Interactive Microscopy Session:

Second Edition: Modern Surgical

Pathology Through the Expert Eyes of
APSS-USCAP: Cases That Will Make You
Love Your Liver
Handout

Laura W. Lamps, MD
Godfrey D. Stobbe Professor of Gastrointestinal Pathology and
Patient Safety Officer
University of Michigan

Course Dates: October 27-30, 2019

Interactive Microscopy Session | Second Edition: Modern Surgical Pathology Through The Expert
Eyes of APSS-USCAP: Cases That Will Make You Love Your Liver | Laura W. Lamps, MD
(Oct. 27-30, 2019)

Cases That Will Make You Love Your Liver

Several viruses that are not considered specific “hepatitis” viruses also cause hepatitis,
often as part of systemic infection. Epstein-Barr virus (EBV) infection should be
considered in any age group, and the liver is affected in over 90% of patients and
symptomatic involvement in 5–10%. Dense mononuclear infiltrates, often containing large
atypical lymphocytes, are found in portal tracts and sinusoids; in the latter, they spread in
a distinctive single-file, ‘string-of-beads’ or ‘Indian-file’ array. Kupffer cells are
hypertrophic, and epithelioid and fibrin-ring granulomas are occasionally found. In situ
hybridization is a useful ancillary tool in confirming the diagnosis; however, EBER-positive
lymphocytes can be sparse and easily overlooked. Occasionally EBV-associated
hepatitis must be distinguished from hepatic involvement by leukemia or lymphoma.

Drug-induced liver injury (DILI) is the leading cause of acute liver failure in the United
States. But recognition is challenging for several reasons, not the least of which is that it
can mimic virtually any other type of liver disease. In addition, the same drug may cause
different patterns of liver damage in different patients; it is often impossible to pinpoint the
causative agent in patients on multiple drug therapy, which usually is the case in elderly
patients, and a patient’s drug history is often far from reliable. Besides medicinal drugs,
one also has to consider hepatotoxicity from herbs and dietary supplements. Common
histologic effects produced by DILI include hepatitis, lipofuscinosis, steatosis,
phospholipidosis, apoptosis, necrosis, granulomas, vascular changes, Ito cell
hyperplasia, cholestasis (the most common), and cholangitis. A ground glass appearance
of hepatocytes in the centrilobular area, similar to that seen in chronic HBV infection, can
be caused by a number of drugs such as phenobarbital, rifampin, dioxin, and cyanamide.
Ito or hepatic stellate cell hyperplasia has also been associated with a number of drugs
including hypervitaminosis A and niacin.

IgG4-related sclerosing cholangitis is often part of the autoimmune pancreatocholangitis

spectrum. Grossly, it may produce fleshy lesions along the biliary tree, and imaging
studies may mimic either PSC or cholangiocarcinoma. One of the most common
histopathologic features is the presence of numerous IgG4+ plasma cells within involved
tissues, as well as lymphoplasmacytic infiltration of the duct with extensive storiform
fibrosis, and obliterative phlebitis, similar to IgG4-associated sclerosing pancreatitis. The
distinction from PSC may be very difficult, but the finding of more than 10 IgG4-positive
plasma cells per high power field) and an IgG4/IgG ratio of more than 40% favor IgG4-
SC, as does the presence of storiform fibrosis, elevation of serum IgG4, and involvement
of other organs. Some cases of PSC may show increased f IgG4 plasma cells, but they
are typically not as numerous as IgG4-SC, and IgG4-SC does not typically have ‘onion-
skin’ fibrosis or significant ductopenia affecting small ducts. Sclerosing cholangitis may
also occur in the context of common variable immunodeficiency and other immune
deficiency disorders, cystic fibrosis, and Langerhans cell histiocytosis.

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Interactive Microscopy Session | Second Edition: Modern Surgical Pathology Through The Expert
Eyes of APSS-USCAP: Cases That Will Make You Love Your Liver | Laura W. Lamps, MD
(Oct. 27-30, 2019)

Epithelioid granulomas are present in 3–10% of liver biopsies. Evaluation of hepatic

granulomatous lesions requires careful histologic evaluation of the granulomas
themselves and of the associated hepatic changes (e.g., hepatitis, bilirubinostasis, bile
duct damage), as well as correlation with clinical history and laboratory information.
According to one study, a combined histologic, clinical, serologic, and molecular approach
can clarify the etiology in up to 64% of cases. The incidence of hepatic granulomas in
patients with established sarcoid varies from 21% to 79%.. The epithelioid granulomas of
sarcoidosis typically occur with greatest frequency in the portal and periportal areas, often
in clusters. The granulomas may be of differing ‘ages’ and typically are associated with
dense fibrosis, so that varying numbers and degrees of epithelioid cells, inflammation,
giant cells, and scarring are often seen in the same biopsy. The differential diagnosis
includes, of course, infection, granulomatous drug reaction, and primary biliary
cholangitis.

Pyogenic hepatic abscesses in the United States are often due to enteric bacteria and
seen in older patients (often with diverticulosis) or in HIV-infected or other
immunocompromised young individuals. Multiplicity of lesions is seen in about half of
pyogenic abscesses and 25% of amebic abscesses. Amebic abscess is usually single,
although in immunocompromised patient there is a greater tendency for multicentricity.
Most cases occur in adults, but they can also develop in infants and children. The necrotic
center usually contains an odorless, pasty, chocolate brown fluid. Microscopically, the
bulk of the lesion consists of necrotic material with few if any neutrophils, surrounded by
a layer of fibrin, macrophages, lymphocytes, and a few fibroblasts. The abscess wall is
thinner than that of bacterial liver abscess. Clusters of amoeba are usually found, but
extensive search may be necessary for their detection.

The differential diagnosis of HCC is broad, and complicated by a number of histologic

variants that have no clinical implications but can make histologic evaluation more
challenging. Clear cell hepatocellular carcinoma is due to the accumulation of glycogen
and/or fat, and may closely resemble clear cell renal cell carcinoma or adrenal cortical
carcinoma . Immunostains for HepPar-1 or arginase-1, PAX-8 (for renal cell carcinoma),
and inhibin, MART-1, or SF-1 for adrenal cortical carcinoma are often helpful. The clear
cell variant of HCC should not be confused with the more recently described steatotic
variant, which is associated with fatty liver disease and metabolic syndrome. Sclerosing
or scirrhous HCCs are rare, and have marked fibrous stroma, lack of a fibrous capsule,
preserved intratumoral portal tracts, and contiguous multinodularity They are much less
likely to express Hep Par-1, and more likely to express markers of adenocarcinoma such
as EpCAM, CK19, and CK7, leading to diagnostic confusion. The vast majority do mark
with arginase-1 and glypican-3. Sarcomatoid (spindle) cell HCC contains spindled and/or
multinucleated cells of mesenchymal appearance, often with areas of conventional HCC
as well. Variable immunoreactivity with Hep Par-1 and keratins has been reported.
Osteoclast-like giant cells bone and cartilage, and skeletal muscle may also be present.
Fibrolamellar carcinoma is a distinctive variant of liver cell carcinoma seen predominantly
in young patients without cirrhosis. The most characteristic microscopic feature is nests
and cords of neoplastic cells surrounded by variably dense lamellar bands of fibrosis. The

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Interactive Microscopy Session | Second Edition: Modern Surgical Pathology Through The Expert
Eyes of APSS-USCAP: Cases That Will Make You Love Your Liver | Laura W. Lamps, MD
(Oct. 27-30, 2019)

tumor cells are polygonal with abundant deeply eosinophilic (oncocytic) cytoplasm, with
prominent nucleoli. Fibrolamellar HCC expresses Hep Par-1, similar to conventional HCC,
as well as cytokeratins 8 and 18. Many cases also express glypican-3, but to a lesser
extent than conventional HCC. FCC may also express cytokeratin 7 and (to a lesser
extent) cytokeratin 19. Recently, it has been demonstrated that CD68 is strongly
expressed by fibrolamellar carcinomas, which may be useful in distinguishing
fibrolamellar HCC from the scirrhous variant.

Immunohistochemistry can be very helpful in the differential diagnosis of hepatocellular

tumors. HepPar-1 (also known as hepatocyte –specific antibody, or HSA) is one of the
most reliable markers of hepatocytic differentiation, but it does not stain most poorly
differentiated or sclerosing HCC; in addition, staining may be patchy within the tumor, and
thus not present on a small needle biopsy sample. Adenocarcinomas of the lung, stomach,
and esophagus may also have immunoreactivity, and as expected, it also stains hepatoid
adenocarcinomas of the gastrointestinal tract and pancreatobiliary tract. Another more
recently available marker that shows a high sensitivity and specificity for benign and
malignant hepatocytes is arginase-1. The overall sensitivity of arginase-1 is better than
Hep Par-1, particularly in poorly differentiated HCC. Furthermore, the specificity is
extremely high, with only rare cases of non-HCC reportedly showing immunoreactivity.
Glypican-3 is another more recent marker that has been added to the hepatocellular
phenotype armamentarium. It stains most HCC, but also stains yolk sac tumor, Wilms
tumor, rhabdomyosarcoma, undifferentiated embryonal sarcoma, mesenchymal
hamartoma, and a subset of hepatoblastomas, as well as a number of metastatic tumors
that can be encountered in the liver, such as melanoma, squamous cell carcinoma of the
lung, and adrenal cortical carcinoma..

In contrast to the antibodies discussed above, MOC-31, a recently described antibody

directed against a cell surface glycoprotein, is regularly expressed in cholangiocarcinoma
and metastatic adenocarcinoma, but only extremely rarely in hepatocellular carcinomas.
A panel consisting of MOC-31 and Hep Par-1 or arginase-1 is sufficient to distinguish the
majority of HCC from cholangiocarcinoma and metastatic adenocarcinoma. HCC may
show aberrant keratin expression, and thus a minority of HCC will show CK7 and/or CK20
immunoreactivity.

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Interactive Microscopy Session | Second Edition: Modern Surgical Pathology Through The Expert
Eyes of APSS-USCAP: Cases That Will Make You Love Your Liver | Laura W. Lamps, MD
(Oct. 27-30, 2019)

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Interactive Microscopy Session | Second Edition: Modern Surgical Pathology Through The Expert
Eyes of APSS-USCAP: Cases That Will Make You Love Your Liver | Laura W. Lamps, MD
(Oct. 27-30, 2019)

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