|Year : 2019 | Volume
| Issue : 4 | Page : 556-560
|Clinicopathological profile of hepatoblastoma: An experience from a tertiary care center in India
B Archana1, J Thanka1, Latha M Sneha2, J Julius Xavier Scott2, M Arunan3, Prakash Agarwal4
1 Department of Pathology, SRIHER, Chennai, Tamil Nadu, India
2 Department of Paediatric Oncology, SRIHER, Chennai, Tamil Nadu, India
3 Department of Radiology, SRIHER, Chennai, Tamil Nadu, India
4 Department of Paediatric Surgery, SRIHER, Chennai, Tamil Nadu, India
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|Date of Web Publication||14-Oct-2019|
| Abstract|| |
Background: Hepatoblastoma is the most common primary hepatic malignancy in the pediatric population. Advances in pathological evaluation, imaging, risk stratification, neo-adjuvant chemotherapy, and surgery including transplantation have improved survival of these children in the western countries. However, a successful outcome in developing countries such as India with limited resources poses great challenges to the clinician and the family. Histology plays a major role in determining the prognosis of these patients. Methods: A retrospective study was done on 10 children diagnosed with hepatoblastoma between January 2010 and December 2015 in our institution. Clinical, laboratory, radiological, histopathological diagnoses, treatment, and outcome data were collected and analyzed. Results: The median age of these children at diagnosis was 11 months, and only 1 child was premature at birth. Most children were presented with abdominal distension. One child had lung metastasis at presentation. Elevated alpha fetoprotein levels were present in 90% of the children. The histological types were fetal, embryonal, macrotrabecular, and mixed epithelial-mesenchymal types. SIOPEL risk stratification was done, which showed 40% of the children to be of high risk. Three children had PRETEXT 1, 2, and 4, respectively. Conclusion: Our study is significant with respect to the information on PRETEXT staging, risk status, and histological favorability. In developing countries with limited resources and low-socioeconomic status, it is important to have a multidisciplinary team approach and tailor treatment to manage these patients effectively and improve the overall survival.
Keywords: Alpha fetoprotein, hepatoblastoma, histology, PRETEXT
|How to cite this article:|
Archana B, Thanka J, Sneha LM, Xavier Scott J J, Arunan M, Agarwal P. Clinicopathological profile of hepatoblastoma: An experience from a tertiary care center in India. Indian J Pathol Microbiol 2019;62:556-60
|How to cite this URL:|
Archana B, Thanka J, Sneha LM, Xavier Scott J J, Arunan M, Agarwal P. Clinicopathological profile of hepatoblastoma: An experience from a tertiary care center in India. Indian J Pathol Microbiol [serial online] 2019 [cited 2019 Nov 18];62:556-60. Available from: http://www.ijpmonline.org/text.asp?2019/62/4/556/269061
| Introduction|| |
Primary hepatic malignancies in children comprise about 0.5–2% of all solid tumors in children of which hepatoblastoma is the most common with an incidence of 1.5 cases per million children less than 18 years of age worldwide, followed by hepatocellular carcinoma.,,, It mostly occurs in children less than 5 years of age with a slight preponderance to males. Factors such as prematurity, low-birth weight, maternal smoking, alcohol, oral contraceptive use, and methods of assisted reproduction are some risk factors. It is also seen to be associated with syndromes such as Beckwith-Wiedemann syndrome, familial adenomatous polyposis, Li-Fraumeni syndrome, trisomy 18, and other metabolic disorders.
Diagnosing hepatoblastoma is challenging for a general pathologist even from specialized institutions owing to its rarity, histological diversity as well as a lack of a current international consensus on its classification. Histology is very important because it is incorporated as a risk stratification parameter in the Children's oncology group (COG) protocols for planning treatment. It is seen that each of the histological parameters have distinct clinical associations. Very few studies have mentioned proper histologic favorability as per College of American Pathologists (CAPs) protocols, correct Pretreatment extent of tumor (PRETEXT) staging, and the risk status. These parameters play a major role in guiding the oncologist to tailor treatment as per the individual's status and needs. Immunohistochemistry and molecular methods are being investigated and may the pave way in future to distinguish hepatoblastoma from hepatocellular carcinoma, which poses a diagnostic difficulty as well as in subclassifying hepatoblastoma, which also has important clinical implications. Recent advances in treatment like neoadjuvant chemotherapy followed by surgical resection and liver transplantation have the potential to improve survival in these children.
| Objectives|| |
To study the clinicopathological profile of hepatoblastoma patients.
| Materials and Methodology|| |
Study design and participants
This retrospective study was carried out on all children diagnosed with hepatoblastoma in our tertiary teaching institute for a period of 5 years between 2010 and 2015. Data pertaining to a total of 10 children were taken up for the study.
Approval was obtained from the Institutional Ethics Committee prior to the commencement of the study.
Institutional ethical clearance obtained on 25/2/2019.
Demographic data; laboratory parameters such as liver function tests; alpha fetoprotein levels (APLs); complete blood count, etc. were recorded. PRETEXT staging was assigned using contrast computed tomography (CT) for all the participants. Histological data on biopsy and/or resection specimens and follow-up data on survival/response to therapy were collected and were analyzed.
| Results|| |
The median age of the 10 children studied was 11 months, which ranged from 6 months to 36 months of age at the time of diagnosis with a mean age of 16 months. The mean birth weight was 2.75 kg. There was a male predilection with a male:female ratio of 2.3:1. One child out of the 10 children was low-birth weight who was presented with stage IV disease, others had a normal birth history with no maternal risk factors. The most common presenting symptom was abdominal distension/mass (70%), jaundice (10%), vomiting (10%), and fever (10%) [Table 1]. Serum AFP levels were elevated in all except one child (90%). The child who had a low AFP level of 9.60 ng/ml presented with stage IV disease and died within 3 months. Thrombocytosis was present in 9/10 children (90%), and abnormal liver function test was noted in 4/10 children (40%). PRETEXT staging was done by CT scan  [Figure 1]a. Three children had PRETEXT I (30%), three children PRETEXT II (30%), one child PRETEXT III (10%), and three children PRETEXT IV (30%). Of the three children with PRETEXT IV; one died, one has been planned for transplant, and one is doing well after neoadjuvant chemotherapy. One child presented with lung metastasis at the time of diagnosis.
|Figure 1: (a) CT whole abdomen showed lobulated, expansile, relatively well-circumscribed, heterogeneous lesion in the left lobe of the liver with intravascular invasion. (b) Gross image: Wedge resection of the right lobe of the liver with grey-brown circumscribed lesion measuring 6/5.5/2 cm. Focal areas appear grey black and grey white. A peripheral rim of normal parenchyma noted|
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There was no statistically significant correlation between the PRETEXT staging and histopathology. Irrespective of the histological type, the PRETEXT staging varied at presentation.
PRETEXT annotation factors such as metastatic disease (M), macrovascular involvement of all hepatic veins (V) or portal vein (P), and contiguous extrahepatic tumor (E) were assessed. Seven of our cases did not belong to any of these classes. One child had extrahepatic extension (E), one had portal vein involvement (P), and one had metastatic disease at presentation (M). Three of these cases who had either one of these factors were classified into the high-risk category for more aggressive treatment.
According to the SIOPEL risk stratification system, 6 (60%) children were classified as standard risk and 4 (40%) as high risk. Out of the 4 children belonging to the high-risk category, two have completed treatment, one died, and one has been planned for transplant.
In most of the resected cases, grossly the tumor appeared grey white with blackish areas representing hemorrhage and pale yellow to friable areas representing necrosis [Figure 1]b.
The most common histology observed was epithelial 8 (80%) followed by mixed epithelial and mesenchymal 2 (20%). Out of the 8/10 (80%) cases of epithelial type, three were 2 pure fetal epithelial [Figure 2]a, mitotically inactive, 1 fetal mitotically active type, 1 with embryonal histology [Figure 2]b, and 4 with mixed epithelial types (varying combination of fetal, embryonal, and macrotrabecular histologies [Figure 2]c). One case showed cholangioblastic differentiation [Figure 2]d. Two cases had mixed epithelial-mesenchymal histological type without teratoid features. The mesenchymal component included spindle cells [Figure 2]e, bone, cartilage, and muscle differentiation. Post chemotherapeutic changes were also seen such as calcification [Figure 2]f, eosinophils, necrosis, and spindled out areas. Histological grading done according to CAP protocol divides these tumors into favorable, less favorable, and unfavorable histology. In our study, six cases belonged to less favorable histology grading, of which 1 died, 4 are on follow-up, and 1 left against medical advice. Four had favorable histology of which 1 has been planned for transplant, and 3 were lost to follow-up [Table 2]. However, the latest CAP protocol has done away with the histological grading.
|Figure 2: (a) H and E, 200×, Fetal type: Polyhedral tumor cells arranged in a trabecular pattern and nests resembling normal liver. (b) H and E, 100×, Embryonal type: Small tumor cells with basophilic cytoplasm, high nucleo-cytoplasmic ratio, and coarse chromatin arranged in rosettes. (c) H and E, 100×, Tumor cells arranged in more than 10 cell thickness between 2 sinusoids. (d) H and E, 100×, cholangioblastic differentiation, tumor cells arranged in glands. (e) H and E, 100×, Mesenchymal differentiation represented by sheets of bland-looking spindle cells. (f) H and E. 40×, Osteoid formation representing post chemotherapeutic change|
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Of the 10 children, 3 were lost to follow-up after the initial cycles of chemotherapy consisting of the PLADO regimen (cisplatin and doxorubicin), one child went against medical advice, and one child died after 2 cycles of PLADO regimen. Four children responded well to chemotherapy with declining AFP levels prior to surgery and are doing well on regular follow-up. One child has been planned for transplant post chemotherapy [Graph 1].
| Discussion|| |
Owing to the rarity of hepatoblastoma, very limited studies from southern India have been published. Eight Indian centers have only published their data. The number of patients included in these studies were limited in the range of 5 to 36 owing to the rarity of these tumors. Of the published studies, key information such as the PRETEXT staging, COG staging, and histological features have not been specified, which limits our understanding from the clinicopathological point of view. The diagnosis of these tumors is challenging owing to a lack of a current consensus classification system.
PRETEXT system of assessment is crucial for risk stratification and further advocating the optimal treatment. It has two components namely, the PRETEXT group and the annotation factors. Although the group denotes the extent of hepatic spread, the annotation factors describe other features such as vascular involvement of the portal vein, hepatic vein, extrahepatic spread, multifocal involvement, tumor rupture, and metastatic disease to the lung and lymph nodes designated as P, V, E, F, R, M, and N respectively.
Thrombocytosis is a specific paraneoplastic phenomenon noted in most of these patients because of excess thrombopoietin secreted by the hepatocytes. Almost all tumors except small cell undifferentiated types have elevated AFP levels. Most tumors are located in the right lobe as the right lobe received blood from the portal vein with lower oxygen saturations, while the left lobe received blood from an umbilical vein with higher oxygen levels. Histology plays a vital role in the risk stratification as per the COG protocols as they have specific clinical associations and for planning treatment. Histologically, according to the CAP, they are classified into epithelial (pure fetal, fetal mitotically active, pleomorphic, embryonal, small-cell undifferentiated, mixed epithelial, macrotrabecular, and cholangioblastic), mixed epithelial, and mesenchymal with or without teratoid features.
According to the Los Angeles Children's oncology group (LACOG) liver tumors symposium consensus, mitotically active fetal type necessitates chemotherapy, and the small cell type requires extensive therapy. Small cell histological type has further been classified into INI positive/negative. INI1 positive tumors are associated with a good prognosis. Histological favorability is also to be incorporated in the final report as favorable histology corresponds to a good prognosis compared to less favorable and unfavorable histological grade.
Pathologists must importantly bear in mind the post chemotherapeutic changes such as ossification, squamous nests, cholangioblastic differentiation, and spindle cells to prevent the misdiagnosis of these tumors.
With the advent of immunohistochemistry (IHC) and molecular methods, insights into the use of IHC markers have been developed to differentiate between the subtypes. Markers such as Glypican 3 have been used to differentiate well-differentiated fetal (fine granular positivity) from other fetal types and embryonal (positive) from cholangioblastic types (negative). Vimentin and Pancytokeratin are being used to identify small cell undifferentiated type; CD34 to highlight the macrotrabecular pattern, which has >5 to 20 cell plate thickness; Heppar 1 to differentiate embryonal type (negative) from fetal type (positive). Glutamine synthase distinguishes normal liver (perivenular staining) from the pure fetal type of hepatoblastoma. pCEA was found to be positive in fetal hepatoblastomas not in embryonal hepatoblastomas.
Hepatoblastomas can also be confused with hepatocellular carcinomas (HCC), apart from IHC, certain molecular signatures such as trisomy 2, 8, 20, and Wnt pathways, which are seen in HCCs play a role to differentiate them. Genomic analysis also revealed a different subset of genes under and overexpressed in the two tumors.
The primary treatment is surgical resection, and the use of neoadjuvant chemotherapy with PLADO (cisplatin and doxorubicin) can increase the resectability of tumors resulting in a good prognosis. In our institution according to the SIOPEL protocol, for standard risk cases, PLADO 4 cycles followed by surgery and 2 more cycles are given. In high-risk cases, carboplatin in addition is given for 6 cycles, followed by surgery and then 3 more cycles of chemotherapy is administered. The outcome for non-resectable cases and recurrent disease remains poor, and thus, newer methods of treatment are needed. Unresectable non-metastatic disease have been offered liver transplantation as an emerging modality of treatment. Follow-up of these patients with AFP levels, and interval ultrasonography is a must.
| Conclusion|| |
This study was carried out as an effort to develop an insight into the PRETEXT staging of hepatoblastoma in children. PRETEXT III was the least common stage observed in this study. Histology and grading done as per CAP grading needs to be revisited, and there is a need to put forth PRETEXT classification in the perspective of grading of these tumors. A multidisciplinary team approach is required to tailor treatment for a better survival outcome.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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Department of Pathology, SRIHER, Chennai, Tamil Nadu
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2]
[Table 1], [Table 2]
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