Inflammatory and Other Nonneoplastic Disorders of the Pancreas
Vikram Deshpande
Introduction
This chapter discusses a range of inflammatory and other non-neoplastic diseases of the pancreas, focusing on recently recognized variants of chronic pancreatitis including autoimmune pancreatitis (AIP) and paraduodenal pancreatitis. In the past, a generic diagnosis of chronic pancreatitis was often sufficient, but with the recent recognition of these unique variants of chronic pancreatitis, the pathologist is required to attempt to further subclassify this disease.
A brief review of the pancreatic duct system is in order before a discussion of pancreatitis. The anatomy of the pancreatic ductal system is unpredictable because of developmental variability. The main pancreatic duct, the duct of Wirsung, carries the bulk of pancreatic secretions and drains into the duodenum at the papilla of Vater. The accessory pancreatic duct, also known as the duct of Santorini, drains into the duodenum through a separate minor papilla that is typically 2 cm cephalad to the papilla of Vater. In most individuals, the accessory pancreatic duct is nonfunctional. The minor papilla may appear as a nodule in the second part of the duodenum and could be mistaken for a polyp.
Acute Pancreatitis
Acute pancreatitis is an inflammatory disease of the pancreas that is characterized clinically by acute abdominal pain and increased levels of serum amylase and lipase.1,2 The incidence of this disease has increased in the past 2 decades, and acute pancreatitis accounts for more than 200,000 hospital admissions every year in the United States. Eighty percent of these episodes are mild and resolve without serious morbidity, but in 20% of cases, the episodes are more severe and are associated with substantially increased morbidity and mortality.1,2 This disease is seldom seen by the surgical pathologist, although it is frequently encountered at autopsy. Very occasionally, pancreatic neoplasms manifest as acute pancreatitis, and foci of resolving acute pancreatitis may be seen adjacent to neoplasms of the pancreas.
Clinical Features
Acute pancreatitis is characterized by acute constant pain that typically radiates to the back. In cases of severe acute pancreatitis, the necrosis tracks into the periumbilical region (Cullen sign) and abdominal flank to cause bluish cutaneous lesions at these sites.1,2 The diagnosis is confirmed by demonstrating elevations in serum amylase and lipase. Contrast-enhanced computed tomography (CT) is used to confirm the diagnosis of acute pancreatitis, demonstrate local complications such as fluid collections and necrosis, and score the severity of the disease.3
There is a wide spectrum of severity, with some episodes of acute pancreatitis being mild and self-limited, requiring only brief hospitalization, and those most severely affected developing persistent hypovolemia and multiorgan dysfunction. A number of scoring systems are used to predict the severity of the disease. The most common is the Sequential Organ Failure Assessment (SOFA) score, the Ranson criteria, and the Acute Physiology and Chronic Health Evaluation (APACHE II) score. The Atlanta classification divides the disease into two grades: mild (80% of cases) and severe (20% of cases).4
Etiology and Pathogenesis
The two most common triggers of acute pancreatitis are obstruction of the common bile duct by stones and alcohol abuse.1,2 Together, they account for approximately 80% of cases of acute pancreatitis in Western countries. Bile stone-induced pancreatitis typically affects elderly women and is caused by gallstone migration and subsequent pancreatic duct obstruction. Although gallstones are the most common cause of biliary obstruction, other forms of obstruction, such as periampullary tumors and neoplasms involving the head of the pancreas, may also provoke acute pancreatitis.
Alcohol-related acute pancreatitis is more frequently seen in middle-aged men. Experimental studies have implicated alcohol in transient increases in pancreatic exocrine secretions, contraction of the sphincter of Oddi, and direct toxic injury to acinar cells. However, the relationship between alcohol and pancreatitis is not completely understood. Acute pancreatitis develops in only a small fraction of alcohol abusers (>80 g daily intake).5 Clearly, other genetic and environmental factors play a major role in the development of alcohol-related acute pancreatitis.
Less common causes of acute pancreatitis are listed in Box 39.1. In a substantial minority of cases the cause is unexplained. In such patients, genetic testing for mutations, including the cationic trypsinogen gene (PRSS1), serine protease inhibitor Kazal type I (SPINK1), or cystic fibrosis transmembrane conductance regulator (CFTR), may provide an explanation for recurrent acute pancreatitis (see later discussion).
Although the precise pathogenesis is controversial, it is nonetheless believed by most investigators that acute pancreatitis is caused by unregulated activation of pancreatic trypsin: The trypsin leads to both autodigestion and local inflammation. After activation of trypsinogen to active trypsin, other pathways and enzymes in the pancreas such as elastase, complement, and kinin systems are activated. The inflammation is further propagated by the production of mediators such as interleukin 1 (IL-1), IL-6, and IL-8, which are produced by neutrophils, macrophages, and lymphocytes that are attracted to the diseased pancreas.
Pathologic Features
The pancreas typically appears swollen and pale. With mild acute pancreatitis, multiple tiny spots of opaque white fat necrosis are seen on the surface of the pancreas (Fig. 39.1).6 Foci of intrapancreatic fat necrosis may also be seen. The amount of intrapancreatic fat varies considerably among individuals, and the presence of intraparenchymal fat necrosis is appreciable only in those with a moderate amount of intrapancreatic fat. In cases of severe acute pancreatitis, large confluent areas of necrosis are identified as well as hemorrhagic areas.
Histologically, the changes of acute pancreatitis have been characterized in autopsy material. In mild forms of acute pancreatitis, the disease is concentrated in the interlobular septa.6 With time, these foci of fat necrosis are replaced by foamy macrophages, and ultimately by fibrosis (Fig. 39.2). In the more severe examples of acute pancreatitis, there is diffuse necrosis involving the acinar and ductal tissue accompanied by acute inflammatory cells. These foci of necrosis may liquefy to form a pseudocyst; less commonly, they may become infected, a complication associated with high mortality. Damage to the vasculature results in diffuse hemorrhage (hemorrhagic pancreatitis). Well-characterized examples of acute pancreatitis triggered by atheroembolism have also been reported.7
Therapy
The treatment for mild forms of the disease is largely supportive and includes fluid resuscitation.1,2 More severe cases require aggressive fluid resuscitation and antibiotics. Pancreatic necrosis and infection are two important local complications of the disease, with the latter being one of the leading causes of morbidity and mortality. When infection is suspected, a fine-needle aspiration (FNA) is performed to obtain material for microbiology studies.
Chronic Pancreatitis
Chronic pancreatitis is a fibroinflammatory disorder in which the pancreatic acinar compartment is replaced by fibrosis, eventually leading to exocrine insufficiency.8–10
Until recently, acute and chronic pancreatitis were viewed as distinct diseases. However, they have now come to be viewed as a continuum.10 This view is supported by the observation that chronic pancreatitis eventually develops in some patients with recurrent acute pancreatitis, and the two diseases share etiologic factors such as alcohol abuse and certain germline mutations.
A number of classification schemes for chronic pancreatitis have been proposed, including the Marseille classification of 1963, the revised Marseille classification of 1984, the Marseille-Rome classification of 1988, the Cambridge classification of 1984, the Zurich classification of 1997, and the Japan Pancreas Society classification of 1997.9 However, there is no single widely accepted system, and most of these schemes are not helpful in clinical practice. Notably, these classification schemes were published before the recognition of autoimmune pancreatitis. Furthermore, many of them focus on the distinction between acute and chronic pancreatitis and pay little attention to histopathologic changes; hence, they are of little interest to the anatomic pathologist. In many circumstances, the composition of the inflammatory infiltrate and the pattern of fibrosis provide clues to the etiology of the disease.
Confirming a Diagnosis
Histology remains the gold standard for the diagnosis of chronic pancreatitis; however, biopsy is impractical in most situations. Histology is typically available only when a tumefactive lesion is identified. Therefore, the most practical and efficient way of establishing a diagnosis of chronic pancreatitis is by demonstrating a reduction in bicarbonate in a duodenal aspirate after secretin stimulation and by detecting abnormalities of the pancreatic ductal system on endoscopic retrograde cholangiopancreatography (ERCP) or magnetic resonance cholangiopancreatography (MRCP).8–10 The presence of chunky intrapancreatic calcifications on plain radiographs or CT scans is also diagnostic of chronic pancreatitis, although these features are seen only in a minority of cases.
Alcoholic Pancreatitis
The most common cause of chronic pancreatitis in developed nations is alcohol ingestion, which accounts for approximately 70% to 95% of cases (Box 39.2). However, clinically apparent chronic pancreatitis develops in only 10% of patients with alcohol abuse.8,9 Therefore, it is likely that additive factors play a role in the development of alcohol-related chronic pancreatitis. Cigarette smoking is an independent, dose-dependent risk factor for chronic pancreatitis.11 It has recently been appreciated that the contribution of alcohol abuse to chronic pancreatitis may have been overestimated, and that cigarette smoking may contribute significantly to the development of the disease, because the vast majority of patients who abuse alcohol are also cigarette smokers.11
Germline genetic defects have a role in the development of chronic pancreatitis, either as the primary driver, as in hereditary pancreatitis, or as a disease modifier, as in individuals with mutations in the CFTR (see later discussion). It is likely that alcohol-related pancreatitis is a multifactorial disease and that environmental and genetic factors play major roles in modifying the disease.
Clinical Features
Alcohol-related chronic pancreatitis is predominantly a disease of men and usually manifests in the fourth and fifth decades of life.8–10 Epigastric pain is the overriding early symptom. The pain typically radiates to the back and can be partially relieved by sitting up and leaning forward. The presentations can be categorized into four groups: (1) acute or recurrent episodes of acute pancreatitis, (2) constant pain, (3) symptoms related to local complications of the disease such as pseudocyst formation, and (4) symptoms related to exocrine or endocrine insufficiency. Exocrine insufficiency in the form of steatorrhea develops late in the disease, after more than 95% of the acinar tissue has been lost.
Pathogenesis
The pathogenesis of chronic pancreatitis is not well defined, although three hypotheses have been proposed.12
Ductal Obstruction Theory
The ductal obstruction theory states that alcohol increases protein concentration in the pancreatic fluid and these proteins plug the pancreatic ducts.13 In fact, such proteinaceous plugs are frequently observed in individuals with significant alcohol exposure. These plugs may also calcify and further contribute to the development of chronic pancreatitis. Although this theory has been ignored in recent years, interest in it has been revived since the discovery of the association between CFTR mutations and idiopathic chronic pancreatitis; specifically, individuals with cystic fibrosis and CFTR mutations show proteinaceous plugs.
Toxic Metabolic Theory
The toxic metabolic theory is based on experimental evidence to suggest that alcohol exerts a direct toxic effect on acinar cells. Similar to the liver, the pancreas metabolizes ethanol via both oxidative and nonoxidative pathways, generating the metabolite acetaldehyde and fatty acid ethyl esters (FAEEs), respectively.14 Experimentally, alcohol has been shown to increase the content of the digestive enzymes trypsinogen and lipase, and this increase is accompanied by a fragility of the organelles that contain these enzymes.15 The net effect is an increased likelihood of premature activation of these digestive enzymes and autodigestion of the pancreas. The most compelling evidence that acinar cells play an important role in the development of chronic pancreatitis is the association between mutations in PRSS1 and pancreatitis.
Necrosis-Fibrosis Theory
Traditionally, chronic alcoholic pancreatitis was believed to be “chronic” at initiation. The necrosis-fibrosis theory suggests that chronic pancreatitis is a consequence of repeated episodes of acute pancreatitis. Pancreatic stellate cells are believed to play a critical role in the development of fibrosis.14 The pancreatic stellate cells are activated either by cytokines (autocrine or paracrine) or by direct effects of alcohol and its metabolites. This persistent activation is believed to be responsible for fibrosis, a defining feature of chronic pancreatitis.
Pathologic Features
The hallmark of chronic pancreatitis is fibrosis, although in the early stages it may be unevenly distributed. Most surgical specimens show diffuse fibrosis and significant induration.16–18 The gland may appear enlarged, but in the late phase of the disease the pancreas is shrunken. Cysts of varying sizes are identified both within and outside the pancreas. The extrapancreatic cysts invariably represent pseudocysts; the intrapancreatic cysts are either pseudocysts or retention cysts.16 Another hallmark of alcoholic chronic pancreatitis is calcification, both within the main pancreatic duct and in the parenchyma. The main pancreatic duct may be obstructed and dilated, although strictures may also be identified. Tapering stenosis of the common bile duct is present in a minority of cases.
Histologically, alcohol-related pancreatitis exhibits varying degrees of atrophy of the exocrine and endocrine components along with calcification and fibrosis (Fig. 39.3).16–18 In the late phase of the disease, overt interlobular fibrosis is seen, and intralobular fibrosis is also invariably present. The fibrosis is relatively acellular, but fibroblasts and myofibroblasts may be seen. Although much of the acinar component may be depleted, foci of well-preserved acinar tissue are seen interspersed. Some of the pancreatic ducts are dilated; they are filled with proteinaceous material and sometimes calculi (Figs. 39.4 and 39.5).
An inflammatory component is invariably identified, but the degree of inflammation is significantly less than that seen in AIP. Most of the inflammatory cells are small lymphocytes, and lymphoid aggregates are also occasionally present. Plasma cells are usually inconspicuous. In contrast to AIP, periductal lymphocytic accentuation is rarely identified. Intraneural and perineural lymphocytic aggregates are usually prominent. The small lymphocytes are predominantly T cells, although scattered B cells are also present. When neutrophils are identified they are usually seen adjacent to pseudocysts and residual foci of acute pancreatitis; intraductal aggregates of neutrophils are uncommon.
In the early stages of chronic pancreatitis, the islets of Langerhans are usually normal in appearance. In the late phase, the pancreatic islets may appear remarkably prominent. This apparent prominence of the endocrine component is primarily related to the preferential loss of acinar tissue. It may occasionally be difficult to distinguish this “pseudohypertrophy” of the endocrine component from a pancreatic endocrine microadenoma. Immunohistochemical stains for insulin and glucagon can assist in making this distinction: Pseudohypertrophic islets show an intimate admixture of insulin- and glucagon-producing cells, whereas a microadenoma is entirely negative for both markers or may show diffuse reactivity for glucagon. Ductular-insular complexes may be seen, but this is a relatively nonspecific finding. In the very late phase of the disease, there is an appreciable decrease in the endocrine component.
Lesions of pancreatic intraepithelial neoplasia (PanIN) are frequently identified in resections from patients with chronic pancreatitis. Most of these are low grade (grade 1 and grade 2); PanIN3 lesions are distinctly uncommon. The risk of carcinoma in the setting of chronic pancreatitis is discussed later.
Differential Diagnosis
Chronic Pancreatitis versus Pancreatic Adenocarcinoma
Distinguishing a well-differentiated pancreatic adenocarcinoma from chronic pancreatitis can be one of the most difficult decisions a pathologist encounters.19 Making this distinction on the basis of a frozen section or needle biopsy specimen exponentially increases the level of difficulty. Nonetheless, attention to the following four features is key to making this distinction (Table 39.1).
Table 39.1
Features to Distinguish Chronic Pancreatitis from Well-Differentiated Adenocarcinoma
| Chronic Pancreatitis | Invasive Ductal Adenocarcinoma | |
| Lobular architecture maintained | Yes | No |
| Nonlobular distribution of glands | No | Yes |
| Nuclear variation >4 : 1 within a gland | No | Yes |
| Nuclear membrane irregularities | No | Yes |
| Cytoplasm | Dense, eosinophilic | Pale, vacuolated |
| Perineural invasion | No | Yes |
| Association of ducts with arteries | No | Yes |
Location of Ducts and Glands.
As a general rule, ducts organized in well-circumscribed lobules are benign, whereas atypical ducts scattered in the interlobular septa or suspended within peripancreatic fat suggest a malignant process (Fig. 39.6). Glands located within lobules, regardless of the degree of atypia, should suggest a “benign” interpretation (Fig. 39.7). Other than an occasional large duct, few other ducts are seen in the interlobular septa in chronic pancreatitis. Furthermore, unlike ducts in the liver, those in the pancreas do not accompany arteries, so the presence of a duct adjacent to an artery is highly suspicious for a pancreatic adenocarcinoma.20 The presence of perineural invasion is diagnostic for carcinoma, although it is important to ensure that the gland is actually infiltrating the perineural space. Vascular invasion is also diagnostic for carcinoma.
Desmoplastic Stroma.
The desmoplastic reaction, a peculiar mesenchymal proliferation composed of fibroblasts suspended within a basophilic stroma, is an important feature of ductal adenocarcinoma. However, distinguishing desmoplastic stroma from the stroma of chronic pancreatitis can be quite subjective.
Cytoplasmic Features.
The identification of cytoplasmic features is underemphasized in the diagnosis of malignancy. Benign ducts show a dense eosinophilic cytoplasm, whereas many (but not all) adenocarcinomas, especially the well-differentiated carcinomas, show abundant pale cytoplasm, giving the cells a low nucleus-to-cytoplasm (N : C) ratio. A low N : C ratio is a common finding in pancreatic ductal adenocarcinoma.
Nuclear Features.
The two most reliable nuclear features of pancreatic ductal adenocarcinoma are markedly irregular nuclear outlines and anisonucleosis (>4 : 1 variation in nuclear size). The variation in nuclear size is appreciable on paraffin and frozen sections, but the nuclear irregularities are less obvious on these preparations. Both features, however, are reliably identified on cytology preparations.
A number of immunohistochemical and molecular markers can help with this distinction, and these are covered in great detail in Chapter 40.
Chronic Alcoholic Pancreatitis versus Autoimmune Pancreatitis
The type 2 variant of AIP is most likely to be confused with alcoholic chronic pancreatitis. The two hallmarks of type 2 AIP—a dense periductal lymphoplasmacytic infiltrate and granulocytic epithelial lesions—are seldom seen in alcoholic chronic pancreatitis. It is important to emphasize that type 2 AIP is not a immunoglobulin G4 (IgG4)-related disease and is not associated with elevated serum or tissue levels of IgG4, although mild elevations may be seen.
In contrast, distinguishing the type 1 variant of AIP from alcoholic pancreatitis is relatively straightforward. Histologically, virtually all cases of type 1 AIP demonstrate a triumvirate of histologic features : (1) a dense and diffuse lymphoplasmacytic infiltrate, unlike the patchy lymphocytic infiltrate of alcoholic pancreatitis; (2) storiform-type fibrosis, unlike the acellular fibrosis of chronic alcoholic pancreatitis; and (3) obliterative phlebitis. Furthermore, almost all cases of type 1 AIP show greater than 50 IgG4-positive plasma cells per high-power field (HPF). However, difficulties arise when interpreting needle biopsy specimens. AIP does not uniformly involve the pancreas, and some biopsies may not demonstrate the full spectrum of histologic findings. In such cases, correlation with clinical and radiologic features as well as serum IgG4 levels is required.
Chronic Pancreatitis and the Risk of Pancreatic Cancer
Chronic pancreatitis has consistently been shown to be a risk factor for pancreatic cancer. In a study of 2015 patients with chronic pancreatitis, a cumulative risk for pancreatic cancer of 4% at 20 years was found.21 Subsequent studies confirmed this increased risk for pancreatic cancer in patients with chronic pancreatitis.22,23 One of the concerns with these studies is the potential for misdiagnosis of pancreatic cancer as chronic pancreatitis, which inflates the risk of malignancy. However, because the association between chronic pancreatitis and pancreatic cancer persists for several years after the initial diagnosis of chronic pancreatitis, this is not believed to represent a confounding factor. In comparison to chronic alcoholic pancreatitis, hereditary pancreatitis carries a far higher risk of pancreatic cancer (approximately 35% during a lifetime).
Therapy
The goals of treatment are to relieve pain, prevent recurrent attacks of acute pancreatitis, and manage the metabolic consequences such as maldigestion and diabetes. Surgery or endoscopic intervention is required to relieve intractable pain or to address specific complications such as pseudocysts. The objective of surgery (pancreatojejunostomy) is to decompress the pancreatic duct (which relieves pain) and to preserve as much of the pancreas as possible (to preserve pancreatic islets).
Genetics of Pancreatitis
There is growing evidence that a significant proportion of patients with apparently idiopathic acute or chronic pancreatitis have underlying genetic abnormalities. Among the genes that predispose an individual to chronic pancreatitis, three are associated with defects in the activation of trypsinogen: PRSS1, SPINK1, and chymotrypsin C (CTRC).24–28 This is not surprising, because one of the fundamental events in the development of pancreatitis is the activation of trypsinogen to trypsin (Fig. 39.8). Trypsin is associated with some unique enzymatic features, because it can both self-activate and deactivate itself. The mutations in PRSS1 that are associated with the development of chronic pancreatitis either cause premature activation of this enzyme or abrogate the inactivation.28 The most common mutation in PRSS1, R122H, abrogates the ability of trypsin to inactivate itself and also enhances trypsinogen autoactivation. The SPINK1 gene encodes for a trypsin inhibitor, and loss of function mutations of this gene abrogate the ability of the protein to inhibit activation of trypsin.26 Other genes implicated in chronic pancreatitis are calcium-sensing receptor, CTRC,27 and CFTR.29
With rapid advances in technology, it is relatively easy to identify mutations in genes that contribute to the development of pancreatitis. Although mutations in each of these genes have unequivocally been linked to pancreatitis, many of the mutations are disease neutral, and some could even be protective. Furthermore, the penetrance is extremely low, in some cases less than 1%. Therefore, the interpretation of these genetic tests is increasingly complex. With some exceptions (discussed later), testing for mutations in unselected patients with suspected pancreatitis is not recommended.25
Trypsinogen Mutations
Since the discovery of the PRSS1 gene, more than 20 mutations have been identified. The clinical relevance of the R122H mutation is supported by data from a transgenic model.30 Gain-of-function mutations, especially R122H and N29I, show a high penetrance (80%). This, coupled with the increased risk of pancreatic cancer (35-fold), supports the use of diagnostic testing for these mutations in young patients with acute or chronic pancreatitis.25
SPINK1 Mutations
The most common SPINK1 mutation, N34S, has a high frequency (approximately 2%) in the general population and is associated with a very low penetrance.26 Another mutation, c.27delC, is associated with a severe phenotype but also shows a relatively low penetrance of 29%.26 Consequently, SPINK1 mutations are thought to be disease predisposing or disease modifying rather than directly causing disease.
CFTR Mutations
Although chronic pancreatitis develops in a substantial majority of patients with cystic fibrosis, a small but distinct group of mutations is associated with isolated involvement of the pancreas (i.e., without pulmonary and other typical manifestations). The mutations seen in this setting are distinct from those associated with cystic fibrosis, and the patients typically do not show other clinical features of cystic fibrosis. Furthermore, their sweat chloride levels are normal.10,24,29 Unlike patients with cystic fibrosis, these patients are diagnosed in adulthood.
The association between CFTR mutations and chronic pancreatitis was first identified more than a decade ago.29 In one study, 43% of patients with idiopathic recurrent acute pancreatitis and 11% of patients with chronic pancreatitis carried CFTR mutations in one or both genes.24 Nonetheless, of the more than 1600 CFTR mutations that have been identified, only a minority are associated with disease. Therefore, genetic testing for CFTR mutations in individuals with acute or chronic pancreatitis is not recommended; the test of choice, even in this era of genomics, is a sweat chloride test.25 Genetic testing is recommended only if full-blown cystic fibrosis (as opposed to isolated involvement of the pancreas) is suspected.
Hereditary Pancreatitis
Clinical Features
Hereditary pancreatitis is an autosomal dominant disease that typically manifests with recurrent attacks of acute pancreatitis in childhood (the first and second decades of life).28 This is an uncommon cause of chronic pancreatitis, accounting for fewer than 2% of all cases. The disease affects men and women equally. A diagnosis of hereditary pancreatitis should be suspected in any individual in whom chronic pancreatitis develops at an early age (<25 years). In 80% of cases, hereditary pancreatitis is caused by a gain-of-function mutation in the PRSS1 gene (see earlier discussion). Although 20 mutations have been identified, the 2 most common mutations are R122H and N29I. The penetrance of these mutations is high, and approximately one half of these patients progress to chronic pancreatitis. In a study of 200 patients with hereditary pancreatitis, the cumulative risk of pancreatic carcinoma at 50 years of age was 11% for men and 8% for women; at 75 years, it was 49% for men and 55% for women.31 The type of genetic mutation did not correlate with the risk of cancer.31
Pathologic Features
Limited information is available on the pathologic changes of hereditary pancreatitis. It appears that the disease is histologically similar to alcoholic chronic pancreatitis with periductal and interlobular fibrosis.16 The dilated ducts show both protein plugs and calculi, although some cases are associated with a periductal collar of inflammation (Fig. 39.9).16
Pancreatic Divisum
Pancreatic divisum occurs when the ventral and dorsal pancreatic ducts fail to fuse during development.32,33 An “incomplete” pancreatic divisum implies that there is a narrow communication between the dorsal and ventral pancreatic ducts. Pancreatic divisum is by far the most common congenital variation of the pancreatic ductal system, occurring in approximately 10% of individuals.32,33
Most individuals with pancreatic divisum are asymptomatic, and pancreatitis develops in only a minority. The disease manifests primarily in adults, and both sexes are affected. Pancreatic disease in the form of acute or chronic pancreatitis is in part caused by inadequate pancreatic drainage through a narrow dorsal pancreatic duct. ERCP reveals a short ventral duct and a main pancreatic duct that communicates with the dorsal duct and drains into the duodenum near the minor papilla.
One of the most controversial aspects of this disease is the difficulty in demonstrating a causal relationship between pancreatitis and this anatomic variation of the ductal system. There is increasing evidence to suggest that pancreas divisum alone is insufficient to precipitate pancreatitis. A recent study showed no difference in the prevalence of pancreatic divisum between patients with idiopathic pancreatitis and a control population, 5% and 7%, respectively.34 However, the authors found that the prevalence of pancreatic divisum in patients with pancreatitis and mutations in CFTR, SPINK1, or PRSS1 was 47%, 16%, and 16%, respectively.34 Therefore, only a small proportion of patients with pancreatic divisum would benefit from decompression of the dorsal pancreatic duct, a procedure that can be performed endoscopically.
Autoimmune Pancreatitis
Definition and Historical Aspects
AIP is a mass-forming inflammatory lesion of the pancreas that may mimic pancreatic carcinoma.34–36 It is only in the last 2 decades that this disease has received the attention it deserves. Previously, these cases were diagnosed nonspecifically as chronic pancreatitis. In retrospect, approximately 25% of pancreatic resections that lack evidence of malignancy may represent AIP.37
AIP was first described by Sarles and colleagues in the 1960s.38 They described four cases of chronic pancreatitis in patients with steatorrhea and obstructive jaundice.38 Histologically, the pancreas showed a dense lymphoplasmacytic infiltrate. Although the histologic descriptions were limited, it is likely that these cases represented AIP. Little progress was made in the subsequent 3 decades, although there were similar sporadic case reports in the literature. Kawaguchi and co-workers are credited with the first modern histopathologic description of this entity.39 They described two men with obstructive jaundice and histologic features that are now considered typical for AIP.39 The term autoimmune pancreatitis was coined by Yoshida and colleagues in a case report in 1995 and this term is now the preferred designation.40,41
A major milestone in understanding of this disease came with the apparently serendipitous discovery of its association with elevated levels of serum IgG4.42 Shortly afterward, it was established that the inflamed pancreas shows a substantial increase in IgG4+ plasma cells.43–46 It was subsequently realized that a sizeable number of patients with AIP also exhibit either synchronous or metachronous fibroinflammatory mass lesions in other organs, including the liver and biliary tract.45,47 This multifocal systemic fibroinflammatory disease is now termed IgG4-related disease.36 In fact, AIP is only one manifestation of IgG4-related disease, and in an attempt to highlight this relationship, some authorities advocate use of the term IgG4-related pancreatitis.40
Subtypes
AIP is not a homogenous entity, because the disease can be clearly segregated into two distinct clinicopathologic subtypes: AIP type 1 and AIP type 2.36,48–53 AIP type 1 is an IgG4-related disease, whereas the type 2 variant is not. There is significant overlap in the clinical and radiologic features of these two variants (see later discussion).36,48–52,54
Clinical Features
AIP is an uncommon disorder. A recent nationwide survey in Japan identified an overall prevalence rate of 45.1 cases per 100,000 patients, with a threefold increase in the number of cases during a decade.55 Although no data are available from North America, this disease is significantly less common than pancreatic carcinoma.
Both the gender ratio and the mean age at presentation vary according to the histologic subtype. Patients with type 1 AIP tend to be older (in their seventies) than patients with the type 2 variant (in their fifties).35,43,48,49,52,54–56 Most patients with type 1 AIP are male, whereas the gender ratio for type 2 AIP is approximately 1 : 1. There is considerable overlap between the demographic and clinical features of alcoholic chronic pancreatitis and those of the type 2 variant of AIP, although the former entity tends to be more common in men.
There appear to be geographic variations in the incidence of the two subtypes: the type 2 variant is extremely uncommon in Asia but constitutes almost half of all cases of AIP in series from Europe and North America.54
Obstructive jaundice and weight loss develop in patients with type 1 AIP.48–50,52,54, 56–58 These symptoms, along with a mass on imaging, make the distinction of this disease from pancreatic ductal adenocarcinoma extremely problematic. Other non-neoplastic lesions that mimic pancreatic cancer are listed in Box 39.3. Other presenting symptoms of patients with type 1 AIP include fatigue and recent onset of diabetes mellitus. Abdominal pain is uncommon, although some patients may complain of vague abdominal pain. Patients with type 1 AIP may have other manifestations of IgG4-related disease, either synchronously or metachronously.48–50,52,54,56–58 One of the more common extrapancreatic manifestations of type 1 AIP is a painless unilateral or bilateral swelling of the submandibular salivary gland. In fact, in an individual with painless obstructive jaundice, bilateral enlargement of the submandibular salivary glands is strongly suggestive of IgG4-related disease (AIP).59
Patients with type 2 AIP have abdominal pain, although the pain is rarely severe enough to suggest acute pancreatitis.48–50,53,55,56–58 In comparison to type 1 disease, a smaller proportion of patients with type 2 AIP have obstructive jaundice at presentation.
Although AIP is an uncommon cause for either acute or chronic pancreatitis, more than 33% of patients with this disease have symptoms that mimic other forms of acute or chronic pancreatitis.57
Serum Markers
Elevated serum IgG4 is the most robust biomarker for this disease.42,60 This test is fairly sensitive for type 1 AIP, and is elevated in 80% of cases, but its specificity, particularly in an unselected population, is low.50,60 A recent survey during a 1-year period identified 59 patients with elevated levels of serum IgG4. Among these, only 10% had unequivocal evidence of IgG4-related disease.61 An even more worrisome observation is that approximately 10% of patients with pancreatic cancer show elevated levels of serum IgG4. The specificity of this test is somewhat improved when the threshold is set at 280 mg/dL (two times normal). Patients with type 2 AIP only occasionally show elevated levels of serum IgG4, and there is currently no reliable biomarker for recognition of this variant.51
A number of other immunologic abnormalities are identified in patients with AIP. These include positive antinuclear antibody, rheumatoid factor, and elevated gammaglobulin levels. A variety of other antibodies have been identified, including anti-lactoferrin and anti–carbonic anhydrase antibodies, although these are not specific and are not used in clinical practice.35,62
A novel autoantibody against a plasminogen-binding protein peptide, although it has yet to be validated, has shown a high sensitivity (94%) and the assay is positive in only 5% of patients with pancreatic ductal adenocarcinoma.62,63
Radiology
During the last decade, radiologists have greatly improved their ability to identify AIP and distinguish it from pancreatic carcinoma. Nonetheless, we continue to see pancreatic resections for AIP.
On imaging, three patterns of AIP are recognized: diffuse, focal, and multifocal.64–66 The diffuse form of the disease (Fig. 39.10) is the most common type; the pancreas appears enlarged and “sausage shaped.” Among these patterns, the focal form of disease is most likely to be confused with pancreatic carcinoma.
The affected regions of the pancreas are hypoechoic on ultrasonography and hypointense on CT. On contrast-enhanced CT, there is decreased enhancement of the mass in the arterial phase and delayed enhancement in the late phase.64,66
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