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Autoimmune pancreatitis: A mimic of pancreatic cancer

Cleveland Clinic Journal of Medicine. 2009 October;76(10):607-615 | 10.3949/ccjm.76a.09039
October 1, 2009|Cleveland Clinic Journal of Medicine
Ryan Law, DO;Mary Bronner, MD;David Vogt, MD;Tyler Stevens, MD
Author and Disclosure Information

Ryan Law, DO
Department of General Internal Medicine, Cleveland Clinic

Mary Bronner, MD
Section Head, Morphologic Molecular Pathology, Pathology and Laboratory Medicine Institute, Cleveland Clinic

David Vogt, MD
Departments of Hepato-pancreatobiliary and Transplant Surgery, General Surgery, and Transplantation Center, Digestive Disease Institute, Cleveland Clinic

Tyler Stevens, MD
Digestive Disease Institute, Cleveland Clinic

Address: Tyler Stevens, MD, Digestive Disease Institute, A31, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail stevent@ccf.org

ABSTRACTAutoimmune pancreatitis is an idiopathic inflammatory disease that produces pancreatic masses and ductal strictures. This benign disease resembles pancreatic carcinoma both clinically and radiographically. The diagnosis of autoimmune pancreatitis is challenging to make. However, accurate and timely diagnosis may preempt the misdiagnosis of cancer and decrease the number of unnecessary pancreatic resections.

KEY POINTS

  • Hallmark features of autoimmune pancreatitis include an elevated serum immunoglobulin G4 level, focal or diffuse pancreatic enlargement on imaging, and dense lymphoplasmacytic infiltrates on histologic study.
  • The disease can be associated with extrapancreatic manifestations, including sclerosing cholangitis, sialadenitis and retroperitoneal fibrosis.
  • Autoimmune pancreatitis responds dramatically to corticosteroid treatment.

Histopathologic findings

Figure 3. Autoimmune pancreatitis with intense and destructive fibroinflammatory replacement of normal pancreatic parenchyma. A focal atrophic lobule of residual acinar tissue can be seen in the upper right-hand corner (arrow).
On gross examination, the pancreas is firm and enlarged with gray-yellow discoloration.1,23,30 The typical lobular architecture is disturbed by diffuse fibrosis (Figure 3). In localized disease, the inflammatory mass is most often in the head of the pancreas. Our patient had features of fibrosis on gross examination during surgery, but he also had a focal inflammatory mass in the pancreatic head.

Histologic evaluation remains the gold standard for diagnosis. The histologic diagnosis can be made in patients who have any or all of the following three most common histologic features of autoimmune pancreatitis10,23,31–33:

  • Parenchymal and often periductal lymphoplasmacytic infiltration, which is typically florid in intensity
  • Storiform fibrosis
  • Obliterative phlebitis.

The histologic findings in our patient included lymphoplasmacytic infiltration and obliterative phlebitis, which were essential to establishing the diagnosis. In a series of 53 patients, parenchymal inflammation with periductal lymphoplasmacytic accentuation was found in all of them.33

Figure 4. IgG4 immunohistochemistry in autoimmune pancreatitis showing more than 30 stained plasma cells (brown cells) per 400X high-power field (dimethylaminoazobenzine chromagen and hematoxylin counterstain).
Infiltration. The lymphocytic response is dominated by CD4+ and CD8+ T lymphocytes. Plasma cells are abundant (> 10 per high-power field) and are positive for IgG4 on immunostaining (Figure 4).31,34,35 In one cohort,11 15 (94%) of 16 patients with autoimmune pancreatitis had abundant IgG4-positive cells in tissue obtained by pancreatic core biopsy. IgG4-positive plasmacytes can also be seen in involved extrapancreatic sites, such as the biliary tree, retroperitoneum, lymph nodes, and salivary glands.8

Biopsy of extrapancreatic sites, including the bile ducts and major duodenal papilla, may also facilitate the diagnosis.34,35 In a recent study,34 80% of autoimmune pancreatitis patients with pancreatic head involvement had significant numbers of IgG4-positive cells on biopsy of the major duodenal papilla. Biopsy of the periampullary duodenum may be a safer alternative to guided fine-needle aspiration or core biopsy.

In addition to lymphocytes, the inflammatory infiltrates in autoimmune pancreatitis may contain macrophages, mast cells, neutrophils, and eosinophils. Nonnecrotizing granulomas are occasionally seen, including periductal granulomas.

Fibrosis. Ductal luminal destruction can be seen in conjunction with fibrosis that thickens the duct wall and forms interlobular septa.33 Fibrosis may also affect the acinar tissue and produce profound lobular atrophy. In severe cases, the fibrotic changes can encompass large areas, with myofibroblasts arranged in a storiform pattern resembling an inflammatory pseudotumor.36

Phlebitis. The vascular changes in autoimmune pancreatitis have been underemphasized relative to the pancreatic parenchymal fibroinflammatory changes. Venulitis is seen mainly in small and medium-size pancreatic and peripancreatic veins. The inflammatory response and fibrosis disrupt the venous endothelium and often result in obliterative phlebitis.

Figure 5. Obliterative venulitis. Panel A shows a hematoxylin and eosin stain, which poorly visualizes obliterative venulitis. The artery is easily found (arrows); however, the paired venule is poorly seen. The lack of visualization of the venule suggests that it is obliterated by the inflammatory process. Panel B shows a Movat pentachrome stain of the same area. This confirms the highly specific obliterative and lymphocytic venulitis of autoimmune pancreatitis (arrows). Fibrosis and lymphoplasmacytic infiltration destroy the vein wall and disrupt its elastin fibers, resulting in narrowing and even occlusion.
The venous lesions can be notoriously difficult to see on hematoxylin and eosin staining alone, whereas the prominent elastin fiber disruption of vein walls in autoimmune pancreatitis is highlighted and made obvious on Movat staining (Figure 5).31 In a recent study,31 a Movat histochemical vascular stain had 100% sensitivity (in 15 cases of autoimmune pancreatitis) and 99% specificity (falsely identifying only 1 of 103 usual chronic pancreatitis, pancreatic cancer, and normal pancreatic controls) for lymphocytic and obliterative venulitis. Sixty-five percent to 100% of patients show obliterative phlebitis on histology enhanced with a Movat vascular stain.31,37 Movat vascular staining should be performed in conjunction with IgG4 immunohistochemistry for all suspected cases of autoimmune pancreatitis.31

However, Movat staining may not be available if an operative frozen section is being analyzed. In these cases, the venous lesions can be found by localizing the paired arteries, which are usually entirely normal and readily evident. If paired veins are not seen in this manner, a high level of suspicion should be raised for autoimmune pancreatitis with lymphocytic vein destruction.

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