Hepatocellular Neoplasm - Not Otherwise Specified (HCN-NOS)

A Mixed Cell Tumor

HCN-NOS or "HEMNOS" (hepatocellular malignant neoplasm NOS) is a new designation that describes a subset of pediatric hepatocellular tumors with features resembling both hepatoblastoma (HBL) and hepatocellular carcinoma (HCC), but remain distinct from both.

Notably,

  • HCN-NOS seems to arise in children older than those who typically develop HBL, and younger than those who typically develop HCC.

  • They are not histologically typical of either HBL or HCC.

  • These tumors are aggressive, and with current treatment paradigms, are associated with outcomes intermediate to HBL (better) and HCC (worse) .

Timeline

Histopathology and Liver Tumors

The basis of the distinction between HCN-NOS and other ones, like hepatoblastoma, is a matter of histopathology. In the United States, histopathology was incorporated early on in diagnostic protocols, due to evidence from reviews of tumor samples that identified histologic subtypes with distinct clinical associations. This work was done by scientists from the Children's Oncology Group (COG), a National Cancer Institute-supported clinical trials group that is "the world's largest organization devoted exclusively to childhood and adolescent cancer research".

The growth of this histopathological system of classification allowed the subdivision of primary liver tumors into various types, including malignant tumors like hepatoblastoma and hepatocellular carcinoma, and benign tumors like hepatic adenomas. Cellular morphology and other histological features differentiated each class, as well as their epidemiological and prognostic characteristics. However, there remained a rare variety of malignant liver tumors that did not fit into the existing schema. It was Prokurat and his colleagues in Europe who first gave a name to this class, calling it "transitional liver cell tumors".

"Transitional Liver Cell Tumors"

The term first appears in the paper in 2002 by Prokurat et al. that first proposed the distinction. His team's hypothesis was that this new type of tumor originated from a cell-of-origin that was intermediate to hepatoblast (more immature) and hepatocyte (more mature) cell lineages.

"As a working hypothesis, we suggest that these apparently novel, unusual, and aggressive tumors occurring in older children and adolescents may form a transition in the putative developmental pathway of hepatocarcinogenesis." (Prokurat et al. 2002)

Prokurat and his colleagues, from the Institute of Pathology of the University in Bern and The Children's Memorial Health Institute in Warsaw, began to characterize a type of hepatocellular tumor that seemed to fit neither of the two most common types of hepatocellular cancers seen in children. These two most common types of primary hepatic neoplasms were and still are hepatoblastoma (HBL), which tends to arise in younger children, and hepatocellular carcinoma (HCC), which tends to arise in older children and adolescents.

Through seven cases, Prokurat and his colleagues outlined features of this tumor. Ranging broadly from 5 to 18 years of age, all but one of these patients were initially diagnosed with HBL, but the unusual age of presentation and poor clinical outcomes were what elicited further attention to these cases.

The International Pathology Liver Symposium

In 2011, the Children's Oncology Group (COG) hosted the International Pathology Liver Symposium in Los Angeles, where scientists around the world came together to formalize a basis for an international hepatoblastoma classification for the first time. The declared aim was to establish standards that would facilitate international collaboration on clinical trials, thus improving treatment stratification based on tumor histopathology. As mentioned in COG's subsequent 2013 paper, a comprehensive, universal classification system linked to prognostic outcomes, is crucial to providing more personalized, effective treatment for children with these rare tumors.

"The lack of diagnostic consensus in a few circumstances highlights the need for establishing clear diagnostic guidelines and morphologic criteria based on a consensus nomenclature, as well as for subsequent case review and working sessions by this international group of experts. These efforts will facilitate correlations between tumor histopathology and outcome by using data such as those collected by the Children’s International Hepatic Tumors Collaboration project database, as well as the creation of a consensus patient stratification system." (Lopez-Terrada et al. 2013)

Just as with Prokurat and his team, a number of the malignant hepatocellular tumors reviewed during this conference did not clearly fit into any preexisting classification. These tumors should considerable variability in histological patterns, with some of them showing mixed features of both hepatoblastoma and HCC that seemed to fit Prokurat's hypothesis of a transitional cell-of-origin.

However, several plausible hypotheses were generated as to the possible origin of these tumors.

Hypotheses on the pathogenesis of this difficult-to-classify tumors:

  • New type of tumor, with the cell-of-origin in a state of transition between hepatoblast and hepatocyte lineages

  • Clonally progressed hepatoblastomas

  • Changes due to chemotherapy*

  • Other type with the cell-of-origin currently unknown

Given these multiple possibilities, the term "transitional cell liver tumor" was abandoned in favor of a more ambiguous moniker: "hepatocellular carcinoma - not otherwise specified" (HCN-NOS).

*It is important to note that the classification criteria proposed during this conference only applies to pre-chemotherapy tumor specimens, given the possibility that chemotherapy itself can alter the histology of the tumor. The comparison of pre- and post-chemotherapy specimens was designated as a subject of future review.

"The existence of this group of difficult-to-classify pediatric hepatocellular tumors highlighted the importance of complying with the specimen submission and clinical information requirements (see Specimen submission section) to facilitate correct diagnosis as well as enrollment in clinical trials, and to facilitate biological studies."


Case Reports