January 2020 Case

Mary Wong, MD (Fellow), Kevin M. Waters, MD, PhD, and Brent K. Larson, DO (Faculty)

The patient is a male in his 60s who presented at an outside hospital with abdominal pain and jaundice, was subsequently diagnosed with pancreatic ductal adenocarcinoma, and underwent a total pancreatectomy. He was unable to start chemotherapy due to persistent jaundice and hyperbilirubinemia.

ERCP showed multiple, diffuse biliary strictures. Biopsy of a hilar biliary stricture showed nonspecific mild to moderate acute and chronic inflammation with reactive epithelial changes.

Slides from the original pancreatectomy specimen were retrieved and reviewed, showing some irregularly shaped glands embedded in the pancreatic parenchyma with architectural effacement by a lobular and interlobular fibroinflammatory process (Figure 1, H&E, 40x). On high power, there is marked chronic pancreatitis with lobules containing a lymphoplasmacytic infiltrate with residual scattered benign-appearing ductal glands (Figure 2, H&E, 400x). There is marked vasculitis, including obliterative phlebitis (Figure 3, H&E, 200x) and dense storiform fibrosis (Figure 4, H&E, 100x). Immunohistochemical staining reveals numerous IgG4-positive plasma cells, up to 191 per high-power field, and a ratio of IgG4-(Figure 5, IgG4 immunostain, 200x) to IgG-positive plasma cells (Figure 6, IgG immunostain, 200x) of approximately 0.64 per high-power field in hotspots. Of note, serum IgG4 was elevated to 441 mg/dL (normal range: 4-86 mg/dL) and total serum IgG was elevated to 2106 mg/dL (normal range: 540-1822 mg/dL).

In addition, the patient was cholestatic and had abnormal liver enzymes (ALT 32 U/L, AST 46 U/L, alkaline phosphatase 367 U/L, and total bilirubin 8.3 mg/dL). A liver biopsy showed a mild portal (Figure 7, H&E, 200x) and lobular lymphoplasmacytic infiltrate with marked ductular reaction and cholestasis.

Immunohistochemical staining revealed increased IgG4-positive plasma cells, up to 26 per high-power field, and a ratio of IgG4-(Figure 8, IgG4 immunostain, 400x) to IgG-positive plasma cells (Figure 9, IgG immunostain, 400x) of 0.43 per high-power field in hotspots.

IgG4-Related Disease: Type 1 Autoimmune Pancreatitis and IgG4 Sclerosing Cholangitis

IgG4-related disease (IgG4-RD) is a systemic autoimmune disease characterized by a fibroinflammatory process, frequently with tumor formation. IgG4-RD was initially described in the pancreas, where this manifestation is now called autoimmune pancreatitis, type 1, but it has now been described in nearly every organ system.

Patients with pancreas involvement may present with abdominal pain, jaundice, weight loss, and even a focal mass in the pancreas, mimicking pancreatic ductal adenocarcinoma. In the liver with bile duct involvement, IgG4-related sclerosing cholangitis may present with strictures and dilatations of bile ducts, mimicking primary sclerosing cholangitis, and less commonly as an intrahepatic/hilar mass, mimicking cholangiocarcinoma.

The diagnostic features of IgG4-RD are similar at most sites, with the key features including:

In both the pancreas and liver/bile ducts, histological examination shows patchy to diffuse dense lymphoplasmacytic infiltration with maintenance of the lobular architecture. There is duct-centric inflammation and portal/periportal fibrosis in the liver. Confirmation of the histologic findings and elevated IgG4-positive plasma cells according to the site-specific cutoff values are highly suggestive of IgG4-RD. Clinical features can also be helpful for diagnosing IgG4-RD, including elevated serum IgG4, response to treatment with glucocorticoids, and other organ involvement.

In the current pancreatectomy case, the fibrotic stroma with residual glands with reactive atypia in autoimmune pancreatitis can be mistaken for desmoplastic response with infiltrating carcinoma. However, on closer examination, the lobular architecture is intact, with the lobules separated by storiform fibrosis rather than haphazard desmoplasia. The inflammatory infiltrate also showed the characteristic duct-centric pattern, was rich in IgG4-positive plasma cells, and included obliterative phlebitis.

The diagnosis of type 1 autoimmune pancreatitis in this patient was key to making the diagnosis of IgG4 sclerosing cholangitis, as other organ involvement strongly suggests IgG4-RD. Some of the key characteristics seen in the pancreas were seen in the liver biopsy, including lymphoplasmacytic inflammation, increased numbers of IgG4-positive plasma cells, and fibrosis, though other features, such as obliterative phlebitis, are not demonstrated in the small biopsy.

The diagnosis of IgG4-RD is important, as steroids can treat this debilitating disease. It is important to keep in mind that autoimmune pancreatitis, type 1, may mimic ductal adenocarcinoma clinically, radiologically, and histologically, and therefore the diagnosis of autoimmune pancreatitis, type 1, may prevent surgical intervention.

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