Case 1: Quarter 1, 2021

Case 1: Quarter 1, 2021

Clinical History

A 73-year-old female with a history of monoclonal gammopathy of undetermined significance (MGUS) and small fiber peripheral neuropathy was found to have elevated transaminases and alkaline phosphatase (ALP) – ALT 54 U/L (normal range 15-41), AST 66 U/L (normal range 14-54), ALP 322 U/L (normal range 38-126) on routine laboratory testing. Total bilirubin was within normal limits (0.3 mg/dL), and gamma-glutamyl transferase was not performed. Abdominal CT showed diffuse thickening and enhancement of the extrahepatic and central intrahepatic biliary tree with associated areas of narrowing as well as mild intrahepatic biliary ductal dilation. During ERCP, mucus was seen extruding from a gaping papilla, thus clinically a pancreatic main duct intraductal papillary mucinous neoplasm (IPMN) was considered. Bile duct brushing cytology showed atypical cells, which were favored to represent a reactive process. Whipple resection was performed for the suspected IPMN. After the Whipple procedure, she experienced an initial improvement in laboratory values. A rheumatologic evaluation was negative, including autoimmune (ANA, ANCA, SSA, SSB, anti-dsDNA, and anti-mitochondrial antibodies), infectious (viral hepatitis, HIV), and immunoglobulin (SPEP, quantitative immunoglobulins, including repeated IgG4) testing. Since her initial improvement, follow-up MRI showed new and worsening areas of stricture and continued thickening and enhancement of her biliary tree. Since optimizing her immunosuppressive regimen, her disease has remained stable.

Macroscopic Description

No mass or cystic lesion was identified in the pancreas, bile duct, or gallbladder on gross examination.

Histologic/Cytologic Features 

Microscopic pictures of the gallbladder, cystic duct, common bile duct, ampulla, small bowel submucosa, and pancreas are shown in Figures 1-8. Sections showed that the small-sized veins of the gallbladder, cystic duct, common bile duct, ampulla, small bowel submucosa, and pancreas were involved by a predominantly lymphocytic infiltrate with rare poorly formed, non-necrotizing granulomas. Focal involvement of a medium-sized vein and artery with associated vessel wall fibrinoid necrosis was also seen. The gallbladder and cystic duct were thickened with marked chronic inflammation.

Figure-1. H&E stain of the gallbladder, 25X
Figure-2. H&E stain of the cystic duct, 50X
Figure-3. H&E stain of the common bile duct, 40X
Figure-4. H&E stain of the pancreas, 100X
Figure-5. H&E stain of the pancreas, 25X
Figure-6. H&E stain of the pancreas, 200X
Figure-7. H&E stain of the ampulla, 40X
Figure-8. H&E stain of the small bowel, 40X


Please select your diagnosis in the poll, then see the answer and the discussion in the links below.


What is the diagnosis of the lesion?

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Answer: Vasculitis-related cholangiopathy



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Final diagnosis:  

Vasculitis-related cholangiopathy

Educational Objectives and Discussion:

Educational Objectives

  1. Recognize important histologic features in the assessment of vasculitis and other inflammatory disorders of the biliary tree.
  2. Understand the integration of histologic and laboratory evidence in generating a specific diagnosis.
  3. Review the differential diagnosis and necessary workup for benign mimickers and inflammatory lesions of the biliary tree.


Vasculitis of the biliary system is rare and can present as a component of systemic disease or as single organ involvement, although progression from single organ to systemic disease can occur. Injury to the biliary tree via vasculitis can result in ischemic cholangiopathy. As an acute insult, ischemic cholangiopathy is characterized by edema, necrosis, and sloughing of the biliary epithelium. A chronic course, as may be seen with vasculitis, results in fibrosis of the bile duct with the risk of eventual obliteration [1, 2].

Immunohistochemical staining was performed for this case. CD3 and CD20 stains showed a lymphocytic inflammatory infiltrate composed of a mixed B and T cell population. CD138, IgG, and IgG4 staining showed no increase in IgG4-positive plasma cells (result not shown).

Classification criteria for more common vasculitides were developed by the American College of Rheumatology (ACR) in 1990. The ACR classification criteria integrate clinical characteristics and histopathologic findings, and efforts to systematically update these criteria are ongoing. The current nomenclature of vasculitis is described in the 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides, which also describes some classification features. Vasculitis can be categorized as infectious vs. noninfectious. Noninfectious vasculitis can then be further subdivided by the type of vessel predominantly affected – small, medium, or large. The presence of immune complexes or autoantibodies further contributes to classification in combination with clinical features (patient age, site of involvement, etc) [3].

Among specific rheumatologic entities, biliary involvement is most frequently seen in polyarteritis nodosa, which typically affects medium-sized arteries with a necrotizing inflammatory process and has no ANCA association [4]. The ANCA-associated vasculitides including microscopic polyangiitis (small vessel involvement without granulomas) and eosinophilic granulomatosis with polyangiitis (small to medium vessel involvement) can affect the biliary system as a component of systemic disease [5, 6]. Vasculitis of the extrahepatic biliary tree has also been reported in association with hepatitis B, cryoglobulinemia (including hepatitis C associated), IgA vasculitis, Takayasu vasculitis, and giant cell arteritis [7, 8].

Differential diagnosis:

While a cholestatic pattern of injury with bile duct thickening raises clinical concern for a neoplastic process, the differential diagnosis includes several benign entities. Choledocholithiasis generally can be detected through radiographic and/or endoscopic studies, but an obstructing stone can occasionally be missed. Infectious causes include bacterial, parasitic (Ascaris lumbricoides, Clonorchis sinensis, Opisthorchis viverrini), and opportunistic/AIDS-related (Cryptosporidium parvum, cytomegalovirus) entities.

IgG4-associated cholangiopathy often presents with diffuse involvement of the biliary tree on imaging studies but can mimic primary sclerosing cholangitis with segmental involvement [9]. Key histologic features in IgG4-related disease include a dense lymphoplasmacytic infiltrate that may preferentially affect peribiliary glands compared to the lamina propria, along with storiform fibrosis, and obliterative phlebitis. Immunohistochemical staining for CD138, IgG, and IgG4 with an IgG4+:IgG+ plasma cell ratio >0.4 supports the pathologic diagnosis when observed in combination with typical histologic features [10].

Primary biliary cholangitis (PBC) typically presents as chronic cholestasis, and an antimitochondrial antibody is identified in 95% of cases. Histologically, PBC is characterized by chronic, nonnecrotizing granulomatous lesions primarily affecting the small, intrahepatic bile ducts, although florid duct lesions with necrosis can be seen. Ductular reaction and ductal epithelial cell injury can be seen in early stage PBC. Ductopenia, septal fibrosis, and even cirrhosis can be seen in late stage PBC [11]. Primary sclerosing cholangitis (PSC), in contrast, frequently involves both the intra- and extrahepatic ducts, classically demonstrating a beaded appearance on imaging, which represents alternating segments of stricture and uninvolved duct. Affected bile ducts show a characteristic onion skin pattern of fibrosis that may be associated with mild chronic inflammation and can ultimately result in duct obliteration.

Sarcoidosis frequently involves the liver, and variable involvement of the extrahepatic biliary tree has been reported. The lesions can cause compressive cholestasis when arising along the biliary tree, thereby mimicking PSC [12]. Well-formed non-necrotizing granulomas comprised of epithelioid histiocytes with or without giant cells characterize this entity, typically with multi-organ involvement. While the granulomas of sarcoidosis are usually morphologically distinguishable from the poorly formed granulomas of PBC, the granulomas of PBC are typically a component of bile duct destruction, whereas granulomas of sarcoidosis generally appear as a “bystander” inflammatory process, providing an architectural aid in discerning these entities [13-16].


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  3. Jennette JC, Falk RJ, Bacon PA, et al. 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013 Jan;65(1):1-11.
  4. Barquist ES, Glodstein N, Zinner MJ. Polyarteritis nodosa presenting as a biliary stricture. Surgery 1991;109:16-19.
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  6. Trabelsi ABS, Issaoui D, Ksiaa M, et al. Sclerosing cholangitis in Behçet’s disease. Case Rep Med. 2013;2013:692980.
  7. Hernández-Rodríguez J, Tan CD, Rodríguez ER, et al. Single-organ gallbladder vasculitis: Characterization and distinction from systemic vasculitis involving the gallbladder. An analysis of 61 patients. Medicine (Baltimore). 2014 Nov; 93(24):405-413.
  8. Zhang X, Furth EE, Tondon R. Vasculitis involving the gastrointestinal system is often incidental but critically important. Am J Clin Pathol. 2020 Sep 8;154(4):536-552.
  9. Deshpande V, Sainani NI, Chung RT, et al. IgG4-associated cholangitis: a comparative histological and immunophenotypic study with primary sclerosing cholangitis on liver biopsy material. Mod Pathol. 2009 Oct;22(10):1287-95.
  10. Deshpande V, Zen Y, Chan JKC, et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol 2012.
  11. Lindor KD, Bowlus CL, Boyer J, et al. Primary biliary cirrhosis: 2018 practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2019 Jan;69(1)394-419.
  12. Selvan O, Vij M, Narasiman G, et al. Sarcoidosis mimicking primary biliary cirrhosis – a clinic-pathological description. Trop Gastroenterol. Jul-Sep 2015;36(3):207-9.
  13. Farooq PD, Potosky DR. The Klatskin tumor that wasn’t: an unusual presentation of sarcoidosis. AGC Case Rep J. 2016 Oct 12;3(4):e141.
  14. Gaduputi V, Ippili R, Sakam S, et al. Extrahepatic biliary obstruction: an unusual presentation of hepatic sarcoidosis. Clin Med Insights Gastroenterol. 2015 Apr 19;8:19-22.
  15. Jebran AF, Schmidt WE, Kahraman A, et al. Sarcoidosis of the intra- and extrahepatic bile ducts with concomitant cholangitis in a patient with ulcerative colitis. Case Rep Gastroenterol. 2019 Mar 29;13(1):153-158.
  16. Lewis J. Histopathology of granulomatous liver disease. Clin Liver Dis (Hoboken). 2018 Apr 6;11(3)77-80.


Case contributed by:

Christopher M Sande MD

Zhaohai Yang MD PhD

Department of Pathology and Laboratory Medicine
Perelman School of Medicine at the University of Pennsylvania

Conflict of Interest: NO