Med Pediatr Oncol 2002;39:478–483

Hepatoblastoma: Assessment of Criteria forHistologic Classification

Jon M. Rowland, MD, PhD*

INTRODUCTION

Hepatoblastoma is a rare tumor, such that no singleinstitution treats sufficient numbers of patients to ade-quately assess the relationship between clinicopathologicfeatures, therapy, and outcome. Comparison of resultsfrom studies in different institutions or those usingdifferent treatment strategies has been hindered byvariations in diagnostic and staging criteria. Recently,significant progress toward standardized staging criteriahas been achieved with the PRETEXT system in use inSIOPEL and COG studies [1]. This review evaluates thediagnostic criteria established to define the differentsubtypes of hepatoblastoma and summarizes how thesehave been modified by different investigators, high-lighting differences between reported studies. Additionalconfounding factors such as sampling methods andtreatment effects are also evaluated.

MATERIALS AND METHODS

Published literature, through the end of 2000, onhistologic classification and outcome of hepatoblastomaare reviewed.

RESULTS AND DISCUSSION

It is important to appreciate that the histologicclassification of hepatoblastoma has slowly evolved overthe past 50 years and represents a collection of subtypesthat were defined by different investigators at differenttimes. This analysis will be restricted to classificationbased on the epithelial component. The major histologic

patterns of epithelial hepatoblastoma are the fetal,embryonal, macrotrabecular, and small cell undifferen-tiated types. Some authors retain the mixed epithelial andmesenchymal tumors as a separate category within theirclassification schemes [2]. However, except for the posi-tive effect of osteoid, chondroid, and squamous differ-entiation in high stage tumors reported by Haas et al. [3],none of the other large studies has demonstrated aninfluence of mesenchymal differentiation on outcome [4–6]. Rare tumors, such as thosewith rhabdoid features [7,8]or aberrant cell types within otherwise typical hepato-blastomas [9–11] are also excluded from this discussion.Regardless of the validity of defining these differentmorphologic subtypes, there is only one subtype thatcurrently leads to a change in therapy. The currentChildren’s Oncology Group protocol for hepatoblastoma(#9645) provides for surgical resection alone as thetherapy for patients with completely resected (Stage I),pure fetal hepatoblastoma (PFH). All other stages andsubtypes are randomized to receive chemotherapy. Sincethe identification of PFH is such an important distinction,the diagnostic criteria for this subtype will be covered indetail.

Awatershed event in hepatoblastoma classificationwasthe landmark study by Ishak and Glunz [12] that first

Background. Comparison of outcomes indifferent clinicopathologic studies of hepatoblas-toma requires reproducible histologic classifica-tion. This review examines the diagnostic criteriaemployed by different pathologists for the classi-fication of subtypes of hepatoblastoma andidentifies specific problem areas. Procedure. Aselected review of published literature is pro-vided. Results. Published studies demonstratethat uniform criteria have not been applied inthe classification of hepatoblastoma. Thesediscrepancies hinder attempts to compare out-come data from different studies. Sampling error

and potential treatment effects further compli-cate analysis of the published literature on therelationship between morphologic classificationand outcome. Conclusions. Standardized cri-teria are essential to allow reproducible histo-logic classification of hepatoblastoma. There issignificant variation in diagnostic criteria usedto define the major subtypes of hepatoblastomain published studies. Additional potential pro-blems are identified in sampling methods andtreatment effects. Med Pediatr Oncol 2002;39:478–483. � 2002 Wiley-Liss, Inc.

Key words: hepatoblastoma classification; histologic criteria

——————Department of Pathology, Children’s Hospital, Oakland, California

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

� 2002 Wiley-Liss, Inc.DOI 10.1002/mpo.10171

proposed specific criteria to define fetal and embryonalcells in hepatoblastoma. Themain purpose of this study, aswith most studies of that era, was to contrast hepatocel-lular carcinoma andhepatoblastoma.These authors retain-ed the epithelial and mixed categories of hepatoblastomaof earlier authors [13] but described the epithelial cells inmuch more detail. One type of cell, designated fetal type,was said to be readily recognizable as a hepatic parenchy-mal cell and to resemble the cells of the prenatal fetal liver.These cells are arranged usually in irregular plates of two-cell thick. The cells are smaller than normal parenchymalcells, have some variation in size of cells and nuclei, andhave nuclear to cytoplasmic ratios ranging from 1:2–1:4compared to 1:4–1:6 in non-neoplastic cells. The nucleiare round or oval with few mitotic figures seen. It is im-portant to note that this definition includes both cytologicand architectural features in the definition. They describedembryonal type cells as much less differentiated. Thesecells show poor cohesiveness and are usually arranged insheets or ribbons or sometimes in acinar, pseudorosette, orpapillary formations. The cells are elongated, small, anddark staining. Cellular outline is poorly defined and irre-gular. There is considerable variation in size of both cellsand nuclei with a nuclear to cytoplasmic ratio of 1:1–1:2.The oval to round nucleus is hyperchromatic with abun-dant chromatin. A large, distinct, and amphophilic oracidophilic nucleolus is present. Mitotic activity is seenmuch more frequently than in fetal type cells. Althoughthese authors described fetal and embryonal cells, they didnot propose that this distinction should be extended todistinguish embryonal and fetal tumors.

Over the next 15 years, several studies used the his-tologic features described by Ishak and Glunz [12], inconjunction with an estimate of the relative percentage oftumor area occupied by those cells to further categorizethese tumors. In 1970, Kasai and Watanabe, basing theiranalysis only on features of the epithelial cells with nocategory ofmixed hepatoblastoma, introduced the conceptof embryonal and fetal type epithelial hepatoblastomas[14]. The predominant cell type defined embryonal andfetal type hepatoblastomas. Predominant was not furtherdefined. Gonzalez-Crussi et al. [15] described fetal andembryonalpatternswithin hepatoblastoma.A fetal patternhad to be present, at least focally, in all cases to be includedas a hepatoblastoma. An attempt was made to subclassifythe tumors based on the predominant pattern; a predomi-nant pattern was defined as occupying at least two-third ofthe area. Lack et al. [16] used a criterion of 50% of crosssectional area to separate embryonal and fetal tumors.Their description of fetal tumors mentions that some had asheet-like configuration. Whether some of these tumorswould qualify now as the macrotrabecular pattern isunknown.

Finally, Weinberg and Finegold [17], building on thecriteria of Ishak and Glunz [12], established two new

criteria to distinguish embryonal and fetal hepatobla-stomas. They quantified infrequent mitoses as less than2 mitoses/10 high power fields (HPF), providing the firstspecific threshold for this feature. They also suggestedthat any deviation from a well-differentiated fetal patternwould indicate a poor prognosis. This is the origin of whathas come to be termed ‘‘pure fetal hepatoblastoma.’’ Ex-tensive histologic sampling, defined as at least one blockper centimeter of tumor, is required to document the his-tologic type. Subsequent studies proposed that anothervariant, termed ‘‘crowded fetal,’’ beused todescribe tumorswith preservation of the hepatocellular cord architecturebut containing cells with larger, more pleomorphic nuclei,and increased mitotic activity [18].

A third distinct pattern, the macrotrabecular pattern, isa hepatocytic proliferation in trabeculae 10, 20, or morecells thick [15]. The macrotrabecular cells can be fetal orembryonal hepatocytes. On occasion, the cell size exceedsthat of normal uninvolved liver tissue. It is important toremember that all macrotrabecular cases had some fetalpattern by definition. The fourth major pattern, small cellundifferentiated, was first labeled anaplastic hepatoblas-toma and described as a tumor composed of very small,immature appearing cellswith scanty cytoplasmandhyper-chromatic nuclei, resembling neuroblastoma cells [14].These cells are stellate or oval in shapewith scanty, faintlyeosinophilic or amphophilic cytoplasm and show littlesimilarity to normal liver cells.Mitosiswas not common intheir cases.Cells grow in sheets in some areas,while otherswere scattered without cohesiveness. Lack et al. [16] alsodescribed anaplastic tumors as more cellular tumors com-posed mainly of poorly differentiated small to mediumsize cells without significant acinar, ductal, or pseudo-glandular components. These had a high mitotic rate, incontrast to the original description [14]. Again, these cellshad to occupy at least 50% of the area to qualify for thediagnosis. Haas et al. [3] proposed small cell undiffer-entiated hepatoblastoma as a more appropriate name forthe tumors previously designated as anaplastic hepato-blastoma [14,16]. A high mitotic rate was again noted.These tumors display sheets and nests of loosely cohesivecells with scanty cytoplasm. A primitive spindle cellcomponent may be present but most cells are round tooval. The undifferentiated cells had to occupy more than50%of the area towarrant the diagnosis. These tumors hadfoci of fetal hepatoblastoma but did not have embryonal ormacrotrabecular features. Some undifferentiated cases inthe Pediatric Oncology Group (POG) study were com-pletely composed of undifferentiated cells with mitosesdescribed as infrequent [18]. Two case reports of small cellundifferentiated hepatoblastoma further document theoccurrence of tumors completely composed of poorlydifferentiated cells [19,20]. Neither of these two casesresembled liver parenchyma on histologic examinationbut each showed ultrastructural features of epithelial

Hepatoblastoma: Histologic Classification 479

differentiation. One of these also had primitive canaliculion ultrastructural examination and polyclonal keratinreactivity on immunohistochemistry [19]. Since small cellundifferentiated hepatoblastoma is considered to repre-sent the least differentiated form of hepatoblastoma, it isnot surprising that some cases may require specialtechniques to demonstrate hepatocellular differentiation.

These studies collectively provide criteria for fourmajor patterns of epithelial differentiation in hepatoblas-toma. It is clear from these studies that no consensuscriteria exist. Furthermore, neither the relevance norreproducibility of many of these features has been tested.Additionally, these criteria do not adequately cover thecontinuum of morphology that exists in these tumors. Ifthe most restrictive of these criteria were used to defineeach pattern, numerous typical hepatoblastomas wouldbe unclassified. Despite these limitations, these criteriaprovide a framework to analyze the published literatureregarding the association between histologic classificationand outcome. Results from theworks discussed above anda number of more recent large studies will be analyzed,specifically focusing on fetal hepatoblastoma. Previousreviews addressing the prognostic importance of histolo-gic subtypes are available [21,22].

The correlation between histologic differentiation inhepatoblastoma and outcomewas first addressed by Kasaiand Watanabe [14]. They found improved survival inchildrenwith fetal hepatoblastoma compared to thosewithembryonal or anaplastic hepatoblastoma with seven ofnine long-term survivors being of fetal type. They alsoreported that 9/11 children with fetal hepatoblastomawhosurvived the initial resection remained alive and well from18 months to 6 years after the operation. Several othersmall-scale studies provided data that suggested thattumors with fetal differentiation had improved outcomecompared to tumors with other patterns of differentiation.Lack et al. [16] had 9/13 long-term survivors in their serieswith predominantly fetal morphology. No long-termsurvivors were found in the anaplastic group. Gonzalez-Crussi et al. [15] had only two patients with Stage 1 purefetal tumors and both were long-term survivors. Threeother tumors with total fetal pattern were found. One ofthese was discovered as an unexpected Stage I tumor atautopsy. The remaining twohadmetastases documented atdiagnosis and died within 8 months of diagnosis. Fivepatients had predominant macrotrabecular tumors and allof these died with progressive disease. No small cellundifferentiated hepatoblastomas were found in thisstudy. Weinberg and Finegold found long-term survivalin 6/6 patients with completely resected PFH [17]. Onlytwo of seven patients with less differentiated histologiesand complete resections survived. The diagnostic criteriafor these four studies have been described above. Heifetzet al. [23] did not find a correlation between proportions offetal or embryonic epithelium and outcome. The mean

mitotic activity of their fetal epithelial components rangedfrom 3.7/10 HPF in resectable tumors to 11.9/10 HPF innonresectable tumors. No macrotrabecular or small cellundifferentiated tumors were found in their series.

Several large studies have provided data on the rela-tionship between histologic differentiation and prognosisin hepatoblastoma [2–4,6,24,25]. Conran et al. [4] did notdemonstrate a relationship between histologic type andsurvival. Two points are important to note. These datareflect cases collected at the Armed Forces Institute ofPathology (AFIP) over a 20-year period and treated withvarying regimens, so caution is warranted about extendingthe analysis too far. Furthermore, their listed criteria forfetal hepatoblastoma do not include a threshold formitoticactivity while they noted isolated tumors with up to 24mitoses per 10 HPF. Several prospective cooperativestudies have shown a correlation between pure fetalhistology and improved survival. In North America, StageI PFH had superior prognosis with 92% 24-month survival[3]. These PFHs were composed of uniformly well-differentiated fetal pattern, lacking features of embryonal,macrotrabecular, and small cell undifferentiated patterns.Mitotic activitywas described as infrequent but no specificthreshold criterion for mitotic activity was used. Theprognostic significance of pure fetal histology was onlyevident in adequately sampled, completely resectedtumors. This study confirmed the poor prognosis of thesmall cell undifferentiated (SCUD) type but did not showstatistically significant differences in outcome for theother types. The subsequent POG study separated fetaltumors with less than 2 mitoses/10 HPF from those withhigher mitotic rates and found that all four patients withcompletely resected, low mitotic activity tumors werealive with no evidence of disease [24]. The GermanPediatric Liver-Tumor Study HB89 showed a statisticallysignificant relationship between fetal differentiation andprognosis. Children with pure fetal tumors and predomi-nantly fetal tumors had disease free survival of 87.5 and84.8%, respectively [6,26].Unfortunately, these reports donot describe the criteria used to define predominantly fetaltumors. It is also important to note that nomacrotrabecularhepatoblastomas were described in this study. An earlierreport from this same study had not demonstrated acorrelation [5]. Most recently, the SIOPEL-1 study classi-fied tumors as ‘‘pure fetal’’ or ‘‘other’’ with no significantdifference in outcome found between these two groups[25]. They do not specifically state their criteria for thesecategories. Sampling issues are a concern, since the diag-noses are basedon biopsyonly.Nodata are provided on theadequacy of sampling. The protocol specifies chemother-apy before resection so that any resection specimens willhave the additional problem of chemotherapy changes tocontend with. These large studies reach different conclu-sions regarding the association between fetal differentia-tion and outcome.More detailed comparisons of treatment

480 Rowland

strategy versus outcome are hindered due to the disparatediagnostic criteria employed in these studies.

What are the key problems in comparing diagnosticcriteria in these studies? A fundamental deficiency is thatmany studies do not adequately describe the criteriaemployed, thus, making it impossible to evaluate theresults. Some studies cite a source for their criteria but thendescribe features that contradict that source.When specificcriteria are provided, several areas appear problematic.The most fundamental controversy concerns the specificcriteria used to define a given pattern. Most importantly,for this discussion, is the wide variation in mitotic activityaccepted within the fetal hepatoblastoma category. Ifthe original criteria of Weinberg and Feingold [17] werefollowed, many of the cases reported as fetal hepatoblas-toma would not qualify. Since absence of mitotic activitywas an independent variable associated with improvedsurvival in both Stage 1 and higher stage tumors [3], andother markers of proliferation [5] have also been found tobe associated with outcome, this seems to be a criticalpoint. The studies that restricted the diagnosis of fetalhepatoblastoma to tumors with the appropriate histologyand mitotic activity below 2/10 HPF found a correlationof fetal differentiation with improved outcome [17,24].Current data are insufficient to determine whether the‘‘crowded fetal pattern’’ will prove useful in predictingoutcome.This variability in allowedmitotic activity is alsoapparent in descriptions of small cell undifferentiatedhepatoblastoma. Two studies indicate that mitoses areinfrequent [14,18] while two others state that there is ahigh mitotic rate [3,16]. None of these quantified themitotic activity. At present, this is a moot point, since theoutcome for this subtype has been so uniformly dismal.However, it may become important if we refine criteria forthis category ormore effective therapy becomes available.

A second obvious point of contention is how much of agiven pattern needs to be present to provide prognosticimportance. Many of these studies define a pattern basedon a percentage of the tumor area. These percentages wereoften arbitrarily established and data are not available tosupport the selected threshold. Gonzalez-Crussi et al. [15]used approximately two-third of the area to classify apattern as predominant. This percentage has remained inwidespread use as a criterion for the macrotrabecularpattern but has not been accepted as a standard for the othertypes. Lack et al. [16] used 50% of the tumor area toclassify the tumor. They suggested that fetal tumors withsmall portions of embryonal histologymayhave prognosisequal to PFH but no crucial proportion was quantified.Weinberg and Finegold [17] suggested that any deviationfrom well-differentiated fetal pattern affected prognosis,thus creating a 100% threshold for PFH. Haas et al. [3]comment that generally embryonal tumors had at least25% embryonal pattern but they did not quantify theproportions. They required that 100%of the tumor be fetal

pattern to define PFH but only required 50% of the tumorto be small cell undifferentiated to qualify as such. Heifetzet al. [23] quantified the proportion of fetal, embryonal,and mesenchymal tissues in pretreatment biopsies andpost-treatment resections but were unable to demonstratea critical percentage. The number of cases in each of thesestudies is too small to derive meaningful conclusionsregarding the significance of a given percentage ofmost ofthese patterns. Except for the data on PFH, no study hasprovided specific data to justify a critical proportion of anyof the other patterns with prognostic significance. It is notclear what label should be attached to a tumor with equalproportions of fetal, embryonal, and small cell undiffer-entiated patterns or a tumor that has 75% fetal histologyand 25% small cell undifferentiated. The poor prognosisassociated with the SCUD pattern, at least, raises thequestion whether even a small percentage of this pattern issufficient to confer unfavorable properties on an otherwisewell-differentiated tumor [18]. As we attempt to deter-mine the prognostic significance of these patterns,we needdata addressing these points.

Two additional factors, other than diagnostic criteria,become apparent from these studies: sampling methodsand treatment effects. A major factor influencing thedebate over the prognostic relevance of histologic sub-types of hepatoblastoma is sampling of the tumor. Evenif we agree on specific criteria for the diagnosis of thesetumors, there is still the problem of adequately sampling atumor. It has been well recognized for many years thathepatoblastomas have quite variable histologic features.Gonzalez-Crussi et al. [15] required at least one sectionper centimeter of tumor diameter to include the case intheir study. This was actually the first study thatestablished any criteria for sampling. Subsequently, threelarge studies provided data on the number of slidesevaluated per tumor, but did not restrict eligibility basedon these data. There were a mean 0.74� 0.62 slides/cmof tumor diameter in the CCG/POG study [3] and0.71� 0.69 slides/cm tumor diameter in the AFIP series[4]. The German HB89 study [5] had an average of sixslides/tumor and an average tumor volume of 494 cc sothat sampling was approximately 0.6 slides/cm tumordiameter. No data are available to define minimumsampling requirements. This is a significant gap in ourknowledge. The traditional standard in histopathology hasbeen that one section per centimeter of tumor diametershould be evaluated. The rationale for this standard is notclear. Since the mathematical formula for the volume of asphere is 4/3pr3, this standard leads to progressively lesscomplete sampling of tumors as they increase in diameter(Table I). Even so, none of the large cooperative studieshas been able to achieve even this degree of sampling. Thisis not simply a matter of small biopsies undersamplinglarge tumors, although the frequent use of needle biopsiesto sample unresectable tumors accentuates the sampling

Hepatoblastoma: Histologic Classification 481

problem. Haas et al. [3] reported that adequate sampling,defined as at least one section per centimeter of tumorcross sectional diameter, was only achieved in 8/29 Stage I(completely resected) PFH tumors.Apart from the numberof sections taken, no criteria are available to guide thetopographic location of the sections. Do sections from thecenter provide the same data as sections from the peri-phery? There are obvious practical limitations on theamount of tissue obtained by biopsy and the number ofblocks submitted on any given case. Within these con-straints, we must seek some reasonable approach that canbe routinely applied and maximizes our ability to detectsignificant histologic features. This cannot be adequatelyaddressed until data are obtained that document thediagnostic yield with different degrees of sampling.

Since many of the tumors are not resectable priorto chemotherapy or are placed on protocols requiringchemotherapy before resection, wemust consider whetherchemotherapy changes the histologic features. Data onthis point are, again, scanty. Saxena et al. [27] compared agroup of 17 patients who received chemotherapy prior toresection with 11 patients who underwent primary resec-tion.They foundmore extensive necrosis andmore osteoidin post-chemotherapy cases, in addition to a variety ofsecondary changes such as fibrosis and hemosiderin de-position. Both treatment groups had pure fetal, embryonal,and mixed epithelial types. No obvious association be-tween the histologic type and response to chemotherapywas found. Heifetz et al. [23] found the number of caseswith mesenchymal tissues increased after therapy. Signi-ficant differences were found in the percentage of em-bryonal/fetal components between pre- and post-treatmentspecimens in a given patient but not in a consistent dir-ection for the groups as awhole.Whether these differencesare due to sampling error or treatment effect is not clear.Bad outcome patients tended to have more embryonalepithelium in the post-treatment specimen but not to astatistically different degree. No cases of small cell undif-ferentiated or macrotrabecular hepatoblastoma were seenin these two studies. von Schweinitz et al. [26] reportedthat after treatment, thefibrous andosteoid tissue increasedin mixed hepatoblastomas. In epithelial tumors, the fetaltissue became more predominant. They did not feel that

the basic histologic type changed after therapy and wereunable to correlate the histology with the sensitivity tochemotherapy.

CONCLUSIONS

Comparison of results fromdifferent studies is hinderedby differences inmethodology. The reviewed studies showsignificant variation in the diagnostic criteria employed tocategorize hepatoblastomas. Specifically, there was widevariation in the degree of mitotic activity allowed withinthe category of fetal hepatoblastoma. Additionally, therequirement of adequate sampling for a diagnosis of PFHhas not been followed in most studies. The percentage ofcases diagnosedasmacrotrabecular hepatoblastomavariesmarkedly between the studies, suggesting that the criteriafor this entity are not being applied uniformly as well.Further refinement of diagnostic criteria for hepatoblas-toma is needed to provide a reproducible classificationsystem. Guidance on appropriate sampling needs to beprovided for future studies. Additional work is needed todefine the role of histologic evaluation of post-treatmentspecimens. Opportunities exist to evaluate many of theseissues using cases collected in the cooperative groupefforts around the world. Appropriate use of these mate-rials should help contribute to better treatment for childrenwith hepatoblastoma.

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TABLE I. Relationship Between Tumor Size and Sampling

Tumor diameter (cm)Tumor

volume (cc)Blocks/cc tumor

volume

2 4 0.484 34 0.126 113 0.058 268 0.03

10 523 0.02

Calculations assume the tumor is a sphere and that one block issubmitted for each centimeter of tumor diameter.

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