August 2020 — Liver

A 45 year-old male with a history of end stage liver disease and cirrhosis due to Hepatitis C is admitted to the hospital for liver transplant. Pre-transplant imaging did not reveal a mass lesion in the liver, but confirmed subcentimeter nodularity consistent with the patient’s long standing cirrhosis. Alpha-fetoprotein was 75 ng/ml (normal <10ng/ml). Grossly, the explanted liver revealed numerous nodules one centimeter or less in greatest dimension. Multiple nodules were sampled for histopathologic evaluation and are shown below.

Based on the history and photomicrographs, which one of the following diagnoses is correct?

  • Cirrhosis
  • Conventional Hepatocellular Carcinoma
  • Fibrolamellar hepatocellular Carcinoma
  • Cirrhosis-like hepatocellular carcinoma

The correct answer is...

The correct answer is Cirrhosis-like hepatocellular carcinoma.

Cirrhosis-like hepatocellular carcinoma (CL-HCC), also known as cirrhotomimetic hepatocellular carcinoma, is a rare variant of hepatocellular carcinoma occurring in cirrhotic livers. By definition CL-HCC is discovered after transplant during histologic evaluation of the liver explant. CL-HCC is unique in that it does not form a mass lesion unlike conventional hepatocellular carcinoma and instead forms numerous, 20 to >1000, subcentimeter nodules that are radiologically and macroscopically indistinguishable from regenerative nodules of cirrhosis.1-3 The numerous nodules are thought to be due to portal vein invasion leading to hepatic dissemination.4,5 Alpha-fetoprotein serum level is usually normal or only mildly elevated (<200ng/ml) and is equivocal for the diagnosis of hepatocellular carcinoma.

Histologically, CL-HCC demonstrates nodules of tumor cells surrounded by fibrotic bands similar to regenerative nodules in cirrhosis and are seen interspersed between non-neoplastic cirrhotic nodules. The tumor cells are typically well to moderately differentiated and often forming pseudoglandular and/or trabecular architecture. Clear cell change, cholestasis, steatosis, balloon cell change, and Mallory-Denk bodies can also be identified in the tumor cells. Frequent vascular invasion is also seen. The immunophentype of the tumor is similar to conventional hepatocellular carcinoma with positivity for HepPar-1, Arginase, and glypican-3.1,2 Of note, the molecular biology of CL-HCC has not been elucidated.

Treatment for hepatocellular carcinoma usually involves liver transplant for patient’s meeting the Milan criteria. In CL-HCC, patient’s are typically diagnosed after definitive treatment (liver transplant) in the setting of no known metastases. One study found the overall risk of recurrence is 57% with the 1 year and 3 year recurrence free rates being 67% and 50%, respectively. The same study also identified patients with CL-HCC involving <50% of the liver and clear cell change show a statistically better recurrence free survival.2

The differential diagnosis for CL-HCC includes conventional hepatocellular carcinoma, fibrolamellar carcinoma, and cirrhosis. Conventional hepatocellular carcinoma can be ruled out based on the absence of a dominate mass and the detection of the tumor histologically rather than on imaging or macroscopic evaluation. Fibrolamellar carcinoma also demonstrates fibrotic bands within the tumor; however, it also forms a dominate mass. Futhermore, fibrolamellar carcinoma usually occurs in young adults and does not occur in the background of cirrhosis. Finally, CL-HCC needs to be distinguished from cirrhosis based on histomorphology, evidence for lymphovascular invasion, and glypican-3 positivity.

1. Jakate S, Yabes A, Giusto D, et al. Diffuse cirrhosis-like hepatocellular carcinoma: a clinically and radiographically undetected variant mimicking cirrhosis. The American journal of surgical pathology. 2010;34(7):935-941.
2. Clayton EF, Malik S, Bonnel A, et al. Liver transplantation and cirrhotomimetic hepatocellular carcinoma: classification and outcomes. Liver transplantation: official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 2014;20(7)> 3. Torbenson MS. Morphologic Subtypes of Hepatocellular Carcinoma. Gastroenterology clinics of North America. 2017;46(2):365-391.
4. Okuda K, Noguchi T, Kubo Y, Shimokawa Y, Kojiro M, Nakashima T. A clinical and pathological study of diffuse type hepatocellular carcinoma. Liver. 1981;1(4):280-289.
5. Kanematsu M, Semelka RC, Leonardou P, Mastropasqua M, Lee JK. Hepatocellular carcinoma of diffuse type: MR imaging findings and clinical manifestations. Journal of magnetic resonance imaging : JMRI. 2003;18(2):189-195.

Photo of Benjamin Van Treeck, M.D. Benjamin Van Treeck, M.D.
Resident, Anatomic and Clinical Pathology
Mayo Clinic
Photo of Rondell Graham, M.B.B.S. Rondell Graham, M.B.B.S.
Consultant, Anatomic Pathology
Mayo Clinic
Associate Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science

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This post was developed by our Education and Technical Publications Team.