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. 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.

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).

Etiology and Pathogenesis

The two most common triggers of acute pancreatitis are obstruction of the common bile duct by stones and alcohol abuse. 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). 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 ). 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.

Acute pancreatitis. This cross section of the pancreas shows yellow specks in the fat, consistent with fat necrosis.

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. 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.

Acute pancreatitis. The upper half of the image shows areas of fat necrosis with specks of calcification. The lower half shows a brisk histiocytic response.

Therapy

The treatment for mild forms of the disease is largely supportive and includes fluid resuscitation. 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. 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.

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. 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. 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 ). 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 ).

Alcoholic chronic pancreatitis. Dense interlobular fibrosis with preserved zones of acinar cells between the septa are seen. In comparison to autoimmune pancreatitis, the stroma is relatively acellular and lacks an inflammatory infiltrate.

Alcoholic chronic pancreatitis. The dilated duct is filled with inspissated proteinaceous material. Also notice the presence of interlobular and intralobular fibrosis.

Alcoholic chronic pancreatitis. An impacted stone is present in a markedly dilated duct.

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. 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. 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.

Chronic pancreatitis. The presence of ductal structures in a lobular configuration virtually rules out the diagnosis of pancreatic adenocarcinoma.

Chronic pancreatitis with cytologic atypia. In isolation, the anisonucleosis and nuclear atypia raise the possibility of a pancreatic adenocarcinoma. However, this duct is located within a lobule (shown in Fig. 39.6 ), supporting a benign interpretation.

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 .

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).

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). 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. The type of genetic mutation did not correlate with the risk of cancer.

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. The dilated ducts show both protein plugs and calculi, although some cases are associated with a periductal collar of inflammation ( Fig. 39.9 ).

Chronic pancreatitis. This pancreas was resected from a 25-year-old man with a cationic trypsinogen mutation. Note the periductal inflammation.

Definition and Historical Aspects

AIP is a mass-forming inflammatory lesion of the pancreas that may mimic pancreatic carcinoma. 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.

AIP was first described by Sarles and colleagues in the 1960s. They described four cases of chronic pancreatitis in patients with steatorrhea and obstructive jaundice. 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. They described two men with obstructive jaundice and histologic features that are now considered typical for AIP. The term autoimmune pancreatitis was coined by Yoshida and colleagues in a case report in 1995 and this term is now the preferred designation.

A major milestone in understanding of this disease came with the apparently serendipitous discovery of its association with elevated levels of serum IgG4. Shortly afterward, it was established that the inflamed pancreas shows a substantial increase in IgG4+ plasma cells. 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. This multifocal systemic fibroinflammatory disease is now termed IgG4-related disease . 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 .

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. 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).

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. 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). 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.

Obstructive jaundice and weight loss develop in patients with type 1 AIP. 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. 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).

Patients with type 2 AIP have abdominal pain, although the pain is rarely severe enough to suggest acute pancreatitis. 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.

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. 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.

Computed tomographic image from a patient with autoimmune pancreatitis. Note the enlarged, “sausage-shaped” pancreas ( arrow ), and the presence of a “halo,” also known as “saran wrap sign,” around the pancreas ( arrowhead ).

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. 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. The presence of all four features is highly specific but only moderately sensitive for AIP. 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.

A pancreatogram from a patient with autoimmune pancreatitis. The pancreatic duct ( arrow ) is narrow and irregular.

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. 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. 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.

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.

This example of autoimmune pancreatitis does not show a discrete mass, but marked fibrosis is present. The pancreatic duct shows a stricture ( arrow ) with mild dilatation distal to the stricture.

Autoimmune pancreatitis. Gross image of a distal pancreatectomy specimen shows a discrete mass in the distal end of the pancreas. The preoperative diagnosis was a neuroendocrine tumor.

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 ).

Type 1 autoimmune pancreatitis shows storiform type of fibrosis.

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