undifferentiated small cell hepatoblastoma

When first distinguished from embryonal epithelium, small undifferentiated cells in hepatoblastoma were noted to resemble neuroblastoma, to have a low mitotic rate, and were called "anaplastic", consistent with the dictionary definition, characterized by imperfect development (anaplastic hepatoblastoma).

Since “anaplastic” was redefined by Faria et al for Wilms tumor as nuclear enlargement to 3 times those of typical tumor cells, hyperchromasia and atypical mitoses, the small cell undifferentiated component no longer is designated as anaplastic.

Beckwith-type anaplasia does occur rarely in hepatoblastoma, and its significance is unknown.

The small cells have been considererd a putative hepatic progenitor cells on the basis of immunohistochemical and electron microscopic studies.

When present in a significant fraction of the hepatoblastoma (75%), or as the sole cell type, the small cell type is typically found in infants younger than 1 year.

Undifferentiated small cell hepatoblastomas have a poor prognosis, with poor response to current therapy. (18985717)

The prognostic significance of smaller proportions of the small cell undifferentiated type is still undetermined.

Microscopy

The small cells of HB are undifferentiated in routine histologic preparations, have minimal cytoplasm and round lightly chromatic nuclei with inconspicuous nucleoli, fail to form tubules or to cohere, infiltrate the liver while sparing bile ducts, and often invade veins. (18985717)

When comprising a portion of an otherwise typical HB with epithelial and possibly mesodermal derivatives, they are identified as discrete small nests most often associated with embryonal elements. (18985717)

Small cell undifferentiated histology, formerly referred to as anaplastic hepatoblastoma, is characterized by masses of cells without architectural organization with cytologic characteristics similar to those of small blue cell tumors of infancy and childhood. (11753992)

These poorly differentiated, small to medium sized cells occasionally appear as primitive spindle cells but always lack acinar, ductal, pseudoglandular, or other features of epithelial tumor cells comprising typical fetal or embryonal hepatoblastoma histology. (11753992)

Physiopathology

The nature and origin of the seemingly undifferentiated cells in small cell hepatoblastoma is not clear. Kasai and Watanabe originally recognized the small cell variant of hepatoblastoma, describing it as anaplastic hepatoblastoma in 1970.

The term “small cell undifferentiated” histology was suggested as an alternative to “anaplastic” to avoid confusion with larger bizarre cells and atypical mitoses comprising anaplasia in Wilms’ tumors.

Other authors have utilized that alternative term, describing such tumors as formless sheets or ill-defined aggregates of small cells without embryonal, fetal, or mesenchymal differentiation.

Gonzalez-Crussi pointed out that although the small cell undifferentiated variant represented the form of hepatoblastoma with the least light microscopic differentiation, electron microscopy and immunohistochemistry revealed features of hepatocyte lineage far more advanced than originally suspected based on hematoxylin and eosin stained slides.

Abenoza et al. suggested the stem cell or pleuripotent nature of hepatoblastoma small cells.

A transition, if not a close association, between small cells, stroma, fetal cells, and embryonal cells may be apparent in some hepatoblastomas.

Ruck et al. pointed out the ultrastructural and immunophenotypic similarity of hepatoblastoma small cells to oval cells in the rat and in injured human livers exhibiting chronic ductal regeneration.

In so doing, they argued strongly for the pluripotent or stem cell nature of the small cell.

Logdberg et al. demonstrated that small cells in hepatoblastoma do not bind the antibody HepPar 1 or a variety of other antibodies believed to bind to hepatic and pancreatic stem cells.

However, the demonstration by Abenoza et al.15 that small cells express α-fetoprotein and low molecular weight keratins is at variance with the data provided by Logdberg et al.

Immunochemistry

Immunohistochemically, small cells of HB share with rhabdoid tumors biphenotypic expression of intermediate filaments typical of epithelial and mesenchymal cells, cytokeratin and vimentin, which facilitates their detection.

INI1 antibody produces a variable degree of nuclear staining, unlike rhabdoid tumor cells, which are always negative. (18985717)

Prognosis

Small undifferentiated cells in hepatoblastoma is associated with an adverse outcome. These tumors appear to be biologically different from non-SCU HB.

Small cell undifferentiated (SCU) histology in patients with stage I hepatoblastoma (HB) predicts an increased risk of relapse.

Evaluation of patient characteristics and outcomes for children with SCU HB and/or those with low AFP levels should be determined from large cooperative group studies.

Patients with unresectable HB containing SCU elements should have careful cytogenetic, molecular, and immunohistochemical evaluation to ascertain rhabdoid features and receive treatment that differs from that provided for other HB patients.

SCU histology in HB patients is associated with an adverse outcome. (18985717)

Even a small proportion of SCU histology may confer this apparent disadvantage on patients with Stage I disease. (18985717)

Only 10% patients with SCU histology are alive without evidence of disease 5 to 70 months following diagnosis. None of studied patients survived 70 months after surgery. (18985717)

In general, these patients are younger, present with higher stage disease, and are more likely to exhibit INI1 gene abnormalities or INI1 expression, similar to patients with rhabdoid tumors.

The stage distribution for patients with SCU histology is not significantly different from patients with other histologic types of HB.

The SCU HB patients with confirmed genetic alterations and/or INI1 negative immunostaining more often present with advanced stage compared with patients with other histologic types of HB (12.5% stage II, 25% stage III and 62.5% stage IV compared with 5% stage II, 64% stage III and 31% stage IV on CCG 8881).

The male predominance of patients with SCU HB in our study is slightly more pronounced than in hepatoblastoma overall: 73% compared with 62% male on CCG 8881.

In the group of SCU HB patients with INI1 alterations and/or negative immunostaining, this slight increase in male gender is similar (75% male) to the male predominance in our study.

Though they had poorer outcomes than patients with Stage I HB without SCU histology, the patients with SCU histology and Stage I disease fared better than those with Stage II to IV SCU HB in our study.

Of the 16 patients with Stage I SCU HB reported by Haas et al, 6 patients survived event-free, 5 patients survived following recurrence, and 5 patients died of recurrent disease. (11753992)

Cytogenetics

 translocation-associated undifferentiated small cell hepatoblastoma

• t(10;22) (1384017)
• t(22;22)(q11;q13) (12010372)

See also

 hepatoblastomas

• epithelial hepatoblastoma
  • pure fetal hepatoblastoma

References

 Small cell undifferentiated variant of hepatoblastoma: adverse clinical and molecular features similar to rhabdoid tumors. Trobaugh-Lotrario AD, Tomlinson GE, Finegold MJ, Gore L, Feusner JH. Pediatr Blood Cancer. 2009 Mar;52(3):328-34. PMID: 18985717 (Free)

 Undifferentiated small cell hepatoblastoma with a chromosomal translocation t(22;22)(q11;q13). Gunawan B, Schafer KL, Sattler B, Lorf T, Dockhorn-Dworniczak B, Ringe B, Fuzesi L. Histopathology. 2002 May;40(5):485-7. PMID: 12010372

 Small cell undifferentiated histology in hepatoblastoma may be unfavorable. Haas JE, Feusner JH, Finegold MJ. Cancer. 2001 Dec 15;92(12):3130-4. PMID: 11753992 (Free)

 Logdberg L, Saxena L, Lal A, de Davila MTG, Greco MA, Mitsudo S, et al. The small cells in hepatoblastoma lack liver stem cell phenotype [abstract]. Mod Pathol 2000; 13: 187A.

 Hepatoblastoma. Stocker JT. Semin Diagn Pathol. 1994 May;11(2):136-43. PMID: 7809507

 Fine needle aspiration cytology of undifferentiated small cell ("anaplastic") hepatoblastoma. Kaw YT, Hansen K. A case report. Acta Cytol. 1993 Mar-Apr;37(2):216-20. PMID: 8385412

 Undifferentiated small cell hepatoblastoma with a unique chromosomal translocation: a case report. Hansen K, Bagtas J, Mark HF, Homans A, Singer DB. Pediatr Pathol. 1992 May-Jun;12(3):457-62. PMID: 1384017

 Hepatoblastoma: the prognostic significance of histologic type. Conran RM, Hitchcock CL, Waclawiw MA, Stocker JT, Ishak KG. Pediatr Pathol. 1992 Mar-Apr;12(2):167-83. PMID: 1315024

 Gonzalez-Crussi F. Undifferentiated small cell (“anaplastic”) hepatoblastoma. Pediatr Path. 1991;11:155–162. PMID: 1849636

 Haas JE, Muczynski KA, Krailo M, Ablin A, Land V, Vietti TJ, et al. Histopathology and prognosis in childhood hepatoblastoma and hepatocarcinoma. Cancer 1989; 64: 1082–95.