Cytopathology

Autoimmune Pancreatitis

Christine Booth
Cleveland Clinic
Cleveland, OH


Key Words:
Autoimmune pancreatitis, Fine-needle aspiration, Autoimmune disease, Chronic pancreatitis

Clinical History:
This 77-year old African American woman presented to her physician complaining of a 25 pound weight loss, abdominal discomfort and a skin rash. The rash was present on her back, hands, and legs, most prominently on the extensor surfaces. An abdominal CT scan showed a 5.5 cm lobulated pancreatic mass. The virtual slide is a Papanicolaou-stained smear of the pancreatic mass ultrasound-guided fine needle aspirate specimen.


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Figure 1
Pap Stain
Figure 2
Pap Stain
Figure 3
Pap Stain
Figure 4
Pap Stain


Cytologic Diagnosis:
Negative for malignant cells. Lymphocytes present.

Histology Diagnosis:
Chronic pancreatitis with fibrosis.

Cytologic Findings:
The fine needle aspirate specimen is moderately cellular and consists of cellular stromal fragments in a lymphocytic background. At higher magnification, the stromal fragments contain bland spindled mesenchymal cells with a lymphocytic infiltrate. Rare plasma cells are also present in the stromal fragments. Of note, there is an absence of normal benign pancreatic ductal and acinar epithelium. No granulomas are seen.

Discussion:
Autoimmune pancreatitis, though a more recently described entity, is important to recognize whenever possible in fine needle aspirate specimens from endoscopic ultrasound guided fine-needle aspirate biopsies. This cytologic diagnosis can be quite challenging, given that the clinical and radiologic impression often suggest a diagnosis of pancreatic adenocarcinoma. However, this distinction from both pancreatic adenocarcinoma and a chronic pancreatitis, not otherwise specified, is particularly important, since resolution of symptoms occur following administration of corticosteroid therapy. In addition, patients with autoimmune pancreatitis can be spared a surgical procedure when the disease presents as a mass lesion.

Patients with autoimmune pancreatitis usually present as adults during the middle of the sixth decade and are predominantly males (1.7-2.1:1). Preceding a diagnosis of autoimmune pancreatitis, patients may a have concurrent autoimmune disease including Sjögren's syndrome, rheumatoid arthritis, retroperitoneal fibrosis, inflammatory bowel disease or primary sclerosing cholangitis. Similar to patients with pancreatic adenocarcinoma, patients with autoimmune pancreatitis often present to their physicians with jaundice and weight loss. In addition, they may complain of a mild vague abdominal pain. Notably absent are acute attacks of pain which are associated more commonly with acute pancreatitis.

Imaging modalities are crucial in contributing to the diagnosis of this entity. Computed tomography (CT) scan may show either focal or diffuse enlargement of the entire pancreas. Focal enlargement, when present, is most often in the pancreatic head. The presence of a mass-like lesion leads to a consideration of pancreatic carcinoma in the differential diagnostic possibilities. When the pancreas is diffusely enlarged, the findings are considered "sausage-like" or "bulky". This diffuse pancreatic enlargement correlates with diffuse edema on gross examination. With the use of endoscopic retrograde cholangiopancreatography (ERCP), the main pancreatic duct shows either focal or diffuse irregular narrowing with concomitant strictures of the distal common bile duct. This narrowing of the ductal lumen is attributed to the histologic findings of diffuse periductal inflammation. This bile duct narrowing can lead to the jaundice seen in the majority of these patients. Similar to CT scans, endoscopic ultrasonography (EUS) demonstrates a hypoechoic pancreas with either focal or diffuse enlargement. Following visualization of the lesion by EUS, fine-needle aspiration can be accurately performed and assist in the cytologic diagnosis of this entity.

Fine-needle aspiration biopsy of autoimmune pancreatitis demonstrates cytologic features which may closely mimic those of chronic pancreatitis. Both ductal and acinar epithelium is usually inconspicuous due to the paucity of cells present in a background of fibrosis. The most notable feature is the presence of cellular stromal fragments with embedded lymphocytes (greater than 30 per 600x field). The ERCP and serologic features are also useful in differentiating autoimmune pancreatitis from chronic pancreatitis. Patients will have elevated serum levels of IgG4. Immunoglobulin G4 is the least common of the IgG subtypes and accounts for approximately 3 – 6% of the total IgG in the serum of normal subjects. It has an intermediate affinity for Fc, its target antigen, and is unique in that it does not activate complement.

It is also important to distinguish a well-differentiated pancreatic adenocarcinoma from autoimmune pancreatitis, due to their overlapping clinical and radiologic features. In addition, autoimmune pancreatitis can be successfully treated with a course of corticosteroids, thereby avoiding a pancreatic surgical procedure. Maintenance of a normal "honeycomb" pattern in any ductal epithelium on the slide, as well as a lack of nuclear membrane irregularities, anisonucleosis and increased nuclear:cytoplasmic ratios in any ductal epithelial cells favor a non-neoplastic etiology. It has been reported that in cases of pancreatic adenocarcinoma in which stromal fragments are present within the fine-needle aspirate specimen, frankly malignant epithelial cells can usually be identified adjacent to the stroma.

The diagnosis of autoimmune pancreatitis by core biopsy can likewise be difficult. Focal to diffuse fibrosis of the pancreatic stroma with acinar atrophy and a diffuse lymphoplasmacytic infiltrate support the diagnosis of autoimmune pancreatitis, though they are not pathognomonic of it. Further excisional pancreatic biopsy or pancreatoduodenectomy of autoimmune pancreatitis histologically show a collar of periductal lymphoplasmacytic inflammation with occasional eosinophils along with periphlebitis or obliterative phlebitis. Of note, granulomas may also be present. However, unlike the granulomas present in sarcoidosis or those with an infectious etiology, these granulomas have a periductal distribution and do not involve lymph nodes. Immunostaining for IgG4 demonstrates staining of plasma cells, often present in a periductal distribution. The lymphoplasmacytic infiltrate is present within a myofibroblastic-like stroma surrounding both large and small interlobular pancreatic ducts. The myofibroblastic proliferation may extend into the peripancreatic soft tissue and coalesce to form a tumor-like lesion (pseudotumor). It is also important to exclude features of chronic alcoholic pancreatitis in these cases. These features include pseudocysts, calcifications, autodigestive necrosis and ductal dilation with mucous protein plugs.

Fine-needle aspiration of the pancreas can help to exclude a pancreatic adenocarcinoma and suggest autoimmune pancreatitis. This is of great clinical benefit to the patient, as autoimmune pancreatitis will respond well to corticosteroid therapy and the patient can be spared a pancreaticoduodenectomy. Associated conditions such as Sjögren's syndrome, rheumatoid arthritis and ulcerative colitis, as well as an elevated serum IgG4 level may assist in the differential diagnosis. Also, core biopsy and resection specimens often show IgG4 immunostaining of the cytoplasm of plasma cells in a ductulocentric distribution. However, the utility of immunostaining of IgG4 in fine-needle aspirate biopsy specimens has not been described. The presence of IgG4-positive plasma cells outside the pancreas, including the common bile duct, liver, salivary glands, and ampulla of Vater has been documented and supports the hypothesis that autoimmune pancreatitis is part of a multisystem disease.

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