Hepatocellular carcinoma (HCC) is a growing global problem1,2 and represents the second leading cause of cancer-related death worldwide.3 Curative treatments, such as resection, ablation, and liver transplantation (LTx), are offered for patients with early-stage tumors and for patients fulfilling criteria for liver transplant outcome and survival are excellent.4 The current American Association for the Study of Liver Diseases (AASLD) and European Association for the Study of the Liver (EASL) clinical practice guidelines for staging patients with HCC before LTx include chest computed tomography (CT) and bone scan (BS) for assessment of extrahepatic disease including bone metastases.5,6 The rationale for this assessment is that patients with extrahepatic disease will be excluded from LTx. However, the current 2011 Organ Procurement and Transplantation Network Policies (9.3.F.ii) no longer include BS in the assessment of extrahepatic disease after it was removed from the 1998 policies which previously included them.7 The use of BS in patients with early-stage HCC has already been challenged.8,9 However, many LTx centers, including our own, continue to use them in staging before LTx and on 6 monthly basis while on the waiting list in accordance with existing guidelines.
Bones represent the third most frequent site, after lungs and lymph nodes, for extrahepatic metastases seen in HCC.10-12 The majority of bone metastases involve the spine, pelvis, and ribs.13-15 These are sites covered by conventional CT imaging of the chest, abdomen, and pelvis. The aim of our study is to review the value of BS in assessment of extrahepatic metastases from early-stage HCC in patients assessed for and on LTx waiting list.
MATERIALS AND METHODS
Patients
The study was approved by our institutional review board. We retrospectively reviewed the medical records of patients with HCC who had at least 1 BS performed between January 2010 and May 2017. All patients in the study were assessed for and/or on the LTx waiting list. At our center, the protocol for screening for metastatic disease, in patients listed for LTx for HCC is to perform a BS and a chest CT on initial assessment and then 6 monthly while on the LTx waiting list.
The diagnosis of HCC was based on radiological findings with histopathological confirmation when necessary in accordance with AASLD guidelines. Our HCC prospective database and medical charts were reviewed for demographics and clinical characteristics of patients including etiology of liver disease, Child-Turcotte-Pugh (CTP) class, number of active tumors at the time of study and presence of extrahepatic disease. The outcome of patients with regard to transplantation, mortality, and follow-up was also recorded. We only included patients who were considered for LTx and excluded patients who had already undergone BS with known advanced-stage HCC or extrahepatic disease. We also excluded patients who had a BS as part of staging before HCC surgical resections.
Bone Scintigraphy
Bone scans were performed 3 hours postintravenous injection of 744 MBq of Tc-99m methyl diphosphonate. Anterior and posterior whole-body images acquired. In addition, single-photon emission computed tomography (SPECT) with a dual-head gamma camera (GE Discovery NM/CT 670 Pro or Siemens Symbia TruePoint SPECT/CT) was occasionally acquired in some body regions. Low-dose CT imaging was used where relevant in a targeted fashion on review of bone scintigraphy findings. Targeted SPECT and SPECT/CT imaging were used when standard planar BS imaging revealed a finding that required clarification or when there was a specific question regarding a body region. Studies were reported by an experienced nuclear medicine physician or nuclear medicine qualified radiologist.
The reports of each BS were reviewed by 1 radiologist who was blinded to patients' HCC burden and outcome. The results were classified into negative, equivocal or positive for bone metastases. Scans with findings explained by physiological change, inflammation, degenerative changes, and/or trauma were considered negative. Clinical and radiological follow-up with radiographs, CT and magnetic resonance imaging (MRI), were used to assess the accuracy of BS findings.
Cost Analysis
A cost analysis was performed. Costs for BS, additional imaging or procedures required for further assessment of BS findings and hospital stay were obtained from the Australian Medicare Benefits Schedule and from the Benefit Requirements (Department of Health, Australian Government). Costs for imaging and procedures including BS did not change over the study period. Costs related to additional physician visits or time spent to correlate BS positive or equivocal findings with other imaging in multidisciplinary meetings were not incorporated into cost estimates. Individual items costs are listed in Table 4. All costs are reported in Australian dollars. For the purposes of this simplified analysis, estimates of total costs in US dollars are also provided using an average of historical exchange rates over the study period obtained from Westpac Banking Corporation (https://www.westpac.com.au/personal-banking/services/historical-rates).
Descriptive results are presented in frequencies and percentages. Continuous variables are presented as mean with range and medians with interquartile range (IQR) where relevant. No statistical comparisons were required or performed for the purposes of this study.
RESULTS
A total of 186 patients were included in this study with a mean age of 58.7 years (range, 34.9-70.4 years) and most were male patients (161/186 [86.6%]). The etiology of liver disease, CTP class, number of viable HCC tumors at the time of BS is given in Table 1. A total of 113 (60.8%) of 186 patients received a transplant during the study period. Fifteen of 73 patients who were not transplanted were still awaiting transplant at the time of assessment (Table 2). Median (IQR) follow-up was 2.3 years (1.1-3.9).
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TABLE 1: Demographics and clinical characteristics of patients
TABLE 2: Outcome of patients
There were 360 BS performed in 186 patients during the study period. Ninety-two patients underwent 1 BS with 94 patients having 2 or more BSs. The majority of BSs (306/360) were performed without SPECT or SPECT/CT imaging, while 46 BSs were performed with SPECT/CT and 8 were performed with SPECT only.
None of the BSs resulted in delisting of patients from LTx waiting list. Three BSs were reported positive for metastases. In 1 of these 3 studies, the patient was reported to have a skull metastasis and underwent an excisional biopsy which revealed a benign sclerotic lesion and was negative for metastasis. The remaining 2 patients with suspected rib and scapular metastases had no diagnostic CT correlates for the suspected metastases and were followed up with repeat BSs which showed resolution of the findings. All 3 studies were considered false-positive BSs (Table 3).
TABLE 3: Results of 360 BSs in 186 patients with follow-up
One patient had a BS to investigate an incidental L3 vertebral body focal lesion identified on lumbar spine MRI performed for evaluation of L1 crush fracture through a known hemangioma (Figure 1). The L3 lesion did not show increased activity on BS (Figure 2) but went on to have a CT-guided biopsy which demonstrated a metastatic HCC deposit. This was considered a false negative BS.
FIGURE 1: Lumbar spine sagittal MRI for assessment of a crush fracture through L1 vertebral body known hemangioma (arrowhead) demonstrating an incidental lesion in L3 vertebral body (arrow) which is low intensity on T1 (A) and T2 (B) sequences with peripheral high intensity on STIR sequence (C). The L3 lesion was biopsied under CT guidance confirming HCC metastasis.
FIGURE 2: Whole-body BS anterior (A) and posterior (B) views performed 8 days after lumbar spine MRI, demonstrating increased uptake at L1 crush fracture site (arrow) and no increased uptake at L3 metastasis detected on MRI.
Fourteen studies reported equivocal findings; none of which were confirmed to be metastases on radiographic, CT, MRI, BS, and/or clinical follow-up. Out of these 14 studies, 10 (71.4%) abnormalities were rib lesions, 3 (21.4%) were lumbosacral spine lesions, 1 was in a humeral shaft, and 1 was in a femoral head. The remainder of BSs were negative (Table 3). Among the negative scans, 67 BSs reported benign findings including arthritic changes and rib fractures.
The use of BS as part of initial and ongoing staging of HCC patients for LTx generated an expenditure of A$185298.30(US $171854.30). Costs for 4 patients who required further imaging and 1 patient who required a surgical biopsy were A$3471.60 (US $3219.72). The grand total costs of BS and additional work-up was A$188769.90 (US $175074) resulting in an average per patient cost of A$1014.89 (US $941.25) (Table 4).
TABLE 4: Costs of BS and additional work-up for positive and equivocal BS findings
DISCUSSION
The rise in incidence and recognition of bone metastases in HCC patients is attributed to improved survival of HCC patients in general due to improvements in primary tumor control.16 However, the incidence of such metastases remains very low in early-stage HCC, the cohort considered for LTx.8,9,17
Our study reviewed the results of BS in assessment of patients with early-stage HCC considered for LTx and has confirmed previously reported data.8,9 In our cohort of patients, BS showed no true bone metastases. We encountered 3 false positives, 14 equivocal findings, and 1 false-negative BS. None of the patients who had positive or equivocal findings were found to have bone metastases on clinical and radiological follow-up. The findings confirm the very low incidence of bone metastases in early-stage HCC with only 1 (0.5%) of 186 patients developing a bone metastasis which was not detected by BS.
Sensitivity, specificity, positive predictive value and negative predictive value of BS were not provided given the absence of a true positive finding on BS and the very low incidence (1 of 186) in this cohort. There was slight heterogeneity in the acquisition of BS with the majority of patients (306 of 360) receiving planar imaging only and some patients (54 of 360) receiving SPECT and SPECT/CT imaging. SPECT/CT imaging is known to improve the specificity, and to a lesser extent sensitivity, of BS.18 However, it is unlikely that performing SPECT/CT on all of these patients would have resulted in improved BS accuracy due to the very low prevalence of bone metastases. In the only case with a bone metastasis in our cohort, a diagnostic CT study could not identify the metastasis despite direct correlation with the MRI study in which the metastasis was detected and therefore performing a SPECT/CT might not have improved the detection of this metastasis.
It is no surprise that BS offers limited additional value in staging patients with early-stage HCC.17 Bone metastases from HCC are osteolytic in the majority of cases.10,11,19 The osteolytic nature of these metastases may lead to false-negative results which have been reported in 27% of patients with HCC-related bone metastases.20 The majority of such metastases are in the axial skeleton involving ribs, thoracic and lumbar spine and pelvis and assessment of such regions can still be made with routine CT imaging performed for primary tumor and chest evaluation.
Whether BS still has a role in staging patients beyond LTx criteria is debatable. The additional value of detecting bone metastases in patients with advanced-stage/metastatic HCC is probably minimal and symptomatic patients will receive targeted radiographic and cross-sectional imaging which probably negates the routine use of whole-body BS.
Our cohort findings confirm findings from similar cohorts with limited value of routine use of BS in early-stage HCC. Koneru et al8 in 2005 first described the limited role of BS in a similar cohort of 117 LTx candidates and found no bone metastases in their patients.8 Rodriguez et al9 assessed a cohort of 328 patients with a total number of 259 patients receiving a BS as part of their assessment for LTx. 276 of their patients were transplanted with 207 of transplanted patients receiving BSs before LTx. They showed no difference in outcome between patients who underwent and did not undergo a BS before LTx. In their cohort, 1 patient developed a bone metastasis before LTx but the patient was symptomatic, and the metastasis was visible on BS as well as targeted imaging. Our study assessed a smaller number compared to the study by Rodriguez et al but the total number of BSs was larger as our patients had repeat BS every 6 months while on the LTx. Data regarding staging of early-HCC patients before surgical resection17,21 and on initial staging for new diagnosis of HCC22 confirm the low diagnostic yield of BS in early-stage HCC.
Patients with HCC undergo multiple diagnostic and therapeutic radiological procedures. The effects of radiation exposure are usually weighed against the benefit of diagnostic work-up and treatments. However, patients with HCC who undergo evaluation for LTx receive significantly high ionizing radiation including from BS.23 If transplanted, such patients have reasonably improved life expectancy and efforts should be made to decrease unnecessary ionizing radiation before transplantation. Furthermore, the costs associated with BS in such cohorts have already been highlighted in 2 similar cohorts.8,9 Omitting unnecessary BS and downstream tests from false positive and equivocal findings can provide significant savings to healthcare systems.
Our study has some limitations. This was a single-center retrospective review of patients who had received at least 1 BS study and were on the LTx assessment/waiting list. Some of our patients were delisted for LTx due to disease progression or other causes and were not followed-up at our institution and data on their mortality was unclear. However, this scenario would not have influenced the results of our study question.
In conclusion, we have demonstrated that the diagnostic yield of BS in early-HCC patients who are candidates for LTx is minimal. Healthcare costs related to unnecessary BS and additional tests and biopsies incurred from false positive and equivocal results are unjustified. In our opinion, clinical assessment for symptomatic patients with targeted imaging rather than routine BS use would be more appropriate for suspected bone metastases. We doubt that randomized-controlled trials assessing the role of BS in such cohorts would yield different results. Given our findings and evidence from previous studies, we recommend that routine ordering of BS in the LTx staging work-up for early-HCC patients is removed from current AASLD and EASL guidelines.
REFERENCES
1. McGlynn KA, Petrick JL, London WT. Global epidemiology of hepatocellular carcinoma: an emphasis on demographic and regional variability.
Clin Liver Dis. 2015;19:223–238.
2. Wong MC, Jiang JY, Goggins WB, et al. International incidence and mortality trends of liver cancer: a global profile.
Sci Rep. 2017;7:45846.
3. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012.
Int J Cancer. 2015;136:E359–E386.
4. Neuberger J. What is the real gain after liver transplantation?
Liver Transpl. 2009;15(Suppl 2):S1–S5.
5. Liver EAftSot. EASL clinical practice guidelines: liver transplantation.
J Hepatol. 2016;64:433–485.
6. Martin P, DiMartini A, Feng S, et al. Evaluation for liver transplantation in adults: 2013 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation.
Hepatology. 2014;59:1144–1165.
7. Network OPaT. Allocation of livers and liver-intestines.
https://optn.transplant.hrsa.gov/governance/policies/. Accessed April 29, 2018.
8. Koneru B, Teperman LW, Manzarbeitia C, et al. A multicenter evaluation of utility of chest computed tomography and bone scans in liver transplant candidates with stages I and II hepatoma.
Ann Surg. 2005;241:622–628.
9. Rodriguez S, Balbinotto Neto G, Kiss G, et al. Cost-effectiveness of whole-body bone scans in the pre-liver transplant assessment of patients with hepatocellular carcinoma in southern Brazil.
Clin Transplant. 2016;30:399–406.
10. Katyal S, Oliver JH 3rd, Peterson MS, et al. Extrahepatic metastases of hepatocellular carcinoma.
Radiology. 2000;216:698–703.
11. Natsuizaka M, Omura T, Akaike T, et al. Clinical features of hepatocellular carcinoma with extrahepatic metastases.
J Gastroenterol Hepatol. 2005;20:1781–1787.
12. Uchino K, Tateishi R, Shiina S, et al. Hepatocellular carcinoma with extrahepatic metastasis: clinical features and prognostic factors.
Cancer. 2011;117:4475–4483.
13. Ho CL, Chen S, Cheng TK, et al. PET/CT characteristics of isolated bone metastases in hepatocellular carcinoma.
Radiology. 2011;258:515–523.
14. Kim SU, Kim DY, Park JY, et al. Hepatocellular carcinoma presenting with bone metastasis: clinical characteristics and prognostic factors.
J Cancer Res Clin Oncol. 2008;134:1377–1384.
15. Seo HJ, Choi YJ, Kim HJ, et al. Evaluation of bone metastasis from Hepatocellular carcinoma using (18)F-FDG PET/CT and (99m)Tc-HDP bone scintigraphy: characteristics of soft tissue formation.
Nucl Med Mol Imaging. 2011;45:203–211.
16. Longo V, Brunetti O, D'Oronzo S, et al. Bone metastases in hepatocellular carcinoma: an emerging issue.
Cancer Metastasis Rev. 2014;33:333–342.
17. Sheth H, Javed SS, Hilson AJ, et al. Radioisotope bone scans in the preoperative staging of hepatopancreatobiliary cancer.
Br J Surg. 2005;92:203–207.
18. Palmedo H, Marx C, Ebert A, et al. Whole-body SPECT/CT for bone scintigraphy: diagnostic value and effect on patient management in oncological patients.
Eur J Nucl Med Mol Imaging. 2014;41:59–67.
19. Santini D, Pantano F, Riccardi F, et al. Natural history of malignant bone disease in hepatocellular carcinoma: final results of a multicenter bone metastasis survey.
PLoS One. 2014;9:e105268.
20. Chen CY, Wu K, Lin WH, et al. High false negative rate of Tc-99m MDP whole-body bone scintigraphy in detecting skeletal metastases for patients with hepatoma.
J Formos Med Assoc. 2012;111:140–146.
21. Witjes CD, Verhoef C, Kwekkeboom DJ, et al. Is bone scintigraphy indicated in surgical work-up for hepatocellular carcinoma patients?
J Surg Res. 2013;181:256–261.
22. Jin YJ, Lee HC, Lee D, et al. Role of the routine use of chest computed tomography and bone scan in staging workup of hepatocellular carcinoma.
J Hepatol. 2012;56:1324–1329.
23. Lee SY, Mooney MA, Inra ML, et al. Exposure to ionizing radiation during liver transplantation evaluation, waitlist time, and in the postoperative period: a cause for concern.
Hepatology. 2014;59:496–504.
