Nestin May Help Diagnose, Risk-Stratify Patients With Rare Form of CCA

New research suggests Nestin expression can help distinguish combined hepatocellular-cholangiocarcinomas (CCAs) from hepatocellular carcinomas and intrahepatic cholangiocarcinomas.

The progenitor cell marker Nestin may be a meaningful diagnostic tool for combined hepatocellular-cholangiocarcinoma (cHCC-CCA) and may help identify a subset of patients with a poor prognosis, according to a new report published in Journal of Hepatology.

The finding could lead to earlier diagnosis and better treatment outcomes for patients with the rare and highly aggressive cancer type.

cHCC-CCA has a phenotype that is like hepatocellular and biliary cancers, noted the study authors. “Although the biological mechanisms leading to its development remain unclear, one hypothesis is that this subset of PLC [primary liver cancer] may arise from progenitor cells, therefore conferring a high degree of cellular plasticity,” they said.

The cancer type can be particularly difficult to diagnose, often sparking disagreement among practitioners.

“Given the challenges in cHCC-CCA diagnosis and its associated clinical implications, the development of biomarkers relevant to this type of PLC is a critical unmet need,” the authors said. They noted tests are frequently performed for CK19 and CD56, but so far both have shown limited specificity and sensitivity as biomarkers.

Some evidence has suggested that Nestin—a class IV intermediate filament expressed by bi-potential liver progenitor cells—might be a potential biomarker for cHCC-CCA, they added.

“It has been shown to be a key regulator of cellular plasticity through the maintenance of an undifferentiated state, thereby enabling the transdifferentiation of neoplastic cells,” they wrote.

Wanting to further evaluate Nestin as a biomarker, the investigators collected 461 samples of cHCC-CCA from 32 clinics, along with 368 cases of HCC and 221 cases of intrahepatic CCA to serve as controls. The authors performed Nestin immunohistochemistry on the samples and analyzed the results to see whether Nestin had potential as a biomarker.

The authors found that Nestin expression levels were useful in distinguishing cHCC-CCA from HCC, with an area under the receiver operating curve (AUC) of 0.85 on surgical samples and 0.86 on biopsy samples. Nestin performed less well in distinguishing cHCC-CCA from intrahepatic CCA, with AUCs of 0.59 and 0.60, respectively.

Overall, they said Nestin was observed in 75% of cHCC-CCA samples and 60% of intrahepatic CCA samples, but was rare in HCC samples.

“Nestin is thus not useful to distinguish cHCC-CCA from [intrahepatic] CCA, but it may however help to differentiate cHCC-CCA from HCC, which is the most critical issue from a clinical standpoint (addition of CK19 immunostaining may also be helpful in this setting),” they said.

The authors also found that patients with samples having greater than 30% of neoplastic cells with positive staining for Nestin (dubbed the “Nestin High” cohort) tended to have worse clinical outcomes. However, they cautioned that their case series was heterogeneous and requires further validation.

The results are preliminary, but the authors highlighted that they point to the possibility that Nestin expression could be a useful tool in diagnosing and assessing patients with cHCC-CCA.

“Provided further validation, Nestin immunohistochemistry may be used to refine patient stratification and improve treatment allocation,” they concluded.


Calderaro J, Di Tommaso L, Maillé P, et al. Nestin as a diagnostic and prognostic marker for combined hepatocellular-cholangiocarcinoma. J Hepatol. Published online August 17, 2022. doi:10.1016/j.jhep.2022.07.019

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