Toshikazu Uchida, MD, Minoru Shibata, MD, and Toshio Morizane, MD.  January 11, 1999.

Irregular regeneration (IR) of hepatocytes is related to the development of hepatocellular carcinoma (HCC) in patients with chronic hepatitis and cirrhosis with hepatitis-C-virus infection.  Those who show intermediate to strong IR are at high risk of developing hepatocellular carcinoma.

We published a paper entitled "Irregular regeneration of hepatocytes and risk of hepatocellular carcinoma in chronic hepatitis and cirrhosis with hepatitis-C-virus infection" in The Lancet (Vol 351, June 13, 1998; 1773-1777).  This home page has been prepared to help understand IR of hepatocytes and to let pathological reviewers to develop skills to evaluate irregular regeneration in liver biopsy specimens.

Basic

IR consists of four components: anisocytosis, pleiomorphism (pleomorphism), bulging, and map-like distribution.  To understand these histological features one has to know typical cases shown below.

The degree of IR is classed as: none or weak (<25% of hepatocytes in the sample affected by anisocytosis, pleiomorphism, bulging, or map-like distribution); intermediate (25 - 50% of hepatocytes affected); or strong (>50% of hepatocytes affected).  We then define two categories, slight IR (none or weak on the histological criteria) and severe IR (intermediate and strong).  Patients whose liver histology is categorized as severe IR are at high risk to develop HCC.

In the following pictures, the degree of IR is shown as percent of hepatocytes affected in each field, which is a part of the whole biopsy specimen.  However, the final assessment of IR should be made by viewing the whole area of the biopsy specimen and evaluating the percent of area of hepatocytes affected by IR in the whole area consisting of hepatocytes.

A: Anisocytosis

Anisocytosis is characterized by variabilities of cell size with focal dysplastic change.  Extreme anisocytosis resembles dysplasia.
Explanation

Pleiomorphism is characterized by variabilities of cytoplasmic appearance.  Extreme pleiomorphism resembles oncocytic change.
Explanation

Bulging is expansive proliferation of hepatocytes compressing the surrounding parenchyma.
Explanation

Distinct population of hepatocytes with a homogeneous appearance within each population are separated from each other by a sharp outline. Hepatocytes on the both sides of the border are usually different from normal hepatocytes in cellular size, nuclear size, and cytoplasmic appearance.
Explanation
 

The cytoplasmic staining of hepatocytes does not seem uniform even in the absence of irregular regeneration. However, this type of variability of cytoplasmic appearance depends on the vascular structure of the liver and does not represent the changes associated with hepatocyte regeneration. Therefore, one should be cautious when judging map-like distribution and pleiomorphism. Here are some examples of non-pathological variability of cell staining.

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In the following samples, the microscopic photograph of a liver biopsy specimen appears when you click the title.  Please evaluate each sample by yourself and proceed to the explanation.  In the explanation figure, types of IR and the degree of IR are shown. In these samples the degree of IR means the percent of the area of IR-affected hepatocytes of the whole area of hepatocytes in each picture field, not the final evaluation of IR of each case. The final evaluation of IR should be made viewing the whole area of the biopsy specimen.

Sample 1: 60 yo male, chronic active hepatitis.  Explanation
Sample 2: 61 yo male, chronic active hepatitis.  Explanation
Sample 3: 58 yo male, chronic active hepatitis.  Explanation
Sample 4: 47 yo female, chronic active hepatitis.  Explanation
Sample 5: 47 yo female, chronic active hepatitis.  Explanation
Sample 6: 55 yo female, chronic active hepatitis.  Explanation
Sample 7: 43 yo female, chronic active hepatitis.  Explanation
Sample 8: 26 yo male, chronic active hepatitis.  Explanation
Sample 9: 59 yo male, chronic active hepatitis.  Explanation
Sample 10: 54 yo male, liver cirrhosis.  Explanation