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Nonneoplastic mimickers of pancreatic neoplasms.

Approximately 5% to 10% of pancreatectomies performed with the clinicoradiologic suspicion of cancer prove to be nonneoplastic masses (pseudotumors). (1,2) Although the advances in imaging have increased the discovery of pancreatic masses, their correct identification as a nonneoplastic process is still difficult. Pancreatic pseudotumors do not represent a single entity, but multiple distinct categories of lesions characterized by an enlargement of nonneoplastic character, which clinically resembles a true neoplasm so closely as to often be mistaken for such. They should be more appropriately called pseudoneoplastic in the sense that the swelling, the cardinal sign of both conditions, has to be differentiated from a true neoplasm.

A precise preoperative diagnosis of a pancreatic mass is very difficult to achieve. The ideal diagnostic test, as in other diseases, should be the tissue diagnosis. (3,4) Unfortunately, diagnostic pancreatic biopsy specimens are rarely available. Surgical sampling of the pancreas, by means of laparoscopy or laparotomy, is considered expensive and a risk to the patient cannot be completely excluded. The less invasive methods, such as fine-needle aspiration cytology with ultrasound guidance or endoscopic ultrasound-guided fine-needle core biopsy, have a better level of safety and are considered reliable in detecting the presence of malignant cells. More importantly, in view of the high success rate of corticosteroid therapy in autoimmune pancreatitis (AIP), it is imperative, in the presence of pertinent clinical, imaging, and laboratory data, to establish an accurate preoperative diagnosis that will spare unnecessary surgery.

The clinical presentation, radiologic findings, and pathologic differential diagnosis vary in accordance with the prevalent solid or cystic appearance.

LESIONS MIMICKING SOLID PANCREATIC NEOPLASMS

If we rule out the very unusual heterotopic spleen in the pancreatic tail, which can simulate an endocrine tumor, 5 and rare cases of infectious conditions such as malakoplakia, 6 mycobacteria, (7) and fungal infections, (8) most of the "solid" cases fall into the category of inflammatory and fibrosis conditions correlated in various ways with chronic pancreatitis (CP).

The crucial lesions of CP are chronic inflammation, pancreatic fibrosis, acinar atrophy, and duct dilation and obstruction. Some morphologic features, such as the composition of the inflammatory infiltrate and the fibrosis pattern, may be a clue to a certain etiology. (9) For instance, the pattern of fibrosis, inter(peri)lobular or intralobular, depends very much on the site of the initial injury in the pancreas and this is related to the etiologic factor. So far, it is possible to distinguish alcoholic CP, hereditary pancreatitis, AIP, obstructive CP, and paraduodenal pancreatitis ("groove pancreatitis" and cystic dystrophy of duodenal wall). (3,10-14)

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Although the classical type of alcoholic CP sometimes presents as a swelling in which the destruction of the exocrine pancreas and the inflammatory and sclerotic reaction may be focal or segmental, creating a suspicion of carcinoma, the types of CP that pose difficulties in the differential diagnosis are those presenting with a pancreatic mass without extensive calcifications and ductal dilation. (3,15-17) Among these types of CP, AIP with the related inflammatory pseudotumor18 and paraduodenal pancreatitis are the most important lesions and are the focus of our review.

AUTOIMMUNE PANCREATITIS

Autoimmune pancreatitis represents a distinct and increasingly frequently detected form of CP with characteristic clinical, radiologic, and histologic features. (19)

It is extremely difficult to estimate the overall prevalence of the disease. In a retrospective series, AIP is found among patients operated on with a presumptive clinical diagnosis of pancreatic tumor as well as CP. (17) In the years between 1960 and 1985, there are only a few case reports that most likely describe AIP. The first series of patients with AIP was reported in the 1990s. (20) In 4 recent series the reported prevalence of AIP ranged from 12% to 26%. In the Mayo Clinic's series, AIP was found in 35 of 254 (13.7%) pancreatic resections with a final diagnosis of CP. (21) On the other hand, AIP was reported in 53 of 200 patients (26.5%) undergoing surgery for CP in a combined Italian and German series. (22) Similar prevalence was found both in the Johns Hopkins' and in the Memorial SloanKettering's series; in the latter 37 cases of AIP were found among 176 pancreaticoduodenectomies performed for CP (21%), (23) while in the former 31 cases of AIP were found in 159 (19.5%) pancreatic resections for benign diseases. (24)

Autoimmune pancreatitis is now considered the pancreatic manifestation of a systemic fibroinflammatory disease in which affected extrapancreatic organs also reveal a lymphoplasmacytic infiltration with abundant immunoglobulin (Ig) G4-positive plasma cells. The first cases of AIP were probably observed by Ball et al and Sarles et al, who described them using the terms chronic interstitial pancreatitis and primary inflammatory sclerosis associated, respectively, with ulcerative colitis (25) and hypergammaglobulinemia. (26) The disease was later referred to by various names, depending on whether it was studied by pathologists, clinicians, or radiologists. The most widely used names are chronic sclerosing pancreatitis, (27) lymphoplasmacytic sclerosing pancreatitis, (28) duct-destructive CP, (29) tumor-forming pancreatitis (30) and mass-forming pancreatitis. (31) The name AIP has the advantage of being simple and suggestive of the etiology, (32) although it is apparent that AIP is a heterogeneous disease. (22,33)

Clinically, it can either present with the classical symptoms of acute or severe pancreatitis or produce a masslike lesion that frequently simulates a carcinoma clinically and radiologically. (34,35) Pathologically, it is characterized by a mixed inflammatory cell infiltrate centered around the pancreatic ducts along with venulitis. In around 40% of the patients a peculiar granulocytic infiltration of the epithelial duct has been reported that was termed granulocytic epithelial lesion (GEL). (22) Two main subtypes with differing clinicopathologic features can be distinguished: one called lymphoplasmacytic sclerosing pancreatitis, (21) lobulocentric, (36) or GEL-negative pancreatitis, (22) and the other ductocentric (21,36) or GEL-positive pancreatitis. (22) Granulocytic epithelial lesion-positive patients had a mean age of 40.5 years, an almost equal male to female ratio, and a high coincidence of ulcerative colitis or Crohn disease, whereas patients without GELs were older (mean age, (64) years), showed a male preponderance, commonly had Sjogren syndrome, and often developed recurrent bile duct stenosis. (22)

Although many reported immunologic and genetic anomalies suggest that autoimmune mechanisms may be involved, the pathogenesis remains largely unknown. Typical immunologic abnormalities are increased levels of serum [gamma]-globulin, IgG, and IgG4 and the presence of autoantibodies (antinuclear, anti-lactoferrin, anti-carbonic anhydrase-II). In patients with a high level of IgG4 in the serum and/or dense IgG4-positive lymphoplasmacytic in filtration, IgG4 has been suggested to play a major role in the pathogenesis. The presence of granular deposits containing IgG4 in renal tubular basal membranes in patients with AIP might suggest an immune complex-mediated disease. (33)

So far, several risk factors have been implicated, including the HLA DRB1*0405-DQB1*0401 haplotype (37) and polymorphisms of the Fc receptor-like gene 3 (FCRL3), which lies outside the major histocompatibility complex region. (38) The lymphocytic infiltration includes predominantly CD4 or CD8 T lymphocytes. [T.sub.H]1-type CD[4.sup.+] T cells have been reported to be increased in the peripheral blood of AIP patients in Japan. (39) Recently, great interest has focused on factors regulating T-cell function as well as the switching of B cells to IgG4-producing plasma cells in the development of AIP. A possible candidate associated with an increased risk for various autoimmune diseases is the inhibitory molecule cytotoxic T-lymphocyte antigen 4 (CTLA4; CD152) expressed on the cell surface of activated memory T cells and on CD[4.sup.+]CD[25.sup.+] regulatory T cells, which acts largely as a negative regulator of the T-cell response. (40) Although CTLA[4.sup.+]6230SNP polymorphism may be functionally linked to AIP, it has been reported to play a role in both susceptibility to and protection from AIP. (41,42) Circulating CD[4.sup.+]CD[25.sup.+] T lymphocytes have been reported to be increased in the peripheral blood of patients with AIP in comparison with both healthy people and people with other types of CP. (43) There is no direct evidence of increased pancreatic infiltration of these CD[4.sup.+]CD[25.sup.+] T lymphocytes, but there is agreement that in many autoimmune diseases there is an increased recruitment at inflammatory sites. Therefore, the increased circulating CD[4.sup.+]CD[25.sup.+] T lymphocytes may correlate with interleukin 10 at the local sites of the pancreas and extrapancreatic lesions, (44) which might influence the switching of B cells to IgG4-producing plasma cells and the production of serum IgG4. (43) Interestingly, in Mikulicz disease, another IgG4-related disease characterized by bilateral lacrimal and salivary gland swelling, some clonally related IgG4-positive cells exist between lacrimal glands and the peripheral blood. This may be important for the understanding of the multiple organ involvement of an IgG4-related disease. (45) The disease-specific antigen resulting in activation of both [T.sub.H]1-type lymphocytes and CD[4.sup.+]CD[25.sup.+] suppressing [T.sub.H]2-type immune cells remains to be clarified. Pancreatic secretory trypsin inhibitor, lactoferrin, and carbonic anhydrase II could be candidates for target antigens in AIP, because they are demonstrated in the commonly involved organs, such as the pancreas, biliary tree, salivary glands, gastrointestinal tract, and distal renal tubules. Anti-carbonic anhydrase II and anti-pancreatic secretory trypsin inhibitor autoantibodies are frequently detected in patients with AIP. (46,47)

Macroscopy

Macroscopically AIP may appear either focal or diffuse; in a few cases the lesions can be multifocal. In most cases the focal type involves the head of the pancreas and strikingly resembles pancreatic or terminal bile duct carcinoma. In both cases, the lesions are typically ill-defined and narrow the pancreatic duct, which, contrary to the usual situation in alcoholic CP, is neither dilated nor contains calculi. If they occur, they seem to do so late in the course of the disease. (48) Stenosis and narrowing of the terminal bile duct are frequently seen. In a minority of cases the inflammatory process is concentrated in the body or tail of the pancreas or can diffusely involve the entire pancreas, mimicking a pancreatic lymphoma. In contrast to other types of CP, such as alcoholic CP, hereditary pancreatitis, and tropical pancreatitis, there are no pseudocysts. Both the reduced vascularization of the involved pancreatic area and its increase in size give it a tumorous appearance. (49)

Microscopy

The microscopic features of AIP are dominated by an intense inflammatory cell infiltration consisting mainly of lymphocytes, plasma cells, and macrophages, which characteristically show a periductal distribution, causing periductal fibrosis, ductal distortion, and obstruction (Figure 1). In many cases, intermingled with the lymphocytes there is an acute inflammatory component, which constitutes the GELs (22) (Figure 2). Characteristic of the GELs is invasion of the ductal structures by neutrophilic granulocytes, with detachment, disruption, and destruction of the duct epithelium (Figure 2). Sometimes the eosinophilic component is conspicuous. (50) The process affects the main and secondary pancreatic ducts and frequently the distal bile duct.

The extension and severity of the chronic and acute changes in AIP vary from case to case and even from one area to another within a single case. Four grades of severity have been proposed that take into account the distribution and intensity of inflammatory infiltration, fibrosis, duct distortion and destruction, the presence of lymphoid follicles, and vasculitis (Table). (22)

In early stages, grade 1 and grade 2, when the pancreatic parenchyma is only slightly affected, the inflammatory infiltration focuses almost entirely on the ducts, which show mild periductal fibrosis and duct obliteration, whereas the acinar component is only focally affected (Figure 3). Grade 1 to 2 AIP may only rarely cause clinical symptoms (eg, pain and jaundice) of such intensity that they become an indication for resection. In advanced stages (grade 3 and grade 4), the diffuse periductal lymphoplasmacytic infiltrates are associated with severe periductal fibrosis, duct obstruction, and eventually duct destruction. The fibroinflammatory process extends to the interlobular and intralobular ducts as well as to the acinar component, which progressively display atrophy and are replaced by fibrosis (Figure 4). At this stage, venulitis is always found (Figure 5), and the lymphoid follicles may be diffusely scattered throughout the lesion. Ninety percent of resected cases of AIP are classified as grade 3 to 4. Another characteristic finding is the patchy distribution of the fibroinflammatory process, with variable involvement of lobules.

A special type of fibrosis with storiform pattern, present in about half of the patients, is characterized by the presence of inflammatory cells and plump myofibroblasts (pancreatic stellate cells) intermingled with collagen bundles (Figure 6). Less frequently, the storiform fibrosis occupies a large area, mimicking a fibroinflammatory pseudotumor. The stellate cells express smooth muscle actin (activated stellate pancreatic cells) (Figure 7), whereas most of the intermingled mononuclear cells are CD6[8.sup.+] macrophages, T lymphocytes, and plasma cells. Scattered HLA-DR expression is seen in duct cells, endothelial cells, inflammatory cells, and myofibroblastic cells. The inflammatory process is usually well demarcated from the sur rounding peripancreatic fatty tissue and only occasionally shows some small tonguelike extensions. The peripancreatic lymph nodes are enlarged and show follicular hyperplasia. If the inflammatory process affects the head of the gland (as in approximately 80% of the cases), it usually also involves the distal common bile duct, where it leads to a marked thickening of the bile duct wall due to a diffuse lymphoplasmacytic infiltration combined with fibrosis. (51) In about 25% of cases the inflammation also extends to the gallbladder. (16)

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Immunohistochemical typing of the lymphocytes reveals a predominance of CD[3.sup.+], CD[4.sup.+], and CD[8.sup.+] T lymphocytes in the inflammatory infiltrates surrounding the medium-sized and large interlobular ducts, with occasional invasion of the duct epithelium. The CD2[O.sup.+] B lymphocytes are sparse or aggregate to form lymphoid follicles, which are found either scattered in sclerotic tissue or around ducts (Figures 8, A and B).

The most relevant and important feature is the increase in IgG4-positive plasma cells reported in most cases (Figure 9). IgG4 levels have been proposed as a useful tool in the differential diagnosis of pancreatic masses; IgG4 levels are low in pancreatic carcinoma and chronic obstructive or biliary pancreatitis and high in AIP. (52,53) The diagnostic significance of IgG4 positivity depends mainly on the cutoff level used. Kojima et al (20) reported a sensitivity of 43% and specificity of 100% for more than 20 IgG4-positive cells at a magnification of <40. With a cutoff of more than 10 IgG4-positive cells per high-power field the sensitivity was 72% and the specificity 88%, (54) whereas Deshpande et al33 reported 76% sensitivity and 70% specificity for more than 10 IgG4-positive cells at a magnification of X20.

Extrapancreatic Involvement

Autoimmune pancreatitis may be a component of a systemic disease that may involve many organs. All of these manifestations show similar lymphoplasmacytic infiltration, fibrosclerosis, and frequently dense IgG4-positive cell infiltration. For this reason Kamisawa et al (55) suggested the term IgG4-related systemic disease. The recognition of this extrapancreatic involvement is of great importance in the diagnosis of so-called mass-forming pancreatitis. (31) The biliary tree is involved in about 70% of cases, with cholecystitis (Figure 10), intrahepatic or extrahepatic sclerosing cholangitis mimicking a cholangiocarcinoma, or primary sclerosing cholangitis. The number of associated conditions recognized has increased immensely and includes ulcerative colitis, Crohn disease, primary sclerosing cholangitis, (56-60) lymphoplasmacytic cholecystitis, (16) primary biliary cirrhosis, (61) Sjogren syndrome, (3,62) chronic sclerosing sialoadenitis resembling Mikulicz disease, (45,63) thyroiditis, (64) the family of tumorlike lesions known as multifocal idiopathic fibrosclerosis, including mediastinal and retroperitoneal fibrosis, Riedel thyroiditis, and inflammatory pseudotumor of the orbit, (65-70) tubulointerstitial nephritis, (71-73) interstitial pneumonia, (74) lymphadenopathy, (75) prostatitis, (76) and inflammatory abdominal aortic aneurysm. (77)

Although some patients improve spontaneously, steroids are the first choice of therapy. (78) Short-term steroid treatment has been demonstrated to be effective in reducing the signs and symptoms related to pancreatic inflammation and leads to a significant improvement at radiologic investigation, (35,62,79) with a significant reduction of IgG4 levels. (48,80) The rate of complete remission, as well as the rate of recurrence, is higher in patients who were treated with steroids than in patients who did not have steroid therapy. Complete remission was observed in 87.5% and 98.4% of patients treated without and with steroids, respectively. Patients who did not have steroids reached complete remission later than patients treated with steroids (149.8 vs 89.7 days). (81)

The recurrences of AIP can approach 20% to 40% in most studies. (81,82) Young patients with GEL-positive lesions have a better response to steroid therapy and do not relapse in a short-term follow-up. (22)

Relapse can be treated with a second steroid course, with low-dose steroid maintenance therapy, or alternatively with immunomodulatory medications. (83) Surgical operation, with major resections, should be limited to those patients who do not respond to steroid therapy, in whom it is necessary to exclude a pancreatic cancer.

Relationship to Inflammatory Pseudotumor

Inflammatory pseudotumor usually presents as a massforming lesion characterized by spindle cell proliferation with a characteristic fibroinflammatory appearance. It has not yet been resolved whether inflammatory pseudotumor is an excessive reactive process (infection-associated inflammatory pseudotumor) or a true neoplasm (neoplastic inflammatory myofibroblastic tumor). (84) The pseudotumoral nature of the lesions can be supported by their clinical, radiologic, and pathologic findings. Clinically, the lesions mimic a neoplastic process, the signs and symptoms depending on the particular site or organ involved and on the production of cytokines by inflammatory cells. Radiologically, the various procedures, ultrasound, computed tomography, and magnetic resonance, reveal the presence of a suspicious mass resembling a carcinoma or a sarcoma.

Inflammatory pseudotumor, originally described in the lung, has been subsequently described in many extrapulmonary locations, including the head and neck region, orbit, gastrointestinal tract, retroperitoneum, genitourinary tract, soft tissue, spleen, liver, lymph nodes, major salivary glands, and submandibular glands. (85-87) There have been a number of reports of inflammatory pseudotumor of the pancreas using different designations: inflammatory pseudotumor, (18,88-93) fibrous pseudotumor, (94) plasma cell granuloma, (95) inflammatory myofibroblastic tumor, (96) localized lymphoplasmacellular pancreatitis, (97) or lymphoplasmacytic sclerosing pancreatitis. (28) All of these cases are characterized, like AIP, by a triad of characteristic histologic features: diffuse infiltration by lymphocytes and plasma cells, myofibroblastic proliferation, and venulitis.

Macroscopically, most of the reported cases were solid lesions with diffuse or indistinct mass. They were frequently localized in the head of the pancreas, were fibrous in appearance, and involved the distal bile duct.

Microscopically, the pancreatic parenchyma is replaced by a proliferation of myofibroblasts with spindle-shaped nuclei and eosinophilic cytoplasm and inflammatory cells consisting mainly of lymphocytes and plasma cells. In some areas fibrosis and atrophy of the parenchyma predominate, in others the inflammatory reaction predominates. Vasculitis and particularly venulitis are frequently present (Figure 11). The fibroinflammatory areas found in AIP share histologic features with those described in inflammatory pseudotumors of the pancreas, (18,68,89,96) including the myofibroblastic proliferation. Autoimmune pancreatitis might be regarded as the initiating event in the evolution of inflammatory pseudotumor, in which the fibroinflammatory storiform fibrosis has acquired a tumorlike appearance. (14,28,97) Evidence supporting an autoimmune etiology include the association of inflammatory pseudotumor with other autoimmune diseases such as Sjogren syndrome (98) and sclerosing cholangitis, (99) retroperitoneal fibrosis, (66-68) and the regression seen in some cases after treatment with corticosteroids. (67) The finding of an oligoclonal pattern of T-cell receptor [alpha]-chain gene rearrangements suggests that the pathogenesis of both inflammatory pseudotumor and AIP could be related to the development of an intense and self-maintaining immune response, with the emergence of clonal populations of T lymphocytes. (90) The frequent association of AIP with inflammatory pseudotumors involving the common bile duct and liver (67,100,101) induced some authors to consider all of these lesions to belong to the spectrum of AIP. More recently, a massive infiltration of IgG4-positive plasma cells in inflammatory pseudotumor of many sites, such as the breast, lung, and kidney, has been reported. (51,72,74,102)

Differential Diagnosis

Clinically, radiographically, and grossly the disease most commonly mimics pancreatic carcinoma, because it predominantly affects the pancreatic head and the bile duct. (16,21,23,24) Histologically, however, it is not difficult to distinguish from ductal adenocarcinoma of the pancreas or other pancreatic malignancies. The association between AIP and pancreatic cancer is still largely unknown. To date only a few cases have been reported. Long-term studies on large cohorts of AIP patients are needed to determine whether AIP predisposes to the subsequent development of pancreatic carcinoma. This may be difficult to prove, because cancer typically occurs decades after the onset of CP and AIP occurs in older men who are likely to die of comorbid conditions before such a complication develops. (47,103,104)

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Autoimmune pancreatitis has to be distinguished from alcoholic CP. Autoimmune pancreatitis almost consistently lacks the features that are common in alcoholic CP: calculi, dilated and tortuous ducts, pseudocyst formation, and areas of fat necrosis. Histologically, alcoholic CP lacks the dense periductal lymphoplasmacytic infiltration, the obliterative venulitis, the often diffuse fibrosis, and the common inflammatory involvement of the bile duct. The immunohistochemical evidence of dense, periductal IgG4positive plasma cells can rule out alcoholic CP. (20)

Fine-Needle Aspiration Cytology and Biopsy

In view of the high success rate of corticosteroid therapy in AIP it can be anticipated that in the future the only AIP patients who will be treated surgically will be those who prove refractory to steroids and in whom pancreatic carcinoma continues to be suspected. The decision to give steroid therapy, however, requires a precise diagnosis. A useful diagnostic tool in clinically and radiologically suspected AIP could be fine-needle aspiration cytology or fine-needle core biopsy. (14,35,36,105) It is therefore essential to increase the ability to recognize AIP features on cytology and on small tissue fragments.

Pancreatic endoscopic ultrasound-guided fine-needle aspiration biopsy proved to be useful for obtaining cytologic material that, in addition to excluding the possibility of a carcinoma, can suggest the diagnosis of AIP. (106) The cytologic features of AIP, more pleomorphic than cancers, are characterized by an underrepresentation of ductal cells, no significant nuclear atypia, and the presence of stromal fragments. The latter, composed of fibroblasts and myofibroblasts, are characteristically infiltrated by lymphocytes, plasma cells, and macrophages. The peculiar features of these stromal fragments (Figure 12) enable the differential diagnosis versus ductal carcinoma, in which the malignant cells are usually seen laying at the edge of stromal fragments, and CP, in which the stromal fragments are lacking or much more fibrotic and acellular. Unfortunately, the presence of a typical dense lymphoplasmacellular infiltrate is seen only in a minority of cases, whereas granulocytes are quite often found.

To overcome the limitations of cytologic examination, endoscopic ultrasound Tru-Cut biopsy has been developed, which allows the preservation of tissue architecture and histologic and immunophenotypical examinations. Although Tru-Cut biopsies have been demonstrated to be safe, the diagnostic accuracy has not yet been clearly determined. The biopsy specimens probably only show changes that are diagnostic or suggestive of AIP in about half of the patients, mainly due either to the acquisition of small fragments or to possible sampling errors as a result of the patchy distribution of the lesions. (22,105) Nevertheless, the importance of preoperative histologic examination should not be underestimated, because even a negative biopsy result can be evidence supporting a nonmalignant condition. (107) On the other hand, the inflammatory process can involve the terminal common bile duct, with stenosis and marked wall thickening. Therefore, an intraductal biopsy may provide an efficient and easily obtainable sample for histology and immunohistochemistry (Figure 13). (108)

The possibility of biopsy diagnosis of AIP relies on the specific features of AIP, which are not found in other types of CP or in ductal carcinoma. (22,107,109) The combination of lymphoplasmacellular infiltration, especially around ducts, granulocytic infiltration with GELs (Figure 14), and phlebitis is diagnostic of AIP, whereas the presence of a highly cellular stroma with a storiform pattern characterized by myofibroblastic proliferation and lymphoplasmacytic infiltration may be suggestive in the appropriate clinical context. Finally, the presence of abundant IgG4-positive cells (>10 per high-power field) in the pancreatic tissue and a high IgG4 serum level are also indicative of AIP (Figure 15, A through C). (20,33,54,55,107) If a high cutoff level of IgG4-positive plasma cells (>20 per high-power field) is chosen, the specificity reaches 100%. (20)

LESIONS MIMICKING CYSTIC PANCREATIC NEOPLASMS

The "cystic" nonneoplastic lesions of the pancreas are usually of inflammatory origin (pseudocysts) or due to duct occlusion (retention cysts). They are the most common type of cystic lesions in the pancreas. (110) Inflammatory pseudocysts, which can present either as extrapancreatic or intrapancreatic cavities, are lined by inflammatory tissue and lack an epithelial lining. Retention cysts, which occasionally can be radiologically detectable, represent a cystically dilated duct with different degrees of inflammation and denudation. The spectrum of pancreatic cystic neoplasms to consider in the differential diagnosis is extremely broad (111); however, the two most important are mucinous cystic neoplasm and intraductal papillary mucinous neoplasm. Mucinous cystic neoplasms occur almost exclusively in women, are usually located in the pancreatic tail, and show no connection with the main pancreatic duct and an ovarian type stroma; intraductal papillary mucinous neoplasms have an equal sex distribution, are usually located in the main duct of the head of the pancreas, and show mucus hyperproduction by an intraductal papillary epithelium. (112)

Other nonneoplastic cysts, such as mucinous nonneoplastic cyst of the pancreas, (113) congenital cysts, (110) single true cysts, (114) lymphoepithelial cysts, (115) enterogenous cysts, (116) and endometrial cysts, (117) or schwannoma of the pancreas with cystic appearance118 are extremely rare.

PARADUODENAL PANCREATITIS

Duodenal involvement is frequently observed in the typical long clinical course of CP, and duodenal stenosis is a well-known complication in a proportion of cases ranging from 19.6% (12) to 31%. (119) Much less common or well known is the occurrence of cysts within the duodenal wall. Duodenal wall cysts may arise in various situations: enterogenous duplication, retention cysts in Brunner glands, or as the result of pancreatitis in duodenal heterotopic pancreas. The latter possibility, described either as a pure lesion or associated with CP, has been reported under many different names. In the World Health Organization classification of tumors and tumorlike lesions of the pancreas it was referred to as para-ampullary duodenal wall cyst, (120) while in 1970 Potet and Duclert (13) suggested the term cystic dystrophy of the duodenal wall. They described the presence of cysts lined by pancreatic ductlike epithelium or surrounded by inflammatory granulation tissue in ectopic pancreas in the duodenal wall although the histology of the pancreas proper was normal. Subsequently, a frequent association with chronic alcoholic pancreatitis was reported. (121-123) Two clinicopathologic forms may be envisaged: a "pure" type, in which only the intraduodenal pancreatic tissue shows pancreatitic changes and the pancreas proper is normal, (124) and a more common type associated with chronic calcifying pancreatitis. (125) Cystic dystrophy of the duodenal wall was found in 26 of 96 cases reported by Martin (126) and in 17 of 50 cases studied by Vankemmel et al. (127) In 1973 Becker (128) described segmental 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. He used the term groove to describe that sliding plane interfacing the 2 organs that serves as a "bed" for the large vessels, lymph nodes, and the common bile duct. All those cases in which the inflammatory and fibrous process involved the groove, he then called groove pancreatitis. In "pure" groove pancreatitis the scarring is restricted to the groove without any pancreatic head involvement. In "segmental" groove pancreatitis the scarring involves the dorsocranial portion of the head of the pancreas without any involvement of the main pancreatic duct. In advanced cases more diffuse pancreatic involvement with duct dilation is present. (119) Although groove pancreatitis represents a heterogeneous group of lesions, that is, the extension of biliary, gastric, or duodenal lesions to the groove, it has many clinical and pathologic aspects in common with cystic dystrophy of the duodenal wall, including the extremely high prevalence of duodenal wall cysts (49%) in cases with groove scarring. (119) In most reported cases, the clinical presentation (pain, vomiting, and jaundice) and radiologic, ultrasonographic, and pathologic features overlap in so many important aspects that they may be considered variants of the same disease.124 For these reasons the unifying name paraduodenal pancreatitis has been proposed. (14) Knowledge of the clinical and pathologic features of this disease allows a preoperative diagnosis that in most cases correctly differentiates it from pancreatic and periampullary neoplasms and may prevent unnecessary surgical resections.

Although sporadic cases have been reported in women (129,130) and in non-alcohol abusers, (124,125) it is important to stress that almost all cases involve young or middle-aged men with a history of alcohol abuse.

In comparison to the long clinical course of the typical diffuse form of CP, in which the symptoms are mainly related to the dilation of the main duct and the loss of the acinar component, the symptoms of patients with paraduodenal pancreatitis are specifically related to the duodenal wall and groove involvement. Typically, the pain and vomiting have a waxing and waning character. In a proportion of patients the stenosis of the distal common bile duct may be associated with jaundice.

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Macroscopy

Most cases present with a stenosis of the second portion of the duodenum. The most characteristic and constant feature is the presence of multiple cysts within a thickened duodenal wall containing clear liquid or in some cases white concretions and stones. (124) These cysts, which occur in the submucosa and in the muscularis, may in some cases extend to the groove compressing the common bile duct. In the involved areas the duodenal mucosa usually shows a nodular appearance, ulcerations, and scarring.

Two types may be distinguished: (1) The "cystic" type shows multiple cysts (Figure 16) ranging in diameter from 1 to 10 cm and protruding the mucosa of the supra-ampullary duodenum. If the cysts are large, they may be confused with an intestinal duplication. (2) The "solid" type is characterized by a marked thickening of the duodenal wall, which contains cysts less than 1 cm in diameter (Figure 17). Both types share a more or less marked thickening of the duodenal wall, more evident at the pancreatic side of the supra-ampullary duodenum, and in connection with the minor papilla. The groove region is markedly broadened, either by fibrotic tissue or by cysts in the duodenal wall. The fibrotic tissue may narrow the common bile duct, and the cysts may lead to duodenal stenosis. The presence of numerous enlarged peripancreatic lymph nodes is also a constant feature of the disease.

The pancreatic parenchyma of the head is normal in the early stages of the disease, whereas at the time of surgery most cases usually show mild to moderate fibrosis. The involvement of the pancreatic parenchyma, at least in the early stage, affects the dorsocranial portion with obstruction and dilation of Santorini duct and spares the remaining pancreatic parenchyma of the head. As the disease progresses the entire pancreatic parenchyma is involved.

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Microscopy

Histologically, the cysts are localized in the submucosal and muscular layers of the duodenal wall, with frequent extension to the groove region (Figure 18). The internal surface is mainly lined by columnar pancreatic ductlike epithelium, which may be lost and replaced by inflammatory granulation tissue. The duodenum shows Brunner gland hyperplasia and variable thickening and disarray of the muscular layer, due to smooth muscle hyperplasia and fibrosis (Figure 19). Heterotopic pancreatic tissue is intimately associated with the cysts either within the muscular layer or in the submucosa. In most cases the groove area shows marked fibrosis and chronic inflammation. The pancreatic parenchyma frequently shows ductal ectasia with calculi (Figure 20), fibrosis, and inflammatory reaction with myofibroblastic proliferation (Figure 21).

Differential Diagnosis

The number of lesions that have to be considered in the differential diagnosis reflects the different facets of paraduodenal pancreatitis. According to the most prevalent finding, paraduodenal pancreatitis has been reported as Brunner gland hamartoma, as leiomyoma or sarcoma, or as duodenal duplication. The term pancreatic hamartoma has been applied to the more complex lesions characterized by a mixture of duct distortion, the presence of intraduodenal pancreatic parenchyma, 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, because 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 differential diagnosis among periampullary carcinoma, pancreatic head carcinoma, and the solid variant of paraduodenal pancreatitis is difficult. (131) In some cases, the definite diagnosis is reached only after histopathologic examination of the resected specimen.

An important differential diagnosis, with therapeutic implications, is with AIP, which is frequently associated with a swollen main duodenal papilla. (132) The pathologic differential diagnosis is based on the presence on endoscopic biopsies of a rich stromal inflammatory cell infiltrate and the presence of an abundant infiltration of IgG4positive plasma cells ([greater than or equal to] 10 per high-power field). (133) These findings may be valuable adjuncts to the diagnosis of AIP as well as for selecting suitable candidates for corticosteroid therapy. (134)

Pathogenesis

Because paraduodenal pancreatitis is preferentially located in the region of the papilla minor, a study of minor papilla in patients with either paraduodenal pancreatitis or unrelated conditions offers a great opportunity to understand the possible pathogenesis of paraduodenal pancreatitis. The minor papilla is composed of a ductal system frequently surrounded by a sphincterlike structure and consistently associated with intraduodenal pancreatic tissue in anatomical continuity with the dorsocranial pancreas (Figure 22, A and B). Therefore, the cysts might be considered to be dilated ducts associated with intraduodenal pancreas that should not be considered ectopic but as a bud of the dorsal pancreas entrapped within the duodenal wall during organogenesis. (135) This view is further supported by the presence of oval Langerhans islets with only peripheral and isolated pancreatic polypeptide cells, which are considered a feature of the dorsal anlage pancreas. (136) The presence of massive pancreatic parenchyma associated with the minor papilla may reflect incomplete migration of the dorsal pancreas and can explain the relatively high percentage of imperforated minor papilla, which occurs in up to 67% of normal pancreas. (12,137) In the presence of a closed minor papilla, Santorini duct must discharge through the duct of Wirsung. Such countercurrent flow may be impaired by a particularly acute angle of the "Wirsungian knee."

Based on these data, we propose that the pathogenesis of paraduodenal pancreatitis is related to anatomical and/ or functional obstruction of the minor papilla. Exogenous factors, such as alcohol and smoking, might act as favoring/ precipitating factors by rendering the pancreatic juice more viscous and inducing intraductal calcifications, (138,139) thus hindering the normal stream through the minor papilla. By further impairing the discharge, the cysts, Brunner gland hyperplasia, and the reactive spindle cell proliferation may cause the extension of the intraduodenal pancreatitis to the groove region, to the dorsocranial pancreas with compression of the duct of Wirsung, thus adding an obstructive component to the damaging effect of alcohol for the development of the paraduodenal pancreatitis.

The occlusion of the ductal system associated with the minor papilla would also explain the multiple and dynamic character of the cysts (waxing and waning character), which is responsible for the clinical failure of derivative surgeries in paraduodenal pancreatitis. In this regard, the temporary relief of symptoms in some patients may result from the spontaneous rupture of submucosal cysts, as suggested by the modification of site and size of cysts at computed tomography during the follow-up of some patients, as well as by the presence of ulcerations and scars in the duodenal mucosa.

The altered discharge through the minor papilla has been proposed as the cause of 2 paraduodenal pancreatitis- related conditions: groove pancreatitis (12,119,129,140,141) and symptomatic pancreas divisum. (142-147) Both the groove region and the dorsal pancreas share the same accessory duct drainage through the minor papilla.

This pathogenetic hypothesis might have therapeutic implications. It could be speculated that in patients with pure paraduodenal pancreatitis it could be beneficial to perform endoscopic drainage of the minor papilla to decompress the intraduodenal and dorsal pancreas.

CONCLUSIONS

Pancreatic pseudotumors are a polymorphous category of lesions in which a correct preoperative diagnosis is difficult to achieve. We have described criteria that may be useful in the histopathologic distinction of AIP and paraduodenal pancreatitis from ductal carcinoma.

Autoimmune pancreatitis can occur in isolated or syndromic forms. For its correct identification in surgically resected specimens and biopsy material, it is crucial to recognize the distinctive fibroinflammatory process, which can either be limited to the pancreas or extend to the biliary tree.

Paraduodenal pancreatitis is a special type of CP that involves predominantly the duodenal wall in the region of the minor papilla with specific clinicopathologic characteristics.

The pseudotumoral presentation is the product of a fibroinflammatory process within the intraduodenal pancreatic parenchyma associated with cystic transformation, myoid stromal proliferation, and Brunner gland hyperplasia. The frequent pseudotumoral common bile duct stenosis is the effect of the extension of fibrosis to the groove region.

This study was supported by European Community Grant FP6, MolDiagPaca.

Accepted for publication October 8, 2008.

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Giuseppe Zamboni, MD; Paola Capelli, MD; Aldo Scarpa, MD, PhD; Giuseppe Bogina, MD; Anna Pesci, MD; Eleonora Brunello, MD; Gunter Kloppel, MD

From the Department of Pathology, University of Verona, Verona, Italy (Drs Zamboni, Capelli, Scarpa, and Brunello); the Department of Pathology, Sacro Cuore Don Calabria, Negrar, Italy (Drs Zamboni, Bogina, and Pesci); and the Department of Pathology, University of Kiel, Kiel, Germany (Dr Kloppel).

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Giuseppe Zamboni, MD, Department of Pathology, University of Verona, Ospedale Sacro Cuore-Don Calabria, Via don Sempreboni, 5, 37024 Negrar-Verona, Italy (e-mail: giuseppe.zamboni@sacrocuore.it).
Grades of Severity of Autoimmune Pancreatitis

Grade 1   Scattered periductal lymphoplasmacytic
          infiltrates; mild duct obliteration; almost
          no interlobular and acinar involvement
Grade 2   Multiple periductal lymphoplasmacytic
          infiltrates; mild periductal fibrosis and duct
          obliteration; mild interlobular and acinar
          involvement; focal inflammatory storiform
          fibrosis; occasional, mild venulitis
Grade 3   Diffuse periductal lymphoplasmacytic
          infiltrates; marked periductal fibrosis and
          duct obstruction; moderate interlobular and
          acinar involvement; moderate focal
          inflammatory storiform fibrosis; frequent
          venulitis; scattered lymphoid follicles
Grade 4   Diffuse periductal lymphoplasmacytic
          infiltrates; severe periductal fibrosis and
          duct obstruction/disappearance; severe
          interlobular and acinar involvement; severe
          inflammatory storiform fibrosis and diffuse
          sclerosis; frequent venulitis and  occasional
          arteritis; scattered and occasionally
          prominent lymphoid follicles
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Author:Zamboni, Giuseppe; Capelli, Paola; Scarpa, Aldo; Bogina, Giuseppe; Pesci, Anna; Brunello, Eleonora;
Publication:Archives of Pathology & Laboratory Medicine
Article Type:Report
Date:Mar 1, 2009
Words:10242
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