Regenerative and Dysplastic Nodules

 Low-grade dysplastic nodules (LGDNs) resemble RN morphologically but are clonal

• High-grade dysplastic nodules (HGDNs): Preneoplastic lesion; likely precursor of hepatocellular carcinoma (HCC)


• > 1 cm but usually < 3 cm


• RN/LGDN: Plates 1-2 cells thick, portal tracts present, no architectural or cytologic atypia
• HGDN: Plates focally up to 3 cells thick; small cell change with increased nuclear:cytoplasmic ratio

image Unpaired arterioles and pseudoacinar architecture can be present

• Reticulin is preserved
image May be focally lost in HGDN

Top Differential Diagnoses

• Small cell change, high nuclear:cytoplasmic ratio, pseudoacinar architecture, and unpaired arterioles favor HGDN over LGDN
• Uniformly thick plates (> 3 cells) are most important feature distinguishing HCC from HGDN

image Prominent pseudoacinar architecture, numerous unpaired arterioles, and loss or fragmentation of reticulin favor HCC

• Stromal invasion distinguishes early HCC from HGDN
image Lack of CK7(+) ductular reaction is useful in demonstrating stromal invasion

• Positive results with 2 out of 3 markers (GPC, GS, HSP70) favor HCC

Small Cell Change
Small cell change (left 2/3 of image) image is characterized by small cells with high nuclear:cytoplasmic ratio leading to increased cell density. When present in a nodule, it is the hallmark of high-grade dysplastic nodule (HGDN).

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

Large RN
Large regenerative nodules (RNs) image resemble other cirrhotic nodules but are > 1 cm. Ductular reaction is usually present at the interface of the nodule with the fibrous septa.

RN: Reticulin Stain
Regenerative nodule containing a portal tract image and an intact reticulin framework is shown. These features and the absence of cytoarchitectural atypia distinguish it from dysplastic nodule and hepatocellular carcinoma (HCC).



• Regenerative nodule (RN), large regenerative nodule (LRN), low-grade dysplastic nodule (LGDN), high-grade dysplastic nodule (HGDN)


• Macroregenerative nodule (MRN), adenomatous hyperplasia

• Borderline nodule, type II MRN, atypical adenomatous hyperplasia, atypical MRN


• Dysplasia: Abnormal histologic growth that does not fulfill criteria of malignancy
image Dysplastic focus: Cluster of dysplastic hepatocytes < 1 cm in diameter

image Dysplastic nodule: Cluster of dysplastic hepatocytes > 1 cm in diameter

• LRN: > 1 cm, usually seen in cirrhosis
image No reliable gross or histologic criteria to distinguish RN and LGDN
– LGDN is clonal proliferation; likelihood of progression to carcinoma is unclear

image 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)
image Large hepatocytes with nuclear enlargement, hyperchromasia, prominent nucleoli, often multinucleated
– Abundant cytoplasm, normal nuclear:cytoplasmic ratio

image Very common in cirrhotic liver

image 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 p 53 mutations also do not support preneoplastic process

• Small cell change (formerly small cell dysplasia)
image Small hepatocytes with increased nuclear:cytoplasmic ratio and hyperchromatic nuclei
– High proliferative activity and p 53 overexpression can occur

image Likely to be preneoplastic when occurring in expansile nodules

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

image 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
image Uncommon in chronic biliary diseases

image Occasionally in chronic liver disease without fully developed cirrhosis

image 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


• RN: Most regress or remain unchanged on imaging follow-up and thus are probably not preneoplastic
image LGDN: Unclear but low likelihood of progression

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Apr 20, 2017 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Regenerative and Dysplastic Nodules

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