Histological features of type 1 AIP. (a, b) The cell-rich form (a) and transitional form between the cell-rich and fibrotic states (b) of storiform fibrosis. (c) Ductal inflammation. A thick inflammatory collar with storiform fibrosis surrounds the intact duct epithelium. (d) Lobular inflammation. The inflamed lobules show a nodular appearance and maintain their original size. (e) Obliterative phlebitis. An inflammatory nodule found adjacent to an arteriole is a clue to identify obliterative phlebitis. (f) Immunostaining for IgG4. Numerous IgG4-positive cells are seen
Storiform fibrosis is most prominent at the border between the pancreas and the peripancreatic adipose tissue. This will be described in detail in a later section.
Pancreatic Parenchymal Inflammation
The pancreatic parenchymal inflammation can be seen in the pancreatic ducts and lobules.
Although on a pancreatogram the main pancreatic duct looks stenotic and irregular in type 1 AIP, ductal lumens are histologically always open, and the duct epithelium is intact. The ductal inflammation consists of lymphoplasmacytic infiltration that surrounds the epithelium. It can be easily identified in the interlobular pancreatic ducts, but the intralobular ducts are also involved.
The ductal inflammation typically consists of a collar of lymphoplasmacytic infiltration with storiform fibrosis, which looks like a thickened duct wall (Fig. 4.1c). However, there are no structures that are histologically identified as a wall in the normal pancreatic ducts, and thus, they are considered to be a pathological structure caused by the inflammation itself.
The ductal inflammation can also be a thin inflammatory collar of lymphoplasmacytic infiltration just beneath the epithelium, which is surrounded by a fibrotic band. Storiform fibrosis is absent in this pattern.
Although it has not been emphasized as a significant finding in previous reports, the pancreatic lobules are inflamed in a peculiar way. The lobular inflammation is characterized by acinar cell loss and lymphoplasmacytic infiltration. Interestingly though, this is in a fashion in which the original lobular contour and size are preserved (Fig. 4.1d). This is in contrast to the lobular atrophy or loss seen in pancreatitis due to other causes. The lobular contours are sharply defined by the interlobular fibrosis, giving rise to the nodular appearance of the pancreatic parenchyma. This is especially evident when special stains for fibrosis such as Verhoeff-van Gieson stain are performed. In addition, the lobular appearance may resemble storiform fibrosis with or without true fibrosis. The pancreatic lobules are often destructive at the margin of pancreatic parenchyma, which is explained in the following section. Rarely, the pancreatic lobules are atrophic in cases of type 1 AIP with regressive changes.
The lack of neutrophilic infiltration is a feature that distinguishes type 1 from type 2 AIP. However, in about one-third of cases, neutrophils are observed in the lobules of type 1 AIP. This is most likely due to a secondary inflammation that is caused by ductal strictures. In this instance, the distinction between type 1 and type 2 AIP should be made based on the findings of other histological features in the lobules as well as the inflammation seen in the connective tissues.
Nonparenchymal Tissue Inflammation
Connective tissues such as peripancreatic tissue (adipose tissue), vessels (arteries and veins), and nerves are also involved in type 1 AIP.
At the border between the pancreas and the surrounding adipose tissue, a collar of inflammation that surrounds the pancreas is formed. At a glance, this looks like the inflammation of the peripancreatic adipose tissue, but in reality both the peripancreatic adipose tissue and the peripheral portion of the pancreas are involved. Involvement of the pancreas can be recognized by identifying residual islets and small ducts within the lesion. As described earlier, storiform fibrosis is most prominent in this area. When the lesion is thick enough, it can be recognized radiologically as a capsule-like rim . The inflammation at this portion may spread to interlobular septa within the pancreas.
Venous involvement is one of the most well known and unique histological features of type 1 AIP. Venous walls are often infiltrated and destroyed by the inflammatory process, which is histologically similar to that seen around the veins. This inflammatory process further involves venous lumens and finally obliterates them (obliterative phlebitis, Fig. 4.1e). Obliterative phlebitis is common in small veins (venules) that cannot be identified macroscopically. Although obliterated venules are difficult to identify on HE-stained slides, nodular inflammatory lesions adjacent to arterioles are the clue to identify them because the arteries and veins run parallel in the pancreas. In addition, obliterative phlebitis is common and involves relatively larger venules, which makes obliterative phlebitis easily identifiable even on HE-stained slides. According to our study, obliterative phlebitis seen in the larger-sized venules (>100 μm in diameter, as a guide) is more diagnostic for type 1 AIP, and smaller venular lesions are nonspecific . Simple fibrous obstruction without inflammatory cells or only inflammatory cell infiltration without fibrosis in the veins should not be included in obliterative phlebitis in type 1 AIP, because those findings may be seen in pancreatic carcinomas and alcoholic chronic pancreatitis . Obliterative phlebitis with storiform fibrosis is typical for type 1 AIP. When the venous inflammation occurs in a larger vein, such as the splenic vein or portal vein, the luminal occlusion does not occur. This is because they are too large to be occluded completely. Even so, I suggest that this finding is also unique to type 1 AIP. In this situation, it is common to observe a local well-marginated involvement of a vein with storiform fibrosis.
Arteries are also involved in type 1 AIP. This is usually limited to the border between the media and adventitia, and it is thus similar to the periaortitis/periarteritis seen in the larger arteries . Because this involvement is continuous with the surrounding inflammation, it is difficult to determine whether the inflammation is present or not in the arteries themselves. Thus, the true incidence of periarteritis in type 1 AIP has been underestimated. Arteries are not completely occluded by the inflammation, probably due to an anatomical reason, that is, the thicker smooth muscle layer in the arteries.
Perinervous inflammation is common and may be prominent in type 1 AIP. This finding alone, however, is not specific for type 1 AIP because it can also be observed in alcoholic chronic pancreatitis and pancreatic carcinomas.
IgG4-positive cells are numerous in type 1 AIP (Fig. 4.1f) . This finding is helpful for the diagnosis of type 1 AIP, but there are some pitfalls in the evaluation of IgG4 immunostaining.
It is important to stress that the presence of numerous IgG4-positive cells alone is not specific to type 1 AIP or IgG4-RD, and it should be evaluated in the context of histological findings. In the present diagnostic criteria for type 1 AIP such as the International Consensus Diagnostic Criteria (ICDC)  and the clinical diagnostic criteria 2011 in Japan (Japan Pancreas Society (JPS) 2011) , the presence of more than 10 IgG4-positive cells in a high-power field (hpf) is considered to be significant. However, this criterion is not entirely specific to type 1 AIP and can be satisfied in pancreatic carcinomas and pancreatitis with other causes including type 2 AIP [22, 25, 26]. In resected tissues of type 1 AIP, there are usually more than 50 IgG4-positive cells/hpf . This finding is more specific to type 1 AIP. However, in the small biopsy tissues, it is rare to observe more than 50/hpf. This is why the criterion of >10/hpf was adopted as part of the abovementioned criteria. In the Consensus Statement regarding the pathology of IgG4-RD, a >40 % IgG4/IgG-positive cell ratio is mandatory to consider the lesion as highly suggestive of IgG4-RD . This finding is also helpful for the diagnosis of type 1 AIP, especially with biopsy samples.
Another pitfall is that numerous IgG4-positive cells are not always found in genuine type 1 AIP cases. This is particularly true in the cases of type 1 AIP with regressive features. I have also encountered some cases in which the IgG4-/IgG-positive cell ratios were under 40 %.
Histological Diagnostic Criteria of Type 1 AIP
As described in the previous section, the finding of numerous IgG4-positive cells is not specific to type 1 AIP. It is now acknowledged that, for the histological diagnosis of type 1 AIP or IgG4-RD, characteristic histological findings such as storiform fibrosis and obliterative phlebitis are important. This way of thinking is adopted in the ICDC and the JPS 2011.
In the ICDC and JPS 2011 guidelines, type 1 AIP can be definitively diagnosed from the histological features alone. In addition to the lymphoplasmacytic infiltration and numerous (>10/hpf) IgG4-positive cells, storiform fibrosis and/or obliterative phlebitis are mandatory to make a definitive diagnosis of type 1 AIP. If only two of the four findings are satisfied, then the diagnosis should be determined with clinical findings. In the Consensus Statement regarding the pathology of IgG4-RD, a different approach is adopted, and histological findings and IgG4 immunostaining alone are not considered to be diagnostic for IgG4-RD. This is due to the fact that the frequency of the appearance and the specificity of storiform fibrosis and obliterated phlebitis may be different among different organs. In the pancreas, however, it is conceivable to consider that those cases with at least three out of four major histological findings are diagnostic for type 1 AIP, because pancreatitis due to other causes almost never satisfies the criteria.
Special Conditions That Could Be Associated with Type 1 AIP
Some cases of type 1 AIP show some regressive features and are difficult to diagnose histologically. In such cases, the diagnostic features should be identified by conducting a thorough sampling of the resection specimen. Understandably, the biopsy diagnosis of type 1 AIP is very difficult in this situation.
Type 1 AIP may be associated with neoplasms. Pancreatic ductal carcinoma associated with type 1 AIP is such an example [28, 29]. There are also anecdotal reports that type 1 AIP and biliary carcinomas [30, 31] or intraductal papillary mucinous neoplasm of the pancreas [32–34] coexisted. These cases are instructive because even if type 1 AIP is diagnosed with a biopsy, the coexistence of a neoplastic disease cannot be excluded. The reason why such combinations happen is as yet unknown. Some authors suggest that such neoplasms correspond to postinflammatory carcinogenesis as a result of type 1 AIP, because some pancreatic carcinomas become clinically evident after the treatment of type 1 AIP . Other authors have proposed that type 1 AIP is a paraneoplastic condition, because the occurrence of neoplastic diseases is common within 1 year after the treatment of type 1 AIP .
Type 2 AIP/IDCP
The inflammation of type 2 AIP is centered on the exocrine pancreas (Fig. 4.2a). In contrast to type 1 AIP with its unique stromal changes such as storiform fibrosis and obliterative phlebitis, in type 2 AIP the findings in the stroma are nonspecific, and they usually consist of myofibroblastic proliferation and fibrosis.
Histological features of type 2 AIP. (a) The inflammation centered on the exocrine pancreas (an interlobular duct in the right lower area and surrounding pancreatic lobules). The entire duct appears entrapped by the densely packed inflammatory cells. (b) Neutrophilic infiltration within the duct epithelium (GEL). There is also a collar of lymphoplasmacytic infiltration around the epithelium. (c) Lobular inflammation. Neutrophils are numerous within the lobules
The histological feature that characterizes type 2 AIP is the duct-centric inflammation centered on the epithelium [5, 6, 14]. Neutrophils are seen within the lumens and/or epithelium (GEL, Fig. 4.2b). Involvement of interlobular ducts is a diagnostic hallmark, but intralobular ducts and the entire pancreatic lobules are also involved. Type 2 AIP can be seen in the setting of inflammatory bowel disease (IBD). From the pathological viewpoint, this seems reasonable because type 2 AIP and IBD (especially ulcerative colitis) share many histological features. In short, GEL in type 2 AIP corresponds to crypt abscess or neutrophilic infiltration within the epithelium seen in IBD.
The inflammation in the ducts may be similar to but apparently different from that of type 1 AIP. Although the presence and absence of GEL in type 2 and type 1 AIP, respectively, is an important histological feature, there are other clues that distinguish the two subtypes. Because the duct epithelium itself is inflamed in type 2 AIP, the epithelial cells may be degenerative or may contain enlarged and vesicular nuclei which reflect a regenerative nature of the epithelium. Such epithelial changes are usually absent in type 1 AIP. Though there is typically a collar of lymphoplasmacytic infiltration surrounding the duct epithelium in type 2 AIP, it lacks storiform fibrosis. In some cases of type 2 AIP, the entire ducts appear to be entrapped by the densely packed inflammatory cells (Fig. 4.2a). This does not happen in type 1 AIP. In addition, the inflamed ducts in type 2 AIP seem tortuous and star shaped rather than the straight- or round-shaped ducts typically seen in type 1 AIP.