Contrast-enhanced CT features of hepatoblastoma: Can we predict histopathology?

Accepted Manuscript Contrast-enhanced CT features of hepatoblastoma: Can we predict histopathology?

Akshay D. Baheti, A. Luana Stanescu, Ning Li, Teresa Chapman PII: DOI: Reference:

S0899-7071(17)30066-9 doi: 10.1016/j.clinimag.2017.03.023 JCT 8228

To appear in: Received date: Revised date: Accepted date:

11 January 2017 4 March 2017 31 March 2017

Please cite this article as: Akshay D. Baheti, A. Luana Stanescu, Ning Li, Teresa Chapman , Contrast-enhanced CT features of hepatoblastoma: Can we predict histopathology?. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Jct(2017), doi: 10.1016/j.clinimag.2017.03.023

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ACCEPTED MANUSCRIPT Contrast-enhanced CT Features of Hepatoblastoma: Can We Predict Histopathology?

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Authors: Akshay D. Baheti, MD,1 A. Luana Stanescu, MD,1 Ning Li, PhD,2 Teresa Chapman, MD*1 1

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Abstract

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*Corresponding Author: Teresa Chapman, MD Associate Professor of Radiology Department of Radiology Mail Stop MA.07.220 Seattle Children’s Hospital 4800 Sand Point Way NE Seattle, WA 98145 United States Phone: (206) 987-1577 Facsimile: (206) 987-2341

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Department of Radiology, Seattle Children’s Hospital, University of Washington, Seattle, Washington 2 Department of Industrial and System Engineering, University of Washington, Seattle, Washington

BACKGROUND: Hepatoblastoma is the most common hepatic malignancy occurring in the pediatric population. Intratumoral cellular behavior varies, and the small-cell undifferentiated histopathology carries a poorer prognosis than other tissue subtypes. Neoadjuvant chemotherapy is recommended for this tumor subtype prior to surgical resection in most

ACCEPTED MANUSCRIPT cases. Early identification of tumors with poor prognosis could have a significant clinical impact. OBJECTIVE: The aim of this work was to identify imaging features of small-cell undifferentiated

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subtype hepatoblastoma that can help distinguish this subtype from more favorable

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tumors and potentially guide the clinical management. We also sought to characterize

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contrast-enhanced CT (CECT) features of hepatoblastoma that correlate with metastatic disease and patient outcome.

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MATERIALS AND METHODS:

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Our study included 34 patients (24 males, 10 females) with a mean age of 16 months (range: 0-46 months) with surgically confirmed hepatoblastoma and available baseline

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abdominal imaging by CECT. Clinical data and CT abdominal images were

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retrospectively analyzed. RESULTS:

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Five tumors with small-cell undifferentiated components were identified. All of these

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tumors demonstrated irregular margins on CT imaging. Advanced PRETEXT stage, vascular invasion and irregular margins were associated with metastatic disease and

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decreased survival. Capsular retraction was also significantly associated with decreased survival. Irregular tumor margins demonstrated statistically significant association with the presence of small-cell undifferentiated components. No other imaging feature showed statistically significant association. CONCLUSION: Tumor margin irregularity, vascular invasion, capsular retraction, and PRETEXT stage

ACCEPTED MANUSCRIPT correlate with worse patient outcomes. Irregular tumor margin was the only imaging feature that significantly associated with more aggressive tumor subtype.

KEYWORDS:

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Children; Computed tomography; Hepatoblastoma; PRETEXT; small-cell

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undifferentiated.

ACCEPTED MANUSCRIPT 1. Introduction Hepatoblastoma is the most common liver cancer in children, but remains a rare tumor, with an annual incidence of 3.1 per million in children between 0-14 years of age in the United States, according to the Surveillance, Epidemiology, and End Results

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(SEER) database for the 2009-2013 period [1-3]. Histologically, hepatoblastomas are

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broadly categorized as either epithelial (56-67%) or mixed epithelial and mesenchymal

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(44-33%), with more detailed subtyping within each category [1, 4]. Specific subtypes of epithelial hepatoblastomas correlate with patient prognosis. Small cell undifferentiated

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(SCUD) subtype (3-5%) is high-risk, with a three-year survival rate of 40-70%, while

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pure fetal subtype with low mitotic activity (PFSLMA) (7%) is very low-risk, with a fiveyear event-free and overall survival rate reaching 100% for patients receiving only

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minimal or no chemotherapy [1, 4-7]. Other tumor features, including PRETEXT

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(pretreatment extent of disease), stage, presence of metastatic disease, vascular invasion, nodal involvement, extrahepatic extension, tumor multifocality, AFP levels, patient age,

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and birth weight have also been found to correlate with patient outcome in various studies

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[8-11].

Management of hepatoblastomas is usually based on the Children’s Oncology

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Group (COG) or the International Childhood Liver Tumors Study Group (SIOPEL) guidelines [1, 6, 12]. SIOPEL advocates neoadjuvant chemotherapy prior to resection in all cases; whereas, COG recommends upfront resection of low-risk PRETEXT I and PRETEXT II lesions (unless they are SCUD subtype) followed by adjuvant chemotherapy, reserving neoadjuvant chemotherapy for the remainder of cases [1, 6, 12]. Furthermore, COG guidelines do not recommend adjuvant chemotherapy for pure fetal

ACCEPTED MANUSCRIPT subtype hepatoblastoma [6, 7]. Tumor classification and neoadjuvant medical versus upfront surgical in certain subtypes management is usually based on a limited biopsy sample. Therefore, histologic sampling error could potentially miss a component of small cell undifferentiated tissue within the tumor, or may demonstrate pure fetal subtype

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within a PRETEXT III tumor, giving rise to management dilemmas. Imaging may assist

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by more specifically identifying patients requiring neoadjuvant chemotherapy. At our

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institution, a contrast-enhanced CT (CECT) is typically performed in patients with clinical or ultrasound findings concerning for hepatoblastoma as part of the baseline

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staging protocol.

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In our experience with hepatoblastoma cases, it was our subjective observation that SCUD-type tumors showed extensive intratumoral cystic/necrotic change, which

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would be expected of more aggressive, rapidly growing neoplasm. Our primary goal was

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to assess if the imaging features of SCUD-type tumors can help differentiate them from other types of hepatoblastoma and as such potentially help in guiding the treatment. We

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also aimed to correlate imaging features of hepatoblastoma on baseline CECT prior to

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therapy with the metastatic pattern and overall patient outcome.

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2. Materials and Methods 2.1 Subjects

This was an Institutional Review Board approved Health Insurance Portability and Accountability Act-compliant retrospective study with waiver of informed consent. An electronic search of radiology reports and oncology patient databases identified 46 patients with hepatoblastoma that had undergone imaging at our institution between 2000

ACCEPTED MANUSCRIPT and 2016. Patients with an initial outside CECT were also included if the outside imaging was complete and of standard quality. A baseline CECT was not available in 11 patients initially imaged at an outside institution, and these were excluded. An additional patient was excluded due to poor quality of the outside baseline CT study. The remaining 34

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patients were included in the study cohort.

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2.2 Clinical and Histopathology Data

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Detailed information was extracted from the electronic medical records regarding patient demographics, site and pathology of the primary tumor, the presence or absence

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of metastatic disease, and the patient outcome at the time of last follow-up. Tumor

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pathology was based on either initial tumor biopsy or surgical specimen. All tissue samples were reviewed by an attending pathologist at our institution, confirming

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diagnosis of hepatoblastoma and histologic subtype. The pathological specimens included

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ten core needle biopsies (3 ultrasound-guided, 7 performed by surgeons in the operating room), 15 open wedge biopsies, and two surgical resections without prior biopsy. Seven

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patients underwent initial biopsy at outside hospitals. Biopsy approach at the outside

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centers was noted in the clinical records for four of these seven: three underwent core needle biopsy and one open wedge biopsy. Apart from two patients who did not undergo

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surgery following biopsy due to unresectable disease, confirmation of histopathology on surgical specimen was available in the other 32 patients.

2.3 Imaging and Image Analysis CECT was performed in all 34 cases. From January, 2000, through July, 2007, scanning was performed on a 16-slice scanner (Toshiba, Irvine, California). From

ACCEPTED MANUSCRIPT August, 2007 – 2016, scanning was performed on a 64-slice helical scanner (GE Healthcare, Germantown, Wisconsin). Scanning parameters were assigned based on patient weight [13]. CT dose index volumes were available for 20 of the 34 cases; 11 of these were performed on the GE scanner after 2007 with a mean CTDI-vol of 1.68; 9 of

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those studies where CTDI-vol is available were performed at outside institutions with a

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mean CTDI of 5.68. The mean CTDI was 3.825 ± 3.02 mGy (range: 0.98 –6.52 mGy).

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The large range of CTDI-vol is attributable to higher doses used at outside centers. The images were reviewed on Centricity PACS RA1000 (GE Health Care, Barrington, IL,

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USA) workstation. Images were reviewed in consensus by three radiologists (A.B.,

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A.L.S., T.C.), with 1, 6, and 10 years experience in pediatric radiology, respectively, and imaging characteristics were documented. The radiologists were blinded to the pathology

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and clinical outcome. A total of 34 baseline CTs were reviewed. In 21 cases, correlative

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baseline ultrasound exams were also available, and in 2 cases, baseline MRI abdominal imaging was also available; these were utilized to verify cystic components. In no case

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did the ultrasound or MR imaging characteristics change the interpretation of the CT. 175

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follow-up CT examinations, 105 follow-up US exams, and six follow-up MR examinations were also reviewed by a single radiologist (A.B.) to evaluate for recurrent/

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metastatic disease.

Various imaging features of the hepatoblastomas on the baseline CTs were recorded. These included size, location, PRETEXT (pretreatment extent of disease) stage, single versus multifocal tumor, margin (well-circumscribed versus ill-defined), morphology (round/lobulated versus irregular), variability in attenuation (homogeneous versus heterogeneous), presence of hemorrhage or calcifications, presence of

ACCEPTED MANUSCRIPT cystic/necrotic change, presence of extrahepatic extension beyond the liver capsule, capsular retraction, and presence of vascular invasion. Presence or absence of metastatic disease at baseline and follow-up and the sites of involvement were also noted. 2.4 Statistical Analysis

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Pearson’s Chi-square test for independence was applied to evaluate the correlation

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of imaging features with histopathology. A p value less than 0.05 was considered

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statistically significant. Pearson’s Chi-square test was also applied to all categorical

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imaging features correlating them with pathology, metastases, and patient outcome.

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3. Results

The study included 34 patients (24 males, 10 females) with a mean age of 16

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months (range: 0-46 months). The median follow-up duration for the patients was 26

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months (range: 1-202 months). Ten patients were born premature, five of them being extremely premature, born prior to 28 weeks gestational age.

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3.1 Imaging features of the primary tumor

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The mean maximum dimension of the hepatoblastoma at presentation was 10.3 cm (range: 2-14 cm). Tumors were predominantly well-circumscribed (29/34 – 85%) and

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heterogeneous (32/34 – 94%) at presentation. 26/34 (76%) tumors were solitary, while 8/34 (24%) were multifocal. PRETEXT classification for this cohort was as follows: two patients presented with stage I, twelve patients with stage II, sixteen patients with stage III and four patients with stage IV. Cystic/necrotic components were present in 21/34 (62%) tumors, and of these, 12 tumors were estimated to contain >5% cystic/necrotic change of the overall tumor volume. Calcifications were present in 7/34

ACCEPTED MANUSCRIPT tumors, including two epithelial and five mixed tumors (20%). Calcifications were coarse, punctate, speckled, or curvilinear. Extrahepatic extension was seen in 14/34 (41%) patients, capsular retraction in 7/34 (20%), and vascular invasion in 11/34 (32%). There were five tumors with small-cell undifferentiated component in the study.

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All of them demonstrated irregular margins, four had extrahepatic extension, and two

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each demonstrated capsular retraction, vascular invasion, and >5% cystic/necrotic

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component (Figure 1 & Figure 2). Among all 34 tumors, 15 showed irregular margins. Five of these 15 tumors with irregular margins had small cell undifferentiated subtype

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pathology. Therefore, the percentage of tumors with irregular margins having SCUD

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subtype pathology was 33.3%.

Two patients had tumors with pathological features of well-differentiated fetal

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subtype with low mitotic activity. One of these tumors was homogeneous and well-

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circumscribed, without hemorrhage, necrosis, calcification, or cystic/necrotic component. The second tumor had a central stellate pattern of hypoattenuation (Figure 3). Neither

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tumor had exophytic extension, vascular invasion, or metastases. A spiculated / stellate

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pattern of central hypoattenuation was present in 8/34 patients (24%), none of which had small cell undifferentiated components identified.

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3.2 Recurrent/Metastatic disease Ten patients (29%) had recurrent or metastatic disease, five of them presenting with metastatic lesions at initial presentation. The most common sites were lung (in six patients) and liver (in five patients), with peritoneal disease in two patients, and brain, bone, and soft tissue involvement in one patient. The median time to development of metastatic disease was 7 months (range: 5-20 months). Three out of the five patients with

ACCEPTED MANUSCRIPT SCUD component developed recurrent/metastatic disease, one patient being diagnosed with metastatic disease at initial presentation. Metastatic/recurrent sites included peritoneal recurrence in one patient, lung metastases at presentation in a second patient, and lung, bone and soft tissue involvement in a third patient.

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3.3 Histopathology Findings and Clinical Outcome

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There were 24 epithelial and 10 mixed epithelial and mesenchymal tumors in the

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study. Among the epithelial tumors, two were well-differentiated fetal subtype, and five demonstrated small-cell undifferentiated component on pathology. Tumors with small-

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cell undifferentiated component included four epithelial and one mixed epithelial and

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mesenchymal tumor.

Out of the 34 patients, 23 were treated with neoadjuvant chemotherapy followed

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by resection, seven with neoadjuvant chemotherapy followed by liver transplant, three

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with surgical resection with or without adjuvant chemotherapy, and one patient with metastases at presentation was treated with chemotherapy and no surgical resection. At

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the time of last follow-up, 27/34 patients were alive, 5/34 were deceased, and 2/34 were

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lost to follow-up. The five patients who expired had recurrent/metastatic disease, one at

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the time of initial presentation.

3.4 Correlation of Imaging Features with Pathology, Metastases, and Patient Outcome A summary of the statistical analysis is provided in Table 1. On statistical analysis, irregular margins had a significant association with the presence of small-cell undifferentiated component (p=0.025). Calcifications were significantly associated with mixed epithelial and mesenchymal tumors (p=0.02), although they were observed in

ACCEPTED MANUSCRIPT epithelial tumors as well. None of the other imaging features showed a statistically significant correlation with tumor pathology. Advanced PRETEXT stage, presence of irregular margins (p=0.019) and vascular invasion (p=0.008) were significantly associated with development of metastases. Among the other parameters, tumor

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multifocality trended toward significance in association with metastatic disease, with a p-

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value of 0.057. Overall, a reduction in patient survival was found to be significantly

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associated with advanced PRETEXT stage (p=0.045), irregular margins (p=0.039), vascular invasion (p=0.043), capsular retraction (p=0.031), and development of

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metastatic/recurrent disease (p<0.001). Exophytic extension and presence of

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cystic/necrotic component on imaging were not found to be significantly associated with

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either metastatic disease or eventual outcome.

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4. Discussion

Hepatoblastomas are rare pediatric tumors with complex pathological subtypes.

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The epithelial hepatoblastomas include well-differentiated fetal subtype with low mitotic

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activity, crowded or mitotically active fetal, embryonal, pleomorphic, macrotrabecular, small-cell undifferentiated, and cholangioblastic subtypes, and may be mixed, with

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different elements present [1, 6]. The mixed epithelial and mesenchymal hepatoblastomas additionally demonstrate stromal derivatives such as spindle cells, bone, cartilage, or skeletal muscle, or may have a teratoid histology [1, 6]. The presence of calcifications in a liver mass, particularly if coarse, is highly suggestive of hepatoblastoma, and is more commonly associated with mixed tumor histopathology, corresponding to the osteoid or chondroid component [14-16]. Of note, calcifications may also be seen in congenital

ACCEPTED MANUSCRIPT hemangioma and in metastatic neuroblastoma, and therefore additional clinical features such as alpha-fetoprotein level must be taken into consideration with a new diagnosis of intrahepatic mass. The PRETEXT (pretreatment extent of disease) classification was introduced by

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SIOPEL to describe baseline tumor extent in a standardized manner, and has been found

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to be prognostically significant [1, 6, 17, 18]. It divides the liver into four sections: right

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anterior (segments 5 and 8), right posterior (segments 6 and 7), left lateral (segments 2 and 3), and left medial (segment 4). Tumors are classified from stage I to IV depending

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on the number and relationship of the sections involved, with all four sections involved in

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PRETEXT stage IV [17, 18]. The Children’s Hepatic tumors International Collaboration (CHIC) recently used data from eight multicenter trials to evaluate 1605 hepatoblastomas

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and concluded that advanced PRETEXT stage, presence of portal or hepatic venous

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involvement, presence of extrahepatic disease, tumor multifocality, metastases at presentation, tumor rupture at presentation, pediatric patients ≥ 8 years old, and low

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alpha-fetoprotein (<100 ng/mL) were associated with a worse outcome [11]. Our study

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found advanced PRETEXT stage, irregular tumor margins on CT, vascular invasion, and capsular retraction to be associated with poor outcome. Tumor multifocality trended

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towards significance in correlating with a poor outcome, but our study lacked sufficient power to further evaluate this observation. Small-cell undifferentiated subtype is a known poor prognostic factor in patients with hepatoblastoma (although of note, it was not evaluated by the CHIC study) [1, 6, 10, 19]. To the best of our knowledge, there is no dedicated study correlating imaging features of hepatoblastomas with small-cell undifferentiated component. We observed

ACCEPTED MANUSCRIPT irregular tumor margins to be significantly associated with the presence of small-cell undifferentiated components. This was a sensitive but not specific finding in our cohort, being seen in all five tumors with SCUD component, but also in 15 of the 34 tumors overall. Our data thus suggest that the absence of irregular margins is predictive of non-

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SCUD histology, but the presence of irregular margins is probably less useful. Our initial

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hypothesis that intratumoral cystic change would strongly correlate with SCUD subtype

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was, however, not proven. No other imaging feature had significant association. Hepatoblastomas with small-cell undifferentiated component usually also have associated

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non-small-cell undifferentiated epithelial or mixed epithelial and mesenchymal

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components [1, 6, 19]. Thus, there may be a broad overlap in the imaging features, depending on the percentage of small-cell undifferentiated component within the tumor.

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required to evaluate them further.

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Given this difficulty in their evaluation and their rarity, larger multicenter studies may be

Our study focused exclusively on imaging by multi-detector CT. At our

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institution, ultrasound and single phase contrast-enhanced CT imaging are the primary

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modalities used for the evaluation of palpable abdominal masses and for hepatic mass screening. This is due to a combination of factors, including institutional protocol,

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preferences of the referring clinicians, the convenience of simultaneously evaluating for pulmonary metastases, and potential side effects from general anesthesia, which would be required for MR imaging in this age group (but is usually not required for single-phase CT imaging) [20]. However, many centers commonly use magnetic resonance imaging for diagnosis of abdominal tumors in children [21]. MR evaluation of hepatoblastomas can be performed using both extracellular and mixed hepatocyte specific/extracellular

ACCEPTED MANUSCRIPT gadolinium contrast [14, 21, 22]. Diffusion-weighted MR imaging can also be potentially useful to evaluate for SCUD given their high cellularity [23-25]. The features we report here on CT as predicting a poor outcome would also be apparent on MR imaging. The limitations of our study include the small sample size (given the rarity of the

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tumor), the retrospective nature of the study, and a possible referral bias given that our

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study was performed at a tertiary care children’s hospital. Correlating imaging features

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with pathology was difficult, as variable proportions of non-small cell epithelial elements are present in tumors with small-cell undifferentiated component as well as in mixed

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epithelial and mesenchymal tumors. Pathology results were based on either initial

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biopsied tissue or on the surgical specimen, which often showed post-treatment changes. Therefore, matching imaging characteristics to the histopathology was inherently subject

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to sampling error.

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In conclusion, hepatoblastomas usually present with a clinically palpable mass in the infant and young child. These tumors are usually well-circumscribed, heterogeneous

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liver masses on imaging. The presence of irregular tumor margins was significantly

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associated with small-cell undifferentiated component in our study. Advanced PRETEXT stage, vascular invasion and irregular margins were associated with metastatic disease

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and decreased survival. We also found that the presence of capsular retraction and development of recurrent/metastatic disease were significantly associated with decreased survival. Larger multi-institutional studies are needed to evaluate these findings further given the rarity of this disease.

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ACCEPTED MANUSCRIPT Figure legends Figure 1: Small-cell undifferentiated histopathology of hepatoblastoma diagnosed in a1year old female presenting with an abdominal mass. Axial CECT demonstrates a heterogeneous liver mass with multilobulated, ill-defined margins, central necrosis, and

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few speckled calcifications, along with lung metastases (not shown here). Biopsy

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demonstrated mixed epithelial and mesenchymal hepatoblastoma with small cell

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undifferentiated component. The patient did not respond to neoadjuvant chemotherapy and was ultimately treated with a liver transplant along with pulmonary wedge resections

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for metastatic disease. She developed recurrent disease and expired after one year.

Figure 2: Small-cell undifferentiated histopathology of hepatoblastoma diagnosed in a

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4-year old male presenting with an abdominal mass. Axial CECT reveals presence of a

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mildly heterogeneous right hepatic tumor with irregular outline along with presence of capsular retraction (arrowheads) and minimal perihepatic fluid (arrow). Biopsy revealed

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epithelial hepatoblastoma with small cell undifferentiated component. The patient was

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treated with neoadjuvant chemotherapy followed by partial hepatectomy and remains

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disease-free for three years at the time of last follow-up.

Figure 3: Well-differentiated fetal histopathology of hepatoblastoma diagnosed in a1year old male presenting with an abdominal mass. Axial CECT shows a heterogeneous liver mass with central stellate hypoattentuation (arrows) and smooth margins. Biopsy demonstrated well-differentiated fetal subtype with low mitotic activity. The patient was

ACCEPTED MANUSCRIPT treated with neoadjuvant chemotherapy and resection in view of the tumor heterogeneity

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on CT, and is disease-free for four years at the time of last follow-up.

ACCEPTED MANUSCRIPT Table 1: Correlation of imaging features with histopathology, presence of metastatic/recurrent disease and clinical outcome.

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0.074 1 1 0.558 0.156 0.573 1

0.274 0.019

0.573 0.039

0.278 1 0.681 0.802 0.290 0.179 0.008

0.546 1 0.267 0.878 0.163 0.031 0.043

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0.748 0.025

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PRETEXT stage Single vs multifocal Homogenous vs heterogeneous Conspicuity of margins Morphology (round vs irregular) Maximum attenuation Hemorrhage present Calcification present Cystic/Necrotic change Extrahepatic extension Capsular retraction Vascular invasion *SCUD=small-cell undifferentiated

Metastatic/Recurrent Survival disease (p-value) (p-value) 0.045 0.04 0.057 0.064 1 1

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SCUD* component (p-value) 0.582 0.44 1

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Imaging Feature

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Fig. 1

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Fig. 2

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Fig. 3

ACCEPTED MANUSCRIPT Highlights 

Small-cell undifferentiated (SCUD) subtype of hepatoblastoma is a high-risk tumor.

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Irregular margins of hepatoblastoma on contrast-enhanced CT are associated with

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SCUD histopathology. Calcification is associated with mixed epithelial and mesenchymal tumors.

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Multifocal hepatoblastoma tends toward significant association with metastases.

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