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.

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

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.

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).

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.

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).

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

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

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 A small, hypodense rim is often identified around the lesion—the so-called “halo sign.” On MRI, the pancreas is diffusely hypointense on T1- and slightly hyperintense on T2-weighted images. The main pancreatic duct is usually narrow, and upstream dilatation of the pancreatic duct should raise concern for a pancreatic carcinoma. Both the bile duct and the pancreatic duct may be narrowed (double duct sign), a feature that is otherwise suggestive of pancreatic carcinoma.

An irregularly narrowed main pancreatic duct is very characteristic of AIP (Fig. 39.11). On ERCP, the following four features help distinguish AIP from pancreatic adenocarcinoma: (1) a long stricture involving more than one third of the main pancreatic duct, (2) lack of upstream dilatation, (3) side branches arising from a strictured segment, and (4) the presence of multiple strictures involving the main pancreatic duct.⁶⁷ The presence of all four features is highly specific but only moderately sensitive for AIP.⁶⁷ Although the Japanese and Korean criteria for diagnosis of AIP are highly dependent on pancreatography, those published from the United States do not require imaging of the pancreatic duct.^68–70

Within 1 to 2 weeks of initiation of steroid therapy, there is a dramatic shrinkage of the mass with partial to complete normalization of the main pancreatic duct. In the late phase of this disease, the pancreas appears shrunken and atrophic.

Pathogenesis

Although one of the defining features of AIP is an elevated level of serum and tissue IgG4, it is unlikely that this antibody is the primary driver behind the tissue destruction seen in this disease.³⁶ In fact, there is evidence to suggest that IgG4 may play an antiinflammatory role. Nonetheless, the IgG4 antibody has some unusual structural and functional properties. It is the least common of the four IgG subclasses, accounting for less than 5% of the total IgG in healthy persons. The molecule binds only weakly to C1q and Fcγ receptors, and therefore is believed not to activate the classic complement pathway.⁷¹ An even more unique aspect of the IgG4 molecule is the half-antibody exchange reaction. The bond between the disulfide chains is weak, resulting in a dissociation of the heavy chains, and this allows for the chains to randomly combine, resulting in asymmetric antibodies with two different antigen combining sites, accounting for the inability to form immune complexes.^36,71

Pathologic Features

The disease can involve any part of the pancreas. In the active phase, the pancreas is enlarged, but in the late phases of the disease, the pancreas may appear shrunken and fibrotic. On gross evaluation, the pancreas is generally bulky and feels firm to hard, although serial sections usually fail to identify a distinct tumor (Fig. 39.12). Occasionally, a distinct mass is identified, in which case the gross appearance is indistinguishable from a pancreatic neoplasm (Fig. 39.13). The main pancreatic duct is typically narrow, and dilatation of the main pancreatic duct is uncommon. Stigmata of alcoholic pancreatitis, such as pseudocysts and calcification, are uncommon as well, although their presence does not exclude the diagnosis of AIP.

Although the principal changes in both variants of the disease are fibrosis and inflammation, the pattern of fibrosis and the type and degree of inflammation are so markedly different that they are discussed separately here.

Type 1 Autoimmune Pancreatitis

Histologically, the type 1 variant of AIP is a prototypical IgG4-related disease that is characterized by a triumvirate of histologic features: dense lymphoplasmacytic infiltrate, storiform-type fibrosis (Fig. 39.14), and obliterative phlebitis (Fig. 39.15).^{17,39,43,44,46,48,53,75–78}

Although in some areas the fibrosis is organized in a patternless pattern, a careful evaluation invariably reveals storiform-type fibrosis (Fig. 39.16). The fibroinflammatory infiltrate also extends into the peripancreatic adipose tissue and the intrapancreatic portion of the bile duct (Fig. 39.17), and careful evaluation of these lesions reveals a substantial population of spindle-shaped cells. These cells, representing either fibroblasts or myofibroblasts, are an important component of this disease and contribute in no small measure to the storiform pattern that is characteristic of this lesion.

The disease is characterized by a dense and diffuse lymphoplasmacytic infiltrate, and an absence of IgG4+ plasma cells is incompatible with a diagnosis of AIP. Eosinophils are identified in virtually every case, with occasional cases showing a marked infiltrate, sufficient to raise the possibility of “eosinophilic pancreatitis.”

Obliterative phlebitis is readily identified, but the vein may be camouflaged by the dense and diffuse inflammatory infiltrate. It is often difficult to identify totally obliterated veins, and an elastic stain may help to uncover these venous channels. However, an elastic stain is not mandatory: medium-sized venous channels are usually accompanied by arteries, which are less likely to be affected by the inflammatory process and can therefore serve as guideposts for identification of the veins. A less widely acknowledged feature of type 1 AIP is obliterative arteritis. As in obliterative phlebitis, the lumen and the wall of the vascular channel are infiltrated by lymphocytes and plasma cells. The presence of necrotizing inflammation involving either the vein or the arteries excludes the diagnosis of AIP.

The ductal epithelium is typically preserved, although occasionally intraepithelial lymphocytes are found. Notably, the ducts are not associated with neutrophils, and erosion and ulceration of the duct-lining epithelium are distinctly uncommon. Although the inflammatory cells tend to aggregate around ducts, this periductal infiltrate is seldom as prominent as in the type 2 variant of the disease.

The regional lymph nodes show a marked increase in IgG4+ plasma cells and may occasionally demonstrate fibrosis of the capsule (Fig. 39.18). Long-standing examples of AIP exhibit extensive atrophy of the exocrine component, although the endocrine component is usually preserved, at least in the initial phases of the disease.

After steroid therapy, there is a rapid depletion of the inflammatory component, leaving behind only a sparse lymphoplasmacytic infiltrate, and IgG4-bearing plasma cells typically are not identified. Such cases do not fulfil the minimum diagnostic criteria for AIP. Nonetheless, a storiform pattern of fibrosis may be recognizable and may provide the only clue to the existence of AIP in the specimen.

Type 2 Autoimmune Pancreatitis

Histologically, type 2 AIP has little in common with the type 1 variant; instead, the morphologic features overlap with other forms of chronic pancreatitis (Table 39.2).

Table 39.2

Differences between Type 1 and Type 2 Autoimmune Pancreatitis (AIP)

	Type 1 AIP	Type 2 AIP
Age	Elderly, seventh decade of life	Middle age, fifth decade of life
Sex	Predominantly male	Males and females equally affected
Presentation	Jaundice (75%), acute pancreatitis (15%)	Jaundice (~50%), acute pancreatitis (~33%)
Systemic disease	Yes	No
Elevated serum immunoglobulin G4	80%	Uncommon
Inflammatory bowel disease	No association	Present in 16-30% of cases
Histopathology	Periductal inflammation with one or more of the following features: 1. Storiform fibrosis 2. Obliterative phlebitis

Periductal inflammation with one or more of the following features:

1. Ductal/lobular abscesses

2. Ductal ulceration with neutrophils

Long-term outcome Frequent relapses No relapses

The most distinctive feature of this variant is a dense periductal collar of lymphocytes and plasma cells, accompanied by neutrophilic microabscesses within the lumen of the duct: the so-called granulocytic epithelial lesion (Fig. 39.19).^{17,39,43,44,46,48,53,78} Erosion and ulceration of the duct lining are frequently seen, occasionally accompanied by complete destruction of the duct. Another characteristic feature of this variant is the presence of neutrophils within acinar units (Fig. 39.20). Storiform-type fibrosis is typically not prominent. Although some veins may be focally involved by the lymphoplasmacytic infiltrate (i.e., phlebitis), overt obliterative phlebitis is uncommon.

Unclassified Autoimmune Pancreatitis

Not all cases of AIP fit into the aforementioned subtypes. Some cases demonstrate the histologic triumvirate of type 1 disease (i.e., dense lymphoplasmacytic inflammation, storiform-type fibrosis, and obliterative phlebitis) but in addition show more than an occasional intraductal aggregate of neutrophils. Others show typical type 2 disease but with diffuse infiltrates of IgG4+ plasma cells, more than 50/HPF. For now, it is prudent not to subcategorize such cases but instead to label them as unclassified variants of AIP, because the therapy (corticosteroids) is similar for both forms of the disease.

Immunohistochemistry

Both variants of AIP show an admixture of B and T cells, although the T cells tend to dominate. The B cells are typically organized as lymphoid aggregates. By definition, both the lymphocyte and the plasma cell populations are polyclonal.

Virtually every case of type 1 AIP shows a markedly elevated number of IgG4+ plasma cells (Fig. 39.21)^43,46,48,79 with a minimum requirement of 50 IgG4+ plasma cells per high-power field on a resection specimen and 10/HPF on a biopsy sample.^51,80 Typically, the IgG4+ plasma cells are diffusely distributed, although focal accentuations around venous channels and ducts may be appreciable.

In contrast, an elevated number of IgG4+ plasma cells is not required for a diagnosis of type 2 AIP.^43,46,48 Nonetheless, occasional pockets of IgG4-bearing plasma cells may be identified in this form of the disease (Fig. 39.22), and they also may be seen in other forms of pancreatitis.

A recent consensus document on IgG4-related disease emphasized the importance of the ratio of IgG4 to total IgG, with a ratio of greater than 40% strongly supporting the diagnosis of AIP.⁸⁰

Autoimmune Pancreatitis versus Other Forms of Chronic Pancreatitis

Histologically, type 1 AIP is unlikely to be mistaken for any other form of pancreatitis. However, the histologic features of type 2 AIP may overlap with those of chronic alcoholic pancreatitis (Table 39.3). Alcohol-related pancreatitis is typified by the presence of dense acellular fibrosis, calcification, and dilated ducts filled with inspissated proteinaceous material; these features are uncommon in the type 2 variant. Furthermore, alcoholic chronic pancreatitis shows only a mild inflammatory infiltrate, composed predominantly of lymphocytes. Nonetheless, in our experience, some pancreata from patients with alcohol abuse show a periductal lymphoplasmacytic infiltrate associated with intraepithelial neutrophils.

Other Diseases That May Mimic Autoimmune Pancreatitis

Additional diseases that should be ruled out include lymphoma, inflammatory myofibroblastic tumor, infectious diseases, and other inflammatory diseases such as granulomatosis and polyangiitis (Wegener granulomatosis).⁸⁰ The morphologic features of AIP do not overlap with these diseases. However, several of these diseases may be associated with elevated numbers of IgG4-bearing plasma cells.^82–84

Diagnostic Criteria

Histology is the gold standard for the diagnosis of AIP, but this statement applies primarily to a resection specimen. On biopsy material, a diagnosis of AIP should not be rendered in a clinical vacuum: Close collaboration among clinician, radiologist, and pathologist is vital. A recently published international consensus document on the diagnostic criteria of AIP has codified this collaborative effort.⁷⁷ A modified version of this algorithm is shown in Figure 39.24.

Diagnostic Value of an Ampullary or Bile Duct Biopsy

A random biopsy specimen from either the ampulla of Vater or the bile duct may provide diagnostically valuable information. In one study, a cutoff value of 10 IgG4+ plasma cells per HPF was used; the sensitivity and specificity were 52% and 89%, respectively, for ampullary biopsy and 52% and 96% for bile duct biopsy.⁸⁵ The results of other studies have been similar, although they have reported higher specificity and sensitivity values.^86,87

Although the presence of more than 10 IgG4-bearing plasma cells per HPF provides another tool for distinguishing AIP from pancreatic carcinoma, several caveats should be considered when interpreting these results:

Definitions and Terminology

Paraduodenal pancreatitis is a distinct form of chronic pancreatitis that involves paraduodenal pancreatic tissue—the duodenum itself—and is invariably centered on the minor papilla.⁹² A multitude of other terms have been used to describe this entity, including cystic dystrophy of heterotopic pancreas,⁹³ pancreatic hamartoma of duodenal wall,⁹⁴ periampullary or periduodenal wall cyst,⁹⁵ adenomyoma/myoadenomatosis, and⁹⁶ “groove” pancreatitis.⁹⁷ Each of these terms describes only one facet of this multifaceted disease. The designation groove pancreatitis is based on the fact that the pancreatitis is located in the groove between the common bile duct and duodenum. Paraduodenal pancreatitis has been proposed as a unifying term for this entity.⁹²

Clinical Features

This disease manifests most commonly in the fourth decade of life and predominantly affects males.^17,92,98,99 Most patients have a history of alcohol abuse and often a history of smoking. The most common clinical symptoms are abdominal pain, vomiting, and weight loss.⁹⁹ Similar to AIP, paraduodenal pancreatitis often forms a tumefactive lesion in the head of the pancreas and thus mimics pancreatic carcinoma. A subset of patients have symptoms related to upper gastrointestinal obstruction, a consequence of duodenal stenosis. The disease can also narrow the common bile duct, resulting in obstructive jaundice.

Radiologic Features

Radiologically, the disease may be limited to the duodenal wall or may extend to both the duodenum and the adjacent pancreas. On CT, a poorly enhancing, hypodense lesion is often identified in the groove between the common bile duct and the duodenum.⁹⁸ The duodenal wall is invariably thickened, and cysts are commonly found within and adjacent to the duodenal wall.^99,100 Luminal narrowing of the distal common bile duct and the main pancreatic duct may be seen. However, an abrupt pancreatic and bile duct cutoff, as seen in pancreatic carcinoma, is not a feature of paraduodenal pancreatitis. Radiologically, this disease may be mistaken for a host of neoplastic entities, including solid pancreatic neoplasms such as pancreatic and duodenal adenocarcinoma, neuroendocrine tumor, and cystic pancreatic neoplasms including intraductal papillary mucinous neoplasm.¹⁰¹

Pathogenesis

The etiology of this disease is uncertain, although data obtained from the histologic evaluation of resected specimens permits us to speculate about the etiopathogenesis of paraduodenal pancreatitis.^17,92 Any hypothesis must take into account two factors: (1) The disease is centered on the accessory pancreatic duct, and (2) there is a strong association with alcohol abuse. There is also evidence to suggest that some types of mass-forming pancreatitis are associated with pancreatic divisum. Therefore, one could speculate that a partially obstructed accessory pancreatic duct precipitates paraduodenal pancreatitis in an individual who is susceptible to alcoholic pancreatitis.

Pathologic Findings

The gross evaluation of the pancreaticoduodenectomy specimen plays a critical role in establishing a diagnosis of paraduodenal pancreatitis.^17,92 The disease is centered either in the duodenal wall or at the interface between the duodenum and the pancreas. It is also vital to document the involvement of the minor papilla. The minor papilla is identified approximately 2 cm proximal to the major papilla. The duodenal wall is thickened, and the mucosal surface appears granular (Fig. 39.25).⁹³ The lobular architecture of the paraduodenal pancreas is replaced by a gray-white fibrotic lesion (Fig. 39.26). The diseased tissue is invariably associated with cysts that contain clear fluid.⁹³ Cysts as large as 10 cm in diameter have been described. Although the lesion is often centered on the accessory pancreatic duct, it is frequently difficult to identify the duct grossly. The scarring process can narrow both the duodenum and the distal common bile duct.

Histologically, no single feature is diagnostic of this disease. However, a constellation of features, when viewed collectively, support a diagnosis of paraduodenal pancreatitis.^17,92,93,98

1. Marked fibrosis of the duodenal wall extends into the adjacent pancreas. Much of the muscularis propria is replaced by fibrosis. Multiple sections demonstrate an accessory pancreatic duct surrounded by fibrosis. Heterotopic pancreas may be identified adjacent to the accessory duct.

2. Multiple cysts are identified within the zones of fibrosis (Figs. 39.27 and 39.28). Some of these cysts are lined by ductal epithelium, although much of the epithelium is eroded. The larger cysts are lined by granulation tissue and may contain proteinaceous material.

3. The diseased tissue may also show a proliferation of myoid cells, either smooth muscle cells or myofibroblasts, particularly in the immediate vicinity of the duodenum. In fact, some examples of this entity may have been diagnosed as “leiomyoma.”

4. Most cases demonstrate a rather dramatic Brunner gland hyperplasia (Fig. 39.29).

5. The inflammatory infiltrate is generally sparse and is composed mostly of lymphocytes. Stigmata of alcoholic chronic pancreatitis may also be identified.

Differential Diagnosis

Although the radiologic features of paraduodenal pancreatitis may mimic carcinoma, histologic evaluation readily excludes ampullary or duodenal adenocarcinoma. However, a relatively small periampullary carcinoma may be associated with a paraduodenal pancreatitis–like lesion. Therefore, a thorough evaluation to exclude the possibility of a carcinoma is necessary.

Therapy

Conservative therapeutic options include alcohol abstinence and smoking cessation. However, it has been argued that surgery is the treatment of choice in symptomatic patients.¹⁰²

Clinical Features

The presenting symptoms vary from abdominal pain to obstructive jaundice.^37,103,104 Some patients show peripheral eosinophilia. A prior history of allergic symptoms is not uncommon. Imaging reveals a pancreatic mass in most cases and may demonstrate stricture of the bile duct.¹⁰⁵ Pseudocyst formation is occasionally seen.² Hypereosinophilic syndrome develops in some of these patients.^37,106

Pathologic Findings

Grossly, the pancreas may be enlarged and fibrotic. Histologically, a diffuse eosinophilic infiltrate is seen around ducts, acini, and interlobular septa.¹⁰⁷ In addition, eosinophilic phlebitis and arteritis may be seen.³⁷ Although lymphocytes and plasma cells are also present, they do not dominate the picture. In addition to this diffuse form of involvement, focal involvement of the pancreas, particularly adjacent to a pseudocyst, has been reported.³⁷ The eosinophilia can also involve the gastrointestinal tract, particularly the duodenum. Involvement of the biliary tract in the form of multiple biliary strictures has also been reported.³⁷

Differential Diagnosis

A diverse group of diseases is associated with increased numbers of eosinophils in the pancreas, including AIP, malignancy, parasitic infections, hypersensitivity reaction to drugs, inflammatory myofibroblastic tumor, and systemic mastocytosis.³⁷ As mentioned previously, the most common concern in the differential diagnosis of eosinophilic pancreatitis is AIP. Findings of elevated levels of serum IgG4, multiorgan tumefactive lesions, the presence of storiform fibrosis, and elevated numbers of IgG4+ plasma cells favor of a diagnosis of AIP. The mainline therapy for both diseases is steroids.

Etiology and Pathogenesis

Historically, suspected causative factors for tropical pancreatitis have included malnutrition and cyanogenic glycosides from consumption of cassava.¹⁰⁹ Mutations and polymorphisms in SPINK1, CFTR, and cathepsin B (CTSB) appear to increase the susceptibility to this disease.^26,110,111 It is likely that the disease involves an interplay between genetic and environmental factors, and the genes implicated are likely to be disease modifiers rather than the direct cause of tropical pancreatitis.^26,110,111

Similar to other forms of pancreatitis, tropical pancreatitis is associated with an increased risk of malignancy—a fivefold increase.¹¹²

Pathologic Features

The pathologic features depend on the duration and severity of disease. At an advanced stage, the pancreas appears shrunken. The most characteristic feature of tropical pancreatitis is the presence of large intraductal calculi in the main duct. Histologically, there appears to be little difference between tropical pancreatitis and alcoholic pancreatitis. The disease shows both intralobular and interlobular fibrosis and a sparse inflammatory infiltrate. It is distinguishable from alcoholic chronic pancreatitis by a younger patient age at presentation and by the presence of large intraductal calculi.

Clinical Features

The mean patient age at presentation is 41 years, and the disease affects both women and men without a distinct difference in sex distribution.¹²² The presenting symptoms are variable, and a significant percentage of patients are identified on cross-sectional imaging performed for symptoms unrelated to the pancreas (Fig. 39.35). However, patients may also have symptoms related to a mass lesion, such as abdominal pain and biliary obstruction. Cross-sectional imaging reveals an intrapancreatic fatty neoplasm. Approximately two thirds of the cases show diffuse involvement of the pancreas, and the remaining one third demonstrate a focal intrapancreatic fatty mass. These tumefactive lesions are typically large, and lesions as large as 24 cm have been recorded.¹²² Lipomatous pseudohypertrophy has been associated with Shwartzman-Diamond syndrome, Bannayan syndrome, Johnson-Blizzard syndrome, and juvenile variant of Parkinson disease.

Pathogenesis

Little is known about the pathogenesis of this lesion. One plausible hypothesis is that it represents an extremely infiltrative lipoma, although some authors have argued persuasively against this possibility.¹²² Before a diagnosis of lipomatous pseudohypertrophy is considered, a well-differentiated liposarcoma should be excluded. Well-differentiated liposarcomas are located mainly in the retroperitoneal region and typically do not manifest as a primary pancreatic mass. Microscopically, large, atypical stromal cells are seen within fibrous septa. Nonetheless, on a FNA or core biopsy specimen, it may not be possible to unequivocally distinguish lipomatous pseudohypertrophy from a lipoma-like well-differentiated liposarcoma. Immunohistochemistry for MDM2 is extremely helpful in such cases; in well-differentiated liposarcomas the atypical stromal cells show nuclear reactivity for MDM2.

Pathologic Features

In cases with diffuse involvement, a massive increase in adipose tissue is identified throughout the pancreas. In individuals with focal involvement, a sharp demarcation between the fatty deposition and adjacent pancreas is present. The lesion may compress the common bile duct.

The tumefactive lesion is composed almost entirely of mature adipose tissue, within which scattered pancreatic elements are identified (Fig. 39.36). Apart from the “dilution” of the pancreatic parenchyma by adipose tissue, the pancreas itself is histologically unremarkable and significantly does not show evidence of either acute or chronic pancreatitis.

Therapy

Asymptomatic cases may be managed conservatively, without resection, provided a secure diagnosis can be established. Resection is required in symptomatic patients.

Pathologic Features

Grossly, these lesions vary from homogenous white, solid nodules to solid and cystic lesions (Fig. 39.37).^{125,128,129,129a} The lesion is composed of mature pancreatic tissue (predominantly mature ducts and acini), albeit disorganized, thus fulfilling the definition of a hamartoma. The ductal structures may show significant dilatation and cystification (Fig. 39.38). Neither acinar nor ductal elements show atypia. While scattered endocrine cells are detected, well-formed islets are absent. A paucity of nerve twigs has also been observed.

Before arriving at a diagnosis of pancreatic hamartoma, other forms of pancreatitis, including AIP, should be excluded. Similar to chronic pancreatitis, pancreatic hamartomas are associated with increased amount of pancreatic stroma. The mesenchymal cells within this stroma are positive for CD34 and CD117, the latter reactivity is generally weak.^127,129a

Clinical Features

This is a disease of adults. The mean patient age in one series was 63 years, with males and females affected equally.¹³⁰ Patients typically have symptoms related to obstruction of the pancreaticobiliary tract, such as jaundice and abdominal pain. On endoscopy, an enlarged ampulla is identified; endosonographically, an ampullary lesion is typically present.

Pathologic Features

On macroscopic evaluation, a firm, nodular lesion is identified in the terminal portion of the bile duct and ampulla. The mucosa overlying the lesion is normal and lacks ulceration. Histologically, this lesion is characterized by lobules of small glands that often surround a larger duct (Fig. 39.39).¹³⁰ The lobular pattern of organization helps distinguish this lesion from an invasive pancreaticobiliary carcinoma. The lobules are, in turn, surrounded by a robust mesenchymal proliferation composed of fibroblasts, myofibroblasts, and scattered smooth muscle cells. Heterotopic pancreatic tissue may be identified adjacent to the lesion.

Clinical Features

Pseudocysts are a consequence of pancreatitis or trauma.^16,18,132 The most common underlying trigger for pseudocysts is alcoholic pancreatitis, and pseudocysts are more common in young to middle-aged men than in women. Nonetheless, almost any form of acute or chronic pancreatitis can trigger the development of a pseudocyst.

Diagnosis of Pseudocyst

Endoscopic ultrasonography plays a major role in both diagnosis and treatment of pseudocysts. Imaging demonstrates a unilocular cyst filled with debris but without a mural nodule. Analysis of the cyst fluid demonstrates an elevated amylase level (by definition >250 IU/mL) and a low level of carcinoembryonic antigen (typically <200 IU/mL). The cytology specimen is typically hypocellular and usually shows a few inflammatory cells only.¹³³ In addition, a large amount of acellular debris associated with blood pigment and hemosiderin is frequently seen.

Pathologic Features

Pseudocysts are for the most part unilocular and contain turbid, sometimes blood-tinged fluid. These cysts can measure greater than 20 cm in size. The wall of the pseudocyst is typically thick and fibrotic (Fig. 39.40). By definition, the cyst lacks a lining epithelium.^16–18,132 However, intrapancreatic pseudocysts frequently show large-caliber pancreatic ducts at the interface between the cyst and adjacent pancreas (Fig. 39.41). The epithelium lining the duct should not be misconstrued for cells lining the cyst. Instead, pseudocysts are lined by granulation tissue and fibrosis. If adjacent pancreatic tissue is present, stigmata of resolving acute pancreatitis or evidence of chronic pancreatitis may be seen.

Differential Diagnosis

When considering the diagnosis of a pseudocyst, it is prudent to histologically examine the entire cyst wall to rule out a cystic neoplasm. Cystic pancreatic neoplasms in which significant denudation of the lining epithelium may be seen include serous cystadenoma, mucinous cystic neoplasm, and, very occasionally, intraductal papillary mucinous neoplasms. Mucinous cystadenomas with total denudation of the lining epithelium will nonetheless show ovarian-type stroma, a feature not seen in a pseudocyst. Serous cystadenomas, particularly the unilocular variant, may exhibit complete loss of lining epithelium. However, this cystic neoplasm shows a unique subepithelial network of delicate capillary channels. Virtually all cases of pseudocysts are associated with a prior episode of acute pancreatitis, and in the absence of such a history, a diagnosis of a pseudocyst should be made with extreme caution.

Therapy

A significant percentage of pseudocysts resolve spontaneously; others progressively increase in size. The available treatment options include medical management, surgical treatment, and percutaneous or endoscopic drainage. The vast majority of pseudocysts are now treated endoscopically.

Clinical Features

The mean patient age at diagnosis is 55 years, and this pancreatic cyst is more common in men than women (male-to-female ratio, 4 : 1). In one series, these lesions constituted 0.5% of all resected pancreatic cysts.¹³⁴ In most contemporary series, the patients have been asymptomatic and the lesions have been detected on cross-sectional imaging. Larger cysts may manifest with abdominal pain.

Pathogenesis

A number of hypotheses have been proposed to rationalize the presence of both lymphoid and epithelial tissue, including (1) origin from epithelial remnants in a lymph node, (2) cystic transformation and squamous metaplasia of pancreatic ducts, and (3) derivation from a branchial cleft cyst that is misplaced and fused with the pancreas during embryogenesis.¹³⁴

Pathologic Features

The cysts vary from unilocular to multilocular lesions and are reported to arise anywhere within the pancreas. The largest cyst in one study was 17 cm.¹³⁴ The cysts are typically filled with cheesy-brown contents (Fig. 39.42), although serous-like fluid may also be identified. A dominant mural nodule is not present.

Microscopically, the cyst is lined by squamous epithelium and shows a dense subepithelial rind of reactive lymphoid tissue (Fig. 39.43). The squamous epithelium typically shows prominent keratinization, and keratinaceous debris is present within the contents of the cyst. Columnar mucinous cells may be detected, albeit uncommonly. Occasionally, sebaceous differentiation may be present. The lymphoid tissue typically shows numerous reactive germinal centers.

Differential Diagnosis

Entities that should be considered in the differential diagnosis of a lymphoepithelial cyst include dermoid cyst, epidermoid cyst within intrapancreatic accessory spleen, and squamoid cyst of the pancreas. A diagnosis of dermoid cyst should not be solely based on the presence of sebaceous tissue; instead, this diagnosis requires the presence of elements such as cartilage and hair follicles. Squamoid cysts of the pancreas lack keratinization and, more crucially, lack lymphoid tissue. Lymphangioma, another lesion associated with prominent lymphoid tissues, demonstrates ectatic spaces lined by endothelial-type cells.

Therapy

An FNA biopsy will reveal innumerable anucleated squamous cells, an appearance that is consistent with a lymphoepithelial cyst, allowing a conservative approach.¹²¹ Symptomatic lymphoepithelial cysts require resection.

Pathologic Features

Grossly, these unilocular cysts are well demarcated and are surrounded by a thin fibrotic wall; like most other benign cysts of the pancreas, they are devoid of solid areas. The cysts are reported to contain clear fluid, although white flaky material may also be identified.¹³⁶

Histologically, these cysts are characterized by the presence of squamous epithelium that can vary from an attenuated layer to a well-developed layer of stratified squamous epithelium (Fig. 39.44). Multilayered epithelium with a transitional appearance is frequently seen, but keratinization is uncommon. The lining epithelium lacks cytologic atypia. By definition, the lesion lacks mucinous or acinar epithelium. By immunohistochemistry, the squamous epithelium is positive for TP63 and cytokeratin 5/6.

Differential Diagnosis

Squamoid cysts are easily distinguished from lymphoepithelial cysts by the absence of lymphoid tissue. Additionally, lymphoepithelial cysts invariably show keratinization and a prominent granular layer, features not seen in squamoid cysts of the pancreas. Squamous metaplasia, such as acinar cell cystadenoma, may occasionally be identified in neoplastic cysts of the pancreas.¹³⁷ However, acinar cell differentiation, a characteristic feature of acinar cell cystadenoma, is absent in a squamoid cyst of the pancreas.

Microscopic incidental cysts lined by squamous epithelium are not uncommon in the pancreas; one study identified such cysts in 10 of 110 pancreatectomy specimens.¹³⁶ Such incidental cysts should not be designated as squamoid cysts. In contrast to squamoid cysts of the pancreas, cystic squamous cell carcinomas always show high-grade cytologic atypia.

Clinical Features

This lesion is seen in young individuals (mean age, 41 years) and shows a distinct female predominance (male-to-female ratio, 1 : 3).^137–140 They are distributed throughout the pancreas. A substantial proportion of patients are asymptomatic, but some have abdominal pain. Although only a handful of cases have been reported, the available evidence suggests that these are benign lesions without malignant potential.

Etiopathogenesis

There is continuing debate as to whether this lesion represents a neoplastic entity.^137,140 The use of the term acinar cystic transformation of the pancreas suggests that this may represent a non-neoplastic dilatation of the acinar and ductal elements of the pancreas.¹³⁹ Notably, microscopic cysts lined by acinar cells are often incidentally detected in pancreatic resections. However, the presence of solid nodules composed of acinar cells and the presence of chromosomal aberrations on microarray-based comparative genomic hybridization suggests that at least a subset of these cysts are neoplastic.¹³⁷

Pathologic Findings

Either a single unilocular cyst is identified or multiple cysts are seen (Fig. 39.45), sometimes involving the majority of the pancreas. The cyst wall is typically thin and translucent; the cysts are filled with clear fluid and are lined by a single layer of cuboidal epithelium.^137–140 In part, the lining epithelium is nondescript, with basally placed nuclei and pale apical cytoplasm, often resembling normal ductal cells. The diagnosis relies on identification of acinar cell differentiation,^134–140 which can be revealed on a hematoxylin and eosin (H&E) stain by the presence of apical acinar granules and architectural evidence of acinar differentiation, either abortive or overt (Fig. 39.46). In a minority of cases, the proliferating acinar cells form intramural nodules. When overt acinar differentiation is identified, the lesional epithelium is readily distinguished from normal acinar cells by the presence of an irregular anastomosing pattern and the lack of intervening ductal structures or islets. Some cases also show intracystic, clublike, pseudopapillary structures with a fibrous stalk. The lining epithelium may be mucinous or squamous, albeit only focally. Within the lumen, eosinophilic lamellar concretions are frequently present.

Immunohistochemistry is usually required to confirm acinar cell differentiation. Staining for trypsin and chymotrypsin ranges from focal to diffuse and is identified in the apical compartment of the cell.