The Characteristic Appearance of Non-Alcoholic Duct Destructive Chronic Pancreatitis.
The majority of the cases of chronic pancreatitis in developed countries are associated with heavy alcohol use. Others cases result from pancreatic neoplasms, pancreas divisum, cystic fibrosis, hyperparathyroidism, or hereditary pancreatitis.[1,2] However, a significant minority of patients lacks these findings. Growing evidence supports a form of chronic pancreatitis, possibly of autoimmune origin, in which the inflammatory and fibrosing process is directed toward the major pancreatic ducts. Non-alcoholic duct destructive chronic pancreatitis (NADDCP) is a recently recognized entity within the broader category of idiopathic chronic pancreatitis.[3,4]
We report 2 patients who presented with lesions in the pancreas thought clinically to represent carcinoma, but who instead had the typical features of this poorly documented form of pancreatitis. Because of the paucity of reports of the histopathologic findings of this entity, we wish to bring these to the attention of surgical pathologists who may encounter this lesion in pancreatic specimens.
REPORT OF 2 CASES
The first patient was a 53-year-old man referred from his primary care physician for surgical evaluation of painless jaundice, polyuria, and polydipsia. He reported an unintentional 13.5-kg weight loss over the prior year The patient's past medical history was significant for a diagnosis of pulmonary sarcoidosis, documented by bronchial biopsy 10 years earlier. He reported moderate alcohol consumption. On physical examination, the patient appeared jaundiced and had mild right upper quadrant tenderness. There were no palpable abdominal masses or lymphadenopathy. Serum alanine transaminase, aspartate aminotransferase, alkaline phosphatase, and bilirubin levels were moderately elevated. A serum viral hepatitis panel was negative. The serum CA19-9 tumor marker was within the normal range. An abdominal ultrasound revealed mild edema around the head of the pancreas and a distended gallbladder without cholelithiasis. An abdominal computerized tomography scan showed intrahepatic and common bile duct dilation as well as an enlarged pancreas. Endoscopic retrograde cholangiopancreatography showed a short distal common bile duct stricture with dilatation proximal to the stricture. A bile duct cytology specimen was negative for malignant cells.
At surgery, there was no evidence of metastatic disease, but the head of the pancreas was diffusely firm and highly suspicious for a malignant process. Intraoperative fine needle aspirates of the pancreas, as well as biopsies from the omentum and regional lymph nodes, were negative for malignancy. A liver biopsy showed a normal capsule and a few normal bile ducts, but no hepatic parenchyma. Nonnecrotizing granulomas compatible with sarcoidosis were noted in the peripancreatic lymph nodes, but not within the pancreatic parenchyma. A pylorus-preserving pancreaticoduodenectomy with cholecystectomy and preservation of the pancreatic body and tail was performed. Postoperatively, the patient's serum was tested for a number of autoimmune antibodies, including antinuclear antibodies, antineutrophil cytoplasmic antibodies, anti-SSA and anti-SSB antibodies, antimitochondrial antibodies, anti-smooth muscle antibodies, antimicrosomal antibodies, and antithyroglobulin antibodies, all of which were negative. The serum rheumatoid factor was mildly elevated. Serum immunoglobulin levels were normal. The patient has fully recovered and is without further problems 12 months postoperatively.
The second patient was a 36-year-old Japanese-American woman admitted to the hospital with a 3-week history of intermittent epigastric pain associated with eating; nausea; diarrhea; and a 6.75-kg weight loss. The patient had no previous significant medical or surgical history and reported only mild alcohol intake. Physical examination upon admission revealed left upper quadrant tenderness. No masses or lymphadenopathy were noted. The patient had a moderately elevated serum lipase level and a mildly elevated serum amylase level. Serum alanine transaminase, aspartate aminotransferase, alkaline phosphatase, and bilirubin levels were normal. The serum CA19-9 level was normal. A computerized tomography scan of the abdomen revealed fullness of the pancreatic body and tail. Magnetic resonance imaging showed a sharply demarcated area of abnormal pancreatic tissue involving the distal body and entire tail of the pancreas. The head of the pancreas appeared normal. An ERCP revealed normal pancreatic duct filling in the head and proximal body of the pancreas, but an abrupt cut-off and an inability to fill the duct within the distal body and tail of the pancreas.
Because of persistent abdominal pain and nausea and the possibility of a malignant process obstructing the pancreatic duct, the patient underwent a distal pancreatectomy with sparing of the spleen. Based on the pathologic findings in the pancreas, the patient's serum was subsequently subjected to a broad array of serologic markers to detect autoimmune disease. She was discovered to have an elevated antinuclear antibody to a titer of 1:80 with a diffusely speckled pattern. Antineutrophil cytoplasmic antibodies, anti-SSA and anti-SSB antibodies, antimitochondrial antibodies, anti-smooth muscle antibodies, antimicrosomal antibodies, and antithyroglobulin antibodies were all negative. Serum immunoglobulin levels were normal. The patient was discharged on a tapering course of prednisone and recovered well.
Gross examination of the surgical specimens from the first patient showed firm, yellow-white, and homogeneous pancreatic tissue measuring 6.0 x 4.5 x 4.5 cm, without any areas of hemorrhage, cystic change, or necrosis. Although firm on palpation, no distinct mass was noted. Histopathologically, the walls of the main pancreatic duct and most of its larger interlobular branches were found to have a patchy, dense, lymphoplasmacytic infiltration with occasional eosinophils (Figures 1 and 2). The ductal epithelium was sloughed off in some areas and in other areas, was partially detached from the basement membrane. The epithelium was focally infiltrated with lymphocytes. There was fibrosis of the involved duct walls, which in combination with the inflammatory infiltration made the duct walls appear slightly thicker than normal. Regenerative changes without dysplasia were seen focally in the duct epithelium. A segment of the common bile duct within the pancreas appeared to be involved with this inflammatory process, whereas the extrapancreatic portion of the duct was uninvolved. Most of the small pancreatic ducts were uninvolved. The lymphocytes were predominantly CD3-positive T cells by immunohistochemical staining (Figure 3). The remainder of the pancreas showed patchy areas of atrophy admixed with thick bands of fibrous tissue that separated the few remaining acini. There was little or no inflammation of the pancreatic tissue in the areas distant from the involved ducts. Fat necrosis, pseudocyst formation, and calculi were absent. Nonnecrotizing granulomas, consistent with sarcoidosis, were present within several of the peripancreatic lymph nodes but not within the pancreas. Intimal hyperplasia of a few arteries was present. The gallbladder showed a chronic inflammatory process principally within the mucosa, consisting mainly of plasma cells and lymphocytes. There were a few scattered lymphoid follicles. The majority of the lymphocytes stained strongly with a CD3 immunohistochemical stain, with the exception of those in the follicles, which were identified as B cells. There were scattered neutrophils within the gallbladder mucosa as well. The gallbladder was without calculi or fibrosis. The cystic duct was unremarkable.
[Figures 1-3 ILLUSTRATION OMITTED]
Gross examination of the distal pancreatectomy surgical specimen received from the second patient revealed alternating firm and edematous areas in the distal 7.3 cm of the pancreas. No discrete mass was identified. Histopathologic examination revealed a dense patchy infiltration of lymphocytes, plasma cells, and eosinophils within most of the larger and midsized pancreatic ducts. The lymphocytes were predominantly T cells (CD3-positive). Small clusters of neutrophils were also evident immediately beneath the duct epithelium and in the adjacent lumen (Figure 4). The inflamed duct walls also exhibited mild fibrosis, making the walls appear slightly thicker than normal. There was a mild patchy proliferation of duct epithelial cells, but no dysplasia. The smaller pancreatic ducts were spared. There was no significant inflammation of the acinar tissue in areas away from the involved duct walls. There was extensive but patchy acinar atrophy and parenchymal fibrosis, but no evidence of fat necrosis, pseudocyst formation, or calculi.
[Figure 4 ILLUSTRATION OMITTED]
In developed countries, chronic pancreatitis is most commonly associated with heavy alcohol consumption. Less frequently reported lesions include those that lead to obstruction of the pancreatic duct, such as trauma, tumor, cysts, or strictures. Rarely, associations are seen with pancreas divisum, cystic fibrosis, genetic abnormalities, or hyperparathyroidism. In about 30% of patients, an underlying cause is not apparent. In recent years, attention has been drawn to cases associated with inflammatory and fibrosing processes of the larger pancreatic ducts and to a possible relationship to autoimmune mechanisms.
Non-alcoholic duct destructive chronic pancreatitis, a term first used by Ectors et al is a form of chronic pancreatitis characterized by a patchy and dense T cell-rich inflammatory infiltrate of the medium and large pancreatic ducts, associated with ductal and periductal fibrosis and focal destruction and regeneration of the duct epithelium. These changes can lead to duct obstruction or even duct destruction. Secondary atrophy of the pancreatic acinar tissue also occurs. Other authors[5-8] have described similar changes in the larger pancreatic ducts, such as duct fibrosis and lymphoplasmacytic infiltration of the duct wall and have suggested that this process may have an autoimmune etiology. Unlike alcoholic pancreatitis, NADDCP is not associated with pancreatic pseudocysts or significant calcification. Despite these descriptions, to our knowledge, there has been limited discussion and histopathologic description of the disease process in the literature.
Yoshida et al first proposed the concept of autoimmune pancreatitis in 1995 and set forth 12 criteria, present in all of the cases they studied: elevated serum gamma globulin or immunoglobulin (Ig) G levels; presence of autoantibodies; diffuse pancreatic enlargement; diffuse irregular pancreatic duct narrowing on endoscopic retrograde cholangiopancreatography; fibrosis and lymphocytic infiltration; absent or mild symptoms, usually without attacks of acute pancreatitis; intrapancreatic common bile duct constriction with proximal dilatation and cholestatic liver dysfunction; absence of pancreatic calcifications or cysts; occasional association with other immune-mediated diseases; and efficacy of steroid therapy. Since then, others have reported meeting some or all of these criteria.[6-8] Kino-Ohsaki et al proposed that antibodies to carbonic anhydrase II antigens, present on the epithelial cells of eccrine ducts, might be responsible for the antibody-mediated reaction that causes the lymphoplasmacytic infiltration of the main pancreatic ducts in patients presenting with idiopathic pancreatitis and Sjogren's syndrome. Sjogren's syndrome has also been described in a patient with chronic pancreatitis, sclerosing cholangitis, and pulmonary infiltrates. Interestingly, the patients of Nieminen et al, like our first patient,
presented with an obstructing mass in the head of the pancreas.
Our 2 patients have exhibited only limited evidence of a possible autoimmune background. Our first patient had granulomas in the lung and lymph nodes compatible with sarcoidosis and a mildly elevated serum rheumatoid factor, and our second patient had an elevated serum antinuclear antibody level. Since our first patient did not have granulomas within the pancreatic parenchyma, his pancreatic disease was not a direct manifestation of sarcoidosis. Neither patient had serologic abnormalities suggesting autoimmune liver disease. It is unclear what relationship, if any, exists between the pancreatic disease and the acalculous form of cholecystitis seen in our first patient. The histopathologic features in the gallbladders are very similar to those described in gallbladders of patients with primary sclerosing cholangitis.[11,12] We have no evidence to date that either of our patients has any evidence of disease of the more proximal extrahepatic or intrahepatic bile ducts. It is interesting that the disease process in these 2 patients and others described with NADDCP is sometimes focal, involving only the head or tail of the pancreas, whereas in an autoimmune process the entire pancreas might be expected to be involved. We are not sure what significance, if any, these findings have in supporting or discounting the theory of an immune-mediated etiology of NADDCP.
We describe 2 cases of NADDCP to bring this entity to the attention of surgical pathologists who may encounter this lesion in resected specimens thought clinically and radiographically to harbor a neoplasm. Hopefully, this mechanism for some cases of chronic pancreatitis will become more widely appreciated, allowing for the use of therapeutic modalities such as steroids or other immunosuppressive agents rather than surgical intervention in these patients.
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Accepted for publication March 1, 2000.
From the Departments of Pathology (Ms Scully and Drs Li and Trainer) and Surgery (Dr Hebert), University of Vermont College of Medicine, Burlington, Vt.
Reprints: Thomas D. Trainer, MD, University of Vermont College of Medicine, Department of Pathology, 111 Colchester Ave, Burlington, VT 05401.