January 2020 Case Cedars-Sinai Skip to content Close Select your preferred language English عربى 简体中文 繁體中文 فارسي עִברִית 日本語 한국어 Русский Español Tagalog English English عربى 简体中文 繁體中文 فارسي עִברִית 日本語 한국어 Русский Español Tagalog Translation is unavailable for Internet Explorer Cedars-Sinai Home 1-800-CEDARS-1 1-800-CEDARS-1 Close Find a Doctor Locations Programs & Services Health Library Patient & Visitors Community My CS-Link Education clear Go Close Academics Academics Faculty Development Community Engagement Calendar Research Research Areas Research Labs Departments & Institutes Find Clinical Trials Research Cores Research Administration Basic Science Research Clinical & Translational Research Center (CTRC) Technology & Innovations News & Breakthroughs Education Graduate Medical Education Continuing Medical Education Graduate School of Biomedical Sciences Professional Training Programs Medical Students Campus Life Office of the Dean Simulation Center Medical Library Program in the History of Medicine About Us All Education Programs Departments & Institutes Faculty Directory Anatomic and Clinical Pathology Residency Back to Anatomic and Clinical Pathology Residency Application Information Explore the Residency Training Curriculum Autopsy Pathology Rotation Bone and Soft Tissue Head and Neck Pathology Rotation Breast Pathology Rotation Cardiovascular Pathology Rotation Clinical Chemistry Rotation Coagulation Rotation Cytopathology Rotation Dermatopathology Rotation Forensic Pathology Rotation Frozen Section Rotation Gastrointestinal and Liver Pathology Genitourinary Pathology Rotation Genomic Pathology Rotation Gynecologic Pathology Rotation Hematopathology Rotation Laboratory Management Rotation Microbiology Rotation Neuropathology Rotation Pulmonary and Mediastinal Pathology Rotation Renal Pathology Rotation Transfusion Medicine Rotation Surgical Pathology Pathology Physician Scientist Training Program Residents Graduates Case of the Month Archive Publications Leadership Frequently Asked Questions January 2020 Case Authors Mary Wong, MD (Fellow), Kevin M. Waters, MD, PhD, and Brent K. Larson, DO (Faculty) Subject Gastrointestinal and Liver Pathology Clinical History 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. Diagnosis IgG4-Related Disease: Type 1 Autoimmune Pancreatitis and IgG4 Sclerosing Cholangitis Discussion 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: Two or more of the following histological features: Dense lymphoplasmacytic infiltration Storiform fibrosis Obliterative phlebitis Both of the following: Abundant IgG4-positive cells, the absolute counts of which vary by specimen site and type (biopsy versus resection) Pancreas: >10/HPF (biopsy), >50/HPF (resection) Bile Duct: >10/HPF (biopsy), and >50/HPF (resection) An increased IgG4+/IgG+ plasma cell ratio: >40% 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. References Bledsoe JR, Shingare SA, Deshpande V. Difficult Diagnostic Problems in Pancreatobiliary Neoplasia. Arch Pathol Lab Med. 2015;139(7):848-57. Chen JH, Deshpande V. IgG4-related Disease and the Liver. Gastroenterol Clin North Am. 2017;46(2):195-216. Deshpande V, Zen Y, Chan JK, et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol. 2012;25(9):1181-92 Detlefsen S, Kloppel G. IgG4-related disease: with emphasis on the biopsy diagnosis of autoimmune pancreatitis and sclerosing cholangitis. Virchows Arch. 2018;472(4):545-556. Odze, Robert D., MD, FRCP(C), Goldblum, John R., MD. Surgical Pathology of the GI Tract, Liver, Biliary Tract and Pancreas, 3rd edition. Philadelphia, PA: Saunders, an imprint of Elsevier Inc.; 2015. Shimosegawa T, Chari S, Frulloni L, et al. International Consensus Diagnostic Criteria for Autoimmune Pancreatitis. Pancreas. 2011;40(3):352-8. Weindorf SC, Frederiksen, JK. IgG4-Related Disease: A Reminder for Practicing Pathologists. Arch Pathol Lab Med. 2017 Nov;141(11):1476-1483. Have Questions or Need Help If you have questions or would like to learn more about the Anatomic and Clinical Pathology Residency Program at Cedars-Sinai, please call or send a message to Academic Program Coordinator, LeeTanya Marion-Murray. Department of Pathology and Laboratory Medicine 8700 Beverly Blvd., Room 8709 Los Angeles, CA 90048-1804 310-423-6941 send a message Please ensure Javascript is enabled for purposes of website accessibility