• hepatoblastoma;
  • serous cavity fluid;
  • cytopathology;
  • hepatic


  1. Top of page
  2. Abstract


Hepatoblastoma (HBL) represents the most common primary hepatic tumor in children. Although the cytologic features of this tumor have been amply elucidated on fine-needle aspiration, exfoliative cytomorphologic characteristics have not been reported. The authors reviewed the cytopathologic features of six serous cavity fluids (SCF) from four patients with histologically proven HBL.


Five of the specimens evaluated were peritoneal fluids, and one specimen was pleural fluid from a patient with suspected pulmonary metastasis. Slides were prepared by cytocentrifugation and stained with Diff-Quik and Papanicolaou stains. The cytomorphologic features of each specimen were characterized, subclassified, and correlated histopathologically.


All specimens showed hypercellular smears in a relatively clean background. Mixed embryonal and fetal subtypes of HBL disclosed three-dimensional clusters of neoplastic cells that formed straight or branched cords and acinus-like structures. The cells were moderately pleomorphic and had high nuclear-to-cytoplasmic (N/C) ratios. Occasional cells had eccentrically placed nuclei and vacuolated cytoplasm. Numerous mitotic figures were present. Rare intranuclear inclusions were noted. The anaplastic (small cell) subtype of HBL showed tight clusters of small, round, primitive cells with hyperchromatic nuclei, high N/C ratios, and prominent nuclear molding. In addition, there were numerous single cells with naked nuclei, often in an Indian-file configuration. Bile pigment, osteoid, and other mesenchymal components were absent in all specimens.


The cytomorphologic features of HBL in SCF are quite characteristic. Although the differential diagnosis includes other childhood small, round, blue cell tumors and hepatocellular carcinoma, the above findings in the appropriate clinical-radiologic setting warrant a diagnosis of HBL. Cancer (Cancer Cytopathol) 2002;96:267–74. © 2002 American Cancer Society.

Although it is rare among neoplasms, hepatoblastoma represents the most common primary hepatic tumor in the pediatric population. With an annual incidence of 0.9 incidents per 1 million children,1 hepatoblastoma is twice as common as hepatocellular carcinoma in this age group.2, 3 It usually presents by the age of 5 years and affects males more commonly than females (males to females, 2:1). Serum α-fetoprotein (AFP) levels are elevated in 84–91% of patients, usually with very high titers.3 Histologically, hepatoblastomas are classified as either pure epithelial or mixed epithelial-mesenchymal types. Distinct subtypes of the epithelial component include fetal, embryonal, anaplastic (small cell), and macrotrabecular.4, 5 In recent years, the cytologic features of this tumor have been amply elucidated on fine-needle aspiration (FNA);6–13 however, its exfoliative cytomorphologic characteristics have not been reported. In this series, we describe the cytopathologic features of six serous cavity fluids (SCF) from four patients with histologically proven hepatoblastoma, discuss potential cytologic imitators, and present ultrastructural and cytogenetic data from a selected patient.


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  2. Abstract

Cytopathology files at The Johns Hopkins Hospital were searched for patients with hepatoblastoma diagnosed in SCF for a period of 10 years (1992–2001). Six SCF specimens with hepatoblastoma were retrieved from four different patients. Patients ranged in age from 4 months to 5 years; three patients were male, and one patient was female. Three of the specimens were intraoperative abdominal washes that were obtained at the time of the initial surgical procedure. Two specimens were abdominal paracenteses: One was obtained at the time of the initial tissue biopsy, and the other was obtained 2 years after the initial biopsy. The sixth specimen was pleural fluid from a patient with suspected pulmonary metastasis. Smears were prepared by cytocentrifugation and either air dried for Diff-Quik staining or fixed in alcohol for Papanicolaou staining. In five patients, additional material was placed in a 1:1 solution of 50% alcohol and Ringer solution, from which cell blocks were prepared, and 4-μm sections were cut and stained with hematoxylin and eosin. Also, in one patient, cellular material was obtained for ultrastructural and cytogenetic analysis. The selected tumor tissue was fixed in glutaraldehyde, and conventional electron microscopy was performed. For karyotypic analysis, a metaphase spread of cultured tumor cells was employed.


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  2. Abstract

The clinical and pathologic data from all four patients are outlined in Table 1. Brief clinical summaries of each patient are provided below.

Table 1. Clinicopathologic Findings
PatientGenderAgeAFP (ng/mL)Radiologic findingsCytology specimenHistologic findingsTherapyFollow-up
  1. AFP: α-fetoprotein; CT: computed tomography; HBL: hepatoblostoma.

1Female5 months35,000CT: 7.5 cm solid central hepatic massabdominal washHBL, predominantly fetal subtype with focal embryonal subtypeChemotherapy and left lobe hepatectomyAlive and well 2 yrs later
2Male4 months881,000CT: 5-cm solid mass in right hepatic lobeabdominal washHBL, mixed embryonal & fetal subtypesChemotherapy and liver transplantationDied 9 months later; no autopsy
3Male5 yrsWithin normal limitsCT: 10-cm nodular liver mass1) Abdominal paracentesis; 2) pleural fluid; 3) abdominal paracentesis1) HBL, anaplastic, (undifferentied small cell) subtype; 2) same specimen; 3) same specimenChemotherapy onlyDied 2 yrs later; no autopsy
4Male3 yrs630,000CT: diffuse nodular liver massAbdominal washHBL, mixed embryonal and fetal subtypes with mature, mesenchymal componentsLeft hepatectomy, partial omentectomy, cholecystectomy, and chemotherapyAlive and well 1 yr later and lost follow-up

Clinical Summaries

Patient 1

A previously healthy African-American female age 5 months presented with increased abdominal girth and frequent emesis for 2 weeks. A computed tomography (CT) scan of the abdomen showed a large, predominantly solid mass located centrally within the liver. The serum AFP level was 35,000 ng/mL. Exploratory laparotomy revealed a 7.5-cm tumor arising in the left hepatic lobe. The patient immediately underwent left lateral hepatic segmentectomy and biopsy of the porta hepatis lymph node. An intraoperative abdominal wash was obtained for cytologic review. The surgical pathology report confirmed the cytopathologic findings. No tumor was found in the lymph node biopsy. The patient received a full course of chemotherapy and was well 2 years after the initial presentation, at which time she was lost to follow up.

Patient 2

A full-term white male infant was discovered with a palpable abdominal mass at age 4 months. A CT scan of the abdomen showed a 5-cm solid mass occupying most of the right lobe of the liver. Liver function tests were slightly elevated, and the serum AFP level was 881,000 ng/mL. The patient underwent an exploratory laparotomy, and it was found that he had a large, unresectable liver tumor with diffuse involvement of both lobes. Biopsies of the tumor, the porta hepatis lymph node, and a mesenteric lymph node were submitted for pathologic evaluation. A cytologic review of peritoneal fluid showed pathologic changes similar to those seen on the liver biopsy. No tumor was found in the lymph node biopsies. Despite four cycles of chemotherapy, the tumor failed to respond. The patient underwent total hepatectomy and orthotopic liver transplantation at age 13 months. Postoperatively, liver function was tenuous and then failed. Six days after surgery, the patient suffered cardiac arrest and died. Permission for an autopsy was denied.

Patient 3

After 3 weeks of fatigue and lethargy, an African-American male age 5 years presented to the Emergency Room with marked abdominal distention. A radiologic work-up revealed a 10-cm nodular liver mass with abdominal adenopathy, ascites, bilateral pleural effusions, and a pericardial effusion. Although the serum AFP level was within normal limits, liver enzymes were mildly elevated. Chemotherapy was administered after surgical biopsies of the liver and excision of a peritoneal nodule. Malignant cytology present on abdominal fluid and pleural fluid specimens supported the histologic diagnosis. The patient clinically deteriorated over the next several months. At age 7 years, he developed marked ascites and a painful 5-cm right supraclavicular lymph node. Repeat cytologic evaluation of the abdominal fluid revealed similar neoplastic cells in a setting of acute bacterial peritonitis. Therapy restricted to comfort measures was instituted. The patient suffered a cardiorespiratory death 2 years after the initial presentation. Permission for an autopsy was denied.

Patient 4

A white male age 3 years presented to his pediatrician with progressive abdominal pain and tenderness. Physical examination was notable for moderate ascites and a palpable right upper quadrant mass. The serum AFP level was 630,000 ng/mL. A diffuse nodular mass involving the left hepatic lobe was noted on CT scan. Exploratory laparotomy revealed a solid 6-cm hepatic tumor and peritoneal implants. The patient underwent a left hepatectomy, partial omentectomy, and cholecystectomy. Cytologic findings on an intraoperative abdominal wash were consistent with the histopathologic changes. The patient completed a course of chemotherapy and was remarkably well at age 4 years. The patient subsequently was lost to follow-up.

Cytopathologic Findings

Three of six SCF specimens (from Patients 1, 2, and 4) showed hypercellular smears in a relatively clean background. The predominant cytomorphologic features of each of these specimens included single discohesive cells, sheets, and three-dimensional clusters of neoplastic cells with hyperchromatic nuclei and high nuclear-to-cytoplasmic (N/C) ratios. Many of the cohesive sheets were in the form of straight or branched cords (Fig. 1), and several of the cell clusters resembled acinar structures (Fig. 2). The cells were relatively small and mildly pleomorphic, and they had predominantly rounded nuclear contours. The nuclei were slightly eccentric and had a coarsely granular chromatin pattern. Occasional mitoses were noted in all three fluids, and several nuclear grooves were noted in the smears from Patients 2 and 4. Occasional cells displayed short, wispy cytoplasmic processes that rendered the cell borders indistinct. Also present were scattered single cells with deeply cleft nuclei with irregular contours, often containing numerous small cytoplasmic vacuoles (Fig. 3). Rare intranuclear inclusions were identified. However, neither nucleoli nor mitoses were apparent. Several benign, uniform mesothelial cells were scattered throughout the smears. Otherwise, the background of the smears consisted only of blood with few mononuclear inflammatory cells. The architectural arrangements of the tumor cells were especially apparent on the cell blocks prepared from the fluids.

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Figure 1. Hepatoblastoma (Patient 1). Serous fluid specimen showing neoplastic cells with a high nuclear-to-cytoplasmic ratio and with barely discernible cytoplasm forming a cord-like arrangement (Diff-Quik stain; original magnification, ×630).

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Figure 2. Hepatoblastoma (Patient 2). Serous fluid specimen showing anaplastic tumor cells with hyperchromatic nuclei and small nucleoli in an acinar-like architecture (Diff-Quik stain; original magnification, ×630).

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Figure 3. Hepatoblastoma (Patient 4). Serous fluid specimen showing single, discohesive neoplastic cells with pleomorphic nuclei depicting cleft or lobulated nuclei. Note the small intracytoplasmic vacuoles (Diff-Quik stain; original magnification, ×630).

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The smears from the two paracentesis fluids and the pleural fluid aspirated from Patient 3 also were markedly cellular. However, those smears demonstrated primitive appearing neoplastic cells with distinctly unique cytomorphologic characteristics. The cytologic findings consisted of small, round, primitive cells arranged in tight clusters and numerous single cells with almost naked nuclei, often arranged in an Indian-file configuration. The cells had scant cytoplasm; often showing single, large vacuoles with inspissated material; and had a high N/C ratio (Fig. 4). The nuclei were monomorphic and hyperchromatic with slightly irregular nuclear contours and coarsely granular chromatin. Papanicolaou stain showed prominent nuclear molding and small, inconspicuous nucleoli. Several mitoses were particularly evident (Fig. 5).

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Figure 4. Hepatoblastoma (Patient 3). Serous fluid specimen showing primitive-appearing neoplastic cells with hyperchromatic eccentrically placed nuclei in a vague Indian-file arrangement. A single cell with large intracytoplasmic vacuole also is evident (Papanicolaou stain; original magnification, ×630).

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Figure 5. Hepatoblastoma (Patient 3). Serous fluid specimen showing small, round, blue, neoplastic cells depicting mitosis (left) and nuclear molding (right). A single cell with intranuclear inclusion also is seen (bottom right; Papanicolaou stain; original magnification, ×630).

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Heterologous cellular elements (i.e., osteoid, cartilaginous stroma, and other mesenchymal components) were notably absent in the smears and in the cell blocks of all six specimens. In addition, there was no evidence of bile pigment, extramedullary hematopoiesis, or multinucleated giant cells.

Histopathology and Ancillary Studies

Based on the histologic evaluation of tumors in this series, only three patients had a pure epithelial type of hepatoblastoma: Two patients had the fetal and embryonal subtype, and one patient had the anaplastic subtype. The remaining patient had a mixed epithelial-mesenchymal type. Review of the tissue specimens from Patients 1 and 2 revealed that the embryonal component was comprised of moderately cohesive cells arranged in nests, trabeculae, and glandular structures (Fig. 6). The malignant features of the cells, which were appreciated clearly in an intraoperative touch imprint of a hepatic resection (Fig. 7), included somewhat pleomorphic cells with round-to-oval nuclei that often were cleft and bilobed, scant amounts of brightly eosinophilic cytoplasm, high N/C ratios, and increased mitotic activity. The smaller fetal component consisted of broad, cohesive sheets and thin, disparate cords of larger cells interspersed among the embryonal subtype. These pure epithelial hepatoblastomas were hypervascular with several large vascular lakes and occasional areas of geographic necrosis. Multiple foci of extramedullary hematopoiesis were associated with the fetal component in Patient 2. The histology from Patient 4 represented a mixed epithelial-mesenchymal type of hepatoblastoma. This tumor also showed fetal and embryonal epithelial components (with rare multinucleated giant cells); however, mesenchymal differentiation was evident in the form of metaplastic foci of mature osteoid matrix. Focal vascular invasion was identified, and additional biopsy results revealed metastatic nodules of the omentum and the gallbladder.

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Figure 6. Hepatoblastoma (Patient 1). Partial hepatectomy specimen showing loosely cohesive, malignant cells with a high nuclear-to-cytoplasmic ratio and hyperchromatic nuclei arranged in vague, trabecular architecture. Note the neoplastic cell aggregation around a luminal space (center bottom; hematoxylin and eosin stain; original magnification, ×400).

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Figure 7. Hepatoblastoma (Patient 1). Intraoperative touch imprint from partial hepatectomy specimen. Primitive-appearing malignant cells with hyperchromatic nuclei, a high nuclear-to-cytoplasmic ratio, and brightly eosinophilic cytoplasm (hematoxylin and eosin stain; original magnification, ×630).

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The liver biopsy from Patient 3 showed a hypercellular pure epithelial hepatoblastoma of anaplastic subtype. The tumor consisted of infiltrating sheets and nests of poorly differentiated, small, uniform cells with scant cytoplasm, hyperchromatic nuclei, nuclear clefts, and numerous mitoses. Individual cell necrosis and apoptosis were prominent. Also, many of the tumor cell nests were remarkable for central necrosis and a mild, mixed, inflammatory infiltrate. Immunohistochemical studies on the paraffin blocks revealed positive staining for antibodies to vimentin and cytokeratin but negative staining for antibodies to common leukocyte antigen, chromogranin, synaptophysin, desmin, and smooth muscle actin. In addition, ultrastructural analysis of these primitive cells revealed well-formed intercellular junctions, abundant intermediate filaments, and sparse cytoplasmic organelles consisting of mitochondria and rough endoplasmic reticulum. Small amounts of glycogen and fat were present in some cells. The cells were embedded in a myxoid matrix comprised of finely granular and fibrillar material. A cytogenetic analysis of the small, round, blue cell tumor yielded complex results. The dominant karyotypic abnormalities included a translocation between chromosomes 1 and 10, a deletion of the short arm of chromosome 17, and a deletion of the short arm of chromosome 1.


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  2. Abstract

Hepatoblastomas are usually large space-occupying neoplasms, often with lymph node metastases and/or peritoneal and mesenteric implants, when first detected. Due to the success of tumor specific therapy, distinction from other hepatic lesions, both primary and metastatic, is necessary for long-term survival. Recent studies have demonstrated that FNA is a reliable means for the diagnosis and management of patients with hepatoblastoma and other pediatric tumors.7, 14–16 FNA is an important diagnostic modality that offers minimal trauma to the patient, a low complication rate, and relatively low cost compared with surgical biopsy.14 In our series, we have shown that cytologic evaluation of SCF, when coupled with the appropriate clinical information, is equally effective in the diagnosis of hepatoblastoma and is critical for accurate clinical staging of the patient's malignant process.

Similar to previous cytology reports, the tumor cells from three of our patients showed differentiation patterns consistent with both fetal and embryonic hepatocytes, as defined in histologic specimens. Architecturally, the cells were arranged uniformly in regular rows, analogous to trabecular plates in the liver, and the presence of pseudoglandular formation was suggestive of early stages of liver differentiation. Other features that typified the hepatocytic nature of individual cells included polygonal shapes, round central nuclei, finely granular cytoplasm, and sharp cytoplasmic borders. Moreover, malignant cytologic features were equally apparent. The cells were moderately pleomorphic and had high N/C ratios with coarse chromatin and small but conspicuous nucleoli. Although individual cell necrosis was not discernible in the aspirated material, occasional mitoses were identified. It is interesting to note that cleft and lobulated nuclei were present in the tumor cells from two of our patients, a feature that has not been reported in histologic material.

Review of the tissue specimens from these three patients confirmed the overall cytologic interpretations of the exfoliated cells. Histologic evaluation revealed solid epithelial hepatoblastomas comprised of embryonal and fetal subtypes. However, surgical material from one patient (Patient 4) also revealed multiple foci of mature osteoid, thereby classifying this tumor as a mixed epithelial-mesenchymal type of hepatoblastoma. Between 23%17 and 34%18 of hepatoblastomas are of the mixed type, fundamentally consisting of neoplastic epithelium and stromal elements in the form of immature spindle cells, cartilage, and/or osteoid-like material. The presence of mesenchymal tissue occurs almost exclusively in the fetal and embryonal subtypes. It has been shown that the presence of stromal elements has no effect on clinical outcome.1 Occasional histologic reports of hepatoblastomas have described epithelial and mesenchymal elements associated with embryonal foci similar to yolk sac tumor or teratoma. Hence, the possibility of a very rare primary hepatic germ cell tumor may have to be considered.19, 20 The lack of neuroectodermal and neural crest derivatives as well as the presence of teratoid foci in hepatoblastoma are important features in the differential diagnosis.3, 21

Another histologic feature that was not recognized on the corresponding fluid was the presence of extramedullary hematopoiesis (EMH) associated with the fetal subtype in Patient 2. Although EMH indicates the presence of a fetal component, it has no independent prognostic significance. However, EMH is an important qualifying feature in distinguishing hepatoblastoma from well-differentiated hepatocellular carcinoma. Childhood hepatocellular carcinomas are generally more aggressive lesions that typically occur in older children with clinical manifestations of hepatitis, cirrhosis, or storage disease. Despite a morphologic overlap between hepatoblastoma and hepatocellular carcinoma, the latter tends to arise in already diseased livers and, thus, indicates a worse prognosis.22 In addition to the absence of EMH, other differential features that favor the diagnosis of hepatocellular carcinoma include larger cell size, marked cellular pleomorphism, numerous intranuclear inclusions, cytoplasmic hyaline globules, macronucleoli, and the presence of tumor giant cells. Nevertheless, in the very well-differentiated form of hepatocellular carcinoma, many of these differences may be either absent or subtle, making the distinction between these two entities potentially difficult.

The cytomorphologic features observed on smears of the ascites and pleural fluids from Patient 3 were consistent with the anaplastic subtype of hepatoblastoma, as noted in the corresponding surgical specimens. These tumor cells were small and round with a primitive appearance and with no resemblance to normal or fetal hepatocytes. They had extremely high N/C ratios with hyperchromatic nuclei, prominent nuclear molding, and scant cytoplasm. Tightly arranged cell clusters reflected the tumor cell nests that were observed in biopsy material. However, the Indian-file configuration of individual neoplastic cells was not evident on histologic review. Mitotic activity was moderately brisk in both the fluids and the tissue specimens.

The lack of clear hepatocytic differentiation coupled with the small, round, blue cell cytology raises a broad differential diagnosis of solid pediatric neoplasms. Common mimickers of anaplastic hepatoblastoma include Wilms tumor, neuroblastoma, lymphoma, Ewing sarcoma, and rhabdoid tumor. Despite morphologic similarities, these various neoplasms are distinct phenotypically. Crucial clinical and radiologic information often favors one type of tumor over another. Moreover, with the application of immunohistochemistry and electron microscopy, a phenotypic diagnosis is possible in approximately 95% of patients.23 Although ancillary studies were not performed on cytologic material from Patient 3 in our series, immunohistochemical and ultrastructural analyses of the tissue specimens were helpful in classifying the lesion as an undifferentiated hepatoblastoma. The diagnostic utility of these ancillary studies in cytologic specimens obtained by FNA has been well-documented.24

The complex karyotype of this tumor produced nonspecific results featuring a t(1;10) translocation and deletions of 17p and 1p. Trisomy 20 and trisomy for all or part of chromosome 2 have been identified repeatedly in other hepatoblastomas.25 In addition, double-minute chromosomes without n-myc amplification have been reported in hepatoblastoma.26 However, no consistent cytogenetic abnormalities have been isolated.

Regardless of the histologic subtype, surgery remains the cornerstone of therapy for patients with hepatoblastoma. Successful outcome is largely dependent on the ability to totally excise the tumor.27 This may now be accomplished in up to 75% of patients, with long-term survival in up to 50% of those who undergo complete resection.3, 28 It has been found that the more favorable, pure, fetal subtype of hepatoblastoma generally is solitary and circumscribed and, thus, is more amenable to surgery.29, 30 In contrast, tumors with an embryonal or anaplastic component tend to be diffuse and unresectable.29 Preoperative chemotherapy has allowed excision of initially inoperable disease in several reported patients.31 Recurrences usually are detected within 36 months but may be delayed up to 5 years. Metastases have been reported at the time of death in 46% of patients, usually to regional lymph nodes and lung.2

The evaluation of exfoliative cytology can play an important role in the management of patients with hepatoblastoma. Accurate diagnosis by nonsurgical techniques can identify patients who may benefit from treatment protocols that may offer preoperative chemotherapy and radiotherapy. When the clinical issue is a question of recurrent or metastatic tumor, an accurate cytologic diagnosis can obviate the need for surgery. Our study demonstrates that, in the appropriate clinical setting, the cytomorphologic features observed in serous cavity fluids are sufficiently unique for definitive diagnosis and classification of hepatoblastoma in infants and young children.


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  2. Abstract
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