Acute and Chronic Alcoholic Pancreatitis, Including Paraduodenal Pancreatitis Open Access

Acute pancreatitis has a variable, but generally increasing, incidence rate in Western countries, ranging from 20 to 45 per 100 000 population per year.^3,4  Chronic pancreatitis affects 3 to 13 per 100 000 population and is mainly observed in industrialized countries.^5,6  Both sexes are almost equally affected. In men, acute pancreatitis usually occurs earlier than in women, because alcohol-related pancreatitis is more common in young men, while pancreatitis associated with biliary tract disease predominates in older women. Chronic pancreatitis, including chronic alcoholic pancreatitis, presents in middle-aged and elderly patients. Younger patients (<35 years) tend to have an inherited genetic etiology.^7,8 

The most important etiologic factors in acute pancreatitis are alcohol overconsumption and biliary tract disease. They are equally common and account for 35% to 40% each.⁴  About 10% of patients have a rare etiology such as shock, drugs, interventional procedures, hypercalcemia, and infections, while another 10% to 20% present with idiopathic acute pancreatitis. In chronic pancreatitis, approximately 50% to 60% of cases are associated with overconsumption of alcohol and/or cigarettes.⁹  The remaining cases develop in association with genetic alterations,¹⁰  immunoglobulin G4 (IgG4)–related disease (autoimmune pancreatitis), metabolic disturbances, and duct obstruction²  (Table 1).

Acute alcoholic pancreatitis results from an autodigestive process that initially involves the intrapancreatic and extrapancreatic fatty tissue and subsequently the acinar cells and ducts. The extent of autodigestive necrosis of the intrapancreatic and extrapancreatic tissue determines the severity and the course of acute pancreatitis and its classification into mild/interstitial or moderately severe and severe/necrotizing pancreatitis.

The revised Atlanta Classification that only considers clinical and radiologic features of acute pancreatitis classifies the severity as mild, moderate, and severe.¹¹  Most patients with acute pancreatitis (approximately 80%–90%) develop a mild form that usually lasts no longer than a week. A minority of patients (about 10%) have a moderately severe or severe form with a prolonged and unpredictable course. The factors that determine the severity of the disease are still not known.

Patients have abdominal pain, occasionally associated with nausea and vomiting, and elevated serum levels of amylase and lipase, but no serious complications such as pseudocyst formation, sepsis, or circulatory failure. The mild form is commonly associated with gallstone disease or alcohol overconsumption.¹¹  The other risk factors are much rarer and include drugs (such as azathioprine or cimetidine),¹²  hypertriglyceridemia, hypercalcemia, or endoscopic retrograde cholangiopancreatography (ERCP).¹³  Infectious pancreatitis, which is often caused by viruses such as coxsackie B and mumps, is mostly associated with a mild form of acute pancreatitis that is histologically characterized by scattered acinar cell necrosis instead of the fat necrosis typical for alcoholic pancreatitis.¹⁴ 

These forms are usually linked to alcohol overconsumption. The moderate form is defined by the presence of transient organ failure and local complications such as pseudocyst, which can significantly prolong hospitalization. The severe form leads to life-threatening systemic and local complications, such as circulatory failure and sepsis due to abscess formation in peripancreatic necrotic areas. Severe acute pancreatitis therefore still has a high mortality rate.¹⁵ 

There is commonly an edematous swelling of the pancreas, but the pancreas may also be normal in size. In addition, the pancreatic tissue displays tiny white disseminated spots of fat necrosis on its surface and in the parenchyma,¹⁴  which are barely detectable by imaging because of their small size of mostly less than 10 mm (Figure 1, A and B). Since this form of pancreatitis has a mild nonlethal course, the study of the histologic changes is nowadays largely limited to rare resected pancreatic tissue specimens in which an interstitial pancreatitis has developed, often in association with preoperative investigations such as ERCP. The tiny foci of fat necrosis and the edema resolve after about 1 week and leave no change behind. The morphologic lesion that appears to be associated with moderately severe acute pancreatitis is a large liquefied peripancreatic fat necrosis, radiologically described as “acute peripancreatic fluid collection.” If such a lesion is delineated by granulation tissue (see also below), it becomes a pseudocyst.

There is extensive fatty tissue necrosis and/or hemorrhagic necrosis involving both the pancreatic parenchyma and the extrapancreatic fatty tissue (Figure 1, C) from where necrosis can extend into the retroperitoneal space.¹⁴  The extent of the parenchymal necrosis is usually less than that of the peripancreatic necrosis. The most extensive fat necrosis can be found in obese subjects. Fat necrosis that involves blood vessels, especially veins, and causes vessel wall rupture appears as hemorrhagic necrosis (Figure 1, D). Arteries, because of their thick walls, are more resistant to necrosis, but if they are affected, they can develop thrombosis, resulting in lobular ischemic necrosis. Another important complication of expanding necrosis is the destruction of interlobular ducts, with subsequent leakage of enzymes into the necrotic areas. Surprisingly, acinar cells adjacent to fat necrosis remain preserved for quite a long time. The only change may be a widening of acinar lumina. The islets are not affected, if they are in preserved lobules. In the course of the disease, the fat cells liquefy, and the necrotic tissues are delimited by a collar of foamy macrophages intermingled with granulocytes. Later, the inflammatory cells are replaced by granulation tissue with myofibroblasts to build up a wall separating the necrosis from intact tissue. Follow-up studies by imaging have shown that small necrotic areas not exceeding 20 to 50 mm in diameter will be reabsorbed in about 4 weeks by macrophages. Extensive necrotic areas (usually >50 mm), radiologically called acute necrotic collections,¹⁶  especially if they involve not only peripancreatic fatty tissue but also pancreatic parenchyma, are usually not spontaneously resolved. After 10 to 20 days of disease onset, the liquefied and hemorrhagic content is demarcated by a layer of granulation tissue containing still some foamy macrophages but also macrophages containing hemosiderin as a sign of phagocytosis of hemorrhagic debris. After 20 to 30 days, there is an increasing number of myofibroblasts producing a ring of extracellular matrix with collagen type 1 and 3. If this demarcation is fully developed, the change is radiologically called walled-off necrosis and represents an “early” pseudocyst.¹⁶  In addition to hemorrhagic debris, the pseudocysts contain enzymes such as amylase, suggesting a communication with the pancreatic duct system. This is especially true for pseudocysts which, in time, increase in size. Most of the pseudocysts are found outside the pancreas, particularly around the head of the pancreas.¹⁷  Through their expansion, they compress or erode structures such as the bile duct, duodenum, stomach, vessels, or peritoneum and cause complications such as bile leakage or sudden hemorrhage. Another severe complication is the infection of the necrotic areas with (mostly gut-derived) bacteria. This usually takes place during the period (days 4–20) when the liquefied necrotic tissue is still only demarcated by a small rim of granulation tissue.

After repeated attacks of necrotizing pancreatitis, the pancreatic tissue shows a juxtaposition of areas of established but still cellular interlobular fibrosis and foci of necrosis in resolution, showing the first deposit of collagen at their edge.^18,19  These changes flow smoothly into the spectrum of findings seen in early chronic pancreatitis (see below) and take place in the clinically ill-defined period when relapsing acute pancreatitis evolves into chronic pancreatitis.²⁰ 

The pathophysiologic mechanisms that lead to sudden alcohol-related autodigestive fat necrosis in the human pancreas are still unidentified or hypothetical. Based on findings in experimental pancreatitis, it has been suggested that disruption of intra-acinar compartmentalization leads to intracellular enzyme activation by lysosomal hydrolases with subsequent lytic destruction of the acinar cell.^10,21–23  However, acinar cell necrosis has not yet been convincingly proven as the initial histologic lesion in human acute alcoholic pancreatitis.²⁴  It must therefore be assumed that alcohol overconsumption leads to functional rather than structural acinar cell changes. The most striking functional change of the acinar cell is the sudden and uncontrolled release of digestive enzymes from the acinar cells into the adjacent interstitial tissue.²⁴  Because most of the enzymes are still inactive when released except lipase, it is this enzyme that could directly cause fat cell necrosis followed by the release of fatty acids.^25–27  Fatty acids, however, can activate trypsinogen and other proenzymes, which then help to destroy more tissues and trigger the inflammatory response.

Chronic alcoholic pancreatitis is characterized by necroinflammatory and fibroinflammatory changes to the pancreatic parenchyma, which are caused by relapsing autodigestive tissue destruction, followed by irreversible fibrosis.

There are several classifications of chronic pancreatitis, all of which try to map its clinical course but have little relation to etiology and morphology (for further discussion see Whitcomb et al²⁸). In this review, we classified chronic pancreatitis by morphology and etiology.² 

Patients with chronic alcoholic pancreatitis have a history of excessive alcohol intake. They often also smoke.^7,8  These patients typically have repeated episodes of acute pancreatitis with abdominal pain, nausea, malaise, and elevated serum levels of amylase and lipase. The age of onset depends upon the severity of alcohol overconsumption, but symptoms of chronic pancreatitis are often present by the age of 40 years. These signs and symptoms include significant pain, fatty stools, weight loss, and ultimately cachexia. Intermittent pain correlates best with necrosis and is common in early chronic pancreatitis, while persistent pain occurs primarily in end-stage chronic pancreatitis and could be associated with the pressure in the duct system, since endoscopic removal of calculi often results in pain relief.²⁹  Fatty stools and weight loss, which develop gradually, are the result of decreasing enzyme production due to loss of acinar tissue that usually becomes manifest when more than 80% of the acinar cell population is destroyed. The islets of Langerhans are preserved relative to the acinar cells, but diabetes mellitus (type 3c diabetes) frequently (up to 80% of patients) develops with increasing fibrosis as a late complication of chronic pancreatitis, predominantly due to inadequate insulin secretion.³⁰  Biliary obstruction is uncommon but may occur. Chronic pancreatitis, especially the hereditary form, is associated with an increased risk for the development of pancreatic ductal adenocarcinoma.³¹ 

The pathologic changes that characterize chronic alcoholic pancreatitis are the result of recurrent episodes of necrotizing, inflammatory, and finally fibrosing processes.²  This implies that early and late morphologic changes can be distinguished that differ in their spectrum depending on the frequency and severity of recurrent acute pancreatitis. Chronic pancreatitis has therefore been histologically staged.¹⁹  The first 2 stages record the onset of chronic pancreatitis in which acute and chronic changes coexist such as resorption of necrosis and fibrogenesis. The 2 late stages record advanced chronic pancreatitis dominated by fibrotic and calcifying changes (Table 2). Although the stages reflect well the general course of chronic pancreatitis, it must be pointed out that chronic alcoholic pancreatitis is very much an individual disease, with rapid progress and development of a diffuse type of fibrosis at one end of the spectrum and a delayed and relapsing course, with development of patchy fibrosis, at the other end.

Early in the course of chronic alcoholic pancreatitis, the changes of the pancreas are focal or multifocal and flank areas with normal lobular architecture. Involved areas present as ill-defined, occasionally enlarged lesions, with barely recognizable lobular structure. The ducts within these areas may have irregular lumina and occasionally already contain small calculi. Adjacent to these areas are often peripancreatic (rarely intrapancreatic) pseudocysts filled with necrotic and hemorrhagic debris rich in pancreatic enzymes (Figure 2, A and B).¹⁹ 

Histologically, changes of acute pancreatitis alternate with those of chronic pancreatitis. There are often necroses in resorption, which are lined by macrophages and nearby myofibroblasts (also called activated pancreatic stellate cells) and are accompanied by interlobular (perilobular) cellular fibrosis. Intralobular fibrosis is lacking, and lymphocytes and plasma cells are few (Figure 3, A and B).¹⁹  The interlobular fibrosis encases the interlobular ducts and nerves but only occasionally leads to duct distortion and plug/calculus formation. The degree of acinar cell loss with transformation of acini into small ductules (also called acinar to ductal metaplasia) is still minimal. At the periphery of the pancreas, interlobular fibrosis often blends with the wall of a pseudocyst typically composed of a rim of granulation tissue containing iron-positive macrophages. As a sign of earlier severe necrotic episodes, focal scars can be found next to the changes described above.

Late in the course of chronic alcoholic pancreatitis there is diffuse and extensive replacement of the lobulated acinar parenchyma by fibrosis. This fibrosis also involves the main duct, leading to distortion, irregular dilatation, and protein plug and calculus formation as a sign of stagnation of secretion (Figure 3, C). In the end, there are variously sized white calculi impacted in the distorted main duct and its branches, and a fibrotic and atrophic pancreas. Pseudocysts are less common than in the early stage, and if present, are thick walled. Rare are persistent stenosis of the bile duct (10% of cases) and duodenal stenosis (3% of cases).

Histologically, the acinar tissue is almost completely replaced by dense fibrosis, which contains only scattered groups of lymphocytes; a few, mostly large ducts with eosinophilic plugs and calculi; irregularly distributed islets; thick nerves; and thick-walled vessels (Figure 3, D). The calculi (which consist of calcium carbonate) are usually impacted and erode the duct epithelium. Adjacent to the duct erosions are small infiltrates of macrophages and myofibroblasts and regenerating duct epithelium, sometimes with substantial reactive nuclear atypia. Low-grade pancreatic intraepithelial neoplasia (PanIN) can occur but is not common, and high-grade PanIN is very rare.³²  Also uncommon is squamous metaplasia of the nonkeratinizing type. If the squamous metaplasia is keratinized, it is associated with duct stenting or large calculi. The islets typically aggregate and form clusters that may mimic infiltrating, small neuroendocrine tumors. Other islets are closely engaged with small ducts forming ductuloinsular complexes. They may also abut nerves encased in the fibrotic tissue, which mimic a perineural islet cell invasion. The total number of islets seems to be reduced, and the proportion of glucagon cells in the islets is increased.³³ 

In all westernized countries, alcohol is the most common cause of chronic pancreatitis. In addition, smoking is an independent etiologic factor.³⁴  The reason that only 10% of persons who overconsume alcohol develop chronic pancreatitis is unclear. Presumably there is an additional factor (such as an SPINK1, a CLDN2, and a PRSS1-PRSS2 gene variant) in the development of alcoholic chronic pancreatitis, which makes certain patients more susceptible to the disease than others.^35–37  Mutations of the cystic fibrosis transmembrane regulator gene (CFTR) have been implicated in the pathogenesis of chronic pancreatitis, and it has been suggested that the functional consequences of these mutations (ie, impaired flow of secretion) could predispose their bearer to the development of chronic pancreatitis.^36,37  Whether a person who overconsumes alcohol, with no clinical signs of chronic pancreatitis, will eventually develop a diffuse form of fibrosis of the pancreas,³⁸  distinct from what can be seen in elderly patients without any known risk factors for chronic pancreatitis,³⁹  has yet to be established.

The interlobular fibrosis pattern, the patchy distribution of fibrotic foci, and the late occurrence of calculi and intralobular fibrosis are best explained by the necrosis-fibrosis sequence concept, which was confirmed by clinicopathologic studies^18,40,41  (Figure 2, B). This concept is based on morphologic observations, starting with the work by Comfort et al⁴²  in 1946, which led to the conclusion that the necrotic areas due to relapses of severe acute pancreatitis are transformed into pseudocysts, and by way of wound healing, into fibroinflammatory changes. The resorption of fat and hemorrhagic necrosis by macrophages activates these cells to release cytokines such as transforming growth factor β and platelet-derived growth factor B, which transform resident fibroblasts into myofibroblasts that produce extracellular matrix rich in collagens.¹⁹  Since intrapancreatic fat necrosis and hemorrhagic necrosis occur mainly in the interlobular space, the ensuing fibrosis develops there. Interlobular fibrosis in turn distorts the interlobular ducts, creating dilatations and strictures. The duct deformations most likely slow down the flow of secretions, and together with the high protein and calcium content in the pancreatic juice, trigger protein precipitation with plug and finally calculus formation with upstream duct obstruction, which induces the disappearance of acinar cells by apoptosis and their replacement by intralobular fibrosis.

If pancreatic carcinoma is omitted from the list of differential diagnoses of diffuse chronic alcoholic pancreatitis, only the other distinct types of chronic pancreatitis such as PP, hereditary/familial pancreatitis, multifactorial (tropical) pancreatitis, autoimmune pancreatitis (AIP), and obstructive pancreatitis remain. This discussion is relatively new, for the pathology of chronic pancreatitis was considered uniform for a long time. Each fibrosing change of the gland was named chronic sclerosing pancreatitis without any consideration of the etiology. In recent years, however, it has been shown that some morphologic features, such as the composition of the inflammatory infiltrate and the fibrosis pattern, may be an indication of the underlying etiology.⁴³  For instance, the fibrosis pattern, whether it is more interlobular, intralobular, or diffuse, depends very much on the site of the initial, etiology-related damage to the pancreas. Thus, the interlobular and peripancreatic space is the typical site of an alcohol-associated injury, while the intralobular area with its structures is primarily affected by duct obstruction. A diffuse pattern of fibrosis is characteristic of AIP, and a fibrosis between duodenum and pancreas is typical for paraduodenal (“groove”) pancreatitis.⁴³ 

Its most distinctive feature is the strikingly limited localization to the area of the minor papilla involving the duodenal wall and the adjacent connective tissue (“the groove”) between the duodenal wall and the pancreatic parenchyma (for further discussion see below).

This form of pancreatitis usually manifests in childhood or adolescence as relapsing acute pancreatitis, which later evolves into chronic pancreatitis. In its early stage there is periductal and interlobular fibrosis with little inflammation. In the advanced stage, the pancreas becomes more fibrotic and shows a beginning lipoatrophic transformation.⁴³  The end stage is characterized by lipoatrophy, periductal fibrosis, and a massively dilated main duct filled with calculi. The acinar cells are largely replaced by lipomatous tissue,⁴⁴  with only few small ducts and scattered islets, changes comparable to those seen in end-stage cystic fibrosis.⁴⁵  Pseudocysts are rare. The ducts may harbor low-grade PanIN or even high-grade PanIN,⁴⁴  indicating an increased risk of developing pancreatic ductal adenocarcinoma.

In Western countries, the germline variants R122H and N29I of the PRSS1 gene (coding for cationic trypsinogen), and the N34S variant of SPINK1 (a serine protease inhibitor) are the most common genetic causes of familial pancreatitis.⁴⁶  The PRSS1 mutations prevent the normal inactivating cleavage of trypsin to trypsinogen, so that the longer-lived trypsin can initiate autodigestion. The illness is autosomal dominant with a penetrance of 80%.³⁵  If the mutation of SPINK1, a protease inhibitor, affects only 1 allele, SPINK1 seems to act as a disease modifier in patients with chronic pancreatitis related to other etiologies such as alcohol abuse. Very rarely CFTR or CTRC mutations are associated with chronic pancreatitis (see below).

Patients with chronic pancreatitis of multifactorial origin have a combination of risk factors such as alcohol, smoking, metabolic syndromes, and genetic alterations. They often have pancreatic changes comparable to chronic alcoholic pancreatitis. This is especially true of the so-called tropical pancreatitis and idiopathic chronic pancreatitis, which seem to be caused by an interaction of alcohol abuse and changes in genes such as SPINK1, CLDN2, and PRSS1-PRSS2 and have the morphologic features of alcoholic pancreatitis.^35,46,47  Chronic pancreatitis associated with metabolic syndromes such as hypercalcemia and hypertriglyceremia also have morphologic changes like those seen in chronic alcoholic pancreatitis.

This form of chronic pancreatitis results from duct obstruction by a tumor, often a ductal adenocarcinoma in the head of the pancreas, which leads to extreme widening (with little distortion) of the main duct and diffuse fibrosis of the surrounding parenchyma. In contrast to chronic alcoholic and hereditary pancreatitis, obstructive pancreatitis lacks calculi and pseudocysts. Histologically, this pancreatitis form retains for a long time the underlying lobular architecture of the pancreas, which can be best recognized by the still “lobular” distribution of islets and small ducts within dense fibrotic tissue.

Morphologic features distinguishing both types of AIP are the absence of pseudocysts, calculi, and irregular ductal dilatation, all common findings in alcoholic pancreatitis. Histologically, the distinguishing features of type 1 AIP include duct-centric lymphoplasmacytic inflammation, cell-rich diffuse storiform fibrosis, obliterative venulitis, and increased numbers of immunohistochemically IgG4-positive plasma cells. In type 2 AIP the main features include lymphoplasmacytic periductal inflammation and fibrosis, granulocytic epithelial lesions of the duct epithelium, and very low numbers or no IgG4-positive plasma cells. In biopsies, AIP is diagnostic in only 70% of the cases, making clinical information critical, especially serum IgG4 elevation in type 1 AIP^48,49  (for further discussion see latter article on AIP).

This very rare type of chronic pancreatitis is histologically characterized by the occurrence of lymphoid follicles with germinal centers in the pancreatic parenchyma.⁵⁰ 

The centrilobular type of fibrosis is characterized by a small “lobular” nodule of fibrosis in the periphery of the pancreas in elderly people without symptoms of chronic pancreatitis. The fibrotic area represents a pancreatic lobule without acinar cells but with islets, ductules, and very often a draining duct, almost occluded by a PanIN 1 lesion. It has been suggested that lobular fibrosis is due to duct narrowing by the papillae of the PanIN 1 lesion in the draining duct.³⁹  A diffuse interstitial type of fibrosis can be observed in hemochromatosis. In advanced cystic fibrosis, there is almost complete (interlobular and intralobular) fibrosis and/or so-called fatty atrophy.⁴⁵  Typical for this condition are obstruction and dilatation of the large ducts by mucus plugs. In cystic fibrosis that is not caused by the common D F508 mutation but results from other mutations such as R117H mutation, acute pancreatitis may develop.

PP is a peculiar form of chronic pancreatitis that develops in the intraduodenal area associated with the minor papilla and usually extends to the adjacent tissue between the duodenal wall and the pancreatic parenchyma (“the groove”). Middle-aged men with alcohol overconsumption are mostly affected.

The term paraduodenal pancreatitis was proposed in 2004 as a parent term for a group of lesions reported under different names that reflected the morphology, the topography, and the country of the different authors.⁵¹  In 1970, French pathologists described cysts lined by pancreatic ductal-like epithelium or surrounded by chronic inflammation within ectopic pancreatic tissue in the duodenal wall, under the term cystic dystrophy of the duodenal wall.^52,53  In Germany, around the same time, the pathologists Stolte et al⁵⁴  and Becker and colleagues^55,56  described a segmental form of pancreatitis involving the dorsocranial portion of the pancreas with extension to the region between the C-loop of the duodenum and the head of the pancreas, which they called groove pancreatitis. Other names that were proposed include pancreatic hamartoma, myoadenomatosis of the duodenum, Brunner gland hamartoma, heterotopic pancreas, duodenal duplication cysts, para-ampullary duodenal wall cysts, and paraduodenal wall cysts.⁵¹  Symptomatic pancreas divisum can be regarded as a PP-related pancreatitis, because its clear distinction from PP can be difficult.⁵⁷ 

PP mostly affects middle-aged men with a history of alcohol overconsumption and smoking. Only a few cases of PP have been reported in women⁵⁸  and in persons who do not overconsume alcohol.⁵⁹  In the 3 largest series of cases^60–62  that have been published so far, the male prevalence was 91%, 97%, and 77%, respectively, with median ages of 46 years and 42 years, and a mean age of 50 years. Of these patients, 86%, 98%, and 77%, respectively, were heavy drinkers, and 97% and 64% were smokers.^60–62 

At clinical onset, about half of the patients have acute pancreatitis with persistent and severe upper abdominal pain and occasionally vomiting.^60,61  Because of these symptoms there is weight loss, sometimes associated with steatorrhea and diabetes. Jaundice is observed in a smaller proportion of patients (11%–13%).^60,61  As the symptomatology is like that of pancreatic cancer, more than half of the patients are diagnosed with pancreatic ductal adenocarcinoma and undergo surgical resection.⁵¹ 

The diagnosis of PP can be assumed if, in the presence of the above-described symptoms, imaging using endoscopic ultrasonography, magnetic resonance imaging, and/or computed tomography demonstrates a thickened duodenal wall with cysts.⁵¹  To relate the clinical presentation to the course of PP, 4 main types of PP have been described on the basis of pathologic features that can be observed⁶²  (see also the section on Pathology below). (1) The “pure” type is limited to the duodenal wall, in which only the intraduodenal pancreatic tissue shows pathologic changes and the pancreas proper is normal. (2) The “groove” type shows an extension of the fibroinflammatory tissue from the intraduodenal region into the paraduodenal space, which is associated with the presence of cysts and often the compression of the distal common bile duct. (3) The “segmental pancreatitis” type is characterized by an involvement of the dorsocranial portion of the head of the pancreas without any involvement of the main pancreatic duct. (4) The “diffuse” pancreatitis type is characterized by the involvement of the entire pancreas with atrophy, marked duct dilatation, and occurrence of calculi. The relationship of the 4 types to the course of PP has been demonstrated in a mixed medical-surgical cohort of 120 Italian patients who received a diagnosis of PP on surgical resection of 63 specimens and on imaging in 57 cases. Calcifications were observed only in 5% of patients at clinical onset, while 61% of patients were affected at the end of follow-up, with a mean time of 8 years for their development. Dilatation of the main pancreatic duct has been observed at the end of follow-up in 76% of patients, while it was found in only 24% of patients at clinical onset, with a significant statistical correlation between dilatation of the main pancreatic duct and development of calcifications.⁶² 

To establish the diagnosis of PP, macroscopic examination of the pancreaticoduodenectomy specimens is a very critical step. Dissection of the pancreatic head along probes in the Wirsung duct and the common bile duct is the best way to appreciate and document the topographic relationship between the typical lesions of PP and the involved anatomic structures, that is, the different layers and portions of the duodenum, the groove region, the bile duct, the dorsocranial and ventral part of the head of the pancreas, and the duct of Wirsung (Figure 4, A).⁶³  The typical lesions (although not always fully present) are found at the level of the minor papilla and include (1) the white fibrous thickening of the duodenal wall and groove region, which distinguishes itself well from the neighboring pancreas parenchyma, and (2) the inclusion of cysts within the fibrous tissue, which are mostly less than 1 cm in diameter and often filled with hemorrhagic fluid. Additional findings can be a dome-shaped alteration of the overlying duodenal mucosa around the minor papilla and areas of scarring of the duodenal mucosa alternating with prominent folds, causing a pseudotumoral appearance. The neighboring ducts, that is, the distal common bile duct and the ducts of Wirsung and Santorini, appear to be normal or are somewhat indented but rarely obstructed. The peripancreatic lymph nodes are often enlarged.

In advanced PP, mild to moderate fibrosis can extend from the groove region into the head of the pancreas. This fibrosis first affects the dorsocranial portion of the pancreatic head and may lead to distortion of the duct of Santorini and formation of small calculi. With further progression of the disease all the pancreatic parenchyma is involved and the Wirsung duct may be dilated.

Histologically, an intraduodenal and paraduodenal fibroinflammatory process extends from the region of the minor papilla to the area between the duodenal wall and the pancreatic parenchyma. Within fibrotic tissue in the minor papilla are single ducts and acinar lobules and rarely also islets. These structures are often associated with patchy lymphocytic infiltrates. Most conspicuous are cystically dilated ducts, which are filled with eosinophilic protein plugs (Figure 4, B).⁶⁴  Their epithelial lining is either intact or partially eroded and even denuded. The denuded cystic spaces have irregular outlines, contain a mixture of blood and secretions, and are surrounded by granulation tissue consisting of granulocytes, macrophages, lymphocytes, plasma cells (some of them can express IgG4), and occasionally clusters of eosinophils. In addition, there is often an extensive, dense population of myoid or myofibroblastic cells that immunolabel with antibodies to smooth muscle actin and desmin. If this reactive myoid cell proliferation is exuberant, it may resemble an inflammatory myofibroblastic tumor, a leiomyosarcoma, or a leiomuscular hamartoma.⁶⁵  A common finding associated with the inflammatory changes is a striking hyperplasia of Brunner glands, which contributes to the thickening of the duodenal mucosa and submucosa (Figure 4, B). If the fibroinflammatory process extends into the adjacent pancreas, it follows the interlobular spaces and loses intensity quickly so that the more central parts of the pancreatic head region remain unaffected. By serial sectioning of multiple paraffin blocks, it is possible to demonstrate the anatomic continuity between the pancreatic tissue of the minor papilla and the dorsocranial pancreas. In advanced stages of PP, the fibroinflammatory process involves the entire pancreatic head and finally the whole pancreas under the profile of diffuse chronic alcoholic pancreatitis.

Depending on whether the fibroinflammatory process or the associated cysts dominate, PP can be subdivided into a “cystic” variant and a “solid” variant. The cystic variant (70%–80% of cases) is characterized by the presence of multiple cysts, protruding with a domelike appearance on the mucosal surface of the supra-ampullary or periampullary duodenum. In most cases the cysts also involve the groove and, in some cases, compress and dislocate the bile duct. The solid variant (20%–30% of cases) is characterized by an ill-defined pseudotumoral mass within and along the muscular layer of the duodenal wall, with no or only few small cysts and small dome-shaped changes of the duodenal mucosa. As a third type, which largely lacks the features of the other 2 variants, an ill-defined type has been suggested.⁶¹ 

Since PP is mainly located in the region of the minor papilla, its examination in patients with either paraduodenal pancreatitis or unrelated conditions is important, to understand the possible pathogenesis of PP. The minor papilla is composed of ducts frequently surrounded by a sphincter-like structure and consistently associated with pancreatic tissue in anatomic continuity with the dorsocranial part of the pancreatic head. The epithelial-lined cysts seen in PP are therefore dilated ducts of the minor papilla–associated pancreatic tissue that should not be considered ectopic, but rather as a bud of the dorsocranial pancreas entrapped within the duodenal wall during organogenesis.⁶⁶  It seems that this dorsocranial pancreatic tissue is part of the dorsal anlage because the islets that are occasionally found in the minor papilla are lacking the predominance of pancreatic polypeptide cells, which is typical for the islets of the ventral anlage. The presence of abundant tissue of the dorsal pancreas anlage could be due to incomplete migration of the dorsal anlage and explain the relatively high percentage (67%) of imperforated minor papilla in normal pancreata.^54,67  If the minor papilla is closed, it is possible to observe an early pure PP, which is characterized by cystic dilatation of the terminal Santorini duct (“Santorinicele”) and its branches. In the usual PP, cystic ducts filled with inspissated pancreatic secretions strongly suggest that an obstruction hampers the flow of secretions, possibly due to abnormal development of the ducts. Accumulation of secretions could then favor premature activation of pancreatic enzymes such as trypsin, leading to autodigestive destruction of the epithelium in cystic ducts and triggering the fibroinflammatory process in the adjacent paraduodenal space, which distinguishes PP. The role of alcohol overconsumption and smoking as factors helping to induce autodigestion is unclear, but in the pancreas with PP these factors could promote premature enzyme activation by rendering the pancreatic juice more viscous.⁶⁸  The occlusion of the ducts in the minor papilla would also explain the dynamic (waxing and waning) behavior of the cysts, which is responsible for the clinical failure of an operation performed for PP. In this regard, the temporary relief of symptoms in some patients may result from the spontaneous rupture of submucosal cysts, which is suggested by ulcerations and scars in the duodenal mucosa as well as changes in the site and size of cysts observed during follow-up of patients by computed tomography.

The pathogenetic hypothesis described above has important therapeutic implications. In patients with pure PP, the endoscopic drainage of the minor papilla, with decompression of the intraduodenal and dorsal pancreas, achieved long-term clinical improvement without surgical resection. Alcohol withdrawal was effective in 33% of patients, with the further advantage of avoiding postoperative diabetes.⁶² 

Approximately 5% to 10% of pancreatectomies performed with the clinicoradiologic suspicion of cancer prove to be nonneoplastic lesions, among them, especially PP.^69,70  The number of lesions that must be considered in the differential diagnosis of PP reflects the different facets of the disease. According to the most prevailing finding, PP has been reported as Brunner gland hamartoma, leiomyoma, or sarcoma, or as duodenal duplication. The term pancreatic hamartoma has been applied to the more complex lesions characterized by a mixture of distorted ducts associated with intraduodenal acinar tissue, Brunner gland hyperplasia, and an excess of smooth muscle cells. The knowledge of the existence of 2 variants of paraduodenal pancreatitis, solid and cystic, is of practical importance, since only the cystic component is easily recognized by standard diagnostic procedures. The differential diagnosis of the cystic variant versus either nonneoplastic or neoplastic cysts is frequently possible, whereas the preoperative distinction of the solid variant of PP from periampullary carcinoma and pancreatic head adenocarcinoma is difficult.⁷¹  The so-called groove carcinoma deserves a special mention as a pancreatic carcinoma occurring in the pancreatoduodenal groove area. Groove carcinoma is associated with duodenal stenosis in 96% of patients, followed by nausea or vomiting in 89% and jaundice in 67%. Important clues for the differential diagnosis are age, as patients with PP are more than a decade younger than the patients with pancreatic and ampullary cancers; history of alcohol and tobacco abuse and previous pancreatitis; and imaging findings.⁷²  In some cases, the definite diagnosis is reached only after histopathologic examination of the resected specimen. Another important differential diagnosis, with therapeutic implications, is with AIP, which is frequently associated with a swollen main duodenal papilla.

Alcohol and also smoking are the main etiologic factors of acute pancreatitis, relapsing acute pancreatitis, chronic pancreatitis, and paraduodenal pancreatitis. Clinical and morphologic studies have shown that acute pancreatitis, relapsing acute pancreatitis, and chronic pancreatitis represent a sequence of diseases that starts with autodigestive tissue necrosis in the pancreas and ends with fibrotic transformation of the pancreas. It is not known how alcohol and smoking damage the pancreas and cause its sudden autodigestion; however, initiation of the necrosis-fibrosis sequence requires heavy drinking and smoking over a long period. It seems that PP, with its peculiar localization in and around the minor papilla and its obstructive duct changes in this area, also follows the alcohol/smoking-associated necrosis-fibrosis sequence. As not all heavy drinkers and smokers develop pancreatitis, there is a current discussion on the role of genetic changes, such as SPINK1 mutations, in promoting the initiation of pancreatitis. Once pancreatitis has been initiated and recurs under continuing exposure of alcohol and smoking, repair of necrotic areas leads to their encapsulation in pseudocysts and/or their fibrotic replacement. The speed of this process and its extent depends on the number of relapses of acute pancreatitis and the severity of the associated autodigestion. In PP, the knowledge of the clinical, radiologic, and pathologic findings is crucial to make the correct preoperative diagnosis and exclude pancreatic or periampullary cancer. A precise diagnosis of PP is frequently done for the “cystic” variant, but still today, a definite preoperative diagnosis of the “solid” variant is difficult and frequently only reached afterwards on the resected specimen.

We are grateful to Atsuko Kasajima, MD, PhD, for helping us to prepare the manuscript and giving us her advice.