|Ahead of print publication
Histomorphological patterns of hepatoblastoma in a tertiary care hospital
Dimple Chaudhary1, Latika Gupta1, Radhika Agarwal1, Varuna Mallya1, Reena Tomar1, Shramana Mandal1, Nita Khurana1, YK Sarin2
1 Department of Pathology, Maulana Azad Medical College, Lok Nayak Hospital, New Delhi, India
2 Department of Paediatric Surgery, Maulana Azad Medical College, Lok Nayak Hospital, New Delhi, India
|Date of Submission||19-Feb-2019|
|Date of Decision||06-Oct-2019|
|Date of Acceptance||19-Dec-2019|
|Date of Web Publication||28-Oct-2020|
Associate Professor, Department of Pathology, Maulana Azad Medical College, New Delhi
Source of Support: None, Conflict of Interest: None
Background: Hepatoblastoma (HB), rare malignancy in itself, is the most common primary liver tumor in children. Most common presenting features are abdominal distension or abdominal mass. Several patterns are associated with HB with different prognosis. Furthermore, some patterns have overlapping features with other childhood tumors. Aims and Objectives: The aim of this study is to discuss various patterns of HB which we came across in a tertiary care hospital during our study. H and E slides were reviewed with respect to different patterns, postchemotherapy changes including extramedullary hematopoiesis, necrosis, osteoid metaplasia, necrosis, and fibrosis. Conclusion: Different patterns of HB should be kept in mind by the pathologists to avoid any misdiagnosis.
Keywords: Abdominal, extramedullary hematopoiesis, hepatoblastoma
|How to cite this URL:|
Chaudhary D, Gupta L, Agarwal R, Mallya V, Tomar R, Mandal S, Khurana N, Sarin Y K. Histomorphological patterns of hepatoblastoma in a tertiary care hospital. J Can Res Ther [Epub ahead of print] [cited 2020 Dec 3]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=299456
| > Introduction|| |
Hepatoblastoma (HB) is the most common primary liver tumor in children, diagnosed during the first 3 years of life. Recently, surveillance epidemiology and end-results data in the US stated that the highest incidence of HB is seen in 0–4 years of age with 10.5 cases/milllion in children <1 year. The incidence of HB in 5–9 years of age is very rare. Histopathologically, HB is classified into two types – epithelial and mixed types. The epithelial variety is further divided into six patterns: small-cell undifferentiated, embryonal, pleomorphic, cholangioblastic, fetal, and macrotrabecular. It is important to be aware of various morphological patterns associated with it to distinguish it from other childhood tumors.
Aims and objectives
The aim was to study the histomorphological patterns of HB in a tertiary care hospital during a period of 5 years (January 2013–January 2018).
| > Materials and Methods|| |
This retrospective study was conducted from January 2013 to January 2018 in the Department of Pathology in Maulana Azad Medical College and included 13 patients. As it was a retrospective study, consent and ethical clearance was not obtained. All cases of HB were diagnosed on trucut or resected specimens. Detailed clinical data were collected, and hematoxylin and eosin-stained slides were reviewed with respect to different patterns, postchemotherapy changes, and extramedullary hematopoiesis (EMH).
The age range varied from 1.5 months to 8 years with a mean age of 35.5 months. The male-to-female ratio was 2.2:1. The most common clinical feature was pain abdomen and lump abdomen, with one case presenting with associated fever and other with malena. On imaging, the mass was unifocal in nine (69.2%) cases, while it was diffuse in four (30.7%) cases [Figure 1]a and [Figure 1]b. Serum alphaprotein Alphafetoprotein (AFP) levels ranged from 1.2 × 104 to 7 × 105 ng/ml [Table 1].
|Figure 1: (a and b) Contrast-enhanced computed tomography of the upper abdomen shows large heterogeneously enhancing mass lesion 10 cm × 7 cm with patchy areas of necrosis and chunks of dense calcification. (c and d) Gross – showing solid cystic growth in the liver with areas of necrosis|
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Trucut was received in all cases, while gross specimens were received in six cases. Size of lesion varied from 3 cm × 3 cm × 2.5 cm to 11.8 cm × 11 cm × 7 cm. All resected specimens were postchemotherapy [Figure 1]c and [Figure 1]d.
In epithelial variety, three cases showed fetal pattern along with embryonal pattern [Figure 2]a and [Figure 2]b, four showed pure fetal pattern [Figure 2]c and [Figure 2]d and [Figure 3]a, [Figure 3]b, [Figure 3]c, [Figure 3]d, while one case showed admixture of fetal and pleomorphic pattern [Figure 4]c and [Figure 4]d. In mixed pattern, one of the case showed admixture of fetal, embryonal and cholangioblastic pattern along with osteoid metaplasia [Figure 4]a and [Figure 4]b. In remaining cases, two showed fetal pattern along with osteoid metaplasia and other two showed fetal, embryonal and osteoid metaplasia [Figure 5]a. This cholangioblastic component was found to be positive for CK7 and CK19.
|Figure 2: (a and b) Embryonal pattern – consisting of atypical, small, basophilic epithelial cells, with high nuclear-to-cytoplasmic ratios, and angulated nuclei (H and E, ×200). (c and d) Fetal pattern in sheets and rosettes. Cells have abundant eosinophilic cytoplasm and bland appearing hepatocytes H and E (×400)|
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|Figure 3: (a and b) Fetal pattern in trabeculae – tumor cells with abundant cytoplasm, opened up nucleus, and arranged in thin trabeculae (3–4 layers thick) H and E (×200). (c and d) Fetal pattern with alternate dark and light areas due to accumulation of glycogen/lipid (H and E × 200 and × 400)|
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|Figure 4: (a and b) (Case 3) Cholangioblastic pattern – showing small ductular structures present within the tumor (H and E, ×400 and × 200). The ductular component is positive for keratins (inset-for CK 19). (c and d) (Case 8) Pleomorphic pattern having increased atypical nuclear features with marked nuclear pleomorphism, coarse, and prominent nucleoli (H and E × 400 and × 600)|
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|Figure 5: (a) (Case 4) Mixed hepatoblastoma – epithelial component admixed with pink amorphous osteoid H and E (×200). (b) Focus of extramedullary hematopoiesis comprising erythropoietic cells with few megakaryocytes H and E (×400). (c and d) Postchemotherapy changes including tumor necrosis and osteoid metaplasia H and E (×200)|
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Extramedullary hematopoiesis was found in two cases comprising predominantly erythroid precursors along with few megakaryocytes [Figure 5]b. Postchemotherapy-related changes included osteoid metaplasia, hemosiderin-laden macrophages, calcification, fibrosis, and tumor necrosis [Figure 5]c and [Figure 5]d. Metastasis was found in none of the cases [Table 2].
| > Discussion|| |
HB accounts for 1% of pediatric tumors. The highest incidence is reported to be in the age group of 0–4 years with male preponderance and rare in >5 years of age. Age range in our series was 1.5 months–8 years with three cases >5 years of age. A study by Pateva et al. in 2017, over a period of 16 years, showed that only 13 cases were more than 5 years of age. Certain associated genetic syndromes are Beckwith–Wiedemann syndrome, familial adenomatous polyposis, and trisomy 18. Other factors associated with it are very low birth weight, fetal alcohol syndrome, oral contraceptive use during pregnancy, and parental occupational exposure to metals. In the present study, no such history was present The most common clinical presentation is abdominal distension or abdominal mass. In our study, most common clinical presentation was lump abdomen and pain abdomen. Some may present with abdominal discomfort, fatigue, and anorexia. Rarely, patients can have precocious puberty due to beta-human chorionic gonadotropin secretion by the tumor. Serum levels of alpha-fetoprotein (AFP) are the most important marker for HB. Its levels correlate with response to treatment, relapse, active disease, and large tumor burden. The AFP levels ranged from 1.2 × 104 to 7 × 105 ng/ml in the present study. Persistence or recurrence of increased AFP level is a sensitive marker of disease activity. Recurrence was found in one of our case, in which AFP levels persistently remained high even after chemotherapy.
Rhabdoid type of HB and some variants of hepatocellular carcinoma are associated with low AFP levels. Societe Internationale d Oncologie Pediatrique - Epithelial Liver tumor Study Group (SIOPEL) (Childhood Liver Tumor Study Group of International Society of Pediatric Oncology) and the Children's Oncology Group investigators stated that HB patients with low AFP levels <100 ng/ml have poor outcome. Maibach et al. found that low AFP level lower than 100 ng/ml and higher than 1.2 × 106 ng/ml are associated with reduced survival. Bilirubin and liver enzymes are not affected, while few cases can have anemia and platelet abnormalities. Both thrombocytopenia and thrombocytosis have been reported.
The right lobe is more commonly affected with bilobar involvement found in 20%–30% of cases, and multicentricity can be seen in 15% of cases. In our study, mass was unifocal in nine (69.2%) cases, while it was diffuse in four (30.7%) cases. Metastases can occur in 20% of patients, with lung being the common site, while rare sites include the brain and bone. No metastasis was found in our study.
Stippled calcification detected in 50% of cases. This calcification correlates with the presence of osteoid and is usually higher than in benign lesions such as hemangiomas and hemangioendotheliomas of the liver.
Histopathologically, HB is classified as epithelial and mixed types. Epithelial type constitutes 56% of cases, while 44% are mixed types. Epithelial pattern was found in 8/13 cases (61.5%), while mixed pattern was found in 5/13 (38.4%) cases. There are six key histologic patterns for the epithelial component of HBs: small-cell undifferentiated, embryonal, pleomorphic, cholangioblastic, fetal, and macrotrabecular. The small-cell undifferentiated subtype shows the least resemblance to hepatocytes, while the fetal type and macrotrabecular type show the most resemblance to hepatocytes. Pure fetal subtype has a favorable prognosis, while small-cell undifferentiated type has poor prognosis. Pleomorphic pattern is uncommon, comprises either fetal or embryonal epithelium with increased atypical nuclear features. In the present study, one case was noted to be of pleomorphic pattern. This subtype can be readily confused with the hepatocellular carcinoma. The age and clinical findings can help to differentiate between the two. The cholangioblastic pattern is also found in few cases of HB comprising small ductular structures. These ductular structures express positivity for keratins and can show aberrant nuclear beta catenin expression. It should be distinguished from benign bile ductular reaction. The mesenchymal elements found are osteoid and cartilage. The presence of these has been associated with better prognosis. EMH is a characteristic feature, more often associated with epithelial histology. EMH was present in two of our cases. In a study by Saxena et al., osteoid made up a small component of 36% of untreated HB but increased to 82% in the treated case. In the present study, osseous component increased significantly in one of the postchemotherapy specimens (case 3).
The comparison of various recent studies with ours has been illustrated in [Table 3]. Age ranged in various studies from 12 to 24 months, with lump abdomen most common presentation. Most common pattern was mixed in some, while epithelial in others. Various differential diagnoses for HB include small, round cell tumors such as Wilms and primitive neuroectodermal tumor for embryonal predominant pattern. Glypican 3 and beta-catenin are found to be positive in HB. Hepatic adenomas can be a differential diagnosis for pure fetal type and hepatocellular carcinomas for macrotrabecular and pleomorphic variants of HB. Other mimickers are teratomas for mixed HB and calcifying nested stromal-epithelial tumor of the liver which comprises spindle-to-epithelioid cells with desmoplastic stroma [Table 4].
The combination of surgery and chemotherapy is an effective treatment for HB. Risk stratification of patients of HB has been proposed by Children's Hepatic Tumors International Collaboration. Low/standard risk is composed of single localized tumor involving three segments of the liver (pretreatment extent of disease I, II, and III) with no extrahepatic features of hepatic vein/portal invovlement, rupture at diagnosis, multifocality, or metatstasis. These patients are treated by primary resection followed by postoperative chemotherapy. Intermediate or high risk involves patients with unresectable tumor at diagnosis and or associated with combi factors without distant metastasis. CDDP (cisplatin) intensification protocols are being used for these patients. Very high-risk patients include older patients (>8 years) and patients with low AFP levels (<100 ng/ml) and with lung metastasis. Planned combination treatment using dose intensified chemotherapy and surgical approach including metastasectomy and liver transplantation is required to treat these patients. Ninety percent of blood supply for HB comes from the hepatic artery, with 75% supplied by the portal vein  to the normal healthy liver. Thus, reducing blood supply to tumor by selective necrosis without affecting blood supply to the normal liver can be effective therapy. Transarterial chemoembolization is also one of the effective procedures for pediatric liver tumors.
To conclude, in this study, an effort has been made to highlight the different common patterns found in HB and how to differentiate these with their close differentials. These patterns should be kept in mind by the pathologists to avoid any misdiagnosis.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3], [Table 4]