Med Pediatr Oncol 2002;39:478483

Hepatoblastoma: Assessment of Criteria for

Histologic Classification
Jon M. Rowland, MD,
Background. Comparison of outcomes in
different clinicopathologic studies of hepatoblastoma requires reproducible histologic classification. This review examines the diagnostic criteria
employed by different pathologists for the classification of subtypes of hepatoblastoma and
identifies specific problem areas. Procedure. A
selected review of published literature is provided. Results. Published studies demonstrate
that uniform criteria have not been applied in
the classification of hepatoblastoma. These
discrepancies hinder attempts to compare outcome data from different studies. Sampling error

Key words:

and potential treatment effects further complicate analysis of the published literature on the
relationship between morphologic classification
and outcome. Conclusions. Standardized criteria are essential to allow reproducible histologic classification of hepatoblastoma. There is
significant variation in diagnostic criteria used
to define the major subtypes of hepatoblastoma
in published studies. Additional potential problems are identified in sampling methods and
treatment effects. Med Pediatr Oncol 2002;39:
478483. 2002 Wiley-Liss, Inc.

hepatoblastoma classification; histologic criteria

INTRODUCTION

Hepatoblastoma is a rare tumor, such that no single

institution treats sufficient numbers of patients to adequately assess the relationship between clinicopathologic
features, therapy, and outcome. Comparison of results
from studies in different institutions or those using
different treatment strategies has been hindered by
variations in diagnostic and staging criteria. Recently,
significant progress toward standardized staging criteria
has been achieved with the PRETEXT system in use in
SIOPEL and COG studies [1]. This review evaluates the
diagnostic criteria established to define the different
subtypes of hepatoblastoma and summarizes how these
have been modified by different investigators, highlighting differences between reported studies. Additional
confounding factors such as sampling methods and
treatment effects are also evaluated.
MATERIALS AND METHODS

Published literature, through the end of 2000, on

histologic classification and outcome of hepatoblastoma
are reviewed.
RESULTS AND DISCUSSION

It is important to appreciate that the histologic

classification of hepatoblastoma has slowly evolved over
the past 50 years and represents a collection of subtypes
that were defined by different investigators at different
times. This analysis will be restricted to classification
based on the epithelial component. The major histologic
2002 Wiley-Liss, Inc.
DOI 10.1002/mpo.10171

PhD*

patterns of epithelial hepatoblastoma are the fetal,

embryonal, macrotrabecular, and small cell undifferentiated types. Some authors retain the mixed epithelial and
mesenchymal tumors as a separate category within their
classification schemes [2]. However, except for the positive effect of osteoid, chondroid, and squamous differentiation in high stage tumors reported by Haas et al. [3],
none of the other large studies has demonstrated an
influence of mesenchymal differentiation on outcome [4
6]. Rare tumors, such as those with rhabdoid features [7,8]
or aberrant cell types within otherwise typical hepatoblastomas [911] are also excluded from this discussion.
Regardless of the validity of defining these different
morphologic subtypes, there is only one subtype that
currently leads to a change in therapy. The current
Childrens Oncology Group protocol for hepatoblastoma
(#9645) provides for surgical resection alone as the
therapy for patients with completely resected (Stage I),
pure fetal hepatoblastoma (PFH). All other stages and
subtypes are randomized to receive chemotherapy. Since
the identification of PFH is such an important distinction,
the diagnostic criteria for this subtype will be covered in
detail.
Awatershed event in hepatoblastoma classification was
the landmark study by Ishak and Glunz [12] that first

Department of Pathology, Childrens Hospital, Oakland, California

*Correspondence to: Jon M. Rowland, Department of Pathology,
Childrens Hospital, Oakland, 747 52nd Street, Oakland, CA 94609.
E-mail: Jrowland@mail.cho.org

Hepatoblastoma: Histologic Classification

proposed specific criteria to define fetal and embryonal

cells in hepatoblastoma. The main purpose of this study, as
with most studies of that era, was to contrast hepatocellular carcinoma and hepatoblastoma. These authors retained the epithelial and mixed categories of hepatoblastoma
of earlier authors [13] but described the epithelial cells in
much more detail. One type of cell, designated fetal type,
was said to be readily recognizable as a hepatic parenchymal cell and to resemble the cells of the prenatal fetal liver.
These cells are arranged usually in irregular plates of twocell thick. The cells are smaller than normal parenchymal
cells, have some variation in size of cells and nuclei, and
have nuclear to cytoplasmic ratios ranging from 1:21:4
compared to 1:41:6 in non-neoplastic cells. The nuclei
are round or oval with few mitotic figures seen. It is important to note that this definition includes both cytologic
and architectural features in the definition. They described
embryonal type cells as much less differentiated. These
cells show poor cohesiveness and are usually arranged in
sheets or ribbons or sometimes in acinar, pseudorosette, or
papillary formations. The cells are elongated, small, and
dark staining. Cellular outline is poorly defined and irregular. There is considerable variation in size of both cells
and nuclei with a nuclear to cytoplasmic ratio of 1:11:2.
The oval to round nucleus is hyperchromatic with abundant chromatin. A large, distinct, and amphophilic or
acidophilic nucleolus is present. Mitotic activity is seen
much more frequently than in fetal type cells. Although
these authors described fetal and embryonal cells, they did
not propose that this distinction should be extended to
distinguish embryonal and fetal tumors.
Over the next 15 years, several studies used the histologic features described by Ishak and Glunz [12], in
conjunction with an estimate of the relative percentage of
tumor area occupied by those cells to further categorize
these tumors. In 1970, Kasai and Watanabe, basing their
analysis only on features of the epithelial cells with no
category of mixed hepatoblastoma, introduced the concept
of embryonal and fetal type epithelial hepatoblastomas
[14]. The predominant cell type defined embryonal and
fetal type hepatoblastomas. Predominant was not further
defined. Gonzalez-Crussi et al. [15] described fetal and
embryonal patterns within hepatoblastoma. A fetal pattern
had to be present, at least focally, in all cases to be included
as a hepatoblastoma. An attempt was made to subclassify
the tumors based on the predominant pattern; a predominant pattern was defined as occupying at least two-third of
the area. Lack et al. [16] used a criterion of 50% of cross
sectional area to separate embryonal and fetal tumors.
Their description of fetal tumors mentions that some had a
sheet-like configuration. Whether some of these tumors
would qualify now as the macrotrabecular pattern is
unknown.
Finally, Weinberg and Finegold [17], building on the
criteria of Ishak and Glunz [12], established two new

479

criteria to distinguish embryonal and fetal hepatoblastomas. They quantified infrequent mitoses as less than
2 mitoses/10 high power fields (HPF), providing the first
specific threshold for this feature. They also suggested
that any deviation from a well-differentiated fetal pattern
would indicate a poor prognosis. This is the origin of what
has come to be termed pure fetal hepatoblastoma. Extensive histologic sampling, defined as at least one block
per centimeter of tumor, is required to document the histologic type. Subsequent studies proposed that another
variant, termed crowded fetal, be used to describe tumors
with preservation of the hepatocellular cord architecture
but containing cells with larger, more pleomorphic nuclei,
and increased mitotic activity [18].
A third distinct pattern, the macrotrabecular pattern, is
a hepatocytic proliferation in trabeculae 10, 20, or more
cells thick [15]. The macrotrabecular cells can be fetal or
embryonal hepatocytes. On occasion, the cell size exceeds
that of normal uninvolved liver tissue. It is important to
remember that all macrotrabecular cases had some fetal
pattern by definition. The fourth major pattern, small cell
undifferentiated, was first labeled anaplastic hepatoblastoma and described as a tumor composed of very small,
immature appearing cells with scanty cytoplasm and hyperchromatic nuclei, resembling neuroblastoma cells [14].
These cells are stellate or oval in shape with scanty, faintly
eosinophilic or amphophilic cytoplasm and show little
similarity to normal liver cells. Mitosis was not common in
their cases. Cells grow in sheets in some areas, while others
were scattered without cohesiveness. Lack et al. [16] also
described anaplastic tumors as more cellular tumors composed mainly of poorly differentiated small to medium
size cells without significant acinar, ductal, or pseudoglandular components. These had a high mitotic rate, in
contrast to the original description [14]. Again, these cells
had to occupy at least 50% of the area to qualify for the
diagnosis. Haas et al. [3] proposed small cell undifferentiated hepatoblastoma as a more appropriate name for
the tumors previously designated as anaplastic hepatoblastoma [14,16]. A high mitotic rate was again noted.
These tumors display sheets and nests of loosely cohesive
cells with scanty cytoplasm. A primitive spindle cell
component may be present but most cells are round to
oval. The undifferentiated cells had to occupy more than
50% of the area to warrant the diagnosis. These tumors had
foci of fetal hepatoblastoma but did not have embryonal or
macrotrabecular features. Some undifferentiated cases in
the Pediatric Oncology Group (POG) study were completely composed of undifferentiated cells with mitoses
described as infrequent [18]. Two case reports of small cell
undifferentiated hepatoblastoma further document the
occurrence of tumors completely composed of poorly
differentiated cells [19,20]. Neither of these two cases
resembled liver parenchyma on histologic examination
but each showed ultrastructural features of epithelial

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Rowland

differentiation. One of these also had primitive canaliculi

on ultrastructural examination and polyclonal keratin
reactivity on immunohistochemistry [19]. Since small cell
undifferentiated hepatoblastoma is considered to represent the least differentiated form of hepatoblastoma, it is
not surprising that some cases may require special
techniques to demonstrate hepatocellular differentiation.
These studies collectively provide criteria for four
major patterns of epithelial differentiation in hepatoblastoma. It is clear from these studies that no consensus
criteria exist. Furthermore, neither the relevance nor
reproducibility of many of these features has been tested.
Additionally, these criteria do not adequately cover the
continuum of morphology that exists in these tumors. If
the most restrictive of these criteria were used to define
each pattern, numerous typical hepatoblastomas would
be unclassified. Despite these limitations, these criteria
provide a framework to analyze the published literature
regarding the association between histologic classification
and outcome. Results from the works discussed above and
a number of more recent large studies will be analyzed,
specifically focusing on fetal hepatoblastoma. Previous
reviews addressing the prognostic importance of histologic subtypes are available [21,22].
The correlation between histologic differentiation in
hepatoblastoma and outcome was first addressed by Kasai
and Watanabe [14]. They found improved survival in
children with fetal hepatoblastoma compared to those with
embryonal or anaplastic hepatoblastoma with seven of
nine long-term survivors being of fetal type. They also
reported that 9/11 children with fetal hepatoblastoma who
survived the initial resection remained alive and well from
18 months to 6 years after the operation. Several other
small-scale studies provided data that suggested that
tumors with fetal differentiation had improved outcome
compared to tumors with other patterns of differentiation.
Lack et al. [16] had 9/13 long-term survivors in their series
with predominantly fetal morphology. No long-term
survivors were found in the anaplastic group. GonzalezCrussi et al. [15] had only two patients with Stage 1 pure
fetal tumors and both were long-term survivors. Three
other tumors with total fetal pattern were found. One of
these was discovered as an unexpected Stage I tumor at
autopsy. The remaining two had metastases documented at
diagnosis and died within 8 months of diagnosis. Five
patients had predominant macrotrabecular tumors and all
of these died with progressive disease. No small cell
undifferentiated hepatoblastomas were found in this
study. Weinberg and Finegold found long-term survival
in 6/6 patients with completely resected PFH [17]. Only
two of seven patients with less differentiated histologies
and complete resections survived. The diagnostic criteria
for these four studies have been described above. Heifetz
et al. [23] did not find a correlation between proportions of
fetal or embryonic epithelium and outcome. The mean

mitotic activity of their fetal epithelial components ranged

from 3.7/10 HPF in resectable tumors to 11.9/10 HPF in
nonresectable tumors. No macrotrabecular or small cell
undifferentiated tumors were found in their series.
Several large studies have provided data on the relationship between histologic differentiation and prognosis
in hepatoblastoma [24,6,24,25]. Conran et al. [4] did not
demonstrate a relationship between histologic type and
survival. Two points are important to note. These data
reflect cases collected at the Armed Forces Institute of
Pathology (AFIP) over a 20-year period and treated with
varying regimens, so caution is warranted about extending
the analysis too far. Furthermore, their listed criteria for
fetal hepatoblastoma do not include a threshold for mitotic
activity while they noted isolated tumors with up to 24
mitoses per 10 HPF. Several prospective cooperative
studies have shown a correlation between pure fetal
histology and improved survival. In North America, Stage
I PFH had superior prognosis with 92% 24-month survival
[3]. These PFHs were composed of uniformly welldifferentiated fetal pattern, lacking features of embryonal,
macrotrabecular, and small cell undifferentiated patterns.
Mitotic activity was described as infrequent but no specific
threshold criterion for mitotic activity was used. The
prognostic significance of pure fetal histology was only
evident in adequately sampled, completely resected
tumors. This study confirmed the poor prognosis of the
small cell undifferentiated (SCUD) type but did not show
statistically significant differences in outcome for the
other types. The subsequent POG study separated fetal
tumors with less than 2 mitoses/10 HPF from those with
higher mitotic rates and found that all four patients with
completely resected, low mitotic activity tumors were
alive with no evidence of disease [24]. The German
Pediatric Liver-Tumor Study HB89 showed a statistically
significant relationship between fetal differentiation and
prognosis. Children with pure fetal tumors and predominantly fetal tumors had disease free survival of 87.5 and
84.8%, respectively [6,26]. Unfortunately, these reports do
not describe the criteria used to define predominantly fetal
tumors. It is also important to note that no macrotrabecular
hepatoblastomas were described in this study. An earlier
report from this same study had not demonstrated a
correlation [5]. Most recently, the SIOPEL-1 study classified tumors as pure fetal or other with no significant
difference in outcome found between these two groups
[25]. They do not specifically state their criteria for these
categories. Sampling issues are a concern, since the diagnoses are based on biopsy only. No data are provided on the
adequacy of sampling. The protocol specifies chemotherapy before resection so that any resection specimens will
have the additional problem of chemotherapy changes to
contend with. These large studies reach different conclusions regarding the association between fetal differentiation and outcome. More detailed comparisons of treatment

Hepatoblastoma: Histologic Classification

strategy versus outcome are hindered due to the disparate

diagnostic criteria employed in these studies.
What are the key problems in comparing diagnostic
criteria in these studies? A fundamental deficiency is that
many studies do not adequately describe the criteria
employed, thus, making it impossible to evaluate the
results. Some studies cite a source for their criteria but then
describe features that contradict that source. When specific
criteria are provided, several areas appear problematic.
The most fundamental controversy concerns the specific
criteria used to define a given pattern. Most importantly,
for this discussion, is the wide variation in mitotic activity
accepted within the fetal hepatoblastoma category. If
the original criteria of Weinberg and Feingold [17] were
followed, many of the cases reported as fetal hepatoblastoma would not qualify. Since absence of mitotic activity
was an independent variable associated with improved
survival in both Stage 1 and higher stage tumors [3], and
other markers of proliferation [5] have also been found to
be associated with outcome, this seems to be a critical
point. The studies that restricted the diagnosis of fetal
hepatoblastoma to tumors with the appropriate histology
and mitotic activity below 2/10 HPF found a correlation
of fetal differentiation with improved outcome [17,24].
Current data are insufficient to determine whether the
crowded fetal pattern will prove useful in predicting
outcome. This variability in allowed mitotic activity is also
apparent in descriptions of small cell undifferentiated
hepatoblastoma. Two studies indicate that mitoses are
infrequent [14,18] while two others state that there is a
high mitotic rate [3,16]. None of these quantified the
mitotic activity. At present, this is a moot point, since the
outcome for this subtype has been so uniformly dismal.
However, it may become important if we refine criteria for
this category or more effective therapy becomes available.
A second obvious point of contention is how much of a
given pattern needs to be present to provide prognostic
importance. Many of these studies define a pattern based
on a percentage of the tumor area. These percentages were
often arbitrarily established and data are not available to
support the selected threshold. Gonzalez-Crussi et al. [15]
used approximately two-third of the area to classify a
pattern as predominant. This percentage has remained in
widespread use as a criterion for the macrotrabecular
pattern but has not been accepted as a standard for the other
types. Lack et al. [16] used 50% of the tumor area to
classify the tumor. They suggested that fetal tumors with
small portions of embryonal histology may have prognosis
equal to PFH but no crucial proportion was quantified.
Weinberg and Finegold [17] suggested that any deviation
from well-differentiated fetal pattern affected prognosis,
thus creating a 100% threshold for PFH. Haas et al. [3]
comment that generally embryonal tumors had at least
25% embryonal pattern but they did not quantify the
proportions. They required that 100% of the tumor be fetal

481

pattern to define PFH but only required 50% of the tumor

to be small cell undifferentiated to qualify as such. Heifetz
et al. [23] quantified the proportion of fetal, embryonal,
and mesenchymal tissues in pretreatment biopsies and
post-treatment resections but were unable to demonstrate
a critical percentage. The number of cases in each of these
studies is too small to derive meaningful conclusions
regarding the significance of a given percentage of most of
these patterns. Except for the data on PFH, no study has
provided specific data to justify a critical proportion of any
of the other patterns with prognostic significance. It is not
clear what label should be attached to a tumor with equal
proportions of fetal, embryonal, and small cell undifferentiated patterns or a tumor that has 75% fetal histology
and 25% small cell undifferentiated. The poor prognosis
associated with the SCUD pattern, at least, raises the
question whether even a small percentage of this pattern is
sufficient to confer unfavorable properties on an otherwise
well-differentiated tumor [18]. As we attempt to determine the prognostic significance of these patterns, we need
data addressing these points.
Two additional factors, other than diagnostic criteria,
become apparent from these studies: sampling methods
and treatment effects. A major factor influencing the
debate over the prognostic relevance of histologic subtypes of hepatoblastoma is sampling of the tumor. Even
if we agree on specific criteria for the diagnosis of these
tumors, there is still the problem of adequately sampling a
tumor. It has been well recognized for many years that
hepatoblastomas have quite variable histologic features.
Gonzalez-Crussi et al. [15] required at least one section
per centimeter of tumor diameter to include the case in
their study. This was actually the first study that
established any criteria for sampling. Subsequently, three
large studies provided data on the number of slides
evaluated per tumor, but did not restrict eligibility based
on these data. There were a mean 0.74  0.62 slides/cm
of tumor diameter in the CCG/POG study [3] and
0.71  0.69 slides/cm tumor diameter in the AFIP series
[4]. The German HB89 study [5] had an average of six
slides/tumor and an average tumor volume of 494 cc so
that sampling was approximately 0.6 slides/cm tumor
diameter. No data are available to define minimum
sampling requirements. This is a significant gap in our
knowledge. The traditional standard in histopathology has
been that one section per centimeter of tumor diameter
should be evaluated. The rationale for this standard is not
clear. Since the mathematical formula for the volume of a
sphere is 4/3pr3, this standard leads to progressively less
complete sampling of tumors as they increase in diameter
(Table I). Even so, none of the large cooperative studies
has been able to achieve even this degree of sampling. This
is not simply a matter of small biopsies undersampling
large tumors, although the frequent use of needle biopsies
to sample unresectable tumors accentuates the sampling

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Rowland

TABLE I. Relationship Between Tumor Size and Sampling

Tumor diameter (cm)

2
4
6
8
10

Tumor
volume (cc)

Blocks/cc tumor
volume

4
34
113
268
523

0.48
0.12
0.05
0.03
0.02

Calculations assume the tumor is a sphere and that one block is

submitted for each centimeter of tumor diameter.

problem. Haas et al. [3] reported that adequate sampling,

defined as at least one section per centimeter of tumor
cross sectional diameter, was only achieved in 8/29 Stage I
(completely resected) PFH tumors. Apart from the number
of sections taken, no criteria are available to guide the
topographic location of the sections. Do sections from the
center provide the same data as sections from the periphery? There are obvious practical limitations on the
amount of tissue obtained by biopsy and the number of
blocks submitted on any given case. Within these constraints, we must seek some reasonable approach that can
be routinely applied and maximizes our ability to detect
significant histologic features. This cannot be adequately
addressed until data are obtained that document the
diagnostic yield with different degrees of sampling.
Since many of the tumors are not resectable prior
to chemotherapy or are placed on protocols requiring
chemotherapy before resection, we must consider whether
chemotherapy changes the histologic features. Data on
this point are, again, scanty. Saxena et al. [27] compared a
group of 17 patients who received chemotherapy prior to
resection with 11 patients who underwent primary resection. They found more extensive necrosis and more osteoid
in post-chemotherapy cases, in addition to a variety of
secondary changes such as fibrosis and hemosiderin deposition. Both treatment groups had pure fetal, embryonal,
and mixed epithelial types. No obvious association between the histologic type and response to chemotherapy
was found. Heifetz et al. [23] found the number of cases
with mesenchymal tissues increased after therapy. Significant differences were found in the percentage of embryonal/fetal components between pre- and post-treatment
specimens in a given patient but not in a consistent direction for the groups as a whole. Whether these differences
are due to sampling error or treatment effect is not clear.
Bad outcome patients tended to have more embryonal
epithelium in the post-treatment specimen but not to a
statistically different degree. No cases of small cell undifferentiated or macrotrabecular hepatoblastoma were seen
in these two studies. von Schweinitz et al. [26] reported
that after treatment, the fibrous and osteoid tissue increased
in mixed hepatoblastomas. In epithelial tumors, the fetal
tissue became more predominant. They did not feel that

the basic histologic type changed after therapy and were

unable to correlate the histology with the sensitivity to
chemotherapy.
CONCLUSIONS

Comparison of results from different studies is hindered

by differences in methodology. The reviewed studies show
significant variation in the diagnostic criteria employed to
categorize hepatoblastomas. Specifically, there was wide
variation in the degree of mitotic activity allowed within
the category of fetal hepatoblastoma. Additionally, the
requirement of adequate sampling for a diagnosis of PFH
has not been followed in most studies. The percentage of
cases diagnosed as macrotrabecular hepatoblastoma varies
markedly between the studies, suggesting that the criteria
for this entity are not being applied uniformly as well.
Further refinement of diagnostic criteria for hepatoblastoma is needed to provide a reproducible classification
system. Guidance on appropriate sampling needs to be
provided for future studies. Additional work is needed to
define the role of histologic evaluation of post-treatment
specimens. Opportunities exist to evaluate many of these
issues using cases collected in the cooperative group
efforts around the world. Appropriate use of these materials should help contribute to better treatment for children
with hepatoblastoma.
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