Regenerative and Dysplastic Nodules

Regenerative and Dysplastic Nodules

Sanjay Kakar, MD

Large cell change is characterized by large hyperchromatic nuclei but preserved nuclear to cytoplasmic ratio image. This change is thought to be degenerative and not preneoplastic.

Small cell change (left 2/3 of image) image is characterized by small cells with high N:C ratio leading to increased cell density. When present in a nodule, it is the hallmark of HGDN.



  • Regenerative nodule (RN), macroregenerative nodule (MRN), low-grade dysplastic nodule (LGDN), high-grade dysplastic nodule (HGDN)


  • RN: Large regenerative nodule, macroregenerative nodule, adenomatous hyperplasia

  • HGDN: Borderline nodule, type II macroregenerative nodule, atypical adenomatous hyperplasia, atypical macroregenerative nodule


  • Dysplasia: Abnormal histologic growth that does not fulfill criteria of malignancy

    • Dysplastic focus: Cluster of dysplastic hepatocytes less than 1 cm in diameter

    • Dysplastic nodule: Cluster of dysplastic hepatocytes greater than 1 cm in diameter

  • Regenerative nodule: Large (greater than 1 cm) nodule usually seen in context of cirrhosis

    • No reliable gross or histologic criteria for distinguishing RN from LGDN, thus they will be considered together here

      • LGDN thought to represent clonal proliferation of hepatocytes although likelihood of progression to carcinoma is unclear

    • Most RN are probably not preneoplastic

  • HGDN: Nodule with atypical cytologic and architectural features believed to be precursor of carcinoma

  • Large cell change (formerly large cell dysplasia)

    • Large hepatocytes with nuclear enlargement, hyperchromasia, prominent nucleoli, often multinucleated

      • Abundant cytoplasm and hence normal nuclear cytoplasmic ratio

    • Very common in cirrhotic liver

    • Formerly thought to be precursor of hepatocellular carcinoma (HCC)

      • No longer considered preneoplastic but rather regenerative or degenerative phenomenon

      • Low proliferation rate and absence of P53 mutations also do not support preneoplastic process

  • Small cell change (formerly small cell dysplasia)

    • Small hepatocytes with increased nuclear to cytoplasmic ratio and hyperchromatic nuclei

      • High proliferative activity and P53 overexpression can occur

    • Likely to be preneoplastic when occurring in expansile nodules

    • Poorly defined or diffuse areas of small cell change without nodular configuration may represent regenerative phenomenon

    • Small cell regenerative foci common in biliary disease, unlikely to be preneoplastic



  • Occur in setting of cirrhosis, usually in background of hepatitis B, hepatitis C, alcoholic liver disease, hemochromatosis

    • Uncommon in chronic biliary diseases

    • Can occasionally occur in chronic liver disease without fully developed cirrhosis

    • Can occur in noncirrhotic liver in Budd-Chiari syndrome, portal vein thrombosis, or regeneration after necrosis

  • May be detected at autopsy, transplantation, or by imaging

  • Serum AFP is normal or mildly elevated


  • RN/LGDN: Follow-up by imaging and serological markers

  • HGDN: No well-defined guidelines; often ablated as they are considered preneoplastic


  • RN: Most RN regress or remain unchanged on imaging follow-up and thus are probably not preneoplastic

    • LGDN: Unclear but probable low likelihood of progression as well

    • Difficult to ascertain prognosis since it is difficult to clearly define entity LGDN

  • HGDN

    • Preneoplastic lesion, likely precursor of HCC

    • Allelic imbalance is seen in > 80% compared to 15% of regenerative nodules

    • Most remain stable or regress on follow-up; progression to HCC in 10-15%, but this data is based on limited studies


Regenerative Nodules (Including LGDN)

  • Larger than typical cirrhotic nodules

  • By definition > 1 cm but usually < 3 cm

  • May be pale yellow to tan compared to other cirrhotic nodules; some can be bile-stained

  • Sharply circumscribed and bulge on cut section

High-Grade Dysplastic Nodule

  • Similar gross appearance as RN/LGDN

  • Some HGDN are not well circumscribed and may show irregular border


Histologic Features

  • Regenerative nodule

    • Resemble cirrhotic nodules; cell plates are 1-2 cells thick

      • Reticulin framework is intact

    • Portal tracts are usually present within nodule, and ductular reaction may be prominent

    • Occasional unpaired arterioles may be seen, but this is not prominent finding

    • Hepatocytes typically appear normal; mild variation in cell size and scattered large cell change can be present

      • Specific morphologic features for low-grade dysplasia have not been established

      • May be indistinguishable from lesions formerly called MRN in the absence of clonality studies

    • May contain Mallory-Denk bodies, bile, clear cell changes, iron, copper, and fat

    • CD34 shows patchy sinusoidal staining at edge; occasional nodules can show more diffuse expression

    • Nodules are negative for α-fetoprotein and GPC with rare exceptions

    • No histologic criteria to distinguish RN from LGDN

  • High-grade dysplastic nodule

    • HG dysplastic changes may involve entire nodule or present as one or more dysplastic foci within nodule

    • By definition, atypical features do not fulfill criteria of diagnosis of HCC

    • Focal areas with up to 3-cell thick plates may be present (normal cell plates are typically 1-2 cells thick)

      • Reticulin network is normal or focally decreased

      • Pseudoacinar architecture can be present but is usually not diffuse

    • Portal tracts are present within nodule

    • Scattered unpaired arterioles are present but not as numerous as in HCC

    • Small cell change with increased nuclear to cytoplasmic ratio is a characteristic feature

      • Results in nuclear crowding and increased nuclear density

      • Large cell change can be seen but is neither sufficient nor necessary for diagnosis

    • May contain Mallory-Denk bodies, fat, clear cell change, cytoplasmic basophilia, bile

    • Tend to lack iron (in contrast to MRN, where iron deposits are more common)

    • CD34 shows patchy sinusoidal staining, usually at edge; occasional nodules can show more diffuse expression

    • α-fetoprotein is negative

    • Glypican-3 (GPC) expression is variable; diffuse strong expression strongly favors HCC


Other Regenerative Nodules

  • By definition, size > 1 cm differentiates RN from other cirrhotic nodules

Hepatic Adenoma

  • Rarely, RN may lack portal zones and resemble hepatic adenoma

  • True adenomas rarely, if ever, occur in cirrhotic liver


  • Cytologic abnormalities like small cell change and nuclear atypia favor HGDN

  • Architectural abnormalities like pseudoacinar architecture, focal reticulin loss, and unpaired arterioles favor HGDN

HGDN vs. Well-Differentiated HCC

  • Cell plates more than 3 cells thick are most important feature distinguishing HCC from HGDN

  • Prominent pseudoacinar architecture and numerous unpaired arterioles are typical of HCC

  • Loss or fragmentation of reticulin network strongly favors HCC

  • CD34 is typically diffuse in HCC and patchy in HGDN, but considerable overlap exists

  • CK7(+) ductular reaction present around over 50% of circumference of HGDN in most cases; this is focal or lost in most HCC

  • GPC expression favors HCC, especially if strong and diffuse

    • GPC expression described in 7-22% of HGDN also

HGDN vs. Early HCC (Early Well-Differentiated HCC or Vaguely Nodular HCC)

Jul 7, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Regenerative and Dysplastic Nodules

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