Inflammatory and Other Nonneoplastic Disorders of the Pancreas

Clinical Features

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. The diagnosis of acute pancreatitis requires at least two of the following three features: (1) abdominal pain, (2) serum lipase and/or amylase levels at least three times that of normal, and (3) evidence of acute pancreatitis on imaging. ^,

Etiology and Pathogenesis

The two most common triggers of acute pancreatitis, obstruction of the common bile duct by stones and alcohol abuse, together account for approximately 80% of cases of acute pancreatitis in Western countries ( Box 40.1 ). ^, 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, direct toxic injury to acinar cells, and contraction of the sphincter of Oddi. However, the relationship between alcohol and acute pancreatitis is not completely understood because acute pancreatitis develops in only a small fraction of patients who abuse alcohol. Clearly, other genetic and environmental factors play a major role in the development of alcohol-related acute pancreatitis.

Drugs appear to account for about 5% of all cases of acute pancreatitis. The drugs most often associated with this disorder include azathioprine, 6-mercaptopurine, valproic acid, angiotensin-converting enzyme inhibitors, and mesalamine.

In a substantial minority of cases, the cause of acute pancreatitis is unexplained. Genetic testing for mutations, including the cationic trypsinogen (PRSS1), serine protease inhibitor Kazal type I (SPINK1), or cystic fibrosis transmembrane conductance regulator (CFTR) gene, may provide an explanation for recurrent acute pancreatitis because these may provide cofactors that precipitate 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, and this enzyme 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.

Pathological 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. 40.1 ). 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, confluent areas of necrosis and hemorrhage are identified.

Histologically, the changes of acute pancreatitis are best 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. 40.2 ). In the more severe examples of acute pancreatitis, there is diffuse necrosis involving the acinar and ductal tissue accompanied by acute inflammatory cells. Infected acute pancreatitis is 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.

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.

Pathogenesis

Etiological factors include toxic metabolic injuries such as those caused by alcohol abuse, tobacco smoking, hypercalcemia, hyperlipidemia, medications, and other toxins. The most common cause of chronic pancreatitis in developed nations is alcohol ingestion, which accounts for approximately 70% to 95% of cases ( Box 40.2 ).

The pathogenesis of chronic pancreatitis is not well defined, although five mechanisms have been implicated in the development the disease : (1) the necrosis-fibrosis sequence argues that chronic pancreatitis develops through multiple episodes of acute pancreatitis, (2) the sentinel acute pancreatitis event that advocates the chronic pancreatitis is triggered by a single attack of acute pancreatitis, (3) the direct toxic metabolic effect is caused by environmental factors, most typically alcohol and tobacco, (4) free radicals contribute to oxidative stress and the expression of transcription factors and release of cytokines, and (5) ductal dysfunction occurs, leading to protein plugs and ductal obstruction. Pancreatic stellate cells are activated and play a critical role in the development of fibrosis.

Pathological 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. 40.3 ). 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 occasional fibroblasts and myofibroblasts are 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. 40.4 and 40.5 ).

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. The inflammatory infiltrate often surrounds peripheral nerve twigs. Plasma cells are usually inconspicuous. In contrast with 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. Attention to the following four features is key to making the distinction of benign ducts from ductal neoplasia ( Table 40.1 ).

TABLE 40.1

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	Frequently dense, eosinophilic	Frequently 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 are concerning for a malignant process ( Fig. 40.6 ). Glands located within lobules, regardless of the degree of atypia, should suggest a “benign” interpretation ( Fig. 40.7 ). Other than an occasional large-caliber duct, ducts within the interlobular septa should be viewed with suspicion. 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. An additional caveat of significance is that pancreatic islets may be identified adjacent to islets. Vascular invasion is also diagnostic for carcinoma. Of note, veins may be inconspicuous on hematoxylin and eosin stain. An elastic stain greatly increases the sensitivity and specificity for detecting venous invasion.

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 latter within a glandular unit. 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 41 .

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

This is an uncommon cause of chronic pancreatitis, accounting for fewer than 2% of all cases. Hereditary pancreatitis is an autosomal dominant disease that typically manifests with recurrent attacks of acute pancreatitis in childhood, typically in the first and second decades of life. A diagnosis of hereditary pancreatitis should be suspected in any individual in whom chronic pancreatitis develops at an early age (<25 years). The disease affects men and women equally.

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. The estimated cumulative risk of pancreatic cancer to 70 years of age in patients with hereditary pancreatitis approaches 40%. The type of genetic mutation does not correlate with the risk of cancer.

Pathological Features

The disease is characterized by fatty replacement of the pancreas. Fibrosis, typically mild, is significantly less than that seen in alcohol-related chronic pancreatitis. Periductal inflammation may be observed. In older patients, PanIN is often seen.

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, it is important to emphasize the fact that this disease is significantly less common than pancreatic carcinoma.

Both the gender ratio and the mean age at presentation vary according to the histological 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 relatively uncommon in Asia but constitutes almost one-half of all patients of AIP in series from Europe and North America. ^{, ,}

Obstructive jaundice and weight loss are characteristic features of type 1 AIP. ^{, , , , ,} These symptoms, along with a mass on imaging, make the clinical distinction of this disease from pancreatic ductal adenocarcinoma extremely problematic. Other nonneoplastic pancreatic lesions that mimic pancreatic cancer are listed in Box 40.3 . Other presenting symptoms of patients with type 1 AIP include fatigue and recent onset of diabetes mellitus. 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, and the involvement of these organs represents one of the most valuable clues to the diagnosis of this inflammatory pancreatic disease. ^{, , , , ,} One of the more common extra-pancreatic manifestations of type 1 AIP is a painless unilateral and, more often, 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). Other sites commonly involved by IgG4-related disease include the biliary system, lung, kidney, and retroperitoneum.

Patients with type 2 AIP often present with abdominal pain, although the pain is rarely severe enough to suggest acute pancreatitis. ^{, , , , ,} In comparison with type 1 disease, a smaller proportion of patients with type 2 AIP have obstructive jaundice at presentation. The disease is confined to the pancreas, and extrapancreatic involvement is type 2 AIP.

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.

Serum Markers

Radiology

During the past decade, radiologists have greatly improved their ability to identify AIP and distinguish it from pancreatic carcinoma.

On imaging, three patterns of AIP are recognized: diffuse, focal, and multifocal. The diffuse form of the disease ( Fig. 40.10 ) 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. ^, A small, hypodense rim is often identified around the lesion—the so-called halo sign. On MRI, the pancreas is diffusely hypointense on T1-weighted images and slightly hyperintense on T2-weighted images. The main pancreatic duct is usually narrow, and upstream dilation of the pancreatic duct should raise concern for 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. 40.11 ). 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 dilation, (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 diagnostic criteria are highly dependent on pancreatography, those published from the United States do not require imaging of the pancreatic duct.

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, a finding that helps reaffirm the diagnosis of AIP. In the late phase of this disease, the pancreas appears shrunken and atrophic.

Etiology

The exposure of genetically susceptible individuals to environmental or intrinsic risk factors triggering a stereotypical orchestral immune reaction represents a likely pathogenetic mechanism for type 1 AIP. It is notable that unlike classic autoimmune diseases, type 1 AIP affects elderly men.