all been shown to increase the risk of pancreatitis.(132, 161) Today, many patients previously diagnosed as having idiopathic pancreatitis, are correctly classified as having a

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familial form of this disease.(162, 163) This obviously has significant implications for other

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family members, and since some forms of inherited pancreatitis are associated with a high

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lifetime risk of developing pancreatic cancer, for the patients themselves.(164)

Conclusions

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The last 50 years have witnessed dramatic advances in pancreatic pathology.(165) Many of these advances have been driven by the revolution in cancer genetics. Unlike some

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other fields, genetics has largely added to, and not replaced, histology in the pancreas.

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Many of the most significant of these advances in pancreatic pathology have been made possible by collaborations, by team science (Figure 3). The pancreas group has been marked by enormous collegiality and warmth (Figure 6). Cases, biosamples and ideas are freely shared, and a sense of comradery prevails over individuality. Our hope looking forward is that that this collegiality will continue, for great challenges remain ahead. As we put the dramatic changes of the past fifty years in perspective, it is clear that change and innovation have been part of medicine from the beginning. While in the past, centuries elapsed between these innovative waves in medicine, today these waves are coming faster and faster. On the crest of one of these waves it all seems clear and inevitable, only to be 20

Journal Pre-proof overturned by the next wave (Figure 7). As soon as we think we understand an entity, our paradigm is quickly overthrown by a new understanding. We should expect that our work, our current understanding of pancreatic pathology, will be overturned. One thing that the history of medicine has taught us- there will always be more waves. Indeed, new waves of innovation are sorely needed in the war against pancreatic cancer as the five year survival rate remains a dismal 8%, and pancreatic cancer is predicted to become the second leading cause of cancer

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death in the United States by the year 2030.(166) As L. Premuda states in the Preface to John

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Howard and Walter Hess’ magnificent book on the history of the pancreas, “its history, centuries

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old, is still in its adolescence.”(1) We have lived through an amazing fifty years, but wonderfully disruptive advances are yet to come.

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The authors should end with a disclaimer. In this review we have attributed some

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discoveries to individual people. We are fully aware that it is impossible to accurately attribute any discovery to a single person, and we remind the reader of Stigler’s law of eponymy, that “no

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scientific discovery is named after its original discoverer.”(167) We apologize to the many

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people who contributed to advancing the understanding of pancreas pathology, but were not

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recognized in this review, although in our defense we note that in an intended act of irony, Stigler was not the first to describe Stigler’s law of eponymy!

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Journal Pre-proof Figure Legends-

Figure 1: The four American Registry of Pathology “Fascicles” that span the last 60 years. The first edition, by Virginia Frantz, was published in 1959. The second edition by Antonio Cubilla and Patrick Fitzgerald, was published in 1984. The third edition, published in 1997, was written by Enrico Solcia, Carlo Capella, and Günter Klöppel. The fourth edition, by Ralph Hruban,

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Martha Pitman and David Klimstra came out in 2007. The dramatic changes in the classification systems described in these Fascicles nicely highlights the changes in pancreas pathology over

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the last 50 years.

Figure 2: The genes somatically targeted in ductal adenocarcinoma of the pancreas can be

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visualized in this plot of the chromosome location (X axis) and prevalence of alterations (Y axis).

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Note the four “mountains,” KRAS, TP53, SMAD4 and p16/CDKN2A. (Courtesy of Duc Nguyen)

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Figure 3: The team approach has characterized pancreatic cancer research. The American Association for Cancer Research awarded their 2013 Team Science Award to the team that

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sequenced the first exomes of pancreatic cancer. (Pictured are some of the awardees. From left

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to right in the first row are D Klimstra, K Kinzler, R Hruban, B Vogelstein. N Papadopolos, M Choti and V Velculescu. Back rows are C Wolfgang, J Herman, S Kern, NV Adsay, LD Wood, A Klein and C Iacobuzio-Donahue).

Figure 4: The 2004 meeting at Johns Hopkins to define the terminology for the classification of precancerous lesions in the pancreas. (Pictured from left to right; first row: Y Kato, NV Adsay, GJA Offerhaus, DS Klimstra, RH Hruban, K Takaori, D Longnecker, T Furukawa, J Lüttges. Second row: N Prasad, JA Albores-Saavedra, D Sui, AV Biankin, A Maitra, M Shimizu, A Yeh,u and N Fukushima) 22

Journal Pre-proof Figure 5: The four most common cystic neoplasms of the pancreas. Serous cystadenoma (A), mucinous cystic neoplasm (B), Intraductal papillary mucinous neoplasm (C) and solid pseudopapillary neoplasm (D). Fifty years ago these entities were broadly lumped together.

Figure 6: The authors, D. Klimstra, R. Hruban, G. Zamboni and G. Klöppel. Together, with others, their years of collaboration and friendship characterize the attitude of the field of

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pancreas pathology.

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Figure 7: “Catch a wave and you can see real far.” On the crest of a disruptive wave of

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innovation, the field seems clear, only to be disrupted by the next innovative wave. (Illustration created by Hannah Ahn for Ralph Hruban’s 2014 Maude Abbott lecture. With permission,

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copyright Hannah Ahn).

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Journal Pre-proof Table : Timeline of milestones in the pathology of epithelial neoplasms with ductal differentiation

1970- Cystic neoplasms lumped together. No driver genes known. 1978- Serous neoplasms separated from mucin-producing neoplasms 1982- Intraductal papillary mucinous neoplasms described 1988- KRAS gene mutations described in pancreatic cancer

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1991- TP53 gene mutations described in pancreatic cancer 1994- p16/CDKN2A gene mutations described in pancreatic cancer

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1996- SMAD4 discovered in pancreatic cancer

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2004- Sendai Criteria for managing cystic neoplasms 2008- Whole-exome sequencing of pancreatic cancer

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2011- Whole-exome sequencing of cystic neoplasms

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2014- Fukuoka criteria for managing cystic neoplasms

2015- Whole-genome sequencing of pancreatic cancer by the International Cancer Genome Consortium

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2016- Whole-genome sequencing of the germline of familial pancreatic cancer

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2017- The Cancer Genome Atlas (TCGA) program reports its characterization of pancreatic cancer

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