Fibrolamellar carcinomas are positive for CD68

Abstract

Fibrolamellar carcinomas are a unique type of liver carcinoma that arise in non-cirrhotic livers of young individuals. Despite their distinctive appearance, recent studies have demonstrated a lack of consistency in how fibrolamellar carcinomas are diagnosed by pathologists. As a potential aide in diagnosis, we investigated the staining properties of CD68. The CD68 gene encodes for a transmembrane glycoprotein located within lysosomes and endosomes. Macrophages as well as other cell types rich in lysosomes/endosomes are CD68 positive. Cases of fibrolamellar carcinoma were collected from four academic centers. Control groups included hepatocellular carcinomas arising in both non-cirrhotic livers and cirrhotic livers. A group of cholangiocarcinomas were also stained. CD68 immunostaining was scored for both intensity and distribution on a scale of 0 to 3+. Twenty-three primary fibrolamellar carcinomas and 9 metastases (total of 24 individuals) were immunostained and showed a distinctive granular, dot-like or stippled pattern of cytoplasmic staining in nearly all cases (31/32), with a median distribution and intensity score of 3+. In control hepatocellular carcinomas that arose in non-cirrhotic livers, 10/39 showed CD68 staining with a median distribution and intensity score of 2+. In hepatocellular carcinomas arising in cirrhotic livers, 3/27 cases showed CD68 positivity, all with stippled dot-like cytoplasmic staining similar to that of fibrolamellar carcinomas. All five cholangiocarcinomas were negative. Overall, CD68 positivity was strongly associated with fibrolamellar carcinomas, P<0.001 and had a sensitivity of 96%, a specificity of 80%, and a negative predictive value of 98%. In sum, tumor positivity for CD68 staining was highly sensitive for fibrolamellar carcinoma and a lack of CD68 staining should suggest caution in making a diagnosis of fibrolamellar carcinoma.

Figure 1

Fibrolamellar carcinomas are CD68 positive. Panel A. H&E, Original magnification, 40X. The typical morphology of fibrolamellar carcinoma can be seen. Panel B, CD68, original magnification, 40X: Fibrolamellar carcinomas show a distinctive granular or stippled cytoplasmic staining pattern. Panel C, CD68, original magnification, 160X: High power image of CD68 staining in fibrolamellar carcinoma. Panel D, CD68, original magnification, 40X: The background liver (same case as B,C) shows CD68 staining in Kupffer cells, but not the hepatocytes. Panel E, CD68, original magnification, 100X: Another case of fibrolamellar carcinoma showing weaker but still positive CD68 staining. Panel F, CD68, original magnification, 100X: In some cases of fibrolamellar carcinoma, the tumor showed a larger circumscribed dot like staining pattern of CD68.

Figure 2

Typical hepatocellular carcinomas were positive for CD68 staining in some cases. Panel A, CD68, original magnification, 100X: A typical hepatocellular carcinoma shows a stippled or granular staining pattern that closely resembles fibrolamellar carcinoma. Panel B, CD68, original magnification, 100X: Typical hepatocellular carcinomas with fatty change were most likely to show a CD68 staining pattern similar to fibrolamellar carcinoma. Panel C, CD68, original magnification, 100X: In rare cases, there was a more diffuse CD68 staining pattern. Panel D, CD68, original magnification, 100X: CD68 positivity could also be seen focally near areas of tumor necrosis.

Figure 3

Fibrolamellar carcinomas (N=7) showed significantly more expression of CD68 than typical hepatocellular carcinomas (N=6). The typical hepatocellular carcinomas arose in livers with cirrhosis and chronic hepatitis C.