A 39-year-old man presents with worsening right upper abdominal pain. He has a history of ulcerative colitis. An ultrasound demonstrates choledocholithiasis and prominent-appearing extrahepatic bile ducts. In addition, a vague mass near the hilum of the liver is visualized. A partial hepatectomy including excision of the mass is performed. Gross examination reveals a fibrous area measuring up to 3.5 cm, adjacent to dilated extrahepatic bile ducts. Representative sections of both the mass and surrounding hepatic parenchyma are submitted for histologic evaluation.

Master List of Diagnoses

  • Autoimmune hepatitis
  • IgG4-associated cholangitis
  • Primary biliary cirrhosis
  • Primary sclerosing cholangitis
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This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2017, Case 08, and is primary sclerosing cholangitis of the liver.

Criteria for Diagnosis and Comments

Histologic sections demonstrate hepatic parenchyma and sampling of extrahepatic bile ducts. Portal tracts appear prominent, and in multiple foci, there is concentric “onion-skin” fibrosis surrounding bile ducts. Some portal tracts contain a mixed inflammatory component which infiltrates bile duct epithelium. These areas also show epithelia with degenerative changes. There is some mild non-specific steatosis. Large bile duct branches demonstrate similar histologic findings, including bile ductular proliferation. Many sections also include sampling of the fibrous area identified grossly, which consists of markedly dilated extrahepatic bile ducts. These areas show mixed inflammation, concentric fibrosis, epithelial ulceration, and intraluminal bile plugs. Surrounding bile ductular proliferation is prominent, but no significant epithelial atypia or perineural invasion is appreciated. The histologic findings, in conjunction with a proper clinical work-up, are diagnostic of primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic disorder of unknown etiology, which is characterized by fibrosis and inflammation, damaging the walls of the biliary tree. This leads to bile duct damage in the form of stenosis and ectasia, and eventual bile duct loss. Progression to biliary cirrhosis and development of cholangiocarcinoma are seen as complications in a subset of cases.

PSC is mainly a disease of extrahepatic and larger intrahepatic bile ducts, though involvement of small bile ducts is usually present. Rare (approximately 5%) of PSC cases involve only small bile ducts; this has been termed “small-duct primary sclerosing cholangitis.” PSC must be differentiated from many secondary causes sharing similar clinicopathologic features; ie, secondary sclerosing cholangitis. Numerous etiologies, including cholelithiasis/choledocholithiasis, infection, bile duct ischemia, previous biliary tract surgery, and congenital bile duct anomalies, need to be ruled out. Indeed, exclusion of these entities formed a prerequisite of the classic diagnostic criteria of PSC. However, it is recognized that some patients with PSC were unrecognized when biliary tract surgery or cholelithiasis/choledocholithiasis occurred prior to the diagnosis. It may be difficult to separate PSC from secondary causes, as they share many radiographic and pathologic features. However, there is an association with inflammatory bowel disease (IBD) not seen in secondary causes of sclerosing cholangitis.

The majority of PSC cases (approximately 50%–75%) are associated with IBD, which is usually ulcerative colitis. However, only a minority (less than 10%) of IBD patients will develop PSC. Crohn disease is also associated with PSC; these patients typically have colonic disease.

PSC is usually seen in patients younger than 50 years of age, though all age groups can be affected. PSC can be seen in infancy and childhood. The male:female ratio is 2–3:1. Initial clinical symptoms are vague and include upper abdominal pain and fatigue. Bouts of cholangitis and recurring jaundice can also be seen. However, the majority of patients are asymptomatic at the time of diagnosis. Some patients are diagnosed when an elevated alkaline phosphatase or gamma-glutamyl-transpeptidase level is detected when IBD patients are screened for liver disease.

Progression to cirrhosis and liver failure occurs in the majority of PSC cases, which has been reported to happen as soon as five years after diagnosis. Treatment with ursodeoxycholic acid alleviates symptoms, but it does not appear to alter progression of the disease. Liver transplantation is the only effective treatment. Even after transplantation, up to approximately 25% of patients can develop a relapse of PSC.

Genetic and autoimmune etiologies have been proposed. Associations with HLA haplotypes and familial cases of PSC have been reported. Aberrant antigen expression in bile duct epithelium and recruitment of mucosal T-cells in the biliary tract have supported an autoimmune mechanism. The same mechanisms for secondary sclerosing cholangitis have been investigated in PSC. However, a definitive causative etiology remains elusive.

Although liver biopsy is important to help stage PSC, it is not considered necessary for the diagnosis. This is because the disease usually manifests itself in large bile ducts. Currently the gold standard for diagnosis is biliary tree imaging, either by endoscopic retrograde cholangiopancreaticography or magnetic resonance cholangiopancreaticography (MRCP). These studies show characteristic strictures and beading irregularly involving the biliary tree. These findings are essentially pathognomonic for PSC. In the minority of patients with small-duct PSC, a liver biopsy can show typical findings (see below). There are currently no diagnostic laboratory studies for PSC. Although alkaline phosphatase is usually elevated, it can be normal. ANCA and other autoimmune serologies can be positive, though they are neither sensitive nor specific. However, anti-mitochondrial antibody (AMA) positivity is not seen in PSC.

The typical histologic findings of PSC are centered around bile ducts. These consist of a fibro-inflammatory attack leading to concentric “onion-skinning” fibrosis surrounding bile ducts. Epithelial atrophy accompanies the fibrosis. Over time, bile ducts are replaced by fibrous cords. When these findings accompany reduced numbers of interlobular bile ducts, they are essentially diagnostic of PSC. Similar findings can be seen in the portal tracts of needle liver biopsies, though they are not considered pathognomonic for PSC as they are shared by other etiologies. However, they are certainly compatible with PSC when biliary tree imaging shows typical findings, as well as cases of small-duct PSC. Bile duct loss is most easily recognized when a lone hepatic arterial branch is identified in portal tracts. Larger intrahepatic and extrahepatic ducts also show fibrosis, and epithelial ulceration and accumulation of intrahepatic bile sludge can occur. Although unusual, granulomatous inflammation can occur in response to inspissated bile salts. This finding should not lead a pathologist to entertain a diagnosis of primary biliary cirrhosis (PBC) without other confirmatory evidence. Bile ductular proliferation can be seen in areas of extensive fibrosis, which may raise the suspicion of cholangiocarcinoma. Unless there is clear evidence of neoplasia (ie, perineural invasion, marked cytologic atypia), a proliferation of small bile ducts should not automatically be considered malignant.

Like PBC, PSC has a four-tiered stage. Stage 1 histologic findings are confined to the portal tract and include mixed inflammation with variable fibrosis and degenerative bile duct epithelial changes. Stage 2 typically shows more extensive bile duct damage and some ductular proliferation, as well as interface inflammation. Stage 3 involves more portal fibrosis as well as portal-portal septal formation. Cirrhosis formation signifies stage 4. As PSC progresses in stages, inflammation usually subsides. Bile duct loss, though not included in stage classification, is typically seen in later stages.

Liver biopsies from patients with PBC show a similar disease progression and end result: loss of bile ducts. In some cases without confirmatory radiographic studies, it can be very difficult to separate early stages of PSC from PBC on histologic grounds alone. Indeed, in one large study of both PSC and PBC cases only 28% were able to be distinguished by routine histology. Features that favor PSC over PBC include concentric periductal fibrosis and lack of granulomas. Clinical findings may help; PBC shows a marked female predominance, a later age presentation, and lack of association with IBD. In difficult cases, pathologists should recommend imaging studies and serology for AMA.

IgG4-associated cholangitis is a recently described entity that shares clinical and radiographic findings with PSC, including beading and strictures on biliary tree imaging. It is considered a secondary cause of sclerosing cholangitis and shares some histologic findings with PSC. Unlike PSC, IgG4-associated cholangitis is steroid responsive, and the risk of subsequent cholangiocarcinoma is considered much lower. In earlier stages of PSC, a mixed inflammatory component can predominate, and can include numerous plasma cells. This finding can mimic the inflammatory component seen in liver biopsies of patients with IgG4-associated cholangitis, though the latter typically shows more periportal extension. When in doubt, immunohistochemical studies to quantify IgG4-positive plasma cells should resolve the diagnosis. If IgG4-positive plasma cells number greater than 10 per high-powered field, IgG4-associated cholangitis is most likely.

As discussed above, PSC may occasionally show a prominent plasma cell infiltrate. In later stages where interface inflammation occurs, this finding may be confused with autoimmune hepatitis (AIH). Compounding the problem is that histologic findings of AIH are more commonly verified in liver biopsies when compared to PSC. Indeed, an overlap syndrome between PSC and AIH is rare but well documented. These cases are typically seen in the pediatric population. In problematic cases, a thorough radiologic and clinical investigation should help distinguish between PSC and AIH. Seropositivity for anti-smooth muscle antibody (ASMA) will point to a diagnosis of AIH. In overlap syndromes, an initial AIH-like picture may progress with cholangiographic findings of PSC. It is important to consider these overlap syndromes, as addition of immunosuppressive therapy can be beneficial.

  1. Which of the following is most characteristic concerning primary sclerosing cholangitis?
    1. ANCA serology is a specific test for the disease.
    2. AMA serology can be positive in primary sclerosing cholangitis.
    3. Histologic features reliably differentiate the later stages of primary sclerosing cholangitis and primary biliary cirrhosis.
    4. Liver biopsy is not considered a requirement for the diagnosis.
    5. Progression to cirrhosis and liver failure only occurs in a minority of patients.
  2. A young adult patient presents with intermittent upper abdominal pain and jaundice. Alkaline phosphatase is elevated, and AST and ALT are mildly elevated. An MRCP demonstrates strictures and beading of extrahepatic ducts. Serologies are positive for ASMA and negative for AMA. A liver biopsy shows a mixed inflammatory infiltrate in portal tracts with degenerative-appearing bile ducts. In some areas, plasma cells appear prominent, and inflammation extends into the lobules. An IgG-4 immunostain highlights less than 10 plasma cells per high-powered field. Which of the following is most characteristic?
    1. A primary sclerosing cholangitis/autoimmune hepatitis overlap syndrome is unlikely.
    2. IgG4-associated cholangitis is the most likely diagnosis.
    3. Immunosuppressive therapy may be beneficial.
    4. Primary biliary cirrhosis is a diagnostic consideration.
    5. Primary sclerosing cholangitis is ruled out.
  3. Which of the following is the most specific histologic finding of primary sclerosing cholangitis?
    1. Concentric “onion-skin” fibrosis surrounding bile ducts
    2. Decreased numbers of portal tracts
    3. Lack of granulomatous inflammation
    4. Large bile duct damage with lack of small duct involvement
    5. Mixed inflammation in bile duct epithelium

References

  1. Chapman R, Fevery J, Kalloo A, et al. Diagnosis and Management of Primary Sclerosing Cholangitis. Hepatology. 2010(51):660-678.
  2. Deshpande V, Sainani NI, Chung RT et al. IgG4-associated cholangitis: a comparative histologic all and immunophenotypic study with primary sclerosing cholangitis on liver biopsy material. Mod Pathol. 2009(22):1287-1295.
  3. Hubscher SG, Burt AD, Portmann BC, Ferrell LD (eds). MacSween’s Pathology of the Liver(6th ed). Edinburgh, UK: Churchill Livingston Elsevier; 2012.
  4. Washington, MK. Autoimmune liver disease: overlap and outliers. Mod Pathol.2007(20):S15-S30.
  5. Zen Y, Nakanuma Y, and Portmann B. Immunoglobulin G4-related sclerosing cholangitis: pathologic features and histologic mimics. Semin Diagn Pathol. 2012;29(4):205-211.

Author

Brad B. Bryan, MD, FCAP
Surgical Pathology Committee
Central Oregon Pathology Consultants
Bend, OR

Answer Key

  1. Liver biopsy is not considered a requirement for the diagnosis. (d)
  2. Immunosuppressive therapy may be beneficial. (c)
  3. Concentric ‘onion-skin’ fibrosis surrounding bile ducts (a)